Principles of Gender-Specific Medicine, Second Edition

PRINCIPLES MEDICINE

OF

GENDER-SPECIFIC

PRINCIPLES OF GENDER-SPECIFIC MEDICINE Second Edition Edited by

Marianne J. Legato, MD Section Editors:

William Byne, MD, PhD Nancy E. Davidson, MD Adrian Dobs, MD, MHS Marilyn K. Glassberg, MD Paula A. Johnson, MD Robert G. Lahita, MD, PhD, FACP, FACR, FRCP George M. Lazarus, MD Linda A. Lee, MD Michael Rendel, MD Lauri J. Romanzi, MD, FACOG

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier

  Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA First edition 2004 Second edition 2010 Copyright © 2004, 2010, Elsevier Inc. All rights reserved No part of this publication may be reproduced, or stored in retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher. Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (44) (0) 1865 843830; fax (44) (0) 1865 853333; e-mail: [email protected]. Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.

Medicine is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administrations, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the authors assume any liability for any injury and/or damage to persons or property arising from this publication.

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-374271-1 For information on all Academic Press publications visit our website at www.elsevierdirect.com Typeset by Macmillan Publishing Solutions www.macmillansolutions.com Printed and bound in the United States of America 10 11 12 13 10 9 8 7 6 5 4 3 2 1

 To Isobel and Marvin Slomowitz, with gratitude   for their generosity and support for the science of   gender-specific medicine.

Contributors

NABIH I. ABDOU, MD, PhD, Clinical Professor of Medicine, University of Missouri School of Medicine and Center for Rheumatic Disease and Center for Allergy and Immunology, Kansas City, MO, USA

ELIZABETH BARBIERI, MD, FACOG, Weill Cornell Medical College, Center for Reproductive Medicine and Infertility, New York, NY, USA BARBARA D. BARTLIK, MD, Assistant Professor of Psychiatry and Psychiatry in Obstetrics and Gynecology, Weill Cornell Medical College, Department of Psychiatry, New York, NY, USA

NAZIA AHMAD, BA, CUNY Hunter College, New York, NY, USA

SHARI S. BASSUK, ScD, Epidemiologist, Brigham and Women’s Hospital, Division of Preventive Medicine, Boston, MA, USA

MUDDASSIR ALINIAZEE, MD, University of Miami, Miller School of Medicine, Pulmonary and Critical Care Medicine, Miami, FL, USA

DAVID BATEMAN, MD, Associate Professor of Clinical Pediatrics, Columbia University Medical Center, Department of Pediatrics, New York, NY, USA

SARAH ALVI, BS, University of Massachusetts, Amherst, MA, USA

KRISTY A. BAUMAN, MD, Assistant Professor, University of Michigan, Division of Pulmonary and Critical Care Medicine, Ann Arbor, MI, USA

JOAN AMATNIEK, MD, MSc, Director, Clinical Development, Ortho McNeil–Janssen Scientific Affairs, Titusville, NJ; Associate Visiting Research Scientist, Columbia University, Gertrude H. Sergievsky Center, Graduate School of Public Health, New York, NY, USA

JENNIFER J. BELL, MD, Special Lecturer in Pediatrics, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY, USA

DAVID E. ANDERSON, PhD, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

KATHRYN BILELLO, MD, Central California Faculty Medical Group and Associate Clinical Professor of Medicine, University of California San Francisco–Fresno Program, Fresno, CA, USA

GAYA S. ARANOFF, MD, Professor of Clinical Pediatrics, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY, USA

JUSTIN D. BLASBERG, MD, Resident, St Luke’s–Roosevelt Hospital Center, Department of Surgery, New York, NY, USA

GLORIA BACHMANN, MD, Associate Dean for Women’s Health, University of Medicine and Dentistry of New Jersey– Robert Wood Johnson Medical School, New Brunswick, NJ, USA

ROGER S. BLUMENTHAL, MD, FACC, FAHA, Professor of Medicine, The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA TAMARA BOCKOW, BS, Medical Student, University of Pennsylvania Medical School, Philadelphia, PA, USA

SANDHYA K. BALARAM, MD, PhD, FACS, Attending Surgeon, St Luke’s–Roosevelt Hospital Center, Division of Cardiothoracic Surgery; Assistant Professor of Clinical Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA

KAREN ELIZABETH BOYLE, MD, Director, Reproductive Medicine and Surgery, Sexuality & Aesthetics Chesapeake Urology Associates, Baltimore, MD, USA

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Contributors

ARTHUR L. BURNETT, MD, Professor of Urology, The Johns Hopkins Hospital, James Buchanan Brady Urological Institute, Baltimore, MD, USA

DIALA EL-MAOUCHE, MD, MS, Post-doctoral Fellow, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

LARA J. BURROWS, MD, The Center for Vulvovaginal Disorders, Washington, DC, USA

KAREN FEISULLIN, MD, Community Health Services, Department of Women’s Health; Department of Obstetrics and Gynecology, Hartford Hospital, Hartford, CT, USA

WILLIAM BYNE, MD, PhD, Staff Physician, Mental Illness Research, Education and Clinical Center, J.J. Peters Veterans Affairs Medical Center, Bronx, NY; Associate Professor of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA KENNETH R. CHAPMAN, MD, MSc, FRCPC, FCCP, Director, Asthma and Airway Centre, University Health Network, Toronto Western Hospital; Professor of Medicine, University of Toronto; GSK-CIHR Research Chair in Respiratory Health Care Delivery; Toronto, Ontario, Canada MARGARET A. CHESNEY, PhD, Professor of Medicine, University of Maryland School of Medicine, Center for Integrative Medicine, Baltimore, MD, USA

LAUREN FREY, MD, Assistant Professor, Department of Neurology, University of Colorado Denver, Denver, CO, USA JAMES H. GARVIN, Jr, MD, PhD, Professor of Clinical Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA KATYA GAYNOR, BA, Research Coordinator, Mount Sinai School of Medicine, Department of Psychiatry, New York, NY, USA SUSAN L. GEARHART, MD, Assistant Professor of Colorectal Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA

DEBRA CHEW, MD, Clinical Assistant Professor, New Jersey Medical School of the University of Medicine and Dentistry of New Jersey, Department of Medicine, Newark, NJ, USA

KHALIL G. GHANEM, MD, PhD, Assistant Professor of Medicine, The Johns Hopkins University School of Medicine, Department of Infectious Diseases, Baltimore, MD, USA

DOREEN E. CHUNG, MD, FRCSC, Weill Cornell Medical College, Department of Urology, New York, NY, USA

MARILYN K. GLASSBERG, MD, Associate Professor, University of Miami Miller School of Medicine, Department of Medicine/Pulmonary and Critical Care Division, Director, Rare and Interstitial Lung Disease Program, Miami, FL, USA

PAK H. CHUNG, MD, Reproductive Endocrinologist and Infertility Specialist, Weill Cornell Medical College, The Center for Reproductive Medicine and Infertility, New York, NY, USA WENDY K. CHUNG, MD, PhD, Herbert Irving Assistant Professor of Pediatrics and Medicine, Director of Clinical Genetics, Columbia University, New York, NY, USA CHRISTINE A. CLARK, PhD Candidate, Mount Sinai Hospital, University of Toronto, LifeQuest Centre for Reproductive Medicine, Toronto, Ontario, Canada MAURIZIO CUTOLO, MD, University of Genoa, Research Laboratories and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, Genoa, Italy

SHERITA HILL GOLDEN, MD, MHS, Associate Professor of Medicine and Epidemiology, The Johns Hopkins University School of Medicine, Division of Endocrinology and Metabolism, Welch Center for Prevention, Epidemiology, and Clinical Research; The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA ANDREW T. GOLDSTEIN, MD, Johns Hopkins Medicine, Division of Gynecologic Specialties, Department of Gynecology and Obstetrics, Baltimore, MD, USA

SERKAN DEVECI, MD, Memorial Sloan Kettering Cancer Center, Department of Urology, New York, NY, USA

MARC GOLDSTEIN, MD, Matthew P. Hardy Distinguished Professor of Reproductive Medicine and Urology, Surgeon-inChief, Male Reproductive Medicine and Surgery, Cornell Institute for Reproductive Medicine, New York-Presbyterian Hospital/ Weill Cornell Medical Center, Weill Cornell Medical College; Senior Scientist, The Population Council, Center for Biomedical Research, New York, NY, USA

ADRIAN DOBS, MD, MHS, Professor of Medicine and Oncology, The Johns Hopkins University School of Medicine, Department of Medicine and Oncology, Baltimore, MD, USA

REBECCA F. GOTTESMAN, MD, PhD, Assistant Professor of Neurology, The Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, USA

NORA J. DOTY, Research Assistant, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ, USA

RAQUEL E. GUR, MD, PhD, Professor of Psychiatry, Neurology, and Radiology, University of Pennsylvania Medical Center, Pennsylvania, PA, USA

CATHERINE E. DUBEAU, MD, Professor of Medicine, University of Massachusetts Medical Center, Departments of Internal Medicine, Family and Community Health, and Obstetrics & Gynecology, Worcester, MA, USA

RUBEN C. GUR, PhD, Professor of Psychology, University of Pennsylvania Medical Center, Department of Psychiatry, Radiology and Neurology, and the Philadelphia Veterans Administration Medical Center, Philadelphia, Pennsylvania, PA, USA

NANCY E. DAVIDSON, MD, Hillman Professor of Oncology, Director, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Contributors MEILAN K. HAN, MD, MS, Medical Director, Women’s Respiratory Health Program and Pulmonary Rehabilitation, University of Michigan, Division of Pulmonary and Critical Care, Ann Arbor, MI, USA MARY L. HARRIS, MD, Medical Director, The Center for Inflammatory Bowel and Colorectal Diseases, Mercy Medical Center, Baltimore, MD, USA W. ALLEN HAUSER, MD, Professor of Neurology and Epidemiology, Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY, USA ARGYE E. HILLIS, MD, Professor of Neurology and Physical Medicine and Rehabilitation, The Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, USA SALLY L. HODDER, MD, Professor of Medicine, New Jersey Medical School of the University of Medicine and Dentistry of New Jersey, Department of Medicine, Newark, NJ, USA AARON HOLLEY, MD, Walter Reed Army Medical Center, Division of Pulmonary/Critical Care and Sleep Medicine, Department of Internal Medicine, Washington, DC, USA DIANE JACOBS, PhD, Consulting Neuropsychologist, San Diego, CA, USA SUZANNE M. JAN DE BEUR, MD, Associate Professor of Medicine, The Johns Hopkins University School of Medicine, Director, Division of Endocrinology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA PAULA A. JOHNSON, MD, Executive Director, Connors Center for Women’s Health and Gender Biology and Chief of the Division of Women’s Health, Brigham and Women’s Hospital, Boston, MA, USA SONYA KASHYAP, MD, Reproductive Endocrinologist, University of California at San Francisco, Center for Reproductive Health and Women’s Health Research Center, San Francisco, CA, USA DAVID M. KAUFMAN, MD, Assistant Clinical Professor of Pediatrics and Neurology, Mount Sinai School of Medicine, Department of Pediatric Neurology, New York, NY, USA HOWARD H. KIM, MD, Fellow in Male Reproductive Medicine and Microsurgery, Department of Urology and Cornell Institute for Reproductive Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College; Research Fellow, The Population Council, Center for Biomedical Research, New York, NY, USA

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JULIE A. KOLZET, MA, Weill Cornell Medical College, Department of Psychiatry, New York, NY, USA AYMAN KOTEISH, MD, The Johns Hopkins University School of Medicine, Department of Gastroenterology and Hepatology, Baltimore, MD, USA KAREN KROK, MD, The Johns Hopkins University School of Medicine, Department of Gastroenterology and Hepatology, Baltimore, MD, USA ROBERT G. LAHITA, MD, PhD, FACP, FACR, FRCP, Chairman of the Department of Medicine, Newark Beth Israel Medical Center, Newark, NJ; Professor of Medicine, New Jersey Medical School, Newark, NJ, USA NICOLE LANATRA, MD, New York University School of Medicine, Division of Oncology, New York, NY, USA CARL A. LASKIN MD, FRCPC, LifeQuest Centre for Reproductive Medicine; Departments of Medicine (Rheumatology), Obstetrics & Gynecology and Immunology, University of Toronto, Toronto, ON, Canada GEORGE M. LAZARUS, MD, Associate Clinical Professor of Pediatrics, Columbia University Medical Center, Morgan Stanley Children’s Hospital, Department of Pediatrics, New York, NY, USA LINDA A. LEE, MD, Assistant Professor, The Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, Baltimore, MD, USA MARIANNE J. LEGATO, MD, Professor Emerita of Clinical Medicine, Columbia University College of Medicine, New York, NY; Adjunct Professor of Medicine, Johns Hopkins, Department of Medicine, Baltimore, USA JASWINDER K. LEGHE, MD, MPH, Clinical Instructor, NYU School of Medicine, Department of Medicine, New York, NY, USA SHARON LEWIN, MD, Fellow, Royal College of Physicians, Canada; Attending Physician, St. Luke’s–Roosevelt Hospital Center, Division of Infectious Disease, New York, NY; Attending Physician, New York Presbyterian Hospital Center, Division of Internal Medicine, New York, NY; Assistant Clinical Professor of Medicine, Columbia University School of Medicine, New York, NY, USA ROBERT H. LIM, MD, Research Associate, Harvard School of Public Health, Department of Environmental Health, and Instructor in Pediatrics Children’s Hospital Boston, Division of Respiratory Diseases, Boston, MA, USA

MATTHEW KIM, MD, Assistant Professor of Medicine, The Johns Hopkins Hospital, Division of Endocrinology, Baltimore, MD, USA

JOANN E. MANSON, MD, DrPH, Professor of Medicine and the Elizabeth F. Brigham Professor of Women’s Health, Harvard Medical School, Brigham and Women’s Hospital, Division of Preventive Medicine, Boston, MA, USA

LESTER KOBZIK, MD Harvard School of Public Health, Department of Environmental Health, and Brigham & Women’s Hospital, Department of Pathology, Boston, MA USA

MARGARET MCCARTHY, PhD, Professor of Physiology, University of Maryland Baltimore School of Medicine, Department of Physiology, Baltimore, MD, USA

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Contributors

TARANEH MEHRANI, Baltimore, MD, USA

MD,

Union

Memorial

Hospital,

JORDAN D. METZL, MD, Co-Founder, The Sports Medicine Institute for Young Athletes, Hospital for Special Surgery, New York, NY LISA MOORES, MD, Assistant Dean for Clinical Sciences, Professor of Medicine, The Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, MD, USA KENDALL F. MOSELEY, MD, Clinical Fellow, Division of Endocrinology, The Johns Hopkins Hospital, Baltimore, MD, USA JOHN P. MULHALL, MD, Director Male Sexual and Reproductive Medicine Program Memorial Sloan Kettering Cancer Center, Department of Surgery/Urology Service, New York, NY, USA GERALD MULLIN, MD, The Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, Baltimore, MD, USA MELISSA MUNSELL, MD, Clinical Fellow, The Johns Hopkins University School of Medicine, Department of Medicine and Gastroenterology, Baltimore, MD, USA SUSAN MURIN, MD, MSc, Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, and Vice-Chair for Clinical Affairs, University of California Davis School of Medicine, Department of Internal Medicine, Sacramento, CA, USA

MICHAEL RENDEL, MD, Senior Attending Physician, St Luke’sRoosevelt Hospital Center, New York; Attending Physician, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College, New York; Associate Professor, Columbia University School of Medicine, New York, NY, USA VIRGINIA RIDER, PhD, Professor of Biology, Pittsburg State University, Department of Biology, Pittsburg, KS, USA LAURI J. ROMANZI, MD, FACOG, Reconstructive Surgery and Urogynecology, Clinical Associate Professor of Gynecology, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College, New York, NY, USA ANNE M. ROMPALO, MD, ScM, Professor of Medicine, The Johns Hopkins University School of Medicine, Department of Infectious Diseases, Baltimore, MD, USA TOVE S. ROSEN, MD, Professor of Clinical Pediatrics/ Neonatology, Columbia University Medical Center, Department of Pediatrics, New York, NY, USA HILARY SANFEY, MB BCh, FACS, Professor of Surgery and Vice-Chair for Education, Southern Illinois School of Medicine Department of Surgery, Springfield, IL, USA MARY SANO, PhD, Director, Alzheimer Disease Research Center; Professor, Department of Psychiatry, Mount Sinai School of Medicine; Director of Research and Development; James J Peters VAMC, New York, NY, USA

CHRISTIAN D. NAGY, MD, Fellow, The Johns Hopkins Hospital, Department of Internal Medicine and Pediatrics, Divisions of Cardiology and Pediatric Cardiology, Baltimore, MD, USA

PETER N. SCHLEGEL, MD, FACS, Professor and Chairman, Department of Urology, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College, New York; Senior Scientist, The Population Council, Center for Biomedical Research, New York, NY, USA

CORAL OMENE, MD, PhD, New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA

MARY V. SEEMAN, MD, Professor Emerita of Psychiatry, University of Toronto, Department of Psychiatry, Toronto, Ontario, Canada

HENRY P. PARKMAN, MD, Associate Professor of Medicine and Physiology, Temple University, Department of Physiology, Philadelphia, PA, USA

SHIRIN SHAFAZAND, MD, MS, Assistant Professor of Medicine, University of Miami Miller School of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Miami, FL, USA

TAHMINA PARVEEN, BA, CUNY Hunter College, New York, NY, USA

KAVITA SHARMA, MD, The Johns Hopkins Hospital, Department of Internal Medicine, Baltimore, MD, USA

MICHELLE PETRI, MD, MPH, Professor, The Johns Hopkins University School of Medicine, Department of Medicine, and Director, Johns Hopkins Lupus Center, Baltimore, MD, USA

BEVERLEY J. SHEARES, MD, MS, Associate Professor of Clinical Pediatrics, Columbia University, Pulmonary Division, Department of Pediatrics, New York, NY, USA

OCTAVIA PICKETT-BLAKELY, MD, The Johns Hopkins University School of Medicine, Department of Gastroenterology and Hepatology, Baltimore, MD, USA

DEBORAH SHURE, MD, Master FCCP, Consultant Medical Reviewer, Center for Devices and Radiological Health, Miami, FL, USA

BRUCE POLSKY, MD, Interim Chairman, St Luke’s–Roosevelt Hospital Center, Department of Medicine, and Chief, Division of Infectious Diseases, New York, NY, USA

MARC SONENSHINE, MD, The Johns Hopkins University School of Medicine, Department of Internal Medicine, Baltimore, MD, USA

CHARLES A. POWELL, MD, Associate Professor of Medicine, Columbia University, Division of Pulmonary, Allergy, and Critical Care Medicine, New York, NY, USA

EMILIA MIA SORDILLO, MD, PhD, Sr, Attending, Medicine and Pathology, Medical Director, Microbiology, and Molecular Diagnostics, St Luke’s–Roosevelt Hospital Center, Department of

Contributors

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Clinical Pathology; Associate Professor of Clinical Medicine and Clinical Pathology and Cell Biology. College of Physicians and Surgeons, Columbia University, New York, NY, USA

REBECCA L. TOONKEL, MD, Postdoctoral Research Fellow, Columbia University, Division of Pulmonary, Allergy, and Critical Care Medicine, New York, NY, USA

KARIN SORRA, PhD, President and Chief Scientific Officer, Arroscience Inc., Toronto, Ontario, Canada

RENUKA TYAGI, MD, Assistant Professor of Urology in Obstetrics and Gynecology, Weill Cornell Medical College, Department of Urology, New York, NY, USA

KAREN A. SPITZER, MSc, University of Toronto, LifeQuest Centre for Reproductive Medicine, Toronto, Ontario, Canada SHOBHA SWAMINATHAN, MD, Assistant Professor, New Jersey Medical School of the University of Medicine and Dentistry of New Jersey, Department of Medicine, Newark, NJ, USA ALEXIS E. TE, MD, Associate Professor of Urology, Weill Cornell Medical College, Department of Urology, New York, NY, USA AMY TIERSTEN, MD, Associate Professor of Medicine (Oncology), New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA

SARA E. WALKER, MD, MACP, Emeritus Professor of Medicine, University of Missouri School of Medicine, Department of Internal Medicine, Columbia, MO, USA CAROLYN WESTHOFF, MD, Columbia University, Department of Obstetrics and Gynecology, Division of Family Planning and Preventive Services, New York, NY, USA

Foreword: Gender-Specific Medicine – Environment and Biology Marek Glezerman, MD Professor and Chairman, Hospital for Women, Rabin Medical Center and Sackler Medical School, Tel Aviv University; Chairman, The Israel Society for Gender Medicine

adults, and no one would doubt that specific expertise is needed for diagnosing and treating children. Equally, it is unquestionable today that research performed in adults is not necessarily applicable to infants, children and adolescents. It is all the more astonishing that the parallel to gender differences is still not sufficiently appreciated and that even a basic understanding of the profound physiological and pathophysiological differences between men and women is still widely missing. Amazingly, not unlike the prevailing attitude towards children 150 to 200 years ago, women are typically regarded as smaller men. The common perception of the main difference between the sexes is usually confined to their different genital organs and to the fact that women are capable of delivering babies, while men are not. The differences are, alas, far more profound. In fact, these differences pertain to virtually all bodily systems, covering the entire life cycle from the antenatal period through infancy and adulthood. In intra-uterine life, fetal gender is independently associated with increased risks for prematurity, operative and cesarean delivery and fetal growth abnormalities. After birth, female and male infants differ in their development, in mortality and morbidity rates and are affected differently by different diseases. Female infants have a substantially higher prevalence of vesicoureteral reflux and persistent ductus arteriosus, while male infants have a higher incidence of transposition of large vessels, aortic stenosis, pylorus stenosis and hernia. Girls have

I vividly recall my first reaction when reading Eve’s Rib by Marianne Legato, about two years ago. It was a strange amalgam between asking myself ‘Where have I been during the past 30 years of my career?’ and a fair amount of skepticism. In the aftermath of an in-depth journey into the vast and largely unexplored realm of gender-related differences in medicine, I encountered very similar reactions with many peers. Subsequently, an interest group for Gender Medicine was created which included 27 department heads from different disciplines and several months later, the Israel Society for Gender Medicine was born. In less than two years, this organization has attracted 110 active members and is conducting dozens of ongoing research projects, some of which are currently in press. Such is the genesis of my personal involvement with gender medicine. As recently as two centuries ago, children were regarded as diminutive adults and were treated accordingly, both in social and in medical terms. Demands on their capacity to provide labor were restricted only by realizing their actual physical limitations and not by understanding the special needs of the growing juvenile body. In fact, the notion of physical health and particular medical treatment of children was virtually non-existent until the early eighteenth century and it required several more decades until pediatrics emerged as a distinct medical discipline. Today, no reasonable person would dare to question the profound differences in physiology and pathophysiology between children and xvii

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Foreword: Gender-Specific Medicine – Environment and Biology

more auto immune diseases, such as systemic lupus and thyroiditis, and have more often precocious puberty. Boys suffer more often from autism, growth hormone deficiency and nephrotic syndrome. In adults, observational studies that indicated the preponderance of many pathologies in women have been available for many years and clinicians observe these differences constantly. For example, the gastrointestinal system functions differently in men and women. Compared to men, women have twice the incidence of colitis or Crohn’s disease, four times the incidence of gallbladder stones, suffer five times more often from irritable bowel syndrome, and 20 times more often from functional bowel disease. Female lungs are more vulnerable to disease than lungs of men. Pulmonary hypertension, asthma, and chronic obstructive lung disease are usually more severe in women than in men. Lung cancer in women is on a steady rise and is currently their most fatal cancer, accounting for 25% of all cancer deaths, with a higher incidence rate than breast cancer. In Europe there are currently about 400 000 new lung cancer cases diagnosed annually, 30% of which occur in women. Alarmingly, 80 000 out of 400 000 new lung cancer patients never smoked and most of those affected are women. Currently, in the United States more women die annually from cardiovascular disease than from all cancers combined. Data from 2005 reveal that 143 000 women died from stroke and 650 000 from cardiovascular disease, while the death toll from all cancers combined amounted to 560 000. The female heart responds differently to continuous stress such as hypertension than the male heart, and diagnostic tools, like the customary stress test, are substantially less significant and less specific in women than in men. Women with myocardial infarction are typically under-diagnosed and under-treated. Yet, until the 1990s almost all research on the cardiovascular system, and indeed on most other bodily systems, was performed exclusively in men and the majority of currently available medications have been evaluated in men only. Moreover, in terms of pharmacokinetics, the large variability of the physiological changes in cyclic women is usually neglected. The roots of this apparent discrimination date back to the mid-twentieth century, when both the treatment of pregnant women for threatened abortion with the synthetic estrogen diethylstilbestrol (DES) and the use of thalidomide for nausea during the pregnancy lead to catastrophic consequences in their offspring, including genital cancer and phocomelia, respectively. Consequently, and mainly in order to protect women, women were excluded from clinical trials. The need for gender-specific medicine emerged when it could no longer be denied that diagnosis and treatment of diseases in men and women may not be identical, and that women and men need to be represented equally in clinical trials. Efforts by the NIH in the mid-1980s to correct this unbalanced state of affairs by declining funding of research projects that did not include both sexes, were ill-fated.

As late as the mid-1990s less than one-third of published research included women, and even those data were often incomplete. Out of 120 randomized controlled trials published in the New England Journal of Medicine between 1994 and 1999, only 14% provided gender-specific analysis. This situation is now slowly but gradually changing. It is now well accepted that clinical and basic research needs to be stratified also by gender and that the gender aspect of medicine needs to be introduced in the training of students and residents. Based on this understanding, gender-specific medicine emerged and developed in the past two decades. Semantics often lag behind the development of new technologies and new scientific endeavors. Sometimes we develop the narrative and terminology before the technology catches up, and sometimes novel approaches are in search of the appropriate terms to explain them. This is also true for gender medicine. So, what is ‘gender medicine’? It is a giant step from the ‘one-size-fits-all’ approach to the direction of personalized medicine, when diagnosis and treatment will become individualized according to the genomics of each individual. This may happen sometime in the future, but first steps are already visible. In breast cancer, for example, genetic testing permits prediction of the efficiency of various medications and is helpful in rendering evidence-based and individualized decisions, concerning the optimal treatment. So, in a sense, gender medicine bridges the gap between past and future medicine. It is based on the understanding that male and female gender is much more than the chromosomal difference between the sexes and requires an in-depth understanding of the profound physiological and pathophysiological differences that have developed as a result of long-term adaptations to environmental effects and the social roles of individuals in their societies. Some of these changes are hard-wired and resulting from millions of years of physiological adaptation and some are the results of short-term expressions of the different roles and lifestyles men and women play in various societies. Being male or female is not synonymous to being masculine or feminine. Both pairs of terms are often but erroneously interchangeably used as synonyms. Yet, they present fundamentally different categories. Maleness or femaleness are chromosomally determined and thus unchangeable. This definition is to some extent a simplification, but is generally accepted in humans. To be feminine or to be masculine are characteristics that are defined by the sociological fabric of our environment, the roles we play in a given society, the functions and habits assigned by the society on us, and the expectations which a given society has set for its members. These roles can change in the course of time and are different in different societies. Whatever is required from us in terms of being feminine or masculine has obviously a strong impact on our health, and may pose gender-specific health risks that are not based on a different biology of men and women, but on the environment in which we live. This immediate impact of our social

Foreword: Gender-Specific Medicine – Environment and Biology

environment on our health is what I would call ‘environmental gender medicine’ (EGM). If the environment affects our day-to-day life long enough, eventually irreversible biological changes will ensue and even our anatomy will adapt. This aspect of gender medicine would then be reflected in the term ‘biological gender medicine’ (BGM). Both are summarized in the general term gender (specific) medicine. While talking to various audiences on gender medicine, one encounters sometimes enthusiastic support and sometimes a rather reserved reaction to what is perceived as the promotion of affirmative action, aimed at improving women’s health. Clearly, gender medicine aims to rectify a longstanding neglect of gender differences, which are mostly related to the physiology and pathophysiology of women. But gender medicine is not an advanced form of gynecology, extended to bodily systems beyond the genital organs. Gender medicine aims also at men’s health: from the onset, men are at a health disadvantage and are more susceptible to disease than women throughout their life cycle. Even their life expectancy is shorter. Male gender is independently associated with adverse pregnancy outcome and male neonates are twice more likely to die at birth. In the first trimester of pregnancy the male : female ratio is 170 : 100, but since male fetuses are spontaneously aborted three times more often than female fetuses, at delivery the male : female prevalence decreases to about 51% to 49%. Actually, all catastrophes that can affect the unborn fetus are more common in males than in females, including brain damage, premature deliveries, skeletal anomalies and stillbirth. Mortality is 20% higher in male than in female newborns and remains higher also throughout infancy and childhood. Morbidity, developmental deficiencies, susceptibility to congenital and acquired diseases are also more common in boys than in girls. As the life cycle continues, male adolescents are more likely to die from accidents or suicide than girls. Recent figures from Romania indicate that 74% out of 11 000 suicides that occurred in 2000 were committed by men. Throughout life, male adults are more susceptible to infectious diseases than women. Because male breast cancer is 100 times rarer in men than in women, this form of deadly cancer has hardly been studied in men. Men are also at a general disadvantage in cancer survival. Osteoporosis is regarded as a female disease with a lifetime risk of 1 : 2 in women but men also suffer from osteoporosis, with a lifetime risk of 1 : 5. Again, research on osteoporosis has been focused almost exclusively on women. So, gender medicine needs to deal with health issues of men and women alike. It is not a new and distinct medical discipline, but rather a new perspective and nexus between existing disciplines. Modern medicine should therefore not only be evidence-based but also gender-based. To accomplish this objective there is a dire need in extensive basic and clinical research, and also in changes in the curriculum of medical studies and of residencies.

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Some universities, such as Georgetown University in the United States, Monash University in Australia and Tel Aviv University in Israel, have already incorporated the gender aspect in their medical curricula, and some residency programs already include explicit gender aspects in their training. The essential prerequisite for these actions is the awareness of the necessity and the willingness to question existing paradigms. Some of these preliminary, but crucial goals are already being met. The World Health Organization has established the ‘Department of Gender, Women and Health’ and NASA has done pioneering work in studying the physiological differences between men and women as related to space travel. Fellowships in women’s health are offered by various universities, such as Columbia in New York, MacNeall in Illinois, East Carolina University, Brigham and Women’s Hospital in Boston, amongst others. Dozens of books dealing with gender medicine are available today and there are scientific journals devoted to women’s health (Gender Medicine, Elsevier), and men’s health (Men’s Health and Gender, Elsevier). An International Society for Gender Medicine has been established, and national societies in Sweden, Germany, Italy, Austria, and Israel are actively involved in the promotion of awareness of gender medicine and research. Gender-medicineoriented national and international congresses are being held worldwide. The number of research projects conducted and published is mushrooming. Obviously, this development increases the demand for scholarly texts. One of the most vocal and effective pioneers who has brought gender medicine to the place it occupies today is undoubtedly Professor Marianne Legato. Having devoted the past two decades of her professional life to the promotion of gender medicine, she has contributed tremendously to the worldwide awakening of awareness to this critically important angle from which medicine should be approached. Besides her scientific contributions, the greatest impact on public awareness of the gender differences in medicine has probably derived from her many books that have addressed the educated general public. Marianne Legato, a cardiologist by training, is founder and editor in chief of the first medical journal devoted to gender medicine, and the editor of this textbook. Now, only five years after the publication of the first edition, this second edition is to be made available to an everincreasing body of readers. As in the first edition, Dr Legato has succeeded in assembling a formidable group of scholars and pioneers in their respective fields. The book is organized in sections, with section editors who have also provided insightful introductions to the respective chapters. Reading through the table of contents is like browsing through all aspects of medicine. Paradoxically, and on first thought, this may seem to be a disadvantage. Why would I, as an obstetrician and gynecologist, choose to divert precious reading time from my own overwhelming and demanding discipline, to topics like immunology, rheumatology, pulmonology or

xx

Foreword: Gender-Specific Medicine – Environment and Biology

the nervous system, which are all beyond the areas of my professional expertise? The answer to this question materialized during my extensive reading of gender-based texts for the past two years. It was then that I became fond of peeking into other fields of medicine and began to appreciate the vastness of the unexplored grounds of gender differences. Thus, like an explorer, I was and still am experiencing the privilege of witnessing the re-writing of virtually all chapters of medicine from the gender perspective. This precisely is what is so exciting about gender medicine in general and about this textbook in particular. This textbook serves up to the reader the essence of contemporary gender medicine on a silver platter. It is in a sense a primary teaching instrument for students, residents, and specialists. It is also a reference

text, aimed to provide specific answers to specific questions. But most of all, it is an eye-opener, raising scientific curiosity and confronting the reader with a wealth of questions that cover virtually every field of medicine while challenging all of us to embark on the relevant research. The silent revolution of gender medicine has broken through the first great wall on its path, namely to be accepted as an undeniable and necessary shift of paradigms. But this is still only the beginning. Now it is time to embark on a truly inter-disciplinary journey and to invest academic and clinical efforts in order to establish gender medicine as an integral part of how we teach and apply modern medicine for the benefit of women and men alike. This textbook is a major tool in this formidable quest.

Preface

Over the arc of the last twenty years, the realization that men and women are significantly different in every system of the body has expanded to inform and refocus all the disciplines of medicine. When we published the first edition of The Principles of Gender-Specific Medicine it was axiomatic that the words ‘gender-specific’ were new and, as my then chairman of internal medicine at Columbia University, Doctor Myron Weisfeldt, pointed out in 1997, very few of us knew what ‘gender-specific’ meant. Indeed, most people who heard the term for the first time assumed it meant women’s medicine. It is still a common misperception. In fact, genderspecific medicine is the study of how the normal function and the experience of disease differs between men and women. It is as dedicated to the study of the unique aspects of men’s biology as it is to that of women; indeed, it is the comparison between the two sexes that has prompted some of the most interesting and novel questions in medicine. Medicine is a reflection of the society in which it is embedded; how we understand the human condition and tend to its ills is impacted by how society views the roles, competencies, and relative importance of men and women. The revolution called ‘gender-specific medicine’ has its roots in the social fabric of the United States in the wake of the Second World War. The events of that world-wide, all-engrossing effort to preserve our institutions and political systems resulted in two new developments: the emerging awareness of the competence of women to do men’s work and an abiding faith in the power of science to solve the problems of the human condition. On the battlefield, for example, we learned to expand the efficacy and safety of anesthesia, to understand the pathophysiology of shock, that hepatitis was caused by a virus, and that antibiotics could save countless lives that would have been lost without them. Americans came out of the war convinced that

science held a virtually limitless ability to improve and preserve human life. That conviction prompted the expansion of the nascent National Institutes of Health, which in the early 1950s was no more than a modest collection of eight buildings in Bethesda that housed the United States Department of Health, Education and Welfare (now renamed the Department of Health and Human Services). Gender-specific medicine began as an uniquely American concept. It was conceptualized and expanded first in this country simply because most of the other areas of the world were so devastated by the ravages of war that rebuilding functioning societies was their only and allconsuming goal. Miraculously, our own country had escaped the direct destruction that most of the rest of the civilized world had experienced and so the fabric of postwar society here was unique. The American feminist movement was an inevitable outgrowth of the experience women had had in filling the positions men had traditionally – and exclusively – occupied until the war left those positions empty. In this country, gender-specific medicine had its roots in the growing confidence of women in their own power, unique needs, and importance in society. During the war, whole units of male subspecialists left the academic medical centers they had dominated for the battlefield. Women filled the vacancies created with enthusiasm and confidence: the first woman chief resident in internal medicine in the history of Columbia University, Doctor M. Irene Ferrer, was appointed in 1943. She went on to create a spectacular career in investigative medicine that included developing the cardiac catheter as an instrument that defined the fundamental dynamics and the pathophysiology of disease of the cardiovascular system. By 1985, laywomen had prompted the formation of a governmental Task Force on Women’s Health, which after xxi

xxii

Preface

three years of study concluded that aside from reproductive biology, we knew nothing about the physiology of women but had always assumed that, beyond the pelvis, the physiology of the two sexes was identical.1 The traditional subjects of scientific investigation at all levels were males and it was assumed that the results of those investigations could be extrapolated to women without direct testing or modification. The 1990s saw an increasing effort by the National Institutes of Health, academic medical centers, the American Congress, and the Federal Drug Administration to study women as well as men and to compare the results of scientific research in both sexes. It has been a slow, painful progression: many – and perhaps unanticipated – obstacles that have been only partially overcome limited our understanding of the sex-specific differences in human structure and function. One of our thorniest problems is how to safely include the premenopausal woman in clinical trials: the fear of harming women’s reproductive capacity and/or the development of a fetus conceived during the conduct of an investigatory protocol remains largely unsolved. It is no surprise that the largest investigative effort mounted on behalf of women, The Women’s Health Initiative, focused on the postmenopausal female.2 Another profoundly important difference between the sexes is the frequently different age of onset and incidence of specific disease entities that make comparison difficult. The spectrum of co-morbidities that affect the two sexes with that disease may also be entirely different. Nevertheless, the results of gender-specific investigations, often completely unanticipated, have yielded an unexpectedly rich harvest and have prompted questions we never would otherwise even have asked. The value of sex-specific research is now so obvious that we are beginning to turn a sex-specific lens on the unique features of male biology. The reasons for men’s shorter lifespan compared with that of women and the two-decade earlier onset of coronary artery disease in men, for example, are subjects of particular interest and deserve intensive investigation.

In a very real sense, we have used men as clinical subjects in an effort to protect women from the risk of harm. But as a matter of justice, women should bear some of the risks of direct investigation, since they benefit from the results of those studies. Gender-specific medicine has expanded over the past 15 years from this country to other capitals of the world; among others, there are centers for the pursuit of this discipline now in Sweden, Japan, Austria, Germany, Korea, Holland and, most recently, Israel. We have formed the International Society for Gender Specific Medicine and I have established two scientific journals devoted to the new science. Both are included in MEDLINE (Medical Literature Analysis and Retrieval System Online), compiled by the US National Library of Medicine. The first was the The Journal of Gender Specific Medicine, and the second, which supplanted the first, Gender Medicine, published by Elsevier, continues to present new information about the sex-specific characteristics of human physiology and the experience of disease. Few developments in medicine have been more rewarding than the realization that the study – and comparison – of men and women has and will continue to produce a stunning flood of unexpected, novel information. Hopefully this second edition of The Principles of Gender-Specific Medicine will help to correct and expand our understanding of the enormously important impact of biological sex on human biology. Marianne J. Legato 2009

References 1. USPHS (US Public Health Service). Report of the public health service task force on women’s health issues. Public Health Rep 1985;100(1):73–106. 2. The Woman’s Health Initiative, National Institutes of Health, Bethesda, MD, 1991.

Section 1

Gender and Normal Development



s e c t i o n 1     Gender and Normal Development l

Introduction

George M. Lazarus On a summer Sunday afternoon, my wife and I attended an outdoor concert in Saint Stephen’s Green in Dublin, Ireland. As the band played music from children’s television programs and popular movies, twenty or thirty young children from about 2 to 4 years of age romped on the grass. The girls danced, ballet-style, to the music. The boys chased and tackled each other like little football players. No one told the children how to play. They just did what came naturally and there was no cross-over behavior between the boys and girls. As I enjoyed watching the children, I was impressed by how different boys and girls are from a young age. Two-year-old children know their sex. A child that age doesn’t know much, but a boy knows he is a boy, a girl knows she is a girl. Young children don’t know exactly how or why boys and girls are different, but they know that they are. In that respect, they are exactly like medical scientists! Pediatricians are well aware of the differences between the sexes that appear from the time of conception. We are learning more and more about gender differences, as will become apparent from reading the chapters in the pediatric section. We can explain the biological reasons for some differences and we can describe many more differences whose etiologies remain obscure.

Sexual differentiation in utero affects more than the external and internal sex organs. The brain is a sexual organ and some of the behavioral differences observed between boys and girls (and men and women) are likely due to the effects of androgens on the male brain before birth. Baby boys are bigger from the time they are only a small bunch of cells. More of them are born. Boys are more suscep­tible to nearly every disease that affects newborns, so more of them die. Many diseases present differently in boys and girls. For example, attention deficit hyperactivity disorder (ADHD) is readily apparent in a hyperactive boy but is more easily overlooked in a well-behaved but inattentive girl. Treatment of disease also may vary with sex. Boys and girls with cancer respond differently to chemotherapy and radiation, and ideal therapeutic regimens may be sexspecific. Prognosis, too, can vary by sex. Boys with cystic fibrosis tend to live longer. These are just a few examples of the importance of gender in pediatric medicine. Many more examples are to be found in the chapters that follow. I thank the pediatric authors for a job well done. They have all looked at their specialties from a new, genderspecific perspective and have gathered and clearly presented a great deal of information. Better understanding of gender differences in health and disease already has led to improved medical care for our patients, and the field is still young.

Chapter

1

The Effects of Gender in Neonatal Medicine Tove S. Rosen1, and David Bateman2 1

Professor of Clinical Pediatrics/Neonatology, Columbia University Medical Center, Department of Pediatrics, New York, NY, USA 2 Associate Professor of Clinical Pediatrics, Columbia University Medical Center, Department of Pediatrics, New York, NY, USA

Introduction

Males also face a higher incidence of neurobehavioral and developmental difficulties during childhood. In epidemiologic surveys, attention deficit hyperactivity disorder (ADHD), characterized by poor concentration ability, motoric hyperactivity, impulsivity, and frequently learning difficulties, is four times more common in boys than in girls. The increased male susceptibility to disease depends upon the interplay of environmental risk factors with fundamental genetic, endocrinologic, immunologic, and metabolic differences between the sexes.11–17

Differences between male and female infants in mortality, growth, and the susceptibility to specific diseases exist during the perinatal period (fetal and neonatal), as is shown by numerous embryologic, physiologic, epidemiologic, and anthropologic observations in humans and by laboratory studies and field observations in animals. For a cohort of individuals at a given point in life, the sex ratio (simple ratio of males to females) depends not only on the different rates of mortality between the sexes but also on the relative numbers of males and females present at birth. In humans, as in most mammalian species, slightly more males are born than females. At birth the sex ratio is approximately 1.05, representing a proportion of male births of about 51.3%. After birth the mortality of males is higher, and the sex ratio declines progressively. By the end of the first year of life, 120 males have died for every 100 females. Males continue to die at a higher rate throughout childhood and adulthood.1–4 Males are not only more numerous and more likely to die at birth, they are also larger. Differences in the rates of growth and metabolism between males and females have been reported from the earliest embryologic period onward and may influence sexual organogenesis, the sex ratio during gestation, and relative male–female survival rates during intra-uterine and extra-uterine life.5–10 Males are more likely to experience stillbirth, premature birth, congenital malformations, pulmonary hemorrhage, intracranial hemorrhage, respiratory distress, perinatal asphyxia, perinatal infection, cerebral palsy, and developmental delay. Sudden Infant Death Syndrome (SIDS) is more common in males. Infants are at highest risk for SIDS during the first 2–4 months of life. Besides male sex, other risk factors include maternal smoking, exposure to a suboptimal uterine environment, poor fetal growth, and prematurity. Principles of Gender-Specific Medicine

The sex ratio during fetal life Sex Ratio at Conception Phenotypic sexual differentiation in mammals consists of a sequence of genetic and hormonal components referred to as the Jost paradigm. The genetic component, consisting of either the XX or XY chromosome complement, is determined at conception. Gonadal differentiation occurs at 6–7 weeks gestation in humans with expression of the Y chromosome-borne SRY gene, resulting in the formation of either male or female gonads. The development of male sex organs and secondary characteristics is an active process controlled by three hormones produced by the testis: Müllerian inhibiting substance (also called anti-Müllerian hormone), testosterone, and insulin-like factor 3 (INSL3). Phenotypic female characteristics develop in the absence of these three testicular hormones.18,19 Evidence of a preponderance of male fetal losses suggests that the sex ratio is even higher around the time of conception than at birth. By assuming a constant male– female ratio of fetal loss during pregnancy, the sex ratio from the earliest point in embryonic life has been estimated to be approximately 1.1 to 1.2. However, the precise 

Copyright 2010 20 , Elsevier Inc. All rights reserved.



s e c t i o n 1     Gender and Normal Development l

point at which male numerical predominance develops is unknown. Several studies have shown that the ratio of Y- to X-bearing spermatozoa in humans is approximately equal; thus, the elevated sex ratio may reflect differences in rates of fertilization, implantation or early survival. The ­classical explanation for the sex ratio of more rapid arrival to the ovum of lighter, faster-swimming Y-bearing spermatozoa has been discounted, and postulates involving an immuno­ logic or hormonal preference of the ovum for Y-bearing spermatozoa remain unsupported.3,12,20–24 An alternative explanation for male predominance is that it occurs after fertilization, at the time of implantation. Two days after fertilization the average number of male embryos exceeds that of female embryos. At the same time the metabolic rate, as measured by glucose and pyruvate uptake and lactate production, is higher in male embryos than female embryos. The higher metabolic rate and larger size of male embryos may confer a survival advantage (albeit temporary) on male embryos at the time of implantation. The enhanced metabolic rate of male embryos may be the result of the action of Y-chromosome-derived transcription factors acting on maternally-derived mitochondria. Higher metabolic rate (and increased temperature) may also play an epigenetic role in male sex differentiation.6,7,19,24–26

Sex Ratios and Periconceptional Influences Male and female fetuses and infants respond differently to biological, environmental, and cultural influences. Environmental stresses including crowding, heat, and nat­ ural catastrophes have been found to alter the birth sex ratio in human populations. A sharp decline in the sex ratio at birth was reported 9 months following the 1995 Kobe earthquake and 320 days after both the 1952 London smog and the 1965 Brisbane flood. Similarly, a drop in the sex ratio to 1 was seen in New York City in 2002 following the terrorist attack on September 11, 2001. Using combined Danish registries, Hansen et al. found that severe periconceptional life events (development of cancer or myocardial infarction in her partner or older children) experienced by the mother during the first trimester result in a smaller proportion of male births. Deviations in monthly environmental temperature above the overall mean were associated with a higher birth sex ratio. Data from California support the hypothesis that the fetal death sex ratio varies positively over time with the unemployment rate. Temporary decreases in the sex ratio such as these might be due to alterations of parental hormones, altered quality of semen or an increased rate of early spontaneous abortion of males. It is notable that the peak drop of the sex ratio in New York City occurred 5 months after the September 11 attacks, making increased male fetal loss, rather than altered conception, the likely mechanism. Interestingly, the sex ratio did not change following the severe Dutch famine during the winter of 1944–45.

In contrast, the proportion of males born increased sharply after both world wars in combatant countries.13,27–37 Lower birth rank, increased parental age, and decreased frequency of coitus have been associated with a lower sex ratio. Psychological stress in one parent has been shown to favor the production of offspring of the opposite sex. Parental social status may alter the sex ratio. Parents engaged in stereotypical ‘masculine’ occupations (law, politics, natural science, medicine, business, etc.) and ‘dominant women’ were more likely to produce sons than daughters.38 James has assessed the numerous, often conflicting studies relating the sex ratio in animals and humans to various environmental, social, and disease-related circumstances and has concluded that the relative parental levels of estrogen, testosterone, and gonadotropin at the time of conception contribute to the determination of fetal sex. Others have argued that the birth sex ratio is influenced by the quality of the ovum at different times in the menstrual cycle.1,24,26,39–44

Sex Ratio and Fetal Loss The results of chromosomal analyses to determine the sex ratio in spontaneous abortions have varied. Several of these studies have found a predominance of female tissue. After carefully excluding maternal contamination of tissue and androgenetic 46,XX hydatidiform moles, Hassold et al. estimated the sex ratio for genetically normal spontaneous abortions to be approximately 1.30. The study also noted an overall male predominance among spontaneously aborted fetuses with various trisomies, with the sex ratio lowest for trisomy 9 and highest for trisomy 21.45

Manipulation of the Sex Ratio Attempts at selecting the sex of an infant by controlling the frequency, timing or position of coitus or insemination in relation to ovulation have a long history of use but have never been shown to be effective. Modern laboratory techniques have been applied to the question of sex selection in an effort to control the expression of serious X-linked diseases. These techniques have attempted to take advantage of potentially differing physical, antigenic, and electrochemical properties that might allow separation of X- and Y-containing spermatozoa. Flow cytometry cell sorting uses fluorescence in-situ hybridization (FISH) to label X- and Y-containing chromosomes, which are then separated by flow cytometry. The technique is advertised to be a highly effective method of sex selection; but several commentators have worried about potential damage to genetic material subjected to fluorochrome staining, laser, and a high voltage electromagnetic field.46–49 Pre-conceptional sex selection for reasons of parental choice (as opposed to the elimination of genetic disease) is ethically controversial. Nevertheless, post-conceptional

C h a p t e r 1   The Effects of Gender in Neonatal Medicine l

sex selection has been a long-standing practice in some cultures, where infanticide or, more recently, selective abortion based on prenatal ultrasonographic determin­ation of fetal sex are the methods of selection. In Korea, the sex ratio climbs with each pregnancy, exceeding 2.0 for the fourth child. In India, where a large gap exists between the expected and actual number of females, the sex ratio for urban births is 1.1–1.2. Similar findings have been described in China where, in census data, the births of girls have not been reported because of early deaths, most likely due to infanticide. The trend toward fewer than expected females in China is now increasingly due to selective abortion after ultrasonographic sex determination. The concept of ‘missing women’ has been advanced to focus attention on the impact of such practices. It has been estimated that there are now 40–50 million missing women in India alone, and perhaps 100 million missing women worldwide.50–54

Sex Ratio and Length of Gestation Male infants are more likely to deliver prematurely. In an analysis involving more than 1.8 million births in six New England states, Cooperstock and Campbell found a 7.2% excess of males among white singleton preterm births (20–37 weeks gestation). Beyond 36 weeks, the proportion of males declined sharply, falling below the mean proportion of all white singleton births (51.3%) by 40 weeks gestation. Among preterm singleton black infants, the male excess was significantly smaller (2.3%). Male excess has also been reported in the birth of preterm twins less than 33 weeks gestation. Female twin pairs have a significantly longer gestation period than either male twin pairs or discordant female/male twin pairs. Mortality also has been reported to be lower in female pair twins than in either male pair or discordant twins. A ‘masculinizing’ effect of the male twin on respiratory morbidity in the female twin partner in very low birthweight (VLBW) male–female twins has been observed.55–58

Sex differences in fetal and neonatal growth Fetal Growth Differences The earliest attempts to assess the rate and range of fetal growth used cross-sectional data from live born infants to construct percentile charts for growth during the third trimester. In these charts gestational age was calculated from the last menstrual period. Lubchenco et al. provided separ­ ate growth charts for male and female newborns. In these the weight of males born at the 50th percentile exceeds that of females born at the 50th percentile by approximately 50 g at 28 weeks gestation and 100 g at term. These percentile charts have been used arbitrarily to define categorical indices



of fetal growth such as small-, appropriate- and large-forgestational age (10th, 10th–90th, 90th percentiles, respectively). By such measures female fetuses have about a 20% greater risk for intra-uterine growth retardation (IUGR) than male fetuses.59,60 Fetal ultrasonography provides a potentially direct, longitudinal measure of fetal growth; however, standard algorithms usually have been constructed from cross-sectional data and are not adjusted for different growth rates of the sexes. In a prospective longitudinal study through the second and third trimester, Moore et al. found significantly different trajectories for male and female head growth, such that the mean biparietal diameter (BPD) for males at 28 weeks gestation was approximately equal to the mean BPD for females at 29 weeks. Pedersen et al. found that male fetuses were larger than female fetuses as early as 8 weeks of gestation. The male–female difference, expressed as the time needed for the female fetus to attain male size, ranged from 1 day at 8–12 weeks gestation to 6–7 days at term.5,61–63 Data on early fetal male–female size difference are supported by animal studies, in which evidence for size differences is present from very early in intra-uterine life, prior to gonadal differentiation. Tsunoda et al. found a size difference in mouse embryos at the blastocyst stage. Prior to implantation into foster mothers, they classified cultured embryos as ‘fast-cleaving’, ‘intermediate-cleaving’ or ‘slow-cleaving’ according to the time between fertilization and blastocyst formation. Fast-cleaving embryos were much more likely to produce males than slow-cleaving embryos. Similar results were found with bovine embryos. In human in vitro fertilization studies, larger embryos at the time of implantation were found to be much more likely to result in male births. These studies suggest that the male– female size difference is genetically rather than hormonally determined. In an article titled ‘Blastocysts prepare for the race to be male’, Mittwoch reviewed evidence in support of the hypothesis that the faster male growth rate is one of the major conditions influencing male anatomic sexual expression; slower growing embryos result in the development of an ovatestis or ovary.7–9,26,64

Neonatal Growth Differences At birth, males are slightly larger than females. In the United States the median birthweight of term males (3530 g) exceeds that of females (3399 g) by 131 g. The respective values for recumbent length and head circumference are 49.98 cm and 35.81 cm for males and 49.23 cm and 34.71 cm for females. Revised postnatal percentile growth charts based on combined cross-sectional and longitudinal data from diverse sources have recently been published by the Centers for Disease Control. These charts show that by one year of life the male–female size difference increases, with the median weight of males exceeding that of females by almost 800 g.10

s e c t i o n 1     Gender and Normal Development



l

Body composition also differs during the first year of life and into childhood. Males demonstrate larger body dimensions (chest circumference, upper arm circumference, calf circumference) but females have larger measures of body fat (skinfold thickness). In VLBW premature infants the intra-uterine sex difference in growth rate carries over into extra-uterine life, with males growing larger and leaner than females. In one study of VLBW infants fed diets in which nutrient content and density were systematic­ ally varied, the growth rate of male infants exceeded that of female infants by approximately 1 g/kg/day. Subscapular skinfold thickness was measured and was greater in females than males but the difference narrowed as the daily caloric intake increased.10,65

Excess male mortality The ‘Male Disadvantage’ In 1971 Naeye et al. analyzed 2735 consecutive autopsies involving both neonatal deaths and stillbirths and found an excessive risk of neonatal death in males. The ratio of male to female deaths overall was 1.28, which differed significantly from the sex ratio at birth for the general population (1.05). The male to female ratio in stillbirths without congenital anomalies was similar to that of the general birth population. However, among neonatal deaths the ratio of males to females was much higher (1.32). Higher male mortality was seen consistently over a wide range of causes of death, including major congenital malformations, hyaline membrane disease, pulmonary hemorrhage, intracran­ ial hemorrhage, aspiration pneumonia, pre- and post-natal infection, and the effects of maternal diabetes and toxemia. The study also examined the effects of socioeconomic status and race on mortality and found that the highest sex ratio occurred among non-poor whites. The authors postulated that while the stillbirths were due to a failure of the maternal environment and therefore affected sexes equally, there existed an inherent ‘male disadvantage’ for survival in the neonatal period that was not related to a specific disease

process. A recent study confirms the presence of a male disadvantage among VLBW infants. Other evidence has pointed to an interaction between male gender and poorer pregnancy outcomes, perhaps due in part to the larger size of male fetuses at a given gestational age. Women carrying male fetuses had higher rates of gestational diabetes mellitus, fetal macrosomia, failure to progress during the first and second stages of labor, cord prolapse, nuchal cord, and true umbilical cord knots. Cesarean sections also were found more frequently with male newborns.11,13,66–68

Sex Ratio, Infant Mortality, and Race In the United States the difference in survival between the sexes is modified by a survival difference between the races. Although infant mortality rates for both black and white infants continue to decline, the infant mortality rate of black infants remains more than double that of white infants, and the relative gap between the races appears to be growing. In 1980 the infant mortality rates for black and white males were 25.9 (per 1000) and 12.3, respectively, a ratio of 2.1. By 2004 the rate for black males had fallen to 13.8 compared to 5.7 for white males, a ratio of 2.4. Infant mortality rates for white and black males are about 23% higher than for white and black females, but the trend toward higher relative mortality in black females compared to white females over time is similar. The excess overall mortality for black infants is related largely to a downward shift in the birthweight distribution and the much greater risk of death for lower birthweight infants regardless of race and sex (see Table 1.1)4,69 Within a given birthweight category the effect of birthweight on survival is contrary to the overall effect: that is, the group with the lowest mean birthweight (black females) has historically had the highest survival rate, while the group with highest mean birthweight (white males) has had the lowest. However, it appears that this hierarchy of birthweight-specific survival may be changing, perhaps due to improved care of extremely low birthweight infants. In New York City white females now have birthweightspecific survival rates which exceed those of black females

Table 1.1  United States Birthweight-specific Survival Rates by Gender for Newborns with Birthweight 1500 g During The First 28 Days of Life, 200469 Females

Males

Birthweight (g)

Deaths

Births

% survival

Deaths

Births

% survival

499 or less 500–749 750–999 1000–1249 1250–1499 Total 1500

2729 2003 537 314 225 5807

3382 5762 5904 6981 8346 30375

19.3 65.2 90.9 95.5 97.3 80.9

3019 2781 895 383 300 7379

3571 5897 6417 7264 8459 31608

15.5 52.8 86.1 94.7 96.5 76.7

C h a p t e r 1   The Effects of Gender in Neonatal Medicine l

in essentially all categories (see Table 1.2). These changing relationships raise complex and disturbing questions about differential access to healthcare and the influence of a host of socioeconomic factors and toxic exposures on neonatal and infant mortality.70

Interaction of Growth and Mortality An intriguing hypothesis discussed by Clarke and Mittwoch postulates a connection between the increased rates of growth, metabolism, and mortality in males compared to females. In vitro populations of fibroblasts cannot divide indefinitely; a so-called species-specific ‘growth crisis’ related to the rate of chromosomal alterations occurs when the number of generations reaches a critical threshold. The authors also note that within a species, lower caloric intake and lower metabolic rates have been associated with increased longevity. Thus, decreased longevity and increased susceptibility to disease from embryonic life onward may be the price males pay for enjoying a higher basal metabolic rate and a faster rate of growth that, initially, may have provided a survival advantage at the time of implantation and contributed to male phenotypic expression 6,7–9,18,19,25

The effect of gender on the incidence and severity of diseases in infancy and childhood Early Metabolic Programming There has been a lot of interest recently in the developmental origins of adult disease, or ‘metabolic programming’. Nutritional and metabolic exposures at critical times during

early development may have long-term effects on the health of the adult. Experience during early life may be predictive of different health outcomes such as body size, body composition, and risk of diseases such as obesity, diabetes, hypertension, stroke, and cardiovascular disease. (For example, infants born to mothers with type 2 diabetes have a higher risk of developing diabetes in later life.) Two factors that appear to be implicated are fetal and postnatal growth rate. As stated previously, there are differences in the allocation of energy between male and female infants. Male newborns are heavier at birth than females at the same gestational age, with greater lean mass in males and greater fat mass in females. Skinfold thickness to birthweight and tricipital skinfold thickness to body weight ratios increase significantly with increased maternal weight gain in 1st and 2nd trimesters of gestation in the female fetus but not in the male fetus.71–74 Chronic hypertension has become an increasing problem because of the rising incidence of obesity, diabetes, and renal disease. Reports have shown an association with low birthweight and the development of adult hypertension. A recent meta-analysis found no significant gender differences in the association between low birthweight and high blood pressure. However, in a rabbit model of maternal hypertension the female offspring exhibited increased risk for the development of hypertension. This finding was thought to be related to changes in the growth and development of renal sympathetic nerves during fetal life which may contribute to the development of hypertension in the adult animal. In another study using a rat model with placental insufficiency and growth restricted offspring, both male and female offspring were hypertensive for the first 10 weeks of life. The male offspring remained hypertensive after puberty. This may be related to the interaction of the sex

Table 1.2  Neonatal Birthweight-Specific Mortality Rates by Ethnicity and Gender, New York City, 2000 Birthweight (g)

Black non-Hispanic

White non-Hispanic

Puerto Rican

Other Hispanic

Asian or Pacific Islander

Total

0–499 500–749 750–999 1000–1499 1500–2499 2500 Females

952.4 500.0 111.1   37.7   5.7   8.3

777.8 571.4 155.6   60.6   14.1   3.6

1000.0   437.5   280.0   12.8    6.9    4.7

866.7 529.4 214.3   28.3   8.7   3.8

1000.0   700.0   200.0   68.2    5.0    2.8

901.2 519.8 164.0   40.5   8.6   4.9

0–499 500–749 750–999 1000–1499 1500–2499 2500

931.0 398.2 142.9   13.3   5.9   7.0

666.7 281.3   28.6   17.5   3.6   2.0

1000.0   310.3   117.6   37.0   12.7    5.0

875.0 321.4   46.5   34.1   5.0   2.6

1000.0   687.5   76.9   87.0    4.2    3.2

884.1 381.8   95.0   26.4   5.7   3.9

Males

Rates are per 1000 live births. Number of births  125 563. Data compiled by NYC Department of Health.





s e c t i o n 1     Gender and Normal Development l

hormones with other regulatory pathways such as the reninangiotensin system during fetal and postnatal life. After puberty estrogen may provide protection in the female from the hypertension. Adverse effects can be passed transgenerationally from mother to daughter and then to her offspring. In rat studies, exposure to maternal protein restriction during pregnancy and postnatally produced female offspring (F1 generation) with increased insulin sensitivity. Her offspring, the F2 generation, showed altered glucose and insulin metabolism in both males and females.75–81

Postnatal Effects of Changes in the Intra-Uterine Environment Maternal Diabetes Abnormal intra-uterine environments have been found to affect male and female fetuses and newborn infants differently. In a retrospective review of singleton term births born to mothers with pregnancies complicated by diabetes, male infants had a higher incidence of hypoglycemia. This observation may be explained by higher levels of human chorionic gonadotropins (HCG) found in the fetuses of mothers with diabetes. Elevated HCG levels cause Leydig cell hyperplasia, resulting in higher levels of testosterone, which in turn produce hyperplasia of the pancreatic beta islet cells and increased insulin secretion. With the abrupt cessation of the transplacental glucose supply at birth, increased insulin in males raises the probability of hypoglycemia.82 A similar explanation may account for the higher incidence of respiratory distress syndrome (RDS) in male offspring of diabetic compared to non-diabetic mothers of comparable gestational ages. Higher levels of androgens have been described in both cord blood and amniotic fluid in such infants. This increased level of testosterone may in turn block the production of surfactant, exposing the male infant to a higher risk for RDS. Studies in the chick show that androgens block glucocorticoid regulation of lung maturation.83,84 Susceptibility and Response to Acidemia and Hypoxia In a Swedish study, male fetuses demonstrated more frequent and more severe episodes of acidemia following a protracted course of abnormal fetal heart tracings indicative of fetal distress. On follow-up evaluations at 4 years of age, these same male children had a higher incidence of neurodevelopmental problems. An in vitro study of the effect of hypoxia on hippocampal neuronal cells demonstrated increased vulnerability of male cells and of female cells primed with testosterone. This finding was postulated to account for some of the gender differences in neuropsychiatric diseases related to hippocampal integrity. Studies in the hypoxic-ischemic neonatal rat model have shown gender-specific differences in caspase-dependent apoptosis that may also help explain gender differences in outcome following hypoxic-ischemic insults in the human neonate.85–87

Alloimmunization, Hyperbilirubinemia Male fetuses have been shown to be more severely affected by alloimmunization of fetal red blood cells to D antigen. Male fetuses required a greater number of intra-uterine transfusions and these were performed at a lower gestational age. The odds ratio for the male developing hydrops fetalis was 13.1. Male newborns also may have higher levels of hyperbilirubinemia: in a study of 840 low birthweight infants, mean peak bilirubin was significantly higher (by 0.8 mg/dl) in males in a regression model controlling for race, birthweight, gestational age, intraventricular hemorrhage, and sepsis.88,89 Effects of Maternal Smoking Maternal smoking during pregnancy reduces fetal growth for both sexes but affects male infants disproportionately. At birth, males born to mothers with a history of heavy cigarette smoking had an 8.2% reduction in weight and a 12% reduction in fat accretion compared to 4.8% and 2%, respectively, in females. In males, head circumference was also significantly smaller, with fall-off in head growth noted as early as the second trimester. Since male fetuses have a higher rate of growth than females, factors limiting growth may have a greater impact on males. Male fetuses may be more sensitive to the direct effect of the toxic byproducts of cigarette smoke in regard to cell replication, changes in the hormonal milieu, and fetoplacental circulation.90 Effects of Drugs of Abuse Drugs of abuse such as heroin and cocaine have been shown to interfere with fetal growth. Significant decreases in birth size have been observed in infants with in utero cocaine exposure as measured by urine toxicology at birth or by analysis of cocaine content in hair or meconium. Several of these studies, using regression models to control for the effects of demographic and other risk factors, found an independent effect of sex on birth size. Although no gender specific effect of cocaine was reported, a re-examination of the original data shows that relatively larger decrements in birth size, particularly of head circumference, are observed in cocaine exposed males (D.A. Bateman, unpublished data). Similar findings of interference with growth have been described in infants born to mothers with heroin addiction. Many of these infants are premature and also exhibit growth retardation. Cell size and cell number have been found to be decreased in autopsy studies compared to infants of mothers with similar socioeconomic status and nutrition.1,91–93 Several studies have been reported on the neurobehavioral development of children exposed to drugs of abuse in utero. Children exposed in utero to cocaine demonstrated a higher incidence of neurobehavioral difficulties such as hyperactivity and language and developmental delays. When the effects were stratified by sex, male children showed a significantly higher incidence of developmental difficulties. The male

C h a p t e r 1   The Effects of Gender in Neonatal Medicine



l

children also scored significantly lower on the Bayley Scales of Infant Development. In one study, school age behavior was altered in males but not in females. Boys with persistent intra-uterine cocaine exposure had more problems with central processing, motor skills, and handling abstract concepts than controls or exposed girls. Similar neurodevelopmental and behavioral difficulties were described in children who were born to mothers on methadone maintenance during pregnancy, with male children affected more than female children. These findings correlated with the exposure to methadone, the quality of mothering and the rearing environment. Male children appeared to be more vulnerable to the interaction of adverse effects of intra-uterine exposure to drugs of abuse, opioids, and environmental factors.94–98

Congenital Anomalies and Gender The incidence of certain congenital anomalies varies with the sex of the infant and survival. The incidence of trisomy 18, for example, is higher among male than female stillbirths, but among live born infants with trisomy 18, females outnumber males three to one. Down syndrome, on the other hand, is more common in males among both live born and stillborn infants. Isolated anomalies of multi­ factorial inheritance that have an unequal sex distribution include pyloric stenosis, clubfoot, and cleft lip (more common in males) and cleft palate alone, meningomyelocele, anencephaly, and congenital hip dislocation (more common in females). Isolated diaphragmatic hernias, especially posterolateral types, occur more frequently in male infants. Congenital diaphragmatic hernias that occur in conjunction with chromosomal anomalies are more common in female infants. A treatment choice for infants with congenital diaphragmatic hernias with severe respiratory decompensation is extracorporeal membrane oxygenation (ECMO). A group of infants treated with ECMO were evaluated for neurocognitive development at 31 months of age. These infants exhibited an increased incidence of developmental difficulties, especially the male children, again illustrating the increased long-term vulnerability of the male child.45,99–102

Congenital Heart Disease and Outcomes of Cardiac Surgery Gender based differences have been documented in the incidence of congenital heart disease, with pulmonary atresia, tricuspid atresia, double outlet right ventricle, transposition of the great arteries, and left-sided lesions (aortic stenosis, coarctation of the aorta, hypoplastic left heart) more common in male infants. Atrial and ventricular septal defects, Ebstein’s anomaly, and patent ductus arteriosus were more common in females (see Table 1.3).103–107 A sex-related disparity in pediatric cardiac surgical mortality was noted in the California statewide hospital discharge database: although there was no crude mortality rate difference between males

Table 1.3  The Gender Ratio Observed for Specific Types of CHD, Described as Male/Female Ratio of Incidence Diagnosis

Samánek105

Calzolari et al.106

Samánek et al.107

All PDA ASD, secundum VSD Aortic stenosis CoA HLHS Pulmonary atresia Tricuspid atresia Ebstein anomaly TOF DORV TGA Truncus arteriosus

1.09:1 1:1.17

1:1

1.28:1

1:1.4 1:1.11

1:1.5 1:1 1.6:1 1.6:1 1.4:1 1.7:1

1.95:1 1.3:1 2.6:1 1.55:1 1.45:1 1:1.6 1:1.1 2.7:1 2.11:1 1:1.2

1.14:1

1.04:1 2.23:1 1:1.11

1.4:1 1.7:1 2.1:1 1.3:1

PDA, Patent ductus arteriosus; ASD, atrial septal defect; VSD, ventricular septal defect; CoA, coarctation of the aorta; HLHS, hypoplastic left heart syndrome; TOF, tetralogy of Fallot; DORV, double-outlet right ventricle; TGA, transposition of the great arteries. From Miller-Hance and Tacy, 2004103; used by permission

and females, the adjusted rate by procedure for females was 18% higher. Animal models, however, suggest that female cardiac tissue may be more resistant than that of males to the effects of hypoxia-ischemia.103,108,109

Asthma and Gender in Children Asthma is nearly twice as common in male children (11.4% vs. 6.9%) and male asthmatic children suffer more frequent attacks during the preschool period. Predictors of childhood asthma have included male gender, low birthweight, and neonatal respiratory distress due to various etiologies. When controlled for birthweight, prematurity, and neonatal respiratory distress, a significant association was found between male gender and preschool asthma. Possible etiologies entertained for the higher incidence of asthma in the male child have been the presence of smaller airways relative to lung size and diminished lung function.110

Gender and Diseases of Premature Birth Effects on Mortality Infants with birthweight less than 1000 g and gestational age less than 28 weeks continue to contribute disproportionately to infant morbidity and mortality. This is compounded by the recent increase in the incidence of multiple births (by 20%) as a result of in vitro fertilization. Mortality is on the decline for extremely premature infants, but major morbidity, especially in those with birthweights 750 g, remains unchanged. The incidence of neonatal complications such

10

s e c t i o n 1     Gender and Normal Development l

as chronic lung disease, necrotizing enterocolitis, intraventricular hemorrhages, and poor postnatal growth may even have risen.111 Table 1.1 displays the neonatal survival rate (during the first 28 days of life) according to birthweight category and gender for all VLBW babies (1500 g) born in the United States in 2004. Both gender and race-ethnicity play significant roles in mortality, morbidity, and neurodevelopmental outcome. The white premature male has the highest rate of mortality (see Table 1.2). Significant predictors of mortality in premature infants are low gestational age (28 weeks, especially 23–26 weeks), intraventricular hemorrhage, Apgar score 3, and male gender. Recently, the National Institute of Child Health and Human Development Neonatal Research Network has published separate graphic estimates for risk of mortality stratified by gender and birthweight (see Figure 1.1). Tyson and co-workers have used the NICHD data set to construct predictive equations for mortality prior to NICU discharge and disability at 18–22 months corrected age, based on expected birthweight, gestational age, gender, plurality, and maternal receipt of antenatal corticosteroids. For example, a 24-week singleton male infant with an expected birthweight of 650 g whose mother received antenatal corticosteroids has a predicted mortality of 45% with a 77% probability of death or severe disability. For females with similar characteristics, the probability of mortality and

death or severe disability are 34% and 62%, respectively. It should be emphasized that these equations are still in the investigational stage and have not been verified with broad population-based data.66,69,111–113 Apgar Score The Apgar score, a tool used to assess well-being at 1 and 5 minutes after birth, incorporates five elements: respiratory effort, heart rate, reflex irritability, muscle tone, and color. In the preterm infant, the Apgar score is directly related to birthweight and gestational age. Among premature infants, Apgar scores are significantly higher at 1 and 5 minutes in females. In addition, male premature infants frequently require more vigorous resuscitation. Higher Apgar scores in the preterm female infant may be related to the higher catecholamine levels found in female infants at birth, resulting in a more normal pressor response and improved cardiovascular stability.114 Cerebral Blood Flow Cerebral blood flow is lower in preterm female infants. This is of particular interest in that it may contribute to the better survival and neurodevelopmental outcome seen in premature females. The reason for these differences is unknown, but may be related to differences in mean arterial blood pressure, cardiac output, and/or sex hormonal influences. Males (n = 1453) 1500

1400

1400

1300

1300

1200

1200

1100

1100

Birthweight (g)

Birthweight (g)

Females (n = 1327) 1500

1000 900 0.1

1000

0.1

900 0.2

800

800

0.3

0.2

0.5 0.6 0.7

600 500

0.4

0.3

700

700

0.4

0.6 0.7

600

0.8

22

0.5

0.8

500 23

24 25 26 27 28 Gestational age (wk)

29

30

22

23

24 25 26 27 28 Gestational age (wk)

29

30

Figure 1.1  Estimated mortality risk by birth weight and gestational age based on singleton VLBW infants born in NICHD Neonatal Research Network Centers between January 1, 1995 and December 31, 1996.111 Reproduced with permission from: Lemons, Bauer, Oh et al. Pediatrics 2001;107: URL:http://www.pediatrics.org/cgi/content/full/107/e1 From: Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Research Network, January 1995 through December 1996. Pediatrics 2001;107: URL:http://www.pediatrics.org/cgi/content/full/107/e1. Used by permission.

C h a p t e r 1   The Effects of Gender in Neonatal Medicine l

Gender-related differences in cerebral blood flow distribution persist through childhood and adulthood, although the patterns change and the significance of the differences is unknown. Improved developmental outcome in males treated in the early perinatal period with indomethacin, which results in decreased cerebral blood flow, has been noted.115–117 Respiratory Distress Syndrome Respiratory distress syndrome (RDS), or respiratory insufficiency of prematurity, is one of the major complications seen in premature low birthweight infants. The incidence of RDS in premature infants between 500–1500 g ranges from 50 to 80%. Infants with lower birthweights and gestational ages have a higher incidence of RDS. The relative risk for developing RDS and its complications is 1.7 for male premature infants compared to female infants of the same gestational age. Gender differences in specific measures of airway function have been demonstrated.118–120 Antenatal steroid administration to women in premature labor has been shown to induce fetal lung maturation and decrease the incidence and severity of RDS in the premature newborn. Usually, either bethamethasone or dexamethasone is administered within 24 hours of delivery to women who are in premature labor at less than 32 weeks gestation. The administration of antenatal steroids was found to be more effective in preventing or ameliorating RDS in the female premature infant than in the male. After steroid administration, the incidence of RDS in the male was 29.1% and in the female 8.6%. In premature sheep, pulmonary function measured by compliance, conductance, lung volume and PaO2 showed greater improvement in females than in males after antenatal steroid administration. The pharmacologic and physiologic response to antenatal steroids may be related to the presence of an endogenous inhibitor of surfactant production in the lung in the male infant. Dehydrotestosterone has been shown to inhibit fetal pulmonary surfactant production. A lag in the production of surfactant has been demonstrated in the male rabbit fetus. An increase in the incidence of RDS has been described in preterm male twin pairs compared to preterm female twin pairs; male twins, although heavier, showed the same blunted response to antenatal administration of betamethasone. An increased incidence of RDS also has been noted in girls of unlike-sex preterm twins compared to girl-girl twins. A transchorionic paracrine effect on the female twin has been proposed to account for this observation.58,118,119,121–125 Surfactant production, reflecting the maturity of the fetal lung, can be evaluated by measuring the L/S (lecithin/sphingomyelin) ratio in amniotic fluid. The L/S ratio for white male fetuses is the lowest (most immature) when compared with white female, black female or black male fetuses. The data suggest a relative delay in surfactant production, which may be genetically determined in white males.

11

The response of the fetal lung to various hormones such as glucocorticoids and androgens may be influenced by genetic factors controlling development.83 Chronic lung disease (CLD) is a complication seen in small premature infants in association with RDS and its treatment modalities (especially mechanical ventilation and supplemental oxygen) and with other complications of prematurity including infection and the presence of a patent ductus arteriosus (PDA). The incidence of CLD varies with gestational age, birthweight, and length of ventilatory therapy. Male gender is also a risk factor for the development of CLD. This is consistent with the increased incidence and severity of RDS in male infants. Male preterm infants also are more likely to experience episodes of apnea and bradycardia and to develop anemia and electrolyte disturbances during the neonatal period. Interestingly, a prospective cohort study from Holland of prematurely born infants with and without CLD found a higher prevalence of asthma and respiratory symptoms in young adult women compared to men.126,127 Septicemia Septicemia is another common complication in low birthweight premature infants. Its incidence is inversely proportional to gestational age and birthweight. The risk of septicemia is 48% higher in male premature infants. Septicemia is associated with increased mortality as well as serious morbidity including severe intraventricular hemorrhage, CLD, and prolonged ventilatory treatment. The reason for the greater male susceptibility to infection is not known.128 Neurobehavior and Pain Perception Gender differences in socio-emotional behavior, well documented in human adults, may have antecedents in the earliest days of life. Neonatal imitation, considered the earliest form of communicative exchange, differed between male and female infants at 3–96 hours of life. In response to an index finger gesture, female infants had a higher number of fine motor movements and specific imitative gestures, faster response, and higher heart rate response than male infants. Early neurobehavioral gender differences on the Newborn Behavioral Assessment Scale (Brazelton Exam) also have been documented. In one study, female infants scored higher than male infants in areas of auditory orientation, alertness, and state regulation. Males had higher irritability scores. In serial assessments of predominant mood during the first two years of life, boys were reported more often to be in happy-excited moods, whereas girls were more often in a quiet-calm mood. Analysis of cord blood sex hormones including androstenedione, estrone, and progesterone showed small but significant associations and interactions between mood and cord hormone levels.129–131 Multiple adult studies have shown gender differences in pain perception but little information is available on

12

s e c t i o n 1     Gender and Normal Development l

whether or not these differences are present in the neonatal period. Interpretation of neonatal studies has been made more difficult because of the use of different instruments to evaluate pain. Biological differences have been described in responses to pain in males and females. Pain thresholds and tolerance are lower in women. Shorter latency time to cry and facial reactions have been described in male newborn infants. In addition, female infants of all gestational ages expressed more facial features of pain than males during capillary stick and 1 minute post procedure. These findings may reflect early developmental differences in pain perception among male and female infants.132

Prognosis The long-term prognosis of low birthweight premature infants is guarded. The smaller, sicker, and more premature the infant is, the higher the incidence of long-term morbidity. A 2–year follow up of low birthweight infants demonstrated that cerebral palsy, sensorineural hearing loss, visual disorders, and developmental delays were related to the severity of illness during the neonatal period. In the same study, male children showed poorer development of language and personal skills than female children, irrespective of neonatal morbidity. In another study from Holland the prevalence of handicaps at 5 years of age was three times greater in boys than girls (21% vs. 7%, odds ratio 3.2). This did not change when adjusted for gestational age and birthweight. A critical review of follow-up studies in school-aged children born at less than 1500 g demonstrated age-appropriate IQ scores but with a large variability. There was a greater need for special education for these children for learning difficulties, motor incoordination, and behavior problems. In studies where gender was examined, the outcome for females was generally better than that of males.14,15,133–136 The results of several multi-center follow-up studies of extremely low birthweight (ELBW, 1000 m) infants have been published recently, showing that approximately onethird to one-half of surviving ELBW infants demonstrate major developmental handicaps by 18–22 months corrected age. Data from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, involving at least 12 centers and collected over an 8-year period, showed that more than half of surviving ELBW children had neurodevelopmental impairment (NDI), consisting of one or more of the following: cerebral palsy, Bayley Mental Developmental Index score (MDI) 70, Bayley Physical Developmental Index Score (PDI) 70, blindness or deafness. Only 21% of infants tested were considered to be unimpaired. Disability occurred in males 1.5–2 times more frequently than in females. In studies out of Cleveland, rates of NDI in ELBW and VLBW cohorts examined over two decades were approximately 30%. Intact survival was noted in half of the infants

examined at 20 months corrected age; however, males were half as likely as females to survive intact. Table 1.4 summarizes the gender-specific outcome differences observed in several large follow-up studies.137–143 Hack et al. have pointed out the poor predictive validity of Bayley scores for cognitive function of ELBW infants at school age. Nevertheless, neurodevelopmental problems persist through early school age and even into young adulthood. The EPICure study used a battery of standardized tests to identify neurologic and developmental disability at 6 years of age in infants born 25 weeks gestational age. Overall, 41% of infants tested had serious impairment (2 SD below comparison mean score); the rates in boys and girls were 49% and 32% respectively. Hack et al. followed a cohort of VLBW survivors born in 1977–9 into young adulthood and found higher rates of neurosensory impairment, lower IQ, and lower academic achievement scores and subnormal height compared to controls. Although many of the male–female differences seen in younger cohorts were not observed, VLBW men (but not women) were significantly less likely than normal-birthweight controls to be enrolled in educational programs after high school. A follow-up study of 8-year-old Finnish children of normal and low birthweight demonstrated that the boys had poorer linguistic and motor skills than the girls. Multivariate logistic regression analyses showed that lower birthweight, young maternal age, more than four children in a family, reconstructed family, hearing impairment, and male gender were the most important determinants of poor speech and language abilities with and without adjustment for neonatal risk factors.79,137,141,143–147 Several studies have examined whether or not data gathered during the perinatal period might be predictive of long-term outcome, in order to identify at-risk children with special needs. In addition to gestational age and birthweight, significant perinatal predictors of poor neurodevelopmental outcome include neonatal sepsis, non-white race, and male gender. Low socioeconomic status and male gender were predictors of educational handicaps. The strongest child-related risk factor in all models tested was male gender. Male children were more than twice as likely to make use of special education services for learning problems. A male child was six times more likely to be referred for services for emotional disorders. The NICHD neonatal network is currently evaluating the validity of a predictive model for survival and survival without profound neurodevelopmental impairment, using risk factors at or before birth for infants born at 23–25 weeks gestation.112,113,148,149

Summary In the fetal and neonatal periods and during infancy, males and females differ in at least three fundamental ways. First,

C h a p t e r 1   The Effects of Gender in Neonatal Medicine

13

l

Table 1.4  Selected Neurodevelopmental Outcomes from Studies in which Differential Gender Outcomes are Explicitly Defined Cohort/year born

Birthweight/ Subset gestation

No. tested/ Age tested Outcome No. enrolled

M/F odds 95% CI ratio

NICHD, 1995–8139

401–1000 g

2755/3782

18–22 mth

NDI

1.6

1.4–1.9

NICHD, 1995–9137

401–1000 g

1427/1749 1278/1749

18–22 mth

CP MDI 70

1.8 2.0

1.2–2.6 1.5–2.6

NICHD, 1993–9138

25 wk GA

839/992

18–22 mth

CP MDI 70 PDI 70 NDI

1.5 1.8 1.6 1.5

1.0–2.3 1.3–2.5 1.1–2.3 1.1–2.1

650/982

20 mth

Intact survival

0.45

0.34–0.62

242

20 yr

Educational, cognitive, academic achievement

Normal Head U/S

Hack et al., 500–999 g 1990–2002141 Survival to young adulthood

Hack et al., 1977–9140

1500 g

EPIPAGE, 1997142

33 wk GA

1662/2382

5 yr

MND-2

EPICure, 1995143

25wk GA

241/308

6 yr

Composite cognitive score

Other measure

M:F half as likely to be enrolled in 4 yr college. IQ scores and rates of chronic conditions similar between M–F. 3.1

1.5–6.4 Males score mean 10 (5–15) points lower than females

NICHD: National Institute of Child Health and Human Development, Neonatal Research Network. EPIPAGE: Etude Epidémiologique sur les Petits Ages Gestationales. EPICure: Extremely Preterm Infants Cure study group. M/F: Male/Female. U/S: Ultrasonogram. MDI: Mental Developmental Index, Bayley Scale of Infant Development-II. PDI: Physical Developmental Index, Bayley Scale of Infant Development-II. CP: Cerebral palsy. NDI: Neurodevelopmental impairment: at least one of the following: CP, MDI  70, PDI  70, blindness or deafness. MND-2: moderate minor neuromotor dysfunctions.

males are more numerous; and their numerical superiority appears to be derived at conception or shortly thereafter. Second, males are larger than females and have higher metabolic rates. This difference also is apparent from very early fetal life, from the blastocyst stage, when the increased cell number and metabolism in males may, in fact, influence phenotypic sexual expression. Third, males have a higher mortality rate than females, are more susceptible to most diseases of infancy, and suffer disproportionately from their long-term consequences. This has been termed the ‘male disadvantage’. Each of these three major differences appears to involve the interplay of genetic, hormonal, metabolic, and perhaps evolutionary influences that are not yet well understood.

References   1. Clutton-Brock T, Iason G. Sex ratio variation in mammals. Quart Rev Biol 1986;61:339–74.   2. Martin J, Hamilton B, Ventura S, Menacke R, Park N. Births: Final data for 2000. National vital statistics reports, National Center for Health Statistics 2002;50:7–18.

  3. Clarke C, Mittwoch U. Puzzles in longevity. Perspect Biol Med 1994;37:327–36.   4. US Bureau of the Census. Statistical Abstract of the United States 2000, 120th edn. Washington, DC: Department of Commerce, US Bureau of the Census; 2000.   5. Pedersen J. Ultrasound evidence of sexual difference in fetal size in first trimester. BMJ 1980;281:1253.   6. Ray P, Conaghan J, Winston R, et al. Increased number of cells and metabolic activity in male human preimplantation embryos following in vitro fertilization. J Reprod Fertil 1995;104:65–171.   7. Pergament E, Fiddler M, Cho N, et al. Sex differentiation and preimplantation cell growth. Hum Reprod 1994;9:1730–32.   8. Clarke C, Mittwoch U. Changes in the male to female ratio at different stages of life. Br J Obstet Gynaecol 1995;102:677–79.   9. Mittwoch U. Blastocysts prepare for the race to be male. Hum Reprod 1993;8:1550–55. 10. National Center for Health Statistics, Division of Data Services. CDC Growth Charts, United States. US Department of Health and Human Services, Centers for Disease Control and Prevention 5/30/2000 (modified 4/20/01). 11. Naeye R, Burt L, Wright D, et al. Neonatal mortality, the male disadvantage. Pediatrics 1971;48:902–6.

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12. Whitfield A, Bayliss R, Clarke C. Deaths in the first 20 years and problems of the sex ratio at birth. J R Coll Phys Lond 1987;21:270–74. 13. Kraemer S. The fragile male. BMJ 2000;321:1609–12. 14. Verllove-Vanhorick S, Veen S, ens-Dokkum M, et al. Sex difference in disability and handicap at five years of age in children born at very short gestation. Pediatrics 1994;93:576–79. 15. Ornstein M, Ohlsson A, Edmonds J, et al. Neonatal follow-up of very low birth weight/extremely low birth weight infants to school age: a critical overview. Acta Paediatr Scand 1991;80:741–48. 16. Hunt C. Sudden infant death syndrome. In: RE Behrman, RM Kleigman, HB Jenson, eds. Nelson Textbook of Pediatrics, 16th edn. Philadelphia, PA: WB Saunders; 2000:2139–43. 17. Daruna J, Dalton R, Forman M. Attention deficit hyperactivity disorder. In: RE Behrman, RM Kleigman, HB Jenson, eds. Nelson Textbook of Pediatrics, 16th edn.. Philadelphia, PA: WB Saunders; 2000:100–3. 18. Mittwoch U. Sex determination in mythology and history. Arq Bras Endocrinol Metabol 2005;49:7–13. 19. Viger RS, Silversides DW, Tremblay JJ. New insights into the regulation of mammalian sex determination and male sex differentiation. Vitam Horm 2005;70:387–413. 20. Graffelman J, Fugger E, Keyvanfar K, et al. Human live birth and sperm-sex ratios compared. Hum Reprod 1999;14:2917–20. 21. Martin R. Sex ratio among sperm cells. Am J Hum Genet 1990;47:349–51. 22. Bowman M, De Boer K, Cullinan R, et al. Do alterations in the sex ratio occur at fertilization? A case report using fluorescent in situ hybridization. J Assist Reprod Genet 1998;15:320–22. 23. Adinolfi M, Polani P, Crolla J. Is the sex ratio at birth affected by immune selection? Exp Clin Immunogenet 1985;2:54–64. 24. Mittwoch U. Differential implantation rates and variations in the sex ratio. Hum Reprod 1996;11:8–9. 25. Mittwoch U. The elusive action of sex-determining genes: mitochondria to the rescue? J Theor Biol 2004;228:359–65. 26. Boklage C. The epigenetic environment: secondary sex ratio depends on differential survival in embryogenesis. Hum Reprod 2005;20:2662–63. 27. Fukuda M, Fukuda K, Shimizu T, et al. Decline in sex ratio at birth after Kobe earthquake. Hum Reprod 1998;13:2321–22. 28. Lyster W. Altered sex ratio after the London smog of 1952 and the Brisbane flood of 1965. J Obstet Gynaecol Br Comm 1974;81:626–31. 29. Hansen D, Moller H, Olsen J. Severe periconceptional life events and the sex ratio in offspring follow up study based on five national registers. BMJ 1999;319:548–49. 30. MacMahon B, Pugh T. Sex ratio of white births in the United States during the Second World War. Am J Hum Genet 1954;6:284–92. 31. Bromen K, Jockel K. Change in male proportion among newborn infants. Lancet 1997;349:804–5. 32. Van den Broek J. Change in male proportion among newborn infants. Lancet 1997;349:805. 33. Lerchl A. Sex ratios at birth and environmental temperatures. Naturwissenschaften 1999;86:340–42. 34. Catalano R, Bruckner T, Gould J, et al. Sex ratios in California following the terrorist attacks of September 11, 2001. Hum Reprod 2005;20:1221–27. 35. Catalano R, Bruckner T, Marks AR, et al. Exogenous shocks to the human sex ratio: the case of September 11, 2001 in New York City. Hum Reprod 2006;21:3127–31.

36. Catalano R, Bruckner T, Anderson E, et al. Fetal death sex ratios: a test of the economic stress hypothesis. Int J Epidemiol 2005;34:944–48. 37. Stein AD, Zybert PA, Lumey LH. Acute undernutrition is not associated with excess of females at birth in humans: the Dutch hunger winter. Proc Biol Sci 2004;271:S138–41. 38. Grant VJ. Sex determination and the maternal dominance hypothesis. Hum Reprod 1996;11:2371–75. 39. James W. Evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels at the time of conception. J Theor Biol 1996;180:271–86. 40. Jongbloet P, Groenewoud J, Zielhuis G. Non-optimal maturation of oocytes and the sex ratio. Hum Reprod 1996;11:2–7. 41. James W. Interpregnancy intervals, high maternal age and seasonal effects on the human sex ratio. Hum Reprod 1996; 11:7–8. 42. Evangelos AC, Yannis A. Secondary sex ratio in Greece: evidence of an influence by father’s occupational exposure. Hum Reprod 2007, dem309. 43. James W. Offspring sex ratios at birth as markers of paternal endocrine disruption. Environ Res 2006;100:77–85. 44. Cameron EZ, Linklater W. Extreme sex ratio variation in relation to change in condition around conception. Biol Lett 2007;3:395–97. 45. Hassold T, Quillen S, Yamane J. Sex ratio in spontaneous abortions. Ann Hum Genet 1983;47:39–47. 46. Simpson J. Pregnancy and the timing of intercourse. N Engl J Med 1995;333:1563–65. 47. Benagiano G, Bianchi P. Sex preselection: an aid to couples or a threat to humanity? Hum Reprod 1999;14:867–70. 48. Simpson J, Carson S. The reproductive option of sex selection. Hum Reprod 1999;14:870–72. 49. Sills E, Kirman I, Thatcher S, et al. Sex-selection of human spermatozoa evolution of current techniques and applications. Arch Gynecol Obstet 1998;261:109–15. 50. Jha P, Kumar R, Vasa P, et al. Low male-to-female sex ratio of children born in India: national survey of 1.1 million households. Lancet 2006;367:211–18. 51. Benagiano G, Bianchi P. Sex preselection: an aid to couples or a threat to humanity? Hum Reprod 1999;14:868–70. 52. Coale A, Banister J. Five decades of missing females in China. Demography 1994;31:459–79. 53. Goodkind D. Do parents prefer sons in North Korea?. Stud Fam Plann 1999;30:212–18. 54. Sharma BR, Gupta N, Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India. Public Health 2007;121:854–60. 55. Cooperstock M, Campbell J. Excess males in preterm birth: interactions with gestational age, race and multiple birth. Obstet Gynecol 1996;88:189–93. 56. McGregor J, Leff M, Orleans M, et al. Fetal gender differences in preterm birth findings in a North American cohort. Am J Perinatol 1992;9:43–48. 57. Chen S, Vohr B, Oh W. Effects of birth order, gender, and intrauterine growth retardation on the outcome of very low birth weight in twins. J Pediatr 1993;123:132–36. 58. Shinwell ES, Reichman B, Lerner-Geva L, et al. ‘Masculinizing’ effect on respiratory morbidity in girls from unlike-sex preterm twins: a possible transchorionic paracrine effect. Pediatrics 2007;120:e447–53.

C h a p t e r 1   The Effects of Gender in Neonatal Medicine l

59. Lubchenco L, Hansman C, Dressler M, et al. Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963;32:793–800. 60. Usher R, McLean F. Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969;74:901–10. 61. Westerway S, Davison A, Cowell S. Ultrasonic fetal measurements: new Australian standards for the new millennium. Aust NZ Obstet Gynaecol 2000;40:297–302. 62. Moore W, Ward B, Jones V, et al. Sex difference and fetal head growth. Br J Obstet Gynecol 1988;95:238–42. 63. Schild RL, Sachs C, Fimmerst R, et al. Sex-specific fetal weight prediction by ultrasound. Ultrasound Obstet Gynecol 2004;23:30–35. 64. Tsunoda Y, Tokunaga T, Sugie T. Altered sex ratio of live young after transfer of fast- and slow-moving mouse embryos. Gamete Res 1985;12:301–4. 65. Karlberg P, Taranger J. The somatic development of children in a Swedish urban community: a prospective study. Acta Paediatr Scand 1976;57:1–148. 66. Stevenson D, Verter J, Fanaroff A, et al. Sex differences in outcomes of very low birth weight infants the newborn male disadvantage. Arch Dis Child Fetal Neonatal Ed 2000;83:F182–F1855. 67. Drevenstedt GL, Crimmins EM, Vasunilashorn S, et al. The rise and fall of excess male infant mortality. Proc Natl Acad Sci USA 2008;105:5016–21. 68. Di Renzo GC, Rosati A, Sarti RD, et al. Does fetal sex affect pregnancy outcome? Gend Med 2007;4:19–30. 69. United States Department of Health and Human Services (US DHHS), Centers of Disease Control and Prevention (CDC). Linked birth/infant death records 2003–2004 on CDC WONDER on-line database: National Center for Health Statistics (NCHS), Office of Analysis and Epidemiology (OAE), Division of Vital Statistics (DVS). 70. Centers for Disease Control and Prevention. Infant mortality and low birth weight among black and white infants, United States, 1980–2000. MMWR 2002:589–92. 71. Demmelmair H, von Rosen J, Koletzko B. Long-term consequences of early nutrition. Early Hum Dev 2006;82:567–74. 72. Wells JC, Chomtho S, Fewtrell MS. Programming of body composition by early growth and nutrition. Proc Nutr Soc 2007;66:423–34. 73. Pineau J-C, Guihard-Costa A-M, Droullé P. Only two-phase models, computed independently for males and females, are appropriate to describe fetal head growth. Fetal Diagn Ther 2003;18:207–16. 74. Pineau J-C, Thiebaugeorges O, Guihard-Costa AM. Optimal standards for fetal biometry: to each measurement its fitting model. Fetal Diagn Ther 2006;21:396–99. 75. Maduwegedera D, Kett MM, Flower RL, et al. Sex differences in postnatal growth and renal development in offspring of rabbit mothers with chronic secondary hypertension. Am J Physiol Regul Integr Comp Physiol 2007;292:R706–14. 76. Maric C. Mechanisms of fetal programming of adult hypertension: role of sex hormones. Hypertension 2007;50:605–6. 77. Ojeda NB, Grigore D, Yanes LL, et al. Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth restricted offspring. Am J Physiol Regul Integr Comp Physiol 2007;292:R758–63.

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78. Ojeda NB, Grigore D, Robertson EB, et al. Estrogen protects against increased blood pressure in postpubertal female growth restricted offspring. Hypertension 2007;50:679–85. 79. Zambrano E, Martinez-Samayoa PM, Bautista CJ, et al. Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation. J Physiol 2005;566:225–36. 80. Lawlor DA, Ebrahim S, Davey Smith G. Is there a sex difference in the association between birth weight and systolic blood pressure in later life? Findings from a meta-regression analysis. Am J Epidemiol 2002;156:1100–14. 81. Matthews F, Johnson P, Neil A. You are what your mother eats: evidence for maternal preconception diet influencing foetal sex in humans. Proc Biol Sci 2008;275:1661–68. 82. Bracero L, Cassidy S, Byrne D. Effect of gender on perinatal outcome in pregnancies complicated by diabetes. Gynecol Obstet Invest 1996;41:10–14. 83. Torday J, Nielsen H. The sex difference in fetal lung surfactant production. Exper Lung Res 1987;12:11–19. 84. Bourbon J, Farrel P. Fetal lung development in the diabetic pregnancy. Pediatr Res 1985;19:253–67. 85. Ingemarsson I, Herbst A, Thorngren-Jerneck K. Long-term outcome after umbilical artery acidaemia at term birth: influence of gender and duration of fetal heart rate abnormalities. Br J Obstet Gynaecol 1997;104:1123–27. 86. Heyer A, Hasselblatt M, von Ahsen N, et al. In vitro gender differences in neuronal survival on hypoxia and in 17[beta]estradiol-mediated neuroprotection. J Cereb Blood Flow Metabol 2005;25:427–30. 87. Nijboer CHA, Kavelaars A, van Bel F, et al. Gender-dependent pathways of hypoxia-ischemia-induced cell death and neuroprotection in the immature p3 rat. Dev Neurosci 2007;29:385–92. 88. Ulm B, Svolba G, Ulm M, et al. Male fetuses are particularly affected by maternal alloimmunization to D antigen. Transfusion 1999;39:169–73. 89. Tioseco JA, Aly H, Milner J, et al. Does gender effect neonatal hyperbilirubinemia in low-birth-weight infants? Pediatr Crit Care Med 2005;6:171–74. 90. Zaren B, Lindmark G, Bakketeig L. Maternal smoking affects fetal growth more in the male fetus. Paediat Perinatal Epidemiol 2000;14:118–26. 91. Bateman D, Ng S, Hansen C, et al. The effects of intrauterine cocaine exposure in newborns. Am J Public Health 1993;83:190–93. 92. Bateman D, Chiriboga C. Dose-response effect of cocaine on newborn head circumference. Pediatrics 2000;106:e33. 93. Naeye R, Blanc W, Leblanc W, et al. Fetal complications of maternal heroin addiction: abnormal growth, infections and episodes of stress. J Pediatr 1973;83:1055–61. 94. Arendt R, Angelopoulos J, Salvator A, et al. Motor development of cocaine-exposed children at age two years. Pediatrics 1999;103:86–92. 95. Koren G, Nulman I, Rovet J, et al. Long-term neurodevelopmental risks in children exposed in utero to cocaine. The Toronto adoption study. Ann NY Acad Sci 1998;846:306–13. 96. Richardson G. Prenatal cocaine exposure. A longitudinal study of development. Ann NY Acad Sci 1998;846:144–52. 97. Jones K, ed. Fetal Alcohol Syndrome, 6th edn.. Philadelphia, PA: WB Saunders; 2006.

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s e c t i o n 1     Gender and Normal Development l

  98. Delaney-Black V, Covington C, Nordstrom B, et al. Prenatal cocaine: quantity of exposure and gender moderation. J Dev Behav Pediatr 2004;25:254–63.   99. Robert E, Kallen B, Harris J. The epidemiology of diaphragmatic hernia. Eur J Epidemiol 1997;13:665–73. 100. Torfs C, Curry C, Bateson T. A population-based study of congenital diaphragmatic hernia. Teratology 1992;46:555–65. 101. Stolar C, Crisafi M, Driscoll Y. Neurocognitive outcome for neonates treated with extracorporeal membrane oxygenation: are infants with congenital diaphragmatic hernia different? J Pediatric Surg 1995;30:366–71. 102. Jones K. Genetics, genetic counseling, and prevention. Smith’s Recognizable Patterns of Human Malformation, 6th edn. Philadelphia, PA: WB Saunders; 2006:796–816. 103. Miller-Hance W, Tacy T. Gender differences in pediatric cardiac surgery: the cardiologist’s perspective. J Thorac Cardiovasc Surg 2004;128:7–10. 104. Klitzner T, Lee M, Rodriguez S, et al. Sex-related disparity in surgical mortality among pediatric patients. Congenital Heart Dis 2006;1:77–88. 105. Samánek M. Boy:girl ratio in children born with different forms of cardiac malformation: a population-based study. Pediatr Cardiol 1994;15:53–57. 106. Calzolari E, Garani G, Cocchi G, et al. Congenital heart defects: 15 years of experience of the Emilia-Romagna registry (Italy). Eur J Epidemiol 2003;18:773–80. 107. Samánek M, Goetzová J, Benesová D. Distribution of congenital heart malformations in an autopsied child population. Int J Cardiol 1985;8:235–50. 108. Klitzner TS, Lee M, Rodriguez S, et al. Sex-related disparity in surgical mortality among pediatric patients. Congenital Heart Dis 2006;1:77–88. 109. Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev 1999;79:635–59. 110. Schaubel D, Johansen H, Dutta M, et al. Neonatal characteristics as risk factors for preschool asthma. J Asthma 1996;33:255–64. 111. Lemons J, Bauer C, Oh W, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Research Network, January 1995 through December 1996. Pediatrics 2001;107:e1. 112. Extremely preterm birth outcome data. (Accessed 06/25/2008 at www.nichd.nih.gov/about/org/cdbpm/pp/prog_epbo/.) 113. Tyson J, Parikh N, Langer J, et al. Intensive care for extreme prematurity: moving beyond gestational age. N Engl J Med 2008;358:1672–81. 114. Hegyi T, Carbone T, Anwar M, et al. The Apgar score and its components in preterm infants. Pediatrics 1998;101:77–81. 115. Baenziger O, Jaggi J, Mueller A, et al. Cerebral blood flow in preterm infants affected by sex, mechanical ventilation, and intrauterine growth. Pediatric Neurol 1994;11:319–24. 116. Tontisirin N, Muangman SL, Suz P, et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics 2007;119:e610–15. 117. Arne O, Robin SR, Barbara S, et al. Male/female differences in indomethacin effects in preterm infants. J Pediatrics 2005;147:860–62. 118. Malloy M, Freeman D. Respiratory distress syndrome mortality in the United States, 1987-95. J Perinatol 2000;20:414–20.

119. Pollak A, Birnbacher R. Preterm male infants need more initial respiratory support than female infants. Acta Paediatrica 2004;93:447–48. 120. Stocks J, Henschen M, Hoo A-F, et al. Influence of ethnicity and gender on airway function in preterm infants. Am J Respir Crit Care Med 1997;156:1855–62. 121. Papageorgiou A, Colle E, Farri-Kotopoulos E, et al. Incidence of respiratory distress syndrome following antenatal betamethasone: role of sex, type of delivery, and prolonged rupture of membranes. Pediatrics 1981;67:614–17. 122. Schwartz R, Luby A, Scanlon J, et al. Effect of surfactant on morbidity, mortality, and resource use in newborn infants weighing 500 to 1500 g. N Engl J Med 1994;330:1476–80. 123. Webb R, Shaw N. Respiratory distress in heavier versus lighter twins. J Perinat Med 2000;29:60–63. 124. Ardila J, Le Guennec J, Papageorgiou A. Influence of antenatal betamethasone and gender cohabitation on outcome of twin pregnancies 24–34 weeks gestation. Semin Perinatol 1994;18:151–58. 125. Willet K, Jobe A, Ikegami M, et al. Postnatal lung function after prenatal steroid treatment in sheep: effect of gender. Pediatr Res 1997;42:885–92. 126. Korhonen P, Tammela O, Koivisto A, et al. Frequency and risk factors in bronchopulmonary dysplasia in a cohort of very low birth weight infants. Early Hum Dev 1999;54:245–58. 127. Vrijlandt E, Gerritsen J, Boezen HM, et al. Gender differences in respiratory symptoms in 19-year-old adults born preterm. Respir Res 2005;6:117. 128. Fanaroff A, Korones S, Wright L, et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. Pediatr Inf Dis J 1998;17:593–98. 129. Nagy E, Kompagne H, Orvos H, et al. Gender-related differences in neonatal imitation. Infant Child Dev 2007;16:267–76. 130. Boatella-Costa E, Costas-Moragas C, Botet-Mussons F, et al. Behavioral gender differences in the neonatal period according to the Brazelton scale. Early Hum Dev 2007;83:91–97. 131. Lundqvist C, Sabel K-G. The Brazelton neonatal behavioral assessment scale detects differences among newborn infants of optimal health. J Pediatr Psychol 2000;25:577–82. 132. Guinsburg R, Peres C de A, Branco de Almeida MF, et al. Differences in pain expression between male and female newborn infants. Pain 2000;85:127–33. 133. Tommiska V, Heinonen K, Ikonen S, et al. A national shortterm follow-up of extremely low birth weight infants born in Finland in 1996–1997. Pediatrics 2001;107:1–9. 134. Borthwood M, Wolke D, Gamsu H, et al. Prognosis of the very low birth weight baby in relation to gender. Arch Dis Child 1986;61:559–64. 135. Hoffman E, Bennett F. Birth weight less than 800 grams: changing outcomes and influences of gender and gestation number. Pediatrics 1990;86:27–34. 136. Paz I, Gale R, Laor A, et al. The cognitive outcome of fullterm small for gestational age infants at late adolescence. Obstet Gynecol 1995;85:45245–46. 137. Laptook AR, O’Shea TM, Shankaran S, et al. NICHD Neonatal Network. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics 2005;115:673–80.

C h a p t e r 1   The Effects of Gender in Neonatal Medicine l

138. Hintz SR, Kendrick DE, Vohr BR, et al. Changes in neuro­ developmental outcomes at 18 to 22 months’ corrected age among infants of less than 25 weeks’ gestational age born in 1993–1999. Pediatrics 2005;115:1645–51. 139. Walsh MC, Morris BH, Wrage LA, et al. Extremely low birth weight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes. J Pediatrics 2005;146:798–804. 140. Hack M, Flannery DJ, Schluchter M, et al. Outcomes in young adulthood for very-low-birth-weight infants. N Engl J Med 2002;346:149–57. 141. Wilson-Costello D, Friedman H, Minich N, et al. Improved neurodevelopmental outcomes for extremely low birth weight infants in 2000–2002. Pediatrics 2007;119:37–45. 142. Arnaud C, Daubisse-Marliac L, White-Koning M, et al. Prevalence and associated factors of minor neuromotor dysfunctions at age 5 years in prematurely born children: the EPIPAGE study. Arch Pediatr Adolesc Med 2007;161:1053–61. 143. Marlow N, Wolke D, Bracewell MA, et al. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9–19.

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144. Hack M, Taylor HG, Klein N, et al. School-age outcomes in children with birth weights under 750 g. N Engl J Med 1994;331:753–59. 145. Tin W, Wariyar U, Hey E. Changing prognosis for babies of less than 28 weeks’ gestation in the north of England between 1983 and 1994. BMJ 1997;314:107–11. 146. Yliherva A, Olsen P, Mäki-Torkko E, et al. Linguistic and motor abilities of low-birth weight children as assessed by parents and teachers at 8 years of age. Acta Paediatr Scand 2001;90:1440–49. 147. Hack M, Taylor HG, Drotar D, et al. Poor predictive validity of the Bayley scales of infant development for cognitive function of extremely low birth weight children at school age. Pediatrics 2005;116:333–41. 148. Andrews H, Goldberg D, Wellen N, et al. Prediction of special education placement from birth certificate data. Am J Preventive Med 1995;11:55–61. 149. Msall M, Buck G, Rogers B, et al. Predictors of mortality, morbidity, and disability in a cohort of infants of 28 weeks gestation. Clin Pediatrics 1993;32:521–27.

C hapter

2

Sexual Development, Growth, and Puberty in Children Gaya S. Aranoff1, and Jennifer J. Bell2 1

Professor of Clinical Pediatrics, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY, USA 2 Special Lecturer in Pediatrics, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY, USA

Introduction

occurs with the onset of testicular Sertoli cell development, under the influence of a testis-determining locus on the Y chromosome (the SRY – Sex-determining Region of the Y locus).2 At about 7 weeks gestation, the Sertoli cells secrete anti-Müllerian hormone (AMH) which diffuses out of the testis to the adjacent Müllerian ducts, causing their dissolution by apoptosis. The Sertoli cells also induce the formation of Leydig cells, first identified at about the 8th week of gestation (60 days). Stimulated by both placental human chorionic gonadotropin (HCG) and, later in gestation, fetal pituitary luteinizing hormone (LH), the Leydig cells begin to synthesize testosterone by the 9th week of gestation. Testosterone diffuses out of each testis to the adjacent Wolffian duct, developing and maturing it into the vas deferens, epididymis, and seminal vesicle. In addition, testosterone is secreted into the bloodstream and circulates to the external genitalia where it is converted to dihydrotestosterone (DHT). DHT is the hormone responsible for the masculin­ ization of the external bipotential primordia, causing the fusion of the urethral folds into the male urethra, the development of the labioscrotal folds into the scrotum, and the transformation of the genital tubercle into the penis. This process of transformation is complete by the 13th week of gestation, at which point the fetus is anatomically identifiable as either male or female. Blood levels of testosterone peak to adult male levels by about 16 weeks gestation, then fall to early pubertal levels after the 24th week. Phallic growth, which is testosterone-dependent, continues to term. Many genes have been identified which are directly involved in the formation of testes and ovaries.2,3 Some (SRY and SOX9) stimulate testicular development; others (e.g. DAX1 and WNT-4) are believed to inhibit testicular development and may actively promote ovarian development. In the female, since the bipotential gonad has not been committed by SRY to become a testis, it will develop as an ovary (if germ cells are present). Ovarian development

Although gender/sex-specific events are multifactorial, the predominant underlying factor is the different hormonal milieu to which males and females are exposed. Pediatric endocrinology is concerned with the fetal determination and development of the two sexes, and the sex-specific hormonal environments experienced by each from fetal life through puberty and adolescence to adulthood. These differences include the testosterone-rich environment of the male fetus and neonate, the subtle hormonal differences between the two sexes during childhood, the differences in growth before and during sexual maturation, and variations in and implications of the timing of sexual maturation. The effects such childhood differences may have on adult ­gender-related disorders are as yet poorly understood.

Sexual development Normal Sexual Development1 In normal circumstances, a fetus’ sexual development is genetically determined in the process of conception, which has resulted in a fertilized egg with either XX or XY chromosomes. Until about the 6th week of gestation, organogenesis has resulted in a phenotypically indifferent, bipotential fetus with no apparent anatomic or metabolic distinction between male and female. In both sexes the gonad that has formed is bipotential, capable of becoming either a testis or an ovary. Both early male (Wolffian) and female (Müllerian) duct systems are present, and the external genitalia consist of a urogenital slit surrounded laterally by periurethral folds, more laterally by labioscrotal folds, and a genital tubercle. In the male, at about 6–7 weeks of gestation, the first step in the sexual differentiation of the bipotential gonad Principles of Gender-Specific Medicine

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Copyright 2010, Elsevier Inc. All rights reserved.

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begins at about the 11th week of gestation. At that time primitive germ cells multiply and enlarge into oogonia. At about the 12th week of gestation the oogonia undergo meiosis into oocytes. The fetal ovary is relatively quiescent hormonally compared to the fetal testis. Very little estrogen is made in the fetal ovary, but estrogen is secreted in large quantities by the placenta in both sexes.4 In the absence of AMH secretion from a fetal testis, the Müllerian ducts develop into fallopian tubes, uterus, and the upper third of the vagina; the lower two-thirds of the vagina are formed from the urogenital sinus. The vagina acquires a perineal opening separate from the urethra. If the external genitalia have not been exposed to testosterone by the 13th week of gestation, the urethral folds do not fuse in midline but remain separate as the labia minora, and the labioscrotal folds form the bilateral labia majora. The small genital tubercle, now called the clitoris, grows little in the absence of circulating testosterone. Unlike the urethral and labioscrotal folds, the clitoris remains potentially responsive to testosterone throughout gestation.1

Disorders of Sexual Development When the sex of a newborn is unclear at birth, investigation must be undertaken to determine whether the genitalia are those of an incompletely virilized male or an inappropriately virilized female. Congenital disorders of sexual development (DSD) can be caused by chromosomal, hormonal, environmental, or developmental (anatomic) factors. DSD is now the accepted terminology to describe atypical sexual development, and replaces older stigmatizing terms like intersex and hermaphroditism (Table 2.1).5 In congenital DSD, the external genitalia of a newborn are not clearly identifiable as male or female. Inspection of the external genitalia may reveal: a phallic structure that may be a small, incompletely formed penis or an enlarged clitoris, a single perineal opening at the base of the phallus or on the penile shaft (which may represent either incomplete migration of the male urethra, or a female urethrovaginal orifice), and fused labioscrotal folds that may be either a poorly formed scrotum, or virilized labia.

●

●

●

Guiding principles in evaluating DSD are: 1. Male differentiation requires functioning testicular tissue; in the absence of this, ductal and external structures appear female. 2. Female differentiation does not require functioning ovarian tissue; in the absence of this, ductal and external structures will still appear female. 3. Internal genital structures are fixed by the 13th week of gestation. After that date, external genitalia can enlarge in response to hormonal stimulation, but their basic structure does not change.

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Table 2.1  Revised nomenclature Previous

Current

Intersex Male pseudohermaphrodite Incompletely virilized or undervirilized male Female pseudohermaphrodite Virilized or masculinized female True hermaphrodite XX male or XX sex reversal XY sex reversal

DSD 46,XY DSD 46,XY DSD 46,XX DSD 46,XX DSD Ovotesticular DSD 46,XX testicular DSD 46,XY complete gonadal dysgenesis

Chromosomal Etiologies of DSD1 If in the first embryonic cell division one X chromosome is lost leaving all the cells with only one X chromosome, functioning ovarian tissue is absent (or deficient in 10%) but external genitalia are those of a normal female. This is true also if all of a Y chromosome is lost, again resulting in all cells with only one X chromosome. In this case the fetus has no functioning testicular tissue because the testis-determining gene of the Y chromosome is missing, and external genitalia are unambiguously female. This is known as XO gonadal dysgenesis or Turner syndrome. If, however, the Y chromosome loss occurs after the first cell division, causing an XO/XY mosaicism, then the phenotype can vary from a Turner phenotype to that of a normal male, depending on to what extent the XO or XY cell line predominates. This also determines whether testicular tissue is present and, if present, is normal or dysgenetic. The appearance of the external genitalia can be female, ambiguous, or male depending on how much functional testicular tissue is present. The same is true if all cells have XY chromosomes but the Y is incomplete, missing all or part of its long or short arms. Children with an ovotesticular disorder of sexual development have both testicular and ovarian tissue present, either as separate gonads or as a combined ovotestis. About half of these children have a 46,XX karyotype; a few of these will have the SRY locus of a Y chromosome translocated to one of the Xs. Others will have a 46,XY karyotype, or some form of sex chromosome mosaicism. The nature of the internal ductal structures will depend on the location and amount of testicular tissue. The side with testicular tissue present will be variably masculinized; the side without testicular tissue will develop female ducts. External genitalia are usually ambiguous. Hormonal Etiologies of DSD The adrenal cortex synthesizes three important classes of steroid hormones – glucocorticoids, mineralocorticoids, and androgens. Hormonal synthesis occurs through an orderly, stepwise enzymatic hydroxylation and dehydrogenation of cholesterol to produce the major glucocorticoid, cortisol, the major mineralocorticoid, aldosterone, and the adrenal

1

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androgens, dehydroepiandrosterone (DHEA) and androstenedione (A). The gonads share the same enzymatic conversion pathways of cholesterol to DHEA and A; in the testes (and to a lesser extent, the ovaries) these mild androgens are metabolized further to the potent androgen, testosterone. In the ovaries (and to a lesser extent, the testes) the testosterone is then aromatized to estradiol, the major estrogenic steroid. Disorders of Adrenal Steroid Biosynthesis6 Abnormalities in the steroidogenic enzymatic pathways of the adrenal cortex are grouped under a family of disorders known as congenital adrenal hyperplasia (CAH). The most common of these, a deficiency of the 21-hydroxylase enzyme (P450c21), results in cortisol and aldosterone deficiency, but, because 21-hydroxylation is not required for androgen biosynthesis, DHEA and A synthesis is intact. The low circulating cortisol level feeds back to the pituitary causing increased adrenocorticotropin hormone (ACTH) release. In response to the increased ACTH, the adrenal cortex becomes hyperplastic and produces increased amounts of DHEA and A, which are in turn converted to testosterone both in the adrenal cortex and peripherally. If the 21-hydroxylase enzyme deficiency is severe enough, and aldosterone synthesis is severely impaired, the affected infant will develop a life-threatening salt-losing condition soon after birth. In simple (aldosterone sufficient) or salt-losing (aldosterone insufficient) CAH, the excess adrenal androgens produced in the fetus result in virilization of the external genitalia. In the male fetus, this virilizing effect is obscured by the much stronger virilizing effect of testosterone from the testes. In the female fetus, the adrenal androgens cause clitoral hypertrophy and labioscrotal fusion to a greater or lesser degree, depending upon the levels of androgens. The second most common enzyme deficiency in CAH, 11-hydroxylase deficiency (P450c11ß), is also characterized by cortisol deficiency and, because of ACTH-induced hyperplasia, adrenal androgen excess. It is not a salt-losing condition because the synthesis of saltretaining desoxycorticosterone (DOC) is preserved. In this condition also, male genitalia appear normal at birth, and virilized female genitalia are ambiguous. Earlier blocks in adrenal steroid synthesis are much rarer. They affect both adrenal and gonadal androgen synthesis. These synthetic blocks (3-hydroxysteroid dehydrogenase (3HSD) deficiency; 17–hydroxylase/17,20-lyase (P450c17) deficiency), in contrast to the previously mentioned enzyme defects, cause defective adrenal androgen and gonadal testosterone and estrogen production. In 3HSD deficiency, DHEA levels are elevated sufficiently to virilize the female fetus. The male fetus, because of the lack of testosterone, is incompletely virilized by the DHEA. Both sexes are born with ambiguous genitalia in 3HSD deficiency. In P450c17 deficiency, all androgen and estrogen production is blocked. If P450c17 deficiency is complete, both sexes have external genitalia that appear female. If P450c17

deficiency is incomplete, external genitalia of a genetic male will appear ambiguous, and the genitalia of a genetic female will be unambiguously female. Disorders of Testosterone Biosynthesis7 Both isolated 17,20-lyase and 17-hydroxysteroid dehydrogenase type 3 deficiencies affect testosterone synthesis in the testis only. Adrenal cortical steroid biosynthesis is normal. The extent of the compromise of the male genitalia depends on how defective testosterone biosynthesis is. Placental Aromatase Deficiency8 In utero, fetal adrenal DHEA metabolites circulate to the placenta where a placental aromatase enzyme converts them to estrogens. If this metabolic pathway is blocked by placental aromatase deficiency, the accumulation of the mild androgen DHEA will cause virilization of the female fetus’ external genitalia. 5-Reductase Deficiency9 Testosterone does not act directly on the fetus’ external genitalia but is converted in the genital tissue into its active form, dihydrotestosterone, by the action of the enzyme 5reductase. Lack of this enzyme will cause ambiguity of the male genitalia. Defects of Androgen Receptor10 Mutations in or deletions of the gene encoding the androgen receptor cause resistance to the virilizing effect of testosterone. Abnormalities of the androgen receptor will block androgen action completely or incompletely. The resulting androgen insensitivity syndrome (AIS) can be complete or partial, depending upon whether the receptor is completely absent or is reduced in numbers or activity. The male fetus with complete AIS will be born with poorly developed internal Wolffian ducts and female external genitalia, sometimes with testes palpable in the labial structures. Male infants with partial AIS may have only partial masculinization of the external genitalia. Anatomic Etiologies of DSD1 Teratogenic abnormalities in the female fetus, such as a persistent cloaca, imperforate anus, and urinary tract abnormalities, are sometimes associated with malformations of the urethrovaginal orifices and thus disorders of development of the external genitalia. Similarly, males with penile agenesis and cloacal extrophy have often been given a female sex assignment. Less extreme examples of DSDs due to congenital anatomic abnormalities in males include perineal hypospadias and cryptorchidism. These conditions occur independent of any chromosomal, hormonal or receptor abnormalities of sexual differentiation.

C h a p t e r 2    Sexual Development, Growth, and Puberty in Children l

Environmental Etiologies of DSD1 Maternal ingestion of testosterone or of certain synthetic derivatives of 19-nortestosterone that have been used as progestational agents in threatened abortion or as part of hormonal treatments given with assisted fertilization, can cross the placenta and may cause virilization of the female fetus. Their effect depends on the time of ingestion as well as the androgen levels attained: if ingested before the 13th week of gestation the androgens may cause labial fusion and clitoral hypertrophy. After the 13th week only clitoral hypertrophy can occur. Maternal virilizing tumors (e.g. arrhenoblastoma) or cysts (luteomas) can also virilize a female fetus. Defining and Assigning Sex in DSD The first question invariably asked by the parents of a newborn infant is: Is it a boy or a girl? Normally, the answer to this question is straightforward, with a consistent response of male or female, no matter how one defines sex. The answer may be determined by inspection of external genitalia at the time of delivery, or prenatally by ultrasound (phenotypic sex), or by prenatal amniocentesis determination of the neonate’s chromosomal sex (46,XX karyotype for females, 46,XY for males). Even in infants born with DSDs, the sex of the baby and the appropriate sex of rearing can usually be determined reasonably quickly, after a thorough investigation is undertaken. In rare cases of infants born with DSDs, there are discrepancies between phenotypic, chromosomal, and gonadal sex (presence of ovaries in females, and testes in males). This may occur, for example, in the case of an infant with both ovarian and testicular tissue, or an infant with partial or complete androgen insensitivity syndrome.11,12 The sex of rearing must be assigned even though the ideal sex of rearing may remain unclear. Ideally, gender identity (how one identifies oneself, as male or female) should determine the sex of rearing, but since gender identity is not manifest in infancy, errors in neonatal sex assignment, though rare, are still possible. Psychosexual development progresses with time, and gender identity and subsequent sexual orientation (male or female partner preference) will take years to become clear. Sex assignment (or reassignment) should be done based on clinical and laboratory investigation obtained as quickly and thoroughly as possible, by an experienced medical team, comprised of specialists in pediatric endocrinology, urology, and psychiatry. The team should include the infant’s pediatrician, or family physician, and may benefit from involvement of social service and clergy as well. Clearly, the infant’s parents must be involved in, and supportive of the decision. In the last quarter of the twentieth century guidelines for determining sex of rearing in cases of infants born with what was then referred to as ‘ambiguous genitalia’ were based mainly on two factors: the potential for sexual function and the potential for fertility.13 These guidelines were based,

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in part, on research that suggested that gender identity was determined by sex of rearing, as long as the sex of rearing was chosen early enough in life.14,15 Long-term follow-up of patients diagnosed with ‘ambiguous genitalia’ has highlighted discrepancies between sex of rearing and ultimate gender identity in some of these patients. It has called into question the wisdom of choosing sex of rearing without consideration of ‘brain sex’. There is increasing evidence to suggest that the brain is a sexual organ, and that it is paramount in determining human gender identity. It is clearly in the best interest of the patient that the sex of rearing be consistent with the patient’s gender identity. Unfortunately, we have no definitive diagnostic tools available to us at the time of birth to clarify the infant’s ultimate gender identity. Fetal exposure to testosterone has been found to be associated with male gender identity.16–18 During the second to fourth month of normal male fetal development, testosterone levels reach a peak as high as mature adult male levels (200–600 ng/dl).3 In 5-reductase deficiency, a 46,XY DSD, exposure of the brain to high intra-uterine levels of testosterone occurs. Despite having been raised unambiguously as girls from birth, many patients with this disorder spontaneously assume a male gender identity at puberty, when testosterone levels again rise.19 Spontaneous adoption of male gender identity in puberty has also been described in 17-hydroxysteroid dehydrogenase deficiency (46,XY DSD) patients, raised as girls from birth.20 The experience of these patients contradicts earlier theories about the primacy of sex of rearing on ultimate gender identity. From both of these populations we can learn that, if a society is accepting of the change, sex reassignment in order to make gender role consistent with gender identity is possible, even as late as puberty. Retrospective studies of women with virilizing CAH (associated with high intra-uterine testosterone levels) also suggest the importance of intra-uterine testosterone exposure on gender identity. Hines et al. found dissatisfaction with female gender identity and decreased heterosexual interest in adult CAH women who had a history of preferring typical male play as children.21 Another factor not adequately considered in the initial guidelines for sex assignment is the effect of genital surgery on genital sensation and its relation to sexual satisfaction.22–23 Although surgical technique has improved greatly over the last quarter century, some patients, now adult, who have undergone genital surgical procedures for correction of phenotypic genital ambiguity, are actively protesting against surgical intervention in cases where it is not considered medically essential for the health of the infant. They say that their ability to be sexually gratified has been impaired by lack of genital sensation due to surgery, and feel that ‘cosmetic’ genital surgery should be a decision

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made by the patient, and not the parents or doctors. The extent of dissatisfaction with the outcome of genital surgery is unknown, as retrospective studies are ethically difficult to carry out, given confidentiality issues.24 Until we are able to unequivocally diagnose gender identity at birth, assignment of sex of rearing may sometimes be an ethically challenging decision. It is a decision that must be made, as neonatal sex assignment of male or female remains socially essential in human society today. In addition to pediatric endocrinologists, specially trained pediatric psychiatrists should be involved in the long-term care of patients born with DSDs. Decisions about the necessity and timing of genital surgery should be made judiciously, taking into consideration the effect of genital surgery on sexual satisfaction in adulthood, as well as the need for phenotypic sex to match the sex of rearing.

Growth Normal Patterns in Boys and Girls Although for a large part of childhood boys and girls grow at the same rate, there are subtle sex differences in growth rates in utero and clear sex differences in growth patterns peripubertally. Boys grow slightly more than girls in utero and are born on average slightly longer than girls by about 0.8 cm. The prenatal difference in growth rates is lost soon after birth and although boys remain on average very slightly taller than girls, the growth rates of the two sexes are almost identical for most of childhood. The growth rate in both sexes is most rapid in the first year (average 25.4 cm), then decelerates over the next few years to an average rate of 5–6.5 cm from about 3 or 4 years until the onset of puberty. During childhood the two hormones most important for growth are growth hormone and thyroid hormone. At puberty, under the influence of the sex hormones estrogen and testosterone, the growth rate increases once more, to a peak annual rate of 8.3 cm in girls and 9.5 cm in boys.25 This increase is associated with an increase in growth hormone secretion correlated with estradiol levels in both sexes.26 The two sexes diverge in the timing of puberty; the pubertal growth spurt starts earlier in girls, usually between 10 and 11 years of age, and continues until the epiphyses of the bones fuse and growth ceases at an average age of 16. Boys start their growth spurt about 2 years later, at an average age of 12.5, at which point they are about 8 cm taller than girls were when their sexual development started. Boys stop growing at an average age of 18, and are on average 12.5 cm taller as adults than women.27 The action of the sex hormones, in particular estrogen, is required for epiphyseal fusion to occur and the potential for further growth to be lost in both boys and girls.

In addition to linear growth, children’s body proportions change as they age and mature. An infant is born with its head and trunk, the so-called ‘upper segment’, being almost twice as long as the lower extremities, the ‘lower segment’. An infant’s upper/lower segment ratio on average equals 1.7. As the child matures, the legs grow faster than the trunk, so that as the child approaches puberty the upper and lower segments are approximately equal (U/L segment ratio  1.0). Under the influence of the sex hormones, the extremities continue to grow faster than the trunk. In midadolescence the U/L segment ratio is about 0.9. The legs stop growing earlier than the trunk, so the adult U/L segment ratio, in both sexes, is again about 1.0.28 The epiphyses of the bones are mostly cartilaginous at birth. As a child matures, the epiphyses calcify. The degree and configuration of calcification change in relation to the shafts of the bones, and have a characteristic appearance at each age. At puberty, under the influence of estrogen in both sexes, the calcified epiphyses eventually fuse with the shafts of the bones. The cartilaginous zone of growth between the epiphysis and shaft disappears, and growth ceases at the end of puberty. As is true of the pattern of overall growth, the progression of epiphyseal changes is sex-specific and differs between boys and girls at any chronological age. The best-studied progression of bone maturation has been in the hands, and an x-ray of the child’s wrist and hand for a ‘bone age’ is the best objective marker we have for assessing the actual maturation of a child’s skeleton.29 Knowing this and the height of the child at the time the x-ray was taken, one can approximate the child’s growth potential and adult height (the ‘predicted adult height’).30–32

Abnormal Growth Patterns in Boys and Girls Charting children’s growth over time is the most efficient way of discerning deviation from normal patterns, and helps a practitioner decide when diagnostic and therapeutic intervention is indicated. Most pediatric clinics in the United States use growth curves provided by the National Center for Health Statistics (of the Centers for Disease Control and Prevention), which are based on cross-sectional data. The main limitations of these curves are that they do not provide norms for growth rates of children who fall below the 3rd or above the 97th percentiles, and they do not take the timing of puberty into consideration. In general, healthy children between the ages of 2 years and the onset of puberty should be growing on a given percentile or parallel to the curve. Crossing percentiles, or failing to grow parallel to the curve, warrants further investigation. Abnormal growth patterns can be the first manifestation of systemic disease unrelated to a hormonal or genetic etiology. A thorough history and physical examination, and appropriate laboratory investigation are indicated in all children who fail to grow normally. In this chapter, we will limit the discussion of pathological growth to genetic and hormonal etiologies, and briefly

C h a p t e r 2    Sexual Development, Growth, and Puberty in Children l

mention skeletal and environmental etiologies. Systemic disease resulting in poor growth will not be discussed. Genetic Etiologies of Short Stature Familial Short Stature and Constitutional Delay of Growth Evaluation of a child’s growth pattern must consider the parents’ heights and childhood growth patterns. Calculating the target height (mean parental height 6.5 cm for boys and 6.5  cm for girls) and comparing it to the child’s calculated predicted height (based on bone age) helps in the assessment. When the child’s growth pattern and potential are deviant from that of the parents and siblings, further evaluation is indicated. In both genetic and constitutional short stature, children are of normal size at birth, and grow at a normal velocity, but usually below the 3rd percentile (starting at about age 2 years). The child with genetic short stature will show a pubertal growth spurt at the expected age. In contrast, a child with constitutional delay will continue to grow at the usual prepubertal rate of growth and thus seem to fall below his or her usual growth curve until he or she begins the pubertal acceleration of growth at a later chronological age. The bone age is age appropriate in familial short stature, but retarded in constitutional delay. Final adult height is characterized by short stature in genetic short stature but may be normal in constitutional delay. In most cases of both constitutional delay and familial short stature, an extensive diagnostic evaluation and therapeutic intervention are not indicated. However, in cases where the height prediction is poor, or significantly below target height, laboratory investigation, and subsequent hormonal therapy may be indicated. In a few instances evaluation may document molecular genetic abnormalities or abnormalities in the growth hormone (GH)/insulin-like growth factors (IGF) receptor axis.25 Boys with constitutional delay of growth (and puberty) usually respond to treatment with oral oxandrolone or to a limited course of monthly testosterone injections with a rapid improvement in growth velocity, as well as improved self-esteem. Short courses of androgen therapy in boys are not thought to have an impact (positive or negative) on final height.33,34 Estrogen receptor blockers (aromatase inhibitors) are currently being investigated for use in boys to delay progression of bone age and to augment final heights.35 Although oxandrolone has been used successfully (in conjunction with growth hormone) to augment growth in girls with Turner syndrome,36 it has not been studied for treatment of constitutional short stature in otherwise normal girls. In girls with constitutional delay of growth, treatment with estrogen also is not used, mainly because of concerns about its effect on final height. Estrogen promotes epiphyseal closure (in males and females),37 and estrogen therapy may cause rapid bone age advancement and subsequent

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shorter final heights. Estrogen receptor blockers are not being studied in females because of concerns about iatrogenic virilization due to elevated testosterone levels with inhibition of aromatase. Intra-uterine growth retardation may be caused by intrinsic abnormalities in the fetus, as seen in a number of genetic syndromes (e.g. Russell Silver syndrome, Seckel syndrome, Noonan syndrome, Cockayne syndrome, Bloom syndrome) or may be the result of maternal disorders or multiple gestation. No matter what the etiology, if these infants do not demonstrate adequate catch-up growth by age 3 years, they may benefit from treatment with growth hormone (Food and Drug Administration (FDA) approved for this purpose). Chromosomal Abnormalities In both boys and girls, when abnormal linear growth is accompanied by the presence of dysmorphic features, the possibility of a major chromosomal abnormality should be considered and a karyotype should be performed. Examples of major chromosomal abnormalities associated with short stature are trisomy 21 (Down syndrome), trisomy 18, and trisomy 13. In boys, trisomy of the sex chromosomes (47 XXY, Klinefelter syndrome) is associated with tall stature. Deletion of the X chromosome in girls (45,XO, Turner syndrome) is invariably characterized by short stature. All short girls with unexplained poor growth and short stature should have a karyotype to rule out Turner syndrome. Mosaicism for Turner syndrome also can be characterized by short stature, even without the presence of other dysmorphic features. Molecular genetic research has attributed the short stature seen in X chromosome deletions to haploinsufficiency of the short stature homeobox (SHOX) gene on the X chromosome. Treatment with growth hormone has been shown to increase growth velocity and final height in girls with Turner syndrome (and its mosaic forms), and is another FDA-approved indication for the use of growth hormone in children. As mentioned earlier, androgen therapy combined with growth hormone augments growth velocity as well as final height in girls with Turner syndrome. Although estrogen combined with growth hormone would be a more physiologic approach, there is concern that early estrogen replacement could cause more rapid epiphyseal maturation, and have a negative impact on final height. Recent studies have shown that when very low dose estrogen is administered systemically to young girls with Turner syndrome, height potential is preserved.38 Early estrogen therapy has also been shown to improve cognitive function.39 Prader–Willi syndrome, characterized by neonatal hypotonia, short stature, and obesity, is frequently associated with partial deletions or uniparental disomy of chromosome 15. Growth hormone therapy has been shown to improve growth as well as body composition in these children, and is also FDA approved for this purpose.

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Hormonal Etiologies of Short Stature Hypothyroidism Insufficient levels of thyroid hormone will cause inappropriately slow growth in children. This is true regardless of the etiology of thyroid hormone deficiency. In cases of congenital hypothyroidism, timely replacement therapy with thyroid hormone can prevent mental retardation and result in normal growth. Permanent brain damage can occur if thyroid hormone replacement is delayed. Acquired hypothyroidism, presenting later in childhood, is characterized by fatigue, constipation, dry skin, weight gain, and mental slowness, in addition to growth failure. The growth failure associated with hypothyroidism is almost always associated with a delay in bone age. Replacement therapy with thyroid hormone results in catch-up growth, restores the child to a normal growth pattern, and resolves the other signs and symptoms of hypothyroidism, including cognitive manifestations. Thyroid hormone deficiency will modify growth hormone response to provocative stimuli during testing for growth hormone deficiency, so it is important to rule out hypothyroidism prior to testing children for growth hormone deficiency.40 Cortisol Excess Excess cortisol, whether its source is endogenous or exogenous, will inhibit linear growth in children. Although endogenous oversecretion of cortisol (due to hypothalamic, pituitary or adrenal pathology) is rarely seen in pediatrics, exogenous, or iatrogenic Cushing’s syndrome is not uncommon. High dose glucocorticoids are an integral part of the therapeutic regimen for certain childhood diseases (some examples are: asthma, malignancies, autoimmune diseases, post-transplantation), and will cause Cushing’s syndrome. Replacement dose glucocorticoids used to treat adrenal insufficiency and congenital adrenal hyperplasia must be carefully adjusted to prevent overtreatment and subsequent iatrogenic growth suppression. Growth failure is common in children on high dose steroids. Poor linear growth also may be associated with excessive use of inhaled and topical steroids.41 Chronically elevated glucocorticoid levels, even when only slightly elevated, will interfere with the complex interactions between growth hormone (GH), insulin-like growth factors (IGFs), and bone metabolism. Normal growth patterns may resume when glucocorticoid levels are restored to the normal range, or when alternate day steroids are given. Growth hormone treatment has been reported to help normalize growth in children who must be kept on chronic steroids for treatment of their underlying disease.42 Growth Hormone Deficiency As pituitary growth hormone secretion depends on stimulatory hypothalamic releasing factors, deficiency of growth hormone can result from congenital malformations or destructive processes involving the hypothalamus or pituitary

(organic causes), or may be idiopathic. Both boys and girls with isolated growth hormone deficiency have proportional short stature, poor growth rates for their age and pubertal stage, delayed bone ages, abnormal body composition (increased body fat), and abnormally low growth hormone values during stimulation testing. The majority of children thought to be deficient in growth hormone (levels less than 10 ng/ml on pharmacologic stimulation testing) have no other pituitary hormone deficiencies and no abnormalities of the pituitary or hypothalamus on brain imaging. Children with GH deficiency by testing in childhood may have normal GH stimulation tests when repeat testing is done after years of exogenous GH therapy.43 As sex steroids play a role in GH responsiveness, some endocrinologists advocate priming prepubertal and early pubertal children with sex steroids prior to assessing their GH secretory ability. A majority of pediatric endocrinologists do not solely consider low GH levels post stimulation testing (with or without sex steroid priming) sufficient reason to treat a child with GH therapy. Poor growth velocity, poor predicted height, and low IGF-1 levels are also taken into consideration when deciding which children to treat.44 The congenital anomalies associated with growth hormone deficiency range from major malformations of the brain (e.g., holoprosencephaly) associated with multiple pituitary hormonal deficiencies, to minor malformations of the brain (e.g., isolated absence of the septum pellucidum) associated with only growth hormone deficiency. In congenital malformations causing growth hormone deficiency, where specific genetic mutations have been found, most are characterized by autosomal recessive inheritance, and are seen with equal frequency in both sexes.45 In cases of organic deficiency of growth hormone due to trauma, brain tumors, or brain irradiation, the incidence is similar for boys and girls, unless the underlying type of brain tumor is more commonly seen in one sex. Treatment of growth hormone deficiency with exogenous growth hormone results in improvement in growth velocity and final height. A preponderance of boys has been observed in most groups of patients treated with growth hormone, regardless of the etiology of the GH deficiency. It is likely that this reflects an ascertainment bias, as more boys than girls are referred for evaluation of short stature.46–48 When GH deficiency persists through adolescence into adulthood, ongoing lifelong therapy with GH is indicated to maintain bone health and body composition. The GH replacement dose is much lower in adults than in children; adult females may require higher replacement doses of GH than adult males.49 Growth Hormone Insensitivity Laron and colleagues first described peripheral resistance to growth hormone.50 Children with growth hormone insensitivity have the phenotypic appearance of growth hormone

C h a p t e r 2    Sexual Development, Growth, and Puberty in Children l

deficiency, but have normal or elevated levels of growth hormone when tested. A variety of GH receptor defects and IGF receptor defects have been found to cause GH insensitivity. Bioinactive GH as well as GH insensitivity caused by circulating antibodies to GH and its receptor also have been described. GH insensitivity has been an area of fertile molecular genetic research over the past decade. Children with insensitivity to GH do not respond to growth hormone therapy, but some will respond to treatment with IGF-1. In 2005, IGF-1 was approved by the FDA to treat children with short stature due to severe primary IGF-1 deficiency.51 Growth Failure Associated with Skeletal Disorders Genetic abnormalities in the formation of cartilage and bone (osteochondrodystrophies) result in profound compromise of stature associated with abnormal body proportions. The disproportion is readily apparent on physical examination, although the various osteochondrodystrophies may affect the growth of the limbs and trunk differently. Identification of the particular disorder causing the growth failure is based on radiological criteria and can be difficult. Only a few of the genetic mutations underlying these disorders have been identified. Of the many osteochondrodystrophies identified, achondroplasia is the most common. It is an autosomal dominant disorder involving a mutation in the gene for the fibroblast growth factor receptor 3 (FGFR3) on the short arm of chromosome 4. Although the growth of the limbs is characteristically affected, changes are seen also in the skull, vertebral column, and pelvis. Infants homozygous for the defect are very severely affected and usually die in infancy from respiratory compromise due to thoracic abnormalities. Heterozygous infants can appear quite normal at birth, and may not be identified for several months until the progressive growth disturbance becomes clear. There is severe short stature with shortening of the bones of the arms and legs proximally more than distally (rhizomelia), a short trunk and a significant lumbar lordosis due to vertebral abnormalities. The head is disproportionately large for the body; the involvement of the facial bones leads to a characteristically flat profile. The foramen magnum is small, which may lead to hydrocephalus, and vertebral compressions may cause significant nerve injuries. Growth charts for achondroplastic children are available. The average final height of achondroplastic males is 131 cm and females 124 cm.52 Growth Failure Secondary to Environmental Factors Internal Environment Normal growth requires a normal metabolism and adequate nutrition. Conditions associated with disturbances in metabolism or deficiencies of essential nutrients can lead to failure to thrive and stunted growth. Such disorders affect both sexes equally.

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Chronic anoxia seen in some forms of congenital cyanotic heart disease is associated with impaired growth, due to an inadequate supply of the oxygen needed for normal energy metabolism, and also to the poor nutritional intake of these severely compromised children. Acidosis secondary to chronic renal failure leads to a significant and characteristic growth failure, associated with an increase in the IGF binding proteins resulting in less free IGF I available for local action on bone growth plates. Protein-calorie malnutrition is an alarming cause of stunted growth worldwide. Malabsorption syndromes like celiac disease or protein-losing enteropathies like regional ileitis lead to secondary growth failure. The various forms of rickets, either secondary to nutritional deficiency of vitamin D or to genetic disorders of vitamin D or calcium metabolism, will result in malformation of the long bones and stunting of their growth. Improving oxygenation, nutrition, and metabolism can improve growth in these children. Exogenous growth hormone has been shown to stimulate growth in children with chronic renal failure and is FDA approved for this indication. External Environment Profound failure to thrive with dramatic growth failure can be seen in both sexes, although more often in boys, in association with psychological stresses caused by an emotionally hostile psychosocial environment. This syndrome is known as psychosocial dwarfism or the emotional deprivation syndrome. In addition to growth failure, children with this syndrome sometimes have a set of bizarre behavioral disturbances, including hyperactivity, drinking out of toilet bowls, and eating garbage. A significant number of these children will test as growth hormone deficient when first seen, but GH secretion will normalize spontaneously and growth will start again when the children are removed from the hostile environment.53,54 Anorexia nervosa, a form of self-induced starvation, can be associated with growth failure and pubertal arrest. It occurs predominantly in girls at the time of puberty, but it is seen in boys also. Although GH may be normal, IGF-1 as well as follicle stimulating hormone (FSH) and LH are inappropriately low. Weight gain restores growth and hormone levels to normal, but resumption of pubertal progression may lag behind improvement in nutritional status for months or even years.

Puberty Puberty is the transitional period between the juvenile state and adulthood during which the adolescent growth spurt occurs, secondary sexual characteristics appear (resulting in the striking sexual dimorphism of mature individuals), fertility is achieved, and profound psychological changes take place. (M.M. Grumbach3)

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Normal Puberty The greatly increased secretion of gonadal hormones in puberty leads to dramatic physical, intellectual, and behavioral differences between the sexes. The adrenal cortex and the gonad are the major organs involved in sexual development. The maturation of the gonads is known as gonadarche, the maturation of the adrenal cortex as adrenarche. Puberty generally refers to the physical changes resulting from gonadarche. There is a marked sex difference in the timing of puberty. Girls enter puberty and complete it about two years earlier than boys. Adrenarche is the earliest pubertal phenomenon in both sexes. Beginning at a skeletal maturation of about 6 in girls and 7 in boys, the androgen-producing zona reticularis of the adrenal cortex increases in size and becomes increasingly sensitive to ACTH. In response to ACTH the adrenal cortex secretes increasing amounts of adrenal androgens, primarily dehydroepiandrosterone sulfate. The physical manifestations of adrenarche are oiliness of the skin, apocrine odor, axillary and pubic hair, and the pigmentation of perineum or scrotum and breast areolae. In girls, as puberty progresses the maturing ovary also secretes androgens, primarily androstenedione. In adult women low levels of testosterone are secreted by both the adrenal cortex and the ovary, but the major hormones responsible for sexual hair, odor, and sebaceous gland function in women are still the adrenal androgens. In pubertal and mature men the effects of the adrenal androgens, although present, are masked by the much stronger virilizing effects of the potent testicular androgen, testosterone. In both sexes, at the physiological levels seen in normal adrenarche, the adrenal androgens are too weak to cause a growth spurt or influence bone maturation. In puberty (gonadarche) the ovaries and testes mature, secrete characteristic hormones, estrogen and testosterone, and initiate the processes leading to fertility. The onset of puberty is marked by a maturation of and disinhibition of the central nervous system (CNS) hypothalamic–pituitary– gonadal (HPG) axis. This axis is also known as the gonadostat, a term reminiscent of a thermostat in recognition of the sensitive system of feedback regulation between the central hypothalamic and pituitary hormones (the furnace) and the gonadal sex steroids (the heat level). The gonadostat is in place early in gestation in both sexes. By the 16th week of gestation, pituitary FSH and LH levels reach postmeno­ pausal levels and the testis of the male fetus secretes high levels of testosterone comparable to those of adult men. The fetal ovary responds little, if at all, to the ­ gonadotropins. Later in gestation, gonadotropin concentrations fall to low levels probably in response to placentally derived estrogen present in both sexes throughout gestation. After birth, the male infant, but not the female, has a 10fold surge of LH and an increase of testosterone in response to it.3 This surge subsides in a few days but a secondary

rise in LH and testosterone begins in the second week after birth and increases to a peak testosterone in the second month of life comparable to levels seen in early puberty. This so-called ‘minipuberty of infancy’55 is transient, and by 6 months of age LH and testosterone have fallen to the low levels seen throughout childhood. Female infants from the first week of life show a gradual rise in FSH and LH (and to a lesser extent estradiol) which peak in the 2nd month of life and then subside to low childhood levels. In both sexes, as inhibitory neural connections mature, the HPG axis is gradually suppressed and under normal circumstances remains almost fully suppressed from the age of 1–2 years throughout childhood (the so-called ‘juvenile pause’.). Inadequate neural maturation due to CNS disease can result in inadequate inhibition of the HPG axis and subsequent sexual precocity. Even during the ‘juvenile pause’ the HPG axis is not totally quiescent. Very small pulses of FSH and LH can be measured in both sexes. Although the frequency of pulses through childhood is the same in both sexes, the FSH pulse amplitude is slightly higher in girls and the consequent secretion of estrogen may explain the small but definite differences in body composition between prepubertal boys and girls.56 Neither the mechanism of suppression of the GnRH pulse generator at the beginning of the ‘juvenile pause’ nor the process of its disinhibition that heralds the onset of puberty is understood. Genetic and nutritional factors, chronic disease, and race influence the age of onset of puberty. Recent evidence suggests that the hormone leptin and, at least in girls, the percent of body fat, may have a permissive effect on the onset of puberty. Once triggered, the process of puberty starts with a marked increase in the amplitude of the pulses of gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus into the hypothalamic-pituitary circulation, causing an increased synthesis and secretion of FSH and LH by the anterior pituitary. The first measurable phenomenon associated with puberty is a dramatic increase in the amplitude of the pulses of FSH and LH in the circulation. At first these large pulses are seen only at night associated with sleep. Later in puberty large pulses of gonadotropin can be measured approximately every two hours throughout the 24 hours, although still with a diurnal variation which persists until late puberty and adulthood. In response to the increased levels of FSH and LH, the ovaries and testes mature and secrete increasing amounts of hormone, in the case of ovaries primarily estrogen but also small amounts of testosterone, and in the case of testes primarily testosterone but also small amounts of estrogen. The increasing levels of estrogen and testosterone in turn cause characteristic secondary sexual changes and an increased velocity of linear growth (the pubertal growth spurt). The gonadal hormones are in large part responsible for the rapid growth of puberty, and in both sexes estrogen is necessary for the maturation and eventual fusion of the epiphyses of the bones, which marks the attainment of adult stature.37

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The first physical sign of puberty in girls is more often breast development than pubic hair, but adrenarche and gonadarche usually occur within 6–12 months of one another. Race influences the age of onset of puberty in girls. For black girls the average age of breast development and pubic hair is about 9½ years and for white girls 10–10½ years. The lower limit of the normal age for the onset of puberty in girls remains controversial. Although recent studies have suggested a significantly lower age for the normal onset of puberty in girls,57,58 the consensus is still that the lower limit of the normal onset of puberty in girls is 8 years.59,60 In developing girls, an increase in fat accumulation and its distribution to the hip and abdominal area result in the characteristic mature female contours. Estrogenization of the perineal area results in hypertrophy of the labia minora. Activation of the mucoid glands of the vagina mirrors maturation of the uterus and estrogenization of the uterine lining; a mucoid vaginal discharge presages the onset of menstruation (menarche). The average age of menarche is about 12 years 8 months in white girls, a few months earlier in black girls. Menarche normally occurs within 2–3 years of the onset of puberty. Regular menstrual cycles and consistent ovulation occurs usually within 1 year of menarche. The ‘secular trend’ refers to the observation that, in economically developed countries over the past 100–200 years, there has been a general trend to earlier sexual maturation and, to a lesser extent, an increase in the average adult size of both men and women. The age at menarche in Western countries had decreased until recently by an average of 3–4 months every decade since the 1850s. The major factors responsible for the secular trend are better nutrition and a lessening of disease. Once the optimal state of general nutrition in a society has been reached, the secular trend levels off. This has happened in the United States and the age at menarche has not changed significantly in a few decades.61 Soon after breast buds appear, girls start their pubertal growth spurt. Major growth is complete and bone fusion well under way by the time of menarche. Following menarche girls normally grow about 5 cm more before total bone fusion occurs and adult height is reached at about 16 years.62 In boys, the first physical sign of puberty is almost always testicular enlargement, which occurs at an average age of 11–12 (lower limit, 9 years) and is followed in a few months by the appearance of pubic hair. In response to the potent virilizing effects of increasing levels of testosterone, the scrotum thins and becomes pendulous and penile dimensions increase. Muscle mass and strength increase, particularly in the upper body, resulting in the characteristic ‘triangular’ male body contour dominated by shoulders and chest. Voice change and the appearance of facial hair occur later in puberty, at about age 15. Spermatogenesis begins at about 13½. The pubertal growth spurt starts also at about 13½ and reaches its maximum velocity at 14–15. Total bone fusion occurs and adult height is reached at

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an average age of 18.63 Because they have more years of prepubertal growth and a longer and greater pubertal growth spurt, adult males are on average about 12.5 cm taller than adult females.57,61,64 The stage of pubertal development is described through the use of Tanner scoring for breast development in girls, testicular enlargement in boys, and the amount and distribution of pubic hair in both. Tanner I is prepubertal; Tanner II, early puberty; Tanner III, mid puberty; Tanner IV, late puberty; and Tanner V, adult. The breasts or testes, and the pubic hair, are scored separately because they reflect different aspects of sexual development – that is, the gonadarche and adrenarche respectively.62,63

Variants of Pubertal Development The question of abnormal puberty arises when the first signs of sexual development appear at too young or too old an age, when puberty progresses too rapidly or too slowly, when it is incomplete, or when there is evidence of heterosexual development. Because the timing, pace and quality of pubertal development vary greatly in normal children, deciding when to evaluate a child for possible pathologic variation can be challenging. The following clinical scenarios require investigation in boys: signs of puberty before the age of 9 years; no signs of puberty by age 14; heterosexual development at any age; incomplete pubertal development; abnormally slow or rapid progression through puberty. In girls, clinical scenarios requiring investigation are similar to those in boys. In girls, however, as mentioned earlier, there is some controversy about the lower limit of normal for the onset of puberty.57,58,65,66 Clinical investigation is always indicated in white girls when the onset of puberty is before age 7 years, or before age 6 years in black girls. Deciding whether clinical investigation should be undertaken when the onset of puberty is between the age of 7 and 8 in white girls, or 6 and 8 in black girls, requires careful clinical judgment. Relatively early pubertal onset can be a benign familial pattern; a detailed family history and physical exam are always indicated in such cases. Referral to a pediatric endocrinologist should be made when the clinician has any doubts about the possibility of a pathologic etiology. Investigation is also indicated in girls when there are no signs of puberty by age 13, when pubertal development is incomplete (e.g. absence of menarche despite adequate feminization), or if there are signs of heterosexual development (e.g. clitoromegaly, virilization) at any age. Premature Pubarche and Premature Adrenarche Premature pubarche is characterized by the appearance of pubic hair (and sometimes also axillary hair and odor) several years prior to the onset of true puberty. Premature adrenarche describes the biochemical and hormonal milieu characteristic of early puberty (Tanner II). In premature

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pubarche, pubertal levels of adrenal androgens (dehydroepiandrosterone and its sulfate) can often be demonstrated. Premature adrenarche is the most common cause of premature pubarche. Children with premature pubarche may have a mild growth spurt associated with bone age advancement of up to 2 years greater than chronological age. Despite the advancement in bone age, final height usually is not compromised in this condition, and true puberty (maturation of the HPG axis) occurs at the normal time. This condition occurs more frequently in girls than in boys, and also may be associated, in girls, with other endocrine abnormalities at a later age. Menstrual irregularities, hirsutism, glucose intolerance, insulin resistance, and obesity occur with increased frequency in women who have a history of premature adrenarche.67 Pathological conditions (e.g. late-onset congenital adrenal hyperplasia, polycystic ovary syndrome, virilization of any etiology) can present with premature adrenarche. Appropriate testing and therapeutic intervention are necessary when clinical signs are progressive. Premature Thelarche Premature thelarche is characterized by the appearance of breast development in girls before the onset of true puberty. It is unaccompanied by signs of androgen effect (i.e., neither pubic nor axillary hair is noted). When premature thelarche occurs in a female infant, it is usually transient. When it is first seen in the toddler years, it may regress or persist until the onset of true puberty. In most girls with premature thelarche, subtle elevations in baseline and stimulated levels of FSH and estrogen can be demonstrated, as well as an increased number of ovarian microcysts. LH levels remain prepubertal until the onset of true puberty. Despite these findings, bone maturation usually is not advanced, and adrenarche and menarche occur at a normal time. Girls with premature thelarche must be followed, as breast development may be the first sign of true precocious puberty or ovarian pathology. Pubertal Gynecomastia Pubertal gynecomastia occurs in almost half of normal boys during Tanner stages II to IV of pubertal development. It is seen more frequently in obese boys, and weight loss can sometimes ameliorate the condition. When gynecomastia occurs before the onset of puberty, or when it persists after the completion of puberty, a diagnostic evaluation is indicated. The etiologies of pre- and postpubertal gynecomastia are myriad, and include conditions that result in inadequate testosterone action (due to low active hormone levels or receptor abnormalities) or excessive estrogen action. Elevations in prolactin or HCG levels, drug reactions, exposure to exogenous estrogens or substances with estrogenic activity,68 hepatic insufficiency, and sex chromosome abnormalities (e.g. Klinefelter syndrome, 47,XXY) should be considered in the evaluation of non-pubertal

gynecomastia. Treatment of persistent or severe gynecomastia is usually surgical. Medical therapy with aromatase inhibitors usually is not effective.69 Constitutional Delay of Puberty Constitutional delay of puberty is characterized by late maturation of the HPG axis in an otherwise normal child. Constitutional delay is seen more often in boys than in girls. Approximately 1% of normal boys will have constitutional delay and will enter puberty spontaneously after 14 years of age. There is often a family history of late menarche in the child’s mother, or late puberty with growth continuing into the late teens or early twenties in the child’s father. Children with constitutional delay tend to be short for age and have delayed skeletal maturation, but growth velocity is in the normal prepubertal range and predicted heights are usually appropriate. When there are no signs of puberty in girls over age 13 years, and boys over age 14 years, an endocrine evaluation and appropriate intervention are indicated. It is sometimes difficult to differentiate between constitutional delay of puberty and true gonadotropin deficiency (hypogonadotrophic hypogonadism.) An 8:00 a.m. testosterone level greater than 20 ng/dl in a boy with a prepubertal physical exam predicts the onset of spontaneous puberty within a year in most cases.70 In boys with pubertal delay, a short course of monthly low dose IM testosterone may be helpful in differentiating constitutional delay from hypogonadotrophic hypogonadism. In constitutional delay, puberty often progresses when the IM testosterone is discontinued, and in hypogonadotrophic hypogonadism, it does not. In girls, measurement of gonadotropins and estradiol will help differentiate constitutional delay from primary ovarian failure, but not from true gonadotropin deficiency. GnRH stimulation testing may be helpful in both sexes. If a pubertal rise in LH is documented during testing, it is likely that clinical evidence of puberty will ensue.

Abnormal Puberty True (complete) Precocious Puberty in Boys True (complete) precocious puberty in boys is defined as the onset of maturation of the HPG axis before age 9. Clinically, this is characterized first by bilateral testicular growth, and the appearance of sexual hair. A morning testosterone level of 20 ng/dl is consistent with early puberty. Supporting laboratory evidence of early puberty includes a pubertal rise in gonadotropins after stimulation with GnRH. Idiopathic true precocious puberty is a diagnosis of exclusion in boys, as the majority presenting with true puberty before 9 years will be found to have a pathologic neurological etiology.71 Lesions causing increased intracranial pressure or lesions destructive to the posterior third ventricle interfere with the normal prepubertal inhibition of gonadotropin secretion and can cause sexual precocity. Because of this, the evaluation

C h a p t e r 2    Sexual Development, Growth, and Puberty in Children l

of true precocious puberty must be extensive and always include imaging of the brain. Hamartomas, gliomas, astrocytomas, ependymomas, germinomas, and choriocarcinomas are some tumors that can present with precocious puberty. Neurofibromas, granulomas, suprasellar or subarachnoid cystic lesions, congenital malformations of the brain, head trauma, and hydrocephalus all can result in disinhibition of the gonadostat, and the subsequent development of precocious puberty. Both boys and girls with neurodevelopmental disabilities and meningomyelocele are at increased risk for precocious pubertal development.72,73 Prepubertal boys exposed to androgen from any cause may develop precocious puberty due to premature disinhibition of the HPG axis. This can be seen clinically in boys with congenital adrenal hyperplasia, androgen-secreting tumors, or in boys who have received androgens for treatment of unrelated diseases. Once the underlying etiology is determined and addressed, treatment of true precocious puberty entails suppression of the HPG axis with potent GnRH analogs. Incomplete Precocious Puberty in Boys Incomplete precocious puberty in boys is characterized by clinical signs of virilization without maturation of the HPG axis. Testosterone levels are high for age, but pituitary gonadotropin response to GnRH is prepubertal (suppressed). In the absence of gonadotropin release, most boys with incomplete precocious puberty will not have testicular enlargement. An exception to this may be found in boys with CAH who often have asymmetric enlargement of testicular adrenal rests. Familial gonadotropin-independent sexual precocity (testotoxicosis) is a sex-limited autosomal recessive disorder, affecting only males, caused by an activating mutation of the LH receptor of the testis, and characterized by premature maturation of testicular Leydig cells, bilateral testicular hypertrophy, and testosterone secretion.74 Gonadotropin levels are suppressed to prepubertal levels, and treatment with GnRH analogs is ineffective. Drugs that interfere with testosterone synthesis and action (e.g., ketoconazole, testolactone, spironolactone) have been used effectively in treatment of this disorder.75,76 There are tumors that secrete HCG, the LH-like action of which will also stimulate testicular Leydig cell growth. The testes are bilaterally enlarged in this condition, but not as large as would be expected in normally progressing puberty or in testotoxicosis. HCG secretion has been described in a number of tumors, including hepatomas, hepatoblastomas, teratomas, chorioepitheliomas, and germinomas. Boys with inadequately treated congenital adrenal hyperplasia due to P450c21 or P450c11 deficiency have excessive adrenal androgen production from both the adrenal glands and any testicular adrenal rest cells, if present. The testicular adrenal rests can become quite large under ACTH stimulation, and result in bilateral irregular testicular enlargement. Treatment consists of adequate suppression of ACTH with

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exogenous glucocorticoids, although once enlarged, testicular adrenal rests may become autonomous. If this condition progresses to true (gonadotropin dependent) precocious puberty, treatment with GnRH analog is indicated. Adrenal and testicular tumors can be virilizing or feminizing, and the clinical picture is determined by the hormones made by the tumor. In adrenal tumors characterized by masculinization, phallic enlargement is present without testicular growth. Testicular tumors cause unilateral, irregular testicular growth associated with virilization and phallic enlargement. The uninvolved testis remains prepubertal in size. The McCune–Albright syndrome was initially described as the clinical triad of polyostotic fibrous dysplasia, café au lait spots and precocious puberty.77 Other signs of autonomous endocrine dysfunction involving the pituitary, adrenal and thyroid glands have since been described in these patients. Activating somatic mutations in G-protein structure have recently been found to cause this unusual syndrome, which is more common in girls.78 Boys with precocious puberty due to McCune–Albright syndrome may initially have asymmetrically enlarged testes due to autonomous testicular function; maturation of the hypothalamic–pituitary axis and true precocious puberty with associated bilateral testicular enlargement can ensue. Treatment is with drugs that inhibit testosterone synthesis or action, or with GnRH analogs if indicated. Incomplete sexual precocity also can be caused by exposure to exogenous androgens, either orally, transdermally or parenterally. Testes are always prepubertal in size when virilization is due to exogenous androgens. Removal of the source of androgen will result in cessation of progression of virilization, unless the exposure was prolonged enough to result in maturation of the gonadostat, and cause true precocious puberty. True (complete) Precocious Puberty in Girls True (complete) precocious puberty in girls is defined as premature maturation of the HPG axis, with a characteristic pubertal rise in serum LH levels on stimulation testing with GnRH. The exact age at which puberty is considered to be premature in girls has been addressed earlier in this section, with the lower limit of normal ranging from 6 to 8 years. Unlike precocious puberty in boys, where underlying pathology is diagnosed in the majority of cases, over 95% of cases of true precocious puberty in girls are idiopathic, and no underlying pathology is found. Idiopathic true precocious puberty is seen with increased frequency in adopted children, possibly related to the nutritional changes in their new environment, and subsequent changes in body composition and leptin levels.79–80 When a pathologic etiology is found, it is usually neurologic, as in boys. Any intracranial condition can cause true precocious puberty by interfering with neurogenic inhibition of the HPG axis.81 Even though no pathologic etiology for precocious puberty is found in most girls, imaging of the

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brain is indicated as part of the evaluation because intracranial pathology may be present. Conditions associated with complete precocious puberty in girls include: hydrocephalus, cerebral palsy, congenital malformations of the brain, irradiation, and trauma. Although any intracranial mass can present with precocious puberty, optic gliomas (often seen in neurofibromatosis type I), hypothalamic hamartomas, and pineal tumors are most frequently associated with precocious puberty in girls. Premature hypersecretion of gonadotropins due to untreated primary hypothyroidism, or to primary ovarian failure, are rare causes of precocious puberty in girls.82–84 In girls as in boys, any condition (feminizing or virilizing) that accelerates somatic maturation (clinically demonstrable by significant bone age advancement), can result in true precocious puberty, even when the underlying condition is treated. Incomplete Precocious Puberty in Girls Incomplete precocious puberty in girls is characterized by premature appearance of either sexual hair or breast development, unaccompanied by laboratory evidence of maturation of the HPG axis. The LH response to GnRH stimulation testing is prepubertal. Most often, when nonprogressive isolated signs of estrogen or androgen effect are noted in girls, no pathology is found, and the diagnosis is premature thelarche or premature adrenarche, as discussed earlier. Benign ovarian cysts are the most common cause of progressive premature feminization in girls. Hormonally active solid tumors of the ovaries or the adrenals (e.g., granulosa, theca cell, Leydig–Sertoli cell, dysgerminomas, carcinomas) present with premature feminization or virilization, or a mixed picture. Progression of pubertal signs may be rapid. The treatment is usually surgical removal of the tumor. If the condition has caused marked bone age advancement and subsequent true precocious puberty, treatment with a GnRH agonist is also indicated. Gonadoblastomas are seen primarily in girls with dysgenetic gonads containing Ychromosome material. Girls with mixed gonadal dysgenesis or Turner syndrome mosaicism with a Y chromosome fragment should have bilateral gonadectomies, as the incidence of gonadoblastoma in these girls is high. McCune–Albright syndrome, described earlier, is seen predominantly in females.77 In this condition gonadotropinindependent ovarian cysts secrete estrogen, with resultant feminization and bone maturation. Initial treatment is with aromatase inhibitors. If true precocious puberty ensues, GnRH agonists may be required. Late onset congenital adrenal hyperplasia can present with premature signs of androgen effect (i.e. the appearance of axillary and or pubic hair). Frank virilization is usually not seen. The diagnosis is based on adrenal enzyme levels pre- and poststimulation with ACTH. Treatment depends on the severity and type of enzyme defect, and usually includes replacement with glucocorticoids.

Exogenous sources of estrogen or androgen must be considered in the differential diagnosis. Oral contraceptives, estrogen-containing creams, and foods and vitamins containing metabolically active hormones have all been implicated in the premature appearance of secondary sexual characteristics in children. Excessive ingestion of products containing phytoestrogens (soy products, ginseng) may also cause premature feminization.85–87 When isolated vaginal bleeding is present, without evidence of breast development or maturation of the labia minora, then sexual abuse, foreign body or genital tract tumors must be considered. Virilization of young children due to transdermal absorption of androgen gels prescribed for their parents has been reported.88 Sexual Infantilism in Boys Hypogonadotrophic Hypogonadism Permanent gonadotropin deficiency can result from congenital or acquired abnormalities of the central nervous system (CNS). In boys, the congenital etiologies are often associated with small genitalia and undescended testes, as well as with delayed puberty, because gonadotropin-stimulated testosterone secretion is required for normal intra-uterine genital development. Midline defects of the brain (e.g., septo-opticdysplasia) and congenital hypopituitarism can be associated with additional pituitary hormone deficiencies. In the past decade, extensive genetic research has expanded our knowledge of specific defects in patients with heritable gonadotropin deficiency. Kallman syndrome (gonadotropin deficiency and anosmia), five times more common in males than females, has been found to have an X-linked form.89 Congenital adrenal hypoplasia, associated with gonadotropin deficiency, is inherited as an X-linked recessive.90 Prader–Willi syndrome (previously discussed) and Biedl–Bardet syndrome (autosomal recessive) are both associated with pubertal delay and gonadotropin insufficiency. Additional rarer genetic defects associated with gonadotropin insufficiency have been described, but are beyond the scope of this chapter. Acquired abnormalities of the CNS resulting in permanent gonadotropin deficiency include midline and other tumors of the brain (e.g., craniopharyngiomas, prolactinomas, germinomas, astrocytomas, gliomas), infiltrative disease of the pituitary or hypothalamus (e.g., histiocytosis X, granulomatous disease, iron deposition in thalassemia major), irradiation, and trauma. Treatment of pubertal delay caused by gonadotropin deficiency is with testosterone replacement, or with HCG. Testicular Failure (Hypergonadotrophic Hypogonadism) Testicular failure (hypergonadotrophic hypogonadism) is characterized by pubertal delay associated with low testosterone levels and elevated gonadotropins. Klinefelter syndrome (47,XXY) is the most common cause of testicular insufficiency in males. Boys with this syndrome may have

C h a p t e r 2    Sexual Development, Growth, and Puberty in Children l

pubertal delay, or lack of normal progression of puberty. Testes are small and firm. Mumps orchitis can cause testicular damage, as can Coxsackievirus B, irradiation, chemotherapy, and trauma. Bilateral undescended testes may be damaged even when early orchiopexy is performed. Treatment of all causes of delayed puberty due to testicular failure is with testosterone replacement. Sexual Infantilism in Girls Hypogonadotrophic Hypogonadism As in boys, congenital gonadotropin deficiency can be seen in midline malformations of the brain, involving the pituitary and hypothalamus. Genetic syndromes associated with obesity (e.g., Laurence–Moon–Biedel, Prader–Willi) also are associated frequently with gonadotropin deficiency. Genetic mutations affecting leptin and its receptors can present with severe obesity and hypogonadism. Kallman syndrome, mentioned earlier, is more common in males than females, due to X-linked recessive inheritance in the majority of cases.89 Rarer genetic causes of gonadotropin deficiency have been reported and most are inherited in an autosomal recessive manner. Acquired gonadotropin deficiency due to brain tumors, irradiation, trauma, inflammatory disease, and chronic illness occur with the same frequency in males and females, unless the underlying disease (e.g., specific brain tumor type) does not. Prolactin levels should be monitored, as hyperprolactinemia, often seen in elevated intracranial pressure, may cause reversible gonadotropin deficiency. Anorexia nervosa, seen more commonly in girls, is also associated with reversible gonadotropin deficiency. Primary amenorrhea is characterized by lack of menstruation by 4½ years after the onset of puberty. Such a delay suggests structural abnormalities of the uterus or vagina, and appropriate studies should be undertaken. Primary amenorrhea is seen in healthy athletic girls with low total body fat; increasing fat intake usually results in menarche. Menarche is also delayed in girls with anorexia, and can be delayed for years even after normal weight is achieved.80 Ovarian Failure (Hypergonadotrophic Hypogonadism) In hypergonadotrophic hypogonadism, low sex hormone levels are accompanied by elevated gonadotropin levels. In girls with delayed puberty, if gonadotropin levels are elevated, the laboratory investigation must include a karyotype to rule out genetic disorders of gonadal development. Disorders of androgen synthesis in genetic males can present as delayed puberty in a phenotypic female. Genetic males who have complete androgen insensitivity can mature sexually in response to testicular estrogens and not infrequently present as a female with primary amenorrhea. Primary ovarian failure may be complete or partial. In this condition girls may start but not progress through

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puberty, or they may present with complete sexual infantilism. The most common cause of primary ovarian failure in girls is gonadal dysgenesis (Turner syndrome) characterized by complete (45,X0) or partial deficiency of genes on the X chromosome (mosaicism for Turner syndrome is frequently found in these patients). Autoimmune oopheritis is characterized by primary or secondary amenorrhea, or premature menopause.91 These girls may have evidence of other autoimmune endocrinopathies which are seen more commonly in females than in males. Hemochromatosis due to recurrent transfusions or other causes of iron overload can result in failure or insufficiency of multiple endocrine glands (including the ovaries, testes and pituitary), and may present as lack of pubertal progression in both sexes.92 Depending on the degree of insufficiency of the glands involved, the hypogonadism may be hyper- or hypogonadotrophic. Ovarian damage due to radiation and chemotherapy given for treatment of childhood malignancies can result in primary ovarian failure, even though prepubertal ovaries are more resistant to the harmful effects of radiation and chemotherapy than mature ovaries. Treatment of both hyper- and hypogonadotrophic hypogonadism in girls consists of cyclic replacement of estrogen and progesterone in increasing doses so that pubertal development progresses as normally as possible. In well-estrogenized girls with primary amenorrhea (if pregnancy has been ruled out), a progesterone challenge may be indicated. Imaging studies can be done to rule out congenital malformations of the female genital tract (e.g., congenital absence of the uterus) and should be done if no menstrual bleeding occurs after progesterone administration. If signs of virilization are present in a girl with primary amenorrhea, the evaluation must include measurement of androgens, which, if elevated, can interfere with normal menstrual cycling. Polycystic ovary syndrome is the most common cause of amenorrhea in girls with normal pubertal development, oligo- or amenorrhea, and mild to moderate hyperandrogenism. When frank virilization or genital ambiguity is noted, an extensive investigation to rule out rare causes of hyperandrogenism (e.g., true hermaphroditism, or androgen-producing tumors) may be indicated.

Acknowledgments We are grateful to Sharon E. Oberfield, MD, for reviewing the manuscript.

References   1. Grumbach MM, Hughes IA, Conte FA. Disorders of sex differentiation. In: PR Larson, HM Kronenberg, S Melmed, KS Polonsky, eds. Williams Textbook of Endocrinology, 10th edn. Philadelphia, PA: W.B. Saunders; 2003:855–76, 2003:, 886–907, 934–5, 961–2.

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  2. Barsoum I, Yao HH-C. The road to maleness: from testis to Wolffian duct. Trends Endocrinol Metab 2006;17:223–28.   3. Tilmann C, Capel B. Cellular and molecular pathways regulating mammalian sex determination. Recent Prog Horm Res 2002;57:1–18.   4. Grumbach MM. Sex begins in the womb. In: TM Wizemann, M-L Pardue, eds. Exploring the Biological Contributions to Human Health: Does Sex Matter?. Washington, DC: National Academy Press; 2001:45–72.   5. Lee PA, Houk CP, Ahmed SF, et al. Consensus statement on management of intersex disorders. International consensus conference on intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics 2006;118(2): e488–500.   6. Donohoue PA, Panker K, Migeon CJ. Congenital adrenal hyperplasia. In: CR Scriver, AL Beaudet, WA Sly, D Vallee, eds. The Metabolic and Molecular Basis of Inherited Diseases, 8th edn. New York, NY: McGraw–Hill; 2001:4091–106.   7. Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20 lyase deficiency: from clinical investigation to molecular definition. Endocr Rev 1991;12:91–108.   8. Grumbach MM, Auchus RJ. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab 1999;84:4677–94.   9. Imperato-McGinley J, Peterson RE. Male pseudohermaphroditism: the complexities of male phenotypic development. Am J Med 1976;61:251–72. 10. Griffin JE, McPhaul M, Russel D, et al. The androgen resistance syndromes: 5 alpha reductase deficiency, testicular feminization and related disorders. In: CR Scriver, AL Beaudet, WA Sly, D Vallee, eds. The Metabolic and Molecular Basis of Inherited Disease, 7th edn. New York, NY: McGraw–Hill; 1995:1919–44. 11. Deeb A, Mason C, Lee YS, et al. Correlation between geno­ type, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clin Endocrinol 2005;63:56–62. 12. Diamond DA, Burns JP, Mitchell C, et al. Sex assignment for newborns with ambiguous genitalia and exposure to fetal testosterone: attitudes and practices of pediatric urologists. J Pediatr 2006;148:445–49. 13. Rappaport R, Forest MG. Disorders of sexual differentiation. In: J Bertrand, R Rappaport, PC Sizonenko, eds. Pediatric Endocrinology: Physiology, Pathophysiology, and Clinical Aspects. Baltimore, MD: Williams & Wilkins; 1993:447–70. 14. Money J, Devore H, Norman BF. Gender identity and gender transposition: longitudinal outcome study of 32 male hermaphrodites assigned as girls. J Sex Marital Ther 1986;12:165–81. 15. Money J, Norman BF. Gender identity and gender transposition: longitudinal outcome study of 24 male hermaphrodites assigned as boys. J Sex Marital Ther 1987;13:75–92. 16. Birnbacher R, Marberger M, Weissenbacher G, et al. Gender identity reversal in an adolescent with mixed gonadal dysgenesis. J Pediatr Endocrinol Metab 1999;12(5):687–90. 17. Reiner WG. Sex assignment in the neonate with intersex or inadequate genitalia. Arch Pediatr Adolesc Med 1997;151:1044–45.

18. Lerman SE, McAleerr IM, Kaplan GW. Sex assignment in cases of ambiguous genitalia and its outcome. Urology 2000;55:8–12. 19. Imperato-McGinley J, Peterson RE, Gautier T, et al. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency. N Engl J Med 1979;300:1233–37. 20. Rosler A. 17beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population. Pediatr Endocr Rev 2006;3:455–61. 21. Hines M, Brook C, Conway GS. Androgen and psychosexual development: core gender identity, sexual orientation, and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH). J Sex Res 2004;41:75–81. 22. Jaaskelainen J, Tiitinen A, Voutilainen R. Sexual function and fertility in adult females and males with congenital adrenal hyperplasia. Horm Res 2001;56:73–80. 23. Meyer-Bahlburg HF. Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:155–71. 24. Sytsma S. Ethical dilemmas in retrospective studies on genital surgery in the treatment of intersexual infants. Camb Q Healthc Ethics 2004;13:394–403. 25. Tanner JM, Whitehead RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976;51:170–79. 26. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 1987;64:51–58. 27. Tanner JW, Davis PWS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;107:317–29. 28. Hall JG, Froster-Iskenius UG, Allanson JE. Handbook of Normal Physical Measurements. New York, NY: Oxford University Press; 1989, 270–5. 29. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist, 2nd edn. Stanford, CA: Stanford University Press; 1959. 30. Bayer LM, Bayley N. Growth Diagnosis. Chicago, IL: University of Chicago Press; 1959, 45–7. 31. Tanner JM, Whitehouse RH, Marshall WA, et al. Prediction of adult height from height, bone age and occurrence of menarche at ages 4–16 with allowance for mid-parental height. Arch Dis Child 1975;50:14. 32. Roche AF, Wainer H, Thissen D. The RWT method for the prediction of adult stature. Pediatrics 1975;56:1026. 33. Kaplowitz P. Delayed puberty in obese boys: comparison with constitutional delayed puberty and response to testosterone therapy. J Pediatr 1998;133(6):724–26. 34. Kaplowitz P. Commentary: Is growth hormone the best treatment for short stature in healthy peripubertal boys? Insights from the field of economics. Endocrinologist 2007;17(4):221–26. 35. Hero M, Wickman S, Dunkel L. Treatment with the aromatase inhibitor letrozole during adolescence increases nearfinal height in boys with constitutional delay of puberty. Clin Endocrinol 2006;64:510–13. 36. Rosenfeld RG, Hintz RC, Johanson AJ, et al. Three-year results of a randomized prospective trial of methionyl human growth

C h a p t e r 2    Sexual Development, Growth, and Puberty in Children l

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51. 52. 53.

hormone and oxandrolone in Turner syndrome. J Pediatr 1986;121:45–55. Morishima A, Grumbach MM, Simpson ER, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metabol 1995;80:3689–98. Rosenfeld RL, Devine N, Hunold JJ, et al. Salutary effects of combining early very low-dose systemic estradiol with growth hormone therapy in girls with Turner syndrome. J Clin Endocrinol Metabol 2005;90(12):6424–30. Ross JL, Roeltgen D, Feuillan P, et al. Use of estrogen in young girls with Turner syndrome. Effects on memory. Neurology 2000;54:164–67. Sizonenko P, et al. Diagnosis and management of GH deficiency in childhood and adolescence. Growth Horm IGF Res 2001;11:137–65. Perry RJ, Findlay CA, Donaldson MDC. Cushing’s syndrome, growth impairment and occult adrenal suppression associated with intranasal steroids. Arch Dis Child 2002;87:45–48. Allen DB, Goldberg BD. Stimulation of collagen synthesis and linear growth by growth hormone in glucocorticoidtreated children. Pediatrics 1992;89(3):416–21. Radovick S, DiVall S. Approach to the growth hormone deficient child during transition to adulthood. J Clin Endocrinol Metabol 2007;92(4):1195–200. Hardin DS, Woo J, Butsch R, et al. Current prescribing practices and opinions about growth hormone therapy: results of a nationwide survey of paediatric endocrinologists. Clin Endocrinol 2007;66:85–94. Rosenfeld RG, Cohen P. Disorders of growth hormone/insulin-like growth factor secretion and action. In: MA Sperling, ed. Pediatric Endocrinology, 2nd edn. Philadelphia, PA: WB Saunders; 2002:247. Vanderschueren-Lodeweyckx M. Who is treated with growth hormone today? The executive scientific committee of the Kabi international growth study. Acta Paediatr Scand Suppl 1990;370:107–13. Root AW, Kemp SF, Rundle AC, et al. Effect of long term recombinant growth hormone therapy in 1985–1994. J Pediatr Endocrinol Metab 1998;11(3):403–12. August GP, Julius JR, Blethen SL. Adult height in children with growth hormone deficiency who are treated with biosynthetic growth hormone: the National Cooperative Growth Study experience. Pediatrics 1998;102:512–16. Attanasio AF, Shavrikova E, Blum WF, et al. Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients. J Clin Endocrinol Metabol 2004;89 (10):4857–62. Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentration of growth hormone – a new inborn error of metabolism. Isr J Med Sci 1966;2:152. FDA Center for Drug Evaluation and Research. Approval package for application number NDA 21-839. Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr 1978;93:435–38. Powell GF, Brasel JA, Blizzard RM. Emotional deprivation and growth retardation simulating idiopathic hypopituitarism I: clinical evaluation of the syndrome. N Engl J Med 1967;276:1271–78.

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54. Powell GF, Brasel JA, Raiti S, et al. Emotional deprivation and growth retardation simulating idiopathic hypopituitarism II: endocrinologic evaluation of the syndrome. N Engl J Med 1967;276:1279–83. 55. Rosenfield R. The ovary and female sexual maturation. In: MA Sperling, ed. Pediatric Endocrinology, 2nd edn. Philadelphia, PA: W.B. Saunders; 2002;458:478–83. 56. He Q, Horlick M, Thornton J, et al. Sex and race differences in fat distribution among Asian, African-American and Caucasian prepubertal children. J Clin Endocrinol Metab 2002;87:2164–70. 57. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings Network. Pediatrics 1997;99:505–12. 58. Kaplowitz PB, Oberfield SE. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics 1999;104(4 Pt1):936–41. 59. Parent AS, Teilmann G, Juul A, et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 2003;24:668–93. 60. Rosenfield RL, Bachrach LK, Chernausek SD, et al. Current age of onset of puberty. Pediatrics 2000;106:622–23. 61. Grumbach MM, Styne DM. Puberty: Ontogeny, neuroendocrinology, physiology, and disorders. In: PR Larson, HM Kronenberg, S Melmed, KS Polonsky, eds. Williams Textbook of Endocrinology, 10th edn. Philadelphia, PA: W.B. Saunders; 2003:1115–70. 62. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in girls. Arch Dis Child 1969;44:291–303. 63. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13–23. 64. Styne DM. The testes: disorders of sexual differentiation and puberty. In: MA Sperling, ed. Pediatric Endocrinology, 2nd edn. Philadelphia, PA: WB Saunders; 2002:595–99. 65. Kaplowitz PB, Slora EJ, Wasserman RC, et al. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics 2001;108:347–53. 66. Papadimitriou A. Sex differences in the secular changes in pubertal maturation. Pediatrics 2001;108(4):E65. 67. Ibanez L, Potau N, Chacon P, et al. Hyperinsulinaemia, dyslipidaemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia 1998;41:1057. 68. Henley DV, Lipson N, Korach K, et al. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med 2007;356:479–85. 69. Shulman DI, Francis GL, Palmert MR, et al. Lawson Wilkins Pediatric Endocrine Society Drug and Therapeutics Committee. Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development. Pediatrics 2008;121(4):e975–83. 70. Wu FC, Brown DC, Butler GE, et al. Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys. J Clin Endocrinol Metabol 1993;76:26. 71. Sizonenko PC. Precocious puberty. In: J Bertrand, R Rappaport, PC Sizonenko, eds. Pediatric Endocrinology,

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72.

73.

74. 75.

76.

77.

78.

79.

80.

81.

s e c t i o n 1     Gender and Normal Development l

Physiology, Pathophysiology and Clinical Aspects, 2nd edn. Baltimore, MD: Williams & Wilkins; 1993:387–403. Siddiqi SU, Van Dyke DC, Donohoue P, et al. Premature sexual development in individuals with neurodevelopmental disabilities. Dev Med Child Neurol 1999;41:392. Trollman R, Strehl E, Dorr HG. Precocious puberty in children with myelomeningocele. Treatment with gonadotropin-releasing hormone analogues. Dev Med Child Neurol 1998;40:38. Laue L, Cutler GBJ. Familial male precocious puberty. Curr Ther Endocrinol Metab 1994;5:296. Holland FJ, Fishman L, Bailey JD, et al. Ketoconazole in the management of precocious puberty not responsive to LHRHanalogue therapy. N Engl J Med 1985;312:1023. Laue L, Kenigsberg D, Pescovitz OH, et al. The treatment of familial male precocious puberty with spironolactone and testolactone. N Engl J Med. 1989;320:496. McCune DJ, Bruch H. Osteodystrophia fibrosa: report of a case in which the condition was combined with true precocious puberty, pathologic pigmentation of the skin and hyperthyroidism, with a review of the literature. Am J Dis Child 1937;54:806. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991;325:1688. Teilmann G, Pedersen CB, Skakkebaek NE, et al. Increased risk of precocious puberty in internationally adopted children in Denmark. Pediatrics 2006;118(2):391–99. Matkovic V, Ilich JZ, Skugor M, et al. Leptin is inversely related to age at menarche in human females. J Clin Endocrinol Metab 1997;82(10):3239–45. Junier M-P, Wolff A, Hoffman G, et al. Effect of hypothalamic lesions that induce precocious puberty on the morphological and functional maturation of the luteinizing hormone-releasing hormone neuronal system. Endocrinology 1992;131:787.

82. VanWyk J, Grumbach M. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960;5:416. 83. Hemady ZS, Siler-Khodr TM, Najjar S. Precocious puberty in juvenile hypothyroidism. Pediatrics 1978;92:55. 84. Baer K. Premature ovarian failure and precocious puberty. Obstet Gynecol 1977;49:15s. 85. Saenz de Rodriguez CA, Bongiaovanni AM, Conde de Borrego L. An epidemic of precocious development in Puerto Rican children. J Pediatr 1985;107:393. 86. Setchell KD, Zimmer-Nechemias L, Cai J, et al. Exposure of infants to phyto-oestrogens from soy-based infant formula (see comments). Lancet 1997;350:23. 87. Hopkins MF, Androff L, Benninghoff AS. Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol 1988:121. 88. Kunz GJ, Klein KO, Clemons RD, et al. Virilization of young children after topical androgen use by their parents. Pediatrics 2004;114(1):282–84. 89. Maya-Nuanez G, Zenteno JC, Ulloa-Aguirre A, et al. A recurrent missense mutation in the KAL gene in patients with X-linked Kallmann’s syndrome. J Clin Endocrinol Metab 1998;83:1650. 90. Francke U, Harper JF, Darras BT, et al. Congenital adrenal hypoplasia, myopathy, and glycerol kinase deficiency: molecular genetic evidence for deletions. Am J Hum Genet 1987;40:212. 91. Betterle C, Rossi A, Pria S, et al. Premature ovarian failure: autoimmunity and natural history. Clin Endocrinol 1993;39:35. 92. Oerter KE, Kamp GA, Munson PJ, et al. Multiple hormone deficiencies in children with hemochromatosis. J Clin Endocrinol Metab 1993;76:357–61.

Chapter

3

Gender Differences in Pediatric Pulmonary Disease Beverley J. Sheares Associate Professor of Clinical Pediatrics, Columbia University, Pulmonary Division, Department of Pediatrics, New York, NY, USA

Introduction1

Developmental Respiratory Physiology Lung development and growth starts in the prenatal period and continues throughout early adulthood.9 Lung development proceeds through five distinct stages:10,11

There is increasing medical interest in differences between females and males in both normal lung development as well as in the incidence and expression of many pediatric lung disorders. The aim of this chapter is to highlight the influence of gender on the development, diagnosis, management, and outcomes of pulmonary diseases. While it is likely that biological, environmental, behavioral, and socio-cultural factors underlie the gender differences in respiratory disease, many of the pathophysiologic mechanisms are not well delineated. This chapter will review the anatomical, functional, and hormonal differences between the respiratory systems of females and males and delineate how changes occur from prenatal development through the adolescent years. Some common respiratory diseases with gender-specific differences will also be reviewed.



Between 3–4 weeks of gestation during the embryonic period, lung development commences as a ventral outpouching of the foregut and results in the formation of the trachea and two bronchial buds that eventually become the right and left mainstem bronchi.9,12 Airway and blood vessel branching and differentiation of epithelial cells into structures that will become submucosal glands, cartilage, and bronchial smooth muscle are the hallmarks of the pseudoglandular phase.9,12–14 Immature type II epithelial cells that will eventually produce surfactant also appear during this period. By 14 weeks gestation, 70% of the total airways that will be present at birth have formed and the entire conducting airway system is developed by the end of this phase.13 The canalicular period is heralded by the development of the pulmonary circulation and the further subdivision of distal airways. Progressive differentiation of epithelial cells into type I and type II pneumocytes occurs during this phase and by 24 weeks surfactant protein production has commenced.10,13 By the end of the canalicular phase gas exchange can be supported after birth; however, infants born during this phase are likely to have respiratory complications resulting

Prenatal lung growth Sex-related factors lead to alterations in the development and the mechanical properties of the lungs and may predispose to respiratory compromise or disease. These differences begin in the prenatal period.2–5 As early as 16–26 weeks in utero, the lungs of the female fetus are more matured.5 In the final stages of prenatal development, from approximately 26–36 weeks gestation, females have a further advantage in that surfactant production is enhanced and airway patency is increased leading to increased airflow rates in female newborns compared to males.6–8

Principles of Gender-Specific Medicine

Embryonic period (3–6 weeks post conception) Pseudoglandular period (6–16 weeks) Canalicular period (16–26 weeks) Saccular period (26–36 weeks) Alveolar period (36 weeks through adolescence)

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Copyright 2010 20 , Elsevier Inc. All rights reserved.

s e c t i o n 1     Gender and Normal Development

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l

from the lack of sufficient endogenous surfactant.11 The development of gas exchange units takes place predominantly during the saccular stage when terminal saccules are subdivided by ridges known as secondary crests.10,15 As the crests protrude into the saccules, capillaries are brought into close contact with the edges of the saccules in preparation for gas exchange. Maturation of type II pneumocytes occurs during this period with increased synthesis of surfactant proteins. Thereafter, in the alveolar stage, a further subdivision of the saccules into subsaccules occurs, leading to the eventual development of alveoli.15 Sex distinctions with regards to lung development and function occur during the pseudoglandular, canalicular, saccular, and alveolar periods (see Table 3.1).4–6,8 During the pseudoglandular and canalicular phases, differences between males and females with regards to fetal mouth movements and fetal breathing patterns that promote lung maturation have been detected.5,16 The canalicular and saccular periods are notable for sexual disparities in the biosynthesis and secretion of surfactant17–19 and for differing patterns of airway and alveoli development.15 Important gender differences also become apparent in the clinical manifestations of disease during the alveolar stage.

Fetal Breathing and Lung Maturation Breathing in the newborn is a result of many weeks or months of intra-uterine activity when the respiratory system transitions from moving fluid up the tracheobronchial tree to moving large amounts of air in and out of the alveoli. Given the efficiency with which changes in the lungs take place at birth, it is not likely that the respiratory system ‘attains such postnatal competence without prenatal practice.’16 Fetal breathing is also essential for lung growth Table 3.1  Stages of Lung Growth Stages of lung development

Time of Sex differences noted development during lung development

Embryonic 0–6 weeks Pseudoglandular 6–16 weeks

Canalicular

16–26 weeks

Saccular

26–36 weeks

Alveolar

36 weeks through adolescence

Fetal mouth movements and breathing advanced in females Hormonal differences are apparent and may enhance surfactant production in females Phospholipid profiles (surfactant production) of females more advanced than males by 1½ weeks Reduced risk of RDS in females Higher flow rates for a given lung volume in females infants

as well as pulmonary cellular differentiation required for functional development of the lung.20 During the intrauterine phase of development, the lungs have three distinct functions.20,21 1. A secretory role that contributes lung liquid to the intrauterine environment (amniotic fluid) in which the fetus grows. 2. Intra-uterine breathing movements that aid respiratory muscle development and pulmonary cellular differentiation. 3. Surfactant synthesis in preparation for postnatal breathing. Fetal respiratory movements were first described by Ahlfeld, a German obstetrician, in 1888, but his observations were largely ignored.3,16 In the 1940s other investigators observed fetal respiratory movements in animals at cesarean section, but attributed them to asphyxia and tactile stimulation.3,16 With the development of the A-scan ultrasound system in the early 1970s, Boddy et al. were able to detect chest wall movements in the fetus as early as 11 weeks gestation.3,16 The investigators used the technology to describe patterns of fetal breathing that delineated normal respiratory function for gestational age from fetal distress. During early fetal development, the breathing pattern is irregular and infrequent. By 24 weeks in utero breathing consists of clusters of breaths occurring periodically. A regular pattern of breathing does not usually appear until approximately 34 weeks gestation.16 When a normal pattern of breathing movements was observed 50% or more of the time, fetal distress and intrauterine or neonatal deaths were extremely rare.3,20,22 Thus, normal patterns of fetal respiratory movement suggest neonatal well-being. Decreased respiratory movement has been associated with the development of pulmonary hypoplasia.23,24 Fetal lung maturation is reflected also in fetal mouth movements. Hepper et al. demonstrated in serial sonograms taken at 16, 18, and 20 weeks gestation that fetal mouth movements increased with gestational age.5 Moreover, females had significantly more fetal mouth movements than males at each stage of development.5 Mouth movements are thought to reflect fetal breathing, a critical contributor to lung development and an indicator of fetal maturation.3,5,6 While this study made no causal inferences related to the subsequent development of lung disease in infants, it suggests that differences in pulmonary-related morbidity and mortality, as in respiratory distress syndrome (RDS) of the newborn, may be rooted in differences in lung maturation between females and males in the prenatal period.

Differences Between Males and Females in Surfactant Production In 1959, Avery and Mead reported that prematurely born infants with hyaline membrane disease had an abnormal surface tension at the air–liquid interface.25 They attributed this abnormality to a deficiency in pulmonary surfactant.

C h a p t e r 3     Gender Differences in Pediatric Pulmonary Disease l

Pulmonary surfactant, a combination of phospholipids and surface-associated proteins, produced in type II epithelial cells,26 is responsible for maintaining alveolar stability.27 Surfactant production is apparent by approximately 20 weeks gestation. By 22–24 weeks there are numerous lamellar inclusion bodies containing surfactant within the type II cells.28 Females have a more mature phospholipid profile by 26 weeks, indicating earlier production of surfactant.6,8 Although the lungs have an insignificant role in gas exchange during fetal development, they must produce enough surfactant during the prenatal period so that postnatal lung function is unencumbered. It is now well established that lung maturation as measured by surfactant protein production differs between females and males.8,29,30 As early as 1968, sex differences in the incidence and severity of RDS were recognized.18 Miller and Futrakul were the first to suggest that these differences in outcomes may be due to variations in surfactant metabolism.18 It was also postulated that male fetuses have a delay in surfactant synthesis during late gestation.6,29,31 These findings are supported by the fact that lung phospholipid profiles – lecithin/sphingomyelin (L/S) ratio, the percent of desaturated lecithin, phosphatidylglycerol (PG), and phosphatidylsitol, all markers of lung maturation – are reduced in males.6 During the saccular period of fetal lung development between 26 and 36 weeks of gestation, there is thinning of the respiratory epithelium, growth of lung acini, and the development of the capillary network necessary for gas exchange.28 Type II epithelial cells mature and biosynthesis of surfactant increases.28 Surfactant production is accelerated by a number of hormones, the best studied of which are glucocorticoids. Surfactant synthesis is controlled by complex cell-to-cell interactions between pulmonary fibroblasts and type II epithelial cells. When pulmonary fibroblasts are exposed to glucocorticoids they release fibroblast pneumocyte factor (FPF), an oligopeptide, which subsequently induces the type II cells to mature and rapidly synthesize and secrete surfactant.8,32 This is the basis for antepartum use of glucocorticoids to prevent or modulate RDS in premature infants.33 Additionally, estrogen, prolactin, ACTH, thyroxin, and catecholamines have been shown to augment pulmonary surfactant production.8,34–36 Earlier production of surfactant results in increased airway patency and flow rates in females and female newborns are less likely to develop transient tachypnea or RDS.37

The Role of Sex Hormones on Lung Physiology and the Development of RDS Hormonal differences are present in the fetus as early as 14–20 weeks.17,35 Estrogens and androgens have been examined as potential factors that affect fetal lung maturation. Animal studies reveal that following the administration of 17-estradiol, the lung lavage of newborn rabbits showed

37

increased levels of phosphatidylcholine production and an elevated phosphatidylcholine/sphingomyelin ratio, suggesting that estrogen may play a role in hastening fetal lung maturation and surfactant production.17,35,38 More extensive investigation has focused on the role of androgens. Circulating androgens, specifically dihydrotestosterone (DHT), inhibit the production of fetal surfactant at least in part by antagonism of glucocorticoid-induced fibroblast-epithelial cell inter­actions.8,39 When cortisol is added to fetal rat lung tissue culture it stimulates the synthesis of phosphatidylcholine via fibroblast-type II cell interaction mediated by FPF. However, when the cultures were pre-treated with DHT and then challenged with cortisol, there was no cortisol-stimulated phosphatidylcholine synthesis. This led investigators to conclude that androgens inhibit cortisol stimulated phosphatidylcholine production by interfering with the fibroblast-type II epithelial cell interaction, thereby reducing surfactant production.40 Additionally, maternal dexamethasone treatment in guinea pigs appears to increase the level of plasma cortisol in females, but decrease cortisol levels in males, indicating that the response to synthetic glucocorticoids might be sex-specific.41,42 The clinical significance of these findings is found in lower female morbidity and mortality in RDS.

Postnatal lung growth Early postnatal life is a period of rapid growth and development of the airways, alveoli, and vasculature. These structures have their own patterns of growth that are distinct with respect to number, size, and complexity.10,43,44 Differences in airway structure and function place males at greater risk of morbidity and death from respiratory dysfunction throughout early childhood.44–46 Although males have larger lung volumes compared to girls of the same height47 due to an increased total number of alveoli,48 females have higher sizecorrected flow rates,44–46,49,50 reduced resting airway tone,51 lower specific airway resistance (sRaw), and higher specific airway conductance (sGAW).2,4,42 When sex differences with regards to the degree of lung maturation are coupled with biochemical differences such as surfactant production during the gestational period, one begins to understand why the incidence, prevalence, and mortality of RDS are higher in boys.

Sex Differences in Alveolar and Airway Development A major development in the lungs at birth is a rapid increase in functional residual capacity (the amount of air left in the lungs at the end of a passive respiration) as a result of breathing air. This change is accomplished by an increase in the number of alveoli at birth. It has been estimated that there are 50 million alveoli present at birth21 (range 17–70 million)10,52 and they rapidly multiply during the first 2 years of life.48

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s e c t i o n 1     Gender and Normal Development l

In 1982 Thurlbeck reported findings from the examination of 56 children (36 boys and 20 girls) aged 6 weeks to 14 years who died as a result of trauma or acute illnesses.48 Alveolar size and the number of alveoli per unit area did not differ between boys and girls of the same height. However, the lungs of girls were smaller than those of boys of the same stature. He concluded that this sex difference is explained by the larger total number of alveoli and larger surface area of alveoli in boys compared to girls.48 He also found that boys have more respiratory bronchioles than girls.48 The airways follow a different pattern of growth from the alveoli. Normally, bronchial formation, branching, and the ratio of large to small airways are complete by the end of the pseudo-glandular period (16 weeks gestation). Hence, the number of conducting airways is fixed at birth. Thereafter the airways increase in size and complexity. Conversely, alveolar formation does not commence until late in gestation during the saccular phase (26 weeks) and alveoli continue to increase in size, number, and complexity, resulting in a doubling of the lung volume in the first 6 months of life and tripling by 1 year of age.43 Females have proportionately larger airways relative to lung parenchyma size during early childhood.44,53 Sex-related differences in airway diameter, tone, and resistance are important risk factors for numerous respiratory diseases in childhood and they explain differences in prevalence and severity of a variety of pulmonary diseases.

Lung Function in Infancy and Childhood Lung growth in children occurs in a dysanaptic manner. Specifically, airways grow more slowly than does the lung parenchyma (dysanapsis).54 This phenomenon has been used to explain some of the differences between males and females in lung function during infancy and early childhood. In addition to the female advantage with respect to RDS in premature infants, sex also plays a role in airway function in healthy preterm infants. Stocks et al. measured forced expiratory flow rates in 56 preterm infants matched for birth weight, gestational age, postnatal age, weight, and length.50 The study results revealed that girls have a 20% higher maximal flow at functional residual capacity (VmaxFRC) and 10% lower respiratory system resistance (Rrs), although the difference failed to reach statistical significance due to small sample size.50 Increased flow rates and reduced resistance corrected for lung size in girls have been demonstrated in other studies.44,55 Taussig et al. obtained partial and maximal expiratory flow-volume curves on 47 healthy children between 3 and 13 years of age. The investigators demonstrated that girls had significantly higher size-corrected flows at VmaxFRC after deep inspiration.44 They concluded that these differences in the mechanical properties of the airways are related to the sex of the child and the degree of resting airway tone.44 In longitudinal studies of lung growth, Hibbert confirmed

findings of previous studies showing that girls generated higher absolute and size-corrected maximal expiratory flow rates, although by approximately 18 years of age there was a reversal in that males had higher volume-corrected flow rates.45 These studies show that while lung size is greater in boys, girls generate higher forced expiratory flow rates, suggesting they have larger airways. As children grow, lung function increases with height.4 During puberty, thoracic height increases twice as rapidly in boys.56 Additionally, thoracic width in boys increases during adolescence while no significant change is noted in girls.56 This pattern of thoracic growth results in approximately 25% greater lung function in males than in females of identical height during late adolescence.56

Lung disorders of childhood Asthma Asthma, the most common chronic disease of childhood, is a complex disorder characterized by acute and remitting exacerbations of wheeze, cough, shortness of breath, and chest tightness. These symptoms result from airway narrowing secondary to airway inflammation, bronchoconstriction, and airway hyperresponsiveness. The reason that some children develop asthma while others do not is under intensive investigation. Host or genetic susceptibility, environmental exposures both pre- and postnatally, as well as sex-related physiologic differences in the airways play significant roles. Host susceptibility may be greater in males than females before puberty.57 Asthma often begins in early childhood and male sex is a known risk factor.58 Males under the age of 6 years have a higher prevalence of asthma and wheeze.59–61 By some estimates young boys have 1.5–2.0 times the incidence of lower respiratory tract illnesses.62,63 The increased morbidity from lower respiratory tract disease in boys is in part due to narrower airways resulting from increased resting airway tone44 and dysanaptic lung growth. Boys have lower expiratory flow rates at any given lung volume.54 Between the ages of 6 and 15 years gender-related differences in the prevalence of asthma decrease and by late adolescence the incidence, prevalence, and morbidity associated with asthma begins to reverse and rise in females.64,65 Additionally, there is evidence that males have more airway hyperresponsiveness to methacholine in early childhood, with females having more hyperresponsiveness during adolescence.66,67 Young adult females report more asthma symptoms, have more hospitalizations, use more asthma medications, and describe an increased burden of disease.61,68,69 While many studies show that young boys wheeze more frequently than young girls and have lower expiratory flow rates (particularly mid maximal expiratory flow [MMEF] and forced expiratory flow at 75% of vital capacity [FEF75%]), Sennhauser and Kuhni revealed that even at

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ages when there were no significant differences between males and females in symptoms, boys were twice as likely to be diagnosed with asthma.61 This may be explained by: 1. Reporting bias on the part of parents, with symptoms in boys getting reported more frequently particularly if they are perceived to interfere with physical activity. 2. Variable or atypical presenting symptoms in girls (boys tend to have wheezing as a predominant presenting symptom while girls have more nonspecific symptoms). 3. Subconscious diagnostic bias on the part of physicians. There are several well-publicized studies examining the effect of gender on physicians’ diagnosing and managing acute and chronic diseases. In studies of coronary heart disease, investigators showed that the patient’s gender independently influenced physicians’ recommendations for cardiac catheterization even after controlling for symptoms.70,71 In Utero Tobacco Smoke Exposure and Asthma The phenotypic expression of asthma is determined by complex interactions between genes and the environment. Children who are exposed to tobacco smoke in utero are at increased risk of developing abnormal lung function.63,72–76 In a prospective cohort study of the environmental influences on the development of asthma, Young et al. demonstrated reduced maximal expiratory flows at functional residual capacity (VmaxFRC) in both males and females who were exposed to cigarette smoke in utero.63 Boys, however, had consistently lower lung function than girls.63 Li et al. confirmed that children with in utero exposure to maternal smoking independent of environmental tobacco smoke (ETS) exposure postnatally had abnormal lung function in infancy that persisted through adolescence.74,77 Moreover, boys who were exposed to in utero tobacco smoke showed significantly greater peak expiratory flow variability, suggesting increased airway hyperresponsiveness.78 Specific deficits in lung function associated with in utero exposure to tobacco smoke include reductions in small airway flow rates, namely MMEF and FEF75%. The lung function reduction that is related to in utero tobacco smoke exposure is substantially greater than the reductions seen when children are exposed to postnatal maternal or paternal smoking.73 The exact mechanism of the increased susceptibility in boys to in utero tobacco smoke is unknown. Childhood and Teen Smoking Cigarette smoking by children and teens remains prevalent79 and has been associated with new onset asthma in adolescents. Gilliland reported that among adolescents who reported smoking 300 or more cigarettes per year (regular smokers), the relative risk for the development of asthma was 3.9.80 Regular smokers who were also exposed to tobacco smoke in utero had the largest relative risk (8.8) for new onset asthma. Recent work reveals that the risk of recurrent

39

wheeze or asthma is greater in males who smoke compared to females.81 This finding was attributed to differences in airway lability between boys and girls. It was postulated that females with airway lability are less likely to smoke whereas males smoke irrespective of their level of airway lability.82 There is emerging evidence that early smoking confers an increased risk for the development of lung cancer independent of the number of years of smoking or number of packs per day.83,84 Sex-related differences in lung growth may play a role in the observation that males and females differ in their lung cancer risk for a given level of smoking.85 Females experience lung growth until approximately 18 years of age while males continue to have lung growth through their mid 20s. There is thought to be a critical period in which tobacco carcinogen exposure during the period of lung growth increases one’s susceptibility to lung cancer. It has been suggested that tobacco carcinogen exposure during pulmonary cellular proliferation can alter epithelial cells in the airway and later lead to the development of a malignancy.86 Because lung growth plateaus earlier in females than males, if the initiation of smoking occurs in late adolescence, it has been proposed that females may have a lower probability of inducing mutations that have malignant potential.85 Atopy The immunologic response of the body that results in IgE antibody production after exposure to allergens in one’s environment is termed atopy. IgE development has been shown to increase with age and several studies have shown that males have higher IgE levels and atopy rates than females.87 Male sex is associated with higher IgE levels at age 6 months and this higher level persists at age 2 and 4 years.87 However, the relationship between atopy, asthma, age, and sex is a complicated one with findings dependent on the window of time that these factors are examined. Prenatal and early life events are crucial in programming the infant’s immune system. The immune environment of a fetus is tilted toward the TH2 response, one that favors the development of atopy, allergy, and asthma resulting from the production of cytokines, IL-4 and IL-10, by the amnion and placenta.88 The TH2 tilt is maintained during early postnatal life, a time when chronic exposure to a number of antigens could result in consolidation of TH2 memory. Children who are at risk for the development of asthma and allergic disorders have delayed maturation in their capacity to develop TH1 cytokines such as interferon gamma (IFN).88 Studies indicate that T-lymphocytes in the cord blood of infants born to atopic mothers are capable of responding to allergens and aeroallergens.89 This finding suggests that fetal programming by the mother contributes to the increased prevalence of allergy and asthma in children born to mothers with allergies and asthma. It also explains why the history of maternal asthma has greater influence on the child’s outcomes than paternal asthma.

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s e c t i o n 1     Gender and Normal Development l

The risk of developing asthma is related to the age of onset of atopy. Those who were atopic in early life are at a higher risk of developing respiratory disease than those who acquire atopy later.90 Examining the relationship between atopy and allergic sensitization and asthma has been the focus of a number of studies as a way of explaining the gender differences in the prevalence of asthma. In a populationbased birth cohort, investigators demonstrated that total IgE levels increased over the first 4 years of life in boys and girls. The increase was much higher in boys at both 2 years and 4 years of age even though there were no sex-specific differences noted in cord blood concentrations of IgE.87 Another birth cohort of 662 children in New Zealand was examined for the association between asthma in childhood and allergic sensitization demonstrated by skin prick testing to common aeroallergens.91 Boys and girls who were 13 years of age participated in the study. The proportion of boys with a diagnosis of asthma was 1.6 times higher than that of girls and the prevalence of having an asthma diagnosis increased with increasing numbers of positive skin tests.91 Boys were more likely to have a positive skin test.91 Other studies confirm a higher prevalence of atopic sensitization in boys.92 In a twin study examining the contribution of genetic susceptibility, environmental exposures, and the sex of the child to the development of asthma and other atopic diseases, Lichtenstein et al. demonstrated gender differences in disease manifestation with boys having two times the risk of being diagnosed with asthma and hay fever.93 On the other hand, girls were diagnosed with eczema more frequently. This has been seen in other studies.94 The different manifestations might be explained by differences in environmental exposures or differences in the types of physical activity. The fact that boys have more airway symptoms can be ascribed to physiologic differences in airway caliber, tone, and growth. Not all studies show an association between gender and atopy. Anderson et al. followed a birth cohort through age 23 years and showed similar ratios for the incidence of asthma with males 0–7 years of age having a ratio of 1.23 and rising to 1.48 between the ages of 12–16 years. The ratio reversed to 0.59 in the 17–23 year group. In this study reports of hay fever or eczema each increased the subsequent incidence of asthma with the highest incidence of asthma among those reporting both eczema and hay fever independent of gender. The investigators concluded that gender differences seen in the incidence of asthma vary by age and are not explained by differences in the occurrence of atopy.64 Hormonal Influences As children get older, there is a reversal in the male:female ratio of asthma, with a female predominance.64,95 Factors that influence changes in the prevalence of asthma are being investigated. One factor that could play a role in the reversal of prevalence of asthma between boys and girls is hormonal changes that occur during puberty and at the onset of

menstruation, although studies have yielded inconsistent results. Airway function is influenced by variations in sex hormone levels in relation to menses, the use of oral contraceptives, and pregnancy. In older women, menopause and postmenopausal hormonal changes affect ventilatory function.2 Premenstrual aggravation of asthma has been reported in many women. Using questionnaires and twice daily peak expiratory flow measurements to evaluate the effects of the menstrual cycle on asthma symptoms and flow rates in women with asthma, 40% reported premenstrual worsening of asthma symptoms confirmed by peak flow recordings.96 This finding was confirmed in a US study.97 To determine whether there is a relationship between phases of the menstrual cycle and asthma exacerbations resulting in emergency department visits, investigators surveyed 182 females, the youngest age of whom was 13 years. Information was collected regarding the asthma exacerbation, treatment, presenting peak expiratory flow rate, and the phase of the menstrual cycle. The investigators demonstrated that 46% of women coming to the ED with an asthma exacerbation were in the perimenstrual phase of the cycle and concluded that monthly variations in sex hormones levels associated with the premenstrual period may influence the severity of asthma in adult females.97 However, Zimmerman et al. found that women were more likely to present to the ED with an asthma exacerbation during the preovulatory phase and that few women cited menses as an important trigger of their asthma.98 The adverse effect of estradiol on asthma can be mitigated by the use of progesterone.99 When women with severe premenstrual exacerbations of asthma were treated with intramuscular progesterone, better control of asthma was achieved.99 Others have examined the link between asthma and estrogens in women, demonstrating that postmenopausal women who never used replacement hormone therapy had a significantly lower age-adjusted risk for developing asthma compared to premenopausal women.100 Among women who were current users of estrogens, there was a positive dose–response relationship between the daily dose of estrogens and the risk of developing asthma.100 Finally, the influence of the menstrual cycle on reactivity to skin-prick testing has been investigated. Preliminary results show that in both atopic and nonatopic women there is a significant increase in the size of the skin reaction on days of the menstrual cycle corresponding to peak estrogen levels associated with ovulation.101 These studies suggest that hormonal changes associated with the menstrual cycle can have an important impact on asthma symptoms, lung function, and skin reactivity and is an important area for future clinical and mechanistic research.

Cystic Fibrosis Cystic fibrosis (CF) is the most common life-threatening, autosomal recessive disease in North America and Europe.102 The disorder has variable phenotypic manifestations.103

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The CF gene, CF transmembrane conductance regulator (CFTR), is located on the long arm of chromosome 7 and codes for a cyclic adenosine monophosphate-dependent (cAMP) chloride channel found in membranes of cells that line the airways, pancreas, liver, intestines, reproductive tract, and skin. Defects in CFTR caused by CFTR gene mutation can lead to the clinical manifestations of CF. In the presence of impaired chloride transport, a milieu for bacter­ ial colonization emerges. In the case of CF, Staphylococcus aureus, Pseudomonas aeruginosa, and Burkholderia cepacia complex have been shown to be frequent and virulent colon­ izers. In severe cases, CF is characterized by progressive pulmonary disease and pancreatic insufficiency that leads to intestinal malabsorption.104 In the most recent report from the CF Foundation (CFF) Patient Registry, there are 24 511 patients receiving care at a CF foundation-accredited care center in the United States and of those, 52% are males.105 Morbidity and mortality vary with age at the time of diagnosis, genotype, nutritional status, fitness, colonizing organisms, co-morbid conditions, and severity and progression of lung disease resulting in loss of lung function.106–111 The median survival age for females is 3–4 years less than for males.107 According to the 2007 annual data report published by the CFF, the predicted median survival age has increased since 1985 from 25 years of age to 37.4 years in 2007.105 However despite the increase in life expectancy, mortality among females between the ages of 1 and 20 years consistently exceeds that of males.107,111 The fact that higher mortality rates for females are seen in this age group and then subsequently dissipate suggests that factors operating in early life result in earlier death of females. Although sex differences in mortality rates are well described, the reason for the survival advantage among males with this disease is not well understood. Factors Contributing to the Gender Gap in Cf Survival Age at Diagnosis Previous studies have shown that children who are diagnosed with CF at an early age have improved outcomes because of better maintenance of lung function and improved nutritional status.112 A 12-year review of the CF Foundation Registry examined the gender gap with respect to delayed diagnosis in females in the United States.110 Lai et al. reported that of the 11 275 newly diagnosed patients with CF between 1986 and 1998, 70% were identified on the basis of symptoms other than meconium ileus. The most common clinical presentations were combined respiratory and gastrointestinal symptoms (36%), predominantly respiratory symptoms (22%), and predominantly gastrointestinal symptoms (22%). Among these groups, females were diagnosed at significantly older ages (median age of 12.7 months) compared to males (median age 8.7 months). When respiratory symptoms were the predominant manifestation

41

of the disease, the gender gap was most striking with girls being diagnosed a median of 18 months later than boys.110 There was no statistically significant difference between girls and boys among factors that might impact survival such as genotype, acquisition of Pseudomonas aeruginosa, and radiographic findings. In a subsequent study of age at diagnosis in the United Kingdom, McCormick showed that while females who presented with respiratory symptoms alone were diagnosed significantly later (9 months) than boys, there were no differences in clinical outcomes between males and females.102 Given the prevalence of respiratory symptoms in boys in early childhood due to factors such as dysanaptic growth of the airways and airspaces discussed earlier in the chapter, physicians may be more aware of symptoms in boys and refer them for diagnostic evaluation earlier in the course of symptoms, resulting in earlier diagnosis for boys. There also may be sociocultural differences in the way parents perceive symptoms between boys and girls that lead them to seek care earlier for boys. Lai points out that it is unclear that the delay in diagnosis has a significant impact on survival.110 However, the delay occurs during the first year of life during a time when early intervention might have a more significant impact on disease course and survival.110 Pulmonary Function Given the male disadvantage with regards to morbidity from lung disease and diminished airway function particularly in the first 6 years of life, the fact that males have a survival advantage in CF is somewhat surprising. Chronic progressive, suppurative lung disease is the predominant cause of morbidity and death in CF. The rate of decline of lung function varies widely. To further investigate the rate of decline, Corey et al. studied 366 patients who had at least two measures of lung function, with at least one occurring prior to age 10 years. Females, patients who died before 15 years of age, and those with pancreatic insufficiency had significantly greater rates of lung function decline.113 In a subset of 197 who were genotyped, the rate of decline was greater in those who were homozygous for the  F508 mutation. Patients who died before 15 years of age had a rate of decline in FEV1 of 9.16% predicted per year compared to 1.79% predicted per year for survivors.113,114 Of note, among those who died before 15 years of age, many had normal pulmonary function test in early childhood.113 A review of data from the CF registry revealed that girls have significantly lower FEV1 from age 6 to 15 years of life, similar FEV1 from 16 to 20 years, and better lung function thereafter compared to boys.115 The impact of early diagnosis on pulmonary function was studied in a cohort of children with CF who were diagnosed between 1982 and 1990 and who were categorized as either early asymptomatic or early symptomatic diagnosis if diagnosed before 6 weeks of

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life; or as later asymptomatic or later symptomatic diagnosis if the diagnosis was made from 6 weeks to 36 months. The study showed no differences in pulmonary function among the four groups, but children in the early asymptomatic group who were born in 1987 or later had higher FEV1 compared with the other groups, suggesting that children who were born more recently may have better pulmonary function throughout early childhood.116 Despite major improvements in lung health, the data show that the rate of decline in FEV1 has not changed significantly in recent decades. Future studies will be required to assess the impact of new therapies on lung function and survival in CF.

organism.121 Lewin et al. also demonstrated that patients with CF who become colonized with B. cepacia complex have higher mortality rates in the year after acquisition of the organism, with 30% of female patients dying compared to 21% of males.120 They also reported lower lung function in the three years prior to and two years following the date of first acquisition, with the impact on lung function in females being significantly greater than in males. In this study, it appears that only females colonized with B. cepacia complex had increased mortality compared with controls and compared with males who were colonized with the organism.120

Bacterial Colonization Another possible explanation for the increased mortality among females with CF is the significantly higher prevalence111 of Pseudomonas aeruginosa, a common colonizing organism in CF. This colonization in girls precedes colonization in boys. Once P. aeruginosa is repeatedly recovered in sputum from the lower respiratory tract, it is difficult to eradicate. The mucoid type of P. aeruginosa that is frequently associated with CF leads to poorer clinical status, worsening lung function, and poorer survival.117,118 Demko et al. demonstrated that the median age for the acquisition (initial positive culture) of mucoid P. aeruginosa was 7.4 years for girls and 8.4 years for boys. The median age of chronic colonization is 9.5 years for girls compared with 11.2 years for boys. Additionally, children under the age of 6 years who are chronically colonized with mucoid P. aeruginosa have worse chest radiographic scores and significantly higher mortality rates.117 In children older than 6 years of age, chronic colonization was associated with lower lung function. Colonization with mucoid P. aeruginosa is associated with significantly worse clinical outcomes, irrespective of gender. While this study showed that girls acquired and became chronically colonized with mucoid P. aeruginosa at an earlier age, this finding did not fully explain the gender gap in CF survival.117 Burkholderia cepacia complex is another colonizing organism found in patients with CF. Its clinical course is quite variable with early reports of rapid deterioration, particularly in females, after acquisition of the organism.119–122 Isles describes three outcomes after colonization with B. cepacia:

Dietary Intake, Nutritional Status, and Fitness It has been postulated that differences in dietary intake, nutritional status, and fitness between males and females could explain the gender differences in survival. Rosenfeld found that among young children, the height and weight percentiles were similar for both sexes. Females bettered males between the ages of 16 and 25 years, but this nutritional advantage did not translate into improved survival.111 Several authors report similar outcomes.117 When the level of fitness of patients has been examined as a possible factor to explain the mortality gap between males and females in CF, investigators have found that cardiovascular fitness predicted survival better that FEV1. Females achieved a lower peak work load relative to their male counterparts.123 When Nixon et al. used exercise testing to determine the relative risk of mortality from CF they found that patients with the highest levels of aerobic fitness (VO2 peak  82% predicted) had an 83% survival rate at 8 years, compared with those in the mid range (VO2 peak  59–81% predicted) with a 51% survival rate and those in the low range (VO2 peak 58% predicted) with a 28% 8-year survival rate.123 They concluded that patients with higher levels of fitness were three times more likely to survive compared with the group with low levels of fitness.123 Resting energy expenditure is increased by 4–33% in patients with CF.124 In a study of 25 prepubertal children, aged 5–10 years, with pancreatic insufficiency and an FEV1   60% predicted, Zemel et al. demonstrated that boys experienced a decline in growth status and pulmon­ ary function without a significant change in resting energy expenditure.124 Girls had an increase in resting energy expenditure, decline in growth status, but no change in pulmonary function. These findings suggest that measurement of pulmonary function may not be indicative of nutritional requirements and energy balance in girls. Pubertal growth spurt in children with CF is often delayed and attenuated.125 Although the degree of growth retardation that occurs in males is greater, it is not affected by the genotype. Girls who are homozygous for F508 experience later growth spurts compared to girls with one or more other CF mutations. Interestingly, while the timing

1. An unchanged clinical course following colonization with the organism. 2. A progressive decline in pulmonary status. 3. A rapid, fulminant clinical decline resulting in death. The investigators reported 7 deaths among 18 patients colonized with B. cepacia complex compared with 4 deaths among 67 patients with CF who had not acquired the organism.119 In a study closely matched on parameters that characterized disease severity, Tablan et al. found that 49% of patients died in the first year following acquisition of the

C h a p t e r 3     Gender Differences in Pediatric Pulmonary Disease l

of the growth spurt is affected by genotype, the final adult height of girls is less affected than in boys.125 Cystic Fibrosis-Related Diabetes (CFRD) Diabetes contributes significantly to CF-related morbidity and mortality126 and may play a substantial role in differences in CF survival.127 Cystic fibrosis-related diabetes affects 20–30% of patients with CF and is associated with exaggerated loss of lung function, decreased body mass index (BMI)128,129, and increased likelihood of acquiring Pseudomonas infection.129 There are reports indicating that females with CFRD have significantly lower survival compared to females without CFRD and males with CF regardless of CFRD status.130 A survival analysis of patients with CF performed to determine the impact of the development of CFRD on survival revealed that females with CFRD who had fasting hyperglycemia have a lifespan 17 years shorter than females with CF but without CFRD and all males with CF.127 Sims et al. reported that the FEV1 of females with established CFRD who were not colonized with Pseudomonas was 20% lower than sex-matched controls.131 This was not true in males, suggesting that CFRD in combination with female sex has an adverse impact on outcomes. In females with newly diagnosed CFRD, the decline in lung function does not occur in the first 12 months after CFRD diagnosis, suggesting that early intervention after CFRD diagnosis might reduce the decline in lung function.131 It has been postulated that an interaction between hormones and diabetes via an inflammatory mechanism may be responsible for these findings since sex differences in survival did not appear until after puberty. Whether estrogen contributes to reduced survival or testosterone is protective is unclear.127 Sex Hormones In animal models, sex hormones play a role in the expression of CFTR. Mutations in CFTR result in defective cAMP-mediated chloride secretion and increased sodium absorption, leading to abnormal airway surface liquid and reduced mucociliary clearance. This creates an environment conducive to bacterial infection. Sweezey et al. demonstrated that sex hormones, androgen and estrogen, differentially influence gene expression and functional activity of CFTR in rat lung models.132 Androgens increase,132 while estrogens decrease,132,133 the functional activity of the CFTR chloride channel. Others have shown that estrogens are responsible for cyclic changes during the menstrual cycle in the number of airway goblet cells, thereby affecting airway physiology in females with CF.134 Although the mechanisms by which sex hormones affect CFTR have not been fully delineated, it has been postulated that small changes in the functional activity of CFTR caused by androgen stimulation and/or estrogen inhibition may be sufficient to explain the survival difference between males and females with CF.

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The gender gap in CF mortality is multifactorial. While age at diagnosis, rate of decline in pulmonary function, colonizing organisms, nutritional status, presence of co-morbid conditions such as CFRD, and level of fitness all play a role in determining CF survival, they do not fully account for the poorer survival among females. More studies are needed to better delineate the factors that may play a key role in CF survival.

Sleep Disorders Parasomnias Parasomnias are common sleep disorders in children. They are considered transient and often disappear during adolescence. Although not a medical condition per se, parasomnias can cause major disruption in sleep.135 Night terrors, leg restlessness, sleepwalking, somniloquy, enuresis, body rocking, and sleep bruxism are the most common parasomnias of childhood. It is estimated that over 75% of children between the ages of 3 and 13 years have had at least one parasomnia.136–138 A brief description of common parasomnias of childhood is listed below: Night terrors are disorders of arousal that occur early during the night and are associated with the feeling of extreme panic or fear, a loud piercing scream during sleep, and motor activities such as hitting objects.135 Leg restlessness has been considered a parasomnia of adulthood and there are currently no specific diagnostic criteria for children. Generally, it presents with insomnia and leg restlessness at bedtime. Symptoms are described as worsening with rest and temporary improvement is noted with activity.137 During a sleepwalking episode, the child performs a series of complex behaviors that can result in wandering aimlessly during sleep. Behaviors can range from sitting up in bed to going outdoors.137,138 Somniloquy consists of talking during sleep. It is the most frequent parasomnia in children. Enuresis (bedwetting) is characterized by the presence of involuntary micturition during sleep in children with normal bladder control when awake. Enuresis is diagnosed as an abnormal condition when persistent bedwetting occurs after 5 years of age.137 Nocturnal body rocking represents rhythmic movements of the axial muscles in the back and forth or right and left motion occurring mostly during the transition from wakefulness to sleep.137 Sleep bruxism is characterized by grinding or clenching of the teeth during sleep. In a longitudinal cohort study of dyssomnias and parasomnias, Petit et al. report that at age 6 years, boys were significantly more likely than girls to experience sleepwalking and enuresis.138 Although the peak occurrence for sleep walking is 11–12 years of age, there are reports emerging

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of increased incidence in younger children.139 Differences between males and females in the prevalence of enuresis among 5- and 6-year-olds are well established.1,137,140,141 A longitudinal study of children ages 6–16 years demonstrated that girls at age 11 years experienced leg restlessness significantly more than boys (p  0.05), boys were three times more likely to have enuresis compared to girls (p  0.001), and significantly more boys were somniloquists (p  0.05).137 The reasons for the gender differences noted in parasomnias are unclear. Obstructive Sleep Apnea Hypoventilation Syndrome Obstructive sleep apnea hypoventilation syndrome (OSAHS) is a relatively common disorder characterized by recurrent episodes of upper airway narrowing and/or collapse resulting in either complete or partial airflow obstruction. The physiologic response to OSAHS is hypoxemia, hypercapnia, recurrent arousals, and sleep disruptions.142 It is estimated that 2–24% of the adult population is affected by OSAHS, and as such, it is a significant public health problem.143–146 Gender differences in the prevalence of OSAHS have been well characterized in the adult population, with women having overall lower prevalence rates (2–9%) than men (4–24%).147 The initial studies of OSAHS reported that few women, approximately 4–12% of the cases, were affected by the disorder.148 Other studies indicated that the male to female ratio for the disorder varied from as high as 60:1 to 8:1.149–151 More recent rigorous studies reveal that the male and female ratio may be closer to 2:1 with a prevalence in women of 2% and 4% in men.152,153 The wide range of prevalence rates as well as lower than expected ratio of men to women in some studies raises the question of whether the increased prevalence in men that has been widely reported is due to underreporting of symptoms by women, differences in clinical presentation leading to fewer referrals for formal evaluation and polysomnography testing in women, or subconscious selection bias on the part of physicians because they perceive that there is a much higher prevalence of the disorder in males and are more likely to refer males for evaluation. As shown in other chronic disorders such as asthma61,154 and cardiovascular disease,70,71 females may present with nonspecific symptoms that do not get recognized, may not report symptoms at the same rate as males and may, in fact, have symptoms that go untreated for a longer duration than males. To determine if women with sleep apnea have unique symptoms or complaints compared to men, Redline et al. examined two groups: a clinical sample of 36 patients (31 males, 5 females) who had been referred for polysomnography with confirmed OSAHS; and a community sample of 65 patients (41 males, 24 females) who were the friends and family members of the clinical sample found to also have OSAHS. In the clinical sample classical symptoms usually associated with OSAHS (snoring, gasping, daytime somnolence, and apnea that was witnessed)

were equally present in both men and women. In the community sample, however, men were 2–3 times more likely to report the symptoms than women.155 Other studies have confirmed these findings.156 To further test the hypothesis that the male prevalence of OSAHS was due to under-reporting of symptoms by women, Young et al. undertook the Wisconsin Sleep Cohort Study, a community-based study of the natural history of sleep apnea involving 551 men and 388 women.153 Data were obtained via interviews regarding typical sleep apnea symptoms and the degree of sleepdisordered breathing was determined from the frequency of apneic and hypopneic events during sleep as recorded by polysomnography in the laboratory during a full night of sleep. Young et al. showed that women with OSAHS did not report symptoms that differed significantly from those reported by men with the same levels of OSAHS.153 Snoring was the best and most sensitive predictor of OSAHS. The authors concluded that there must be reasons other than differences in the symptoms reported that explain the gender disparity in OSAHS. A closer look at the data reveals that women in the study reported daytime fatigue, morning headaches, anxiety, insomnia, and other signs of depression more frequently than men. These complaints as well as the misguided notion that OSAHS is a ‘male disorder’ could lead clinicians to diagnose depression in women and delay the evaluation and subsequent diagnosis of OSAHS. Pathogenesis Anatomy and Patency of the Upper Airway During Sleep Investigators have focused on sex-related differences in the anatomy and patency of the upper airway, particularly during sleep, as possible explanations for gender differences in the prevalence of OSAHS. Maintenance of upper airway patency depends on a dynamic interaction between pharyngeal muscle activity and airway structure. It has been postulated that despite females having structurally smaller airways, heightened activity of the genioglossus muscle in females could result in better upper airway stability and less likelihood of upper airway collapse during sleep.157 This has not been a consistent finding.158,159 Another study concluded that differences in airway anatomy account for the gender disparities.158,159 Malhotra et al. report that pharyngeal airway length, soft palate area, and pharyngeal volume are greater in men. These findings indicate that the male airway is significantly more collapsible based solely on anatomical differences.158,159 Obesity and Body Fat Distribution Obesity has been clearly shown to be associated with the development of OSAHS. Obesity alone, however, is neither necessary nor sufficient to cause the physiologic abnormalities associated with OSAHS. Female patients with OSAHS are more obese than males147,148,153 and the evidence shows that obesity is a characteristic of young, premenopausal

C h a p t e r 3     Gender Differences in Pediatric Pulmonary Disease l

women with OSAHS. This is not to say that obesity is not a characteristic of males with OSAHS. Body fat distribution in males tends to play a larger role. Upper body obesity, particularly with fat accumulation in the neck, leads to narrowing of the airway and increases the likelihood of airway closure during sleep. Childhood OSAHS While OSAHS in adults has received increasing attention over the past 2–3 decades, it is still an under-recognized and underdiagnosed disorder in children. The prevalence and risk factors for OSAHS in children have not been well studied. It is not clear how the findings in adult-onset OSAHS relate to childhood sleep-disordered breathing. It has been estimated that habitual snoring occurs in 7–12% of children and, as in adults, snoring is the most common presentation of OSAHS in children.160,161 However, not all children who snore have OSAHS with physiologic abnormalities such as hypoxemia, hypercapnia, sleep disruption, and daytime somnolence. Ali et al. estimated that 0.7% of the general childhood population has significant sleep-related breathing disorders,160 although in another study OSAHS was found in 2.9% of children 6 months to 6 years of age.161 To determine the prevalence of OSAHS and the signs and symptoms that could lead to early diagnosis of OSAHS, Chay et al. undertook a three-phase study of Singapore schoolchildren (age 1–18 years). Initially 3671 children referred for obesity were screened by questionnaire. From the initial 3671 children, those who had a percent ideal body weight 180 and those reporting symptoms that were suggestive of OSAHS were recalled for further evaluation. A total of 146 children underwent polysomnography and 26 of the 146 had abnormalities on sleep study. Chay concluded that the prevalence in the general population of OSAHS was 0.7%, similar to findings in the Ali study.162 Risk Factors The major risk factors in adults for OSAHS include male sex (on the basis of both anatomical and physiologic differences), obesity, aging, alcohol use, craniomandibular anomalies, familial predisposition, menopause, and chronic rhinitis. In children, adenotonsillar hypertrophy, nasal obstruction, craniofacial anomalies, neuromuscular disease, and genetic disorders such as Down syndrome are risk factors for OSAHS.163 These findings are taken from a population of children referred for evaluation of daytime somnolence, behavioral problems, or right heart failure. In adults, obesity as measured by body mass index, neck circumference, and skinfold thickness are strongly related to OSAHS.147 To determine the role of obesity in childhood OSAHS, several investigators undertook small studies with conflicting results. In a 1989 study, Mallory et al. enrolled 41 morbidly obese (mean percent of ideal body weight was 208  42.2) children and adolescents (mean age was

45

10.3  4.4 (SD) years) with a history consistent with sleepdisordered breathing. All of the patients reported snoring; 32% reported apnea. All 41 underwent polysomnography and 37% (15/41) had abnormalities such as apnea, hypopnea, excessive arousals, hypoxemia or hypercapnia. No significant association between gender and any of the physiologic measures on the sleep study was found. The authors concluded that obesity may play a role in OSAHS in childhood, and although the polysomnography abnormalities were mild, they were significant enough to require intervention.164 Similar results were reported in the Singapore study.162 Of the children with polysomnographic evidence of OSAHS, 13.3% were obese.162 Other investigators in 1992 reviewed the charts of 93 patients (18 months to 12 years of age) who had symptoms suggestive of OSAHS. All 93 underwent polysomnography with a similar percentage (36%) of children meeting the polysomnography criteria for OSAHS. No significant differences in age, sex or symptoms were found between the children who were positive for OSAHS by sleep study and the children with normal studies. Surprisingly, obesity was not significantly associated with OSAHS.165 Rosen also showed that the association of OSAHS with obesity in childhood was weak relative to the adult population.142 Unlike in the adult population, the major risk factor for OSAHS in children is adenotonsillar hypertrophy. While many children without OSAHS have enlarged adenoids and tonsils, relatively few of them develop sleep disordered breathing. Tonsillar hypertrophy reduces upper airway caliber, thereby increasing the risk of airway obstruction during sleep. In general, once the child undergoes adenotonsillectomy, many of the symptoms of OSAHS improve or completely resolve. Another important difference between adult and childhood OSAHS is that gender differences in the pediatric population are not as apparent. Girls are as likely to have OSAHS as boys. In a study of 326 children between the ages of 1 and 12 years, Rosen reported that the gender distribution of the children referred to the sleep laboratory and those who were subsequently diagnosed with OSAHS was nearly equal.142 This is consistent with findings from other studies showing no difference in the prevalence of snoring between girls and boys161 and that sex does not significantly impact risk of developing sleep-disordered breathing.166 In a study examining sex-dependent differences in the craniofacial morphology of children with OSAHS, Kawashima showed that boys with OSAHS had larger anterior lower facial height and a more anterior hyoid bone position than girls with sleep disordered breathing, but girls with OSAHS had a sagittally narrower pharyngeal airway space than affected boys. The study suggested that craniofacial skeletal differences in boys with OSAHS placed them at increased risk for sleep disordered breathing problems whereas narrower airways was a risk factor in girls with OSAHS.167 The increased risk of OSAHS later in life in men may start with skeletal differences in

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childhood. This study was limited by small sample size so it is difficult to draw inferences from the data regarding the role of gender in the development of OSAHS in children. The reason that there is such a clear gender-related difference in the prevalence of OSAHS in adults and not in children has not been delineated. It has been suggested that hormonal factors affecting body fat distribution may play a significant role. More studies are needed.

References   1. Touchette E, Petit D, Paquet J, et al. Bed-wetting and its association with developmental milestones in early childhood. Arch Pediatr Adolesc Med 2005;159(12):1129–34.   2. Becklake MR, Kauffmann F. Gender differences in airway behaviour over the human life span. Thorax 1999;54(12):1119–38.   3. Boddy K. Fetal breathing: its physiologic and clinical implications. Hosp Pract 1979;14(2):89–96.   4. Boezen HM, Jansen DF, Postma DS. Sex and gender differences in lung development and their clinical significance. Clin Chest Med. 2004;25(2):237–45.   5. Hepper PG, Shannon EA, Dornan JC. Sex differences in fetal mouth movements. Lancet 1997;350(9094):1820.   6. Fleisher B, Kulovich MV, Hallman M, et al. Lung profile: sex differences in normal pregnancy. Obstet Gynecol. 1985;66(3):327–30.   7. Holt PG, Macaubas C, Cooper D, et al. Th-1/Th-2 switch regulation in immune responses to inhaled antigens. Role of dendritic cells in the aetiology of allergic respiratory disease. Adv Exp Med Biol. 1997;417:301–6.   8. Torday JS, Nielsen HC. The sex difference in fetal lung surfactant production. Exp Lung Res 1987;12(1):1–19.   9. Joshi S, Kotecha S. Lung growth and development. Early Hum Dev 2007;83(12):789–94. 10. Merkus PJ, ten Have-Opbroek AA, Quanjer PH. Human lung growth: a review. Pediatr Pulmonol 1996;21(6):383–97. 11. Whitsett J, Wert S. Molecular determinants of lung morphogenesis. In: V Chernick, T Boat, R Wilmott, A Bush, eds. Kendig’s Disorders of the Respiratory Tract in Children, 7th edn. Philadelphia, PA: Saunders Elsevier; 2006:1–16. 12. Jeffrey PK. The development of large and small airways. Am J Respir Crit Care Med 1998;157(5 Pt 2):S174–80. 13. Kotecha S. Lung growth for beginners. Paediatr Respir Rev 2000;1(4):308–13. 14. Kotecha S. Lung growth: implications for the newborn infant. Arch Dis Child Fetal Neonatal Ed 2000;82(1):F69–74. 15. Thurlbeck W. Pre- and postnatal organ development. In: V Chernick, R Mellins, eds. Basic Mechanisms of Pediatric Respiratory Disease: Cellular and Integrative. Philadelphia, PA: BC Decker; 1991:23–35. 16. Boddy K, Dawes GS. Fetal breathing. Br Med Bull 1975;31(1):3–7. 17. Khosla SS, Rooney SA. Stimulation of fetal lung surfactant production by administration of 17beta-estradiol to the maternal rabbit. Am J Obstet Gynecol 1979;133(2):213–16. 18. Miller HC, Futrakul P. Birth weight, gestational age, and sex as determining factors in the incidence of respiratory distress syndrome of prematurely born infants. J Pediatr 1968;72(5):628–35.

19. Torday JS. The sex difference in type II cell surfactant synthesis originates in the fibroblast in vitro. Exp Lung Res 1984;7(3-4):187–94. 20. Inanlou MR, Baguma-Nibasheka M, Kablar B. The role of fetal breathing-like movements in lung organogenesis. Histol Histopathol 2005;20(4):1261–66. 21. Murray J. Prenatal growth and development of the lung. The Normal Lung. Philadelphia, PA: WB Saunders; 1986, 1–21. 22. Platt LD, Manning FA, Lemay M, et al. Human fetal breathing: relationship to fetal condition. Am J Obstet Gynecol. 1978;132(5):514–18. 23. Inanlou MR, Kablar B. Abnormal development of the diaphragm in mdx:MyoD-/-(9th) embryos leads to pulmonary hypoplasia. Int J Dev Biol 2003;47(5):363–71. 24. Tseng BS, Cavin ST, Booth FW, et al. Pulmonary hypoplasia in the myogenin null mouse embryo. Am J Respir Cell Mol Biol 2000;22(3):304–15. 25. Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child 1959;97(5, Part 1):517–23. 26. Yee WF, Scarpelli EM. Surfactant replacement therapy. Pediatr Pulmonol 1991;11(1):65–80. 27. Griese M. Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J 1999;13(6):1455–76. 28. Kirkpatrick B, Mueller D. Respiratory disorders in the newborn. In: V Chernick, T Boat, eds. Kendig’s Disorders of the Respiratory Tract in Children. Philadelphia, PA: WB Saunders; 1998:328–64. 29. Nielsen HC, Torday JS. Sex differences in fetal rabbit pulmonary surfactant production. Pediatr Res 1981;15(9):1245–47. 30. Torday JS, Dow KE. Synergistic effect of triiodothyronine and dexamethasone on male and female fetal rat lung surfactant synthesis. Dev Pharmacol Ther 1984;7(2):133–39. 31. Nielsen HC, Kirk WO, Sweezey N, et al. Coordination of growth and differentiation in the fetal lung. Exp Cell Res 1990;188(1):89–96. 32. Smith B. Fibroblast-pneumonocyte factor. Intercellular mediator of glucocorticoid effect on fetal lung. In: L Stern, W Oh, B Friis-Hansen, eds. Neonatal Intensive Care. New York: Masson; 1978:25–32. 33. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50(4):515–25. 34. Hitchcock KR. Hormones and the lung. I. Thyroid hormones and glucocorticoids in lung development. Anat Rec 1979;194(1):15–39. 35. Khosla SS, Gobran LI, Rooney SA. Stimulation of phosphatidylcholine synthesis by 17 beta-estradiol in fetal rabbit lung. Biochim Biophys Acta 1980;617(2):282–90. 36. Mendelson CR, Johnston JM, MacDonald PC, et al. Multihormonal regulation of surfactant synthesis by human fetal lung in vitro. J Clin Endocrinol Metab 1981;53(2): 307–17. 37. Dani C, Reali MF, Bertini G, et al. Risk factors for the development of respiratory distress syndrome and transient tachypnoea in newborn infants. Italian Group of Neonatal Pneumology. Eur Respir J 1999;14(1):155–59. 38. Khosla SS, Smith GJ, Parks PA, et al. Effects of estrogen on fetal rabbit lung maturation: morphological and biochemical studies. Pediatr Res 1981;15(9):1274–81.

C h a p t e r 3     Gender Differences in Pediatric Pulmonary Disease l

39. Torday J. Dihydrotestosterone (DHT) uncouples cell interactions in developing lung. Prog Clin Biol Res 1986;217B: 425–28. 40. Torday JS. Dihydrotestosterone inhibits fibroblast-pneumonocyte factor-mediated synthesis of saturated phosphatidylcholine by fetal rat lung cells. Biochim Biophys Acta 1985;835(1):23–28. 41. Dean F, Matthews SG. Maternal dexamethasone treatment in late gestation alters glucocorticoid and mineralocorticoid receptor mRNA in the fetal guinea pig brain. Brain Res 1999;846(2):253–59. 42. Pollak A, Birnbacher R. Preterm male infants need more initial respiratory support than female infants. Acta Paediatr 2004;93(4):447–48. 43. Dezateux C, Stocks J. Lung development and early origins of childhood respiratory illness. Br Med Bull 1997;53(1):40–57. 44. Taussig LM, Cota K, Kaltenborn W. Different mechanical properties of the lung in boys and girls. Am Rev Respir Dis 1981;123(6):640–43. 45. Hibbert M, Lannigan A, Raven J, et al. Gender differences in lung growth. Pediatr Pulmonol 1995;19(2):129–34. 46. Schwartz J, Katz SA, Fegley RW, et al. Sex and race differences in the development of lung function. Am Rev Respir Dis 1988;138(6):1415–21. 47. Hsu KH, Jenkins DE, Hsi BP, et al. Ventilatory functions of normal children and young adults – Mexican-American, white, and black. I. Spirometry. J Pediatr 1979;95(1):14–23. 48. Thurlbeck WM. Postnatal human lung growth. Thorax 1982;37(8):564–71. 49. Leeder SR, Swan AV, Peat JK, et al. Maximum expiratory flow-volume curves in children: changes with growth and individual variability. Bull Eur Physiopathol Respir 1977;13(2):249–60. 50. Stocks J, Henschen M, Hoo AF, et al. Influence of ethnicity and gender on airway function in preterm infants. Am J Respir Crit Care Med 1997;156(6):1855–62. 51. Landau LI, Morgan W, McCoy KS, et al. Gender related differences in airway tone in children. Pediatr Pulmonol 1993;16(1):31–35. 52. Dunnill MS. The problem of lung growth. Thorax 1982;37 (8) :561–63. 53. Tepper RS, Morgan WJ, Cota K, et al. Physiologic growth and development of the lung during the first year of life. Am Rev Respir Dis 1986;134(3):513–19. 54. Green M, Mead J, Turner JM. Variability of maximum expiratory flow-volume curves. J Appl Physiol 1974;37(1):67–74. 55. Pagtakhan RD, Bjelland JC, Landau LI, et al. Sex differences in growth patterns of the airways and lung parenchyma in children. J Appl Physiol. 1984;56(5):1204–10. 56. DeGroodt EG, van Pelt W, Borsboom GJ, et al. Growth of lung and thorax dimensions during the pubertal growth spurt. Eur Respir J 1988;1(2):102–8. 57. Postma DS. Gender differences in asthma development and progression. Gend Med 2007;4(Suppl B):S133–46. 58. Schaubel D, Johansen H, Dutta M, et al. Neonatal characteristics as risk factors for preschool asthma. J Asthma 1996;33(4):255–64. 59. Dodge RR, Burrows B. The prevalence and incidence of asthma and asthma-like symptoms in a general population sample. Am Rev Respir Dis 1980;122(4):567–75.

47

60. Gissler M, Jarvelin MR, Louhiala P, et al. Boys have more health problems in childhood than girls: follow-up of the 1987 Finnish birth cohort. Acta Paediatr 1999;88(3):310–14. 61. Sennhauser FH, Kuhni CE. Prevalence of respiratory symp­ toms in Swiss children: is bronchial asthma really more prevalent in boys? Pediatr Pulmonol 1995;19(3):161–66. 62. Redline S, Gold D. Challenges in interpreting gender differences in asthma. Am J Respir Crit Care Med 1994;150(5 Pt 1):1219–21. 63. Young S, Sherrill DL, Arnott J, et al. Parental factors affecting respiratory function during the first year of life. Pediatr Pulmonol 2000;29(5):331–40. 64. Anderson HR, Pottier AC, Strachan DP. Asthma from birth to age 23: incidence and relation to prior and concurrent atopic disease. Thorax 1992;47(7):537–42. 65. Sweeting H, West P. Sex differences in health at ages 11, 13 and 15. Soc Sci Med 2003;56(1):31–39. 66. Le Souef PN, Sears MR, Sherrill D. The effect of size and age of subject on airway responsiveness in children. Am J Respir Crit Care Med 1995;152(2):576–79. 67. Paoletti P, Carrozzi L, Viegi G, et al. Distribution of bronchial responsiveness in a general population: effect of sex, age, smoking, and level of pulmonary function. Am J Respir Crit Care Med 1995;151(6):1770–77. 68. Gold DR, Rotnitzky A, Damokosh AI, et al. Race and gender differences in respiratory illness prevalence and their relationship to environmental exposures in children 7 to 14 years of age. Am Rev Respir Dis 1993;148(1):10–18. 69. Schatz M, Clark S, Camargo CA Jr. Sex differences in the presentation and course of asthma hospitalizations. Chest 2006;129(1):50–55. 70. Schulman KA, Berlin JA, Harless W, et al. The effect of race and sex on physicians’ recommendations for cardiac catheterization. N Engl J Med 1999;340(8):618–26. 71. Steingart RM, Packer M, Hamm P, et al. Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement Investigators. N Engl J Med. 1991;325(4):226–30. 72. Cunningham J, Dockery DW, Gold DR, et al. Racial differences in the association between maternal smoking during pregnancy and lung function in children. Am J Respir Crit Care Med 1995;152(2):565–69. 73. Gilliland FD, Berhane K, McConnell R, et al. Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function. Thorax 2000;55(4):271–76. 74. Li YF, Gilliland FD, Berhane K, et al. Effects of in utero and environmental tobacco smoke exposure on lung function in boys and girls with and without asthma. Am J Respir Crit Care Med 2000;162(6):2097–104. 75. Lux AL, Henderson AJ, Pocock SJ. Wheeze associated with prenatal tobacco smoke exposure: a prospective, longitudinal study. ALSPAC Study Team. Arch Dis Child 2000;83(4):307–12. 76. O’Connor GT, Sparrow D, Demolles D, et al. Maximal and partial expiratory flow rates in a population sample of 10to 11-year-old schoolchildren. Effect of volume history and relation to asthma and maternal smoking. Am J Respir Crit Care Med, 2000;162(2 Pt 1):436–39. 77. Cunningham J, O’Connor GT, Dockery DW, et al. Environmental tobacco smoke, wheezing, and asthma in children in 24 communities. Am J Respir Crit Care Med 1996;153(1):218–24.

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s e c t i o n 1     Gender and Normal Development l

78. Kuehr J, Frischer T, Karmaus W, et al. Cotinine excretion as a predictor of peak flow variability. Am J Respir Crit Care Med 1998;158(1):60–64. 79. Prevention CfDCa. Tobacco use among high school students – United States, 1997. MMWR 1998;47:229–33. 80. Gilliland FD, Islam T, Berhane K, et al. Regular smoking and asthma incidence in adolescents. Am J Respir Crit Care Med 2006;174(10):1094–100. 81. Strachan DP, Cook DG. Health effects of passive smoking. 6. Parental smoking and childhood asthma: longitudinal and case-control studies. Thorax 1998;53(3):204–12. 82. Rasmussen F, Siersted HC, Lambrechtsen J, et al. Impact of airway lability, atopy, and tobacco smoking on the development of asthma-like symptoms in asymptomatic teenagers. Chest 2000;117(5):1330–35. 83. Doll R, Peto R. Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers. J Epidemiol Community Health 1978;32(4):303–13. 84. Moolgavkar SH, Dewanji A, Luebeck G. Cigarette smoking and lung cancer: reanalysis of the British doctors’ data. J Natl Cancer Inst 1989;81(6):415–20. 85. Wiencke JK, Kelsey KT. Teen smoking, field cancerization, and a ‘critical period’ hypothesis for lung cancer susceptibility. Environ Health Perspect 2002;110(6):555–58. 86. Gold DR, Wang X, Wypij D, et al. Effects of cigarette smoking on lung function in adolescent boys and girls. N Engl J Med 1996;335(13):931–37. 87. Johnson CC, Peterson EL, Ownby DR. Gender differences in total and allergen-specific immunoglobulin E (IgE) concentrations in a population-based cohort from birth to age four years. Am J Epidemiol 1998;147(12):1145–52. 88. Holt PG, Sly PD. Allergic respiratory disease: strategic targets for primary prevention during childhood. Thorax 1997;52(1):1–4. 89. Miles EA, Warner JA, Jones AC, Colwell BM, Bryant TN, Warner JO. Peripheral blood mononuclear cell proliferative responses in the first year of life in babies born to allergic parents. Clin Exp Allergy 1996;26(7):780–88. 90. Xuan W, Marks GB, Toelle BG, et al. Risk factors for onset and remission of atopy, wheeze, and airway hyperresponsiveness. Thorax 2002;57(2):104–9. 91. Sears MR, Burrows B, Flannery EM, Herbison GP, Holdaway MD. Atopy in childhood. I. Gender and allergen related risks for development of hay fever and asthma. Clin Exp Allergy 1993;23(11):941–48. 92. Arshad SH, Tariq SM, Matthews S, Hakim E. Sensitization to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study. Pediatrics 2001;108(2):E33. 93. Lichtenstein P, Svartengren M. Genes, environments, and sex: factors of importance in atopic diseases in 7-9-year-old Swedish twins. Allergy 1997;52(11):1079–86. 94. Wieringa MH, Weyler JJ, Van Bever HP, Nelen VJ, Vermeire PA. Gender differences in respiratory, nasal and skin symptoms: 6-7 versus 13-14-year-old children. Acta Paediatr 1999;88(2):147–49. 95. Schachter J, Higgins MW. Median age at onset of asthma and allergic rhinitis in Tecumseh, Michigan. J Allergy Clin Immunol 1976;57(4):342–51.

  96. Gibbs CJ, Coutts II, Lock R, Finnegan OC, White RJ. Premenstrual exacerbation of asthma. Thorax 1984;39(11): 833–36.   97. Skobeloff EM, Spivey WH, Silverman R, et al. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch Intern Med 1996;156(16): 1837–40.   98. Zimmerman JL, Woodruff PG, Clark S, et al. Relation between phase of menstrual cycle and emergency department visits for acute asthma. Am J Respir Crit Care Med 2000;162(2 Pt 1):512–15.   99. Beynon HL, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet 1988;2(8607):370–72. 100. Troisi RJ, Speizer FE, Willett WC, et al. Menopause, postmenopausal estrogen preparations, and the risk of adultonset asthma. A prospective cohort study. Am J Respir Crit Care Med 1995;152(4 Pt 1):1183–88. 101. Kalogeromitros D, Katsarou A, Armenaka M, et al. Influence of the menstrual cycle on skin-prick test reactions to histamine, morphine and allergen. Clin Exp Allergy 1995;25(5):461–66. 102. McCormick J, Sims EJ, Mehta A. Delayed diagnosis of females with respiratory presentation of cystic fibrosis did not segregate with poorer clinical outcome. J Clin Epidemiol 2006;59(3):315–22. 103. Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996;154(5):1229–56. 104. Wood RE, Boat TF, Doershuk CF. Cystic fibrosis. Am Rev Respir Dis 1976;113(6):833–78. 105. Cystic Fibrosis Foundation, Patient Registry 2006 Annual Report. Bethesda, MD; 2006. 106. Britton JR. Effects of social class, sex, and region of residence on age at death from cystic fibrosis. BMJ 1989;298(6672): 483–87. 107. Davis PB. The gender gap in cystic fibrosis survival. J Gend Specif Med 1999;2(2):47–51. 108. FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993;122(1):1–9. 109. Hudson I, Phelan PD. Are sex, age at diagnosis, or mode of presentation prognostic factors for cystic fibrosis? Pediatr Pulmonol 1987;3(5):288–97. 110. Lai HC, Kosorok MR, Laxova A, et al. Delayed diagnosis of US females with cystic fibrosis. Am J Epidemiol 2002;156(2):165–73. 111. Rosenfeld M, Davis R, FitzSimmons S, et al. Gender gap in cystic fibrosis mortality. Am J Epidemiol 1997;145(9): 794–803. 112. Farrell PM, Kosorok MR, Laxova A, et al. Nutritional benefits of neonatal screening for cystic fibrosis. Wisconsin Cystic Fibrosis Neonatal Screening Study Group. N Engl J Med 1997;337(14):963–69. 113. Corey M, Edwards L, Levison H, et al. Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J Pediatr 1997;131(6):809–14. 114. Davis PB. The decline and fall of pulmonary function in cystic fibrosis: new models, new lessons. J Pediatr 1997;131(6): 789–90. 115. Cystic Fibrosis Foundation, Patient Registry 2001 Annual Report. Bethesda, MD; 2002.

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116. Wang SS, O’Leary LA, Fitzsimmons SC, et al. The impact of early cystic fibrosis diagnosis on pulmonary function in children. J Pediatr 2002;141(6):804–10. 117. Demko CA, Byard PJ, Davis PB. Gender differences in cystic fibrosis: Pseudomonas aeruginosa infection. J Clin Epidemiol 1995;48(8):1041–49. 118. Henry RL, Mellis CM, Petrovic L. Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992;12(3):158–61. 119. Isles A, Maclusky I, Corey M, et al. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984;104(2):206–10. 120. Lewin LO, Byard PJ, Davis PB. Effect of Pseudomonas cepacia colonization on survival and pulmonary function of cystic fibrosis patients. J Clin Epidemiol 1990;43(2): 125–31. 121. Tablan OC, Chorba TL, Schidlow DV, et al. Pseudomonas cepacia colonization in patients with cystic fibrosis: risk factors and clinical outcome. J Pediatr 1985;107(3):382–87. 122. Thomassen MJ, Demko CA, Klinger JD, et al. Pseudomonas cepacia colonization among patients with cystic fibrosis. A new opportunist. Am Rev Respir Dis 1985;131(5):791–96. 123. Nixon PA, Orenstein DM, Kelsey SF, et al. The prognostic value of exercise testing in patients with cystic fibrosis. N Engl J Med. 1992;327(25):1785–86. 124. Zemel BS, Kawchak DA, Cnaan A, et al. Prospective evaluation of resting energy expenditure, nutritional status, pulmonary function, and genotype in children with cystic fibrosis. Pediatr Res 1996;40(4):578–86. 125. Byard PJ. The adolescent growth spurt in children with cystic fibrosis. Ann Hum Biol 1994;21(3):229–40. 126. Finkelstein SM, Wielinski CL, Elliott GR, et al. Diabetes mellitus associated with cystic fibrosis. J Pediatr 1988;112(3): 373–77. 127. Milla CE, Billings J, Moran A. Diabetes is associated with dramatically decreased survival in female but not male subjects with cystic fibrosis. Diabetes Care 2005; 28(9):2141–44. 128. Lanng S. Diabetes mellitus in cystic fibrosis. Eur J Gastroenterol Hepatol 1996;8(8):744–47. 129. Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med 2000;162(3 Pt 1):891–95. 130. Milla CE, Warwick WJ. Risk of death in cystic fibrosis patients with severely compromised lung function. Chest 1998;113(5):1230–34. 131. Sims EJ, Green MW, Mehta A. Decreased lung function in female but not male subjects with established cystic fibrosisrelated diabetes. Diabetes Care 2005;28(7):1581–87. 132. Sweezey NB, Ghibu F, Gagnon S. Sex hormones regulate CFTR in developing fetal rat lung epithelial cells. Am J Physiol May 1997;272(5 Pt 1):L844–51. 133. Singh AK, Schultz BD, Katzenellenbogen JA, et al. Estrogen inhibition of cystic fibrosis transmembrane conductance regulator-mediated chloride secretion. J Pharmacol Exp Ther Oct 2000;295(1):195–204. 134. Taussig L. Cystic Fibrosis. New York: Thieme-Stratton Inc; 1984.

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135. Sharma S. Parasomnias. eMedicine 2007, Available at http://emedicine.medscape.com/article/291931-overview. Accessed May 25, 2009. 136. Kales JD, Kales A, Soldatos CR, et al. Night terrors. Clinical characteristics and personality patterns. Arch Gen Psychiatry 1980;37(12):1413–17. 137. Laberge L, Tremblay RE, Vitaro F, et al. Development of parasomnias from childhood to early adolescence. Pediatrics 2000;106(1 Pt 1):67–74. 138. Petit D, Touchette E, Tremblay RE, et al. Dyssomnias and parasomnias in early childhood. Pediatrics 2007;119(5):e1016–25. 139. Klackenberg G. Somnambulism in childhood – prevalence, course and behavioral correlations. A prospective longitudinal study (6–16 years). Acta Paediatr Scand. 1982;71(3):495–99. 140. Byrd RS, Weitzman M, Lanphear NE, et al. Bed-wetting in US children: epidemiology and related behavior problems. Pediatrics 1996;98(3 Pt 1):414–19. 141. Stein MA, Mendelsohn J, Obermeyer WH, et al. Sleep and behavior problems in school-aged children. Pediatrics 2001;107(4):E60. 142. Rosen CL. Clinical features of obstructive sleep apnea hypoventilation syndrome in otherwise healthy children. Pediatr Pulmonol 1999;27(6):403–9. 143. Mohsenin V. Gender differences in the expression of sleepdisordered breathing: role of upper airway dimensions. Chest 2001;120(5):1442–47. 144. Schwab J. Sex differences and sleep apnoea. Thorax 1999;54(4):284–85. 145. Strollo PJ Jr, Rogers RM. Obstructive sleep apnea. N Engl J Med. 1996;334(2):99–104. 146. Young T, Finn L. Epidemiological insights into the public health burden of sleep disordered breathing: sex differences in survival among sleep clinic patients. Thorax 1998;53 (Suppl 3):S16–9. 147. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328(17):1230–35. 148. Guilleminault C, Quera-Salva MA, Partinen M, et al. Women and the obstructive sleep apnea syndrome. Chest 1988;93(1):104–9. 149. Block AJ, Boysen PG, Wynne JW, et al. Sleep apnea, hypopnea and oxygen desaturation in normal subjects. A strong male predominance. N Engl J Med. 1979;300(10):513–17. 150. Chaudhary BA, Speir WA Jr. Sleep apnea syndromes. South Med J 1982;75(1):39–45. 151. Guilleminault C, Stoohs R, Kim YD, et al. Upper airway sleep-disordered breathing in women. Ann Intern Med. 1995;122(7):493–501. 152. Gislason T, Benediktsdottir B, Bjornsson JK, et al. Snoring, hypertension, and the sleep apnea syndrome. An epidemiologic survey of middle-aged women. Chest 1993;103(4):1147–51. 153. Young T, Hutton R, Finn L, et al. The gender bias in sleep apnea diagnosis. Are women missed because they have different symptoms? Arch Intern Med. 1996;156(21):2445–51. 154. Kuhni CE, Sennhauser FH. The Yentl syndrome in childhood asthma: risk factors for undertreatment in Swiss children. Pediatr Pulmonol 1995;19(3):156–60.

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155. Redline S, Kump K, Tishler PV, et al. Gender differences in sleep disordered breathing in a community-based sample. Am J Respir Crit Care Med 1994;149(3 Pt 1):722–26. 156. Ambrogetti A, Olson LG, Saunders NA. Differences in the symptoms of men and women with obstructive sleep apnoea. Aust N Z J Med 1991;21(6):863–66. 157. Popovic RM, White DP. Influence of gender on waking genioglossal electromyogram and upper airway resistance. Am J Respir Crit Care Med 1995;152(2):725–31. 158. Malhotra A, Huang Y, Fogel RB, et al. The male predisposition to pharyngeal collapse: importance of airway length. Am J Respir Crit Care Med. 2002;166(10):1388–95. 159. Pillar G, Malhotra A, Fogel R, et al. Airway mechanics and ventilation in response to resistive loading during sleep: influence of gender. Am J Respir Crit Care Med 2000;162(5):1627–32. 160. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance, and behaviour in 4-5 year olds. Arch Dis Child 1993;68(3):360–66. 161. Gislason T, Benediktsdottir B. Snoring, apneic episodes, and nocturnal hypoxemia among children 6 months to 6 years old. An epidemiologic study of lower limit of prevalence. Chest 1995;107(4):963–66.

162. Chay OM, Goh A, Abisheganaden J, et al. Obstructive sleep apnea syndrome in obese Singapore children. Pediatr Pulmonol. Apr 2000;29(4):284–90. 163. Brouilette R, Hanson D, David R, et al. A diagnostic approach to suspected obstructive sleep apnea in children. J Pediatr. Jul 1984;105(1):10–14. 164. Mallory GB Jr, Fiser DH, Jackson R. Sleep-associated breathing disorders in morbidly obese children and adolescents. J Pediatr 1989;115(6):892–97. 165. Leach J, Olson J, Hermann J, et al. Polysomnographic and clinical findings in children with obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 1992;118(7):741–44. 166. Redline S, Tishler PV, Schluchter M, et al. Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems. Am J Respir Crit Care Med 1999;159(5 Pt 1):1527–32. 167. Kawashima S. Sex-dependent differences in the craniofacial morphology of children with a sleep-related breathing disorder. Oral Surg Oral Med Oral Pathol Oral Radiol Endod Aug 2002;94(2):167–74.

Chapter

4

Gender-Specific Aspects of Pediatric Hematology and Oncology James H. Garvin, Jr Professor of Clinical Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA

Introduction

the hemoglobin level continues to rise throughout puberty to higher levels characteristic of adult men. Thus, the mean hemoglobin level in healthy white children age 11–14 years is 14.0 g/dl in boys and 13.5 g/dl in girls, with the same lower limit (95% range) of 12.0 g/dl (Table 4.1).1 For older adolescents age 15–19 years, the mean hemoglobin level in boys is 15.0 g/dl (lower limit 13.0 g/dl), whereas in girls it remains 13.5 g/dl (lower limit 12.0 g/dl). The difference results from the stimulatory effect of androgen secretion. Indeed, androgenic steroids are used therapeutically in certain bone marrow failure states, notably Fanconi anemia. Because of the difference in hemoglobin levels, the packed cell volume (PCV) will also be higher in adolescent males than females. However, the mean corpuscular volume (MCV) varies only with age, with average values of 85 fL (lower limit 77 fL) in boys and girls age 11–14, and 88 fL (lower limit 79 fL) in boys and girls age 15–19. The blood

While normal developmental changes in fetal and postnatal hematopoiesis are identical in males and females, genderrelated differences in red blood cell production are noted in adolescence and persist throughout adult life. Iron deficiency anemia is particularly common in adolescent girls. Although white blood cell and platelet counts do not differ between males and females, and coagulation factor levels are normally identical, certain disorders of neutrophil function and clotting such as chronic granulomatous disease and hemophilia are X-linked and therefore occur overwhelmingly in males. Sickle cell anemia affects males and females equally but morbidity appears to be increased in males. Childhood cancer is more common in males than females, particularly hematological cancers such as acute lympho­ blastic leukemia and non-Hodgkin’s lymphoma. Gender differences in survival and patterns of late effects are reported for certain diagnoses. An appreciation of genderspecific aspects of hematologic and oncologic disorders of childhood has resulted in the application of risk-adapted therapeutic strategies, and raises questions about gender differences in disease susceptibility and treatment response. More research is required to understand the molecular and pharmacogenetic basis for these differences.

Table 4.1  Normal values for hemoglobin and mean corpuscular volume Age (yr)

0.5–4 5–10 11–14

Normal hematopoiesis

15–19

Hemoglobin levels are identical in male and female infants and gradually rise at the same rate during childhood. Gender-related differences in hemoglobin concentration begin to emerge in adolescence. In females, the hemoglobin level reaches a plateau during early puberty, while in males Principles of Gender-Specific Medicine

20–44

Gender

M/F M/F F M F M F M

Hemoglobin (g/dl)

MCV (fl)

Mean

Lower limit

Mean

Lower limit

12.5 13.0 13.5 14.0 13.5 15.0 13.5 15.5

11.0 11.5 12.0 12.0 12.0 13.0 12.0 13.5

80 83 85 85 88 88 90 90

72 75 77 77 79 79 80 80

Lower limit of normal is 95% range. From Dallman and Slimes, 19791

51

Copyright 2010 20 , Elsevier Inc. All rights reserved.

52

s e c t i on 1     Gender and Normal Development l

volume depends on weight, averaging 75–77 ml/kg in children and adults of both genders. Bone marrow cellularity and differential cell count are comparable in males and females. However, subtle genderrelated differences have been noted, such as the more pronounced age-related decline in alkaline-phosphataseexpressing colony forming units (CFU-AP) seen in women compared to men,2 which could be relevant to gender differences in bone loss and osteoporosis. Recent research on determinants of hematopoietic and mesenchymal stem cell differentiation in healthy subjects and patients with osteo­arthritis and rheumatoid arthritis reveals age-related increases in RANKL and PPAR-gamma levels (osteoclast and adipocyte determinants) and DRAK1 expression (apoptosis-related gene) in females but not males.3 Peripheral blood white cell count, platelet count, and coagulation factor levels are all independent of gender, but there may be functional differences. For example, an influence of the menstrual cycle on monocyte cytokine release in response to lipopolysaccharide stimulation has been demonstrated.4 Studies of the immune response to hemorrhagic shock have shown enhanced immune function and lower mortality from subsequent sepsis in females compared to males.5 In a murine model, interleukin-10 treatment restored depressed immune responses (splenocyte proliferation, interferon-gamma, and interleukin 1-) preferentially in male animals, without further enhancing immune function in female animals, suggesting a potential relative deficit or inhibition of IL-10 in males.

Iron deficiency anemia Iron deficiency in American children occurs mainly in older infants and adolescents. Rapidly growing infants are subject to inadequate dietary intake of iron and possible intestinal blood loss due to sensitivity to cow’s milk protein; male and female infants are equally at risk. Among adolescents, rapid growth with the expansion of the total blood volume and lean body mass may also lead to iron deficiency, and there are additional gender-specific factors. In males, there is a more substantial increase in hemoglobin level due to androgen secretion, with corresponding greater need for iron, while females begin to experience menstrual blood loss and may deplete iron stores. Overall iron requirements increase from a preadolescent level of 0.7–0.9 mg of iron per day to as much as 2.2 mg per day or more in heavily menstruating young women.6 Based on the third National Health and Nutrition Examination Survey (1988–1994), the prevalence of iron deficiency in the United States is estimated to be 9% among toddlers aged 1–2 years, and 9–11% among adolescent girls and women of child-bearing age.7 The corresponding prevalence of iron deficiency anemia was 3% among toddlers and 2–5% among adolescent girls and young women. Iron deficiency was found in no more

than 1% of adolescent boys and young men. Among adolescents in Japan, mild hypochromic anemia was detected in 5% of girls compared to 2% of boys, and it was suggested that the difference might be due in part to dieting.8 Iron deficiency anemia is a much greater problem in the developing world. The World Health Organization estimates that 46% of the world’s children aged 5–14 years are anemic. Assessment of iron bioavailability from dietary sources in both developing and industrialized countries suggests that a negative iron balance is likely in many female adolescent populations. Other nutritional anemias are more likely to be related to underlying disease states rather than gender.

Glucose-6-phosphate dehydrogenase deficiency G6PD deficiency is relatively common, with sex-linked recessive inheritance because the G6PD locus is on the X chromosome. G6PD deficiency affects more than 1% of males in Mediterranean and Middle Eastern regions, 5% of Chinese males, and 10% of black males. Clinical manifestations of episodic acute hemolysis following infection or ingestion of certain drugs will be seen either in affected males or rare female homozygotes. Female heterozygotes are usually unaffected, but may have excess enzyme deficient cells due to random X chromosome inactivation and can potentially be symptomatic. Definitive diagnosis is by quantitative enzyme assay in red cell lysates, but screening tests are available for identification of susceptible individuals. The standard fluorescent spot test reliably detects hemizygous totally G6PD-deficient males but fails to detect heterozygous partially G6PD-deficient females. Newer fully quantitative screening tests will detect the latter individuals.

Sickle cell disease Sickle cell disease is an inherited chronic hemolytic anemia primarily affecting children of black ancestry. The most common forms are sickle cell anemia, sickle -thalassemia, and sickle hemoglobin C disease. All occur equally in males and females. However, there may be gender-related differences in some of the acute and chronic complications of this disease. For example, hyper-hemolytic crisis is associated with red cell G6PD deficiency, and therefore considerably more likely in boys than girls. Gender differences in morbidity and mortality are reported in adults with sickle cell disease. The Cooperative Study of Sickle Cell Disease reported a median age of death of 42 years for men and 48 years for women, a greater difference than in black control subjects.9 There is a striking increase in veno-occlusive crisis after age 15 years, with a greater rate of pain attacks in males than females.10 Female patients have slightly greater fetal hemoglobin

C h a p t e r 4     Gender-Specific Aspects of Pediatric Hematology and Oncology l

levels, which may be protective. The basis for these differences could lie in the observation that nitric oxide bioavailability and responsiveness are reduced in males but not females with sickle cell disease.11 Nitric oxide is thought to be important in maintaining vasomotor tone, limiting platelet aggregation, inhibiting ischemia-reperfusion injury, and modulating endothelial adhesion molecule expression. Sickle cell-related vascular phenomena of increased shear stress and compensatory responses to chronic vascular injury normally promote increased endothelial nitric oxide production, but this system is impaired in males. Estrogens facilitate nitric oxide production and limit its consumption. Moreover, nitric oxide has been linked to transcriptional control of fetal hemoglobin and could therefore contribute to gender differences in fetal hemoglobin expression.12 Therapies that restore nitric oxide bioactivity or reduce its consumption (or enhance non-nitric oxide induced vasodilatation) could be particularly beneficial in male patients with sickle cell anemia. The onset of puberty may be delayed by several years in both boys and girls with sickle cell disease. Various nutritional abnormalities have been reported. A study of adolescents and young adults in Nigeria found that, compared to controls, male patients had a significantly lower mean weight, body mass index, mid-arm circumference, and triceps and subscapular skinfold thickness, whereas these differences from controls were not noted in female patients. This was not due to any difference in intake of calories and micronutrients (when corrected for body weight), and suggested a gender-related difference in somatic growth.

Chronic granulomatous disease (cgd) CGD is a neutrophil function defect inherited predominantly in an X-linked manner, and therefore affects mainly boys. In CGD, the oxidative reactions required for bacterial killing by neutrophils are impaired, resulting in recurrent infection. There is an autosomal recessive form of CGD, affecting girls as well as boys, but the genetic abnormality is different. The X-linked disorder involves absence of membrane cytochrome b558, a heterodimer with 91 and 22 kilodalton subunits, due to a defect in the gene encoding the 91 kD protein. In the autosomal recessive form, there is lack of a neutrophil cytosolic oxidase protein.13

Coagulation defects Classic hemophilia (hemophilia A; factor VIII deficiency) is the most common hereditary deficiency of a coagulation factor with clinically severe manifestations. The disease is transmitted by females as a sex-linked recessive trait, and the estimated incidence is 1 per 10 000 white male births

53

in the United States. Severely affected males generally have factor VIII levels below 1% of normal, while levels between 1 and 5% are associated with moderate disease severity. Female carriers are usually asymptomatic, but the majority have subnormal levels of factor VIII activity in the range of 30–50%. Because factor VIII is bound to von Willebrand factor (VWF) in the circulation, carriers can be suspected based on low ratio of factor VIII activity to VWF antigen, and the carrier state can be confirmed by molecular genetic testing using DNA probes. von Willebrand disease is considerably more common than factor VIII deficiency, but affects males and females equally. Most often VWD is inherited as an autosomal dominant trait with mild to moderate bleeding tendency. The autosomal recessive form of VWD is associated with more severe bleeding. Factor IX deficiency (hemophilia B; Christmas disease) is sex-linked and accounts for about 12% of hemophilia. Factor IX deficiency is clinically indistinguishable from hemophilia A; female carriers may have subnormal levels of factor IX, and carrier status can be confirmed by molecular genetic testing. The remaining clotting factor deficiencies are not sexlinked, but in at least one case, that of factor VII, gender related differences in concentration (determined by monoclonal antibody) and pro-coagulant activity (determined by clotting assay) have been described in healthy adolescents and adults.14 There appears to be a gender dependent effect of factor VII gene polymorphisms on plasma levels of factor VII.15 The clinical significance of these differences is uncertain.

Childhood cancer Incidence Childhood cancer, the leading cause of non-accidental deaths below age 15 years, is more frequent in males than females. For the period 1990–7, the incidence of cancer in all children in the United States under age 15 years was 141 per million, or 1 in 7000.16 The incidence in males was 152 per million, compared to 130 per million females (male: female ratio 1.2). Similarly, the overall incidence for adolescents age 15–19 years was 207 per million, or 1 in 4800, but the incidence in males was 212 per million compared to 201 per million in females (male:female ratio 1.1). Cancer incidence in young persons increased between 1975 and 2000, with disproportionate increases among males in the age groups 0–1 year, 10–14 years, and 15–19 years. Data for the year 2004 continue to show an excess incidence as well as excess mortality in males (Table 4.2). The age-adjusted cancer incidence rates for males and females age 0–19 years were 176 and 157 per million, respectively, while the age-adjusted mortality rates for males and females

s e c t i on 1     Gender and Normal Development

54

l

Table 4.2  Age-adjusted invasive cancer incidence rates for ages 0–19 by International Classification of Childhood Cancer Subgroup, United States, all races, 2004 Diagnosis

All diagnoses Lymphoid leukemia Acute myeloid leukemia Hodgkin’s disease Burkitt’s lymphoma Other non-Hodgkin’s lymphoma Ependymoma/choroid plexus Astrocytoma CNS embryonal tumor Other glioma Other specified CNS tumor Neuroblastoma Retinoblastoma Nephroblastoma Renal cell carcinoma Hepatoblastoma Hepatocellular carcinoma Osteosarcoma Chondrosarcoma Ewing’s sarcoma Rhabdomyosarcoma Fibrosarcoma Other specified soft tissue sarcoma CNS germ cell tumor Gonadal germ cell tumor Extragonadal germ cell tumor Thyroid carcinoma Nasopharyngeal carcinoma Malignant melanoma

Incidence rates M

Fe

M:F

176.2 36.4 9.0 11.8 3.5 10.4 2.8 14.6 7.2 4.7 0.8 8.2 3.0 5.5 0.5 1.9 0.6 5.0 0.7 2.7 4.8 1.1 5.0 2.4 9.9 1.1 2.4 0.7 5.7

157.2 27.3 7.0 11.3 1.1 6.2 2.5 14.5 5.7 4.6 0.6 7.6 3.1 5.8 0.5 1.6 0.5 5.1

1.1 1.3 1.3 1.0 3.2 1.7 1.1 1.0 1.3 1.0 1.3 1.1 1.0 0.9 1.0 1.2 1.2 1.0

2.4 3.6 1.5 4.8 1.1 4.6 1.4 11.0

1.1 1.3 0.7 1.0 2.2 2.2 0.8 0.2

6.8

0.8

Rates are per 1 000 000 and are age-adjusted to the 2000 US standard population. Source: US Cancer Statistics Working Group42

were 30 and 24 per million, respectively. There is a striking male preponderance for non-Hodgkin’s lymphoma (male:female ratio 3.2 for Burkitt’s lymphoma and 1.7 for other non-Hodgkin’s lymphoma). Other pediatric cancers showing a 1.2-fold or higher male predominance are acute lymphoblastic leukemia (the commonest type of childhood cancer), acute myeloid leukemia, central nervous system embryonal and germ cell tumors, hepatoblastoma, hepatocellular carcinoma, rhabdomyosarcoma, and gonadal germ cell tumors. Langerhans cell histiocytosis, a monoclonal neoplastic disorder with variable clinical manifestations, is also more common in males than females. Remarkably, thyroid cancer is five times more frequent in females than males. Other cancers with a female predominance are fibrosarcoma and extragonadal non-CNS germ cell tumors. Of note, the incidence of malignant melanoma,

which affects 20% more girls than boys, is rising faster than that of any other cancer in the United States. Data from other countries confirm the general finding that childhood cancer is more common in males than females. Registry data for 53 countries show male:female ratios ranging from 1.09 to 2.05.17 The greatest excess of males in childhood cancer registrations tends to be reported from developing countries, and may reflect socioeconomic factors as well as underlying disease incidence.

Risk Factors Gender-specific risk factors for cancer in children include cryptorchidism (testicular germ cell tumors) and X-linked immunodeficiencies such as Wiscott–Aldrich syndrome and X-linked lymphoproliferative disorder (non-Hodgkin’s lymphoma). Phenotypic females with all or part of a Y chromosome are at risk for development of gonadoblastoma in the streak gonads.18 Included in this group are girls with androgen resistance syndromes, gonadal dysgenesis, and Turner syndrome with mosaicism (45X,46XY). Gonadoblastoma in these conditions has been linked to the TSPY gene on the Y chromosome.19 Prophylactic removal of the gonads (which are generally nonfunctional) is recommended because the risk of gonadoblastoma can be as high as 25%. Males with Klinefelter syndrome (47XXY) appear to have an increased risk of dysgerminomas20 and extra-gonadal germ cell tumors21 as well as breast cancer,22 but probably not leukemia23 as previously thought. Beckwith–Wiedemann syndrome is associated with an increased risk of Wilms tumor and hepatoblastoma, and although independent of the patient’s gender, this syndrome can be traced specifically to the child’s mother or father. For example, the autosomal dominant form of BWS (linked to chromosome 11p15) is more likely to be inherited from the mother,24 while a sporadic form may result from inheritance of two copies of a paternal chromosome 11,25 an example of genomic imprinting. The excess of males with acute lymphoblastic leukemia is more pronounced among pubertal children, but a role for sex hormones has not been conclusively demonstrated. There is some evidence for an impact of genetic polymorphisms. One study found a protective effect for girls having a particular cytochrome P-450 allele.26 Another study found an increased risk for boys who were HLA-DRB4*01 and had a certain mutation in the hereditary hemochromatosis gene.27 The male predominance in ALL is also particularly evident in the T cell subtype of the disease.28 A nonrandom chromosomal translocation, t(11;14)(p13;q11), involving the T cell receptor, is associated with T cell phenotype, male gender, high white blood count, and extramedullary disease. Another clonal chromosomal aberration in ALL, del(6q), is also more frequent in males than females, whereas t(1:19) in ALL and del(5q) in myelodysplastic syndrome is more common in females than males.29

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The male predominance in pediatric CNS tumors results from the excess of males with medulloblastoma (the commonest malignant brain tumor) and CNS germ cell tumors. The biologic basis for gender differences in CNS tumor incidence is unclear. The larger head size in boys compared to girls has been attributed to the relatively larger posterior fossa CSF spaces in males, allowing higher peak pressure in the lateral ventricles during fetal development;30 restriction of posterior fossa growth in girls has been hypothesized to explain the higher incidence of spina bifida in girls, but as yet there is no corresponding hypothesis to account for differential incidence of posterior fossa medulloblastoma. Germ cell tumors of the pineal region are up to nine times more common in males than females, whereas suprasellar germ cell tumors and pineal parenchymal tumors (pineoblastomas) affect males and females equally. Wilms tumor is slightly more frequent in girls than boys. Interestingly, the male:female ratio is 0.92:1 for unilateral tumors, and 0.60:1 for bilateral cases.31 The mean age of presentation is 3–5 months earlier for boys. Wilms tumor is associated with pseudohermaphroditism (Denys–Drash syndrome, associated in turn with mutations in chromosome 11p).32 An impact of gender is noted in renal cell carcinoma, which affects mainly adults but also adolescents.33 Males have an excess incidence of renal cell carcinoma, and present with larger, higher stage, and higher grade tumors. Since obesity is a risk factor, it has been suggested that adipocytokines such as leptin may be implicated in tumor growth;34 gender differences in adipocytokines are noted during pubertal progression, related to changing serum androgen levels.35 Both hepatoblastoma and hepatocellular carcinoma are more common in boys than girls. Although likely multifactorial, this difference could be due in part to gender disparities in inflammatory cytokine production and prevailing levels in the tumor microenvironment.36 Pediatric germ cell tumors occur predominantly in the 15–19 year age group, with a male:female ratio of 2.4:1. Testicular germ cell tumors in adolescent males and ovarian germ cell tumors in adolescent females have common features of aneuploidy and isochrome 12p, and appear to arise in premeiotic germ cells37,38 with progression following puberty, implicating hormonal factors. Additional histologies seen in ovarian germ cell tumors include mature and immature teratoma, suggesting possible clonal evolution in females. The development of an aneuploid endodermal sinus tumor with i(12p) within a diploid ovarian immature teratoma lacking i(12p) has been described.39 Clinically, ovarian teratomas may be associated with peritoneal implants of mature glial tissue (gliomatosis peritonei), while testicular germ cell tumors can be accompanied by neoplasia in situ in adjacent seminiferous tubules (intra­ tubular germ cell neoplasia). Pediatric thyroid carcinoma occurs predominantly in adolescent females. Radiation is known to be causative,

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but without gender-specificity; the male:female ratio for papillary thyroid carcinoma in children of the Republic of Belarus exposed after the Chernobyl nuclear reactor accident was 1.0:1.2. Gender differences in thyroid cancer incidence are more likely due to genetic and immunologic factors. For example, papillary and follicular thyroid cancers have been reported in children with Hashimoto’s thyroiditis, which has a marked predilection for females and may be associated with altered immune surveillance. An influence of sex hormones on the immune system is suggested by studies in mice showing that estrogen treatment induces polyclonal B cell activation with increased expression of autoantibodies characteristic of autoimmune disease.40 While few cancers in children and adolescents can be directly attributed to environmental exposures, one genderspecific example is clear cell adenocarcinoma of the vagina or uterine cervix in teenage girls whose mothers took diethylstilbestrol (DES) prenatally.41 A case-control interview study of maternal hormone and fertility drug use and its possible association with neuroblastoma (the commonest cancer of infancy) in offspring found no consistent increased risk, but suggested an increased risk only for males after exposure to oral contraceptives or clomiphene.42

Survival Outcome Overall survival rates for children with cancer have improved substantially. Five-year survival was only 28% in the 1960s, but increased to 75% by the 1990s. Age-adjusted cancer death rates in children and adolescents age 0–19 years decreased from 34.2 per million in 1990 to 27.3 in 2004.43 The death rate in males decreased from 37.8 to 30.1 per million, while the death rate in females decreased from 30.4 to 24.3 per million. Gender-specific differences in survival outcome are apparent in several childhood cancers. The prognosis for girls with ALL is consistently better than for boys.44 This has been attributed to the increased frequency of T cell ALL in boys, with associated shorter remission duration, but a survival advantage for girls has been noted in both T cell and pre-B cell ALL.45,46 Boys also have an additional risk of relapse in the testicles; with recent advances in therapy this risk is now approximately 5%. The testes may be a sanctuary site for occult disease due to limited access of systemic chemotherapy, but evidence for involvement of the ‘blood–testis barrier’ is inconclusive. Moreover, male gender has been a significant predictor of late relapse even when adjusted for isolated testicular relapse.47 Ovarian relapse is evidently rare.48 The survival advantage for females with ALL is likely due to additional unidentified genetic, endocrine, and metabolic differences. Like other prognostic variables, the influence of gender may be treatment-dependent and change with therapeutic advances, as in recent Children’s Cancer Group trials.49 Interestingly,

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gender differences in survival and mortality are not seen in children with acute myelocytic leukemia. Because girls have had superior survival in ALL, treatment duration is often shorter than for boys. Typically, girls may be treated for two years, compared to three years for boys. One study found that 1.5 years of treatment was sufficient for girls, but not boys.50 Less is known about the possible influence of gender on survival from solid tumor malignancies. Females have superior survival outcome in primary cutaneous melanoma,51 which could be due to earlier detection, but also in metastatic melanoma, which may be explained by differential effects of female and male hormones on tumor cell invasiveness.52 A prospective study of adults with colorectal cancer found significantly longer disease-free and overall survival in women compared to men following curative rectal cancer resection,53 suggesting possible differences in the immunological response to surgery. A tumor registry study of non-small cell lung carcinoma in adults found that men had significantly shorter median survival than women, independent of disease stage, and also lost significantly more weight over the course of the disease,54 suggesting possible gender determinants of cancer cachexia. The possible relevance of these observations to pediatric solid tumors such as neuroblastoma remains to be determined. Gender differences have been noted in interval from symptom onset to diagnosis of certain pediatric solid tumors. Compared to boys, girls had increased lag time to diagnosis of non-Hodgkin’s lymphoma but shorter lag time to diagnosis of Ewing sarcoma.55 However, age, gender, and race together accounted for only 16% of variance in lag time, which ranged from 21 days for neuroblastoma to 72 days for Ewing sarcoma.

Acute and Late Effects of Treatment Gender-related differences in susceptibility of children to the toxic effects of cancer chemotherapy are illustrated by doxorubicin-induced cardiomyopathy. The incidence of cardiac abnormalities at any cumulative dose of doxorubicin is higher in girls than boys,56 and female gender, together with young age and high cumulative dose, is a major risk factor for late-onset cardiotoxicity which may be life-threatening.57 Because of relatively more body fat, girls may have decreased clearance of anthracycline drugs, prolonging exposure. Myocardial damage may be more critical in girls than boys because of smaller ventricular mass and wall thickness relative to body size. Late-onset cardiomyopathy may also be provoked by pregnancy.58 Doxorubicin therapy is a risk factor for excess mortality in long-term survivors of childhood cancer.59 Cardioprotective agent, dexrazoxane, has been shown to be efficacious in children.60 There may be gender differences in the severity of other acute toxicities of treatment. For example, a review of infections occurring in children being treated for cancer found

what appeared to be an excess of girls among children dying of Gram-negative sepsis.61 Girls may be more susceptible to chemotherapy-induced nausea and vomiting, and tend to use different coping strategies compared to boys.62 A major concern of patients and families is gonadal toxicity of treatment for childhood cancer. Radiation therapy and alkylating agents such as cyclophosphamide can cause infertility and endocrine dysfunction. Although these effects are age- and dose-dependent in both males and females, there are gender differences in the pattern of toxicity. Infertility is more common in male than female survivors of childhood cancer. Relatively low doses of radiation and moderate doses of certain chemotherapy agents cause permanent azoospermia in males, whereas Leydig cell dysfunction is seen only with higher radiation doses and may remain subclinical after chemotherapy if compensated (low normal testosterone with elevated LH). Permanent azoospermia was found after radiation therapy for Hodgkin’s disease with testicular exposures of 140–300 cGy,63 and 8 of 10 survivors of Wilms tumor treated before puberty with abdominal irradiation (testicular exposure 268–983 cGy) had oligospermia or azoospermia.64 Leydig cell function was preserved following fractionated doses up to 1200 cGy in prepubertal boys,65 while decreased testosterone levels are seen in boys treated with 2400 cGy for testicular leukemia,66 and doses exceeding 3000 cGy cause Leydig cell failure in at least half of patients.67 Chemotherapy with mechlorethamine, vincristine, prednisone, and procarbazine (MOPP) for Hodgkin’s disease caused permanent azoospermia in 80%,68 while the alternative regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) caused azoospermia in only 38%, reversible in all.69 Small testes are reported following prepubertal treatment with MOPP for Hodgkin’s disease,70 nitrosoureas for brain tumors,71 and cyclophosphamide for paratesticular rhabdomyosarcoma.72 Compensated Leydig failure may be found at diagnosis or following MOPP chemotherapy for Hodgkin’s disease,68,73 but Leydig cell function is preserved following chemotherapy for ALL.74 In females, adverse effects of cancer treatment on fertility and ovarian endocrine function tend to occur in parallel. Radiation doses of 400–700 cGy caused irreversible ovarian failure in adult women,75 but not necessarily in prepubertal or adolescent girls, in whom exposure of one or both ovaries to doses of 90–1000 cGy caused ovarian failure in only 23%.76 However, total body irradiation in a single fraction of 1000 cGy caused primary amenorrhea in most young girls, and premature menopause has also been reported.77 MOPP chemotherapy for Hodgkin’s disease in young women resulted in amenorrhea in 30% of cases,78 a substantially lower incidence of infertility than in males. Even after six cycles of alkylator-based chemotherapy, ovarian function was preserved in at least 80% of females.79 Ovarian failure was transient in prepubertal girls receiving MOPP,80 and chemotherapy for ALL caused no gonadal dysfunction.

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For males, sperm banking prior to treatment may be recommended, and normal children have been born following artificial insemination with patients’ cryopreserved sperm.81 For females, cryopreservation of ova prior to treatment remains investigational,82 but a successful term pregnancy has been achieved following ovarian cryopreservation in a woman treated for Hodgkin’s disease.83 Suppression of ovarian function with oral contraceptives may reduce the risk of ovarian damage during cancer treatment; a gonadotropin-releasing hormone agonist was protective in young women with lymphoma.84 Surgical oophoropexy to transfer ovaries out of the radiation field has afforded preservation of ovarian function in female patients requiring abdominal and pelvic irradiation.85 Although chemotherapy is likely to be teratogenic in the first trimester of pregnancy, children of cancer survivors who completed intensive chemotherapy (including myeloablative chemotherapy with bone marrow transplant) prior to pregnancy tend to be normal.86 In a survey of more than 6000 pregnancies in couples one of whom was a childhood cancer survivor, no excess adverse outcomes were attributed to chemotherapy with the possible exception of procarbazine received by males.87 Neurocognitive and Psychological Outcomes Neurocognitive deficits following radiotherapy for medulloblastoma and ALL are more frequent in girls than boys;88,89 girls’ intellectual performance was also worse than boys’ following ALL treatment in which prophylactic irradiation was abandoned in favor of more intensive systemic and intrathecal chemotherapy.90 Hormonal factors appear to interact with both radiation and chemotherapy in the developing brain, accounting for differential genderrelated treatment toxicity. Long-term survivors of childhood leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma, although generally psychologically healthy, were 1.6–1.7 times more likely than siblings to report depressive symptoms and somatic distress.91 The relative risk for women was significantly higher than for men among survivors, but also among sibling controls. Further research is necessary to determine if female survivors experience more depression and somatic distress than male survivors, or whether the test measures used are simply more sensitive to females’ expression of their psychological status. Regardless, female gender may compound other risk factors for adverse psychological outcome. Recent research on childhood brain tumor survivors found greater risk of depression in girls than boys, particularly in girls with more limited social skills or lower selfconfidence.92 Even girls with high social skills but low self-worth scores reported significant depression. Among boys, risk of depressive symptoms was increased only in those with low scores for both attributes. Girls may be more vulnerable to low self-worth following diagnosis of a brain tumor, or may simply be better than boys at expressing their negative feelings.

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Second Malignant Neoplasms The most serious late effect of cancer treatment is the development of a second malignant neoplasm. Females are almost twice as likely as males to develop a second cancer after treatment for Hodgkin’s disease in childhood.93 The actuarial risk at 20 years was 9.7% for males and 16.8% for females. The difference in females was due to a 9.2% risk of breast cancer, and subsequent studies have confirmed that the risk of breast cancer is uniquely high in females treated below age 19 years for Hodgkin’s disease.94 The risk of breast cancer may approach 35% by age 40 years, with the majority of the breast cancers occurring within radiation fields.95 Awareness of gender-specific toxicities of cancer therapy has prompted new strategies to reduce late effects, involving risk-adapted treatment with different regimens for male and female patients. The best example is Hodgkin’s disease, where high cure rates can be achieved with several different radiation and chemotherapy combinations. Thus, in males, who have an excess of infertility with MOPP chemotherapy, the alternative regimen of ABVD may be preferred, with or without radiation therapy according to other risk factors. In females, who have a substantial risk of radiation-induced breast cancer, chemotherapy may be intensified to minimize the need for radiation therapy. It is anticipated that riskadapted therapy for Hodgkin’s disease with gender-specific chemotherapy and low-dose radiotherapy will be associated with a reduction in secondary breast cancer and male infertility, but prospective trials are required to confirm that cure rates will be preserved. Bone Marrow Transplant Bone marrow transplant and the related techniques of peripheral blood stem cell transplant and placental cord blood transplant are potentially curative for a variety of malignant and non-malignant conditions in childhood. Major indications for bone marrow transplant include acute leukemia and lymphoma, advanced neuroblastoma, severe aplastic anemia, and severe combined immunodeficiency disease. Among these disorders, there is a male predominance in acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, and congenital immunodeficiency. Taking into account this biological difference in disease incidence, there is no male bias in referral for stem cell transplant, in contrast to renal transplantation, where a bias against females has been documented.96 A serious complication of allogeneic bone marrow transplant is graft versus host disease. Although GVHD occurs equally in males and females, there is a greater risk of acute GVHD when the donor is female, and gender mismatch between donor and recipient tends to increase the risk of chronic GVHD.97 GVHD is a major contributor to transplant-related mortality (TRM) at day 100; female to male transplant for pediatric leukemia was associated with

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increased risk of TRM, particularly if there was HLA mismatch.98 An earlier study found that female donor gender was associated with increased severity of acute GVHD, particularly with female donors of older age compared to recipient.99 This could not be attributed to gender-related differences in the marrow content of immunoreactive cells. Increasing parity in female donors further increases the risk of acute GVHD, suggesting some female donors have been presensitized to their respective recipients by prior pregnancies. It is known that sex chromosome-linked minor histocompatibility determinants are important in acute GVHD, and it had been assumed that this was simply due to female donor cell recognition of recipient male HY antigens as foreign. Studies in mice indicate that reaction against recipient female HX antigen is also possible, and suggest that sex chromosome-linked minor histocompatibility determinants may be polymorphic and capable of multiple allelic expression.100

Chronic Pain An important feature of childhood cancer and certain hematologic disorders such as sickle cell disease is chronic pain-related to the underlying disease, as well as acute pain related to diagnostic and therapeutic procedures. Genderrelated differences in pain tolerance and coping strategies are widely reported in adults, but less is known about children. Tools such as the Pain Experience Interview provide insight into the experience of acute, recurrent, and chronic pain by children at different ages and developmental stages.106 Using such methodology, investigators are conducting exploratory analyses of age- and gender-related differences in children’s pain experience.

Suggestions for further investigations Gender-specific determinants of somatic growth and vaso-occlusive crisis pain in sickle cell anemia. Potential gender differences in tumor immunity, tumor invasiveness, immune response to surgery, and susceptibility to immunotherapy, as may be revealed from gene expression profiling. Risk-adapted treatment of childhood cancers with the goal of reducing gender-specific late effects, using the model of Hodgkin’s disease.

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Pharmacokinetics and Drug Toxicity Potential gender-related differences in drug metabolism and toxicity are increasingly appreciated. Among the drugs implicated are some which are important in cancer treatment and supportive care. Gender differences in drug metabolism and elimination are mainly related to steroid hormone levels. Cytochrome P450 isozyme CYP3A4, which is responsible for the metabolism of the majority of therapeutic drugs, is reported to exhibit higher activity in females than males.101 Conversely, the activity of other cytochrome P450 isozymes (CYP2C19, CYP2D6, and CYP2E1), as well as glucuronidation activity, may be higher in males than females. Among the newer immunosuppressive agents used to prevent GVHD following bone marrow transplant, sirolimus may be more potent in adult males than females, based on inhibition of lymphocyte proliferation in vitro.102 Gender-related differences in adverse reactions to antibiotics and other drugs have been noted in adults.103 The extent of gender differences, if any, in drug metabolism, efficacy, and toxicity in the pediatric age group is beginning to be investigated. A study of pediatric ALL patients receiving high-dose methotrexate found a genderspecific impact of a particular adenosine triphosphate-binding cassette class transporter polymorphism (-24T allele); girls carrying at least one -24T allele had two-fold higher mean plasma methotrexate area under the curve compared to all other patients,104 and were substantially more likely to require intensified folinic acid rescue. An early review of experience with investigational cancer chemotherapy trials in children found no significant gender differences in response, disease progression, or death on study,105 but with new classes of agents entering phase I trials, further study of gender influences on drug metabolism is warranted.

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References 1. Dallman PR, Slimes MA. Percentile curves for hemoglobin and red-cell volume in infancy and childhood. J Pediatr 1979;94:26. 2. Muschler GF, Nitto H, Boehm CA, et al. Age- and genderrelated changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res 2001;19:117–25. 3. Jiang Y, Mishima H, Sakai S, et al. Gene expression analysis of major lineage-defining factors in human bone marrow cells: effect of aging, gender, and age-related disorders. J Orthop Res Feb 2008;26, (epub ahead of print). 4. Schwarz E, Schafer C, Bode JC, et al. Influence of the menstrual cycle on the LPS-induced cytokine response of monocytes. Cytokine 2000;12:413–16. 5. Kahlke V, Dohm C, Brotzmann K, et al. Gender-related therapy: early IL-10 administration after hemorrhage restores immune function in males but not in females. Shock 2000;14:354–59. 6. Beard JL. Iron requirements in adolescent females. J Nutr 2000;130:440S–442S. 7. Looker AC, Dallman PR, Carroll MD, et al. Prevalence of iron deficiency in the United States. JAMA 1997;277:973–976. 8. Maeda M, Yamamoto M, Yamauchi K. Prevalence of anemia in Japanese adolescents: 30 years’ experience in screening for anemia. Int J Hematol 1999;69:75–80. 9. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med 1994;330:1639–1644.

C h a p t e r 4     Gender-Specific Aspects of Pediatric Hematology and Oncology l

10. Baum KF, Dunn DT, Maude GH, et al. The painful crisis of homozygous sickle cell disease: a study of the risk factors. Arch Intern Med 1987;147:1231–1234. 11. Gladwin MT, Schechter AN, Ognibene FP, et al. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation 2003;107:271–278. 12. Ikuta T, Ausenda S, Cappellini MD. Mechanism for fetal globin gene expression: role of the soluble guanylate cyclasecGMP-dependent protein kinase pathway. Proc Natl Acad Sci USA 2001;98:1847–1852. 13. Curnutte JT, Scott PJ, Babior BM. Functional defect in neutrophil cytosols from two patients with autosomal recessive cytochrome-positive chronic granulomatous disease. J Clin Invest 1989;83:1236. 14. Albrecht S, Kotzsch M, Siegert G, et al. Detection of circulating tissue factor and factor VII in a normal population. Thromb Haemost 1996;75:772–777. 15. DiCastelnuovo A, D’Orazio A, Amore C, et al. Genetic modulation of coagulation factor VII plasma levels: contribution of different polymorphisms and gender-related effects. Thromb Haemost 1998;80:592–597. 16. Ries LAG, Smith MA, Gurney JG, eds. Cancer incidence and survival among children and adolescents: United States SEER program 1975–1995. National Cancer Institute, SEER Program, NIH Pub No 99-4649. Bethesda, MD, 1999. 17. Pearce MS, Parker L. Childhood cancer registrations in the developing world: still more boys than girls. Int J Cancer 2001;91:402–406. 18. Manuel M, Katayama PK, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol 1976;124:293–300. 19. Lau YF. Gonadoblastoma, testicular and prostate cancers, and the TSPY gene. Am J Hum Genet 1999;64:921–927. 20. Chaussain JL, Lemerle J, Roger M, et al. Klinefelter syndrome, tumor, and sexual precocity. J Pediatr 1980;97:609–611. 21. Bussey KJ, Lawce HJ, Olson SB, et al. Chromosome abnormalities of eighty-one pediatric germ cell tumors: sex-, age-, site-, and histopathology-related differences – a Children’s Cancer Group study. Genes Chromosomes Cancer 1999;25:134–146. 22. Hultborn R, Hanson C, Köpf I, et al. Prevalence of Klinefelter’s syndrome in male breast cancer patients. Anticancer Res 1997;17:4293–4297. 23. Horsman DE, Pantzar JT, Dill FJ, et al. Klinefelter’s syndrome and acute leukemia. Cancer Genet Cytogenet 1987;26:375–376. 24. Viljoen D, Ramesar R. Evidence for paternal imprinting in familial Beckwith–Wiedemann syndrome. J Med Genet 1992;29:221–225. 25. Slatter RE, Elliott M, Welham K, et al. Mosaic uniparental disomy in Beckwith–Wiedemann syndrome. J Med Genet 1994;31:749–753. 26. Krajinovic M, Labuda D, Richer C, et al. Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood 1999;93:1496–1501. 27. Dorak MT, Burnett AK, Worwood M, et al. The C282Y mutation of HFE is another male-specific risk factor for childhood acute lymphoblastic leukemia [Letter; comment]. Blood 1999;94:3957.

59

28. Neglia JP, Robison LL. Epidemiology of the childhood acute leukemias. Pediatr Clin North Am 1988;35:675–692. 29. Mertens F, Johansson B, Mitelman F. Age- and gender-related heterogeneity of cancer chromosome aberrations. Cancer Genet Cytogenet 1993;70:6–11. 30. Williams H. Gender, head size and disease: a hypothesis related to posterior fossa growth. Med Hypotheses 2008, doi:10.1016/j.mehy.2007.10.015. 31. Breslow N, Olshan A, Beckwith JB, et al. Epidemiology of Wilms tumor. Med Pediatr Oncol 1993;21:172–181. 32. Coppes MJ, Huff V, Pelletier J. Denys–Drash syndrome: relating a clinical disorder to genetic alterations in the tumor suppressor gene WT1. J Pediatr 1993;123:673–678. 33. Aron M, Nguyen MM, Stein RJ, et al. Impact of gender in renal cell carcinoma: an analysis of the SEER database. Eur Urol 2007, doi:10.1016/j.eururo.2007.12.001. 34. Murai M. Editorial comment on: Impact of gender in renal cell cardinoma: an analysis of the SEER database. Eur Urol 2007, doi10.1016/j.eururo.2007.12.002. 35. Böttner A, Kratzxch J, Muller G, et al. Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metab 2004;89:4053–4061. 36. Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317:121–124. 37. Inoue M, Fujita M, Azuma C, et al. Histogenetic analysis of ovarian germ cell tumors by DNA fingerprinting. Cancer Res 1992;52:6823. 38. Jorgensen N, Rajpert-De Meyts E, Graem N, et al. Expression of immunohistochemical markers for testicular carcinoma in situ by normal human fetal germ cells. Lab Invest 1995;72:223. 39. Speleman F, DePotter C, Dal Cin P, et al. i(12p) in a malignant ovarian tumor. Cancer Genet Cytogenet 1990;45:49. 40. Verthelyi D. Sex hormones as immunomodulators in health and disease. Int Immunopharmacol 2001;1:983–993. 41. Melnick S, Cole P, Anderson D, et al. Rates and risks of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix: an update. N Engl J Med 1987; 316:514–519. 42. Olshan AF, Smith J, Cook MN, et al. Hormone and fertility drug use and the risk of neuroblastoma: a report from the Children’s Cancer Group and the Pediatric Oncology Group. Am J Epidemiol 1999;150:930–938. 43. US Cancer Statistics Working Group: United States cancer statistics: 1999–2004 incidence and mortality Webbased report. Atlanta, US Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute, 2007. Available at www.cdc. gov/uscs. 44. Pui CH, Boyett JM, Relling MV, et al. Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol 1999;17:818–824. 45. Imbach P, Fuchs A, Berchtold W, et al. Boys but not girls with T-lineage acute lymphocytic leukemia (ALL) are different from children with B-progenitor ALL. Population-based data results of initial prognostic factors and long-term eventfree survival. Swiss Pediatric Oncology Group. J Pediatr Hematol Oncol 1995;17:346–949.

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46. Shuster JJ, Wacker P, Pullen J, et al. Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 1998;16:2854–2863. 47. Baum E, Sather H, Nachman J, et al. Relapse rates following cessation of chemotherapy during complete remission of acute lymphoblastic leukemia. Med Pediatr Oncol 1979;7:25–34. 48. Heaton DC, Duff GB. Ovarian relapse in a young woman with acute lymphoblastic leukemia. Am J Hematol 1989;30:42–43. 49. Steinherz PG, Gaynon PS, Breneman JC, et al. Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognosis features: randomized controlled trial from the Children’s Cancer Group. Cancer 1998;82:600–612. 50. Medical Council Working Party on Leukemia in Childhood. Duration of chemotherapy in childhood acute lymphoblastic leukemia. Med Pediatr Oncol 1982;10:511. 51. Lasithiotakis K, Leiter U, Meier F, et al. Age and gender are significant independent predictors of survival in primary cutaneous melanoma. Cancer Feb 2008;27, epub ahead of print. 52. Richardson B, Price A, Wagner M, et al. Investigation of female survival benefit in metastatic melanoma. Br J Cancer 1999;80:2025–2033. 53. Wichmann MW, Muller C, Hornung HM, et al. Gender differences in long-term survival of patients with colorectal cancer. Br J Surg 2001;88:1092–1098. 54. Palomares MR, Sayre JW, Shekar KC, et al. Gender influence on weight-loss pattern and survival of nonsmall cell lung carcinoma patients. Cancer 1996;78:2119–2126. 55. Pollock BH, Krischer JP, Vietti TJ. Interval between symptom onset and diagnosis of pediatric solid tumors. J Pediatr 1991;119:725–732. 56. Silber JH, Jakacki RI, Larsen RI, et al. Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol 1993;21:477–479. 57. Lipschultz SE, Lipsitz SR, Mone SM, et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 1995;332:1738–1743. 58. Katz A, Goldenberg I, Maoz C, et al. Peripartum cardiomyopathy occurring in a patient previously treated with doxorubicin. Am J Med Sci 1997;314:399–400. 59. Green DM, Hyland A, Chung CS, et al. Cancer and cardiac mortality among 15-year survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol 1999;17:3207–3215. 60. Wexler LH, Andrich MP, Venzon D, et al. Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol 1996;14:362–372. 61. Auletta JJ, O’Riordan MA, Nieder ML. Infections in children with cancer: a continued need for the comprehensive physical examination. J Pediatr Hematol Oncol 1999;21:501–508. 62. Tye VL, Mulhern RK, Jayawardene D, et al. Chemotherapyinduced nausea and emesis in pediatric cancer patients: an analysis of coping strategies. J Pain Symptom Manage 1995;10:338–347. 63. Speiser B, Rubin P, Casarett G. Aspermia following lower truncal irradiation in Hodgkin’s disease. Cancer 1973;32:692. 64. Shalet SM, Beardwell CG, Jacobs HS, et al. Testicular function following irradiation of the human prepubertal testes. Clin Endocrinol 1978;9:483.

65. Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol 1999;33:2. 66. Brauner R, Czernichow P, Cramer P, et al. Leydig-cell function in children after direct testicular irradiation for acute lymphoblastic leukemia. N Engl J Med 1983;309:25. 67. Izard MA. Leydig cell function and radiation: a review of the literature. Radiother Oncol 1995;34:1. 68. Sherins RJ, Olweny CLM, Ziegler JL. Gynecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin’s disease. N Engl J Med 1978;299:12. 69. Santoro A, Bonadonna G, Valagussa P, et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin’s disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 1987;5:27. 70. Green DM, Brecher ML, Lindsay AN, et al. Gonadal function in pediatric patients following treatment of Hodgkin’s disease. Med Pediatr Oncol 1981;9:235. 71. Ahmed SR, Shalet SM, Campbell RHA, et al. Primary gonadal damage following treatment of brain tumors in childhood. J Pediatr 1983;103:562. 72. Heyn R, Raney RB, Hayes DM, et al. Late effects of therapy in patients with paratesticular rhabdomyosarcoma. J Clin Oncol 1992;10:614. 73. Chapman RM, Sutcliffe SB, Malpas JS. Male gonadal dysfunction in Hodgkin’s disease: a prospective study. JAMA 1981;245:1323. 74. Blatt J, Poplack DG, Sherins RJ. Testicular function in boys after chemotherapy for acute lymphoblastic leukemia. N Engl J Med 1981;304:1121. 75. Lushbaugh CC, Casarett GW. The effect of gonadal irradiation in clinical radiation therapy; a review. Cancer 1976;37:1111. 76. Ortin TTS, Shostak CA, Donaldson SS. Gonadal status and reproductive function following treatment for Hodgkin’s disease in childhood: the Stanford experience. Int J Radiat Oncol Biol Phys 1990;19:873. 77. Liesner RJ, Leiper AD, Hann IM, et al. Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood. J Clin Oncol 1994;12:916. 78. Chapman RM, Sutcliffe SB, Malpas JS. Cytotoxic-induced ovarian failure in women with Hodgkin’s disease. JAMA 1979;242:1877. 79. Horning SJ, Hoppe RT, Kaplan HS, et al. Female reproductive potential after treatment for Hodgkin’s disease. N Engl J Med 1981;304:1377–1382. 80. Nicosia SV, Matus-Ridley M, Meadows AT. Gonadal effects of cancer therapy in girls. Cancer 1985;55:2364. 81. Scammell GE, White N, Stedionska J, et al. Cryopreservation of semen in men with testicular tumors or Hodgkin’s disease: results of artificial insemination of their partners. Lancet 1985;1:31. 82. Grundy R, Gosden RG, Hewitt M, et al. Fertility preservation for children treated for cancer (1): scientific advances and research dilemmas. Arch Dis Child 2001;84:355–359. 83. Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;364:1405–1410. 84. Blumenfeld Z, Avivi I, Linn S, et al. Prevention of irreversible chemotherapy-induced ovarian damage in young women

C h a p t e r 4     Gender-Specific Aspects of Pediatric Hematology and Oncology l

85.

86. 87.

88.

89.

90.

91.

92.

93.

94.

95.

with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum Reprod 1996;11: 1620–1626. Le Floch O, Donaldson SS, Kaplan HS. Pregnancy following oophoropexy in total nodal irradiation in women with Hodgkin’s disease. Cancer 1976;38:2263. Blatt J. Pregnancy outcome in long-term survivors of childhood cancer. Med Pediatr Oncol 1999;33:29. Green DM, Fiorello A, Zovan MA. Birth defects and childhood cancer in offspring of survivors of childhood cancer. Arch Pediatr Adolesc Med 1997;151:379–383. Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol 2001;19:3470–3476. Waber DP, Tarbell NJ, Kahn CM. The relationship of sex and treatment modality to neuropsychological outcome in childhood acute lymphoblastic leukemia. J Clin Oncol 1992;10:810–817. Von der Weid N, Mosimann I, Hirt A, et al. Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sexrelated differences. Eur J Cancer 2003;39:359–365. Zebrack BJ, Zeltzer LK, Whitton J, et al. Psychological outcomes in long-term survivors of childhood leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma: a report from the Childhood Cancer Survivor Study. Pediatrics 2002;110:42–52. Barrera M, Schulte F, Spiegler B. Factors influencing depressive symptoms of children treated for a brain tumor. J Psychosoc Oncol 2008;26:1–16. Wolden SL, Lamborn KR, Cleary SF, et al. Second cancers following pediatric Hodgkin’s disease. J Clin Oncol 1998;16:536–544. Aisenberg AC, Finkelstein DM, Doppke KP, et al. High risk of breast carcinoma after irradiation of young women with Hodgkin’s disease. Cancer 1997;79:1203–1210. Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second malignant neoplasms after childhood Hodgkin’s disease. N Engl J Med 1996;334:745–751.

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  96. Mehta P, Pollock BH, Nugent M, et al. Access to stem cell transplantation: do women fare as well as men? Am J Hematol 2003;72:99–102.   97. Eisner MD, August CS. Impact of donor and recipient characteristics on the development of acute and chronic graft-versus-host disease following pediatric bone marrow transplantation. Bone Marrow Transplant 1995;15:663–668.   98. Gustafsson Jernberg Å, Remberger M, Ringdén O, et al. Risk factors in pediatric stem cell transplantation for leukemia. Pediatr Transplant 2004;8:464–474.   99. Atkinson K, Farrell C, Chapman G, et al. Female marrow donors increase the risk of acute graft-versus-host disease: effect of donor age and parity and analysis of cell subpopulations in the donor marrow inoculum. Br J Haematol 1986;63:231–239. 100. O’Kunewick JP, Kociban DL, Machen LL, et al. Effect of donor and recipient gender disparities on fatal graft-vs.-host disease in a mouse model for major histocompatibility complex-matched unrelated-donor bone marrow transplantation. Exp Hematol 1993;21:1514–1516. 101. Tanaka E. Gender-related differences in pharmacokinetics and their clinical significance. J Clin Pharmacol Ther 1999;24:339–346. 102. Ferron GM, Pyszczynski NA, Jusko WJ. Gender-related assessment of cyclosporine/prednisone/sirolimus interactions in three human lymphocyte proliferation assays. Transplantation 1998;15:1203–1209. 103. Tran C, Knowles SR, Liu BA, et al. Gender differences in adverse drug reactions. J Clin Pharmacol 1998;38:1003–1009. 104. McGrath PA, Speechley KN, Seifert CE, et al. A survey of children’s acute, recurrent, and chronic pain: validation of the pain experience interview. Pain 2000;87:59–73. 105. Rau T, Erney B, Göres R, et al. High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 2006;80:468–476. 106. Weitman S, Ochoa S, Sullivan J, et al. Pediatric phase II cancer chemotherapy trials: a Pediatric Oncology Group study. J Pediatr Hematol Oncol 1997;19:187–191.

C hapter

5

Gender Differences in Neurological Conditions of Children David M. Kaufman Assistant Clinical Professor of Pediatrics and Neurology, Mount Sinai School of Medicine, Department of Pediatric Neurology, New York, NY, USA

This chapter discusses some of the differences between the brains of boys and girls, in terms of early brain growth, normal development, and in some specific neurological conditions. It is not meant to be a comprehensive review, but rather an overview. At the end of the chapter there is a listing of several other neurological conditions/diseases in which there is a gender predilection. The reader is invited to delve further into areas of interest.

greater in the male because a greater number of neurons are present, preventing some of the functional losses. This, of course, does not imply that one is ‘better’ than the other. Some functions may benefit from the presence of more cells, while others may be enhanced because of the larger number of connections.1 The human brain develops early in prenatal life, three weeks after conception. The brain develops throughout the pregnancy, and continues to develop throughout infancy and childhood, into adult life. Genes and environment interact as the brain develops, but they play very different roles. Generally, genes are responsible for the basic anatomical substrate of the brain – forming the neurons and connections between the different regions of the brain. Experience is responsible for fine-tuning the connections and allowing children to adapt to their particular environment.2 By 3 months of age, the brains of boys and girls react differently to the sound of the human voice. These differences are presumably due to the presence of sex chromosomes, or hormonal influences, or both. As early as 7 weeks of gestation, testosterone levels rise in the male fetus and this affects the growth and development of neurons in many areas of the brain. Female sex hormones may also play a role, but their function is currently not well understood. By most measures of cognitive and sensory development, young girls are slightly more advanced. Vision, hearing, memory, and smell are all more acute in female than in male infants. Girl babies are also somewhat more attuned socially than their male counterparts, and they usually lead boys in terms of their fine motor and language skills. By age 3, however, boys generally catch up, and they will be superior to girls on tests of visual-spatial integration (involving puzzles, and certain types of eye–hand coordination tasks). Recently, scientists at UCLA Medical Center studied the brains of normal boys and girls between the ages of 3

Introduction Boys and girls have distinctly different brains. This becomes apparent right from birth. A newborn’s brain is only about one-quarter the size of an adult’s. It will grow to about 80% of adult size by 3 years of age, and 90% by age 5. The average head circumference in the full term, newborn female is 34 cm, while in the male it is 35 cm. This is unrelated to birthweight or body size. The average adult male head circumference is almost 56 cm, while that of the average adult female is 55 cm. The average weight of the male newborn brain is about 370 g, while that of the average female newborn brain is somewhat less (about 300 g). For men 21–25 years of age, 1400 g is considered average brain weight, and for women, 1250 g (Volpe). Men also have more neurons in the cerebral cortex while women have more neuropils, which contain the processes that promote cell communication. The cerebral cortex is responsible for voluntary movements, sensory perception, memory, language, reasoning, and learning. Research has shown that women are more prone to dementing illnesses than men. Although a man and a woman might lose the same number of neurons, the woman’s functional loss may be greater because the lost cells are more densely connected to other neurons. Conversely, the functional reserve may be Principles of Gender-Specific Medicine

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and 15 years, using magnetic resonance imaging (MRI) technology.3 They discovered a massive growth spurt from ages 3 to 6 in the frontal regions of the brain. These areas are involved in organizing and planning new behaviors, and during these ages, children are learning a wide variety of new behaviors. They also found that brain areas involved in learning language skills grew extremely rapidly from 6 until puberty in both boys and girls. These areas then experience a dramatic slow-down in growth between the ages of 11–15 years. This coincides with the period during which children no longer learn new languages. No differences were noted between boys and girls. With norms now established, these researchers will start to look at abnormal growth patterns and study conditions such as autism, attention deficit hyperactivity disorder, Tourette’s syndrome, and childhood onset schizophrenia, among others.

Attention deficit hyperactivity disorder (ADHD) Although there are some who doubt the validity of the diagnosis of ADHD, most clinicians agree that this is a legitimate condition that affects many children and adults. ADHD is thought to affect 3–5% of children, or as many as 2 million school-age children in the United States.4 The criteria for diagnosis will not be reiterated here, as they are readily available in many other sources. It has long been held that the male:female ratio of ADHD is 4:1, and may be as high as 6:1. Recent studies suggest that the true incidence is probably closer to 2:1. Attention deficit disorder (ADD) in girls is more subtle because there is a lower incidence of hyperactivity; affected girls are more often diagnosed with the inattentive type of ADD rather than the hyperactive type. Dr Judith Rapoport, Director of Child Psychiatry at the National Institute of Mental Health, has been tracking long-term changes in brain anatomy in children with or without neurological or psychiatric conditions. Among many other findings, Dr Rapoport has reported that children with ADHD have smaller brains, differences in the frontal regions, basal ganglia, and cerebellar vermis (these latter two regions control movement and planning, while the frontal lobes are involved in ‘executive functioning,’ all areas of dysfunction in children with ADHD). These changes are non-progressive, and suggest that they may have been present since birth, have biologic underpinnings, and help explain some of the symptoms seen in these children.5 Another study, carried out by Mostofsky et al.6 at the Kennedy Krieger Institute at Johns Hopkins, found smaller prefrontal and premotor brain volumes in boys with ADHD, which may also help to explain why the symptoms of ADHD are more pronounced in boys. Girls with ADHD are less likely to have an associated learning disability,

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but are more likely to have lower IQ scores, impaired social and family functioning, and co-morbid conduct, mood, and anxiety disorders. Interestingly, the response to stimulant medication is the same in boys and girls, suggesting that although there may be anatomic differences in their brains, the neurotransmitter deficiencies are the same.7

Tourette’s syndrome (TS) Tourette’s syndrome is a neurobiological condition characterized by vocal and motor tics that change over time, and wax and wane in severity. Tourette’s syndrome is part of a spectrum of tic disorders, including transient tic disorder (tics lasting less than one year) and chronic tic disorder (motor or vocal tics lasting more than one year). As many as 10–20% of all school-age children have transient motor tics, and less commonly, vocal tics, lasting less than one year. This is more common in boys than girls. In 3–4% of these children, motor or vocal tics, but not both, will persist for more than one year. Again, this is more common in boys. TS (motor and vocal tics of more than a year’s duration) is said to be present in 1% of school-age boys, and 0.1% of school-age girls.8 Several studies have reported an increased risk for TS of 11.5% of brothers and 4.8% of sisters of children with TS (Tourette Syndrome International Consortium for Genetics). Most researchers also have found a high incidence of obsessive– compulsive disorder and ADHD in people with TS. It appears that this is a spectrum of expressions of the same underlying genetic disorder. An autosomal dominant model with sex-specific penetrance, accounting for the higher incidence in boys, has been postulated.9

Epilepsy In most population-based studies, the incidence of epilepsy is higher in males than in females. The consistency of the male–female difference suggests that males are at higher risk to develop epilepsy and unprovoked seizures.10 This suggests that gender factors are important for epileptogenesis, and may lead to different treatment regimens for boys and girls. The overall incidence of epilepsy in the United States (based on population studies done in Rochester, Minnesota) is 49 per 100 000 person-years in males, and 41 per 100 000 person-years in females.11 During the first five years of life, however, females have a slightly higher incidence, especially of generalized seizures. Among specific seizure types, the incidence for all categories of partial seizures (simple, complex, and secondarily generalized), and for generalized tonic-clonic seizures is greater in males. The incidence of absence seizures is slightly higher in females. Among some of the childhood epilepsy

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syndromes, childhood absence and photosensitive epilepsy are more prevalent in males. The incidence of a first unprovoked seizure is somewhat greater in males than females (68 vs. 56 per 100 000 person-years). However, there is no gender difference in the risk of recurrence within two years.12,13 Epilepsy is also seen in Aicardi syndrome and in Rett syndrome, both of which occur almost exclusively in females. Aicardi syndrome is characterized by agenesis of the corpus callosum, lacunar retinopathy, and infantile spasms. This is an X-linked condition, which is believed to be lethal to males, as there is a high incidence of spontaneous abortion of male fetuses in mothers of affected girls. Presumably, girls are affected by a new X-linked dominant spontaneous mutation that is lethal to a male fetus. Affected girls are mentally retarded, and continue to have refractory seizures. Rett’s syndrome is a progressive encephalopathy characterized by autism, hand-wringing motions, and an acquired microcephaly. Rett’s syndrome is also felt to represent new mutations of a gene on the X chromosome, lethal to males.

Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD), a sex-linked recessive disorder, affects 1 in 3500 live born males, most of whom have not had, nor will have another case in their families. Since the affected males virtually never survive into their reproductive years, a DMD mutation usually lasts for only one generation. Boys affected by DMD develop calf hypertrophy and gait disturbance as toddlers, usually require wheelchairs by the end of the first decade, and succumb by the end of the second decade. In Becker muscular dystrophy (BMD), onset and progression is slower, and most affected boys will survive into middle age. For women, the most common clinical problem posed by DMD or BMD is the birth of an affected son. Female carriers are usually asymptomatic, although there have been reports of girls with a Duchenne phenotype, usually with a negative X-chromatin pattern, XO/XX mosaicism, or a structurally abnormal X chromosome. DMD in females has also been reported in several girls with X chromosome translocations, and these have been helpful in identifying the DMD gene.12,14 DMD and BMD are caused by defects in the same gene. DMD patients produce virtually no dystrophin, a protein found in the muscle cell membrane, while BMD patients produce an abnormal but partially functional protein. The role of dystrophin is poorly understood, although it may be involved in the maintenance of the membrane in muscular contractions and/or in transmembrane ion fluxes. Approximately 70% of female carriers for DMD have an elevated level of creatine kinase in their serum. Affected males have high levels of creatine kinase detectable from birth. Presently, demonstration of absent dystrophin and/or deletion in the DMD gene is required for definitive diagnosis.

Fragile x syndrome More males are mentally retarded than females. Much of this disproportion may result from mutations of an as yet unspecified number of genes located on the X chromosome. This gives rise to phenotypes that behave as X-linked recessives, with no detectable abnormality in women. In a few of these disorders, however, there is some phenotypic expression in females, usually quite minor compared to that of hemizygous males. Fragile X syndrome is the most common form of inherited mental retardation. The Fragile X syndrome is most appropriately classified as an X-linked dominant condition with reduced penetrance in females. Fragile X results from a defect in the X chromosome (the FMR1 gene), which cannot manufacture a protein (FMRP) which it normally makes. FMRP is believed to be a regulatory protein essential for normal brain functioning. The genetic code for the FMR1 gene usually contains a limited number of CGG sequences (usually 5–50 repeats). When the number of CGG repeats is between 50 and 200, the individual is a carrier and has a premutation of Fragile X syndrome. When the number of repeats exceeds 200, this disrupts the code, prevents the production of the FMR protein, and these individuals have the full mutation and are affected by Fragile X syndrome.15 Males and females who possess the intermediate length permutation are often phenotypically normal, but there may be subtle facial dysmorphisms in males, or lowering of the IQ scores in both males and females. Fragile X affects 1 in 2000 boys and 1 in 4000 girls. One in 260 women are believed to be carriers.16 Carriers are not usually affected by Fragile X syndrome, but they are at risk of having affected children. 90% of Fragile X patients have autistic features, and 6% of autistic individuals have Fragile X. The effects of Fragile X are seen more frequently and with more severity in males. Each child of a carrier woman has a 50% chance of inheriting the gene. The Fragile X permutation can be passed silently through generations in a family before a child will be affected by the syndrome.

Pelizaeus–merzbacher disease (PMD) PMD begins in infancy (as early as 8 days of age, and usually before 3 months), is seen predominately in males, and is very slowly progressive (patients may live into middle age). The initial symptoms are pendular eye movements, head shaking, hypotonia, choreoathetosis, and pyramidal signs. Three types of PMD have been recognized. The classic type, with onset in infancy and death in late adolescence or early adulthood, is characterized by nystagmoid eye movements, jerking, and rolling head movements, or head tremor. The nystagmus disappears, and as the patient matures, ataxia, spasticity, and involuntary movements become apparent.

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Optic atrophy, microcephaly, and failure to thrive may also be features of this type. A second type will present with rapid progression and is fatal in infancy or childhood. The third type is a transitional or intermediate form, and may present with stridor early in life. Some heterozygous females may show symptoms as well. PMD has been determined to be a result of a mutation in the gene encoding proteolipid protein-1 (PLP1) which is located in the proximal long arm of the X chromosome (Xq22).14 The resulting leukodys­ trophy is limited to the central nervous system. There are a number of other X-linked neurodegenerative disorders that mostly affect boys, which will be listed here, but not further discussed. These include adrenoleukodystrophy, adrenomyeloneuropathy, ornithine transcarbamylase deficiency, X-linked spastic paraplegia, X-linked aqueductal stenosis with hydrocephalus, Menkes kinky-hair disease, Lesch–Nyhan syndrome, Hunter syndrome (mucopolysaccharidosis II), incontinentia pigmenti, X-linked lissencephaly, and Lowe oculocerebrorenal syndrome. This is by no means a complete list, but merely meant to allow the reader to look further, if interested.

Conclusion Neurologic disease can present in very different ways in children and adults, and also differs in boys and girls. Diseases may be specific to a certain developmental period (autism, Rett’s syndrome, absence seizures) or they may affect the physical development of the brain (neuronal migration disorders). In some conditions, only children are affected due to shortened lifespan. In others life expectancy is normal and disease may be diagnosed in childhood and continue into adulthood (Tourette’s syndrome). Children also may experience the same disease as adults, but with different symptomatology (migraines). With increasingly precise understanding of many genetic disorders, early diagnosis in childhood will permit appropriate genetic and prognostic counseling for families.

References 1. De Courten-Myers G. Gender-Specific Differences Found in Human Brain. American Academy of Neurology 51st Annual Meeting. Toronto; April 17–24, 1999. 2. Peterson BS. Neuroimaging Studies of Sex, Maturation, and Impulse Control: NYU Child Study Center Grand Rounds; 15 September, 2000. 3. Sowell ER, Thompson PM, Tessner KD, et al. Mapping continued brain growth and gray matter density reduction in dorsal frontal cortex: inverse relationships during postadolescent brain maturation. J Neurosci 2001;22:8819–29. 4. Szymanski ML, Zolotor A. Attention-deficit/hyperactivity disorder: management. Family Phys 2001;64(8):1355–62. 5. DeFrancesco L. Watching how the brain grows. The Scientist 2002;16:27.

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  6. Mostofsky S, Cooper K, Kates WR, et al. Smaller prefrontal and premotor volumes in boys with attention-deficit/hyper­ activity disorder. Biol Psychiatry 2002;52:785–94.   7. Bukstein OG, Lerner MA. The changing face of AD/HD: a clinical practice update. Clin Cour 2002;20:1–4.   8. Schapiro NA. ‘Dude, you don’t have Tourette’s’: Tourette’s syndrome, beyond the tics. Pediatr Nurs 2002;28(3):243–46, 249-53.   9. Alsobrook JP, Pauls DL. The genetics of Tourette syndrome. Neurol Clin North Am 1997;15:381–93. 10. Kotagal P, Luders HO, eds. The Epilepsies: Etiologies and Prevention. San Diego, CA: Academic Press; 1999. 11. Irizarry MC. Epilepsy. In: ME Cudkowicz, MC Irizarry, eds. Neurologic Disorders in Women. Newton, MA: Butterworth– Heinemann; 1997:1–16. 12. Aicardi J. Diseases of the Nervous System in Childhood. London: MacKeith Press; 1998. 13. Wyllie E. The Treatment of Epilepsy: Principles and Practice. Philadelphia, PA: Lea & Febiger; 1993. 14. Hurko O. Genetic disorders. In: PW Kaplan, ed. Neurologic Disease in Women. New York, NY: Demos Medical Publishing; 1998:53–83. 15. Hagerman RJ, Lampe ME. Fragile X syndrome. In: S Goldstein, CR Reynolds, eds. Handbook of Neurodevelopmental and Genetic Disorders in Children. New York, NY: The Guilford Press; 1999:298–316. 16. Turner G, Webb T, Wake S, et al. Prevalence of the fragile X syndrome. Am J Med Genet 1966;64:196–97.

Further reading Alves FE. Do women fare worse: a meta-analysis of gender differences in traumatic brain injury outcome. J Neurosurg 2001;93:862–64. Anon. New study shows prevalence of ADHD may be underestimated. Brown Univ Child Adolesc Behav Lett 2002;18:1–4. Aylward EH, Minshew NJ, Field K, et al. Effects of age on brain volume and head circumference in autism. Neurology 2002;59:175–83. Biederman J, Mick E, Faraone SV, et al. Influence of gender on attention deficit hyperactivity disorder in children referred to a psychiatric clinic. Am J Psychiatry 2002;159:36–42. Briellmann RS, Berkovic SF, Jackson GD. Men may be more vulnerable to seizure-associated brain damage. Neurology 2000;55(10):1479–85. Brown RT, Ievers CE. Gilles de la Tourette syndrome. In: S Goldstein, CR Reynolds, eds. Handbook of Neurodevelopmental and Genetic Disorders in Children. New York, NY: The Guilford Press; 1999:185–215. Bukstein OG, Lerner MA. The changing face of AD/HD: case studies. Clin Cour 20 April, 2002. Carey JC, McMahon WM. Neurobehavioral disorders and medical genetics. In: S Goldstein, CR Reynolds, eds. Handbook of Neurodevelopmental and Genetic Disorders in Children. New York, NY: The Guilford Press; 1999. Elliott H. Attention deficit hyperactivity disorder in adults: a guide for the primary care physician. South Med J 2002;95:736–42. Goldman LS, Genel M, Bezman RJ, et al. Diagnosis and treatment of attention deficit/hyperactivity disorder in children and adolescents. JAMA 1998;279:1100–7.

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Goldstein S. Attention deficit/hyperactivity disorder. In: S Goldstein, CR Reynolds, eds. Handbook of Neurodevelopmental and Genetic Disorders in Children. New York, NY: The Guilford Press; 1999:154–84. Hindmarsh GJ, O’Callaghan MJ, Mohay HA, et al. Gender differences in cognitive abilities in extremely low birth weight infants. Early Hum Dev 2000;60:115–22. Hong KE, Ock SM, Kang MH, et al. The segmented regional volumes of the cerebrum and cerebellum in boys with Tourette syndrome. J Korean Med Sci 2002;17:530–36. Jankovic J. Tourette’s syndrome. N Engl J Med 2001;35:1184–92. Kadesjo B, Gillberg C. Tourette’s disorder: epidemiology and comorbidity in primary school children. J Acad Child Adolesc Psychiatry 2000;39:548–55. Korn ML. Understanding and treating obsessive–compulsive disorder. US Psychiatr Ment Health Congr 2001. Kreeger KY. X and Y chromosomes concern more than reproduction. The Scientist 2002;16:25. Kurlan R. New treatments for tics. Neurology 2001;56:580–81. Mejias-Aponte CA, Jimenez-Rivera CA, Segarra AC. Sex differences in models of temporal lobe epilepsy: role of testosterone. Brain Res 2002;944:210–18. Mink JW, McKinstry RC. Volumetric MRI in autism: can hightech craniometry provide neurobiological insights?. Neurology 2002;59:158–59. Parraga HC, Parraga MI, Spinner LR, et al. Clinical differences between subjects with familial and non-familial Tourette’s syndrome: a case series. Int J Psychiatry Med 1998;28:341–51. Pary R, Lewis S, Arnpl C, et al. Attention-deficit/hyperactivity disorder: an update. South Med J 2002;95:743–49. Peterson BS, Pine DS, Cohen P, et al. Prospective, longitudinal study of tic, obsessive-compulsive and attention-deficit/hyperactivity

disorders in an epidemiological sample. J Am Acad Child Adolesc Psychiatry 2001;40:685–95. Plenge RM, Stevenson RA, Lubs HA, et al. Skewed X-inactivation is common in carriers of X-linked mental retardation (XLMR). Am J Hum Genet 2002;71:168–73. Resnick SM, Maki PM. Sex differences in regional brain structure and function. In: PW Kaplan, ed. Neurologic Disease in Women. New York, NY: Demos Medical Publishing; 1998:3–10. Roberts JE, Bell MA. The effects of age and sex on mental rotation performance, verbal performance, and brain electrical activity. Develop Psychobiol 2002;40:391–407. Rutledge SL, Mussell HG. Neurologic disease in girls. In: PW Kaplan, ed. Neurologic Disease in Women. New York, NY: Demos Medical Publishing; 1998:97–114. Scudder L. Recognition and management of attention deficit disorders. National Conference for Nurse Practitioners. 2001. Singer HS, Naidu SB. Rett syndrome: ‘We’ll keep the genes on for you’. Neurology 2001;56:582–85. Tourette Syndrome Association International Consortium for Genetics (TSAICG). A complete genome screen in sib pairs affected by Gilles de la Tourette syndrome. Am J Hum Genet 1999;65:1428–1436. Tsai EC, Santoreneos S, Rutka JT. Tumors of the skull base in children: review of tumor types and management strategies. Neurosurg Focus 2002;12(5):e1. Volpe J. Neurology of the Newborn. Philadelphia, PA: WB Saunders; 1987. Zohar AH, Apter A, et al. Epidemiological studies. In: JF Leckman, DJ Cohen, eds. Tourette’s Syndrome – Tics, Obsessions, Compulsions: Developmental Psychopathology and Clinical Care. New York, NY: Wiley & Sons; 1999:177–92.

Chapter

6

Gender and Sports: Past, Present, and Future Jordan D. Metzl Co-Founder, The Sports Medicine Institute for Young Athletes, Hospital for Special Surgery, New York, NY

Introduction

sex. Since this included all school-sponsored extracurricu­ lar activities, sports teams were affected. Although Title IX does not mandate equal funding for male and female sport­ ing teams in practice, it does mandate that the ratio of male to female athletes be equal to the ratio of males to females at the institution. Following on the heels of Title IX was the Amateur Sports Act of 1978, which extended the policy of nondiscrimination to amateur sports. This increased opportu­ nities for women to participate in amateur events like the Olympics and other international sporting events. Before Title IX, it is estimated that about 1 in 27 American high school girls participated in varsity sports. In 1999 it was estimated to be 1 in 3, closely approximat­ ing the 1 in 2 American high school boys participating in varsity sports. The increase in participation has spawned a revolution in female athletics, and has opened new direc­ tions of research in Sports Medicine. Women and men clearly occupy different niches in sports, with areas of overlap and areas of divergence. Differences in performance between male and female ath­ letes can partly be explained by physiology. Separating these differences from those caused by cultural and societal expectations, environment, upbringing, coaching, and train­ ing is difficult.

The demographics of sports participation have changed considerably over the past 20 years. Sports participation used to be restricted to high level male athletes competing in high school, collegiate, and professional sports. With the advent of Title IX in 1972, the landscape of the sports world changed considerably. As of 2008, there are record numbers of female athletes participating in sports both in the United States and around the world. In the high school age group, the numbers of male and female participants are nearly equal. This has changed the very nature of the term ‘athlete.’ In today’s culture, sports participants are equally likely to be female as male. There are significant differences between female and male athletes. These differences include physiologic abil­ ity to achieve maximum potential, injury patterns related to gender, and specific medical issues related to sports partici­ pation. This chapter will explore the differences between male and female athletes.

Sports in america: a changing demographic The demographics of sports and physical activity have changed dramatically over the past 40 years in the United States. Whereas sports participation and viewing was once dominated by males, female participation has increased more than 500% in the past 20 years. There are several important reasons for these changes. Title IX of the Education Amendments of 1972 prohi­ bited institutions receiving federal funds from discriminating in admissions, access, and treatment of students based on

Principles of Gender-Specific Medicine

Physiology Size There are numerous physiologic differences between men and women that contribute to differences in sports perform­ ance and experience. The first and most obvious is the fact

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s e c t i o n 1     Gender and Normal Development l

that men are usually taller and weigh more than women. As a corollary, men have longer limbs, especially advanta­ geous in sporting activities where the arms or legs are used for lever-like motions. Men also have greater muscle mass, with a greater area of muscle fibers. Until the age of 10–11 years, boys and girls are roughly similar in size and sports ability. Females experience puberty first, and have their growth spurt around 12 years of age. Boys have their growth spurt later, around 13 years of age, but grow more during their period of rapid growth than females. Girls usually attain skeletal maturity at 18 years of age, while boys attain skeletal maturity at about 21 years of age.

Body Proportions Until roughly the age of 11, the ratio of sitting height to standing height is similar for boys and girls. After age 11, this ratio increases in girls and remains higher in adult females than adult males. Even if they are the same height, women will have shorter legs than men, giving them a rela­ tively lower center of gravity. Men also have broader shoulders as compared to their hips, whereas women usually have wider hips as compared to their shoulders. This has been demonstrated by measuring the ratio between the biacromial breadths. This ratio remains relatively constant in males between the ages of 9 and 18 years, while in females during this time it steadily decreases.

Composition Females consistently have an increased percentage of body fat compared to males. The percentage body fat in females on average is about 22–26%, while in males it ranges from 13 to 16%. The distribution of this fat is also different. Women tend to store more fat in the lower half of the body, concen­ trating on the thighs and buttocks, while men tend to concen­ trate more fat in the upper half of the body in the abdomen. Basal metabolic rate is 6–10% lower in non-pregnant females than in males; females need fewer calories to maintain the same level of activity as males.

Cardiorespiratory System The cardiovascular and respiratory systems also show sig­ nificant differences between men and women. Men have larger hearts, with increased pumping force and increased stroke volume. At rest, women have a slightly faster heart rate than men, but this is not enough to equalize cardiac output. Women also have a smaller blood volume than men and a lower hemoglobin concentration. For the respiratory system, men have larger chest wall size, larger lung vol­ umes, larger vital capacity, and larger residual volumes. Maximal oxygen uptake, or VO2max as expressed in l/min, is the best measure of overall functional capacity. VO2 is similar in boys and girls before puberty. In adults, however,

VO2max is 40% greater in males than females. When this is adjusted for body weight, VO2max is about 20% greater in males than females. When adjusted for lean body mass to take into account the greater percentage of body fat in females, the VO2 is still around 8–10% greater in males than females.

Other Differences There are many other factors to consider when assess­ ing physical and functional differences between male and female athletes. Women have an increased carrying angle of the arm at the elbow and thighs that slant more inward toward the knees. These differences affect the biomechanics of motion differently for different activities. Bone mineral density is an important issue for females, with osteoporosis more prevalent in the female population in general. No sig­ nificant differences have been demonstrated in temperature regulation and gender. There exists an entire realm of societal and cultural influences to study when comparing male and female ath­ letic performance. In addition to body habitus, sportsrelated skills also determine level of athletic performance. Traditionally, women have not received the same amount of encouragement, training or coaching as men. With changes in demographics of participants, this is changing.

SpecifIc issues of gender and sport The issues of gender and sport are of paramount importance to both improving performance and preventing injury. As has been previously mentioned, there are fixed physiologi­ cal differences that affect performance in male and female athletes. In terms of injury prevention, there are specific injury patterns that are unique to both genders. These are important when considering safe and healthy participation. This section will explore these issues in terms of gender.

Female Athlete The Female Athlete Triad One of the issues specific to the female athlete which is receiving a great deal of attention is the female athlete triad of disordered eating, amenorrhea (absence of menses), and osteoporosis (low bone density). The risk in terms of the athletic population is that women with low bone density are particularly prone to stress fractures, injuries to the bone from repetitive use. Disordered eating in female athletes can manifest in different ways. Restrictive eating patterns and compulsive exercise habits contribute to a total energy and caloric defi­ cit. Athletes most at risk for disordered eating are those who participate in sports that emphasize thinness for either mechanical or aesthetic reasons, such as gymnastics, ballet,

C h a p t e r 6     Gender and Sports: Past, Present, and Future l

figure skating, and cross-country running. Most of these athletes maintain body weight through restriction of calo­ ries, but others do engage in activities such as binge eating, purging, and laxative use. The DSM-IV manual describes the clinical criteria for eating disorders. Poor nutrition and inadequate caloric intake can result in hormonal changes in the athlete, most important of which is loss of the luteinizing hormone (LH) surge. Normal men­ strual function is dependent on having normal levels of estrogen and normal LH pulsatility. LH pulsatility, how­ ever, is dependent on energy availability. Without adequate caloric intake, the LH surge is absent or reduced, and men­ struation is impaired. Women athletes have a high incidence of primary amenorrhea (absence of menses by the age of 16 years), secondary amenorrhea (absence of 3–6 menstrual cycles in a menstruating woman), and oligomenorrhea as compared to controls. Amenorrhea and associated low levels of estrogen con­ tribute to osteoporosis. Estrogen slows bone resorption and contributes to the maintenance of strong and functional bone architecture. Bone mineral density tests demonstrate that adolescents with amenorrhea or oligomenorrhea may lose up to 2% of bone mass per year as opposed to the normal annual gain of 3%. Some of this bone loss may not be completely recoverable despite the resumption of normal menses. Women with lower bone density, either osteopenia (greater than one standard deviation from normal values) or osteoporosis (greater than two standard deviations from nor­ mal), are more prone to bone-related injuries such as stress fracture from overuse. Athletes with stress fractures can be recognized by having gradually worsening pain associated with a particular activity. Physical exam is usually remark­ able for a point of tenderness in the bone, difficulty bear­ ing weight, and sometimes mild swelling. Although plain radiographs are usually the first test of choice in evaluation, they are often unremarkable, and radiographic findings can lag behind clinical findings by weeks. Common findings are mild lucencies in the compact bone, and the gray cortex sign in focal areas of stress injury. MRI and sometimes bone scan are often used to confirm the diagnosis of a stress fracture. Treatment of stress fractures generally does not require surgery; most injuries heal within 4–6 weeks with rest, ice, and non-steroidal anti-inflammatory (ibuprofen) as needed. Once stress fractures are healed, prevention of recurrence is important. Ensuring proper foot biomechanics through the use of orthotics and promoting adequate muscle strength to lessen the load on the affected area are both useful. Good rehabilitation and the maintenance of strong muscles can help to prevent future injuries. Awareness of the female athlete triad is extremely impor­ tant. The physician, coach, or parents should inquire about nutritional practices, with a concentration on eating pat­ terns, caloric intake and any purging activities. Prevention of the female athlete triad lies in a careful history and good anticipatory guidance.

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Ligamentous Injury Since the increase in women’s participation in sports, the prevalence of injuries has risen. Over the past 15 years it has been noted that female athletes in sports such as soc­ cer and basketball are at least four times as likely as males to suffer injury to the anterior cruciate ligament (ACL), the major stabilizing ligament in the knee. These injuries are significant and usually require surgery and 7 months of rehabilitation before return to activity. Several theories have been proposed to explain this gender difference. Women in general have greater ligamentous laxity than men, although men’s and women’s measurements overlap. It was thought earlier that this increased laxity could predis­ pose women to ACL injuries. Ligaments do have estrogen receptor sites, although the significance of these receptors is not known. Some studies have shown increased ligamen­ tous laxity associated with higher estrogen levels and have postulated that athletes may be at more risk for injury dur­ ing certain periods of the menstrual cycle. This theory has recently fallen from favor. More recently, joint proprioception has been studied as a factor in ACL injury. Detection of joint movement is critical to determining the position of the knee and its risk for injury from intrinsic or extrinsic forces. Some experiments have shown decreased joint proprioception in females as com­ pared to males. One interesting study showed that although female proprioception was inferior, females demonstrated superior balancing ability and a greater activity of the lateral hamstring muscles when landing from a jump. This could possibly represent a compensatory mechanism for decreased proprioception and increased ligamentous laxity. With females at higher risk of ACL injury and with more women participating in twisting and pivoting sports such as soccer and basketball, it is no wonder that ACL injuries have increased considerably, both in absolute number and as a percentage of sports injuries. Effective prevention programs can reduce the risk of ACL injury in female athletes. Prevention is important, not only for the immediate complications of ACL injury, but also for the long-term consequences. The post-ACL injured knee is at high risk for arthritic degeneration with or with­ out surgical treatment. ACL injury prevention programs are available both over the Internet and in person. They gen­ erally combine hip strengthening, plyometric jump, and landing exercises, and screening for at-risk athletes. These programs should be the hallmark of pre-sports preparation for female athletes over the age of 12 and are starting to be implemented at the junior high and high school level. Nutrition Female athletes have special metabolic and nutritional needs. One of the primary issues facing female athletes is finding the healthy balance between caloric intake and expenditure. Thinness is desired by many women, especially

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those involved in athletics. In any sport or training program, it is essential to consume enough energy to cover the basic energy costs of building and repairing muscle mass. Many women, and frequently women and girl ath­ letes, express a desire to lose weight. Some attempt to lose weight through food restriction and exercise, which can result in a negative energy balance. Some sports empha­ size a thin physique, and female athletes often feel pres­ sure to create a negative energy balance. Long term energy restriction can contribute to fatigue, poor concentration, increased risk for injury, and prolonged recovery time after an injury. Concentration on thinness also can contribute to the increased prevalence of eating disorders among certain athletes. If an athlete does need to lose weight, aerobic and strength exercise should be judiciously combined with mild to moderate decreases in energy intake. Training should be increased in intensity by small amounts only, with adequate periods of rest for building and repairing muscle. Special care must be shown to consume a diet with appropriate bal­ ance of carbohydrate, protein and fat. A sports nutritionist is often a helpful ally in creating a healthy diet. In the adolescent female athlete, these issues are espe­ cially important. Adolescent female athletes not only have to consume enough energy to meet basic metabolic and nutritional demands, but also need substrates with which to grow. Female adolescents who engage in strenuous activ­ ity may need to consume up to 2400–2600 kcal to allow for optimal growth and prevent muscle breakdown. Healthy nutrition also requires the proper amounts of vitamins and minerals such as calcium, iron, and vitamin B. These nutrients are essential for enzyme function, energy production, heme (blood) synthesis, and the maintenance of appropriate bone mineral density. These issues are particu­ larly important to the female adolescent athlete whose body is undergoing rapid growth and development. Calcium is deficient in the diet of most Americans. For women between 9 and 18 years, the recommended daily intake (RDI) is 1500 mg/day, while for adult women the RDI is 1000 mg/day. On average, the calcium intake for adult women in the United States is about 770 mg/day. Calcium is necessary for the maintenance of healthy bones and for the prevention of stress fractures. In order to absorb adequate calcium, female athletes also must maintain ade­ quate vitamin D and estrogen levels. Clinically, poor bone health evidenced by a stress frac­ ture in a young female athlete should prompt concern regarding possible osteopenia as a causative factor. In addi­ tion to a good menstrual and dietary history, DEXA scan­ ning has become the standard of care as a screening tool for low bone density. This test should be utilized to screen any athlete suspected to have low bone density. If osteopenia or osteoporosis is present, effective nutritional counseling with respect to calcium and vitamin D is indicated. Iron deficiency is also common in female athletes. Many limit meat intake and have increased iron losses through

menstruation, sweat, and urine. Many iron-fortified foods have low bioavailability and must be consumed in great quantities to achieve positive iron balance. Iron is necessary for heme synthesis and also for effective energy metabolism. Female athletes tend to be mildly deficient in most of the B complex vitamins, especially folate and vitamin B12. It is critically important for women of childbearing age to be in a positive folate balance to prevent neural tube defects in children. Even with the increased requirements of exercise, female athletes should be able to consume their daily recommended vitamins and minerals through a healthy, well-balanced diet. Anticipatory guidance through preventive counseling and education programs can help athletes better understand the importance of nutrition.

Specific Issues of Male Athletes Ergogenic Aids Ergogenic aids are substances used by athletes to enhance ath­ letic performance. Although ergogenic aids are used by both male and female athletes, they traditionally have been more of a problem in the male population. Anabolic-androgenic steroids are the most serious of the compounds commonly used by athletes; studies estimate a 5–10% user rate in the adolescent male population. Anabolic steroids are testoster­ one derivatives that are taken orally or injected. In 1990, the United States Congress passed the Anabolic Steroids Control Act, which added these compounds to Schedule III (non-narcotic substances) of the Controlled Substances Act. Some steroid precursors such as androstenedione are pack­ aged as nutritional supplements and are legal in some sports. The Food and Drug Administration does not regulate these so-called nutritional supplements. The effects sought from steroid-based compounds are anabolic: increased skeletal muscle mass, decreased catab­ olism, increased aggressiveness, and decreased fatigue. Many different synthetic steroids have been formulated in an attempt to maximize the perceived benefits of anabolicandrogenic steroids and minimize the undesirable side effects, with varying degrees of success. Steroid use does increase muscle mass and decrease catabolism. The effects are most pronounced in athletes combining steroid use with strength training. Side effects are due to the androgenic properties of the steroids. Side effects that are relatively reversible include decreased sperm production, infertility, male pattern bald­ ness, gynecomastia, acne, and increased rates of hepatic cancer. Anabolic steroids have been implicated in altering lipoprotein profiles, with increased low-density lipoprotein (LDL) levels and decreased high-density lipoprotein (HDL) levels, thus increasing the risk of atherogenic changes and cardiovascular heart disease. Anabolic steroids can also increase both systolic and diastolic blood pressures, espe­ cially at high serum concentrations. Finally, these substances

C h a p t e r 6     Gender and Sports: Past, Present, and Future l

are mind-altering. Psychiatric changes sometimes associated with anabolic steroid use include depression, aggression, hostility, and paranoia. These are often referred to as the ‘steroid rage.’ Estimating the prevalence of steroid use as an ergogenic aid is difficult, due to its illegal status and the stigma associ­ ated with its use. Some sporting associations have stringent drug testing and zero tolerance policies, while others are pur­ ported to turn a blind eye to rampant use. The level of com­ petition is an important factor in determining the pressure on an athlete to use supplemental steroids, as is the prevalence of use by peers. Dissatisfaction with body image and weight, perfectionism, and a drive to win at all costs are characteris­ tics attributed to many anabolic-androgenic steroid users. Most alarming are the data collected from different anony­ mous adolescent surveys, including the Youth Risk and Behavior Surveillance System data collected by the Centers for Disease Control and Prevention. These studies consist­ ently show that approximately 6% of adolescent males and 1% of adolescent females admit to using illegal steroids. Exogenous androgens can lead to premature fusion of the epiphyses, termination of growth, and ultimate short stature. Other ergogenic aids are used and discussed more freely because they are legal and exist under the nebulous category of ‘dietary supplements.’ Creatine, a compound made up of three amino acids, has received a great deal of publicity due to its use by high-profile elite athletes. Creatine taken orally in powder form can increase muscle stores of phos­ phocreatine, which is thought to facilitate faster regenera­ tion of muscle adenosine triphosphate (ATP) and decrease muscle fatigue. This would be especially useful for activi­ ties requiring a high intensity of energy over a short period of time, like swinging a baseball bat. The major side effects are abdominal bloating, weight gain, muscle cramps, and mild hypertension. Several reports of renal failure in patients with underlying renal disease make creatine a sub­ stance to be used with caution and discouraged in adoles­ cent athletes. No study has tested the safety of creatine in subjects less than 18 years of age. The number of nutritional supplements on the market continues to increase exponentially, making it impossible for anyone to maintain a comprehensive body of knowl­ edge about the safety and side effects of these products. It is imperative to keep in mind that for most of the dietary supplements used as ergogenic aids, the Food and Drug Administration has no legislative control over the efficacy or even the content of the products sold. The concentration of the desired substance has been shown to vary widely from package to package, often with unknown and poten­ tially harmful ingredients mixed in for added effect. Until there is strict regulation of the use and abuse of all of these substances, the incentive to achieve and maintain a com­ petitive edge at all costs will perpetuate the use of ergo­ genic aids. The physician, parent, or coach must be vigilant to the possibility of the use of ergogenic aids and must be

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able to provide a non-judgmental environment to facilitate candid discussions and counseling about the risks of these products. Males, Sports, and Violence Aggression, often necessary for winning, is acceptable and indeed encouraged in many sports. Sports provide a con­ trolled and acceptable venue for physical aggression. Occasionally sports violence on and off the field is excessive and harmful. These episodes can be defined as ‘aggression outside of the rules of acceptable competition with the intent to harm another person.’ Stories of exces­ sive sports violence often receive significant attention in the media, sending an unsatisfactory message to the general community that unchecked violence is condoned. These violent actions are almost exclusively perpe­ trated by male athletes. Behavior that is clearly unaccept­ able in general society may be tolerated or even rewarded in the sporting arena. A disproportionate number of athletes are accused of sexual assault or domestic violence against women. Children are sensitive to media messages and the most aggressive athletes, as defined by their physicality and will­ ingness to risk serious injury, may be glorified. Sports cov­ erage often shows ‘highlights’ of fights occurring during a game, reinforcing the concept that fights are expected and acceptable. In American culture men face societal expectations of being strong and aggressive. They are encouraged to play sports at an early age, often bonding with fathers or other older male figures through athletic endeavors. While they are likely to receive encouragement, support, and better coaching and training, boys face more pressure to succeed in physical and athletic arenas than do girls. Studies show that among American athletes, aggression and violence is best associated with lower socioeconomic status. A structured and supportive family unit provides some protection against violence. Sports can also provide an acceptable vehicle for physical aggression without crossing the line into violence. Athletics in general promote socializa­ tion and young athletes learn to relate to each other in a com­ petitive environment. It is tremendously important, however, for those supervising male athletes, including parents and coaches, to ensure that the healthiest message is presented. This includes teaching the value of fair competition and demanding appropriate behavior both on and off the field.

Conclusion This chapter has examined the issue of sports participa­ tion and gender. Overall, sports participation is a favorable lifestyle choice that encourages fitness and activity. The number one cause of mortality for men and women con­ tinues to be related to obesity and cardiovascular disease.

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Physical activity and a healthy diet reduce the incidence of many common diseases that contribute to this mortality. Sports participation continues to increase for male and female athletes and is an important part of the American lifestyle and culture. Physical activity has many benefits and participation should be strongly encouraged. Although some medical issues of the athlete are similar for men and women, there are many differences in physiology, psychology, and culture to be addressed. Greater awareness of the specific issues concerning male and female athletes will encourage important preventive health measures in the future.

Further Reading Abdal-Haqq I. Violence in Sports: ERIC Digest, American Association of Colleges for Teacher Education; 1989. Ahrendt DM. Ergogenic aids: counseling the athlete. Am Fam Phys 2001;63(5):913–22. American Academy of Pediatrics. Medical concerns of the female athlete. Committeee on sports medicine and fitness. Pediatrics 2000;106(3):610–13. Blue JG, Lombardo JA. Nutritional aspects of exercise: steroids and steroid-like compounds. Clin Sports Med 1999;18(3): 667–89. Callahan L. Stress fractures in women. Clin Sports Med 2000;19(2):303–14. Centers for Disease Control and Prevention. www.cdc.gov; 2002. Children Now. Boys to men, sports media – message about mas­ culinity. www.childrennow.org. (accessed October 2007). Garrett WE, Kirkendall DT, eds. Exercise and Sport Science. Philadelphia, PA: Lippincott Williams & Wilkins; 2000.

Harmon KG, Ireland ML. Gender differences in noncon­ tact anterior cruciate ligament injuries. Clin Sports Med 2000;19(2):287–302. Hewett TA. Predisposition to ACL injuries in female athletes ver­ sus male athletes. Orthopedics 2008;31(1):26–28. Hobart JA, Smucker DR. The female athlete triad. Am Fam Phys 2000;61(11). Humara M. The relationship between athletics, hispanics, and aggression. Athletic Insight 2002;1(1), online. Lopiano DA. Modern history of women in sports. Clin Sports Med 2000;19(2):163–73. Loud KJ, Gordon CM, Micheli LJ, et al. Correlates of stress fractures among preadolescent and adolescent girls. Pediatrics 2005;115(4):e399–406. Manore MM. Nutritional aspects of exercise: nutritional needs of the female athlete. Clin Sports Med 1999;18(3):549–63. Micheli L. The Sports Medicine Bible. New York, NY: HarperCollins; 1995. Renstrom P, Ljungqvist A, Arendt E, et al. Non-contact ACL inju­ ries in female athletes: an international olympic committee cur­ rent concepts statement. Br J Sports Med 2008;42(6):394–412. Rozzi SL, Lephart SM, Gear WS, et al. Knee joint laxity and neu­ romuscular characteristics of male and female soccer and bas­ ketball players. Am J Sports Med 1999;27(3):312–19. Shangold M, Mirkin G. Women and Exercise: Physiology and Sports Medicine, 2nd edn.. Philadelphia, PA: FA Davis; 1994. Shangold M, Rebar RW, Wentz AC, et al. Evaluation and management of menstrual dysfunction in athletes. JAMA 1990;263(12):1665. Sullivan JA, Anderson SA. Care of the Young Athlete. Rosemont, IL: American Academy of Pediatrics and the American Academy of Orthopedic Surgeons; 2000.

Section 2

Gender and the Nervous System

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s e c t i o n 2     Gender and the Nervous System l

Introduction William Byne

Men and women differ in their vulnerabilities to particular neurological and psychiatric disorders, as well as in the particular manifestations of those disorders, their clinical course, and response to therapy. Such differences are not surprising considering that each cell within the central nervous system differs chromosomally and genetically between the sexes, with women having perhaps as many as 130 more active genes per cell than men. Moreover, genetic and endocrine factors interact in early development to produce brains that are sexually dimorphic in their rates of development and senescence as well as in their structural and functional organization. Added to the contribution of these biological differences is the medical impact of social, cultural, and economic factors associated with living in a particular gender role. The goal of gender-specific medicine is to take all of these factors into account in order to optimize the healthcare of all patients, regardless of gender. Particularly when the brain is involved, however, gender-specific medical research carries the risk of contributing to gender-based social discrimination by widening the perception of gender inequalities. That risk cannot be denied and we must take steps to mitigate it. We should not, however, be deterred by it. The potential benefits of a gender-specific approach to healthcare are too great. I thank the authors who have contributed to this section for the superb job they have done in providing the most current information available in their respective specialties.

Gur et al. provide a comprehensive overview of sex differences in the structural and functional organization of the brain. Drawing largely on animal work, McCarthy provides a state of the art review of the cellular mechanisms that underlie sex differences in brain structure and function, emphasizing how these mechanisms are brain regionspecific. My own chapter then addresses parallel research in humans where much less is known. Amatniek et al. provide a comprehensive review of the gender-specific incidence rates of neurological disorders and explain how these are a necessary first step toward development of gender-specific interventions. Gottesman and Hillis describe gender differences in the epidemiology and mechanisms of stroke as well as in stroke symptoms and recovery. Seeman reviews gender differences in psychiatric disorders that present during childhood, adulthood, or old age in order to draw inferences pertaining to possible etiological mechanisms. Finally, Sano et al. review clinical trials of a gender-specific intervention, postmenopausal hormonal replacement therapy. Cognitive data in adulthood and aging through the menopause are reviewed as are the effects of hormone replacement therapy on cognitive functions. Given the complexity of the CNS and the disorders that affect it, many important issues could not be accommodated within the pages of this section. Nevertheless, we hope that we have drawn attention to the importance of a genderspecific approach to disorders of the CNS and to current gaps in our knowledge. Above all, it is hoped that an appreciation of those gaps will encourage gender-specific research that will culminate in improved healthcare for all.

Chapter

7

Gender Differences in the Functional Organization of the Brain Ruben C. GUR 1, Tamara Bockow 2, and Raquel E. Gur3 1

Professor of Psychology, University of Pennsylvania Medical Center, Department of Psychiatry, Radiology and Neurology, and the Philadelphia Veterans Administration Medical Center, Philadelphia, Pennsylvania, PA, USA 2 Medical Student, University of Pennsylvania Medical School, Philadelphia, PA, USA 3 Professor of Psychiatry, Neurology, and Radiology, University of Pennsylvania Medical Center, Pennsylvania, PA, USA

Introduction

objections are based on the notions that when there is a dif­ ference between two groups then one must be ‘better,’ and that biology is destiny and, therefore, that differences are not malleable. Of course, these are misconceptions. Apples and oranges are different without one being inherently bet­ ter, and genetic predisposition for high cholesterol can be countered by diet and other means. Thus, the discovery of a biological basis for sex differences should not imply dif­ ferential treatment, social or individual, nor should it entail acceptance and inaction. It should be studied in a way that can improve understanding of brain behavior relation and enhance patient care.

Converging lines of research suggest that sex differences may modulate healthy behavior across the lifespan1,2 as well as brain structure3–5 and function.6,7 Sex differences are evident in the presentation and course of a range of mental disorders,8–10 other brain disorders,11–13 and autoim­ mune disorders.13 The growth of divergent methodologies has reached the level of maturity necessary for integrative research that can help advance understanding of such sex differences. It is important to keep in mind that sex differ­ ences exist against a background of fundamental similari­ ties, and that aspects of behavioral differences between men and women vary across cultures. However, there is increas­ ing evidence for neurobiological substrates. Animal and human studies have suggested that reproductive hormones play a significant neuroregulatory role in brain develop­ ment and sexual dimorphism.14–19 The existence of sex dif­ ferences in brain anatomy and physiology has implications for understanding the neural organization of behavior in healthy people, and its disruption in illness. The purpose of this chapter is to review the available evidence for sex dif­ ferences in behavior that may relate to differences in brain anatomy and physiology. While the implications of these sex differences are still unclear, we will attempt to outline some general directions that may help improve patient care. One issue merits mention prior to examining specific evidence. Reporting the discovery of sex differences in neu­ robiology requires sensitivity to potentially strong social and public reactions. Investigators who have been studying such differences since the late 1970s have experienced the intensity of both positive and negative reactions. The main

Principles of Gender-Specific Medicine

Sex differences in behavioral measures While behavioral measures do not provide direct evidence for neurobiological substrates, linkage between behavioral domains and regional brain function can help guide hypo­ theses on brain dysfunction. A comprehensive review of this literature is beyond our scope, but we will highlight the main findings in the area of sex differences in cognitive and emotion processing that can be linked to neurobiology.

Cognitive Processing Sex differences in cognition have been well documented with standardized measures. Women perform better on some verbal and memory tasks, whereas men excel in spatial tasks.1,2,20,21 These differences were attributed to variation in hemispheric specialization of cortical function. While

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Copyright 2010 20 , Elsevier Inc. All rights reserved.

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the left hemisphere is generally dominant in verbal and the right in spatial processing,22 some neuropsychological studies have suggested less hemispheric specialization in women compared to men.23,24,25 Gender-related differences in behavior have been observed across species and are increasingly being linked to sex differences in neurobiologic substrates. The dimen­ sion of processing capacity has not been systematically disentangled from that of memory, although there are some indications that these factors have an additive influence, and perhaps interact. For example, evidence for better verbal memory in women is stronger than for other verbal process­ ing tasks,26 and while better performance has been consist­ ently shown for men on spatial tasks,21 there is evidence for equal performance on episodic memory for geometric designs.27,28 0.5 0.4

Sex differences in cognition need evaluation from a devel­ opmental perspective.14,19,26 Studies in children with Turner’s syndrome dramatize the pivotal role played by gonadal hor­ mones in shaping sex differences in cognitive functions.16 In a sample of healthy young adults (age 18–45), consisting of 124 men and 117 premenopausal women, we have observed sex differences in 3 of 8 behavioral domains (Figure 7.1a). Women had better verbal memory, and men performed better on spatial and motor tasks. In examining compo­ nents of domains that show sex differences, we find that the verbal memory advantage for women is accounted for pri­ marily by performance on the California Verbal Learning Test29 whereas the advantage for men in spatial abilities is accounted for by performance on Benton’s Line Orientation Test.30 Some sex differences are manifested not in the pro­ file of abilities, but in the effects of healthy aging within 0.6

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Figure 7.1  Sex differences in neurocognitive profile (a) and age effects (b) on performance in the traditional neuropsychological bat­ tery and on the computerized battery (c) for accuracy (top panel) and speed (bottom panel) in healthy men and women. Reproduced from Gur, Ragland, Moberg, et al., 2001.31

C h a p t e r 7     Gender Differences in the Functional Organization of the Brain l

the range of young adulthood. In our sample, age range of 18–45, no significant correlations were observed between age and any of the behavioral measures in women. For men, however, increased age was associated with decrease in per­ formance on attention, verbal memory, spatial memory, and spatial abilities (Figure 7.1b). To enhance efficiency, we have developed a computerized battery.31 The pattern of sex differences seen with this computerized battery duplicates that obtained with traditional paper and pencil batteries, but adds the finding that women do better in facial memory, not available in the traditional battery (Figure 7.1c). Efforts to relate gender differences in cognition to neuro­ biologic substrates have followed three main avenues: cor­ relation of cognitive performance with hormonal state, examination of neuroanatomic measures in structural imag­ ing and post-mortem studies, and examination of neuro­ physiologic measures using functional imaging. While this area is relatively early in development, and there are several inconsistent reports, some convergence does seem to emerge. Both animal and human research on gonadal hormones indicates that they play a neuroregulatory role in early CNS organization, and modulate the activity of mature neural pathways.16,17 Estradiol, the major estrogen in premenopausal women, affects neurotransmitters in brain regions presumably involved in memory.32 The relation of hormones and human behavior has been examined by stud­ ies of hormone levels and cognition. In premenopausal women fluctuation in hormone levels during the menstrual cycle has been associated with performance on cognitive and motor tasks. Better performance in verbal fluency33 and memory34 has been reported during the high-estrogen and low-progesterone phase of the cycle, relative to improved spatial performance during menses, the low estrogen and progesterone phase.35–37 On the other hand, Janowsky et al.18 found negative correlations between estradiol levels and ver­ bal performance and positive correlations with spatial per­ formance for women studied during the mid-luteal phase as well as for men. They propose that in addition to the well-established effects of sex hormones during develop­ ment, ‘testosterone continues to play a modulatory role in the function of the prefrontal cortex, particularly working memory, throughout life’ (p. 410). The mechanism for such effects could include receptor androgen genomics or aroma­ tization of testosterone to estrogen with downstream effects on estrogen receptors or synaptic morphology or function.

Emotion Processing In the constellation of factors affecting sex differences in cognition, the role of emotion has received relatively limi­ ted attention. Dysphoric mood has been associated with the onset of menses in healthy women38 and the effects of mood on cognitive performance have been demonstrated in sev­ eral studies,39,40 but few links have been established between menstruation-related mood changes and performance. Memory and emotion have not been separated in most studies.

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Attempts to dissect these components suggest that emotional stimuli may enhance or impair recognition memory. Perceiving, experiencing, and expressing emotions seem essential capacities, and more recently the study of emotion has benefited from converging methodologies in animals and humans.41,42 The face has been the main target of study in humans, and methods were applied to quantify expression of emotion with cross-cultural consistency.43–45 Standardized tools have been developed for measuring emotion discrimination,46 mood induction,47,48 affective valence, and arousal.49 Emotional displays that can be reli­ ably coded in the face are happiness, sadness, anger, fear, and disgust, while surprise is more controversial. There is also increased agreement that emotion processing is not restricted to the ‘limbic system’ and involves cortical regions, where it seems to be organized, perhaps paral­ lel to the ‘cognitive’ system, along laterality and anterior– posterior dimensions.50,51 There is controversy about whether emotional expression is lateralized, although a meta-analysis by Borod et al.52 seems to confirm that nega­ tive emotions are expressed more intensely on the left side of the face whereas the opposite may hold for positive emo­ tions.53 There is more agreement, though less data, that receptive, experiential, and expressive aspects of emotion processing can be mapped to frontal, temporal, and pari­ eto-occipital involvement, respectively. This interaction between the emotion and cognitive systems, particularly as it applies to memory, is an issue of current interest. Sex differences were observed in affect and emotion processing.54,55 Women perform better in speeded emotion recognition tasks56 and in tasks requiring facial expression of emotions.54 In a study of facial recognition, we reported sex differences in sensitivity to happy and sad expressions depending on the poser’s sex. Women were more sensi­ tive to opposite than to same-sex expressions, whereas men were differentially poor at detecting sadness in female faces.46 Regarding emotional experience, women are more prone to clinical depression.8 Mood fluctuations associated with phases of the menstrual cycle have been documented, and such phase associated hormonal changes may relate to cognitive performance.33–37 There is increased evidence that men and women may differ in their emotional memory. Cahill and colleagues found gender-related hemispheric asymmetry of amygdala function related to emotional memory. Memory of emo­ tional ma­terial seems to involve mostly the right hemisphere of the amygdala in males and mostly the left hemisphere of the amygdala in females.57,58 Using this evidence, and the hypothesis that the brain has a bias for processing holistic information on the right and detail information on the left, Cahill and colleagues tested sex differences in the effects of a beta-adrenergic receptor antagonist, propranolol, on longterm memory of an emotionally arousing story. Although the propranolol was given systemically, it was expected to disrupt the memory-modulating function only of the hemisphere containing the amygdala most involved in the

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emotional learning situation (amygdala in the left hemi­ sphere of women, in the right hemisphere of men). Indeed with propranolol, which is expected to deactivate the limbic system bilaterally, men were impaired in remembering glo­ bal aspects of the story, while women showed the opposite effect, impairment with the story details but not the cen­ tral information.58 This experiment supports both the role of sexually dimorphic lateralization in the amygdala and the information processing biases in the two hemispheres. This work on gender differences in memory and emotions has implications for understanding clinical disorders such as posttraumatic stress disorder (PTSD). The incidence of PTSD is approximately twice as high in women as in men, and neural mechanisms may underlie some of these gender differences.58 More recently, sex differences have been reported in the way men and women perceive and anticipate rewards. Dreher et al. showed that gonadal steroid hormones, such as estrogen and progesterone, can influence the human reward system. Using functional MRI, they found that when anticipating a reward, women activate the orbitofrontal cortex and amygdala during the midfollicular phase (days 4–8 after onset of menses when estrogen is unopposed by progesterone). These cortical areas are crucially involved with emotion, arousal, and autonomic and endocrine func­ tion. In contrast, during the luteal phase (days 6–10 after luteinizing hormone surge) women showed the greatest activation in the midbrain, striatum, and left frontopolar cortex. Thus, women showed activation in different regions depending on their levels of sex hormones. On the other hand, men activated the ventral putamen more than women during anticipation of reward. Such evidence that sex-related ovarian steroids modulate the neural activity associated with receiving rewards may have implications for understanding sex differences in mood disorders, neuro­ psychiatric diseases, and susceptibility to drug abuse.59

Psychological Stress Response According to Mary Seeman, women are twice as likely to suffer mood and anxiety disorders as men, while men are more likely to experience alcohol abuse disorders (see Chapter 12). While environmental factors certainly play a role, this may, in part, reflect sex differences in biological responses to stress. Men and women likely differ in their response to stress. The human stress response has been characterized as ‘fight-or-flight.’ This makes sense for males who, evolutionarily, confront a stressor either by aggres­ sive fighting or fleeing. Females’ response to stress may fit a dimension of ‘tend-and-befriend’.60 In that perspective, tending involves nurturing and protecting one’s self and offspring while befriending relates to creating social net­ works to aid in protection and maximize survival. There is neuroendocrine evidence to suggest that oxytocin may be critical in this response.60

Wang and his colleagues investigated the gender-specific neural circuitry of psychological stress in male and female brains using fMRI. Stress in men was associated with cere­ bral blood flow (CBF) increase in the right prefrontal cortex (RPFC) and CBF reduction in the left orbitofrontal cortex (LOrF). In contrast, stress in women primarily activated the limbic system, including the ventral striatum, putamen, insula and cingulate cortex.61 This is consistent with the ‘fightor-flight’ and ‘tend-and-befriend’ models. ‘Fight-or-flight’ requires increased focus, alertness, and fear. The RPFC is important for vigilance, awareness, and negative emotion. In contrast, the limbic system is involved with emotion regula­ tion, and the areas activated in the female response to stress are rich in receptors for oxytocin, vasopressin, dopamine, and endorphin. This indicates a consistency with the ‘tendand-befriend’ model.61 Other hormones are also modulated in the stress response. The hypothalamic–pituitary–adrenal (HPA) axis is one of the major systems involved in responses to stress. Corticotropin-releasing hormone (CRH) neurons project into the brain and stimulate the secretion of adrenocortico­ tropic hormone (ACTH) from the anterior pituitary. ACTH then travels through the blood and triggers the secretion of glucocorticoids such as cortisol from the adrenal glands. It is hypothesized that this release of glucocorticoids is activated in depression and induces symptoms (Seeman, Chapter 12 this volume). There is evidence that this system is influenced by ovar­ ian hormones.62 Animal studies show that the corticosterone response to stress differs in male and female rats. Female rats demonstrate a greater overall response, a faster onset of corticosterone secretion, and a faster rate of rise of cor­ ticosterone.62 Additionally, chronic administration of estro­ gen enhances the corticosterone response to stress. While conclusions are more difficult to draw in human studies, depressed premenopausal women show greater increases in baseline cortisol levels than postmenopausal depressed women and depressed men.62 These gender differences in response to stress may play a role in risk factors for genderspecific health problems.

Sex differences in neuroanatomic measures Animal studies on sex differences in neuroanatomy have reported dimorphism in regions involved in gonadal hor­ mone regulation such as the bed nucleus of the stria ter­ minalis.63 This finding was replicated in humans with post mortem data, which demonstrated that the sex differences in this structure emerged only during adulthood.64 Most human neuroanatomic studies on sex differences have focused on measures related to hemispheric specialization of func­ tion.65 A neuroanatomic basis for functional asymmetry has been suggested, with larger volumes of left cortical regions

C h a p t e r 7     Gender Differences in the Functional Organization of the Brain l

implicated in language.66 However, evidence for sex differ­ ences in this asymmetry is inconsistent. Furthermore, some of the neuroanatomic differences may reflect the confound of lower cranial volume in women.67 It would seem impor­ tant to link the neuroanatomic parameters with performance measures, as was done by Davatzikos and Resnick.68 They used an innovative image analysis technique, which allows investigation of local variability in brain morphology, in magnetic resonance images (MRI) from 114 individuals. There was a robust sex difference in the splenium of the corpus callosum, suggesting greater interhemispheric con­ nectivity in women. Furthermore, size of the splenium ‘cor­ related with better cognitive performance in women than in men, indicating that the degree of interhemispheric connec­ tivity has different implications for men and women.’ MRI studies enable volumetric three-dimensional meas­ ures of brain parenchyma and cerebral spinal fluid (CSF). Studies of healthy people across the lifespan have provided valuable data regarding normal brain development against which changes associated with diverse brain disorders can be examined. Sex differences emerge as an important mode­ rating variable for whole brain and regional volumes.

Whole Brain Sex differences in brain anatomy have been increasingly documented with methods for morphometric analysis of MRI data.3,4,67–74 Quantitative MRI studies using algo­ rithms for tissue segmentation suggested that men have

55 %Volume

higher white matter (WM) volumes than women.5,74 Using algorithms for automated tissue segmentation of MRI, we examined sex differences in the volume, hemispheric asym­ metry, and distribution of intracranial compartments related to cytoarchitecture and connectivity: gray matter (GM), white matter (WM), and CSF. Higher percent GM in left subregions relative to the right and higher percent GM in women than men were observed.3 Because GM largely con­ sists of the somatodendritic compartment of neurons (cell body and dendrites) while WM contains the axonal com­ partment (myelinated fibers), verbal functions may require substrates that facilitate processing within regions whereas spatial performance is optimized by transfer across regions. Indeed, women had a higher percent GM whereas men had higher percent WM and percent CSF (Figure 7.2). The find­ ing that women have higher percent GM than men repli­ cates earlier studies with the 133Xenon clearance method.75 Our finding of lower overall proportion of WM in women seems to contrast with reports of higher volumes of corpus callosum,76,77 which is a white matter structure. While the corpus callosum findings have been challenged as an artifact of smaller cranial volume,78 investigators have reported that sex differences in the callosum have sustained corrections for cranial volume.68,76 Conceivably, men and women differ in the relative amount of inter- and intrahemispheric communi­ cation. This possibility can be tested more specifically using neurobehavioral and functional imaging methods. The sex difference in intracranial tissue composition may reflect adaptation to the smaller cranial volumes of

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Figure 7.2  Sex differences in the percent of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) in healthy people. The top row shows percent of volume out of the entire cranial supertentorial volume and the bottom shows laterality (left minus right) of volume. Reproduced from Gur, Turetsky, Matsui, et al., 1999.3

80

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women. Sexual anatomic dimorphism has been comparable at least since the Middle Pleistocene hominids.79 Because GM is the somatodendritic compartment, where computa­ tion is done, while WM is the myelinated connecting tis­ sue needed for information transfer across distant regions, higher percent GM in women increases the proportion of tissue available for computational processes. This is a rea­ sonable evolutionary strategy, as smaller crania require shorter distances for information transfer, hence there could be relatively less need for WM. The higher percent GM is bilateral in women, with lat­ erality effects – higher left hemispheric percent GM and right hemispheric percent CSF – evident only in men. This is consistent with some behavioral and neurobiologic data suggesting less hemispheric asymmetry in women.24 In a functional MRI (fMRI) study, Shaywitz et al.6 reported that for phonological tasks men showed left lateralized inferior frontal gyrus activation whereas women showed more bilat­ eral activation in this region. The results were considered consistent with the hypothesis that men are more highly lateralized for language functions. On the other hand, it is noteworthy that the hemispheric asymmetries for our whole brain measures were small relative to the sex differences in compartmental percentages. Thus, while men have rela­ tively higher percent GM in the left, they still have lower percent GM than women in either hemisphere. This may differ for smaller structures.

in men.82 Although two MRI studies that measured the orbital frontal cortex failed to note a similar effect, neither of these studies statistically adjusted the regional volumes for intracranial volume.67,83 The behavioral implications of women’s relatively larger orbital frontal regions warrant further investigation in light of evidence for the critical role of the orbital frontal cortex in social behavior, emotional functioning and higher order cognitive skills, such as rea­ soning and decision making.84 Indeed, reduced frontal volume has been associated with greater tendency toward psychopathy in men who were screened for psychiatric dis­ orders in themselves and first-degree relatives85 and in anti­ social personality disorder.86 The frontal lobes are involved in decision-making, as several lesion studies have con­ firmed that decision-making is impaired with frontal lobe lesions. However, most of these studies have involved only men and lesions on the right side. Notably, in 2005, Tranel et al. reported that right hemisphere lesions impair men, but not women. Additionally, left-sided lesions alter women’s decision making but do not impair men.87 The significance of larger orbital volumes can be interpreted relative to the volume of the amygdala, whose output is modu­ lated by this region.41,42,89–93 We found that women, correcting for cranial volume, have equal volumes to men in temporolimbic regions (Figure 7.3). Thus, the increased orbital volume relative to amygdala volume in women compared to men sup­ ports the hypothesis that women have greater tissue volume available for modulating amygdala action. In addition, several

Regional Volumes 10 9 8 Lateral orbital gray/Amygdala

Volumetric MRI studies of specific regions have also sug­ gested sex differences.73,80,81 Regional sex differences may shed light on the neurobiologic substrates of behavioral sex differences in healthy people and may provide insight into sex differences in behavior and hence the prevalence and severity of certain neurobehavioral disorders. There is evidence that the hippocampus, a part of the brain associated with learning and memory, is significantly differ­ ent in men and women.116 In his review of sex differences, Cahill concludes that imaging studies consistently find that the hippocampus is larger in women compared to men when adjusted for brain size. Additionally, when comparing female and male rats raised in an enriched environment, females tend to generate dendritic spines with more branching com­ pared to males. This may have implications for learning and memory. For example, the estrus cycle may influence maze learning tactics in rats; it seems that sex hormones alter the balance of hippocampal and striatal learning strategies in female rats.57 However, there is also evidence that, within the hippocampus, the CA1 region is larger in male compared to female rats. How gender influences hippocampal function in humans is not yet well understood, but given the evidence in rats, this area of study merits further investigation. In humans, following adjustment for intracranial volume, we observed sex differences in the frontal lobes, where orbital frontal regions were relatively larger in women than

7 6 5 4 3 2 1 Men

Women

Figure 7.3  The ratio of orbital frontal to amygdala volume in healthy men and women. Reproduced from Gur, Gunning-Dixon, Bilker, and Gur, 2002.82

C h a p t e r 7     Gender Differences in the Functional Organization of the Brain l

imaging studies have found differences in hemispheric lateral­ ization of the amygdala with regard to memory of emotional material. Cahill et al. reported that women show preferential involvement of the left amygdala for memory of emotional material, while the same material involves mostly right amyg­ dala activation in men.88 These findings may contribute to gender differences in emotional memory and emotional behav­ ior, particularly aggression. The sex difference in the ratio of orbital to amygdala volume is quite marked. It is noteworthy that only five men had values in the range recorded in over half the women, and conversely only a handful of women had ratios as low as seen in about half the men. It is likely that such a neuro­ anatomic difference will have functional significance. While environmental and cultural factors undoubtedly contribute to sex differences in aggression, the existence of such marked neuroanatomic differences in brain structure related to emo­ tion regulation warrants systematic effort to link emotional behavior to neural substrates. These anatomic differences also need to be considered when interpreting functional neuro­imaging studies. Finally, animal studies may help determine whether these sex differences exist in other spe­ cies and relate to differences in emotional behavior.

Sex differences in neurophysiologic measures The feasibility of studying neural substrates of behavior is enhanced by functional imaging methods for measuring regional brain activity. Both resting metabolism and activa­ tion patterns are linked to performance on neurobehavioral tasks requiring verbal, spatial, attention, memory and facial processing. Unlike neuroanatomic studies that have consist­ ently examined sex differences and age effects, there is a paucity of neurophysiologic studies that have examined these factors.

Cerebral Blood Flow Women have higher rates of basal cerebral blood flow (CBF) than men75,94–96 and equal rates of cerebral glucose metabolism.97 There is no evidence for sex differences in the laterality of regional brain activity. In early studies, with the 133Xenon CBF method, we reported that women have higher rates of cortical CBF75 and this finding was repli­ cated and extended to other methods that measure CBF for the entire cranium.94–96 We found about equal rate of ageassociated reduction in CBF in men and women98 and this too has been reported in other studies,99 although samples were usually small in the elderly range. Functional MRI (fMRI) has been increasingly used for measuring regional brain activation. The method has several potential advantages: higher spatial and temporal resolu­ tion, noninvasiveness and lack of ionizing radiation, direct

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correlation with anatomical imaging, greater repeatability, and economy. Disadvantages of fMRI techniques include loud background noise generated by the gradients, difficul­ ties in presenting stimuli and performing tasks in the magnet bore, claustrophobia, low signal-to-noise for most methods in high susceptibility areas and lack of quantitation in physi­ ologic units for most methods. Among the various fMRI methods, blood oxygenation level-dependent (BOLD) imag­ ing has been most widely applied. This technique relies on magnetic susceptibility effects of deoxyhemoglobin, which cause regional decreases in signal in imaging sequences sensitive to susceptibility (e.g. echoplanar). With regional brain activation studies a net increase in signal intensity is observed in regions known to be activated by the task. The increase in image intensity corresponds to a local decrease in deoxyhemoglobin. This is attributed to an increase in regional blood flow compared to regional oxygen consump­ tion. A typical response is a 1–25% increase in regional image intensity, which develops over 3–8 sec following task initiation. Susceptibility effects are field-dependent so, using the 4T magnet available to us, an initial decrease in signal intensity is detectable in the first 1–2 sec following stimu­ lation, corresponding to a focal increase in deoxyhemo­ globin. When combined with ultrafast echoplanar imaging (100 msec per slice), the time course of signal change in response to individual stimuli can thus be observed. Shaywitz et al.6 reported a CBF activation study with fMRI where women showed more bilateral activation dur­ ing a phonemic task. We reported an fMRI study examining CBF changes during the performance of a verbal analogies and a spatial line orientation task.7 Task difficulty effects were tested by dividing conditions into easy and hard. Complementing Shaywitz et al.’s results for the phonemic task, men showed more bilateral activation for the spa­ tial task. When activation was examined for target regions of interest, the planum temporale and the inferior parietal lobe, both men and women showed equally left lateral­ ized activation for the verbal task. However, whereas men activated the right hemisphere for the spatial task, women showed left hemispheric activation for the easy spatial prob­ lems and bilateral activation for the hard problems. Thus, it appears that spatial processing requires, for harder tasks, greater reliance on visual association cortex with minimal activation of other areas. Poorer performance in women may relate to continued reliance on supplementary strate­ gies, perhaps verbal, which is ineffective for the success on the harder spatial items. We also have evidence from posi­ tron emission tomography (PET) that better verbal memory in women is associated with higher mid-temporal resting CBF, and positive correlations with left lateralized CBF in mid-temporal and temporal pole regions.94 Such studies may help elucidate neural substrates of sex differences in cognitive strategies for problem solving. There is evidence that neurobiologic processes triggered by the hormonal changes exert influence by affecting neu­ rotransmitter availability, cerebral perfusion, and perhaps

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by eliminating neuroprotective effects of estrogen.100,101 Matteis et al.,102 using transcranial Doppler ultrasonogra­ phy, found, as we did, higher flow estimates in women than men overall. However, a subgroup of 15 postmenopausal women aged 48–53 had lower flow values than 15 premen­ opausal women of the same age, or any other group.

Cerebral Metabolism Unlike CBF, where women consistently show higher val­ ues, there are no sex differences in whole brain rates of glu­ cose metabolism. Basal metabolic rates for glucose were measured in 37 men and 24 women.97 Average metabolism, calculated from whole-brain counts, did not differ between men (4.66  or 0 97 ml/100 g/min) and women (4.62  or 1.09). However, regional differences were notable. The groups had identical metabolism in all non-limbic frontal, parietal, and occipital regions, but sex differences were prevalent in temporal-limbic regions, basal ganglia, brain stem, and cerebellum. Men had higher relative metabolism in all lateral and ventromedial aspects of temporal lobe regions, including occipito-temporal, superior, middle, and inferior temporal cortices, the temporal pole, parahippo­ campal, and entorhinal regions, hippocampus, amygdala, insula, fusiform and rectal gyri, and orbital-frontal cortex. They did not differ from women in relative activity of the anterior cingulate, but had lower relative metabolism in the middle and posterior cingulate gyrus. It is noteworthy that while asymmetries in metabolic rates were ubiquitous, there were largely similar in men and women. The findings indicate sex differences in the regional topography of resting cerebral metabolic activity and sys­ tematic asymmetries in regional metabolism that are largely shared by men and women. The higher relative metabo­ lism in men in the entire temporo-limbic system, and the reversal of this difference for the middle and posterior cin­ gulate gyrus, where women had higher metabolism, reflect a different baseline activity. This could help explain sexrelated differences in emotional processing. The cingulate is cytoarchitecturally one of the most complex components of the limbic system. Since behavior evolves from instru­ mental to increasingly symbolic modes of processing, we may speculate that the higher metabolic activity of men in phylogenetically older limbic regions relates to their greater proclivity toward instrumental expression of emotion, such as through violence. Similarly, higher activity in the cingu­ late may explain why women seem to have better access to emotional expression through symbolic mediation, such as vocal and gestural means.

Neuroreceptors In humans, dopamine (DA) neural transmission participates in the mediation of motor and cognitive tasks, and its pharma­ cological or pathophysiological depletion is associated with

performance decrements, independent of age-associated loss of neural tissue.103,104 Estrogen regulates DA transmission,105–107 perhaps in an antidopaminergic fashion in women.108 Estrogen receptors are found in cortical and subcortical areas, includ­ ing the DA-rich caudate and putamen.15,16,100,101 The DA transporter is a primary regulator of intra-synaptic DA lev­ els109 and its concentration reflects the homeostatic tone of the dopaminergic system.110 Behavioral studies have demon­ strated that women perform better than men on verbal learning tasks.111,112 In addition, verbal learning performance deterio­ rates with age and is adversely affected by menopause.113,114 Taken together, these findings suggest sex differences in the neuromodulatory effects of DA on behavior. However, stud­ ies of the coupling between DA and behavior in humans have been lacking because of the scarcity of reliable ligands for measuring dopamine transporter availability. In a singlephoton emission computed tomography (SPECT) study with TRODAT, a technetium-99m-labeled dopamine transporter imaging agent, 32 healthy men and 36 healthy women were examined.115 Coupling between dopamine transporter avail­ ability and learning was noted. Women and younger partici­ pants had higher dopamine availability in the caudate nucleus, and this was associated with their stronger performance scores on verbal learning tasks. Additionally, studies suggest that there are neurochemi­ cal differences within the hippocampus, a major region involved in learning and memory. Neurotransmitter systems within the hippocampus, such as the serotonergic, adrener­ gic, cholinergic, glucocorticoid, benzodiazepine, and chole­ cystokinin systems, may differ with regard to their receptor affinity and cell excitability in males and females. Such dif­ ferences may have implications for learning and memory. For example, Shors et al. showed that in rats, exposure to stressful learning situations (brief tail shocks) increases the number of dendritic spines in males but decreases the den­ sity of dendritic spines in females. This finding was similar with Pavlovian conditioning; stress enhanced performance for male rats but impaired performance in female rats.116 Such gender differences in neuroreceptors and receptor activity may contribute to difference in learning, and how men and women deal with stress.

Implications for sex differences in functional brain organization The extent and nature of sex differences in brain function indicates that men and women differ in important aspects of functional brain organization. These differences are likely to manifest in behavior throughout the developmental span. While very little is known about sex differences in brain maturation, tools are available to link known differences in the rate of behavioral development to the underlying cere­ bral processes. With regard to functional organization, the neurobiological data suggest several areas where men and

C h a p t e r 7     Gender Differences in the Functional Organization of the Brain l

women may differ. Perhaps the most conspicuous differ­ ences in anatomy indicate that women have a higher percent of gray matter tissue and correspondingly lower volume of white matter. At the same time women seem to have rela­ tively larger posterior corpus callosum, which is the largest body of white matter fibers in the brain. The combined pat­ tern of lower overall white matter with increased callosal volume suggests a fundamental difference in the direction of optimizing interhemispheric connectivity in women, rela­ tive to connectivity within the hemisphere. Thus, we would expect to find sex differences in behavior where different amounts of interhemispheric communication – relative to intrahemispheric connectivity – is required. Although we have focused on findings in healthy people, the effects have implications for brain disorders where gen­ der differences have been observed across the lifespan. For example, neurodevelopmental disorders such as attention deficit and learning disabilities are more common in boys, schizophrenia is more severe in young men, autism is more prevalent in men, while depression is more common in women. Similarly, effects of acquired brain disorders such as stroke, traumatic brain injury, Parkinson disease and Alzheimer’s disease, differ in men and women. For exam­ ple, occlusive stroke is more frequent in men while hemor­ rhagic stroke is more frequent in women, and Alzheimer’s disease has greater prevalence and severity in women even when corrected for longevity. Notably, in reviewing avail­ able studies in neurological populations, Amatniek and col­ leagues (Chapter 10) found a higher overall incidence for females in vascular dementia, multiple sclerosis, migraine and tension headache, pseudotumor cerebri, Bell palsy, meningioma, and myasthenia gravis. For males, the studies showed a greater incidence of epilepsy, amyotrophic lateral sclerosis, Parkinson disease, and Guillain–Barré syndrome. Considering sex differences in brain function can advance understanding of the neural basis of these disorders. The clinical implications of these findings need to be examined in relation to disease presentation and course.8–13 In view of the greater vulnerability of males in prefrontal regions, one would expect brain disorders affecting these regions to be more severe in men and perhaps requiring multi­modal therapeutic interventions. For females, with improved understanding of regional brain activity during emotion processing, we may be in a position to explain the neuro­ biology of increased vulnerability to depression.

Questions for future An impediment for understanding the effects of sex differ­ ences on brain function is the lack of data on the relationship between neurobiologic and behavioral measures. Available studies have suggested tantalizing parallels between sex dif­ ferences in behavioral measures and sex differences in neuro­ anatomy and neurophysiology. However, very few studies

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have actually correlated behavior with biologic parameters of such differences. Once we have a better appreciation of the nature and magnitude of these correlations, we will be able to answer several questions regarding the etiology and consequences of sex differences in health and disease. Can we capitalize on these sex differences to help amel­ iorate disease processes? For example, would gonadal hormones help in disorders that are less frequent or less severe in one sex or the other? Could strategies be devised in a manner that would be more gender-specific for detection, prevention, and treat­ ment of brain disorders? Can we gain further insights on sex differences in brain behavior relations by incorporating genomic strategies?

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Acknowledgment Supported by NIH grants MH-60722 and MH-64045.

References   1. Halpern DF. Sex Differences in Cognitive Abilities. Hillsdale, NJ: Lawrence Erlbaum Associates; 1992.   2. Caplan PJ, Crawford M, Hyde JS, et al. Gender Differences in Human Cognition. New York, NY: Oxford University Press; 1997.   3. Gur RC, Turetsky BI, Matsui M, et al. Sex differences in brain gray and white matter in healthy young adults: correlations with cognitive performance. J Neurosci 1999;19:4065–72.   4. Coffey CE, Lucke JF, Saxton JA, et al. Sex differences in brain aging: a quantitative magnetic resonance imaging study. Arch Neurol 1998;55:169–79.   5. Passe TJ, Rajagopalan P, Tupler LA, et al. Age and sex effects on brain morphology. Prog Neuropsychopharmacol Biol Psychiatry 1997;21:1231–37.   6. Shaywitz B, Shaywitz SE, Pugh KR, et al. Sex differences in the functional organization of the brain for language. Nature 1995;373:607–9.   7. Gur RC, Alsop D, Glahn D, et al. An fMRI study of sex dif­ ferences in regional activation to a verbal and a spatial task. Brain Lang 2000;74:157–70.   8. Hartung CM, Widiger TA. Gender differences in the diagno­ sis of mental disorders: conclusions and controversies of the DSM-IV. Psychol Bull 1998;123:260–78.   9. Gur RE, Petty RG, Turetsky BI, et al. Schizophrenia through­ out life: sex differences in severity and profile of symptoms. Schizophr Res 1996;21:1–12. 10. Gaub M, Carlson CL. Gender differences in ADHD: metaanalysis and critical review. J Am Acad Child Adolesc Psychiatry 1997;36:1036–45. 11. Gao S, Hendrie HC, Hall KS, et al. The relationships between age, sex, and the incidence of dementia and Alzheimer dis­ ease: a meta-analysis. Arch Gen Psychiatry 1998;55:809–15. 12. Savic I, Engel J Jr. Sex differences in patients with mesial temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 2009;65:910–12.

84

s e c t i o n 2     Gender and the Nervous System l

13. Whitacre CC, Ereingold SC, O’Looney PA, et al. A gender gap in autoimmunity. Science 1999;283:1277–78. 14. Collaer ML, Hines ML. Human behavioral sex differences: a role for gonadal hormones during early development? Psychol Bull 1995;118:55–107. 15. McEwen BS. Steroid hormone actions on the brain: when is the genome involved? Horm Behav 1994;28:396–405. 16. McEwen BS, Woolley CS. Estradiol and progesterone regu­ late neuronal structure and synaptic connectivity in adult as well as developing brain. Exp Gerontol 1994;29:431–36. 17. Woolley CS, Weiland NG, McEwen BS, et al. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density. J Neurosci 1997;17:1848–59. 18. Janowsky JS, Chavez B, Zamboni BD, et al. The cognitive neuropsychology of sex hormones in men and women. Dev Neuropsychol 1998;14:421–40. 19. Berenbaum SA. Gonadal hormones and sex differences in behavior. Dev Neuropsychol 1998;14:175–96. 20. McGivern RF, Huston JP, Byrd D, et al. Sex differences in visual recognition memory: support for a sex-related dif­ ference in attention in adults and children. Brain Cogn 1997;34:323–36. 21. Voyer D, Voyer S, Bryden MP. Magnitude of sex differences in spatial abilities: a meta-analysis and consideration of criti­ cal variables. Psychol Bull 1995;117:250–70. 22. Springer SP, Deutsch G. Left Brain, Right Brain: Perspectives from Cognitive Neuroscience, 5th edn. New York, NY: W. H. Freeman & Co.; 1998. 23. Witelson DF. Sex and the single hemisphere: specializa­ tion of the right hemisphere for spatial processing. Science 1976;193:425–27. 24. Hiscock M, Israelian M, Inch R, et al. Is there a sex differ­ ence in human laterality? II. An exhaustive survey of visual laterality studies from six neuropsychology journals. J Clin Exper Neuropsychol 1995;17:590–610. 25. Herlitz A, Nilsson LG, Backman L. Gender differences in episodic memory. Mem Cognit 1997;25:801–11. 26. Kramer JH, Delis DC, Kaplan E, et al. Developmental sex differences in verbal learning. Neuropsychology 1997;11:577–84. 27. Saykin AJ, Gur RC, Gur RE, et al. Normative neuropsy­ cholgical test performance: effects of age, education, gender and ethnicity. Appl Neuropsychol 1995;2:79–88. 28. Gur RE, Gur RC. Gender differences in aging: cognition, emotions and neuroimaging studies. Dialogues Clin Neurosci 2002;4:197–207. 29. Delis DC, Kramer JH, Kaplan E, et al. California Verbal Learning Test: Adult Version. San Antonio, TX: Psychological Corporation; 1987. 30. Benton AL, Varney NR, Hamsher KdeS. Judgment of Line Orientation. Iowa City: Form V. University of Iowa Hospitals; 1975. 31. Gur RC, Ragland JD, Moberg PJ, et al. Computerized neuro­ cognitive scanning: I. Methodology and validation in healthy people. Neuropsychopharmacology 2001;25:766–76. 32. Woolley CS, Weiland NG, McEwen BS, et al. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density. J Neurosci 1997;17:1848–59.

33. Hampson E. Variations in sex-related cognitive abilities across the menstrual cycle. Brain Cogn 1990;14:26–43. 34. Phillips S, Sherwin BB. Effects of estrogen on memory func­ tion in surgically menopausal women. Psychoneuroendocrinol 1991;17:485–95. 35. Hampson E. Estrogen-related variations in human spa­ tial and articulatory-motor skills. Psychoneuroendocrinol 1990;15:97–111. 36. Silverman I, Phillips K, Silverman LK. Homogeneity of effect sizes for sex across spatial tests and cultures: implica­ tions for hormonal theories. Brain Cogn 1996;31:90–94. 37. Saucier DM, Kimura D. Intrapersonal motor but not extraper­ sonal targeting skill is enhanced during the midlutel phase of the menstrual cycle. Dev Neuropsychol 1998;14:385–98. 38. Freeman EW, Rickels K, Schweizer E, et al. Relationships between age and symptom severity among women seeking medical treatment for premenstrual symptoms. Psychol Med 1995;25:309–15. 39. Papousek I, Schulter G, Lang B. Effects of emotionally con­ tagious films on changes in hemisphere-specific cognitive performance. Emotion 2009;9:510–19. 40. Levine LJ, Burgess SL. Beyond general arousal: effects of spe­ cific emotions on memory. Social Cognition 1997;15:157–81. 41. LeDoux JE. Emotion: clues from the brain. Ann Rev Psychol 1995;46:209–35. 42. Rolls ET. A theory of emotion and its application to understand­ ing the neural basis of emotion. Cogn Emotion 1990;4:161–90. 43. Ekman P, Rosenberg EL. What the Face Reveals. New York, NY: Oxford University Press; 1997. 44. Ekman P. Strong evidence for universals in facial expres­ sions: a reply to Russell’s mistaken critique. Psychol Bull 1994;115:268–87. 45. Izard CE. Innate and universal facial expressions: evidence from developmental and cross-cultural research. Psychol Bull 1994;115:288–99. 46. Erwin RJ, Gur RC, Gur RE, et al. Facial emotion discrimina­ tion: I. Task construction and behavioral findings in normal subjects. Psychiatry Res 1992;42:231–40. 47. Velten E Jr. A laboratory task for induction of mood states. Behav Res Ther 1968;106:473–82. 48. Schneider F, Gur RC, Gur RE, et al. Standardized mood induction with happy and sad facial expressions. Psychiatry Res 2004;51:19–31. 49. Watson D, Clark LA, Tellegen A. Development and valida­ tion of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988;54:1063–70. 50. Heilman KH. The neurobiology of emotional experience. J Neuropsychiatry Clin Neurosci 1997;9:439–48. 51. Cancelliere AE, Kertesz A. Lesion localization in acquired deficits of emotional expression and comprehension. Brain Cogn 1990;13:133–47. 52. Borod J, Haywood JC, Santschi C, et al. Neuropsychological aspects of facial asymmetry during emotional expression: a review of the normal adult literature. Neuropsychol Rev 1997;7:41–60. 53. Sackeim HA, Gur RC, Saucy MC. Emotions are expressed more intensely on the left side of the face. Science 1978;202:434–36. 54. Kring AM, Gordon AH. Sex differences in emotion: expres­ sion, experience, and physiology. J Pers Soc Psychol 1998;74:686–703.

C h a p t e r 7     Gender Differences in the Functional Organization of the Brain l

55. Bettencourt AB, Miller N. Gender differences in aggression as a function of provocation: a meta analysis. Psychol Bull 1996;119:422–47. 56. Natale M, Gur RE, Gur RC. Hemispheric asymmetries in processing emotional expressions. Neuropsychologia 1983;21:555–65. 57. Cahill L. Why sex matters for neuroscience. Nat Rev Neurosci 2006, Online publication. 58. Cahill L. Sex related influences on neurobiology of emotion­ ally influenced memory. Ann NY Acad Sci 2003;985:163–73. 59. Dreher JC, Schmidt PJ, Kohn P, et al. Menstrual cycle phase modulates reward-related neural function in women. Proc Natl Acad Sci U S A 2007;104(7):2465–70. 60. Taylor S, Klein L, Lewis B, et al. Biobehavioral responses to stress in females: tend-and-befriend, not fight-or-flight. Psychol Rev 2000;107(3):411–29. 61. Wang J, Korczykowski M, Rso H, et al. Gender difference in neural response to psychological stress. Soc Cogn Affect Neurosci 2007;24(3):227–39. 62. Young EA, Altemus M. Puberty, ovarian steroids, and stress. Ann N Y Acad Sci 2004;1021:124–33. 63. Allen LS, Gorski RA. Sex difference in the bed nucleus of the stria terminalis of the human brain. J Comp Neurol 1990;22:697–706. 64. Chung WC, De Vries GJ, Swaab DF. Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend to adulthood. J Neurosci 2002;22:1027–33. 65. Witelson SF, Glezer II, Kigar DL. Women have greater den­ sity of neurons in posterior temporal cortex. J Neurosci 1995;15:3418–28. 66. Harasty J, Double KL, Halliday GM, et al. Language-associated cortical regions are proportionally larger in the female brain. Arch Neurol 1997;54:171–76. 67. Gur RC, Mozley PD, Resnick SM, et al. Gender differences in age effect on brain atrophy measured by magnetic reso­ nance imaging. Proc Natl Acad Sci U S A 1991;88:2845–49. 68. Davatzikos C, Resnick SM. Sex differences in anatomic measures of interhemispheric connectivity: correla­ tions with cognition in women but not men. Cereb Cortex 1998;8:635–40. 69. Courchesne E, Chisum HJ, Townsend J, et al. Normal brain development and aging: quantitative analysis at in vivo MR imaging in healthy volunteers. Radiology 2000;216:672–82. 70. De Bellis MD, Keshavan MS, Beers SR, et al. Sex differences in brain maturation during childhood and adolescence. Cereb Cortex 2001;11:552–57. 71. Goldstein JM, Seidman LJ, Horton NJ, et al. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb Cortex 2001;11:490–97. 72. Nopoulos P, Flaum M, O’Leary D, et al. Sexual dimorphism in the human brain: evaluation of tissue volume, tissue com­ position and surface anatomy using magnetic resonance imaging. Psychiatry Res 2000;98:1–13. 73. Raz N, Gunning FM, Head D, et al. Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cereb Cortex 1997;7:268–82. 74. Filipek PA, Richelme C, Kennedy DN, et al. The young adult human brain: an MRI-based morphometric analysis. Cereb Cortex 1994;4:344–60.

85

75. Gur RC, Gur RE, Obrist WD, et al. Sex and handedness differences in cerebral blood flow during rest and cognitive activity. Science 1982;217:659–61. 76. Steinmetz H, Staiger JF, Schlaug G, et al. Corpus callosum and brain volume in women and men. Neuroreport 1995;6:1002–4. 77. Witelson SF. Hand and sex differences in the isthmus and genu of the human corpus callosum. A postmortem morpho­ logical study. Brain 1989;112:799–835. 78. Jäncke L, Staiger J, Schlaug G, et al. The relationship between corpus callosum size and forebrain volume. Cereb Cortex 1997;7:48–56. 79. Arsuaga JL, Carretero JM, Lorenzo C, et al. Size variations in middle pleistocene humans. Science 1997;277:1086–88. 80. Cowell PE, Turetsky BI, Gur RC, et al. Sex differences in aging of the human frontal and temporal lobe. J Neurosci 1994;14:4748–55. 81. Schlaepfer TE, Harris GJ, Tien AY, et al. Structural differ­ ences in the cerebral cortex of healthy female and male sub­ jects: a magnetic resonance imaging study. Psychiatry Res 1995;61:129–35. 82. Gur RC, Gunning-Dixon F, Bilker WB, et al. Sex differ­ ences in temporo-limbic and frontal brain volumes of healthy adults. Cerebral Cortex 2002;12:998–1003. 83. Szeszko PR, Robinson D, Alvir JM, et al. Orbital frontal and amygdala volume reductions in obsessive–compulsive disor­ der. Arch Gen Psychiatry 1999;56:913–19. 84. Fuster JM. The prefrontal cortex and its relation to behavior. In: G Holstege, ed. Progress in Brain Rresearch. New York, NY: Elsevier Science; 1996:318–66. 85. Matsui M, Gur RC, Turetsky BI, et al. The relation between tendency for psychopathology and reduced frontal brain vol­ ume in healthy people. Neuropsychiat Neuropsychol Behav Neurol 2000;13:155–62. 86. Raine A, Lencz T, Bihrle S, et al. Reduced prefrontal gray matter volume and reduced autonomic activity in antisocial personality disorder. Arch Gen Psychiat 2000;57:119–27. 87. Tranel D, Damasio H, Denburg NL, et al. Does gender play a role in functional asymmetry of ventromedial prefrontal cor­ tex? Brain 2005;128:2872–81. 88. Cahill L, Haier RJ, White NS, et al. Sex-related difference in amygdala activity during emotionally influenced memory storage. Neurobiol Learn Mem 2001;75:1–9. 89. Davidson RJ, Putnam KM, Larson CL. Dysfunction in the neural circuitry of emotion regulation – a possible prelude to violence. Science 2000;289:591–94. 90. Damasio AR. Towards a neuropathology of emotion and mood. Nature 1997;386:769–70. 91. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci 2000;23:155–84. 92. Price JL. Prefrontal cortical networks related to visceral func­ tion and mood. Ann N Y Acad Sci 1999;877:383–96. 93. Rolls ET. The Brain and Emotion. New York, NY: Oxford University Press; 1999. 94. Ragland JD, Coleman AR, Gur RC, et al. Sex differences in behavior relationships between verbal episodic memory and resting regional cerebral blood flow. Neuropsychologia 2000;38:451–61. 95. Esposito G, Van Horn JD, Weinberger DR, et al. Gender dif­ ferences in cerebral blood flow as a function of cognitive state with PET. J Nucl Med 1996;37:559–64.

86

s e c t i o n 2     Gender and the Nervous System l

  96. Kastrup A, Li TQ, Glover GH, et al. Gender differences in cerebral blood flow and oxygenation response during focal physiologic neural activity. J Cereb Blood Flow Metab 1999;19:1066–71.   97. Gur RC, Mozley LH, Mozley PD, et al. Sex differences in regional cerebral glucose metabolism during a resting state. Science 1995;267:528–31.   98. Gur RC, Gur RE, Obrist WD, et al. Age and regional cer­ ebral blood flow at rest and during cognitive activity. Arch Gen Psychiatry 1987;44:617–21.   99. Madden DJ, Turkington TG, Coleman RE, et al. Adult age differences in regional cerebral blood flow during visual world identification: evidence from H215O PET. Neuroimage 1996;3:127–42. 100. McEwen BS. Possible mechanisms for atrophy of the human hippocampus. Mol Psychiatry 1997;2:255–62. 101. McEwen BS, Alves SE, Bulloch K, et al. Ovarian ster­ oids and the brain: implications for cognition and aging. Neurology 2007;48:S8–S15. 102. Matteis M, Troisi E, Monaldo BC, et al. Age and sex dif­ ferences in cerebral hemodynamics: a transcranial Doppler study. Stroke 1998;29:963–67. 103. Volkow ND, Wang GJ, Fowler JS, et al. Parallel loss of pre­synaptic and postsynaptic dopamine markers in normal aging. Ann Neurol 1998;44:143–47. 104. Volkow ND, Gur RC, Wang GJ, et al. Association between decline in brain dopamine activity with age and cogni­ tive and motor impairment in healthy individuals. Am J Psychiatry 1998;155:344–49. 105. Halbreich U. Role of estrogen in postmenopausal depres­ sion. Neurol 1997;48:S16–20.

106. Lindamer LA, Lohr JB, Harris MJ, et al. Gender, estrogen, and schizophrenia. Psychopharm Bull 1997;33:221–28. 107. Nordström A-L, Olsson H, Halldin C. A PET study of D2 dopamine receptor density at different phases of the men­ strual cycle. Psychiatry Res Neuroimaging 1998;83:1–6. 108. Pohjalainen T, Rinne JO, Någren K, et al. Sex differences in the striatal dopamine D2 receptor binding characteristics in vivo. Am J Psychiatry 1998;155:768–73. 109. Jaber M, Jones S, Giros B, et al. The dopamine transporter: a crucial component regulating dopamine transmission. Mov Disord 1997;29:633. 110. Jones SR, Gainetdinov RR, Jaber M, et al. Profound neu­ ronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci U S A 1998;95:4029–34. 111. Kramer JH, Delis DC, Kaplan E, et al. Developmental sex differences in verbal learning. Neuropsychol 1997; 11:577–84. 112. Reite M, Cullum CM, Stocker J, et al. Neuropsychological test performance and MEG-based brain lateralization: sex differences. Brain Res Bull 1993;32:325–28. 113. Chalfonte BL, Johnson MK. Feature memory and binding in young and older adults. Mem Cognit 1996;24:403–16. 114. Craik FI, McDowd JM. Age differences in recall and rec­ ognition. J Exp Psychol Learning, Memory, Cognition 1987;13:474–79. 115. Mozley LH, Gur RC, Mozley PD, et al. Striatal dopamine transporters and cognitive functioning in healthy men and women. Am J Psychiatry 2001;158:1492–99. 116. Shors T, Chua C, Falduto J. Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J Neurosci 2001;16:6292–97.

Chapter

8

Sexual Differentiation of Brain Structure and Function Margaret M. McCarthy Professor of Physiology, University of Maryland Baltimore School of Medicine, Department of Physiology, Baltimore, MD, USA

Introduction

sets the stage for sex differentiation, the process whereby the body and the brain become differentiated between males and females. Hormones synthesized and released by the gonads, predominantly androgens and anti-Müllerian hormone by the testis, will direct the formation of the gonadal duct system, genitalia, and secondary sex characteristics, as well as sex differences in the brain. However, unlike the differentiation of the Wolffian ducts into the vas deferens or the formation of a penis and scrotum instead of a vagina and uterus, processes which are absolute and irreversible, the differentiation of the brain is regionally specific, highly variable and often a matter of degree. Moreover, despite 50 years of research, our understanding of sexual differentiation of the brain remains rudimentary, with considerable controversy surrounding such core questions as whether there are separate neural circuitries controlling male versus female sex behavior, the nature of the critical hormones and their receptors, the timing of specific events and the precise cellular mechanisms mediating neuronal differentiation, and lastly, whether the changes induced are permanent or merely enduring. Finally, central to understanding sexual differentiation of the brain is identifying what it is not. All sex differences in brain and behavior are not necessarily the result of differentiation. Multiple factors can result in sex differences that are temporary due to changes in reproductive status, previous experience or chronological age.3 For example, the threshold for long-term potentiation (LTP) in the hippocampus, a phenomenon considered a physiological manifestation of learning, varies in females across stages of the estrus cycle and encompasses a range that includes the relatively constant threshold for LTP observed in males. Thus, at some points in the estrus cycle there is a sex difference in threshold, but the direction of the sex difference reverses, and at other times there is no sex difference at all. Although important, this is not an

Gender is the first and most salient attribute we integrate into our perception of other individuals, being signaled to us via multiple modalities that include dress, tone of voice, odors, and even name. Animals also readily signal their own sex and immediately perceive it in conspecifics. But how do these external manifestations of sex or gender reflect the phenotype of the brain? Is there a male brain and a female brain? Or, are our brains relatively gender-neutral but limited in range of function by the physical attributes associated with the sex of the body they happen to inhabit? The goal of this chapter is to review the current state-of-the-art in the study of sex differences in the brain and to put forward the argument that the answer to the above questions lies somewhere in the middle. It is a gross oversimplification to suggest that the entire brain, in all its complexity and diverse functionality, is ubiquitously male or female. But it is equally egregious to ignore sex and gender as variables in brain function, or to assume that these differences are only relevant to reproduction. As our understanding of the origins of sex differences in the brain becomes more sophisticated, we will better succeed at understanding what is nature, what is nurture, what are their interactions, and what is of value to the practitioner of gender-specific medicine. Sex begins with the chromosomes, specifically the Sry gene on the Y chromosome which codes for tdf, the testis determining factor. In response to expression of this single gene, the bipotential gonadal rudiment will be directed toward development as a testis. In the absence of this gene, regardless of whether an individual is XX or XY, the gonad will develop along its default pathway, which is to become an ovary.1,2 This process occurs early in embryogenesis and is referred to as sex determination. Sex determination then

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Copyright 2010 20 , Elsevier Inc. All rights reserved.

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endpoint that is subject to sexual differentiation and therefore mechanistically and functionally distinct from those endpoints that are differentiated. Tremendous advances are being made in identifying gender differences and their relevance to the human brain, much of it reviewed in this volume. Equally important advances are being made with the more empirical approach afforded by animal models. Gender is a uniquely human construct, as it involves both self-identification as a member of a particular gender category, and the societal and cultural factors that are associated with gender. Animals, however, have only sex. This both simplifies and limits the study of sexual differentiation of the brain. Moreover, one overarching rationale for understanding the nature of the variables and cellular mechanisms mediating sex differences in the brain is to gain insight into basis of gender biases in neurological and mental health disorders. Males are at higher risk for autism, dyslexia, stuttering, early-onset schizophrenia, and attention deficit and hyperactivity disorders, whereas females are at greater risk for being diagnosed with disorders of mood and affect. Thus males suffer disproportionately from disorders with origins in early development, whereas females are more likely to suffer adult onset disease.4 The variables contributing to this difference are surely complex, including societal, cultural, and biological components. The study of animal models is an important contributor to achieving the goal of understanding, but is limited by our inability to truly model complex and uniquely human conditions such as autism or schizophrenia.

Historical overview The origins of the study of sexual differentiation of the brain are generally attributed to a single iconic paper published by Phoenix, Goy, Gerall, and Young in 19595 on the impact of hormonal treatment of pregnant guinea pigs on the adult sexual behavior of their offspring. In a remarkably insightful synthesis of converging evidence, the authors proposed for the first time the notion that differences in hormone exposure to the developing male and female brain permanently organized the neural substrate such that it was then selectively activated in adulthood to induce the appropriate behavioral repertoire. Now codified as the Organizational/Activational Hypothesis, this postulate has stood the test of time and trial exceedingly well and provided a constructive framework from which to begin the investigation of the origins of sex difference.6,7 The guinea pig quickly proved to not be the optimal species for such studies as the majority of its brain sex differentiation occurs in utero, thereby complicating manipulation with exogenous steroids. The rat, by contrast, is readily sex reversed (at least to a first approximation) with neonatal castration of males or treatment of females with androgens during the

first few days of life. A sensitive period was identified that is operationally defined as the onset of testicular androgen synthesis in the late-gestational male and the postnatal day at which females become refractory to the masculinizing effect of exogenous hormone administration. The timing of the offset of the sensitive period varies with the endpoint under study, but the window of opportunity has usually closed by postnatal day 10, although recent evidence supports the existence of a second sensitive period associated with the hormonal changes of puberty8 (Figure 8.1). During the course of studies exploring the dose and duration of androgen exposure required to differentiate the brain of a female into a male, investigators detected an unexpected anomaly. A hormone that was used as a control, estradiol, was found to be even more effective than testosterone at masculinizing sex behavior. Several pieces of evidence converged to coalesce as the Aromatization Hypothesis.9,10 These included the fact that estradiol is a byproduct of testosterone produced by the aromatization of its A-ring, that the aromatase enzyme is found at high levels in neurons in sexually dimorphic brain regions, particularly during the sensitive period, and that estrogen receptors are also found at high levels in these same brain regions. The final piece of the puzzle was the discovery that fetal and neonatal rat blood carries alpha-fetoprotein, a steroid binding globulin with high affinity for estradiol but none for testosterone (in the rodent). This allows for sequestering of maternal estrogens in the fetal blood, permitting testosterone to enter into neurons where it is locally converted to estradiol which then masculinizes the neural substrate.11 This counter-intuitive observation, that a hormone largely identified with the ovary and considered to be a ‘female hormone’, estradiol, is the masculinizing hormone in brain development, does not extend to the primate brain. Both naturally occurring endocrine variations in humans and exhaustive empirical studies in captive primates indicate that in primates, in contrast to rodents, androgens are the masculinizing hormones, not estrogens. What role, if any, estradiol plays in primate brain development remains to be discovered. Around the same chronological time that the role of aromatization in brain masculinization was identified, the first replicable reports of major neuroanatomical sex differences were confirmed in animals, substantiating the view that male and female animals brains are different and fueling speculation regarding differences between the brain of men and women. Cleverly noting that male canaries sing a complex and alluring song, while females do not, Nottebohm and Arnold surmised there must be a brain difference controlling the behavioral difference.12 We now know there is an entire song control circuit that is highly sexually dimorphic and many of the guiding principles establishing this difference are still being determined.13 In response to the report in birds, mammalian researchers took a closer look at the rodent brain and made the startling discovery of a small

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Figure 8.1  Hormonally induced sexual differentiation of the brain occurs during a restricted sensitive period. In rodents, a perinatal sensitive period for sexual differentiation of the brain is operationally defined as the onset of testosterone synthesis by the fetal gonad beginning around embryonic day (E) 18, followed by a second surge in testosterone levels on the day of birth (PN 0), and the loss of sensitivity of females to exogenous steroid administration, which is usually around postnatal day (PN) 10. The Organizational/ Activational Hypothesis of steroid action postulated in 1959 that steroids exert distinct effects during two different life phases. During the sensitive period, steroid actions are referred to as organizational because they are largely permanent, altering multiple aspects of brain development including cell birth, death, migration, and differentiation. The organized neural substrate is then acted upon by adult circulating steroid hormones to mediate the expression of sexually dimorphic behaviors, such as sexual behavior. In primates, including humans, the sensitive period appears to be entirely prenatal with the critical period for fetal steroid exposure being at the end of the second and beginning of the third trimester.

dense sub-nucleus in the preoptic area that was 5–7 times larger in males than females, aptly naming it the sexually dimorphic nucleus of the preoptic area or SDN-POA.14 The fact that the preoptic area is a major brain region controlling male sexual behavior in animals had not escaped their notice and voluminous follow up studies have sought to identify the etiology and function of the SDN-POA, an effort that continues to this day.15 The discovery of the SDN-POA in the rat also prompted interest in similar neuro­ anatomical sex differences in humans.16 Recent advances in in vivo neuroimaging techniques have pushed the frontier in the study of sex differences in the human brain.17,18 In addition, the tragic consequences of the AIDS epidemic in the 1990s provided an abundance of tissue from men of known sexual orientation which allowed investigators to test the hypothesis that sexual orientation is dependent on the sexually differentiated state of the brain. More recently the field has seen advances on both conceptual and mechanistic fronts. The advent of transgenic mice has produced a wide-ranging array of sexual pheno­ types and renewed interest in both the steroid hormone receptors and their effectors that mediate differentiation. Sorting out the genuine from the artifact in genetic mutants will be a long but essential process. But the genetic facileness of mice has also brought to light a new principle, that genes associated with the X and Y chromosomes might importantly contribute to sex differences in brain and behavior.19 Lastly, there has been a drive to re-examine our old biases and assumptions about both the importance and purpose of sex differences in the brain. Paradoxically, some of the neuroanatomical differences we observe may in fact be for the purpose of converging the behavior of the two sexes

toward a common goal when one sex is deprived of the endocrine state that would normally induce the behavior.20 A clear example is parenting. Only females experience the hormonal milieu associated with pregnancy, parturition, and lactation, but it is often in the male’s vested interest to provide paternal care for his offspring. Compensatory changes exclusive to the male brain appear to drive this behavior and represent a circumstance where a sex difference in the brain eliminates a sex difference in behavior.21

Sex differences in neuroanatomy There are three fundamental ways in which male and female brain anatomy can differ: (1) size (usually but not always a function of cell number); (2) pattern of synaptic connectivity; and (3) neurochemical phenotype. While each of these refers to a distinct quantifiable endpoint, they are not necessarily separate. For example, the number and nature of the synapses evident in a particular nucleus might be a function of the size of the afferent projection it receives, which may in turn differ in the dominant neurotransmitter involved in males versus females. Examples of all varieties of sex differences have been identified and continue to be reported. The great challenge ahead is to characterize and understand functional neural circuits that differ in meaningful ways in males versus females.

Volumetric Sex Differences The size of a region, nucleus, projection or individual cell can be larger or smaller in either sex. Examples of all have

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been noted, beginning with the overall larger male brain, an effect which is diminished but not eliminated when corrected for body size. As a general rule, structures tend to be larger in male brains, and considerable attention is given to those instances in which the opposite is reported. There are limited ways in which a brain region, nucleus or projection can be larger in one sex. Essentially there can be the same number of cells but they are larger and/or more widely spaced in one sex than the other. Alternatively, there can be more cells coalesced to constitute a particular region, such as is the case for the SDN-POA in the rat. Here, the density and size of the neurons is the same in males and females; however, there are simply more neurons in males, thereby occupying a larger volume. The SDN-POA is probably the most famous brain sex difference, if such a moniker can be applied to a small collection of Nissl dense cells embedded within a large and complex brain region, the preoptic area. The attention given the sex difference in the size of the SDN-POA is in part a function of its magnitude, which is substantial as it is 5–7 times larger in males, and in part a function of its simplicity. The sex difference is entirely due to the actions of a single hormone, estradiol, acting during a restricted perinatal period to influence cell survival.22 The functional impact of this nucleus being larger in males remains elusive but of continuing interest. A projection can be larger in one sex because more cells contribute axons to the pathway, and this has been documented for the posterior portion of the bed nucleus of the stria terminalis (pBNST) in rats which projects to the anteroventroperiventricular nucleus (AVPV) of the preoptic area, together constituting a component of a synaptic circuit regulating gonadotropin secretion.23 Alternatively, a projection can be larger as a function of the degree of myelination of the axons, as has been speculated for the corpus callosum, one of the more controversial and direction-changing of sex differences in the human brain. The corpus callosum is the major projection between the cortical hemispheres. The callosum, or various of its subregions, have variously been reported to be larger in females, larger in males or the same size in both sexes depending on the laboratory doing the measurements as well as the particular subregion examined and the species in which it was examined.24,25 The reversing fortunes of the corpus callosum provides a cautionary tale in the study of sex differences. Precisely why there have been so many conflicting reports is unclear, but a desire to provide a structural underpinning to the perception that the two hemispheres of male brains function more asymmetrically than those of females may have generated inappropriate enthusiasm. That is, the underlying assumption of many studies has been that female brains function more symmetrically and should, therefore, have more or larger fibers interconnecting the two hemispheres. There are numerous other volumetric sex differences reported in the mammalian brain, but none matches those observed in the song-control nuclei of the avian brain, with

the exception of the spinal nucleus of the bulbocavernosus which consists of motor neurons that control the penis. In humans, volumetric sex differences have been described but generally of a smaller magnitude than seen in our animal models and varying substantially across the lifespan,26–29 highlighting the ever-changing nature of the brain.

Synaptic Patterning Sex Differences Synapses come in two flavors, excitatory and inhibitory. Synaptic patterning refers to the number and/or density of excitatory versus inhibitory synapses found within a particular brain region, meaning a specific nucleus or a particular cell layer in a larger brain region such as the hypothalamus or hippocampus. To truly identify a synapse as excitatory or inhibitory requires electron microscopy to distinguish the shape, location, and nature of the vesicles. Fortunately, where a synapse is located on a neuron is a pretty good indicator of the type, with inhibitory synapses generally being on the soma (cell body) and excitatory synapses found on the dendrites. Even more fortunately, specialized protuberances on dendrites, called dendritic spines, are almost exclusively excitatory and can be easily quantified with the use of Golgi cox impregnation or proxy markers such as the protein, spinophilin.30 Early and heroic EM studies from the laboratory of Arai in Japan, exhaustively characterized the synaptic profiles in sexually dimorphic brain regions such as the ventromedial and arcuate nuclei of the hypothalamus,31 revealing that the proportion of presumptively excitatory versus inhibitory synapses in these regions is profoundly different between male and female rats and is sex reversed by hormone treatment of neonatal females. The same has subsequently been confirmed for the preoptic area and subregions of the amygdala. Interestingly, despite the overwhelming perception to the contrary, no such sex difference has been identified for the hippocampus or cortex. And more importantly, sex differences in synaptic profiles have not been explored in the primate, leaving a major gap in our knowledge of the nature of sex differences in the human. In the continuing effort to understand how sex differences in synaptic profile impact on physiology and behavior, it is essential to place the findings in the context of a circuit. For example, in the preoptic area, males have a twoto three-fold greater density of dendritic spine synapses, whereas in the ventromedial nucleus, males have a two- to three-fold greater number of dendritic spines.32 The difference between the two brain regions is the nature of the dendrites themselves, which are similar in the sexes in the preoptic area, but are longer and branch more frequently in the male ventromedial nucleus than the female (Figure 8.2). How this changes the response to afferent stimuli is unclear, but the consequences for behavior are profound. The male pattern of synapses in either brain region is essential for the normal expression of male sexual behavior in adulthood, a topic discussed in greater detail below.

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Figure 8.2  Sex differences in dendritic spine synapses can be in number or density. One of the more profound sex differences in the brain is the pattern of synaptic connections. Dendritic spines are the primary site of excitatory synapses. In the preoptic area, a major brain region controlling male sexual behavior, the dendrites of males have twoto three fold greater density of spine synapses, revealing a higher level of excitatory input onto these neurons. In the ventromedial nucleus, a major brain region controlling female sexual behavior, the dendrites of males are longer and branch more frequently, resulting in overall more dendritic spine synapses and suggesting a broader array of afferent inputs to this region in males, although this remains to be determined.

Neurochemical Sex Differences The third major neuroanatomical sex difference possible is the neurochemical phenotype of a set of neurons, which may differ in abundance and/or projections.33 Quantifying sex differences in neurons of a particular phenotype often provides the advantage of being one step closer to the functional significance of any observed differences. For example, a collection of galanin-positive neurons in the brainstem project to motor neurons of the spinal cord and have been identified as the ejaculation center.34 Not surprisingly, there are few if any of these galanin-positive neurons in the female brainstem. In this case the female lacks the peripheral structures involved in the behavioral response, making the connection between neuroanatomy and functional output relatively unambiguous. However, this is not always the case. There is a marked male bias in the density of vasopressin innervation of the septum in both rats and other rodents, including voles.35 Vasopressin, similar to the closely related oxytocin, is strongly associated with the control of affiliative behaviors such as parenting and pair bonding.36,37 The denser vasopressin innervation in males is speculated to provide the neurological underpinnings for inducing males to provide parental care of their offspring,38 an endpoint achieved in females by the hormonal milieu of pregnancy, parturition, and lactation.39,40 A sex difference in the number of vasopressin-positive neurons in the human pBNST is of unknown significance but notable in that it is not apparent until puberty.41 There is also a sex difference in the number of dopamine synthesizing neurons of the AVPV and this again seems to be directly tied to reproduction in that this nucleus plays a critical role in the control of the GnRH neurons that regulate the release of gonadotropins

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from the anterior pituitary.42 So in three different instances there is a direct connection between sex differences in defined populations of neurochemically identified neurons and a reproduction-related output. When the discussion of sex differences in neuroanatomy and function strays outside of the immediate realm of reproduction in laboratory animals, such direct connections have not been established, and perhaps may not exist. For example, the sexual neuro­anatomical dimorphisms in the particular circuits that regulate gonadotropin secretion in rats are unlikely to have counterparts in primates, including humans, since the function they mediate is sexually dimorphic in rats but not in a primate that has been studied to date.

Cellular mechanisms establishing sex differences in brain A Critical Role for Naturally Occurring Cell Death After confirming that a particular brain region or structure is larger in one sex versus the other, and that the difference is due to the number of neurons and not cell size or spacing, the next critical question is how does this sex difference come about? There are three fundamental strategies by which the size of a collection of neurons, meaning a nucleus, can be altered: (1) more cells are born, (2) more cells migrate into the region, or (3) more cells die. There is also the potential for cells to be larger or have more associated neuropil in one sex versus the other, but this would impact cell density, not cell number, which is the basis of most volumetric sex differences. Estimates are that 50% of the cells generated in the nervous system are ultimately fated to die during early periods of development. Analyses of numerous volumetric sex differences, including the song control nuclei of birds, the SDN-POA of rats and the AVPV and SNB of mice and rats, consistently conclude that volumetric sex differences are established when males and females begin with the same number of neurons but that differential hormonal exposure results in sex differences in cell death. The identification of apoptosis as a mechanism for establishing sex differences in the vertebrate nervous system was made over 20 years ago,43,44 but has been investigated mechanistically only recently. The greatest advances have been made in the study of the SNB, which consists of motor neurons that innervate the penis. The size of the SNB is, not surprisingly, substantially larger in males. Ciliary neurotrophic factor (CNTF) is upregulated by androgens in the bulbocavernosus muscle, which is innervated by the SNB motor neurons, and then retrogradely transported to act on the CNTF receptors on the motor neurons, promoting their survival. Mutant mice lacking receptors for CNTF have no sex difference in the size of the SNB. CNTF administered to females rescues the motor neurons, and treating males with antagonists to CNTF receptor reduces

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the number of motor neurons.45 Thus, testosterone regulates cell death in a specific CNS region because it has evolved control of a well-established neurotrophic mechanism that controls apoptosis in numerous neural tissues. Developmentally restricted sex differences in cell death leading to adult volumetric dimorphisms have been well characterized, and well reviewed for several other brain regions, most notably the SNB and SDN-POA of rats, the AVPV of mice and rats and the song control nuclei of birds.22,44,46 In each case there is a temporal disconnect of days between hormone exposure and maximum cell death, suggesting an initiation of a long-term cellular process by estradiol or testosterone, perhaps involving afferent input or efferent connections. The delay in dying further complicates attempts at identifying the mechanism of hormone action, which can vary from neuroprotection (SDN-POA, SNB, song nuclei) to death promoting (AVPV). Mice with a null mutation in the Bcl-2 gene, a potent inhibitor of cell death, or in Bax, a promoter of cell death, have been usefully exploited to advance our understanding. Sex differences in the SNB and AVPV were eliminated in Bax   / mice, indicating Bax is required for sexually dimorphic cell death in the mouse forebrain and spinal cord. Interestingly, Bax is involved in death that is increased by estradiol (in the AVPV) as well as that decreased by testosterone (in the SNB). One advantage of this approach is that the number of neurons observed in Bax   / adults represents the original number generated in each sex, whereas the difference in cell number between Bax   / and Bax   / adults reveals the total number of neurons lost ‘integrated over the entire developmental cell death period’,45 further supporting the notion that sex differences in cell death contribute to volume differences in multiple brain regions. However, it would be simplistic to suggest that this is the only basis for volumetric sex differences. Brain nuclei are defined by a combination of their histological appearance, the neurochemical phenotype of the cells and the function attributed to that group of cells. They are not monomorphic collections of identical neuronal phenotypes. The ability of steroids to distinguish the phenotype of neurons, and perhaps even to determine the fate of precursor cells as neurons versus glia, is an important and still relatively poorly understood mechanism for distinguishing male from female brains.

An Emerging Role for Cell Genesis and/or Cell Differentiation The importance of cell death in sculpting the differential size of specific nuclei in males and females is clear, but an emerging view is that this is not the sole mechanism either establishing, or even maintaining volumetric sex differences. When brain regions are examined for sex differences in cell genesis during the developmental peak of cell birth (usually prenatally), there has been no good evidence for sex differences in the number of cells born. However, the

tremendous interest in neurogenesis in the adult brain has also brought attention to the possibility of important cell genesis in the early postnatal brain. In rats the hippocampus is larger in males than females, but both the magnitude and reliability of the difference is small (reviewed in McCarthy and Konkle3). Nonetheless, more new cells are detected in the one-week-old male rat hippocampus than the female hippocampus, particularly in the CA1 region of Ammons horn.47 Treatment of females with either testosterone or estradiol increases the number of new cells to that of males, but the hormonal modulation appears to be complex and multifactorial, as there are differential effects on neurons versus glia and androgens versus estrogens. This evolving story is further complicated by the difficulty in resolving whether more new cells are born or more cells simply survive in the hippocampus of males compared to females. However, the phenomenon seems relatively specific since there is no difference in the number of new cells detected in the hypothalamus of the same animals at the same developmental time point. Similar questions are being asked in regard to a profound sex difference in vasopressin positive neurons in the rat and vole brain.48 Again, the issue of differential birth versus survival arises, with the latter being importantly impacted by differentiation. New cells that do not differentiate into either neurons or glia are destined to die. Stimuli that promote movement along a dedicated differentiation pathway increase survival. Steroids are very likely to regulate, if not determine, cell fate but to date this has not been definitively demonstrated. In the arena of areas to watch, the importance of sex differences in cell genesis and differentiation is at the top of the list.

Importance of Cell-to-Cell Communication Sexual differentiation of neuroanatomy is determined by neonatal steroid action. Steroids act via receptors that are transcription factors and induce gene expression followed by protein synthesis. The steroid receptors of greatest interest are the estrogen receptor (ER), which has two isoforms, ER and ER, and androgen receptors (AR), which bind both testosterone and dihydrotestosterone (DHT). The distribution of steroid receptors in the brain is characterized by receptor autoradiography, immunocytochemistry or in situ hybridization for detection of the mRNA,49–52 all of which allow for identification of individual cells. The limits of sensitivity of each not withstanding, a consistent conclusion is that some brain regions, such as the POA or VMN of the mediobasal hypothalamus, have dense collections of neurons that express ER and/or AR, whereas others do not. This pattern seems to hold across species and is seen also in humans. However, even within those regions where this is a high level of steroid receptor expression, not every neuron is presumed to express the receptor, and evidence for steroid receptors in non-neuronal astrocytes is notably

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lacking. Thus, a natural corollary of a restricted expression of ER and AR is that estradiol- or androgen-induced differentiation would be restricted to those cells possessing the receptor. In other words, steroid-mediated differentiation of neuroanatomy would be expected to be cell autologous, with only those neurons expressing ER or AR changing morphology in response to steroids. But contrary to this prediction, the data suggest otherwise. Quantification of morphometric endpoints, such as dendritic length, branching and density of dendritic spines within a particular nucleus (i.e. medial pre optic nucleus, VMN, arcuate), consistently indicate that the entire population of neurons has shifted its phenotype in response to steroid stimulation.30 The key to understanding this apparently contradictory observation is the importance of cell-to-cell communication in transmitting the signal to change. Gaba in the Arcuate Nucleus of the Hypothalamus The arcuate nucleus is located at the ventral border of the hypothalamus in close proximity to the median eminence through which it exerts influence over the anterior pituitary gland. A variety of neuropeptide releasing factor expressing neurons and GABA interneurons are interspersed with protoplasmic astrocytes distinguished by their early maturation in relation to other hypothalamic nuclei. Neurons of the arcuate nucleus are sexually dimorphic, with males having fewer dendritic spine synapses than females.53,54 The astrocytes of the arcuate nucleus are also sexually dimorphic, with males having more stellate-shaped glia that have longer and more highly branched processes than females.55 In an effort to understand the relationship between neuronal and glial morphology, Mong and colleagues determined that in developing males, estradiol (aromatized from testicular androgens) induces expression of the rate-limiting enzyme in GABA synthesis, GAD, thereby increasing levels of GABA which is made exclusively in neurons. Astrocytes do not make GABA, therefore limiting the primary site of steroid action to the neuron, but astrocytes do respond to GABA with increased process growth and branching.56 In the adult, astrocytes of the arcuate nucleus regulate the synaptic profile of immediately adjacent neurons57 and a similar phenomenon is presumed to occur during development. Thus a neuron-to-astrocyte-to-neuron loop is established in which steroids, i.e. estradiol, act first in the neuron and then indirectly modify the morphology of neighboring astrocytes which in turn modify the neuron (Figure 8.3). Prostaglandins in the Preoptic Area An analogous yet distinct process occurs in the preoptic area. In this brain region males have a greater density of dendritic spines, but surprisingly they also have more stellate and complex astrocytes compared to females.58,59 The astrocytes of the preoptic area are similar to the arcuate in that they are also highly mature at birth as evidenced by

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Figure 8.3  GABA mediates neuronal-astrocytic communication to induce sex differences in the arcuate nucleus. An emerging principle in the organizational actions of steroids is the importance of cell-to-cell communication. In some regions, astrocytes are a critical component of this communication. The arcuate nucleus of the rat exhibits sexually dimorphic synaptic patterning and this is established by estradiol (E2) binding to its receptor (ER) primarily within neurons to increase expression of the rate-limiting enzyme in GABA synthesis, GAD (glutamic acid decarboxylase), which is then released from neurons to act on the neighboring astrocytes to induce them to differentiate into a more complex stellate morphology. This increased complexity of the astrocytes is correlated with a reduction in the density of dendritic spine synapses in this brain region.

dense expression of glial fibrillary acid protein (GFAP), yet the relationship between astrocyte morphology and dendritic morphology is the opposite in the POA compared to the arcuate nucleus. Neuron-to-astrocyte-to-neuron communication also plays a critical role in establishing the sexually dimorphic neuroanatomy of the preoptic area, but the nature of the signaling molecules is profoundly and surprisingly different. Rather than a classic neurotransmitter, the initiating event in the cellular cascade leading to changes in astrocytic and neuronal morphology is increased synthesis of the prostaglandin E2 (PGE2). The synthesis of all the prostanoids begins with the oxygenative cyclization of arachidonic acid by cyclooxygenase. The inducible isoform of cyclooxygenase, COX-2, is an immediate early gene responsive to a variety of stimuli including infection, injury, and stimuli associated with neuronal plasticity.60–62 As early as the day of birth, COX-2 mRNA and protein are significantly higher in the POA of males than females and treating females with estradiol increases COX levels to that of males. Increased COX-2 is directly correlated with increased PGE2 production and treating newborn females with estradiol increases PGE2 levels in the POA almost seven-fold. Most importantly, administrating PGE2 to newborn females induces a permanent two- to threefold increase in dendritic spines on neurons in the preoptic

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area, but not the ventromedial nucleus or the hippocampus. Conversely, blocking PGE2 synthesis temporarily in newborn males by inhibiting the COX enzymes, significantly reduces POA dendritic spines to the level seen in normal females.58,63 The neighboring astrocytes also change their morphology in response to PGE2, with increased process length and branching, although the magnitude of the response is about half that seen with estradiol treatment. The COX enzymes, COX-1 and COX-2, are present in neurons of the POA, and the receptors for PGE2 (EP1-4) can be found in this brain region as well, including on astrocytes. One established effect of PGE2 on astrocytes is the induction of glutamate release,64 and this appears to be true in the POA as well. Moreover, the induction of dendritic spines on POA neurons by PGE2 requires at least in part the activation of the AMPA-type glutamate receptor. Taken together, these data present a working model in which estradiol upregulates the expression of COX-1 mRNA and protein in neurons and thereby markedly increases the production of PGE2. The prostanoid is released by neurons to act on neighboring astrocytes, causing them to release glutamate which in turn acts back on the neurons inducing the formation of dendritic spines (Figure 8.4). Thus once again there is presumptive neuron-to-astrocyte-to-neuron communication that coordinates the induction of morphological changes over an entire, but limited, region of the brain. The preoptic area is the critical brain region controlling male sexual behavior, and the importance of these morphological changes for behavior will be discussed below. Glutamate in the Ventromedial Nucleus of the Hypothalamus In rats, the ventromedial nucleus (VMN) is to female sexual behavior what the preoptic area is to male sexual behavior, a critical node in a complex circuit and a central site of steroid-induced sexual dimorphism. Dendrites on neurons of the VMN have more branches, and as a consequence more dendritic spines in males than females,65,66 and just like the POA and the arcuate, this sex difference is mediated by estradiol (derived from testicular androgen) during the first few days of life. However, in contrast to the POA and arcuate nucleus, the astrocytes of the developing VMN are notably immature and appear to play no role in the process of sexual differentiation. This does not mean there is no role for cell-to-cell communication, however. In this brain region, estradiol acts in one neuron to induce changes in another neuron. What makes the situation even more unique in this brain region is the mechanism of estradiol action, which is non-genomic. As discussed above, steroids act via transcription factors to directly alter gene expression and protein synthesis. An emerging concept in steroid action has been the direct activation of signaling molecules at the membrane, in particular membrane-bound kinases such as MAP kinase or PI3 kinase.67–71 These interactions are generally rapid and transient, but can have long-term

Figure 8.4  PGE2 mediates neuronal-astrocytic communication to induce sex differences in the preoptic area. Astrocytes of the preoptic area (POA) are also sexually dimorphic, with males having more complex cells that have longer processes which branch more frequently. In this brain region, estradiol (E2) again binds to its receptor (ER) and upregulates the expression of the cyclooxygenase enzyme, COX-2, which is a principle enzyme in the production of the prostaglandin, PGE2. Astrocytes respond to PGE2 by releasing glutamate, and glutamate acting at AMPA receptors induces the formation of dendritic spine synapses. In this way, neuronal-to-astrocyte-to-neuronal communication establishes a sexually dimorphic pattern of dendritic spine synapse density.

consequences for the cell by secondarily inducing gene transcription via changes in intracellular calcium or other signaling molecules.72 Because these effects are rapid, however, it was generally assumed that they would not be involved in the process of sexual differentiation of the brain since it is a process that permanently alters brain structure. But the data remind us why we should never make assumptions. In the developing mediobasal hypothalamus, estradiol activates PI3 kinase within one hour and this leads to increased release of glutamate from presynaptic terminals. The released glutamate acts on postsynaptic NMDA receptors and induces the formation of dendritic spine excitatory synapses. There is no direct role for estradiol in the post-synaptic neuron.65 Thus, the primary event in the sexual differentiation of synaptic patterning in the VMN is non-genomic, rapid, and requires cell-to-cell communication (Figure 8.5).

Sex differences in physiology and behavior The term ‘sexually dimorphic’ is frequently used to describe any observed sex difference and as a result has lost its true meaning. To be dimorphic means to be of two forms, and most sex differences in brain and behavior, including gender differences in psychiatric and neurological disorders, are not dimorphic, they are allomorphic, meaning of one form but differing in incidence or degree. For example, both

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Figure 8.5  Estradiol induces glutamate release from hypothalamic neurons to induce sex differences in the ventromedial nucleus. A different form of cell-to-cell communication occurs in the ventromedial nucleus of the hypothalamus, and in this brain region there is no identified role for astrocytes. Instead, estradiol (E2) acts primarily in one neuron to non-genomically activate PI3 kinase which induces the release of the neurotransmitter glutamate (through mechanisms that are not understood). The released glutamate then acts on neighboring neurons to activate AMPA and NMDA receptors, leading to calcium influx and activation of MAP kinases and the construction of dendritic spines. Experimental evidence confirms that estradiol acts only in the presynaptic neuron to induce organizational effects on the synaptic profile of the post-synaptic neuron. Via this mechanism, the actions of estradiol are extended beyond the principle neuron that expresses estrogen receptor.

males and females exhibit aggression, but males do so more frequently and generally at a higher intensity, depending in part on the provocation. There are, however, two genuinely sexually dimorphic endpoints: (1) the control of gonadotropin secretion from the anterior pituitary in rodents and (2) sexual behavior, including the propensity to become sexually aroused by members of the same or opposite sex. Early studies of sexual differentiation were unambiguous in their focus on these two dimorphic endpoints which were assessed in the context of the Organizational/Activational Hypothesis. These remain useful today as valuable tools for elucidating the cellular mechanisms mediating sex differences in the brain, as illustrated above, and it can be argued that we have the greatest traction in identifying mechanisms of differentiation when using behavior as the endpoint. Therefore we will further exploit this model system for purposes of discussion.

Sexual Behavior as a Readout of Brain Differentiation Sexual behavior in males is commonly regarded as opportunistic and readily expressed when a receptive female is present, provided there is an absence of other more salient stimuli such as an approaching predator. In most species studied female sexual behavior is physiologically constrained

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to be expressed only in proximity to ovulation. A fascinating but mechanistically unexplained distinction in male and female sexual behavior is the impact of experience. Males improve with practice and if testosterone is removed (via castration), will continue to exhibit high levels of copulatory behavior that only gradually extinguishes over a period of months. In contrast, the female receptive posture, lordosis, does not require practice but will only be displayed under the proper hormonal umbrella. If steroids are eliminated, so is the behavior. In terms of ultimate causation, the adaptive basis for the distinction is obvious, there is no benefit and possible cost to females mating outside the window of opportunity for conception, whereas in species in which males make little parental investment, males maximize their evolutionary fitness by never missing an opportunity to reproduce. This is not true in humans where copulations outside the period of fertility are believed to play an important role in maintaining the pair bond. Proximately, however, this dichotomy in the nature of the plasticity attendant to both behaviors is suggestive of distinct and separate neuronal circuitries, be they physically or merely functionally so. A useful framework for investigating mechanistic questions of sexual differentiation is the operationally defined and distinct processes of masculinization, feminization, and defeminization. Masculinization refers to an active developmental process initiated by gonadal steroids during the perinatal sensitive period followed by expression of normal male copulatory behavior in adulthood. Feminization is essentially what happens in the absence of masculinization, meaning it is the default pathway leading to expression of lordosis under the proper hormonal conditions in adulthood. Defeminization is distinct from but normally occurs in tandem with masculinization and refers to the process whereby the ability to express female sexual behavior is lost. In rats the neural circuitry controlling male sexual behavior has been mapped by lesion studies and expression of the immediate early gene, c-fos. Olfactory input is received via the main and accessory olfactory bulbs and transferred to the sub-nuclei of the amygdala before converging on the POA. From there the information is sent down to the midbrain and critical spinal cord nuclei for the control of the penis and suppression of micturition.73–75 The POA serves as a critical nodal point for the integration of sensory cues and is a principle site for steroid hormone action. As discussed above, in the rat there are two major sex differences in the POA, one is the overall size of the SDN-POA, and the other is the density of dendritic spine synapses. To date, there has been no clear relationship between the volume of the SDN-POA and a behavior­al output, and the size of the SDN-POA has been distinctly dissociated from male sexual behavior in that females masculinized by PGE2 have a small female-sized SDN-POA but show robust male sex behavior while males treated neonatally with an inhibitor of PGE2 synthesis have a normal male-sized SDN-POA but exhibit almost no male sex behavior.76 This does not preclude the possibility that the rat

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SDN-POA is a neuroanatomical substrate for the process of defeminization, as has been suggested by others, however a growing body of evidence suggests the SDN-POA may be important to partner preference. This is best exemplified in recent studies of a naturally occurring animal variant of same sex preference, male sheep preferring domestic rams. In at least two different herds of domestic sheep, approximately 8% of rams prefer to mount other males. These animals also have a smaller SDN-POA that contains fewer aromatase-expressing neurons, suggesting they may have been exposed to lower levels of endogenous estradiol early in development.15,77 The preoptic area and the anterior hypothalamus have also been implicated in influencing the sex of the conspecifics toward which one displays sexual interest in rodents, ferrets, and humans,16,78,79 but this remains a controversial and poorly developed research area. Considerably more progress has been made in associating the changes in the synaptic profile and behavioral output. There is a direct correlation between the presence of a high density of dendritic spines on POA neurons and the expression of male sexual behavior in adulthood.63 This does not preclude the expression of female sexual behavior, which appears to be under distinct control from a separate neural circuitry.76 Thus, neonatal females treated with PGE2 in order to induce the organization of a male dendritic profile, will exhibit robust male sexual behavior as adults if provided with exogenous testosterone and a sexually receptive female. These same masculinized females will also show robust female sexual receptivity (i.e. lordosis) if provided with exogenous estradiol and progesterone and a sexually experienced male. Similar plasticity in sexual behavior was recently reported in mice lacking a functional form of the Trp2c channel in the vomeronasal organ, only in this instance the behavioral changes were independent of gonadal hormone.80 Both of these sets of studies reflect how much we have to learn regarding the biological basis of sex behavior and how it differs in males and females.

Sex Differences in Aggression Sex differences in aggression are best illustrated in seasonally breeding animals, in which testosterone levels fluctuate widely and male-to-male aggressive interactions increase dramatically as males compete for mates, territory or other limiting resources relevant to reproductive success, and then drop precipitously with falling testosterone levels. But it is somewhat disingenuous to call this a sex difference in aggression since the entire constellation of variables dictating a species-specific mating strategy confines the behavioral repertoire of males and females such that it is advantageous for males to compete and females not to. Similarly, maternal aggression, a particularly vicious form of aggression, occurs only in females, only in response to certain threats, and only during a restricted postpartum period when offspring are vulnerable. This can hardly be considered a sex difference

in aggression since only females give birth, and it clearly illustrates that the capacity exists for females to exhibit high levels of aggression. Displays of aggression are further constrained by variables extrinsic to the individual such as the social structure, availability of resources, artificial conditions associated with laboratory settings, etc. Despite the many variables influencing expression of aggressive behavior, questions can still be asked regarding organizational versus activational hormonal control. Unlike sexual behavior which involves distinct motor patterns in males versus females, aggression is expressed in the same way by both sexes, but it is the frequency and intensity of the expression that varies. A naturally occurring source of variability in prenatal exposure to gonadal steroids provides some of the best evidence that at least some components of adult expressions of aggression are organized during early life. Species with large litter sizes, such as rats and mice, have a bifurcated uterus that allows for fetuses to be packed in as peas in a pod. Because of the copious quantities of androgens produced by late gestation male fetuses, a female fetus that finds herself sandwiched between two males in the uterine horn experiences a distinctly different endocrine environment from a female that develops between two sisters. By delivering the rat or mice pups via Caesarean section, the relative position of a fetus in relation to other fetuses can be noted, the individual marked and then development monitored. Modest changes in the external genitalia of females developing between males confirms that hormonal exposure has been different. When animals are monitored through to adulthood, it is apparent that females that developed between male littermates are more likely to exhibit aggression, and their responsiveness to the effects of androgen treatment on inducing aggression is also greater.81 This phenomenon is referred to as the intra-uterine position effect or IUP, and has also been used to explain subtle individual variability in sexual and social behaviors.82 But in many ways what the IUP effect is best at illustrating is the tremendous sensitivity of the developing brain to even subtle perturbations in the hormonal milieu. While there is good evidence for organizational effects of hormones on adult expression of aggression, there is equally good evidence that it is a relatively weak effect. This stems in part from observations of the importance of adult circulating hormone levels, which are tightly linked to fluctuating aggression in seasonal breeders, but can also be associated with changes in the perception of and response to a social threat in non-seasonal breeders, including rodents and humans. Anabolic steroids lower the threshold to respond to provocation in a laboratory setting, and cortical regions associated with aggression and impulsivity disorders show greater activation in females treated with testosterone compared to placebo.83,84 But the hegemony of testosterone begins to break down when one tries to correlate individual serum levels with behavior. This is in part because, as with all steroids, testosterone levels vary throughout the day, and

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relative levels of free to bound hormone can impact access to the brain, something we still cannot assess accurately. Perhaps more importantly, behavior itself has an enormous influence on circulating androgen levels. Individuals who experience victory in a competitive situation will show a significant and sustained increase in serum testosterone, while those experiencing defeat show a decrease. Remarkably, even just observing one’s favorite sports team win or lose can alter hormonal profiles as demonstrated by tracking salivary steroid content in fans watching a World Cup soccer match.85 Even winning a contest that is purely a matter of chance and involves only a small reward ($5) will increase serum testosterone in young men.86 Women do not respond to chance victories with an increase in serum testosterone, suggesting an interesting sex difference in parameters associated with reward value, dominance and obtainment and defense of resources. Children as young as 5 years old exhibit sex differences in aggression, and while these do not neatly correlate with androgens, there is an effect in each sex, with androstenedione being a better predictor of provocation in males and testosterone of affectivity in females.87 A second major variable dissociating early organization actions of androgens and adult aggressive behavior is the importance of genetics. The notion that genetic differences originating with the X or Y chromosome might contribute to sex differences in behavior is a relatively new one,88,89 but the empirical evidence that genetics is important to variability in aggression is long standing and unquestioned.90 Interestingly, much of the attention on genetic variation is on how it influences an individual’s sensitivity to steroids, in particular androgens and estrogens. In summary, aggression is a sexually dimorphic trait not because it takes a different form in males versus females, but rather because it is expressed at different levels of intensity and frequency and can be evoked in response to distinct stimuli. Normally docile, or at least civil, females can become viciously aggressive when under the hormonal grip of early postpartum and lactation, but only when the perceived threat is toward their young, not themselves. Males are on average more likely to be aggressive than females, and this is a product of both early exposure to androgens during a perinatal sensitive period and the impact of testosterone on reactive thresholds as an adult. But prior experience, both immediate and long term, combined with genetic predispositions, can introduce far more variability in responsiveness than hormone levels. Thus, sex differences in aggression are not so easily attacked from a mechanistic standpoint as those seen for reproductive behavior.

Sex Differences in Stress and Anxiety Sex differences in stress and anxiety are less clear and far more complicated than sex differences in aggression. Animal models reveal that in adult animals, females are generally more sensitive to any given stressor and take longer to

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recover from stress when quantified as the duration of time required for corticosterone to return to basal levels.91 This sex difference is in part organized by perinatal hormones and in part a function of adult circulating steroids, with estrogens generally exacerbating stress responding while androgens temper the response to stress. However, any simple conclusions regarding sex differences in stress and anxiety are precluded by the major confounding impacts of early life experience, adult hormonal milieu, nature of the stressor, and endpoint being measured. In classic eye blink conditioning studies, males respond positively to stress with both an increase in dendritic spine synapses on hippocampal neurons and improved learning, whereas females show the opposite, reduced dendritic spine synapses and impaired learning.92 But in studies using spatial learning as the endpoint and restraint as a mild stressor, females show improved performance post-stressor while males are impaired.93 A systematic comparison of the impact of very early to adolescent stress on anxiety responses in adulthood in rats revealed multiple sex differences.94 Some have speculated that stress responding in males is relatively uniform across the lifespan whereas females possess an early resilience that is compromised with increasing age,93 although others suggest females are particularly sensitive to stressors during the adolescent period.95 A meta-analyses of human studies focusing on major life stressors indicates females subjectively experience more stress than males and report more symptoms of depression, anxiety, and psychosomatic problems,96 but this accounts for only a small percentage of the variance in life events. Thus any meaningful discussion of sex differences in stress and anxiety must include consideration of the life history of the individual, including extrinsic factors that can introduce gender bias independent of biology.

Suggestions for future investigations This is an exciting time for the study of sex differences in brain and behavior and the impact of gender on disorders that affect the nervous system. There has never been more attention on the topic and the level of discourse has moved beyond the merely descriptive. We are now making genuine strides in understanding the sources of the variables contributing to sex differences, with appropriate weight given to hormones, genes and environment. We are also making progress, albeit slowly, in elucidating the cellular mechanisms leading to the establishment and maintenance of sex differences in the brain. Some may question why this is an important thing to understand. For this investigator there are a number of reasons why it is essential to explore mechanism. One important reason is that the study of sex differences is a model system that can provide unique insights into both male and female brain development. This is evident in the discovery that prostaglandins play a role

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in masculinization of the brain, something that might not have been discovered in the absence of comparing males and females. Moreover, all of the processes fundamental to brain development; neurogenesis, apoptosis, synaptogenesis, myelination, axonal and dendritic growth, and phenotypic differentiation are regulated by gonadal steroids and many times are different in males and females. By establishing the mechanisms of hormone action we can increase our knowledge of these pivotal events. Clinically, the need to understand the origins of sex differences in the brain is self-evident in the profound impact of gender on the relative risk of various mental health and neurological disorders. As reviewed elsewhere in this volume, males are at greater risk of disorders that originate early in development, whereas females are at greater risk of adult onset disorders. By understanding the basics of brain development in males versus females we can hope to gain insight into the biological underpinnings of this gender bias. Likewise, males frequently suffer worse outcomes to pediatric brain damage, and the source of this vulnerability is largely unknown. Finally, there is increasing evidence of compounds in our environment that either mimic or disrupt the actions of steroids. Neonates are among the highest risk group for exposure due to transfer from the mother’s milk, ingestion directly from the environment, and indirect exposure via the plastics used in many modern day baby products. Evaluating the true nature of the risk involved requires that we understand how both these artificial and natural steroidal compounds act on the developing brain. Lastly, as important as understanding sex differences is to the practice of gender-specific medicine, it is equally important that we recognize that few gender differences in the brain and its functions are simple sexual dimorphisms, most are statistical differences between the sexes in the distribution of particular measures. Group statistics apply to groups and do not predict the behavior of their individual members. This is particularly relevant in areas of cognition and emotionality where presumptions of greater skill in one sex versus the other become a restrictive principle that limits individual growth due to either internal perceptions or external pressures.

References 1. Harley V, Goodfellow P. The biochemical role of SRY in sex determination. Mol Reprod Dev 1994;39:184–193. 2. Koopman P, Gubbay J, Vivian N, et al. Male development of chromosomally female mice transgenic for Sry. Nature 1991;351(6322):117–121. 3. McCarthy MM, Konkle AT. When is a sex difference not a sex difference? Front Neuroendocrinol 2005;26(2):85–102. 4. Levy J, Heller W. Gender differences in human neuropsychological function. In: AA Gerall, H Moltz, IL Ward, eds. Handbook of Behavioral Neurobiology: Sexual Differentiation. New York, NY: Plenum; 1992:363. 5. Phoenix CH, Goy RW, Gerall AA, et al. Organizing action of prenatally administered testosterone proprionate on the

6.

7. 8. 9.

10.

11.

12. 13. 14.

15.

16. 17.

18.

19. 20.

21. 22.

23.

24.

25.

26.

tissues mediating mating behavior in the female guinea pig. Endocrinology 1959;65:369–382. Becker JB, Arnold AP, Berkley KJ, et al. Strategies and methods for research on sex differences in brain and behavior. Endocrinology 2005;146(4):1650–1673. Becker JB, Breedlove SM, Crews D, et al. Behavioral Endocrinology, 2nd edn. Cambridge, MA: MIT Press; 2002. Sisk CL, Foster DL. The neural basis of puberty and adolescence. Nat Neurosci 2004;7:1040–1047. McEwen BS, Lieberburg I, Chaptal C, et al. Aromatization: important for sexual differentiation of the neonatal rat brain. Horm Behav 1977;9:249–263. Naftolin F, Ryan KJ, Davies IJ, et al. The formation of estrogens by central neuroendocrine tissues. Recent Prog Horm Res 1975;31:295–319. Bakker J, De Mees C, Douhard Q, et al. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat Neurosci 2006;9(2):220–226. Nottebohm F, Arnold AP. Sexual dimorphism in vocal control areas of the songbird brain. Science 1976;194:211–213. Arnold AP, Wade J, Grisham W, et al. Sexual differentiation of the brain in songbirds. Dev Neurosci 1996;18(1–2):124–136. Gorski RA, Gordon JH, Shryne JE, et al. Evidence for a morphological sex difference within the medial preoptic area of the rat brain. Brain Res 1978;148:333–346. Roselli CE, Larkin K, Resko JA, et al. The volume of a sexually dimorphic nucleus in the ovine medial preoptic area/ anterior hypothalamus varies with sexual partner preference. Endocrinology 2004;145:478–483. LeVay S. A difference in hypothalamic structure between heterosexual and homosexual men. Science 1991;9:497–506. Pruessner JC, Collins DL, Pruessner M, et al. Age and gender predict volume decline in the anterior and posterior hippocampus in early adulthood. J Neurosci 2001;21(1):194–200. Hamann S, Herman RA, Nolan CL, et al. Men and women differ in amygdala response to visual sexual stimuli. Nat Neurosci 2004;7(4):411–416. Arnold AP. Sex chromosomes and brain gender. Nat Rev Neurosci 2004;5:701–708. De Vries GJ. Minireview: sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology 2004;145(3):1063–1068. De Vries GJ, Boyle PA. Double duty for sex differences in the brain. Behav Brain Res 1998;92(2):205–213. Davis EC, Popper P, Gorski RA. The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area. Brain Res. 1996;734:10–18. Simerly RB. Development of sexually dimorphic forebrain pathways. In: A Matsumoto, ed. Sexual Differentiation of the Brain. Boca Raton, FL: CRC Press; 2000:175–202. Bishop KM, Wahlsten D. Sex differences in the human corpus callosum: myth or reality. Neurosci Biobehav Rev 1996;21(5):581–601. Fitch RH, Berrebi AS, Cowell PE, et al. Corpus callosum: effects of neonatal hormones on sexual dimorphism in the rat. Brain Res 1990;515(1–2):111–116. Driesen NR, Raz N. Sex, age, and handedness-related differences in human corpus callosum observed in vivo. Psychobiology 1995;23:240–247.

C h a p t e r 8     Sexual Differentiation of Brain Structure and Function l

27. Swaab DF, Hofman MA. Sexual differentiation of the human hypothalamus in relation to gender and sexual orientation. Trends Neurosci 1995;18:264–270. 28. Hofman MA, Swaab DF. The sexually dimorphic nucleus of the preoptic area in the human brain: a comparative morphometric study. J Anat 1989;164:55–72. 29. Giedd JN. Structural magnetic resonance imaging of the adolescent brain. Ann N Y Acad Sci 2004;1021:77–85. 30. Schwarz JM, McCarthy MM. Steroid-induced sexual differentiation of the brain: multiple pathways, one goal. J Neurochem 2008;105:1561–1572. 31. Matsumoto A. Sexual Differentiation of the Brain. Boca Raton, FL: CRC Press; 2000. 32. McCarthy MM. Estradiol and the developing brain. Physiol Rev 2008;88(1):91–124. 33. De Vries GJ, Buijs RM, Van Leeuwen FW. Sex differences in vasopressin and other neurotransmitter systems in the brain. Prog Brain Res 1984;61:185–203. 34. Coolen LM. Neural control of ejaculation. J Comp Neurol 2005;493:39–45. 35. Wang Z, Zhou L, Hulihan TJ, et al. Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: a quantitative comparative study. J Comp Neurol 1996;366(4):726–737. 36. Insel TR. Oxytocin – a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies. Psychoneuroendocrinology 1992;17(1):3–35. 37. Lim MM, Young LJ. Neuropeptidergic regulation of affiliative behavior and social bonding in animals. Horm Behav 2006;50(4):506–517. 38. De Vries GJ, Villalba C. Brain sexual dimorphism and sex differences in parental and other social behaviors. Ann N Y Acad Sci 1997;807:273–286. 39. Lonstein JS, De Vries GJ. Influence of gonadal hormones on the development of parental behavior in adult virgin prairie voles (Microtus ochrogaster). Behav Brain Res 2000;114(1–2):79–87. 40. Gonzalez-Mariscal G. Neuroendocrinology of maternal behavior in the rabbit. Horm Behav 2001;40(2):125–132. 41. Chung WC, De Vries GJ, Swaab DF. Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood. J Neurosci 2002;22(3):1027–1033. 42. Simerly RB. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu Rev Neurosci 2002;25:507–536. 43. Konishi M, Akutagawa E. Neuronal growth, atrophy and death in a sexually dimorphic song nucleus in the zebra finch brain. Nature 1985;315:145–147. 44. Nordeen EJ, Nordeen KW, Sengelaub DR, et al. Androgens prevent normally occurring cell death in a sexually dimorphic spinal nucleus. Science 1985;229:671–673. 45. Forger NG. Cell, death and sexual differentiation of the nervous system. Neuroscience 2006;138(3):929–938. 46. Park JJ, Tobet SA, Baum MJ. Cell death in the sexually dimorphic dorsal preoptic area/anterior hypothalamus of perinatal male and female ferrets. J Neurobiol 1998;34(3):242–252. 47. Zhang J-M, Konkle ATM, Zup SL, et al. Impact of sex and hormones on new cells in the developing rat hippocampus: a novel source of sex dimorphism?. Eur J Neurosci 2008;27:791–800.

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48. De Vries GJ, Panzica GC. Sexual differentiation of central vasopressin and vasotocin systems in vertebrates: different mechanisms, similar endpoints. Neuroscience 2006;138(3):947–955. 49. DonCarlos LL, Handa RJ. Developmental profile of estrogen receptor mRNA in the preoptic area of male and female neonatal rats. Brain Res Dev Brain Res 1994;79(2):283–289. 50. Pfaff D, Keiner M. Atlas of estradiol concentrating cells in the central nervous system of the female rat. J Comp Neurol 1973;151:121–158. 51. Shughrue PJ, Komm B, Merchenthaler I. The distribution of estrogen receptor-beta mRNA in the rat hypothalamus. Steroids 1996;61:678–681. 52. Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-alpha and beta mRNA in the rat central nervous system. J Comp Neurol 1997;388:507–525. 53. Matsumoto A, Arai Y. Sexual dimorphism in ‘wiring pattern’ in the hypothalamic arcuate nucleus and its modification by neonatal hormonal environment. Brain Res 1980;19(1):238–242. 54. Mong JA, Glaser E, McCarthy MM. Gonadal steroids promote glial differentiation and alter neuronal morphology in the developing hypothalamus in a regionally specific manner. J Neurosci 1999;19(4):1464–1472. 55. Mong JA, Kurzweil RL, Davis AM, et al. Evidence for sexual differentiation of glia in rat brain. Horm Behav 1996;30:553–562. 56. Mong JA, Nunez JL, McCarthy MM. GABA mediates steroidinduced astrocyte differentiation in the neonatal rat hypothalamus. J Neuroendocrinol 2002;14:1–16. 57. Garcia-Segura LM, Cardona-Gomez GP, Trejo JL, et al. Glial cells are involved in organizational and activational effects of sex hormones in the brain. In: A Matsumoto, ed. Sexual Differentiation of the Brain. Boca Raton, FL: CRC Press; 2000:83–93. 58. Amateau SK, McCarthy MM. A novel mechanism of dendritic spine plasticity involving estradiol induction of prostglandin-E2. J Neurosci 2002;22:8586–8596. 59. Amateau SK, McCarthy MM. Sexual differentiation of astrocyte morphology in the developing rat preoptic area. J Neuroendocrinol 2002;14:904–910. 60. Camu F, Shi L, Vanlersberghe C. The role of COX-2 inhibitors in pain modulation. Drugs 2003;63(Suppl. 1):1–7. 61. Giovannini MG, Scali C, Prosperi C, et al. Experimental brain inflammation and neurodegeneration as model of Alzheimer’s disease: protective effects of selective COX-2 inhibitors. Int J Immunopathol Pharmacol 2003;16(2 Suppl.):31–40. 62. Hoffmann C. COX-2 in brain and spinal cord implications for therapeutic use. Curr Med Chem 2000;7(11):1113–1120. 63. Amateau SK, McCarthy MM. Induction of PGE(2) by estradiol mediates developmental masculinization of sex behavior. Nat Neurosci 2004;7(6):643–650. 64. Bezzi P, Carmignoto G, Pasti L, et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 1998;391(6664):281–285. 65. Schwarz JM, Liang S-L, Thompson SM, et al. Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: a mechanism for organizational sex differences. Neuron 2008;58:584–598. 66. Todd BJ, Schwarz JM, Mong JA, et al. Glutamate AMPA/ kainate receptors, not GABAA receptors, mediate estradiolinduced sex differences in the hypothalamus. Developmental Neurobiology 2007;67:304–315.

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67. Mannella P, Brinton RD. Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. J Neurosci 2006;26(37):9439–9447. 68. Ivanova T, Karolczak M, Beyer C. Estrogen stimulates the mitogen-activated protein kinase pathway in midbrain astroglia. Brain Res 2001;889(1–2):264–269. 69. Kuroki Y, Fukushima K, Kanda Y, et al. Putative membranebound estrogen receptors possibly stimulate mitogen-activated protein kinase in the rat hippocampus. Eur J Pharmacol 2000;400(2–3):205–209. 70. Setalo G Jr, Singh M, Guan X, et al. Estradiol-induced phosphorylation of ERK1/2 in explants of the mouse cerebral cortex: the roles of heat shock protein 90 (Hsp90) and MEK2. J Neurobiol 2002;50(1):1–12. 71. Abraham IM, Todman MG, Korach KS, et al. Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain. Endocrinology 2004;145(7):3055–3061. 72. Dolmetsch RE, Pajvani U, Fife K, et al. Signaling to the nucleus by an L-type calcium channel- calmodulin complex through the MAP kinase pathway. Science 2001;294:333–339. 73. Coolen LM, Olivier B, Peters HJ, et al. Demonstration of ejaculation-induced neural activity in the male rat brain using 5-HT1A agonist 8-OH-DPAT. Physiol Behav 1997;62(4):881–891. 74. Murphy AZ, Rizvi TA, Ennis M, et al. The organization of preoptic-medullary circuits in the male rat: evidence for interconnectivity of neural structures involved in reproductive behavior, antinociception, and cardiovascular regulation. Neuroscience 1999;91(3):1103–1116. 75. Wood RI. Thinking about networks in the control of male hamster sexual behavior. Horm Behav 1997;32:40–45. 76. Todd BJ, Schwarz JM, McCarthy MM. Prostaglandin-E2: a point of divergence in estradiol-mediated sexual differentiation. Horm Behav 2005;48(5):512–521. 77. Roselli CE, Resko JA, Stormshak F. Hormonal influences on sexual partner preference in rams. Arch Sex Behav 2002;31(1):43–49. 78. Baum MJ. Mammalian animal models of psychosexual differentiation: when is ‘translation’ to the human situation possible?. Horm Behav 2006;50:579–588. 79. Houtsmuller EJ, Brand T, De Jonge FH, et al. SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD. Physiol Behav 1994;56:535–541. 80. Kimchi T, Xu J, Dulac C. A functional circuit underlying male sexual behavior in the female mouse brain. Nature 2007;448:1009–1015.

81. vom Saal FS. The intrauterine position phenomenon: effects on physiology, aggressive behavior and population dynamics in house mice. Prog Clin Biol Res 1984;169:135–179. 82. Ryan BC, Vandenbergh JG. Intrauterine position effects. Neurosci Biobehav Rev 2002;26(6):665–678. 83. McGinnis MY. Anabolic androgenic steroids and aggression: studies using animal models. Ann N Y Acad Sci 2004;1036:399–415. 84. Hermans EJ, Ramsey NF, van Honk J. Exogenous testosterone ehances responsiveness to social thresat in the neural circuitry of social aggression in humans. Biol Psychiatry 2008;63:263–270. 85. Bernhardt PC, Dabbs JM Jr, Fielden JA, et al. Testosterone changes during vicarious experiences of winning and losing among fans at sporting events. Physiol Behav 1998;65(1):59–62. 86. McCaul KD, Gladue BA, Joppa M. Winning, losing, mood, and testosterone. Horm Behav 1992;26(4):486–504. 87. Azurmendi A, Braza F, Garcia A, et al. Aggression, dominance, and affiliation: their relationships with androgen levels and intelligence in 5-year-old children. Horm Behav 2006;50(1):132–140. 88. Arnold AP, Burgoyne PS. Are XXX and XY brain cells intrinsically different?. Trends Endocrinol Metab 2004;15(1):6–11. 89. Arnold AP, Rissman EF, De Vries GJ. Two perspectives on the origin of sex differences in the brain. Ann N Y Acad Sci 2003;1007:176–188. 90. Carlier M, Roubertoux PL, Kottler ML, et al. Y chromosome and aggression in strains of laboratory mice. Behav Genet 1990;20(1):137–156. 91. McCormick CM, Linkroum W, Sallinen BJ, et al. Peripheral and central sex steroids havea differential effects on the HPA axis of male and female rats. Stress 2002;5:235–247. 92. Shors TJ, Chua C, Falduto J. Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J Neurosci 2001;21(16):6292–6297. 93. Bowman RE. Stress-induced changes in spatial memory are sexually differentiated and vary across the lifespan. J Neuroendocrinol 2005;17:526–535. 94. Pohl J, Olmstead MC, Wynne-Edwards KE, et al. Repeated exposure to stress across the childhood-adolescent period alters rats’ anxiety- and depression-like behaviors in adulthood: the importance of stressor type ad gender. Behav Neurosci 2007;121:462–474. 95. McCormick CM, Robarts D, Kopeikina K, et al. Long-lasting, sex- and age-specific effects of social stressors on corticosterone responses to restraint and on locomotor responses to psychostimulants in rats. Horm Behav 2005;48:64–74. 96. Davis MC, Matthews KA, Twamley EW. Is life more difficult on Mars or Venus? A meta-analytic review of sex differences in major and minor life events. Ann Behav Med 1999;21:83–97.

Chapter

9

The Sexed and Gendered Brain William Byne Staff Physician, Mental Illness Research, Education and Clinical Center, J.J. Peters Veterans Affairs Medical Center, Bronx, NY; Associate Professor of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

gender-specific medicine. The primary aim here is to review our current understanding of potential neurobiological con­ tributions to the differentiation of sexual orientation and gender identity. As addressed in Chapter 8, much is known about sexual differentiation of the rodent brain, particularly with regard to the substrates that mediate sexual behaviors. The current chapter addresses parallel human research. First, the terminology necessary for a discussion of psy­ chosexual differentiation will be reviewed. Neuroendocrine research relevant to psychosexual differentiation will then be explored and questions for future research will be presented.

Introduction Although the Oxford English Dictionary tracks the use of gender as a signifier of sexual categories as far back as the fifteenth century, its first edition, published in 1899, described that usage as jocular. The principal definition of the word in the nineteenth century did not refer to categor­ ies of people, but to categories of nouns and pronouns. As documented by Haig,1 prior to the 1960s uses of gender in a nongrammatical sense were exceedingly rare in medical dis­ course. The introduction of gender into the lexicon of medi­ cine is usually credited to the writings of John Money and his colleagues based on their studies of intersexed individ­ uals conducted in the 1950s.2 Although their subjects were neither fully male nor fully female in a biological sense, the majority identified and behaved as unambiguously belonging either to the category of boys and men, or to that of girls and women. Money and his colleagues, therefore, introduced the term gender to facilitate discussing social roles and identities separately from biological sex. According to Money, ‘The new term … made it possible to formulate such statements as, for example, a male gender role despite a female (46,XX) genetic sex.’ He criticized the subsequent interpretation of his work as suggesting that sex is what one is born with, while gender is a socially acquired script or role. To him, gender was instead ‘an umbrella under which are sheltered all the different components of sex difference, including the sex-genital, sex-erotic, and sex-procreative components’.3 Gender-specific medicine is medicine guided by the sci­ ence of how normal function and disease are influenced by factors that are associated with gender. As evidenced by a survey of over 30 million academic articles; however, gen­ der is often used as a synonym for sex.1 Thus, gender-spe­ cific medicine is often reduced to medical practice guided by the study of sex differences. This chapter will use a broad definition of gender, similar to Money’s, which brings all aspects of sex differences and psychosexual differentiation under the umbrella of gender and thus within the purview of Principles of Gender-Specific Medicine

Terminology Sex, as used here, will refer to the status of biological vari­ ables that can be described as either male-typical or femaletypical in normatively developed individuals (e.g., genes, chromosomes, gonads, internal and external genital struc­ tures, and hormonal profiles). Particular features of the human brain also appear to be sexually dimorphic,4–6 and may one day be considered among the variables of sex. At present, however, and in contrast to the situation in labora­ tory animals (Chapter 8), the brain variables that have been described as sexually dimorphic in humans are only dimor­ phic in a statistical sense and do not have the same sexual specificity as the genetic, chromosomal, gonadal and genital variables. Irrespective of one’s biological status, gender identity will refer to the persistent sense of belonging to a par­ ticular gender category. In the majority of cases, this reduces to one’s sense of belonging to the male gender category (comprising boys and men) or the female gender category (comprising girls and women). Gender role behaviors will refer to behaviors (e.g., unconscious mannerisms, style of dress, activities, etc.) that are statistically associated with a particular gender category. The course of development usually culminates in full concordance among all of the biological variables of sex 101

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(i.e., either all are male or all are female in a given individ­ ual). Some disorders of sex development (DSDs), however, lead to intersex conditions in which one or more of those variables is discordant with the others or its differentiation is intermediate between male and female statistical norms. The term intersex* encompasses a variety of conditions previously classified on the basis of gonadal histology as true hermaphroditism, in which both testicular and ovarian tissue are present in a single individual, and pseudohermaphroditism, in which only one type of gonadal tissue is present. In that system of taxonomy, precedence was given to gonadal his­ tology as the arbiter of ‘true sex,’ against which expectations regarding gender identity and gender role behaviors were judged. With the advent of karyotype analysis, chromosomal sex became widely viewed as the arbiter of ‘true sex’.7 The notion of ‘true sex,’ however, is problematic. When there is discordance among the biological variables of sex in an indi­ vidual, there is no reason that one variable should hold prec­ edence over the others as the indicator of that person’s sex. Instead, the status of each variable must be stated to accu­ rately describe that person’s sex status. More importantly, in persons with intersex disorders and related DSDs the status of biological variables should not be used as the basis for asserting either whether (or not) a person is cross-gendered or whether that individual is homosexual or heterosexual.† Transgenderism involves identifying oneself as a mem­ ber of the gender category that is discordant with one’s biological sex and can only be applied in the absence of an intersex condition. The term transsexual refers to a trans­ gendered individual who has, or plans to, employ hormonal or surgical means to modify the body so that it conforms better to that individual’s gender identity. A man or boy who transitions to live as a woman is a male to female (MTF) transgendered/transsexual individual. Similarly, a

girl or woman who transitions to live as a man is called a female to male (FTM) transgendered/transsexual individ­ ual. Transwoman and transman are gaining currency in the vernacular to refer to MTFs and FTMs, respectively. The terms transgender and transsexual do not appear in psychiatry’s Diagnostic and Statistical Manual (DSM). Instead, when certain other conditions are met they are subsumed under the diagnosis of gender identity disorder (GID). GID entails the presence of persistent and marked stereotypical cross-gender behaviors, interests, and identi­ fications, and gender dysphoria is defined as unhappiness or a sense of inappropriateness with one’s biological sex. Importantly, cross-gender identifications and behavior, no matter how extreme, are not sufficient to meet the diagnos­ tic criteria for GID. To meet diagnostic criteria, the gender dysphoria must be severe enough to cause clinically signifi­ cant distress or functional impairment. Sexual orientation refers to one’s pattern of erotic responsiveness to others of a particular gender category. It is conceptually distinct from gender identity and gender role behaviors. It is a mistake to assume that homosexual individuals have gender identity conflicts, and equally erro­ neous to assume that all individuals seeking sex reassign­ ment surgery are erotically attracted to members of their natal gender. In fact, the majority of men seeking reassign­ ment as women in the USA today are sexually attracted to women.10‡ The terms gay, lesbian and bisexual may be used to signify sexual identities based upon the recognition of, and identification with, similar others who experience same-sex attraction. Some individuals acknowledge their homosexual attractions and/or behaviors without identifying as gay, lesbian or bisexual. Apparent discrepancies (in the eyes of the clinician) between sexual orientation and sexual identity are beyond the scope of the present chapter, and are

*

intersex conditions and other DSDs. Moreover, clinicians must bear in mind that their patients will require psychoeducation in order to appreciate such distinctions. For example, if a 46XY young wom­ an with complete androgen insensitivity is told that she is a male pseudohermaphrodite, she is likely to understand that to mean that she is a boy and, consequently, she may draw incorrect inferences regarding her sexual orientation and that of her boyfriend. While the recently proposed DSD terminology9 replaces such potentially damaging terms as male or female pseudohermaphrodite, clinicians must anticipate and appropriately address their patients’ concerns, including the questions they might be afraid to ask. ‡ Some have suggested that gynephilic MTFs eroticize the fantasy of having a woman’s body, a phenomenon referred to as auto­ gynephilia. They subdivide transsexual men into ‘homosexual’ (i.e., androphilic) and ‘nonhomosexual’ (i.e., autogynephilic) categories and suggest that the ‘nonhomosexual’ category may represent a form of paraphilia rather than a gender identity disturbance. On the other hand, their ‘homosexual MFTs’ are seen as representing an extreme variant of homosexuality. Thus, their system of taxonomy does not clearly distinguish between homosexual and transgender phenomena.11

Recently the Consortium on Disorders of Sex Development and other professional organizations have suggested that the term disor­ der of sex development (DSD) replace the term intersex; however, while all intersex conditions arise from DSDs, not all DSDs involve discordance among the biological variables of sex or lead to ambi­ guities regarding gender assignment. †

In the author’s experience, most clinicians and medical students regard anyone with a Y chromosome as male. For example, they might regard a 46XY woman with the complete androgen insensi­ tivity syndrome (described more fully below) as biologically male even though she appeared unambiguously female at birth, was raised as a girl, feminized at puberty, and presented with her husband for evaluation of infertility. In reference to such an individual, a medical student recently commented, ‘She doesn’t know that she’s really a man.’ Even sexologists with the esteemed Kinsey Institute for Sex Research wrote that such women, all of whom have been reported to be sexually attracted to men, could be considered homosexual because they are genetically male.8 Clinicians must fully appreci­ ate the distinction between sexual constitution on the one hand and gender identity and role on the other. Those who fail to do so may unwittingly inflict great psychological harm on their patients with

C h a p t e r 9    The Sexed and Gendered Brain l

of little relevance in the vast majority of clinical situations. Instead, in most medical settings sexual behavior is more salient and should be elicited instead of, or in addition to, a sexual identity label. No assumptions about behavior should be based on the patient’s reported identity label. For example, in a recent random survey of men in New York City, 9.3 % admitted to having only male sex partners during the previ­ ous year, but only 4.9% described themselves as homosex­ ual or bisexual.12 Those who did not identify as homosexual were more likely to engage in unprotected sexual intercourse. Sexual orientation can be characterized irrespective of one’s biological sex or gender identity as androphilic (attracted to men, e.g. heterosexual women, homosexual men), gynephilic (attracted to women, i.e, heterosexual men, homo­ sexual women), or bisexual (attracted to both). The use of these terms in medical settings avoids ambiguity in describing the sexual orientation of individuals whose gender is ambigu­ ous as well as individuals who have transitioned, or are in the process of transitioning, from one gender to another. For instance, the phrase ‘homosexual transsexual woman,’ could be interpreted in a variety of ways (i.e, a homosexual man who became a woman, a man who became a homosexual woman, or a homosexual woman who became a man). On the other hand, ‘androphilic male to female transsexual’ is unambiguous. While clinicians should use unambiguous lan­ guage with their colleagues, they should employ the patient’s preferred identity label in conversations with the patient. It is medically necessary to clarify the patient’s gonadal, hormo­ nal, and surgical status, but this should be done without chal­ lenging the patient’s identity and sense of self.

Sexual differentiation of the brain The Prenatal Hormonal Hypothesis Psychosexual differentiation as used here will refer to the processes leading to differences among individuals with respect to gender identity, gender role behaviors, and sexual orientation. The most developed and researched biological hypothesis regarding psychosexual differentiation is the prenatal hormonal hypothesis. Support for this hypothesis is based largely on animal research such as that reviewed in Chapter 8. According to this hypothesis, prenatal hormones act, primarily during late embryonic and fetal development, to mediate the sexual differentiation not only of the genita­ lia but also of the brain. The sexually differentiated state of the brain is then hypothesized to influence the subsequent expression of gender identity, gender role behaviors and sexual orientation.13 This hypothesis views homosexuality and transgenderism as two forms of psychic intersexuality, reflecting an intersexed brain.14 This line of thinking can be traced to the nineteenth and early twentieth century sexolo­ gists who, prior to the recognition of sexual orientation and

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gender identity as separate phenomena, considered them collectively as ‘inversion of the sexual instinct.’ Inversion was described variously as ‘hermaphoditism of the soul’ or a ‘woman’s brain in a man’s body and vice versa’14 and was used to refer to individuals that today would be catego­ rized as either homosexual or transgendered. Subsequently, the eminent sexologist Richard von Kraft-Ebbing suggested that homosexuality need not entail a woman’s brain in the body of a man and vice versa, but rather simply a brain with female psychosexual centers in a man’s body and vice versa. The concept of a brain of one sex in the body of the other, however, remains as a popular conceptualization of transgenderism, while some speculate that sexual atypicality of the brain in homosexual individuals is not strictly limited to the circuits that are dedicated to sexuality. The premises of the prenatal hormonal hypothesis are critically addressed elsewhere, including the assumptions and evidence that link same-sex desire to sexual and gender atypicality.15

Sexual Differentiation of the Brain in Rodents As reviewed in Chapter 8, the mammalian embryo is ini­ tially sexually bipotential with respect to somatic and CNS morphology. In the usual course of male differentia­ tion a testis-determining region (SRY) of the Y chromo­ some directs the fetal gonadal precursor to form testes.16 Testicular secretions subsequently orchestrate the dif­ ferentiation of the male genitalia and brain. In addition to normally functioning testes, differentiation of the male phe­ notype requires intact receptors and intracellular pathways that mediate the actions of testicular secretions on the target organs.17 In the absence of the cascade set in motion by the testis-determining gene, normal female development ensues in most respects. Although other genetic contributions to sexual differentiation have historically been regarded as insignificant, they have only recently begun to be explored18 and are potentially more important than previously thought. Sexual differentiation of the brain is generally regarded as involving both suppression of female characteristics (defeminization) and development of male characteristics (masculinization).19* In rats, defeminization includes sup­ pression of the brain’s potential to mediate a stereotypi­ cally female mating posture called lordosis, and its ability to regulate the pituitary responses necessary for the ovar­ ian cycle and ovulation. Masculinization in rats includes development of a propensity to exhibit mounting behavior. * Recent work, however, suggests that normal female mice may possess the brain circuitry required for the full expression of male behaviors but that expression of male behaviors by females is inhibited by input from the vomeronasal organ.20 Whether these findings generalize to other rodents is not clear; however, they are unlikely to generalize to old world primates and humans that lack a functional vomeronasal organ in adulthood.

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Testosterone acts on the brain by two primary pathways: (1) an androgen pathway in which either testosterone or its 5-reduced metabolite, dihydrotestosterone, interacts with androgen receptors in target cells and (2) an estrogen pathway in which testosterone is converted to estrogen by aromatase enzymes in the brain.19 In the latter pathway the brain-derived estrogen interacts with estrogen recep­ tors. In rodents, both defeminization and masculinization are mediated primarily via the estrogen pathway. In labora­ tory animals, masculinization and defeminization of differ­ ent brain functions have somewhat different developmental time courses and involve different brain regions, different metabolites of androgen and different signaling pathways (Chapter 8). Thus, various aspects of brain sexual differ­ entiation can be manipulated somewhat independently of one another (Chapter 8). That is, animals can be produced in which sex behavior patterns are completely reversed as well as animals that display various combinations of maletypical and female-typical behaviors.

Sexual Differentiation of the Human Brain Limits of Extrapolations from Laboratory Animals to Humans Many problems are encountered when one attempts to use rat research as the basis for implications regarding psycho­ sexual differentiation in humans. First, tremendous variation exists even among various rodent species in the details of sexual differentiation. Second, systems that are sexually dif­ ferentiated in the rodent brain are not necessarily sexually dimorphic in primates. A case in point is the hypothalamic component of the hypothalamic–pituitary–gonadal axis that regulates cyclic ovarian function. In rats, but not in primates, prenatal androgen exposure defeminizes this substrate such that it will not support cyclic ovarian function. The hypotha­ lamus of normal adult male primates, unlike that of nor­ mal adult male rats, is capable of supporting cyclic ovarian function. Additionally, while sexual differentiation of the brain in rats is largely mediated via the estrogen pathway of androgen action, that pathway is not believed to play a significant role in sexual differentiation of the human brain. Instead, as discussed below, human psychosexual differenti­ ation is believed to involve androgen but not estrogen recep­ tors. Third, while sexual orientation in humans may have parallels in animals,21 gender identity does not. Moreover, as discussed below, the neurosurgical and/or endocrinological manipulations that are most commonly used to produce cross-sex behaviors in laboratory animals produce neuroen­ docrine states that deviate sharply from naturally occurring states in humans regardless of sexual orientation. Timing of Brain Sexual Differentiation in Humans Based largely on extrapolations from studies of sexual dif­ ferentiation in rodents, psychosexual differentiation of the

human brain has been conjectured to depend primarily on midtrimester androgen exposure. This conjecture, however, does not take into account disparities between rodents and primates in the relative sizes of mature limbic and corti­ cal regions which indicate that these regions develop on a somewhat different timetable in primates compared with rodents.22,23 Events in primate cortex occur later than expected on the basis of extrapolations from rodent data, while events in primate limbic systems occur earlier. This issue can be addressed by statistical-based algorithms that integrate hundreds of empirically derived developing neu­ ral events across multiple species including rhesus monkeys and humans.24 The period during which prenatal expo­ sure to androgens in female rhesus monkeys is effective in masculinizing their mating behavior is gestational days 40–60.25 According to the statistical-based developmental algorithms, this corresponds roughly to weeks 7–10 in the human, completely within the first trimester when andro­ gen secretion by the fetal testis is regulated by the placenta. In the female monkey late androgen administration (ges­ tational days 115–39) increases juvenile rough and tumble play behavior but not mounting. This corresponds to the midtrimester in humans (weeks 19–23) when the regula­ tion of testicular secretion by the fetal testis has switched from the placenta to the fetal hypothalamus and pituitary. Sexual differentiation of the human brain may also be influ­ enced by a neonatal surge of testosterone secretion in males as well as by postpubertal hormonal differences;26 however, such potential postnatal hormonal influences have yet to be thoroughly investigated and are generally believed to be minor relative to prenatal hormonal influences.

Testing the prenatal hormonal hypothesis in humans Two main strategies have been employed in attempts to establish a link between prenatal hormonal exposure and psychosexual differentiation: (1) Examination of presumed correlates of such exposure in male and female individu­ als with varying sexual orientations and gender identities; (2) examination of sexual orientation and gender identity in individuals with known prenatal hormonal irregularities as well as in developmentally normal males who were cas­ trated and assigned to the female gender in infancy. These will be discussed in turn.

Presumed Correlates of Prenatal Hormonal Exposure Because psychosexual differentiation, like genital differ­ entiation, is hypothesized to be mediated by gonadal hor­ mones, the most obvious correlates of the brain’s prenatal hormonal exposure would be variations of gonadal func­ tion and external genital morphology. Differences in neither

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gonadal function nor genital morphology, however, distin­ guish neither homosexual nor transgendered individuals from their heterosexual and nontransgendered counterparts. Prenatal androgens could, nonetheless, contribute to sexual orientation and/or gender identity. For example, genital morphology and brain function might be sensitive to the organizing effects of androgens during different periods of development. As noted in the preceding section, however, extrapolation from nonhuman primate data suggests that masculinization of the external genitalia and of reproduc­ tive behaviors would be expected to occur concurrently. Alternatively, the level of a hormone is merely one of the indices that interactively determine the strength of a hormo­ nal signal. External genital and psychosexual differentia­ tion might require different tissue-specific cofactors or they might be mediated by different metabolites of androgens or by different signaling pathways. Variations in tissue-specific cofactors or signaling pathways that mediate androgens’ actions could, therefore, reduce androgen responsivity in some regions of the brain or body but have no impact on androgens’ actions in other regions. Presumed correlates of prenatal androgen exposure that have been examined recently with respect to sexual orientation and/or gender identity include neuroanatomical sexual dimorphisms, sex differences in neurophysiological activity and finger length ratios. These will be addressed in turn. Neuroanatomical Sexual Dimorphisms In response to Kraft-Ebbing’s conjecture that masculine inverts have a female brain in a male body, Freud astutely commented, ‘But we do not know the characteristics of a “female brain”’.27 That critique remains largely valid today. In other words, the hypothesis that homosexuals and trans­ sexuals have sexually atypical brains is only testable to the extent that sexual dimorphism, and, therefore, sexual typi­ cality, can be reliably defined and demonstrated. Unlike the animal literature where sexual dimorphism of the brain has been consistently and convincingly demonstrated, the human literature is fraught with failures of replication. Although evidence for human dimorphism is now compel­ ling, to date no putative sex difference in the human brain has been conclusively demonstrated to have a prenatal hor­ monal dependency.28 Sex differences in the human brain are addressed fully in Chapter 7. Only a few examples will be addressed in the present chapter. The search for sex differences in the human brain was reinvigorated 30 years ago when a hypothalamic nucleus was found to occupy much larger volume in male than in female rats. This nucleus was designated as the sexually dimorphic nucleus of the preoptic area (SDN-POA). Like sex differences in copulatory behaviors in rats, this sex difference develops in response to sex differences in early androgen exposure. High aromatizable androgen levels at the appropriate time, together with the metabolic machinery to respond to them, lead to male-typical anatomy, whereas

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low levels lead to female-typical neuroanatomy regardless of genetic sex (Chapter 8). The third interstitial nucleus of the anterior hypothalamus (INAH3) in humans has been identified as a candidate for homology with the rat’s SDNPOA. Four independent laboratories found it to be larger in presumed heterosexual men than in presumed heterosexual women and two laboratories found the nucleus to contain more neurons in men.4,5,6,29 More limited evidence suggests that INAH3 may be smaller in homosexual men than in heterosexual men, but that the number of neurons within the nucleus does not vary with sexual orientation.4,5 Speculation regarding the function of INAH3 has been based on the assumption that it is the homologue of the rat’s SDN-POA. The size of the SDN-POA in rats correlates positively with the frequency of mounting behavior while electrical stimulation in the vicinity of the nucleus triggers mounting behavior. Consequently, the nucleus has been con­ jectured to play a role in male-typical mounting behavior. That interpretation is at odds with the observation that the rat’s nucleus can be destroyed bilaterally without discernible effect on mounting behavior.30 Following lesions that include the SDN-POA, however, male rats can be induced to display the female copulatory response called lordosis if they are also injected with estrogen and progesterone.31 The SDNPOA in male rats may, therefore, play a role in inhibiting the expression of female-typical mating behaviors in rats. How the expression of stereotypically male and female mating behaviors in rats might relate to erotic responsivity in humans is not clear. In addition, the display of cross-sex behaviors in the rat model requires not only brain surgeries or perinatal hormonal manipulations, it also requires the administration of cross-sex hormones after puberty. This postpubertal hormonal requirement severely limits extrapo­ lations to humans since adult hormonal profiles do not differ as a function of sexual orientation. Although some labora­ tory animals spontaneously exhibit only homosexual behav­ ior, they have yet to be extensively employed in research that seeks to shed light on sexual orientation. One exception is male sheep that only mount other males. Sheep possess a nucleus that resembles the SDN-POA of rats, and that nucleus is smaller in the so called ‘homosexual’ sheep than in male sheep that mount females.32 While these ‘homo­ sexual’ sheep display male-typical mounting behavior, that behavior is directed only toward other males. ‘Homosexual’ sheep are not sexually receptive with other males. Thus, the recipients of mounts are not willing participants in a homo­ sexual sex act. Instead they tend to be weak or incapacitated males. The sheep data are, therefore, inconsistent with the rat data since the volume of their sexually dimorphic nucleus does not appear to correlate either with mounting behavior or with the suppression of female-typical receptive behavior. Instead, the volume of the sheep’s nucleus appears to cor­ relate with whether a male is sexually oriented toward other males or toward females, as has been conjectured to be the case for INAH3 in humans.4

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Another putatively sexually dimorphic nucleus in the vicinity of the hypothalamus, the central part of the bed nucleus of the stria terminalis (BSTc), has been investi­ gated in a small number of postmortem brains for vari­ ation with both gender identity and sexual orientation.33 That study measured the BSTc in postmortem tissue from six male to female transsexuals (two of whom were exclu­ sively androphilic, three of whom were gynephilic, and one bisexual), 12 presumed heterosexual men, 11 presumed het­ erosexual women, and nine homosexual men. The BSTc was found to be larger and to contain more neurons that were immunopositive for somatostatin in both the homo­ sexual and heterosexual nontranssexual men than in women; however, among the male to female transsexual individuals, the nucleus was the same size and had the same number of neurons as in the women. Within the transsexual group the size of the nucleus did not appear to vary with sexual orien­ tation. Thus it was suggested that the volume of the BNSTc varies as a function of gender identity but not sexual orien­ tation. Similarly, INAH3 was recently examined in a study that included many of these same subjects. The nucleus was reported to be female-typical in both volume and neu­ ronal number in male to female transsexuals regardless of their sexual orientation.29 Thus, contrary to previous con­ jecture,4 INAH3 structure may not be a reliable predictor of sexual orientation. The findings regarding both the BNSTc and INAH3 and gender identity must be viewed tentatively pending replication studies. If the structural differences prove replicable, the next challenge for the prenatal hormo­ nal hypothesis will be to demonstrate that the structural dif­ ferences have a developmental hormonal dependence. The brain commissures, the fiber bundles that connect the left and right hemispheres of the brain, have also been studied for sexual variation in humans. This research has been conducted in an effort to elucidate the neuroanatomi­ cal basis for statistical sex differences in the degree of the hemispheric lateralization of particular cognitive func­ tions. Over 50 studies have examined the corpus callosum, the largest of the commissures, with no consensus regard­ ing the existence of a sex difference.34 One possibility for the contradictions in this literature is that callosal structure appears to be influenced by age and handedness in addition to sex. A research group that controlled for handedness and age found the width of the isthmus of the corpus callosum to be greater in women than in heterosexual men. They also found the isthmus to be larger in right-handed homosexual men than in right-handed heterosexual men. No difference was seen between homosexual and heterosexual men who were not right-handed.35 The isthmus interconnects brain regions involved in aspects of language and spatial cogni­ tion which have been reported to vary with both sex and sexual orientation. Several studies have examined the ante­ rior commissure, a small bundle of fibers that connects por­ tions of the left and right temporal lobes, but no consistent findings have emerged. One laboratory found the structure

to be larger in men than in women. Another found it larger in heterosexual women and homosexual men compared to heterosexual men, while the largest study to date found no difference related to either sex or sexual orientation.36 While the search for neuroanatomical correlates of psy­ chosexual differentiation has produced some findings that are broadly consistent with predictions based on the prena­ tal hormonal hypothesis, only the sex difference in INAH3 has been replicated by independent laboratories. That sex difference, however, has not been shown to have a prena­ tal hormonal dependence. Demonstration that IHAH3 is, indeed, the human counterpart of the rat’s SDN-POA would provide indirect evidence that the dimorphism in INAH3 has a similar hormonal dependence; however, there is a major caveat: the dimorphism in the SDN-POA depends on the aromatase pathway of androgen action, a pathway that is not believed to contribute to psychosexual differentiation in humans. At present no strong conclusions may be drawn from the studies of the commissures given the inconsisten­ cies in the literature and an absence of independent replica­ tions of the suggestive findings. Neural Function Statistical differences between the sexes are reliably observed on some cognitive tasks, including mental rotation, judgment of line orientation, and verbal fluency. Several studies have asked whether homosexual individuals perform in a sex-atypical way on such cognitive measures. These studies have produced mixed results.37,38 Studies involving transgendered individuals have been similarly suggestive but inconclusive, with some studies finding that perform­ ance correlates better with biological sex than with gender identity or post-sex reassignment hormonal status.39,40 Positron emission tomography (PET) and functional mag­ netic resonance imaging (fMRI) allow regional brain activ­ ity to be visualized and quantitatively assessed. As reviewed in Chapter 7, these methods have demonstrated differences between the sexes in patterns of regional brain activation. Very few PET or fMRI studies have addressed sexual ori­ entation or gender identity. One study, however, found that homosexual men and women exhibit sex-atypical correlations among the activity levels of various brain regions.41 Similarly, another laboratory found that patterns of regional brain acti­ vation in response to putative pheromones are sexually atypi­ cal in transgendered and homosexual men and women.42–44 Otoacoustic emissions, echo-like waves emitted by the inner ear response to brief sounds, differ between men and women. These emissions have been reported to be male-like in lesbi­ ans but not to vary with the sexual orientation of men.45 While the neurophysiological function studies have pro­ duced some findings consistent with the hypothesis that homosexual and transgendered individuals exhibit some degree of sexually atypical brain function, those findings must be regarded as preliminary pending adequate replication

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studies. In addition, with the exception of the otoacoustic emissions that have been found to be shifted in the male direction in women who were exposed to elevated androgens prenatally, the other neurophysiological parameters have not been shown to have a prenatal hormonal dependence. Finger Length Ratios Since 1998 over 100 published studies have used the ratio of length of the second to fourth finger (2D:4D) as a puta­ tive marker of prenatal androgen exposure.26 Some but not all studies suggest that compared to men, adult women tend to have longer index fingers (second digits) relative to the length of their ring fingers (fourth digit). Similarly, stud­ ies of the 2D:4D ratio as a function of sexual orientation have produced discrepant results. A ‘male-typical’ ratio has been reported with more consistency in lesbians than has a ‘female-typical’ ratio in gay men.46 This area of research does not currently provide substantial support for the prena­ tal hormonal hypothesis for several reasons. In addition to the inconsistencies across replication studies, finger length ratios have yet to be definitively linked to levels of prena­ tal androgen exposure.26 Moreover, the hypothesized link between finger length ratios and prenatal androgen that pre­ cipitated these studies was based on the faulty premise that particular hox genes are involved in the development of both the digits and the gonads.26 These genes, however, influence genital, not gonadal, development47 and thus would not be expected to influence prenatal androgen levels.

Orientation Following Documented Prenatal Endocrine Abnormalities Beginning in the 1950s, John Money and colleagues2 observed that since intersexed individuals are neither com­ pletely male nor completely female they ‘are likely to grow up with contradictions existing between the sex of assignment and rearing, on the one hand, and various physical sexual var­ iables, singly or in combination, on the other.’ They, therefore, collected data on the psychosexual development of children born with various intersex conditions in order to determine whether gender role and identity are more likely to be con­ cordant with the sex of assignment and rearing, or whether they are predominantly concordant with one or another of the physical variables of sex. Of 105 intersexed individuals stud­ ied, they reported that only five had a gender role or identity that was ‘ambiguous and deviant from the sex of assignment and rearing.’ Thus, they concluded that the gender of assign­ ment and rearing is a much better prognosticator of gender role and identity than the biological variables of sex, provided that the gender is assigned prior to 18 months of age and unambiguously reinforced through rearing practices. Following Money’s study and continuing at least into the 1990s, infants with intersex conditions and disorders involving severe genital trauma or malformation were

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often assigned to the female gender even if they possessed normally functioning testes and tissues capable of fully responding to androgen. This practice was premised on the assumption that normal-appearing, gender-concordant geni­ talia are necessary for normal psychosexual development. In addition, vaginoplasty was considered to yield cosmetic­ ally and functionally acceptable results whereas phallo­ plasty did not. Although it was appreciated at that time that intra-uterine hormones might exert sexually differentiating effects on the fetal brain, it was widely believed that the effects of nurture outweighed those of nature with respect to psychosexual development. Prompt surgical normaliza­ tion of external genital anomalies was, therefore, viewed as necessary to establish the dominance of nurture over nature. That view, however, is at odds with the initial stud­ ies of psychosexual development in intersexed individuals that were conducted prior to the advent of genitoplasty.2,48 More recently, the practice of surgically reinforcing gender reassignment in infancy has been challenged on a variety of scientific and ethical grounds,49–51 and revised guidelines for the management of intersex conditions and other DSDs have been published.50,51 Outcomes with respect to gender identity and sexual ori­ entation will now be examined in several conditions that involve endocrine and/or genital variance. More complete reviews are found elsewhere.7,52,53 The aim here is to see if outcome data fit better with the hypothesis of gender neu­ trality at birth or with the prenatal hormonal hypotheses for gender identity and sexual orientation. Conditions will be grouped on the basis of the degree of functional andro­ gen exposure prenatally, beginning with individuals who were assigned female despite having been exposed to the full complement of masculinizing influences prenatally and concluding with individuals with a complete lack of functional androgen exposure. Generalizations that can be drawn from the outcome studies across all conditions will be presented at the end of this section. Female Assignment After Full Complement of Prenatal Masculinizing Influences Ablatio penis: Zucker7 reviews six cases of normal males who suffered accidental or traumatic loss of the penis in infancy and were reassigned to the female gender prior to 2 years of age. Reliable information regarding gender iden­ tity development is available for only four of these individ­ uals. At least two had switched to a male gender identity by or during puberty while two still retained a female iden­ tity at the time of last follow-up. Detailed information into adulthood is available for only two of these cases: One had undergone surgical reassignment as a man, married a woman, and reported a history of exclusive gynephilia. The other was living as a woman and was married to a man. She described her sexual fantasies as predominantly gynephilic and her sexual orientation as bisexual.

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46XY individuals with penile agenesis and micropenis are believed to have normal functioning testes and normal androgen receptor sensitivity. The very limited data avail­ able on such individuals suggest that they are equally capa­ ble of accepting a male or a female gender assignment.7 Cloacal exstrophy is a complex disorder of embryo­ genesis involving the genitourinary and intestinal tracts. In genetic males, the external genitalia are often grossly anomalous or absent; however, testicular function is gen­ erally believed to be normal. Until recently, long-term sur­ vival with cloacal exstrophy was relatively rare. Emerging data on children and adolescents suggest that those assigned female may have a particularly high rate of rejecting that assignment.54 There are no reported cases of affected indi­ viduals rejecting assignment as male. Data on sexual ori­ entation are not available. Longitudinal follow-up will be crucial, as gender transition may occur quite late. For example, one 46XY individual with cloacal exstrophy who was assigned female in infancy transitioned to live as a man at the age of 52 following the death of the parents.7 Syndromes with Variable Degrees of Functional Androgen Exposure Prenatally Partial androgen insensitivity syndrome refers to disorders in which the testes are normal but there is partial resistance to androgens at the cellular or receptor level. Data from case studies are available for only 24 subjects.7 Of these, eight were assigned as boys with no known complications. Of the 16 assigned female, at least one transitioned to live as a male (at age 30) and one child exhibited such ‘boyish behavior’ that the authors concluded that the gender assignment had been wrong. No sexual orientation data are available. Classical congenital adrenal hyperplasia involves an enzymatic abnormality in cortisol synthesis that results in an overproduction of androgens beginning as early as the first trimester. In contrast to the partial androgen insensi­ tivity syndrome, congenital adrenal hyperplasia is much more common and has been extensively studied. Among 46XX individuals raised as males, there are no reported complications involving gender dysphoria. Female assign­ ment is now the rule, however, due to early detection and the desire to maintain fertility as females. The vast majority of those assigned female are believed to retain their female gender identity into adulthood although with a statistically increased incidence of childhood gender nonconformity, gender dysphoria, and ambivalence about gender as well as gynephilia in adulthood.52 Among severely masculinized 46XX individuals assigned as female, perhaps as many as one out of fifty transition to live as men. This is a much higher proportion compared to women with no known his­ tory of increased prenatal androgen exposure (estimated to be roughly one per 34 0007). Interpretation of these results is complicated by several complex variables. For exam­ ple, even with genitoplasty, parents of children born with

masculinized genitalia may remain ambivalent about a female gender assignment and communicate this unwit­ tingly and nonverbally to the child. Additionally, these female-assigned children exhibit masculinized interests and play. Some might, therefore, temperamentally iden­ tify more with boys than with girls. Outcome with respect to gender identity and sexual orientation could, therefore, be indirectly influenced by these temperament-based iden­ tifications rather than by an androgen effect that directly organizes the neural circuits that mediate gender identity. 46XY 5-reductase deficiency is a condition in which the gonadal primordia differentiate into normal testes and secrete appropriate amounts of testosterone; however, due to the deficiency of 5-reductase affected individuals are unable to convert testosterone to dihydrotestosterone in amounts sufficient for the external genitalia to masculinize normally. Consequently the newborn may have a phal­ lus that more closely resembles a clitoris than a penis, and unfused labioscrotal folds resembling labia majora. In the absence of sophisticated diagnostic testing, affected individ­ uals have often been assumed to be females at birth and have been reared accordingly.55 At puberty, however, testosterone rises to a level sufficient to override the 5-reductase defi­ ciency. Thus, these individuals experience a masculinizing puberty: the phallus markedly enlarges, the testes descend into the labioscrotal folds, the voice deepens, and a mascu­ line habitus develops. This syndrome has been most exten­ sively studied in a region of the Dominican Republic where its prevalence is unusually high due to consanguineous mar­ riages. Of 18 cases reported, 16 changed to a male gender identity and role at puberty.55 Similar gender transforma­ tions from female to male have been observed in cohorts from Mexico, Papua New Guinea, Brazil, and India.52,56 Four affected individuals have been studied postpubertally in Oman, only one of whom was unequivocally male in gen­ der role and identity and only one of whom was unequivo­ cally female.57 Another (age 16) expressed erotic interest in females and requested gender-reassignment but continued to live publicly as a female. The final subject (age 26) ‘engaged in sexual activity as a male’ but would dress as a male only when away from his home community. Collectively these studies suggest that male gender identity and gynephilia can develop in individuals with reduced functional andro­ gen exposure (i.e., reduced levels of dihydro­testosterone, the most potent androgen) relative to normal males. Others have concluded that female rearing appears to have had a lesser role than the presence of two masculin­izing events – testosterone exposure in utero and again at puberty with the development of a male phenotype.55 The Omani cases clearly suggest that social factors constrain the full public expression of what is experienced internally. 17-hydroxysteroid dehydrogenase deficiency usually occurs as a missense mutation of the enzyme that catalyzes the terminal step in testosterone synthesis.58 As a conse­ quence of the reduced inability to synthesize testosterone,

C h a p t e r 9    The Sexed and Gendered Brain l

affected 46XY infants are born with female external geni­ talia despite the presence of testes and male internal struc­ tures. The deficiency usually becomes less severe with time and many affected individuals eventually have male-typical testosterone levels. They are usually assigned female at birth and come to medical attention because of virilization at puberty (similar to that seen in 5-reductase deficiency) or a failure to menstruate. Between 40% and 50% of the affected individuals studied switch from a female to male identity.58 It is not clear why this switch occurs in only some affected individuals. Wilson notes that outcomes vary even within a given pedigree and that a switch in gen­ der identity has been observed in one individual who made essentially no 17-hydroxysteroid dehydrogenase. He sug­ gests that the variability in gender outcome is probably not due to differences in the severity of the mutation and that the predominant outcome for a particular mutation may vary according to culture.58 Sexual orientation has not been systematically reported for individuals with this syndrome. Complete Absence of Functional Androgen Exposure Complete androgen insensitivity is a syndrome in which 46XY individuals lack functional androgen receptors. Des­ pite having normal testes, their tissues are unable to respond to androgens. Development of their external genitalia, there­ fore, follows the female pattern. Untreated, they develop breasts and female-typical fat distribution at puberty in response to estrogens derived from the testosterone syn­ thesized by their testes. Historically, these individuals were assumed to be normal females at birth and did not come to medical attention until testes descended into their labia, or until they failed to menstruate or to conceive children. The literature does not contain any reports of affected individuals changing to a male gender identity.53 Thus, in the absence of functional androgen receptors, female gender identity and androphilia are the rule in individuals with an XY karyotype and normally functioning testes. This is despite the fact that the pathways necessary for defeminization and masculiniza­ tion of the rodent brain (i.e. aromatase enzymes, estrogen receptors, estrogen signaling pathways) are intact in such individuals. It has, therefore, been suggested that humans, in contrast to rodents, require functional androgen receptors for male brain development.59 From a psychosocial standpoint, however, one might suggest that psychosexual outcome in humans with complete androgen insensitivity reflects, at least in part, the fact they were assumed to be biologically normal females at birth, and reared unambiguously as girls. Synthesis of Intersex and Related Outcome Studies The outcome studies reviewed here suggest that the effects of prenatal androgen exposure on psychosexual differentiation are much stronger than Money initially imagined. In addi­

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tion, they allow several generalizations to be drawn regarding which aspects of androgen action are most likely to contribute to psychosexual differentiation. First, the complete androgen insensitivity syndrome suggests that the role of androgen in psychosexual differentiation in the human is largely, perhaps completely, independent of the aromatase/estrogen receptor pathway of androgen action. Second, the data on individuals with 17-hydroxysteroid dehydrogenase deficiency suggest that very little functional androgen exposure prenatally is necessary to bias an individual toward a male gender identity in adulthood. Third, the 5-reductase deficiency syndrome suggests that conversion of testosterone to its more potent metabolite, dihydrotestosterone, may not be necessary for this bias to occur. These syndromes also show that the prob­ ability of switching to a male gender identity and role after female assignment is increased in androgen-sensitive indi­ viduals whose testes are left in place until puberty. When the testes are left in place, the effect of prenatal androgens might be reinforced by the elevated androgen secretion that occurs in the neonatal period and again at puberty. At puberty, the psychological impact of somatic virilization in response to elevated androgens must be considered in addition to the pos­ sibility of physiological effects on the brain. Fewer data are available regarding outcome with respect to sexual orienta­ tion; however, androgen effects on sexual orientation appear parallel to those for gender identity: very little functional androgen exposure seems to be required to produce a bias toward gynephilia. The outcome data do not justify the conclusion that the brain is hardwired for either gender identity or sexual ori­ entation at birth. A more conservative interpretation is that prenatal androgens facilitate the emergence of male identity and gynephilia. The question then becomes how does that facilitation occur: Is it mediated via a direct organizational effect on hypothetical psychosexual brain circuits, or is it mediated more indirectly. The variability of gender out­ comes even among related intersexed individuals known to share identical genetic mutations suggests the importance of psychological, social, and cultural factors as co-mediators of gender development.

Conclusions Biological research on sexual orientation and gender identity has been driven largely by the prenatal hormonal hypothesis and has focused on the potential role of prenatal androgens. Early androgen exposure clearly organizes the mating behavioral repertoires of laboratory animals; how­ ever, it is not clear how the regulation of stereotyped repro­ ductive behaviors in animals pertains to sexual orientation in humans. Nevertheless, it does not seem likely that early androgen exposure influences the adult sexual behaviors of all mammals studied except humans. It is clear, how­

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ever, that the role of aromatization of androgens to estro­ gens within the developing brain plays a lesser, if any, role in primates compared to rodents. Although early androgen exposure in human females increases the likelihood of some degree of gynephilia in adulthood, there is no com­ pelling evidence for differences in prenatal androgen levels between heterosexual and homosexual men, or between het­ erosexual women and the majority of homosexual women. Similarly, there is an association between high prenatal androgen levels and rejection of female gender assignment, but no clear association between low androgen levels pre­ natally and rejection of male gender assignment.

Questions for future research (1) What accounts for the apparent association between early androgen levels and sexual orientation in women but not in men? Similarly, what accounts for the associa­ tion between high prenatal androgen levels and rejection of female gender assignment in the absence of an associa­ tion between low prenatal androgen levels and rejection of male gender assignment? One possibility is that yet-tobe-identified androgen signaling pathways selectively con­ tribute to a bias toward gynephilia and against androphilia, but do not influence external genital development and other aspects of somatic virilization. Variations in one or more of the components of these hypothetical pathways, includ­ ing brain specific co-mediators of androgen action, could prevent androgen from biasing the brain toward gynephilia and against androphilia. Because homosexuality in men is rare, such pathway variations would necessarily have to be rare. Because they are rare, the majority of females would not possess these variants and would be biased toward some degree of gynephilia by elevated prenatal androgen levels. Similarly, the majority of males would not possess these rare pathway variants. The data from intersex condi­ tions suggests that very little functional androgen exposure is required to bias brain development in the male direc­ tion. Thus, even those males exposed to lower androgen levels than those that usually occur in male development would also be biased toward gynephilia and away from androphilia. On the other hand, males with the rare pathway variant(s) would have low functional androgen exposure in the involved brain regions and would be biased toward androphilia regardless of high androgen levels prenatally. Androgen signaling pathway variants could conceivably also influence gender identity in a similar manner. Very little is currently known regarding signaling path­ ways downstream of the androgen receptor in the brain. Modern full transcriptome microarray technologies and high throughput protein expression analyses provide mech­ anisms for rapidly addressing this deficit in our knowledge base. Such approaches could reveal pathways of androgen action in the brain that are distinct from those that mediate

genital differentiation and the development of male second­ ary sex characteristics. Genes in these pathways could then become candidates in studies that seek genetic associations with sexual orientation and/or gender identity. (2) How might biological and psychosocial factors inter­ act in shaping sexual orientation and gender identity? The identification of genes or other biological factors associ­ ated with sexual orientation or gender identity will be rel­ atively uninformative in the absence of studies to identify their mechanisms of action. Such mechanisms could prove to be mediated via very indirect mechanisms. For example, comparable ranges of heritability have been reported for sexual orientation60 and the probability of being divorced.61 While there has been much speculation in the scientific62 as well as popular media63 concerning the existence of ‘gay genes,’ divorce researchers have not searched for ‘divorce genes.’ Instead they have focused on heritable personality and temperamental traits that might influence the likelihood of divorce.64 Research into such indirect biological effects on sexual orientation and gender identity are currently lack­ ing. A number of potentially heritable childhood behavioral traits have been identified as predictors of adult sexual ori­ entation.8 While some have viewed these as the manifesta­ tions of a brain that is hardwired for sexual orientation from birth, the alternative hypothesis has not been explored – namely, that inborn temperamental differences influence how an infant interacts with others from the moment of birth in shaping the psychosocial interactions that influence subsequent sexual orientation and gender identity. (3) What characteristic or combination of characteristics reliably distinguish male from female brains in humans? When in development do they emerge and can they be detected by non-invasive techniques? Do such distinguishing characteris­ tics influence gender identity and might they one day predict postoperative adjustment and quality of life for adults seeking sex reassignment surgery? Might they one day facilitate opti­ mal initial gender assignment of intersexed infants? (4) What are the similarities and differences between male to female transsexuals who are androphilic and those who are gynephilic? Might the prenatal hormonal hypoth­ esis be of relevance to one category but not the other? To answer these questions future investigations must consider this fundamental distinction in their research designs. (5) What constitutes optimal evaluation and management of extreme gender dysphoria in children and adults? The con­ ventional standards for medically assisted gender transition are viewed as authoritative by providers but as restrictive by many clients.65 These constraints are greatest for youth and are imposed not only by healthcare providers but by parents, schools, and other institutional settings. Overt discourage­ ment of their cross-gender identifications and behaviors can be extremely damaging to their self-esteem, and the physical outcome of gender reassignment surgery is better if initiated prior to the development of secondary sex characteristics. On the other hand, transgender surgeries are essentially irre­

C h a p t e r 9    The Sexed and Gendered Brain l

versible, and hormonal replacement regimens are not without risk. In accordance with the dictum, ‘First do no harm,’ pro­ viders understandably cannot provide all requested services on demand and most would prefer to proceed cautiously and only after a sometimes protracted period of thorough evalua­ tion. Research is clearly needed to expedite the evaluation of individuals, particularly youths, requesting assistance with gender transformation, and to identify the treatments associ­ ated with the best outcomes. Do those outcomes depend on the sexually differentiated state of the brain, and will brain studies one day inform decision making in this area?

19.

20. 21. 22.

23.

References   1. Haig D. The inexorable rise of gender and the decline of sex: social change in academic titles, 1945–2001. Arch Sex Behav 2004;33(2):87–96.   2. Money J, Hampson JG, Hampson JL. Imprinting and the establishment of gender role. AMA Arch Neurol Psychiatry 1957;77(3):333–36.   3. Money J. Gay, Straight, and In-between: The Sexology of Erotic Orientation. New York, NY: Oxford University Press; 1988.   4. LeVay S. A difference in hypothalamic structure between hetero­ sexual and homosexual men. Science 1991;253(5023):1034–37.   5. Byne W, Tobet S, Mattiace LA, et al. The interstitial nuclei of the human anterior hypothalamus: an investigation of variation with sex, sexual orientation, and HIV status. Horm Behav 2001;40(2):86–92.   6. Allen LS, Hines M, Shryne JE, et al. Two sexually dimorphic cell groups in the human brain. J Neurosci 1989;9(2):497–506.   7. Zucker KJ. Intersexuality and gender identity differentiation. Annu Rev Sex Res 1999;10:1–69.   8. Hughes IA. Disorders of sex development: a new definition and classification. Best Pract Res Clin Endocrinol Metabol 2008;22(1):119–34.   9. Lawrence AA. Sexuality before and after male-to-female sex reassignment surgery. Arch Sex Behav 2005;34(2):147–66. 10. Blanchard R. Early history of the concept of autogynephilia. Arch Sex Behav 2005;34(4):439–46. 11. Pathela P, Hajat A, Schillinger J, et al. Discordance between sexual behavior and self-reported sexual identity: a popula­ tion-based survey of New York City men. Ann Intern Med 2006;145(6):416–25. 12. Gooren L. The biology of human psychosexual differentia­ tion. Horm Behav 2006;50(4):589–601. 13. Herrn R. On the history of biological theories of homosexual­ ity. J Homosex 1995;28(1–2):31–56. 14. Byne W, Parsons B. Human sexual orientation. The biologic theories reappraised. Arch Gen Psychiatry 1993;50(3):228–39. 15. Vilain E, McCabe ER. Mammalian sex determination: from gonads to brain. Mol Genet Metab 1998;65(2):74–84. 16. Sobel V, Zhu YS, Imperato-McGinley J. Fetal hormones and sexual differentiation. Obstet Gynecol Clin North Am 2004;31(4), 837-56, x–xi. 17. Arnold AP, Rissman EF, De Vries GJ. Two perspectives on the origin of sex differences in the brain. Ann N Y Acad Sci 2003;1007:176–88. 18. Goy RW, McEwen BSNeurosciences Research Program. Sexual Differentiation of the Brain Based on a Work Session

24.

25. 26. 27. 28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

111

of the Neurosciences Research Program. MIT Press: Cambridge, MA; 1980. Kimchi T, Xu J, Dulac C. A functional circuit underlying male sexual behaviour in the female mouse brain. Nature 2007;448(7157):1009–14. Bagemihl B. Biological Exuberance Animal Homosexuality and Natural Diversity. New York: St Martin’s Press; 1999. Finlay BL, Darlington RB, Nicastro N. Developmental struc­ ture in brain evolution. Behav Brain Sci 2001;24(2):263–78. Clancy B, Darlington RB, Finlay BL. Translating develop­ mental time across mammalian species. Neuroscience 2001; 105(1):7–17. Clancy B, Kersh B, Hyde J, et al. Web-based method for translating neurodevelopment from laboratory species to humans. Neuroinformatics 2007;5(1):79–94. Goy RW, Bercovitch FB, McBrair MC. Behavioral masculi­ nization is independent of genital masculinization in prena­ tally androgenized female rhesus macaques. Horm Behav 1988;22(4):552–71. Gooren L, Byne W. Sexual orientation in men and women. Hormones, Brain and Behavior, 2nd edn.; 2009. Freud S, Brill AA. Three Contributions to the Theory of Sex. Mineola, NY: Dover Publications; 2001. Legato MJ, Bilezikian JP. Principles of Gender-Specific Medicine. Amsterdam: Elsevier Academic Press; 2004. Garcia-Falgueras A, Swaab DF. A sex difference in the hypothalamic uncinate nucleus: relationship to gender iden­ tity. Brain 2008;131:3115–17. Arendash GW, Gorski RA. Effects of discrete lesions of the sexually dimorphic nucleus of the preoptic area or other medial preoptic regions on the sexual behavior of male rats. Brain Res Bull 1983;10(1):147–54. Hennessey AC, Wallen K, Edwards DA. Preoptic lesions increase the display of lordosis by male rats. Brain Res 1986;370(1):21–28. Roselli CE, Larkin K, Resko JA, et al. The volume of a sexu­ ally dimorphic nucleus in the ovine medial preoptic area/ anterior hypothalamus varies with sexual partner preference. Endocrinology 2004;145(2):478–83. Zhou JN, Hofman MA, Gooren LJ, et al. A sex difference in the human brain and its relation to transsexuality. Nature 1995;378(6552):68–70. Bishop KM, Wahlsten D. Sex differences in the human corpus callosum: myth or reality? Neurosci Biobehav Rev 1997;21(5):581–601. Witelson SF, Kigar DL, Scamvougeras A, et al. Corpus cal­ losum anatomy in right-handed homosexual and heterosexual men. Arch Sex Behav 2008;37:857–63. Lasco MS, Jordan TJ, Edgar MA, et al. A lack of dimorphism of sex or sexual orientation in the human anterior commis­ sure. Brain Res 2002;936(1–2):95–98. Rahman Q, Wilson GD, Abrahams S. Biosocial factors, sexual orientation and neurocognitive functioning. Psycho­ neuroendocrinology 2004;29(7):867–81. Maylor EA, Reimers S, Choi J, et al. Gender and sexual ori­ entation differences in cognition across adulthood: age is kinder to women than to men regardless of sexual orientation. Arch Sex Behav 2007;36(2):235–49. Haraldsen IR, Egeland T, Haug E, et al. Cross-sex hormone treatment does not change sex-sensitive cognitive perform­

112

39.

40.

41.

42.

43.

44.

45.

46. 47. 48.

49.

50.

51.

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ance in gender identity disorder patients. Psychiatry Res 2005;137(3):161–74. Wisniewski AB, Prendeville MT, Dobs AS. Handedness, functional cerebral hemispheric lateralization, and cognition in male-to-female transsexuals receiving cross-sex hormone treatment. Arch Sex Behav 2005;34(2):167–72. Savic I, Lindstrom P. PET and MRI show differences in cerebral asymmetry and functional connectivity between homo- and heterosexual subjects. Proc Natl Acad Sci USA 2008;105(27):9403–8. Savic I, Berglund H, Lindstrom P. Brain response to putative pheromones in homosexual men. Proc Natl Acad Sci USA 2005;102(20):7356–61. Berglund H, Lindstrom P, Savic I. Brain response to puta­ tive pheromones in lesbian women. Proc Natl Acad Sci USA 2006;103(21):8269–74. Berglund H, Lindstrom P, Dhejne-Helmy C, et al. Male-to-female transsexuals show sex-atypical hypothalamus activation when smelling odorous steroids. Cereb Cortex 2008;18(8):1900–8. Loehlin JC, McFadden D. Otoacoustic emissions, auditory evoked potentials, and traits related to sex and sexual orienta­ tion. Arch Sex Behav 2003;32(2):115–27. McFadden D, Loehlin JC, Breedlove SM, et al. A reanalysis of five studies on sexual orientation and the relative length of the 2nd and 4th fingers (the 2D:4D ratio). Arch Sex Behav 2005;34(3):341–56. Kondo T, Zakany J, Innis JW, et al. Of fingers, toes and penises. Nature 1997;390(6655):29. Ellis A. The sexual psychology of human hermaphrodites. Psychosom Med 1945;7(2):108–25. Consortium on the Management of Disorders of Sex Development. Clinical Guidelines for the Management of Disorders of Sex Development in Childhood. Rohnert Park, CA: Intersex Society of North America; 2006. Lee PA, Houk CP, Ahmed SF, et al. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006;118(2):e488–500. Houk CP, Hughes IA, Ahmed SF, et al. Summary of consen­ sus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics 2006;118(2):753–57. Byne W. Developmental endocrine influences on gender iden­ tity: implications for management of disorders of sex devel­ opment. Mt Sinai J Med 2006;73(7):950–59.

52. Meyer-Bahlburg HF. Gender assignment and reassignment in 46,XY pseudohermaphroditism and related conditions. J Clin Endocrinol Metabol 1999;84(10):3455–58. 53. Reiner WG. Psychosexual development in genetic males assigned female: the cloacal exstrophy experience. Child Adolesc Psychiatr Clin N Am 2004;13(3), 657–74, ix. 54. Imperato-McGinley J, Peterson RE, Stoller R, et al. Male pseudohermaphroditism secondary to 17 beta-hydroxysteroid dehydrogenase deficiency: gender role change with puberty. J Clin Endocrinol Metab 1979;49(3):391–95. 55. Praveen EP, Desai AK, Khurana ML, et al. Gender identity of children and young adults with 5alpha-reductase deficiency. J Pediatr Endocrinol Metabol 2008;21(2):173–79. 56. al Attia HM. Male pseudohermaphroditism due to 5 alphareductase-2 deficiency in an Arab kindred. Postgrad Med J 1997;73(866):802–7. 57. Wilson JD. Androgens, androgen receptors, and male gender role behavior. Horm Behav 2001;40(2):358–66. 58. Goy RW, McEwen BS. Sexual Differentiation of the Brain. Cambridge, MA: MIT Press; 1980. 59. Bailey JM, Dunne MP, Martin NG. Genetic and envi­ ronmental influences on sexual orientation and its cor­ relates in an Australian twin sample. J Pers Soc Psychol 2000;78(3):524–36. 60. Lykken DT, Bouchard TJ Jr, McGue M, et al. The Minnesota twin family registry: some initial findings. Acta Genet Med Gemellol (Roma) 1990;39(1):35–70. 61. Marshall E. NIH’s ‘gay gene’ study questioned. Science 1995;268(5219):1841. 62. Wilkins AS. Jurassic Park and the ‘gay gene’: the new genet­ ics seen through the distorting lens of the media. FASEB J 1993;7(13):1203–4. 63. Jockin V, McGue M, Lykken DT. Personality and divorce: a genetic analysis. J Pers Soc Psychol 1996;71(2):288–99. 64. Bell AP, Weinberg MS, Hammersmith SK, et al. Sexual Preference: Its Development in Men and Women. Bloomington, IN: Indiana University Press; 1981. 65. Lombardi E. Enhancing transgender health care. Am J Public Health 2001;91(6):869–72.

Chapter

10

Age and Gender-Specific Patterns of Neurologic Illness Joan Amatniek1, Karin Sorra2, Lauren Frey3, and W. Allen Hauser4 1

Director, Clinical Development, Ortho McNeil–Janssen Scientific Affairs, Titusville, NJ; Associate Visiting Research Scientist, Columbia University, Gertrude H. Sergievsky Center, Graduate School of Public Health, New York, NY, USA 2 President and Chief Scientific Officer, Arroscience Inc., Toronto, Ontario, Canada 3 Assistant Professor, Department of Neurology, University of Colorado Denver, Denver, CO, USA 4 Professor of Neurology and Epidemiology, Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY, USA

Introduction

Are There Clinical Advantages for Understanding Disease Frequency by Gender?

Gender-specific analyses in neurology and other health fields reveal that particular diseases may affect females and males differently. Management of conditions may vary by gender for biologic and sociologic reasons, although more basic research questions of epidemiologic interest also arise. For example, are there conditions that are differentially distributed in populations by gender; and, if so, how does one interpret the differences in distribution to develop meaningful interventions?

Identification of conditions that differentially affect one gender can alert healthcare providers to altered risk of disease, and allow for the development of gender-specific preventive strategies or the development of gender-specific therapeutic interventions. Although recent emphasis in this area has been on the uniqueness of female gender, a better understanding of biophysiologic and neuropharmacologic factors such as hormonal influences on the disease process could be of benefit to all people. Additionally, the frequency of an illness is important in public health decision-making regarding preventive strategies. For instance, if a disease is more common in one gender, recommending screening for that gender only might be an appropriate public health response.

How Can Gender-Specific Frequencies Provide Clues to Overall Etiology? Basic descriptive epidemiologic data are important in hypothesis generation, both to understand disease processes and to develop interventions. Conditions that affect the genders with different frequencies across studied populations similarly, either throughout the lifespan or at particular life stages, suggest that biologic factors associated with gender (or cross-cultural gender-specific environmental factors) function as modifiers of disease susceptibility or expression. Effects of gender that are different in different study populations suggest that gender-specific environmentspecific factors are important in the underlying disease mechanisms. When such variation is present within multiple studies of certain countries or regions but not in other cultural or geographic regions the assessment by gender is further complicated.

Principles of Gender-Specific Medicine

Strategies for identifying differential disease frequencies A number of strategies have been used to identify differential disease frequency by gender, none of which are without limitation. While each of the strategies discussed below is important for hypothesis generation, we consider studies of incidence to be the gold standard for determining frequency of illness.

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Why Aren’t Clinical Impressions Sufficient? Each physician has an impression of the differential frequency of disease based upon her or his clinical experience. This may be driven by the most recent cases evaluated, or, for specialists, by referral patterns. Although such impressions may contribute to hypothesis generation, such observations remain anecdotal until confirmed by data generated from more rigorous methods that eliminate critical interpretation-limiting biases.

Are Clinical Series More Useful Than Clinical Impressions? Collections of cases from individual clinicians, referral centers, or hospitals may provide somewhat better information regarding gender specificity. Despite larger numbers of patients, conclusions regarding the ratio of male to female cases from such collections may remain flawed. Medical practitioners are seldom aware of their general referral base, much less the patterns of referral by gender. For example, there are clearly differences in health-seeking behavior between the elderly and the young. In addition, even when care is sought at a primary care level, referral to specialty centers is much more likely for younger individuals and, in many societies, elderly men are more likely to be referred than elderly women. Because of this differential referral pattern, the age distribution of patients with Parkinson’s disease (PD), for example, reported in clinical series from referral centers under-enumerates the oldest age groups,1 and possibly the oldest women in particular. For another example, many studies of people with epilepsy depend upon the identification of cases through clinical neurophysiology laboratories. Since the elderly may be less frequently referred to specialty care (or specialized tests),2 failure to take these referral patterns into account may in part explain differences in the frequency and gender distribution of epilepsy cases in some studies within the same region.3,4 One needs to remember that an inappropriate perception of both age and gender distribution may occur in clinical series or epidemiologic studies if incomplete methods of ascertainment are used. When health-seeking behavior is studied specifically, such as in the young with headache, other patterns with a gender basis may emerge. Women are more likely to seek medical care for headache than men.5 Thus, if one makes judgments based upon data from medical contact alone, an erroneous perception of gender or age distribution may occur.

How Can Epidemiologic Strategies Assist in Understanding? All the potential biases associated with clinical series can also influence epidemiologic studies. Hopefully, the epidemiologic investigator considers some of these factors

during study design and interpretation. A large denominator, reflecting the strength of population-based surveys, often, but not always, provides some reassurance regarding the validity of gender-specific comparisons.

Why Isn’t Prevalence Useful? Prevalence is the proportion of the population with a specific condition at a specific point in time. Prevalence is a complex measure driven by the incidence and duration of an illness. When survival differs by gender, which may be the case for amyotrophic lateral sclerosis (ALS)6 and epilepsy,7,8 for example, one may reach erroneous conclusions about gender-specific frequency from prevalence data. Also, not all diseases are life-long. An example of this is epilepsy, in which 65–70% of cases are controlled by chronic medication use.9 Differential remission by gender could again provide misleading signals regarding the true frequency of a condition. Although prevalence studies, which frequently are less costly and time-consuming than incidence studies, exist for most neurologic conditions, these studies may provide data that for the reasons just stated can result in unjustified conclusions regarding gender-specific disease frequency.

Why Is Incidence Preferred? A much better assessment of gender-specific frequency is provided through the study of newly identified, or incident, cases. Such cases are assembled by counting cases of new onset in an identified population over a set time. The use of incident cases eliminates interpretation difficulties, or biases, associated with differential mortality or disease duration found in prevalence studies, although problems of interpretation related to patient identification remain. In designing incidence studies, knowledge of healthcare practices and patterns is critical in preventing biases resulting from data collection and is exquisitely unique by disease. For conditions in which patients would invariably seek medical attention, such as ALS, hospital or medical referrals may suffice as a source of patient identification because all new cases will be identified.10 For conditions during which medical care is not universally sought, such as headache or movement disorders, population surveys may be necessary for full enumeration. Unfortunately, because of the expense and time required, few incidence studies of neurologic conditions exist. Those that do exist have been done predominately in developed countries, although recently more such incidence studies are being conducted outside of North America and traditionally defined Western Europe. The differences of age and gender in population structures between developed and other nations may result in less robust generalizability of gender-specific frequency findings.

C h a p t e r 1 0    Age and Gender-Specific Patterns of Neurologic Illness l

Are There Multiple Designs for Incidence Studies? Several design strategies are used in incidence studies providing gender-specific data. Each strategy has advantages and disadvantages. Among these designs are the historical, cross-sectional and prospective cohorts. The determination of incidence through the retrospective review of medical records for a defined community is a low-cost and effective strategy. The historical cohort design has been used most successfully in studies of neurologic disease in Rochester, Minnesota. Such studies require medical records from the entire population at risk, both inpatient and outpatient. The researchers from the Rochester Epidemiologic Project catalogue medical records for residents of the community from multiple sources (including records from the Mayo Clinic as well as surrounding hospitals, medical clinics, private practitioners, health departments and other sources of medical care from the medical community in the region). Such aggregate records provide reliable data for conditions likely to require medical attention. Thus, under these circumstances, gender-specific data are likely to be more reliable for conditions such as stroke or epilepsy where most individuals affected will seek medical care and less reliable for conditions such as migraine for which a substantial proportion of people (particularly males) will not seek care. These studies also capture details regarding onset of disease and its associated factors that are documented in the medical records. A disadvantage of this methodology is that researchers cannot obtain information that was not part of medical concerns at the time of an individual’s initial presentation. Another disadvantage is that changes in diagnostic criteria and in perceptions regarding disease may need to be taken into account when the data cover long intervals. The possibility of time- or gender-specific trends in disease frequency unrelated to technology advancement or diagnostic classification is also important. A variation on the historical cohort design is the reconstructed cohort, in which reconstruction of incidence occurs through interviews of prevalent cases to obtain date of disease onset. For fatal conditions, such as ALS, this strategy would not be successful. Conversely, for nonfatal conditions, this could be a successful strategy if diagnoses can be verified and steps taken to minimize the effect of recall bias. Cross-sectional studies are advantageous because they may be conducted relatively rapidly, requiring only a single point-in-time measurement. These studies also permit case verification because they are in the moment. Incidence has been determined in cross-sectional studies associated with community-based prevalence surveys. In this setting, incidence has an adapted definition because there is only a single determination of cases, rather than multiple determinations. Here incident cases are those with a pre-specified recent onset of symptoms, rather than an observed new onset occurring during the study. If the patient or other informant is reliable, these surveys can be successful in conditions

115

without rapid fatality. Because of the rarity of many neuro­ logic conditions, however, sizeable populations are often required for this type of study to be successful and can result in correspondingly large expense. Prospectively followed cohorts can be designed to gather targeted data not only on incidence but also on factors associated with onset. Examples of these studies include the North Manhattan and EURODEM studies. Studies by health maintenance organizations (HMOs) might also be done prospectively although HMO studies may be difficult to interpret due to subject selection. For HMO populations, data are, in all likelihood, reliable for conditions affecting healthy young individuals such as migraine, but unreliable for diseases associated with poverty or with highest frequency in the elderly, since these individuals are less likely to be seen in HMOs.

Is Age Adjustment Necessary? Regardless of the method of incidence determination, age adjustment, although necessary for understanding when illnesses occur across the lifespan, is seldom reported. If wide variation occurs in the age distribution by gender, crude incidence may be misleading. An example is the frequency of PD in Rochester.11 Crude incidence was equal for males and females, but age-adjusted incidence was 60% higher in males compared with females.

Should One Also Assess Gender as a Risk Factor? Gender may be assessed as a dependent variable in either case control or cohort studies. The advantage of using gender in this fashion is the ability to control for other factors besides age and gender in order to establish any independent contribution of gender. For example, the age-adjusted incidence of stroke was 10% higher for men compared with women in the Cardiovascular Health Study.12 In proportional hazards analysis, where covariates can be incorporated into the analysis resulting in ratios adjusted for these other variables, the adjusted risk for male gender was 0.97. In this case, the simple age-adjusted analysis is misleading because it does not incorporate the other factors that affect the incidence.

Are there data regarding genderspecific frequency of neurologic diseases? The data in this chapter are limited to that from incidence studies. Further, age- and gender-specific incidence must have been provided in the source papers to allow age adjustment to a standard population (2000 US Census population), or the paper authors must have applied a similar adjustment. For studies reporting age-adjusted incidence, the standard population and the age groups used for adjustment are shown in Table 10.1. All comparisons are made

s e c t i o n 2     Gender and the Nervous System

116

l

Table 10.1  Age/gender-adjusted incidence (per 100 000 population) to 2000 US Census (unless noted) Location (subpopulations)

Ref.

Duration

Male

Female

Age

Barbados (black) S London, England (black) Sweden (hospitalized) N Manhattan, NY N Manhattan, NY (black) N Manhattan, NY (white) N Manhattan, NY (Hispanic) Melbourne, Australia S Greece Lund–Orup, Sweden Shiga, Japan Belluno, Italy Warsaw, Poland Shibata, Japan Vittoria, Italy Sweden (hospitalized) Perth, Australia Fredericksburg, Denmark Malmo, Sweden Valle d’Aosta, Italy Umbria, Italy Perth, Australia Dijon, France Soderham, Sweden Auckland, New Zealand Oxfordshire, England Soderham, Sweden Fredericksburg, Denmark Stroke: Pediatric

13 13 14 15 15 15 15 16 17 18 19 20 21 22 23 14 24 25 26 27 28 29 30 31 32 33 31 25

2001–03 1995–2002 1998–2000 1993–96 1993–96 1993–96 1993–96 1996–97 1994–95 1993–95 1989–93 1992–93 1991–92 1977–92 1991 1989–91 1989–90 1989–90 1989 1989 1986–89 1986 1985–86 1983–86 1981–82 1981–82 1975–78 1972–74

143.92 192.40 34.99 212.83 259.00 118.00 232.00 153.00 362.40 194.20 268.70 218.95 174.81 793.43 241.81 28.67 236.22 227.69 172.26 243.51 199.17 352.78 196.39 441.24 210.38 184.85 400.65 170.55

139.52 174.97 19.79 149.75 222.00 80.00 172.00 117.00 276.10 126.20 167.50 180.83 134.06 650.04 142.53 14.08 143.79 138.48 118.06 189.40 157.38 163.68 109.47 409.84 194.55 166.67 295.13 127.47

California (ischemic, hospitalized) California (SAH, hospitalized) California (ICH, hospitalized) Stroke: Ischemic

34

1991–2000

1.30

1.05

30 days to 20 yr

34 34

1991–2000 1991–2000

0.40 0.97

0.32 0.65

30 days to 20 yr 30 days to 20 yr

Basle, Switzerland Sweden Bavaria, Germany N Manhattan, NY (black) N Manhattan, NY (white) N Manhattan, NY (Hispanic) Belluno, Italy Hisayama, Japan Shibata, Japan Perth, Australia Valle d’Aosta, Italy Oxfordshire, England Stroke: ICH

35 36 37 15 15 15 20 38 22 24 27 39

2002–03 1987–2001 1994–98 1993–96 1993–96 1993–96 1992–93 1961–93 1977–92 1989–90 1989 1981–86

101.70 118.65a 129.60 195.70 98.00 181.40 155.69 640.00 442.97 170.44 170.00 1752.18

78.81 63.34a 101.40 184.20 57.60 134.00 118.56 340.00 335.27 93.99 126.00 1530.25

Sweden (hospitalized) Sweden N Manhattan, NY (black) N Manhattan, NY (white)

36 40 15 15

1987–2001 1996 1993–96 1993–96

31.57b 32.20 37.20 15.30

16.22b 24.70 34.90 10.80

Other comparator population

Stroke: Total 15 to 85 15 to 85 30 to 65 20 to 85 20 to 85 20 to 85 20 to 85 0 to 85 18 to 85 15 to 85 35 to 85 35 to 85 30 to 85 40 to 70 0 to 85 30 to 65 0 to 85 55 to 85 45 to 85 55 to 85 55 to 85 30 to 85 15 to 85 25 to 85 15 to 85 55 to 75 25 to 85 55 to 85

0 to 85 30 to 69 0 to 85 20 to 85 20 to 85 20 to 85 35 to 85 40 40 to 70 0 to 85 55 to 85 15 to 85 30 to 69 0 to 85 20 to 85 20 to 85

1990 N Manhattan with ethnicity 1990 N Manhattan with ethnicity 1990 N Manhattan with ethnicity ‘World’ of Segi Europe, standard Europe, standard 1980 Japan

Europe, standard 1990 N Manhattan with ethnicity 1990 N Manhattan with ethnicity 1990 N Manhattan with ethnicity Unidentified, standard

1988 Italy, working

Sweden 1990 N Manhattan with ethnicity 1990 N Manhattan with ethnicity

(Continued)

C h a p t e r 1 0    Age and Gender-Specific Patterns of Neurologic Illness

117

l

Table 10.1  Continued Location (subpopulations)

Ref.

Duration

Male

Female

Age

Other comparator population

N Manhattan, NY (Hispanic) Belluno, Italy Shiga, Japan Shibata, Japan Perth, Australia Valle d’Aosta, Italy Oxfordshire, England Stroke: SAH

15 20 19 22 24 27 39

1993–96 1992–93 1989–93 1977–92 1989–90 1989 1981–86

44.20 34.56 58.00 84.81 23.46 22.00 227.64

22.00 36.54 47.50 152.91 16.38 30.00 193.30

20 to 85 35 to 85 35 to 85 40 to 70 0 to 85 55 to 85 15 to 85

1990 N Manhattan with ethnicity

S Sweden C Sweden N Sweden Sweden (ICH and SAH) N Manhattan, NY (black) N Manhattan, NY (white) N Manhattan, NY (Hispanic) S Sweden C Sweden N Sweden Belluno, Italy Shiga, Japan Shibata, Japan Perth, Australia Valle d’Aosta, Italy Oxfordshire, England Epilepsy and seizures

41 41 41 40 15 15 15 41 41 41 20 19 22 24 27 39

1995–2002 1995–2002 1995–2002 1996 1993–96 1993–96 1993–96 1987–94 1987–94 1987–94 1992–93 1989–93 1977–92 1989–90 1989 1981–86

8.47 9.56 9.87 6.40 26.20 4.90 6.30 9.39 10.03 11.77 6.13 18.00 35.34 170.44 5.00 105.73

10.48 12.28 14.33 13.50 3.20 11.90 15.60 11.56 13.38 16.15 5.30 22.60 39.03 93.99 5.00 210.09

0 to 90 0 to 90 0 to 90 0 to 85 20 to 85 20 to 85 20 to 85 0 to 90 0 to 90 0 to 90 35 to 85 35 to 85 40 to 70 0 to 85 55 to 85 15 to 85

Manhattan, NY (unprovoked seizures) Iceland (unprovoked seizures) Martinique (all first seizures) Houston, TX (epilepsy) Estonia (recurrent seizures) Umea, Sweden (unprovoked seizures) Iceland (rural) (epilepsy) Geneva, Switzerland (seizures) C Ethiopia (rural) (epilepsy) El Salvador, Chile (epilepsy) Umea, Sweden (unprovoked seizures) Rochester, MN (epilepsy) Rochester, MN (epilepsy unknown cause) Rochester, MN (unprovoked seizures) Rochester, MN (acute symptomatic seizures) Status epilepticus

42

2003–05

47.00

36.00

0 to 85

43 44 45 46  4

1995–99 1994–95 1988–94 1994 1992–94

59.81 117.33 30.25 55.74 55.37

54.96 55.41 32.05 20.30 52.65

0 to 85 1 to 70 0 to 75 20 to 80 17 to 80

47 48 49 50 51

1991 1990–91 1986–90 1984–88 1985–87

56.00 91.12 24.53 100.80 67.70

35.89 51.84 34.11 89.78 89.70

0 to 85 1 to 80 1 to 70 0 to 60 0 to 15

52 52

1935–84 1935–84

49.45 29.95

42.00 26.47

0 to 85 0 to 85

52

1935–84

68.61

56.77

0 to 85

53

1935–84

47.29

30.10

0 to 75

56 57 58 59 60

2003 2002–4 1997–99 1997–98 1965–84

41.70 14.00 26.10 12.10 23.20

12.30 12.50 13.70 7.80 13.10

0 to 75 0 to 15 18 to 60 0 to 75 0 to 80

Ferrara, Italy London, England Hessen, Germany W Switzerland Rochester, MN

1980 Japan

1988 Italy, working

Sweden 1990 N Manhattan with ethnicity 1990 N Manhattan with ethnicity 1990 N Manhattan with ethnicity

1980 Japan

1988 Italy, working

Europe, standard 2001 England and Wales Germany 1980 USA 1980 USA

(Continued)

118

s e c t i o n 2     Gender and the Nervous System l

Table 10.1  Continued Location (subpopulations)

Ref.

Duration

Male

Female

Age

Other comparator population

38.80

57.40

0 to 80

Full cohort

Sudden unexpected death from epilepsy Midwestern USA Alzheimer’s disease

61

1991–96

Seattle, WA Catanduva, Brazil (random sample) India (rural) C Spain (sampled) Baltimore, MD EURODEM Incidence Research Group Manitoba, BC, Canada (sampled) Stockholm, Sweden Rochester, MN Rochester, MN Rochester, MN Rochester, MN Rochester, MN Rochester, MN Cambridge, England (mild severity plus) Cambridge, England (minimal severity plus) Vascular dementia

62 63

1994–2002 1997–2000

49.33 596.02

111.16 978.75

65 to 85 65 to 90

64 65 66 67

1991–99 1994–98 1985–98 1992–97

22.96 621.48 56.69 34.62

50.38 1123.60 125.44 108.42

55 to 85 65 to 90 55 to 85 65 to 85

68

1991–96/97

993.71

1332.72

65 to 90

69 70 71 71 71 71 71 72

1990–92 1299.92 1985–89 44.08 1980–84 105.69 1975–79 93.31 1970–74 60.62 1965–69 66.79 1960–64 76.73 Unspecified 1476.61

3149.81 89.26 103.47 96.57 91.16 59.97 78.51 3304.78

75 to 90 50 to 85 0 to 85 0 to 85 0 to 85 0 to 85 0 to 85 75 to 85

72

Unspecified 6330.53

9386.18

75 to 85

67

1992–97

16.92

21.10

65 to 85

73 74

1991–96 1985–89

320.36 11.87

94.01 19.46

65 to 85 50 to 85

SW France Italy Multiple sclerosis

75 76

1988–98 1992–96

30.83 2043.81

21.10 2796.14

70 to 85 65 to 84

Saskatchewan, Canada Ferrara, Italy Canary Islands, Spain United Kingdom Minnesota N Sweden Newcastle, Australia Enna, Italy Bagheria City, Sicily Catania, Sicily Sassari, Sardinia Olmsted County, MN Rochester, MN Perth, Australia Newcastle, Australia Hobart, Australia Barbagia, Sardinia Migraine

77 78 79 80 81 82 83 84 85 86 87 81 81 88 88 88 89

1970–2004 1990–2003 1998–2002 1993–2000 1985–2000 1988–97 1986–96 1986–95 1985–94 1975–94 1965–85 1905–84 1905–84 1961–81 1961–81 1961–81 1961–80

4.56 2.67 1.75 3.30 4.61 3.86 1.47 2.36 1.64 1.09 3.17 2.80 3.40 0.63 2.16 3.55 4.76

10.96 7.27 5.46 7.66 10.08 7.40 3.36 2.97 2.92 1.35 6.52 6.80 7.70 2.24 2.60 4.09 6.33

0 to 75 10 to 75 0 to 5 0 to 85 0 to 65 0 to 75 0 to 70 0 to 45 0 to 45 0 to 75 10 to 54 0 to 65 0 to 65 0 to 85 0 to 85 0 to 85 10 to 49

Copenhagen, Denmark Olmsted County, MN

90 91

1989–2001 1989–90

329.87a 93.57

1619.45a 230.06

25 to 64 0 to 60

EURODEM Incidence Research Group Canada Rochester, MN Mild cognitive impairment

Canada, undemented cohort

1950 USA, white 1950 USA, white

(Continued)

C h a p t e r 1 0    Age and Gender-Specific Patterns of Neurologic Illness

119

l

Table 10.1  Continued Location (subpopulations)

Ref.

Washington County, MD (with   92 aura) Washington County, MD 92 (without aura) Olmsted County, MN 93 Tension type headache Copenhagen, Denmark Amyotrophic lateral sclerosis Greece Lombardy, Italy Puglia, Italy Guam W Washington Sardinnia, Italy Parma, Italy Harris County, TX Messina, Italy Palermo, Italy Minnesota Ferrara, Italy Middle Finland Sardinia, Italy Florence, Italy Israel Mexico

Duration

Male

Female

Age

1986–87

592.91

1651.80

4 to 29

1986–87

1314.38

2639.19

4 to 29

1979–81

137.83

272.55

0 to 60

1078.87a

2521.03a

25 to 64

Other comparator population

90

1989–2001

94 95 96 97 98   99 100 10   10 101 102   10 103   10 104 105 99   10 106   10 107   10 108

1990–2003 1998–2002 1998–99 1995–99 1990–95 1981–90 1960–90 1985–88 1976–85

1.40 2.09 1.81 3.55 2.11 0.97 0.92 1.81 0.90

0.82 1.22 0.96 4.36 1.87 0.51 0.68 1.47 0.22

18 to 80 0 to 75 0 to 85 20 to 70 0 to 85 0 to 80 0 to 70 15 to 75 0 to 85

1973–84 1925–84

0.77 2.91

0.47 1.89

20 to 79 0 to 85

1970 USAc

1964–82

0.62

0.34

0 to 85

1970 USAc

1976–81 1971–80 1967–76

5.36 0.62 0.68

6.01 0.43 0.47

40 to 79 0 to 80  0 to 85

1970 USAc

1959–74

0.93

0.56

0 to 85

1970 USAc

1962–69

0.31

0.46

0 to 85

1970 USAc

109 110 111 112 113 114

2001–02 1990–99 1997–98 1994–95 1993–95 1989–91

32.34 218.56 351.86 18.80 11.10 31.90

28.21 130.62 119.05 9.87 9.80 10.30

50 to 80 55 to 85 65 to 85 0 to 89 40 to 80 45 to 85

1970 USA 1990 Washington Heights

114

1989–91

13.30

11.80

45 to 85

1990 Washington Heights

114

1989–91

12.20

11.30

45 to 85

1990 Washington Heights

115 116 117 116, 118

1962–87 1985–86

9.30 13.00

10.70 10.00

35 to 75 0 to 85

Italy, working 1970 USAd

1967–79

25.00

16.00

0 to 85

1970 USAd

119 116 120 116 121

1975–79 1968–70

163.84 13.00

178.49 12.00

30 to 80 0 to 85

1970 USAd

2.10

1.70

0 to 85

1970 USAd

1990 USA

1970 USAc

Parkinson’s disease Singapore Netherlands Spain California Ilan County, Taiwan Washington Heights, NY (black) Washington Heights, NY (white) Washington Heights, NY (other) Ferrara, Italy Pozan, Poland Rochester, MN (also arteriosclerotic and postencephalitic) Yonago, Japan Turku, Finland (also postencephalitic) China, 20 provinces (population screening)

1986

(Continued)

120

s e c t i o n 2     Gender and the Nervous System l

Table 10.1  Continued Location (subpopulations)

Ref.

Duration

Male

Female

Age

Other comparator population

Rochester, MN Benghazi, Libya Guillan–Barré syndrome

122 123

1976–90 1982–89

0.16 0.22

1.56 5.99

0 to 45 0 to 60

Ferrara, Italy United Kingdom Spain Harbin, China Emilia–Romagna, Italy Ferrara, Italy Stockholm County, Sweden Benghazi, Libya Bell palsy

124 125 126 127 128 129 130 131

1981–2001 1992–2000 1998–99 1997–98 1992–93 1981–93 1973–91 1983–85

1.84 1.42 1.79 0.74 1.43 1.75 1.55 2.06

1.23 1.21 0.75 0.57 0.66 1.13 1.47 2.42

0 to 80 0 to 100 20 to 80 0 to 60 0 to 70 0 to 70 0 to 80 0 to 60

Laredo, TX Rochester, MN Rochester, MN Primary intracranial tumors

132 133 134

1974–82 1968–82 1955–67

32.01 26.83 24.88

38.23 28.58 27.67

0 to 70 0 to 70 0 to 70

US Central Brain Tumor Registry US Central Brain Tumor Registry (neuroepithelial) US.Central Brain Tumor Registry (glioblastoma) US Central Brain Tumor Registry (of meninges) Valle d’Aosta, Italy (meningioma) Valle d’Aosta, Italy (epithelial) New York (anaplastic astrocytoma) New York (astrocytoma, unspecified) New York (glioblastoma multiforme) Valle d’Aosta, Italy Switzerland (glioblastoma) Myasthenia gravis

135

1998–2002

14.50

15.10

0 to 85

by CBTRUS to 2000 USA

135

1998–2002

7.67

5.35

0 to 85

by CBTRUS to 2000 USA

135

1998–2002

3.86

2.39

0 to 85

by CBTRUS to 2000 USA

135

1998–2002

2.95

6.18

0 to 85

by CBTRUS to 2000 USA

136

1992–99

9.80

16.70

1 to 85

1991 Italy

136 137

1992–99 1976–95

10.60 0.28

8.10 0.18

0 to 85 0 to 80

1991 Italy 1970 USA

137

1976–95

1.48

1.05

0 to 80

1970 USA

137

1976–95

3.49

2.27

0 to 80

1970 USA

138 139

1986–91 1980–84

21.62 4.60

28.09 2.90

0 to 75 Not stated

1988 Italy Europe, standard

142 143 144 145 146 147 148 149 150

1997–2001 1991–2000 1976–96 1970–96 1993–94 1983–92 1975–89 1970–87 1951–81

0.46 1.49 0.48 0.27 0.96 0.66 0.40 0.35 0.27

0.86 2.17 0.69 0.51 1.31 0.82 0.57 0.49 0.55

0 to 65 0 to 65 0 to 70 0 to 80 0 to 75 0 to 80 0 to 80 0 to 85 0 to 80

Pseudo–tumor cerebri

Nagano, Japan Spain Croatia Estonia Italy Belgrade, Yugoslavia W Denmark E Denmark Norway

N, North; S, South; E, East; W, West; C, Central. SAH, subarachnoid hemorrhage; ICH, intracerebral hemorrhage. a Estimated from figure. b Precise numbers from personal correspondence with author. c As reported by Annegers. d As reported by Zhang.

C h a p t e r 1 0    Age and Gender-Specific Patterns of Neurologic Illness l

across gender within studies. Comparisons across studies can be made, but the varying age groups and disease definitions make such comparisons difficult; and are not the purpose of this chapter. Conditions that are determined through modification of the X or Y chromosome are not included. Table 10.1 lists the studies reviewed in this chapter.

Is the Clinical Perception of a Male Stroke Preponderance Accurate? Stroke is a generic term for an acute localized central nervous system deficit secondary to alteration of the blood supply to the brain. This includes a heterogeneous set of underlying conditions and multiple distinct pathophysiologies. Total stroke incidence, although important for public health planning and basic medical care, can be misleading because there are known differences based on gender in several of the stroke sub-types. For stroke overall, the age-adjusted incidence across all age groups is substantially higher in men than in women across all studies. This finding holds true across racial lines, in the one study where the researchers examined age, sex, and race together. A review of gender-specific incidence within age strata, however, suggests a substantially higher incidence in women in the oldest age group (85). This is true for many studies (North Manhattan, Warsaw, Belluno, Malmo, and Barbados) but not all. In the younger age groups, depending on age breakdown, no single pattern of gender predominance exists across studies. Interestingly, in the two studies focusing only on black populations, identically designed and conducted in South London and Barbados, female predominance is found in the 35 years old group. There is one study focusing on the incidence of stroke in a pediatric population. In a California study of hospital discharges of children 30 days and 20 years of age researchers found a slight male predominance in each stroke subtype – ischemic, subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH). Why might these gender-specific differences by life stage exist? Statistical artifacts, i.e. few cases with less stability, might account for the variability of gender incidence of stroke in young people. More thought-provoking, however, is an hypothesis of causality. For example, one could point to the etiologic heterogeneity of young stroke, which ranges from inherited causes such as hematologic mutations to highrisk behaviors for stroke such as cocaine abuse, smoking with concomitant birth control pill use, and pregnancy. The male predominance in later middle to middle–old age, a time of peak stroke risk, is associated with traditional risk factors for stroke, i.e. those coincidental with cardiovascular disease. As for the substantially higher female incidence often found in the 85 years and older age group, a plausible hypothesis is the occurrence of amyloid angiopathy. Many of the gender-specific patterns reported for cere­ brovascular disease overall also hold true for ischemic stroke, which is by far the preponderant stroke subtype.

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Once again, the age-adjusted incidence is substantially higher in men when compared to women across all studies. This is also true when analyzed by race or ethnic group. The consistent pattern of a substantially higher incidence in women in the oldest old is no longer as pronounced. Additionally, in the age groups less than 35–50 years, when the ischemic stroke subtype is ascertained, there is inconsistency in gender predominance. For stroke subtypes other than ischemic, the case for gender specificity is less clear. Both for ICH and SAH studies vary in regard to gender predominance. For the North Manhattan study, in which researchers examine age, race, and sex, a male excess of ICH exists for each racial group, while a female excess of SAH exists for whites and Hispanics but not blacks.

Are Convulsive’s Disorders and Epilepsy Always More Frequent in Boys and Men? A seizure is the clinical manifestation of an uncontrolled and excessive electrochemical discharge involving a set of neurons in the brain. Seizures may occur in the presence of any alteration of brain homeostasis. When seizures occur at the time of an acute systemic metabolic abnormality or in the context of a brain insult, they are referred to as ‘acute symptomatic seizures’.54 There is a consistent male preponderance of this category of seizure. A special category of acute symptomatic seizures is febrile seizures. Between 3 and 5% of all children will experience a convulsion with fever in childhood.4,55 Epilepsy is a condition in which seizures tend to recur in the absence of an identifiable precipitant. Such conditions as a group are referred to as ‘convulsive disorders.’ Regardless of the category of convulsive disorder evaluated, almost all studies indicate that males are more frequently affected than females. This is true for epilepsy, status epilepticus, all unprovoked seizures, acute symptomatic seizures, and febrile seizures. The higher incidence of acute symptomatic seizures in men is not surprising, since many of the conditions associated with this class of seizure are more frequent in men. There is a consistent male predominance among those with unprovoked seizures or epilepsy. About one-third of all epilepsy can be attributed to brain insults associated with conditions such as brain trauma or stroke, which are more frequent in males, but the male excess persists after an exclusion of cases of epilepsy of presumed cause. People with epilepsy, generally severe and of long standing, can experience a condition called sudden unexplained death in epilepsy. A single study has been done to determine the gender-specific incidence of these unexpected deaths. The study shows a female predominance, a finding that requires confirmation from additional studies. The cumulative incidence of epilepsy through age 85 in Rochester is 5% in men compared to 4% in women.55 A reversal in epilepsy risk by gender may occur in the oldest age groups (over age 75). This may be driven by the observed increased incidence in stroke in women in the

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oldest old since stroke is the predominant identified antecedent of epilepsy in the oldest age groups.

Is Alzheimer’s Disease (AD) Always More Frequent in Women? The age-adjusted incidence of AD is substantially higher in women compared with men across all studies. A review of gender-specific incidence within age strata is consistent with a slightly higher incidence in men in the younger age groups (cuts of 65–74 or 70–74) in some studies (Rochester 1975–79 and 1980–84, Catanduva, Manitoba, and Central Spain). The overall differences, therefore, may be driven by a dramatically higher female incidence with advancing age, although two recent studies (Central Spain, Brazil) have contradicted this assumption.

Is There Gender Specificity to Other Adult Cognitive Impairments? Clinical attention is being focused increasingly on two other subtypes of cognitive dysfunction: vascular dementia (VAD) and mild cognitive impairment (MCI), a predementia state that does not always progress to dementia. Data from two studies now support the hypothesis that the incidence of VAD may be higher in women, an unexpected finding given the male predominance of cerebrovascular disease. One study from Canada shows male excess in the incidence of VAD, although, in multivariate analysis, gender is not a significant predictor of disease. Two studies of the incidence of mild cognitive impairment, both in Western Europe, are inconsistent in their findings. There was a slight male predominance in a study done in South-West France and a female predominance in a study in Italy. Clearly, additional studies are needed for further delineation.

Is Multiple Sclerosis (MS) Always More Frequent in the Female Gender Regardless of Age? Data on the gender-specific incidence of MS are consistent with clinical series and with prevalence studies. A consistently higher incidence of MS occurs in women than men. This holds true for all age groups.

For Headache, is Age and Gender Specificity Consistent across Age Groups and Types? All except one incidence study of headache is on migraine, a headache type that is universally believed to affect females more frequently. However, with migraine divided into those with and without aura, and when age-specific incidence is evaluated, incidence is higher in males than females in the youngest age groups for migraineurs without aura. The female excess is then not evident until age group

10–11 years. For the one incidence study of tension type headache, in a working age population in Copenhagen (ages 25–64), there is an age-adjusted predominance in females, which is consistent across the mid-life age strata studied.

Is Frequency by Gender Consistent Across All Studies of ALS? Incidence studies of ALS, an upper and lower neuron disease and universally fatal illness, are consistent in showing an excess of males; this is true for age-adjusted incidence and for incidence within age groups. The sole exception is a study from Mexico, performed almost 40 years ago, in which incidence was substantially lower in men than that observed in the other studies. A unique syndrome called the ALS-PD Complex is found only in Guam. For this syndrome, a female predominance is observed.

Is Age and Gender Specificity a Temporal Phenomenon for PD? Recent incidence studies of PD, most known diagnostically for presenting with a resting tremor although not always, suggest a slight excess of males. This observation differs somewhat from older studies. In Italy, a slight excess of females occurs, and in Japan, the female preponderance is substantial. An excess of males was identified in studies in Washington Heights mainly attributable to the substantially greater incidence in black men. The substantial male excess for ‘parkinsonism’ noted in Rochester may be misleading, because it includes cases with ‘arteriosclerotic’ and ‘postencephalitic’ features.

Does the Consistency of Data from Pseudotumor Cerebri Make It Convincing Despite Few Studies? Studies of the incidence of pseudotumor cerebri, an illness that often presents with headache and visual field deficits, are few but show a consistent female excess across and within age brackets.

Is Guillain–Barré Syndrome (GBS) More Frequent in Males? Several studies of a frequently rapidly progressive poly­ neuropathy, often presenting after a viral illness, provide gender-specific incidence. Most papers report a slight excess in males. The exception is a study from Libya.

Does Age Make a Difference in Regards to Bell Palsy? Bell palsy, a paralysis of the facial nerve, is another peripheral neuropathy for which incidence has been systematically

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studied and for which gender-specific incidence is available. A slight excess of females is noted consistently. The difference may be greater in younger age groups.

Does Gender-Specific Frequency Vary by Brain Tumor Type? Data from a number of studies of brain tumor incidence using national registries suggest that brain tumor incidence may be increasing, although this may be a reflection of the greater use of imaging procedures. Detailed statistical evaluation fails to confirm this observation – at least in the United States.140 In studies in Rochester almost 35% of brain tumors are noted incidentally at autopsy. The majority of these incidental tumors are meningiomas.141 No statistically significant increase in total incidence over time has occurred in Rochester. The gender-specificities in incidence of primary brain tumors vary by tumor type, with a slightly higher incidence of gliomas and astrocytomas in men. The incidence of meningiomas is consistently higher in women.

Are Clinical Perceptions Regarding Myasthenia Gravis Consistent with Age- and GenderSpecific Incidence? Studies on the incidence of the neuromuscular junction illness, myasthenia gravis, suggest an age-adjusted female excess overall. For women, two peaks emerge: the first in the 20–30 year age group, and the other for women over the age of 70. Comparisons of gender- and age-specific incidence rates within studies reveal a higher incidence in men than women only in the older age groups (i.e. 60 years), despite the noted peak within the oldest women.

Summary and discussion Determining the differences and similarities in the presentation of disease by gender is important not only to document incidence but also to help elucidate the underlying pathophysiologic mechanisms potentially associated with gender and their possible effect on disease susceptibility or expression and treatment.

Gender and Disease Incidence At the most basic level, gender-specific factors could be driving occurrence of a certain disease. Two examples of uniquely female disease, albeit not neurological, are uterine and ovarian cancers. Among neurologic conditions, also uniquely female are neurologic diseases of pregnancy such as eclampsia. Most of the time, however, diseases occur in both men and women, necessarily making the effect of gender on disease incidence much more complex and difficult to understand. In Table 10.1 the data are consistent, with a

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higher frequency in women in AD and VAD, MS, migraine, and tension headache, pseudotumor cerebri, Bell palsy, meningioma, and myasthenia gravis. The data are also consistent with an excess of males in epilepsy, ALS, PD, and Guillain–Barré syndrome. In other conditions the effect of gender is not as clear. For example, an excess of males is generally seen for cerebrovascular disease, although this is not consistent for SAH or ICH and perhaps not in the younger or oldest years for the ischemic subtype of stroke. Physicians and scientists often use hypotheses about how disease differentially affects genders as possible clues to disease pathophysiology. Gender-specific hormones are likely to play a critical role. Women and men have different hormonal profiles, particularly with respect to the gonadal steroids; and these profiles are more variable in women with age (pre-menarche, reproductive age, post-menopause), time of month cycling during reproductive age, and body type (e.g. adipose tissue is linked to estrogen synthesis). Several very important questions to answer are: how do estrogen and progesterone fluctuate during the menstrual hormonal cycle so as to make migraine occurrence likelier with menses or ovulation? Can hormonal changes of pregnancy result in variations of disease, such as in migraine, or occurrence of others, such as ‘dementia of pregnancy’? Or are such phenomena indirect and related to other stresses placed upon the neurological system at that time, such as rapid changes in fluid load? Similarly posed questions could be asked of other neurological conditions as well as of the effects of androgen on men’s vulnerability to disease expression throughout the life cycle. In addition to sex differences in circulating hormones that influence brain physiology and function after puberty, as reviewed in Chapter 8, considerable evidence suggests that prenatal and neonatal sex differences in androgen exposure influence brain organization. How such sex differences in brain organization influence disease manifestations at present is only speculative as best. Importantly, not all biological, central nervous system, sex differences are mediated by sex steroids. For example, in rodents, the dopaminergic neurons of the substantia nigra from males express genes that are present only on the Y chromosome151 and when cultured function differently from XX neurons.152 This difference in the function of XX and XY neurons in culture has been shown to be independent of gonadal hormone exposure. Also hypothesized, with a basis in animal research, is that incomplete X inactivation may also result in sex differences in dosing of some X-linked genes in particular regions of the central nervous system.153 Such gene dosing effects might also be considered when pondering gender differences in disease vulnerability.

Gender and Disease Manifestations In addition to disease occurrence, gender-specific factors can also influence the expression of a disease, thus potentially affecting the age of occurrence or disease severity or

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manifestations. For example, the male predominance in AD sometimes seen in the younger old is lost among the oldest old (between 80–85 and 90). Could this be due to the loss of a protective effect of estrogen that remains even after menopause and wanes after several decades? The potential role of estrogen in the development of AD is further examined in Chapter 13, which reviews the large multicenter trials involving hormonal replacement therapy. Gender-specific factors can also impact risk factors for a disease. Some of these risk factors, such as degree of risky behavior, are disease-independent, while others may be diseases themselves that then put patients at risk for further disease. For instance, high blood pressure, a medical condition in itself, also puts patients at risk for additional problems, such as strokes or heart attacks. Also, conversely, for example, behaviors thought of as gender predominant, such as affiliation behaviors, such as having a strong network of support through family or friends, may exert a protective effective against certain diseases and provide an alternative hypothesis to estrogen or other hormone-related explanations of causality. Finally, as we learn more about disease occurrence and gender, aspects such as differential exposure to environmental risks and different genetic backgrounds across nations and races will also need to be considered.

Gender and Disease Treatment Ultimately, gender-specific differences in disease occurrence will affect the way diseases are treated. Genderspecific preventive strategies can be developed and differential treatment options based on gender or, even more specifically, based on gender and age, are not hard to imagine. Even today, there are examples of the widespread use of gender-specific preventive strategies, such as the global push to have women of reproductive age take supplementary folate to help reduce the risk of neural tube defects in their children. Continuing to explore the scientific evidence for gender-specific disease incidence and manifestations can only lead to further breakthroughs in disease prevention and treatment.

Further unexplored questions If disease incidence by gender varies within economically and geographically similar countries, a cultural element, such as the status of women in each of the countries, might be considered as well. This is an unexplored question.

References   1. Kurland LT, Hauser WA, Okazaki H, et al. Epidemiologic studies of Parkinsonism with special reference to the cohort hypothesis. Proceedings Symposium on Parkinson’s Disease. Edinburgh: E&S Livingstone; 1970.

  2. Ólafsson E, Hauser WA, Luovigsson P, et al. Incidence of epilepsy in rural Iceland. Epilepsia 1996;37:951–55.   3. Forsgren L. Prospective incidence study and clinical characterization of seizures in newly referred adults. Epilepsia 1990;31:292–301.   4. Forsgren L, Bucht G, Eriksson S, et al. Incidence and clinical characterization of unprovoked seizures in adults: a prospective population-based study. Epilepsia 1996;37:224–29.   5. Lipton RB, Stewart WF, Celentano DD, et al. Undiagnosed migraine headaches. A comparison of symptom-based and re­ported physician diagnosis. Arch Intern Med 1992;152:1273–78.   6. Grundman M, Donnenfeld H, Masdeu JC, et al. Do women with ALS present with more severe disease? Neurology 1992;42:3–16.   7. Hauser WA, Annegers JF, Elveback LR. Mortality in patients with epilepsy. Epilepsia 1980;21:399–412.   8. Ólafsson E, Hauser WA, Luovigsson P, et al. Incidence of epilepsy in rural Iceland. Epilepsia 1996;37:951–55.   9. Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979;20: 729–37. 10. Annegers JF, Appel S, Lee RJ, et al. Incidence and prevalence of amyotrophic lateral sclerosis in Harris County, Texas, 1985–1988. Arch Neurol 1991;48:590–94. 11. Rajput AH, Offord KP, Beard CM, et al. Epidemiology of Parkinsonism: incidence, classification, and mortality. Ann Neurol 1984;16:278–82. 12. Manolio TA, Kronmal RA, Burke GL, et al. Short term predictors of incident stroke in older adults. The Cardiovascular Health Study. Stroke 1996;27:1479–86. 13. Wolfe CDA, Corbin DOC, Smeeton NC, et al. Estimation of the risk of stroke in black populations in Barbados and South London. Stroke 2006;37:1986–90. 14. Medin J, Nordlund A, Ekberg K. Increasing stroke incidence in Sweden between 1989 and 2000 among persons aged 30 to 65 years: evidence from the Swedish hospital discharge register. Stroke 2004;35:1047–51. 15. Sacco RL, Boden-Albala B, Gan R, et al. and the Northern Manhattan Stroke Study Collaborators. Stroke incidence among white, black and hispanic residents of an urban community. Am J Epidemiology 1998;147:1–10. 16. Thrift AG, Dewey HM, Macdonell RA, et al. Stroke incidence on the east coast of Australia: the North East Melbourne Stroke Incidence Study (NEMESIS). Stroke 2000;31:2087–92. 17. Vemmos KN, Bots ML, Tsibouris PK, et al. Stroke incidence and case fatality in southern Greece: the Arcadia stroke registry. Stroke 1999;30:363–70. 18. Johansson B, Norrving B, Lindgren A. Increased stroke incidence in Kund-Orup, Sweden, between 1983 to 1985 and 1993 to 1995. Stroke 2000;31:481–86. 19. Kita Y, Okayama A, Ueshima H, et al. Stroke incidence and case fatality in Shiga, Japan 1989–1993. Int J Epidemiol 1999; 28:1059–65. 20. Lauria G, Gentile M, Fassetta G, et al. Incidence and prognosis of stroke in the Belluno province, Italy. First-year results of a community-based study. Stroke 1995;6:1787–93. 21. Czlonkowska A, Ryglewicz D, Weissbein T, et al. A prospective community based study of stroke in Warsaw, Poland. Stroke 1994;25:547–51.

C h a p t e r 1 0    Age and Gender-Specific Patterns of Neurologic Illness l

22. Nakayama T, Date C, Yokoyama T, et al. A 15.5-year followup study of stroke in a Japanese provincial city. The Shibata Study. Stroke 1997;28:45–52. 23. Iemolo F, Beghi E, Cavestro C, et al. Incidence, risk factors and short-term mortality of stroke in Vittoria, southern Italy. Neurol Sci 2002;23:15–21. 24. Anderson CS, Jamrozik KD, Burvill PW, et al. Determining the incidence of different subtypes of stroke: results from the Perth community Stroke Study, 1989–1990. Med J Aust 1993;158:85–89. 25. Jorgensen HS, Plesner AM, Hubbe P, et al. Marked increase of stroke incidence in men between 1972 and 1990 in Frederiksberg, Denmark. Stroke 1992;23:1701–4. 26. Jerntorp P, Berglund G. Stroke registry in Malmo, Sweden. Stroke 1992;23:356–61. 27. D’Alessandro G, Di Giovanni M, Roveyaz L, et al. Incidence and prognosis of stroke in the Valle d’Aosta, Italy: first year results of a community-based study. Stroke 1992;23:1712–15. 28. Ricci S, Celani MG, La Rosa F, et al. SEPIVAC: a communitybased study of stroke incidence in Umbria, Italy. J Neurol Neurosurg Psychiatry 1991;54:695–98. 29. Ward G, Jamrozik K, Stewart-Wynne E. Incidence and outcome of cerebrovascular disease in Perth, Western Australia. Stroke 1988;19:1501–6. 30. Giroud M, Gras P, Chadan N, et al. Cerebral haemorrhage in a French prospective population study. J Neurol Neurosurg Psychiatry 1991;54:595–98. 31. Terent A. Increasing incidence of stroke among Swedish women. Stroke 1988;19:598–603. 32. Bonita R, Beaglehole R, North JDK. Event, incidence and case fatality rates of cerebrovascular disease in Auckland, New Zealand. Am J Epidemiol 1984;120:236–43. 33. Oxfordshire Community Stroke Project. Incidence of stroke in Oxfordshire: first year’s experience of a community stroke register. Br Med J 1983;287:713–17. 34. Fullerton H, Wu Y, Zhao S, et al. Risk of stroke in children: ethnic and gender disparities. Neurology 2003;61:189–94. 35. Gostynski M, Engelter S, Papa S, et al. Incidence of first-ever ischemic stroke in the Canton Basle-City, Switzerland: a population based study 2002/2003. J Neurol 2006;253:86–91. 36. Sundquist K, Li X, Hemminki K. Familial risk of ischemic and hemorrhagic stroke: a large-scale study of the Swedish population. Stroke 2006;37:1668–73. 37. Kolominsky-Rabas PL, Weber M, Gefeller O, et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001;32:2735–40. 38. Tanizaki Y, Kiyohara Y, Kato I, et al. Incidence and risk factors for subtypes of cerebral infarction in a general population: the Hisayama study. Stroke 2000;31:2616–22. 39. Bamford J, Sandercock P, Dennis M, et al. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981–86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 1990;53:16–22. 40. Nilsson OG, Lindgren A, Stahl N, et al. Incidence of intra­ cerebral and subarachnoid hemorrhage in southern Sweden. J Neurol Neurosurg Psychiatry 2000;69:601–7.

125

41. Koffijberg H, Buskens E, Granath F, et al. Subarachnoid haemorrhage in Sweden 1987–2002: regional incidence and case fatality rates. J Neurol Neurosurg Psychiatry 2008;79:294–99. 42. Benn EK, Hauser WA, Shih T, et al. Estimating the incidence of first unprovoked seizure and newly diagnosed epilepsy in the low-income urban community of Northern Manhattan, New York City. Epilepsia (Epub ahead of print) 2008;Mar 10. 43. Olaffson E, Ludvigsson P, Gudmundsson G, et al. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol 2005;4:627–34. 44. Jallon P, Smadja D, Cabre P, et al. EPIMART: prospective incidence study of epileptic seizures in newly-referred patients in a French Caribbean island (Martinique). Epilepsia 1999;40:1103–9. 45. Annegers JF, Dubinsky S, Coan SP, et al. The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance organizations. Epilepsia 1999;40:502–6. 46. Õun A, Haldre S, Mägi M. Incidence of adult epilepsy in Estonia. Acta Neurol Scand 2003;108:245–51. 47. Ólafsson E, Hauser WA, Luovigsson P, et al. Incidence of epilepsy in rural Iceland. Epilepsia 1996;37:951–55. 48. Jallon P, Goumaz M, Haenggeli C, et al. Incidence of first epileptic seizures in the canton of Geneva, Switzerland. Epilepsia 1997;38:547–52. 49. Tekle-Haimamot R, Forsgren L, Ekstedt J. Incidence of epilepsy in rural central Ethiopia. Epilepsia 1997;38:541–46. 50. Lavados J, Germain L, Morales A, et al. A descriptive study of epilepsy in the district of El Salvador, Chile, 1984–1988. Acta Neurol Scand 1992;85:249–56. 51. Sidenvall R, Forsgren L, Blomquist HK, et al. A communitybased prospective incidence study of epileptic seizures in children. Acta Paediatr 1993;82:60–65. 52. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota, 1935–1984. Epilepsia 1993;34:453–68. 53. Annegers JF, Hauser WA, Lee JR-J, et al. Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935–1984. Epilepsia 1995;36:327–33. 54. Hauser WA, Annegers JF, Kurland LT. Prevalence of epilepsy in Rochester, Minnesota: 1940-1980. Epilepsia 1991;32:429–45. 55. Tsuboi T. Prevalence and incidence of epilepsy in Tokyo. Epilepsia 1998;29:103–10. 56. Govoni V, Fallica E, Monetti VC, et al. Incidence of status epilepticus in southern Europe: a population study in the health district of Ferrara, Italy. Eur Neurol 2008;59:120–26. 57. Chin RF, Neville BG, Peckham C, et al. NLSTEPSS Collaborative Group. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:222–29. 58. Knake S, Rosenow F, Vescovi M, et al. Status Epilepticus Study Group Hessen (SESGH). Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 2001;42:714–18. 59. Coeytaux A, Jallon P, Galobardes B, et al. Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR). Neurology 2000;55:693–97. 60. Hesdorffer DC, Logroscino G, Cascino G, et al. Incidence of status epilepticus in Rochester, Minnesota, 1965–1984. Neurology 1998;50:735–41.

126

s e c t i o n 2     Gender and the Nervous System l

61. Walczak TS, Leppik IE, D’Amelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology 2001;56:519–25. 62. Kukull WA, Higdon R, Bowen JD, et al. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 2002;59:1737–46. 63. Nitrini R, Caramelli P, Herrera E Jr, et al. Incidence of dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc Disord 2004;18:241–46. 64. Chandra V, Pandav R, Dodge HH, et al. Incidence of Alzheimer’s disease in a rural community in India: the IndoUS study. Neurology 2001;57:985–89. 65. Bermejo-Pareja F, Benito-Leon J, Vega S, et al. Neurological Disorders in Central Spain Study Group. Incidence and subtypes of dementia in three elderly populations of central Spain. J Neurol Sci 2008;264:63–72. 66. Kawas C, Gray S, Brookmeyer R, et al. Age-specific incidence rates of Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 2000;54:2072–77. 67. Andersen K, Launer LJ, Dewey ME, et al. Gender differences in the incidence of AD and vascular dementia: the EURODEM studies. EURODEM Incidence Research Group. Neurology 1999;53:1992–97. 68. Tyas SL, Tate RB, Wooldrage K, et al. Estimating the incidence of dementia: the impact of adjusting for subject attrition using health care utilization data. Ann Epidemiol 2006;16: 477–84. 69. Lavados J, Germain L, Morales A, et al. A descriptive study of epilepsy in the district of El Salvador, Chile, 1984–1988. Acta Neurol Scand 1992;85:249–56. 70. Edland SD, Rocca WA, Petersen RC, et al. Dementia and Alzheimer disease rates do not vary by sex in Rochester, Minnesota. Arch Neurol 2002;59:1589–93. 71. Kokmen E, Beard CM, O’Brien PC, et al. Is the incidence of dementing illness changing? A 25-year time trend study in Rochester, Minnesota (1960-1984). Neurology 1993;43:1887–92. 72. Brayne C, Gill C, Huppert FA, et al. Incidence of clinically diagnosed subtypes of dementia in an elderly population. Cambridge Project for Later Life. Br J Psychiat 1995;167:255–62. 73. Hebert R, Lindsay J, Verreault R, et al. Vascular dementia: incidence and risk factors in the Canadian Study of Health and Aging. Stroke 2000;31:1487–93. 74. Knopman DS, Rocca WA, Cha RH, et al. Incidence of vascular dementia in Rochester, Minnesota, 1985–1989. Arch Neurol 2002;59:1605–10. 75. Larrieu S, Letenneur L, Orgogozo JM, et al. Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology 2002;59:1594–99. 76. Solfrizzi V, Panza F, Colaccio AM, et al. Italian Longitudinal Study on Aging Working Group. Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 2004;63:1882–91. 77. Hader WJ, Yee IM. Incidence and prevalence of multiple sclerosis in Saskatoon, Saskatchewan. Neurology 2007;69: 1224–29. 78. Granieri E, Economou NT, De Gennaro R, et al. Multiple sclerosis in the province of Ferrara: evidence for an increasing trend. J Neurol 2007;254:1642–48.

79. Aladro Y, Alemany MJ, Perez-Vieitez MC, et al. Prevalence and incidence of multiple sclerosis in Las Palmas, Canary Islands, Spain. Neuroepidemiology 2005;24:70–75. 80. Alonso A, Jick SS, Olek MJ, et al. Incidence of multiple sclerosis in the United Kingdom: findings from a populationbased cohort. J Neurol 2007;254:1736–41. 81. Mayr WT, Pittock SJ, McClelland RL, et al. Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 1985-2000. Neurology 2003;61:1373–77. 82. Sundstrom P, Nystrom L, Forsgren L. Incidence (1988–97) and prevalence (1997) of multiple sclerosis in Vasterbotten County in northern Sweden. J Neurol Neurosurg Psychiatry 2003;74:29–32. 83. Barnett MH, Williams DB, Day S, et al. Progressive increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 35-year study. J Neurol Sci 2003;213:1–6. 84. Grimaldi LM, Salemi G, Grimaldi G, et al. High incidence and increasing prevalence of MS in Enna (Sicily), southern Italy. Neurology 2001;57:1891–93. 85. Salemi G, Ragonese P, Aridon P, et al. Incidence of multiple sclerosis in Bagheria City, Sicily, Italy. Neurol Sci 2000;21:361–65. 86. Nicoletti A, Lo Bartolo ML, Lo Fermo S, et al. Prevalence and incidence of multiple sclerosis in Catania, Sicily. Neurology 2001;56:62–66. 87. Rosati G, Aieloo I, Mannu L, et al. Incidence of multiple sclerosis in the town of Sassari, Sardinia, 1965 to 1985: evidence for increasing occurrence of the disease. Neurology 1988;38:384–88. 88. Hammond SR, McLeod JG, Millingen KS, et al. The epidemiology of multiple sclerosis in three Australian cities: Perth, Newcastle and Hobart. Brain 1988;111:1–25. 89. Granieri E, Rosati G, Tola R, et al. The frequency of multiple sclerosis in Mediterranean Europe. An incidence and prevalence study in Barbagia, Sardinia, insular Italy. Acta Neurol Scand 1983;28:84–89. 90. Lyngberg AC, Rasmussen BK, Jorgensen T, et al. Incidence of primary headache: a Danish epidemiologic follow-up study. Am J Epidemiol 2005;161:1066–73. 91. Rozen TD, Swanson JW, Stang PE, et al. Incidence of medically recognized migraine: a 1989-1990 study in Olmsted County, Minnesota. Headache 2000;40:214–16. 92. Stewart WF, Linet MS, Celentano DD, et al. Age- and sexspecific incidence rates of migraine with and without visual aura. Am J Epidemiol 1991;134:1111–20. 93. Stang PE, Yanagihara PA, Swanson JW, et al. Incidence of migraine headache: a population based study in Olmsted County, Minnesota. Neurology 1992;42:1657–62. 94. Argyriou AA, Polychronopoulos P, Papapetropoulos S, et al. Clinical and epidemiological features of motor neuron disease in south-western Greece. Acta Neurol Scand 2005;111:108–13. 95. Beghi E, Millul A, Micheli A, et al. Incidence of ALS in Lombardy, Italy. Neurology 2007;68:141–45. 96. Logroscino G, Beghi E, Zoccolella S, et al. Incidence of amyotrophic lateral sclerosis in southern Italy: a population based study. J Neurol Neurosurg Psychiatry 2005;76: 1094–98. 97. Plato CC, Garruto RM, Galasko D, et al. Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol 2003;157:149–57.

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  98. McGuire V, Longstreth WT Jr, Koepsell TD, et al. Incidence of amyotrophic lateral sclerosis in three counties in western Washington state. Neurology 1996;47:571–73.   99. Giagheddu M, Mascia V, Cannas A, et al. Amyotrophic lateral sclerosis in Sardinia, Italy: an epidemiologic study. Acta Neurol Scand 1993;87:446–54. 100. Bettoni L, Bazzani M, Bortone E, et al. Steadiness of amytrophic lateral sclerosis in the province of Parma, Italy, 1960–1990. Acta Neurol Scand 1994;90:276–80. 101. DeDomenico P, Malara CE, Marabello L, et al. Amyotrophic lateral sclerosis: an epidemiological study in the province of Messina, Italy 1976–1985. Neuroepidemiology 1988;7: 152–58, (as cited in Annegers JF, 1991 [ref.10]). 102. Salemi G, Fierro B, Arcara A. Cassata M, Castiglione MG, Savettieri G. Amyotrophic lateral sclerosis in Palermo, Italy:an epidemiological study. Ital J Neurol Sci 1989; 10:505–9. 103. Yoshida S, Mulder DW, Kurland LT, et al. Follow-up study on amyotrophic lateral sclerosis in Rochester, Minnesota:1925 through 1984. Neuroepidemiology 1986;5:61–70, (as cited in Annegers JF, 1991 [ref.10]). 104. Granieri E, Carreras M, Tola R, et al. Motor neuron disease in the province of Ferrara, Italy, in 1964–1982. Neurology 1988;38:1604–8, (as cited in Annegers JF, 1991 [ref.10]). 105. Murros R, Fogelholm R. Amyotrophic lateral sclerosis in middle Finland: an epidemiological study. Acta Neurol Scand 1983;67:41–47, (as cited in Annegers JF, 1991 [ref.10]). 106. Bracco L, Antuono P, Amaducci L. Study of epidemiological and etiological factors of amyotrophic lateral sclerosis in the province of Florence, Italy. Acta Neurol Scand 1979;60:112–24, (as cited in Annegers JF, 1991 [ref.10]). 107. Kahana E, Zilber N. Changes in the incidence of amyotrophic lateral sclerosis in Israel. Arch Neurol 1984;41:157– 60, (as cited in Annegers JF, 1991 [ref.10]). 108. Olivares L, San Estaban E, Alter M. Mexican ‘resistance’ to amyotrophic lateral sclerosis. Arch Neurol 1972;27:397– 402, (as cited in Annegers JF, 1991 [ref.10]). 109. Tan LC, Venketasubramanian N, Jamora RD, et al. Incidence of Parkinson’s disease in Singapore. Parkinsonism Relat Disord 2007;13:40–43. 110. de Lau LM, Giesbergen PC, de Rijk MC, et al. Incidence of parkinsonism and PD in a general population: the Rotterdam Study. Neurology 2004;63:1240–44. 111. Benito-Leon J, Bermejo-Pareja F, Morales-Gonzalez JM, et al. Incidence of Parkinson disease and parkinsonism in three elderly populations of central Spain. Neurology 2004;62: 734–41. 112. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157:1015–22. 113. Chen RC, Chang SF, Su CL, et al. Prevalence, incidence, and mortality of PD: a door-to-door survey in Ilan county, Taiwan. Neurology 2001;57:1679–86. 114. Mayeux R, Marder K, Cote LJ, et al. The frequency of idiopathic Parkinson’s disease among middle-aged and elderly Black, Hispanic and White men and women in New York City. Am J Epidemiol 1995;142:820–27. 115. Granieri E, Carreras M, Casetta I, et al. Parkinson’s disease in Ferrera, Italy 1967 through 1987. Arch Neurol 1991; 48:854–57.

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116. Zhang Z-X, Roman GC. Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepidemiology 1993;12:195–208. 117. Wender M, Pruchink D, Kowal P, et al. The epidemiology of parkinsonism in the Poznan region. Przegal Epidemiol 1989;43:150–55, (as cited in Zhang Z-X [ref.116]). 118. Rajput AH, Offorf KP, Beard CM, et al. Epidemiology of parkinsonism: incidence, classification, and mortality. Ann Neurol 1984;16:278–82, (as cited in Zhang Z-X [ref.116]). 119. Harada H, Nishikawa S, Takahashi K. Epidemiology of Parkinson’s disease in a Japanese city. Arch Neurol 1983; 40:151–54. 120. Marttila RJ, Rinne UK. Epidemiology of Parkinson’s disease in Finland. Acta Neurol Scand 1976;53:81–102, (as cited in Zhang Z-X. [ref.116]). 121. Wang Y, Shi Y, Wu S, He Y, Zhang B. The incidence and prevalence of Parkinson’s disease in the People’s Republic of China. Proceedings National Symp on Neurological Disease of Aging. Lushan, China, 1990:1. (as cited in Zhang Z-X, 1993[ref.116]) 122. Radhakrishnan K, Ahlskog E, Shelley A, et al. Idiopathic intracranial hypertension (pseudotumor cerebri). Descriptive epidemiology in Rochester, Minnesota: 1976–1990. Arch Neurol 1993;50:78–80. 123. Radhakrishnan K, Thacker AK, Bohlaga NH, et al. Epidemiology of idiopathic intracranial hypertension: a prospective and case-control study. J Neurol Sci 1993;116:18–28. 124. Govoni V, Granieri E, Manconi M, et al. Is there a decrease in Guillain–Barré syndrome incidence after bovine ganglioside withdrawal in Italy? A population-based study in the Local Health District of Ferrara, Italy. J Neurol Sci 2003;216:99–103. 125. Hughes RA, Charlton J, Latinovic R, et al. No association between immunization and Guillain–Barré syndrome in the United Kingdom, 1992 to 2000. Arch Intern Med 2006;166:1301–4. 126. Cuadrado JI, de Pedro-Cuesta J, Ara JR, et al. Public health surveillance and incidence of adulthood Guillain–Barré syndrome in Spain, 1998–1999: the view from a sentinel network of neurologists. Neurol Sci 2004;25:57–65. 127. Cheng Q, Wang DS, Jiang GX, et al. Distinct pattern of agespecific incidence of Guillain–Barré syndrome in Harbin, China. J Neurol 2002;249:25–32. 128. Emilia-Romagna Study Group on Clinical and Epidemiological Problems in Neurology. A prospective study in the incidence and prognosis of Guillain–Barré syndrome in Emilia-Romagna region Italy 1992–1993. Neurology 1997;48:214–21. 129. Govoni V, Granieri E, Casetta I, et al. The incidence of Guillain–Barré syndrome in Ferrara, Italy: is the disease really increasing? J Neurol Sci 1996;137:62–68. 130. Jiang GX, de Pedro-Cuesta J, Fredrikson S. Guillain–Barré syndrome in south-west Stockholm, 1973–1991. Quality of registered hospital diagnoses and incidence. Acta Neurol Scand 1995;91:109–17. 131. Radhakrishnan K, El-Manghoush A, Gerryo SE. Descriptive epidemiology of selected neuromuscular disorders in Benghazi, Libya. Acta Neurol Scand 1987;75:95–100. 132. Brandenberg N, Annegers JF. Incidence and risk factors for Bell’s palsy in Laredo, Texas.,1974–1982. Neuroepidemiology 1993;12:313–25.

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133. Katusic SK, Beard M, Wiederholt WC, et al. Incidence, clinical features and prognosis in Bell’s palsy, Rochester, Minnesota: 1968–1982. Ann Neurol 1986;20:622–27. 134. Hauser WA, Karnes WE, Annis J, et al. Incidence and prognosis of Bell’s palsy in the population of Rochester, Minnesota. Mayo Clinic Proc 1971;46:258–64. 135. CBTRUS. Statistical Report:Primary Brain Tumors in the United States, 1998-2002. Central Brain Tumor Registry of the United States: 2005. (www.cbtrus.org/reports/reprints.html) 136. Cordera S, Bottacchi E, D’Alessandro G, et al. Epidemiology of primary intracranial tumours in NW Italy, a population based study: stable incidence in the last two decades. J Neurol 2002;249:281–84. 137. McKinley BP, Michalek AM, Fenstermaker RA, et al. The impact of age and sex on the incidence of glial tumors in New York state from 1976 to 1995. J Neurosurg 2000;93:932–39. 138. D’Alessandro G, Di Giovanni M, Iannizzi L, et al. Epidemiology of primary intracranial tumors in the Valle d’Aosta (Italy) during the 6-year period 1986–1991. Neuro­ epidemiology 1995;14:139–46. 139. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004;64:6892–99. 140. Ahsan H, Neugat AI, Bruce JN. Trends in incidence of primary malignant brain tumors in USA 1981-1990. Int J Epidemiol 1995;24:1078–85. 141. Radhakrishnan K, Mokri B, Parisi JE, et al. The trends in incidence of primary brain tumors in the population of Rochester, Minnesota. Ann Neurol 1995;37:67–73. 142. Matsuda M, Dohi-Iijima N, Nakamura A, et al. Increase in incidence of elderly-onset patients with myasthenia gravis in Nagano Prefecture, Japan. Intern Med 2005;44:572–77. 143. Aragones JM, Bolibar I, Bonfill X, et al. Myasthenia gravis: a higher than expected incidence in the elderly. Neurology 2003;60:1024–26.

144. Zivadinov R, Jurjevic A, Willheim K, et al. Incidence and prevalence of myasthenia gravis in the county of the coast and Gorski kotar, Croatia, 1976 through 1996. Neuroepidemiology 1998;17:265–72. 145. Oopik M, Kaasik AE, Jakobsen J. A population based epidemiological study on myasthenia gravis in Estonia. J Neurol Neurosurg Psychiatry 2003;74:1638–43. 146. Emilia-Romagna Study Group on Clinical and Epidemiological Problems in Neurology. Incidence of myasthenia gravis in the Emilia-Romagna region: a prospective multicenter study. Neurology 1998;51:255–58. 147. Lavrnic D, Jarebinski M, Rakocevic-Stojanovic V, et al. Epidemiological and clinical characteristics of myasthenia gravis in Belgrade, Yugoslavia (1983–1992). Acta Neurol Scand 1999;100:168–74. 148. Christensen PB, Jensen TS, Tsiropoulos I, et al. Incidence and prevalence of myasthenia gravis in western Denmark:1975 to 1989. Neurology 1993;43:1779–83. 149. Somnier FE, Keiding N, Paulson OB. Epidemiology of myasthenia gravis in Denmark. A longitudinal and comprehensive population survey. Arch Neurol 1991;48:733–39. 150. Storm-Mathisen A. Epidemiology of myasthenia gravis in Norway. Acta Neurol Scand 1984;70:274–84. 151. Dewing P, Chiang CW, Sim H, et al. Direct regulation of adult brain function by the male-specfic factor SRY. Curr Biol 2006;16:415–20. 152. Sibug R, Kuppers E, Beyer C, et al. Genotype dependent sex differentiation of dopaminergic neurons in primary cultures of embryonic mouse brain. Brain Res Dev Brain Res 1996;93:136–42. 153. Xu J, Bisteche CM. Sex differences in brain expression of X- and Y-linked genes. Brain Res 2006;1126:50–55.

Chapter

11

Gender Differences in Stroke Rebecca F. Gottesman1, and Argye E. Hillis2 1 Assistant Professor of Neurology, The Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, USA 2 Professor of Neurology and Physical Medicine and Rehabilitation, The Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, USA

Introduction

risk factors (hypertension, diabetes, hyperlipidemia, and obesity),5 by some reports. More recent trends, however, have shown increasing rates of these risk factors in women, as well, likely in parallel to an increase in rates of obesity. Risk assessment is typically based on these standard risk factors, and in fact, most predictors of future cardiovascular or stroke risk were created using primarily male populations. The Framingham risk score, for instance, is felt to under­ estimate risk in women, perhaps due to their later age of onset of cardiovascular disease, compared to men.6 A risk score taking into account risk factors that appear to have a role in women, along with their effect sizes, has been created and validated: the Reynolds Risk Score is based on data from the Women’s Health Study.7

Stroke is a major cause of disability across the world. Despite the frequency and consequences of this disease, there is less research dedicated to the prevention and treatment of women with stroke than there is for men with stroke. Men and women appear to have distinct patterns of stroke risk across their lifespan: men tend to have more coronary disease than cerebrovascular disease, and the opposite is true for women. Thus, men and women may respond differentially to medications used to prevent stroke.

Gender differences in epidemiology of stroke

Gender differences in prevention of stroke

It is estimated that one in five women will have a stroke in her lifetime, whereas only one in six men will.1 This increased risk has been typically due to higher rates of stroke in the elderly (85 years) and in women during the childbearing years, associated with risks from pregnancy itself. In the past, men experienced stroke more frequently than did women in all other age groups.2 However, recent reports have suggested that stroke, and its associated vascular risk factors, have had a surge in prevalence, becoming more frequent in women than in men, even between 45 and 65 years of age.3 Women in clinical stroke programs tend to be older and to have more severe strokes than their male counterparts; in addition, they are less likely to be independent or to be able to walk unaided.4 These factors must be considered in any discussion of differences in outcome or disability resulting from stroke. Risk factors may differ, as well, based on gender. In the past, men have more frequently had the classic microvascular

Principles of Gender-Specific Medicine

Secondary prevention of stroke has an emphasis on treating risk factors that can be intervened upon (such as hyperlipidemia or hypertension), along with use of antiplatelet therapy, in most patients. There are standard goal levels for blood pressure and cholesterol, by which a patient’s individual values are compared to determine if preventive measures are adequate. Women seem to be less frequently treated according to these standard targets than are men.8,9

Aspirin Men and women have clearly distinct responses to aspirin when used for primary prevention of cardiovascular disease, which may reflect their untreated rates of disease: men have more myocardial infarctions than strokes, and women have

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more strokes than myocardial infarctions. The Women’s Health Study, published in 2005, demonstrated in almost 40 000 healthy women over 45 years of age that 100 mg of aspirin, taken every other day, reduced risk of stroke by 17%, but did not reduce risk of other cardiovascular disease endpoints, including myocardial infarction.10 In contrast, in a meta-analysis of trials that enrolled men, men who received aspirin for primary prevention were more likely to have a stroke (OR 1.13, 95% CI 0.96–1.33) and less likely to experience myocardial infarction.11 These differences do not seem to exist, or at least have not been measured, for secondary prevention of stroke. A combined analysis of the two large secondary prevention trials on the early use of aspirin, the Chinese Acute Stroke Trial and the International Stroke Trial, did demonstrate less protection from aspirin for recurrent stroke or death for women than for men, but this effect modification was not significant.12 Hormones affect platelet aggregation, and thus may mediate possible differences between aspirin’s effect in men versus women for secondary prevention. Testosterone activates platelet aggregation,13 whereas estrogen and/or progesterone inhibits platelet aggregation.14,15 Additionally, aspirin leads to further inhibition of ADP- and collageninduced platelet aggregation in men than in women.16 Other authors have described lack of inhibition of platelet reactivity in women, although most women in this study did fully suppress the COX-1 pathway, as should be the case with the use of aspirin.17 Aspirin’s inhibition of platelet aggregation in men may be due to an effect from testosterone. In a study of orchiectomized men, aspirin’s inhibitory effect is reduced, but when these men are given testosterone this inhibition is restored.18

Management of Hypertension In a meta-analysis of prior antihypertensive trials, women enrolled in existing trials were older than enrolled men and had higher baseline values of vascular risk factors (such as blood pressure and cholesterol level). Despite what might appear to be a higher risk, women were not noted to have a significant reduction in death or vascular endpoints other than stroke with treatment of hypertension, although this reduction was clearly present for men. However, both men and women had significant reductions in stroke, with the use of antihypertensives, with a 38% reduction in stroke for women and a 34% reduction for men, when compared with subjects treated with placebo.19 Guidelines for men and women are thus similar in recommendations for blood pressure control in the prevention of stroke.2,20

Management of Hyperlipidemia Statins have a clearly defined role in the secondary prevention of stroke. In a meta-analysis of earlier statin trials, the

combined reduction in stroke was 17% for subjects ran­ domized to statin therapy.21 The SPARCL trial showed a similar reduction (hazard radio 0.84 for fatal or nonfatal stroke) among individuals with a prior history of stroke or TIA.22 However, statin trials in particular have been criticized for their limited representation of women. As of 2004, only 25% of study participants in trials testing the role of statins were female.8 Thus, it is less clear what the role of statins is in stroke reduction in women, as compared to men. There is clearly a reduction in composite vascular endpoints in women (OR 0.80, 95% CI 0.71–0.91), in pooled data from randomized trials, but stroke alone was not reduced significantly in women on statins in this meta-analysis nor in other subgroup analyses of randomized or observational studies.23–25 In summary, the existing literature supports the use of statins for stroke prevention in general, and in men specifically, and there is evidence supporting the use of statins for cardiovascular disease prevention in women. There is no clear evidence, however, supporting the role of statins in stroke prevention in women.

Management of Diabetes Mellitus and the Metabolic Syndrome Diabetes has been found to be a more powerful predictor of overall cardiovascular risk in women than it is in men, according to analyses from the Framingham study. Its impact on stroke specifically, however, is equivalent in men and women.26 The metabolic syndrome, in addition, is an important predictor of stroke and other cardiovascular risk, and is a particular concern in American women. This syndrome, consisting of the combination of insulin resistance, abdominal girth, hypertension, and dyslipidemia, has had a relatively stable prevalence in American men (increasing by 2.2% from the late 1980s to the late 1990s). In contrast, the age-adjusted prevalence in women has jumped 23.5% over the same time period.8 It appears that the metabolic syndrome may differ in the mechanism by which it leads to atherosclerosis. Fan analyzed the relationships between components of the metabolic syndrome and carotid intima-media-thickness (IMT); for men, the strongest associations were found between central obesity and IMT, whereas for women, triglycerides were associated with progression of IMT. Both men and women in this analysis had strong associations between systolic blood pressure and IMT progression.27

Atrial Fibrillation Depending on the source, either men28 or women29 have higher rates of atrial fibrillation. There is agreement, however, that women appear to have a higher risk of stroke resulting from this arrhythmia.28,29 In the Renfrew/Paisley study, 30% of women with atrial fibrillation had a stroke, and their relative risk of stroke was 5.5 (95% CI 1.1–4.3).

C h a p t e r 1 1    Gender Differences in Stroke l

Men, in contrast, had a relative risk for stroke of only 2.1 (95% CI 1.1–4.3), and 17% of men with atrial fibrillation had strokes.30 This discrepancy in stroke rates is particularly true for those individuals who are not treated with anticoagulation. Women on aspirin or not fully anticoagulated had a 1.6 times higher risk of stroke in the SPAF trials (Stroke Prevention in Atrial Fibrillation) when compared with men on the same treatments.31 Because of the higher risk of stroke, the Framingham risk score adds additional points to an individual’s stroke risk with atrial fibrillation if she is female.32 As is the case with many other risk factors for stroke, women with atrial fibrillation (and especially elderly women) are often undertreated.28 They are less likely to be given anticoagulation, although the benefit from anticoagulation is even more apparent in women compared with men. In the ATRIA study, women on warfarin had a reduced RR for combined thromboembolic endpoints of 0.4 (95% CI 0.3–0.5), compared with 0.6 in men (95% CI 0.5–0.8).29

Gender Differences in Extracranial and Intracranial Arterial Disease Treatment recommendations for carotid stenosis differ in men and women. Men have been shown in multiple studies to have higher baseline carotid intima-media-thickness than do women.33,34 Carotid stenosis is also more prevalent in men than in women; 7–9% of men over 65 have at least 50% stenosis, compared with only 5–7% of women in the same age group.35,36 In addition, women have distinct responses to treatment of carotid disease. In pooled data from the NASCET (North American Symptomatic Carotid Endarterectomy Trial) and the ECST (European Carotid Surgery Trial) trials, men had the maximum surgical benefit, and women had 50% higher rates of perioperative stroke and death. The number needed to treat with surgery to prevent one ipsilateral stroke in a man was 9, based on this pooled data, compared with 36 in women.37 This difference between the genders is particularly noted when degree of stenosis is analyzed. Although men benefited from surgical treatment of symptomatic stenosis over 50%, women only had a significant risk reduction for stenosis over 70%. Moreover, timing of surgery is particularly important for women. Both genders benefit most if surgery is performed within 2 weeks of the last minor stroke or TIA. In women, however, the benefit disappears completely when surgery is done beyond 2 weeks.38 The differences between the genders remains in analyses of the asymptomatic carotid surgery trials. In the ACAS trial (Asymptomatic Carotic Atherosclerosis Study), men had a 66% relative risk reduction, compared with a nonsignificant 17% reduction in women. This is most likely due to the higher rates of perioperative complications in women (3.6% versus 1.7% in men).39 Although ACAS has been criticized for having particularly low perioperative complication rates,

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even other studies with more standard complication rates have found this gender difference.40 Size of the vessels is one of the proposed explanations as to why women have worse surgical outcomes than men in these carotid studies. In the WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease), women in the trial had an 85% greater risk of stroke, despite having similar rates of high-grade stenosis to the men in the trial.41 However, in an autopsy series of patients with fatal stroke, men had higher rates of intracranial stenosis than did women.42

Inflammation and Stroke Carotid artery disease has been studied extensively as a representation of systemic atherosclerotic disease, and thus some analyses on gender differences in the development of atherosclerosis have been based on differences in carotid IMT progression. For instance, recent theories have included a critical role of inflammation in the development of atherosclerosis. This may partially explain positive associations between C-reactive protein (CRP) and cardiovascular disease. In the INVADE study, high-sensitivity CRP was a significant predictor of carotid IMT progression in women, but not in men. IMT progression was similar across all quartiles of C-reactive protein for men, but there was an almost three-fold increase in IMT progression in women in the upper quartile when compared to women with CRP levels in the lowest quartile.33 Thus, women may be more susceptible to effects from chronic inflammation. In the Framingham Offspring Cohort, elevated CRP levels were particularly associated with the presence of the metabolic syndrome in women,43 so this (particularly by increasing insulin resistance) could be a potential mechanism by which inflammation leads to increased atherosclerosis. Chronic inflammation in women could mitigate the protective effect of endogenous estrogens on insulin resistance.44

Gender differences in acute treatment of stroke Evaluation of stroke tends to be less thorough in women. Whereas a standard workup for etiology of stroke was completed in 80% of men experiencing first-time stroke, only 67% of women had the same complete workup.45 Perhaps because of differences in distribution of stroke risk factors, men have atherothrombotic and lacunar strokes more frequently than women, whereas women are more likely to have cardioembolic strokes.45 Acute management of stroke differs in men compared with women; this may reflect differences in awareness about stroke (and delays in arrival to the emergency department, for instance), or may reflect differences in physician decisionmaking about stroke management. Among patients who were tPA eligible, only 8.8% of women received tPA, compared

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with 17.9% of men, in one stroke registry.46 Other authors have also reported lower rates of use of thrombolysis in women presenting with ischemic stroke.4,47 In a survey in which subjects were presented with hypothetical scenarios, women were less likely than men to accept thrombolytic therapy in a hypothetical acute ischemic stroke scenario (79% of women compared with 86% of men, p  0.014).48 Although the evidence is fairly consistent that women receive IV tPA less often than their male counterparts, the data on the outcomes resulting from tPA treatment are inconsistent. This may reflect the type of studies in which this question has been assessed. In a clinical population, recanalization of thrombosed vessels was more common in women among a small series of subjects who received IV tPA (94% of women recanalized, compared with 59% of men).49 This could be because of differences in selection of potential tPA candidates, or perhaps due to gender differences in vessel size or in differences in coagulation and fibrinolysis, or due to the greater proportion of embolic strokes in women. In contrast, in a study population (in whom everyone who met the inclusion criteria received IV tPA), men were nearly 3 times as likely to have good functional outcomes as were women,50 a difference that could be explained by the larger number of embolic strokes in women, which are more likely to bleed after recanalization. Another pooled analysis of randomized trial data, however, failed to show as much benefit in men.51 Similar confusion exists in the literature on outcomes after intra-arterial tPA; it has been reported both that men and women have similar outcomes52 and that women with middle cerebral artery strokes, in particular, have more benefit from intra-arterial tPA.53

Gender differences in stroke symptoms and recovery from stroke Some of the observed differences in stroke symptoms in men compared to women may be explained by different types of strokes; as stated above, women are more likely to have cardioembolic strokes and men are more likely to have lacunar strokes. This pattern may change as risk factors for small vessel ischemic disease become more prevalent in women, and at younger ages. However, there may be differences in localization of some functions, as well. In a functional imaging study, women were found to have more bilateral representation of language than men.54 In an epidemiologic study, women experienced aphasia more than men, but this difference went away after adjusting for stroke mechanism.55 Embolic strokes (which are more frequent in women) are much more likely to cause aphasia than are lacunar strokes (more frequent in men). Ringman reported similar rates of neglect, a frequent consequence of right hemispheric cortical stroke, among men

and women with ischemic stroke.56 In contrast, McGlone did find that women had higher incidence of neglect after acute ischemic stroke.57 In our experience, when right-handed patients were studied acutely after right hemisphere ischemic stroke with multiple tests of neglect, we failed to find any gender differences in neglect severity or prevalence.58 Women have more disability as a consequence of stroke than men do.45,59 In 270 stroke survivors in a national registry, women had lower odds (adjusted OR 0.37) of achieving independence in performing activities of daily living as their male counterparts, even after adjustment for age and other potential confounders.59 Other authors have reported similar findings, with lower rates of independence in women, both for physical tasks such as stair climbing and for performing activities of daily living.60 This may be in part because of some differences in treatment in women compared with men (as discussed above),61 but these differences are not so significant to cause this much variability. Quality of life is also worse in female stroke survivors, independent of stroke severity or age.62 In the Copenhagen Stroke Study, men were more likely to die sooner after a stroke.63 However, in the International Stroke Trial, female gender was an independent predictor of death or dependency at six months, and women had higher 14–day and 6–month case fatality rates.64 The consensus of most of the existing literature is that women have worse outcomes after stroke, which may be a partial reflection of their advanced age, as compared to men, when they typically have strokes.

Gender differences in mechanism of stroke Estrogen as a Neuroprotectant In animal models, estrogen functions both as a neuroprotectant and as an antiatherogenic.5 This is demonstrated in population studies because of the lower rates of stroke in premenopausal women, and the rapid rise in stroke after menopause, as estrogen levels decline. The neuroprotective role is also demonstrated in vivo in animal studies: female rats have smaller strokes when given the same insult as male rats. However, when female rats are ovariectomized, their strokes are equivalent in size to those in the male rats.65 In animal studies, use of estrogen, even in male rats, has led to decreased stroke size in a middle cerebral artery occlusion model of stroke. This appears independent of testosterone availability.66 However, in the Honolulu-Asia Aging Study, elderly men with higher estradiol levels had higher rates of stroke, where testosterone levels were not associated with stroke risk.67 In addition to its neuroprotective mechanisms, estrogen acts directly to decrease lipids, decreasing atherogenesis. In addition, it decreases atherosclerosis formation by vasodilation and inhibition of a vessel’s response to vascular injury, as well as via antioxidant mechanisms.68

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Because the focus of this chapter is gender differences in stroke prevention, treatment, and recovery, we have not emphasized specific circumstances leading to stroke in women. They do require a brief review, however, in any discussion of neuroprotection by estradiol. Women are at increased risk for stroke due to variation in endogenous estrogen levels; this includes pregnancy, when levels remain consistently elevated but drop before delivery (and most cerebrovascular problems occur in the peri- or postpartum period), or during menopause when estradiol levels drop.69 In addition, exogenous estrogen use has been associated with risk for stroke. Case-control studies have supported an association between oral contraceptive pills and stroke,2,5 particularly with higher estrogen dose formulations.69 Exogenous estrogen use in the form of hormone replacement therapy (HRT) for postmenopausal women is also associated with increased risk of stroke. Earlier observational studies suggested that HRT was actually preventive of cardiovascular disease.70 With the publication of the randomized Women’s Health Initiative trial, however, it was shown that the combination of estrogen plus progestin increased risk of cardiovascular disease and stroke, when compared to placebo. The hazard ratio for combined hemorrhagic and ischemic strokes was 1.33 (95% CI 1.02–1.68) in women who were on the estrogen replacement.71 The WEST Study (Women’s Estrogen for Stroke Trial) showed similar results, showing that estrogen for secondary prevention increased risk of fatal stroke and did not effect risk of nonfatal stroke.72 The laboratory data supporting the role of estrogen as a neuroprotectant and antiatherogenic appears in direct contrast with clinical trial data. This may reflect inappropriate timing of the estrogen administration, or inadequate dosing or route of administration. The apparent contradiction might also reflect different balances between positive effects (antiatherogenic and neuroprotective) and negative effects (prothrombotic) of estrogen. Because women have increased risk of embolic strokes, the prothrombotic effect may be particularly detrimental for women. This difference might not be apparent in rodent models which do not account for cardioembolic stroke as a potential mechanism of injury. Further studies may help identify whether there are particular circumstances in which the use of estrogen still has a role for neuroprotection in the clinical realm.

Other Differences in Mechanism of Stroke in Men Compared to Women Men and women have been noted to have other differences, physiologically and biochemically, that may lead to differences in stroke mechanism or recovery. Sex differences in cell death pathways have been described in laboratory animals.73 In addition, heritability of stroke may differ in men and women; in a set of Oxford stroke cohorts, women were more likely than men to have a parental history of stroke (which was primarily maternal).74

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Suggestions for future investigations The results of the Women’s Health Study regarding aspirin therapy for primary prevention have clearly demonstrated that men and women differ in response to standard medications used in stroke prevention. Future studies are needed specifically in female populations, to determine if medications, such as statins, are as effective in women, who tend to have different stroke mechanisms than in men and who have intrinsic reduction of lipids in the presence of estradiol. In addition, there are still some unanswered questions regarding the use of hormone replacement therapy in postmenopausal women. Continued laboratory-based research on the mechanisms of estrogen’s neuroprotective effect are needed, as these may lead to the development of future neuroprotective agents that can successfully be translated from the bench to the bedside. The differences in rates of thrombolysis in women compared with men are concerning, and future studies and interventions should involve education, geared toward women in particular, about stroke and the importance of coming to the hospital as soon as possible after stroke symptom onset. The gender differences in outcome after stroke also require ongoing research. Women have worse outcomes after stroke, so future investigations should emphasize rehabilitation therapies specifically geared towards women.

References   1. Seshadri S, Beiser A, Kelly-Hayes M, et al. The lifetime risk of stroke: estimates from the Framingham study. Stroke 2006;37(2):345–50.   2. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke 2006;37(6):1583–633.   3. Towfighi A, Saver JL, Engelhardt R, et al. A midlife stroke surge among women in the United States. Neurology 2007;69:1898–904.   4. Reid JM, Dai D, Gubitz GJ, et al. Gender differences in stroke examined in a 10-year cohort of patients admitted to a Canadian teaching hospital. Stroke 2008;39(4):1090–1095.   5. Egido J-A, de Lecinana MA. Peculiarities of stroke risk in women. Cerebrovasc Dis 2007;24(Suppl 1):76–83.   6. Wenger NK. The Reynolds Risk Score: improved accuracy for cardiovascular risk prediction in women? Nature Clin Pract Cardiovas Med 2007;4:366–67.   7. Ridker PM, Buring JE, Rifai N, et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007;297(6):611–19.

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  8. Wenger NK. Preventing cardiovascular disease in women: an update. Clin Cardiol 5 September, 2008;31(3):109–113.   9. Wexler DJ, Grant RW, Meigs JB, et al. Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes. Diabetes Care 2005;28(3):514–20. 10. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352(13): 1293–304. 11. Berger JS, Roncaglioni MC, Avanzini F, et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006;295(3):306–13. 12. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40,000 randomized patients from the Chinese Acute Stroke Trial and the International Stroke Trial. Stroke 2000;31(6):1240–49. 13. Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 1995;91:2742–47. 14. Feuring M, Christ M, Roell A, et al. Alterations in platelet function during the ovarian cycle. Blood Coagul Fibrinolysis 2002;13(5):443–47. 15. Roell A, Schueller P, Schultz A, et al. Effect of oral contraceptives and ovarian cycle on platelet function. Platelet 2007;18(2):165–70. 16. Nakayasu H, Maeda M, Soda T, et al. The antiplatelet aggregation effects of aspirin suppositories. Cerebrovasc Dis 2003;16(1):31–35. 17. Becker DM, Segal J, Vaidya D, et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. JAMA 2006;295(12):1420–27. 18. Spranger M, Aspey BS, Harrison MJ. Sex difference in antithrombotic effect of aspirin. Stroke 1989;20(1):34–37. 19. Gueyffier F, Boutitie F, Boissel JP, et al. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men: a meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann Intern Med 1997;126(10):761–67. 20. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115(11):1481–501. 21. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Br Med J 2003;326(7404):1423. 22. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorva­ statin after stroke or transient ischemic attack. N Engl J Med 2006;355:549–59. 23. Hague W, Forder P, Simes J, et al. Effect of pravastatin on cardiovascular events and mortality in 1516 women with coronary heart disease: results from the long-term intervention with pravastatin in ischemic disease (LIPID) study. Am Heart J 2003;145(4):643–51. 24. Walsh JM, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004;291(18):2243–52. 25. Herrington DM, Vittinghoff E, Lin F, et al. Statin therapy, cardiovascular events, and total mortality in the Heart and

26. 27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

Estrogen/Progestin Replacement Study (HERS). Circulation 2002;105(25):2962–67. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241(19):2035–38. Fan AZ. Metabolic syndrome and progression of atherosclerosis among middle-aged US adults. J Atheroscler Thromb 2006;13:46–54. Lip GYH, Watson T, Shantsila E. Anticoagulation for stroke prevention in atrial fibrillation: is gender important? Eur Heart J 2006;27:1893–94. Fang MC, Singer DE, Chang Y, et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study. Circulation 2005;112(12):1687–91. Stewart S, Hart CL, Hole DJ, et al. A population-based study of the long-term risks associated with atrial fibrillation: 20year follow-up of the Renfrew/Paisley study. Am J Med 2002;113(5):359–64. Hart RG, Pearce LA, McBride R, et al. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke 1999;30(6):1223–29. Wang TJ, Massaro JM, Levy D, et al. A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community. JAMA 2003;290:1049–56. Sander K, Horn CS, Briesenick C, et al. High-sensitivity Creactive protein is independenty associated with early carotid artery progression in women but not in men: the INVADE Study. Stroke 2007;38(11):2881–86. Howard G, Sharrett AR, Heiss G, et al. Carotid artery intimalmedial thickness distribution in general populations as evalu­ ated by B-mode ultrasound. ARIC Investigators. Stroke 1993;24(9):1297–304. Fine-Edelstein JS, Wolf PA, O’Leary DH, et al. Precursors of extracranial carotid atherosclerosis in the Framingham Study. Neurology 1994;44(6):1046–50. O’Leary DH, Polak JF, Kronmal RA, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. Stroke 1992;23(12):1752–60. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet 2004;363(9413):915–24. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Sex difference in the effect of time from symptoms to surgery on benefit from carotid endarterectomy for transient ischemic attach and nondisabling stroke. Stroke 2004;35(12):2855–61. Executive Committee for the Asymptomatic Carotid Athero­ sclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273(18):1421–28. Goldstein LB, Samsa GP, Matchar DB, et al. Multicenter review of preoperative risk factors for endarterectomy for asymptomatic carotid artery stenosis. Stroke 1998;29:750–53. Williams JE, Chimowitz MI, Cotsonis GA, et al. Gender differences in outcomes among patients with symptomatic intracranial arterial stenosis. Stroke 2007;38(7):2055–62. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke 2009;40(3):713–718.

C h a p t e r 1 1    Gender Differences in Stroke l

43. Rutter MK, Meigs JB, Sullivan LM, et al. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham offspring study. Circulation 2004; 110(4):380–85. 44. Nakanishi N, Shiraishi T, Wada M. C-reactive protein concentration is more strongly related to metabolic syndrome in women than in men. The Minoh study. Circulation J 2005; 69:386–91. 45. Roquer J, Rodriguez Campello A, Gomis M. Sex differences in first-ever acute stroke. Stroke 2003;34:1581–85. 46. Deng YZ, Reeves MJ, Jacobs BS, et al. IV tissue plasminogen activator use in acute stroke: experience from a statewide registry. Neurology 2006;66:306–12. 47. Lisbeth LD, Brown DL, Morgenstern LB. Barriers to intravenous tissue plasminogen activator for acute stroke therapy in women. Gender Med 2006;3(4):270–78. 48. Kapral MK, Devon J, Winter A-L, et al. Gender differences in stroke care decision-making. Med Care 2006;44(1):70–80. 49. Savitz SI, Schlaug G, Caplan L, et al. Arterial occlusive lesions recanalize more frequently in women than in men after intravenous tissue plasminogen activator administration for acute stroke. Stroke 2005;36:1447–51. 50. Elkind MS, Prabhakaran S, Pittman J, et al. Sex as a predictor of outcomes in patients treated with thrombolysis for acute stroke. Neurology 2007;68(11):842–48. 51. Kent DM, Price LL, Ringleb P, et al. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke 2005;36(1):62–65. 52. Shah SH, Liebeskind DS, Saver JL, et al. Influence of gender on outcomes after intra-arterial thrombolysis for acute ischemic stroke. Neurology 2006;66:1745–46. 53. Hill MD, Kent DM, Hinchey J, et al. Sex-based differences in the effect of intra-arterial treatment of stroke: analysis of the PROACT-2 study. Stroke 2006;37(9):2322–25. 54. Shaywitz BA, Shaywitz SE, Pugh KR, et al. Sex differences in the functional organization of the brain for language. Nature 1995;373:607–9. 55. Hier DB, Yoon WB, Mohr JP, et al. Gender and aphasia in the Stroke Data Bank. Brain Language 1994;47(1):155–67. 56. Ringman JM, Saver JL, Woolson RF, et al. Frequency, risk factors, anatomy, and course of unilateral neglect in an acute stroke cohort. Neurology 2004;63:468–74. 57. McGlone J, Losier BJ, Black SE. Are there sex differences in hemispatial visual neglect after unilateral stroke? Neuropsychiatry Neuropsychol Behav Neurol 1997;10(2): 125–34. 58. Kleinman JT, Gottesman RF, Davis C, et al. Gender differences in unilateral spatial neglect within 24 hours of stroke. Brain Cogn 2008;68(1):49–52.

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59. Gargano JW, Reeves MJ. Paul Coverdell, National Acute Stroke Registry Michigan Prototype Investigators. Sex differences in stroke recovery and stroke-specific quality of life: results from a statewide stroke registry. Stroke 2007;38(9):2541–48. 60. Paolucci S, Bragoni M, Coiro P, et al. Is sex a prognostic factor in stroke rehabilitation? A matched comparison. Stroke 2006;37(12):2989–94. 61. Gargano JW, Wehner S, Reeves M. Sex differences in acute stroke care in a statewide stroke registry. Stroke 2008;39:24–29. 62. Gray LJ, Sprigg N, Bath PM, et al. Sex differences in quality of life in stroke survivors: data from the Tinzaparin in Acute Ischemic Stroke Trial (TAIST). Stroke 2007;38(11):2960–64. 63. Anderson MN, Anderson KK, Kammersgaard LP, et al. Sex differences in stroke survival: 10-year follow-up of the Copenhagen Stroke Study Cohort. Stroke 2005;14(5):215–20. 64. Niewada M, Kobayashi A, Sandercock PA, et al. Influence of gender on baseline features and clinical outcomes among 17,370 patients with confirmed ischaemic stroke in the international stroke trial. Neuroepidemiology 2005;24(3):123–28. 65. Alkayed NJ, Harukuni I, Kimes AS, et al. Gender-linked brain injury in experimental stroke. Stroke 1998;29(1):159–65. 66. Toung TJK, Traytsman RJ, Hurn PD. Estrogen-mediated neuroprotection after experimental stroke in male rats. Stroke 1998;29:1666–70. 67. Abbott RD, Launer LJ, Rodriguez BL, et al. Serum estradiol and risk of stroke in elderly men. Neurology 2007;68(8):563–68. 68. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801–11. 69. Bushnell CD. Stroke and the female brain. Nature Clin Pract Neurol 2008;4(1):22–33. 70. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133(12):933–41. 71. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003;289(20):2673–84. 72. Viscoli CM, Brass LM, Kernan WN, et al. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243–49. 73. McCullough LD, Zeng Z, Blizzard KK, et al. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 2005;25:502–12. 74. Touze E, Rothwell PM. Sex differences in heritability of ischemic stroke: a systematic review and meta-analysis. Stroke 2008;39(1):16–23.

C hapter

12

Gender Differences in Disorders that Present to Psychiatry Mary V. Seeman Professor Emerita of Psychiatry, University of Toronto, Department of Psychiatry, Toronto, Ontario, Canada

Introduction

10 to 1 in clinic samples but only 3 to 1 in the community. This suggests that boys suspected of suffering from ADHD are more often referred to specialized clinics than are girls, either because the syndrome is more easily identifiable in boys or because boys are more disruptive at home and in school and are, therefore, referred more readily. Girls, twice as often as boys, are diagnosed with the primarily ‘inattentive’ form of the disorder, more difficult to ascertain. In addition, girls suffer less often from co-morbid conditions such as behavior disorders, major depression, and learning disabilities, which may be another reason why boys are more likely to be referred. But community ADHD populations (without gender difference in subtype or in comorbidities) still show a large 3/1 discrepancy between boys and girls, a finding that requires explanation.4 Sex-linked genetic factors are an unlikely explanation since familial transmission patterns of ADHD in boys and girls are identical.5 And if a protective factor existed in girls (a feminized brain for instance), one would expect more of a family history of ADHD among relatives of girls, i.e. more familial factors to overcome the inherent protection. This possibility has been investigated and is not present.

Rutter and colleagues have stated that ‘the systematic investigation of sex differences constitutes an invaluable tool for the study of the causal processes concerned with psychopathology.’1 At present, relatively little is certain about the mechanisms that underlie such differences but it is important to test plausible hypotheses because they may, as Rutter et al. suggest, lead to better understanding of the causes of mental illnesses. This chapter will review selective and generally acknowledged gender differences in psychiatric diseases of childhood, adulthood, and old age, and will discuss possible mechanisms.

Child psychiatry Age is a key factor in predicting gender ratios in psychopathology. In child mental health services, the patients are mostly male. Boys suffer more than girls from autism and related disorders, hyperactivity syndromes, learning disabilities, dyslexias, stuttering, tic disorders, conduct disorders, and also from depressive and anxiety syndromes, especially phobias. Somatic stress symptoms occur more frequently in boys; boys do less well academically in the earlier grades and, overall, display more troublesome behavior than girls do.2

Autism Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions that show a marked male preponderance, with a gender ratio in the range of 4:1 to 7:1. The gender discrepancy is highest in higher functioning individuals whose IQ is in the normal or only mildly retarded range (20% of ASD patients). In contrast to this, when autism is accompanied by severe mental retardation, the gender ratio is 1:1. In other words, girls with ASD tend to be severely retarded. The family loading is slightly, but

Attention Deficit Hyperactivity Disorder (ADHD) Of US children aged 8–15 years, 8.7%, an estimated 2.4 million, meet DSM-IV criteria for ADHD.3 The male/ female ratio in ADHD depends on whether one looks at samples from the community or from the clinic. The ratio is Principles of Gender-Specific Medicine

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significantly, higher when autism is accompanied by severe retardation, the phenotype in family members showing itself as academic difficulty. Males also predominate among affected relatives. This suggests a protective factor operative in females.6 One explanatory hypothesis is the ‘extreme male brain’ theory. This theory proposes that autism represents an extreme of the general male pattern: impaired empathizing (ability to infer and appropriately respond to the emotional states of others) and enhanced systemizing (ability to infer deterministic rules of behavior of nonhuman systems). It suggests that the behaviors seen in autism are an exaggeration of typical sex differences attributable perhaps to high levels of prenatal testosterone.7 A corollary is that the neuro­ anatomy of autism represents extremes of male neuroanatomy.8 Some adult patterns of cerebral sexual dimorphism are present at birth; others develop after birth.9 Human total brain size is consistently reported to be approximately 8–10% larger in males, although consensus on regionally specific differences is weak. Using magnetic resonance imaging in 387 subjects, robust male/female rain differences have been found, with total cerebral volume peaking at age 10.5 in females and 14.5 in males. White matter steadily increases between age 3 and 27, with males having a steeper rate of increase during adolescence. Both cortical and subcortical gray matter trajectories follow an inverted U-shaped path with peak sizes 1–2 years earlier in females.10 It has long been assumed that gender differences primarily arise from hormonal masculinization of the male brain (and, to a lesser extent, hormonal feminization of the female brain) during fetal life. Neonatal testes produce androgens that are partly converted to estradiol in the neonatal brain. Males are thus exposed to both testosterone and estradiol, whereas females are not exposed to high concentrations of either hormone until puberty. While gonadal hormones must play an important role in sexual differentiation of the brain, there are other possible mechanisms that need to be considered.11 There is evidence, for instance, of relatively specific effects of X-linked genes on intelligence, social cognition and emotional regulation.12 While male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance of autism, the X chromosome remains a fertile area of inquiry. Of interest is the fact that 30% of individuals with Fragile X Syndrome (FXS) fall within the autistic spectrum, and recent epidemiologic studies have documented rates of FXS between 7% and 8% in populations with autism.13 While not the only genes involved, X linked genes may nevertheless play a part in autism since data from whole-genome screens in multiplex autism families suggest interactions of at least 10 genes.14,15 Skewing of X chromosome inactivation could be contributory. While most genes on one X chromosome are silenced as a result of X-chromosome inactivation, many (approximately 20%) human X-linked genes outside the

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X–Y pairing pseudoautosomal regions escape X-inactivation, leading to dosage increases in the expression of these genes. Such genes are potential contributors to sexually dimorphic traits and have been reported in girls with autism and in 50% of their mothers.16 The expression of several X genes that have escaped inactivation have been found to be higher in brain tissues from females compared to males.17,18 The imprinted-X liability threshold model hypothesizes that the threshold for phenotypic expression of many autistic characteristics is influenced by protective imprinted X-linked genes. These genes are expressed only on the X-chromosome that is inherited from the father (the one boys don’t have) and raises the threshold for phenotypic expression.19 Studies in Turner’s syndrome patients support this hypothesis. Turner syndrome girls have only one X chromosome. When that chromosome comes from the father, the girls are relatively better adjusted, with superior verbal and higher-order executive function skills.20 Puberty is a time when increasing levels of gonadal steroids activate the neural circuits first organized during perinatal development, and it also serves as a second ‘critical period’ of rewiring of the Central Nervous System, in preparation for adulthood.21 The adolescent brain undergoes remarkable changes in both structure and function, with a prolonged reaction to stressors relative to childhood and adulthood. It is not yet clear whether stress experienced during adolescence leads to altered physiological and behavioral potential in adulthood especially in response to stress.22,23 Sex differences in hypothalamic-pituitary-adrenal (HPA) function emerge over adolescence with stressor-specific and sex-specific behavioral responses to challenge.24,25 There are also consistent differences across phases of the menstrual cycle, menopausal stages and pregnancy and the postpartum.26 Pregnancy is associated with an attenuated response of the sympathoadrenal and HPA systems to stress, thus protecting the fetus from undue exposure to glucocorticoids.

Adult psychiatry With puberty, the preponderance of male psychopathology reverses.27 After adolescence, virtually all the major psychiatric disorders (substance abuse, schizophrenia, and impulse control disorders are the exceptions) become substantially more prevalent in women than in men.

Depression/Anxiety A recent European prevalence study of mental disorders (ESEMeD) as defined by DSM-IV, recently found 14% of the population had a lifetime history of a mood disorder, 13.6% of an anxiety disorder, and 5.2% of an alcohol disorder. Major depression and specific phobia were the most common single mental disorders reported. There was considerable overlap or co-morbidity between depressive and

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anxiety symptoms. Women were twice as likely to suffer mood and anxiety disorders as men, while men were more likely to report alcohol abuse disorders. While women are more likely to acknowledge and seek help for psychological symptoms, this does not account for the gender ratio.28 In the STAR*D study (1500 outpatients with major depressive disorder), women had a younger age at onset of the first major depressive episode than men and commonly reported concurrent symptoms consistent with anxiety disorders, somatoform disorder, and bulimia as well as atypical symptoms (e.g., hypersomnia, hyperphagia).29 Mental disorders are more common in the unemployed. The relative economic disadvantage of women in relation to men is undoubtedly contributory since the rate of all mental illnesses rises sharply in the context of poverty and economic hardship.30 Friendship networks (larger in women than in men), in theory, buffer stress. On the other hand, women more than men pay the ‘price of caring,’ their extended social circles positioning them in proximity to large numbers of individuals they identify with, large numbers of individuals whose personal problems become their own.31 As a subset of social agents, family members have long been suspect in their role as both triggers and buffers of psychiatric symptoms. Family ties are perceived and experienced differently by men and women. Marriage, for instance, has repeatedly been found to shield men against psychiatric disease; the opposite, intriguingly, is true for women.32 Marriage paradoxically puts women’s mental health at risk perhaps because women, in general, act as caretakers of spouses, children, and aging parents so that the emotional burdens of family life weigh proportionally more on their shoulders. Men try to cope by increasing their sports activity and consumption of alcohol (which puts them more at risk for substance abuse disorders) while women develop sleep and general health problems as a result of stress.33 Sex-specific genes may contribute to differences in depression and anxiety but, alone, they do not explain gender differences in vulnerability to illness. A complex interaction must exist between genes and environment. Genetic endowment elicits and shapes a person’s environment (the nature of nurture) while experience and learning modulates gene expression (the nurturing of nature).34 Exposure to overwhelmingly stressful life events has been postulated as the medium through which genetically vulnerable individuals develop psychiatric disease. Such stressful life events may result from the accident of being born into economic disadvantage, especially during a period of social upheaval. Alternatively, a difficult temperament, shaped by genes and early experience, can make stress happen. It is currently thought that physical and sexual abuse in children (sexual abuse being more prevalent in girls) is an especially important risk factor for adult emotional impairment.35 Gender-specific hormonal effects play an important role in gender differences in adult psychopathology. Gonadal steroid receptors are expressed in areas of the cerebral cortex that

mediate cognition and affect and the female hormone, estrogen, is known to regulate neuronal function in a number of important ways, essentially to prevent cell death and to promote growth of cell connections and, thus, to enhance neural communication.36 It is hypothesized that a subgroup of corticotropinreleasing hormone (CRH) neurons that projects into the brain is activated in depression leading to the release of glucocorticoids from the adrenal glands and inducing symptoms. Organizing effects of sex hormones during fetal life and during puberty may predispose women to depression, the relative levels of sex hormones probably playing a more important role than their absolute levels.37 Monthly fluctuations in gonadal hormone levels may sensitize women’s brains to the potentially harmful effects of stress axis hormones.38 Many women suffer from premenstrual, pregnancy, postpartum, and menopause related depression and, while psychosocial factors undoubtedly play a role in these types of depression, hormonal fluxes are probably the triggers. For instance, women who enter the menopausal transition relatively early have a significantly increased risk for first onset of depression.39 A disruption of the normal temporal relationship between sleep and other biological rhythms, such as melatonin, cortisol, thyroid stimulating hormone or prolactin, occurs during the menopausal transition that can trigger depression in predisposed women.40 Six estrogen-related genes have been screened with respect to depressive symptoms in middle aged women as part of the Study of Women’s Health Across the Nation (SWAN). DNA was genotyped from 1538 black, white, Chinese, and Japanese women aged 42–52 years. Women with specific CYP1A1 genotypes had greater odds of depression than those with other genotypes, but this varied according to ethnic background. This is evidence that selected genes involved in estrogen synthesis and metabolism increase the odds of depressive symptoms in women who are premenopausal or perimenopausal.41

Schizophrenia Men and women show approximately the same incidence of schizophrenia, but onset age is later for women, a paradoxical finding in that the brain develops faster in females so should theoretically reach the threshold for schizophrenia earlier (since schizophrenia is considered a developmental disorder). Tim Crow and colleagues attempt to resolve this paradox by hypothesizing that psychosis results from impairment of cerebral asymmetry and that women are partially protected by the different shape of their corpus callosum.42 Another explanation of male/female onset age difference rests on hormones. It is possible that fetal hormones set the pace for the process that leads to schizophrenia, propelling girls and boys along slightly divergent cerebral paths. Pubertal hormones subsequently trigger (or delay) the onset

C h a p t e r 1 2     Gender Differences in Disorders that Present to Psychiatry l

of psychosis. The hypothesis is that estrogens protect against psychosis in adolescence and early adulthood and that, when their influence begins to wane, schizophrenia incidence in women ‘catches up’, explaining the preponderance of women in the later onset group. Onset age is similar in the two genders in families with high genetic loading, suggesting that the influence of genetic factors overrides protective mechanisms, whether they be structural or hormonal. On the other hand, subtle variation in the regulation of gene expression may be what is involved in complex human disease such as schizophrenia. Gene ‘dose’ (the degree to which the gene is expressed) rather than polymorphism may be what is operative in schizophrenia. Estrogens could control gene dose via epigenetic mechanisms and prove protective for women during their reproductive years.43 Besides onset age, there are also some symptom differences between men and women in schizophrenia. Women, for instance, have more mood symptoms than men. Men have more severe negative symptoms, poorer premorbid functioning in terms of school performance, social networks and sociosexual development, whereas women have more severe hallucinations. More men than women use substances, are unemployed, and live alone. Women have poorer self-esteem than men and make more suicide attempts, despite objectively better functioning.44,45 Follow-up over 15 years shows women with psychotic illness to have better functioning, more frequent periods of recovery, less likelihood of poor ultimate outcome, and fewer and shorter rehospitalizations.46 This may be because women respond better than men to antipsychotic drugs – either because they are more adherent to treatment, smoke fewer cigarettes and, therefore, keep antipsychotic levels in the brain high, or because they are aided by the neuroprotective actions of estrogen, or because of sexspecific drug metabolic effects. Women also suffer correspondingly more from the side effects of these drugs. The SOHO (Schizophrenia Outpatient Health Outcomes) study of 4529 men and 3461 women revealed a superior response in women, especially with the older generation antipsychotics and with clozapine. There were minor gender differences with olanzapine and no differences with risperidone.47

Geriatric psychiatry Dementia The majority of individuals with Alzheimer’s disease (AD) are women but it is not clear whether this is due to higher risk of disease or solely to the larger number of women still alive at ages when AD is common. A Boston study followed a cohort of elderly individuals for 11 years and found that the age-specific incidence of AD did not differ significantly by gender, nor did the increase in risk of mortality due to AD. These findings suggest that the excess number of women with AD is due to the longer life expectancy of

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women rather than to sex-specific risk factors for the disease.48 Gender differences in real risk may emerge only at later ages. The Eurodem incidence research group found significant gender differences in AD risk. The cumulative risk for 65–year-old women developing AD by the age of 95 years was 0.22 compared with 0.09 for men. By contrast, the cumulative risk for developing vascular dementia at the age of 95 years was similar for men and women.49 AD women have also been found to have more brain pathology than AD men, mainly in the form of neurofibrillary tangles.50 In an effort to look for contributory genes, the Study of Women’s Health Across the Nation (SWAN) screened six estrogen-related genes with respect to their association with cognitive functioning in women at midlife. DNA was genotyped from 875 black, white Chinese, and Japanese women aged 45–56 years. Selected genes involved in estrogen synthesis and metabolism (CYP 19) were associated with performance differences on cognitive function tests; the association varied by race/ethnicity.51 Endogenous sex hormones appear to play an important role in the maintenance of cognitive function in older adults.52 There is evidence that inflammation may be a critical component of AD. Neuroinflammatory mediators such as cytokines may be involved in a number of key steps in the pathological cascade of events leading to neuronal injury and estrogens may play a role in the inhibition of the inflammatory response.53 After menopause, circulating levels of estrogens markedly decline (whereas brain estradiol continues to be generated from testosterone in men) so that neuroprotective effects on inflammation and on oxidative stress and on beta-amyloid plaque formation are lost.54,55

Future research directions In psychiatric illnesses, being female may be advantageous or disadvantageous, depending on the nature of the illness. Since some of actions of estrogens appear to be neuroprotective, the analysis of estrogen metabolism genes56 and estrogen receptor genotypes57 appear to be promising pathways of research. This is a way to find out how estrogens protect neuronal tissue and against what injury – in other words, a way to delineate what processes may be impaired in mental illnesses (see Chapter 13 for further information.) Since normatively developed female mammals have two X chromosomes while normatively developed males have one, further study of mechanisms of X inactivation and escape from inactivation also appears promising.58

Conclusion There are considerable differences in psychopathology between men and women in addition to the biosocial

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issues that most notably differentiate them: reproduction and investment in parenting, susceptibility to victimization, unequal distribution of resources, status and power. Developmental problems, perhaps related to X chromosome gene dosage effects, appear more prevalent in boys. The majority of adult mental illnesses are more common in women, and this may have to do with the nature and peri­ odicity of gonadal hormone levels post puberty, rendering women relatively more susceptible to the effects of specific stressors. Schizophrenia, although it begins in adulthood, behaves more like a developmental disorder and gender differences in this disorder may turn out to be a function of early X chromosome gene dosage. Dementia appears to affect women to a greater degree than men, but this may be more apparent than real, related to the fact that women live longer. Women may, in fact, live longer because of the indirect effects of gonadal hormones, whose withdrawal renders them susceptible to dementia. Other gender differences in psychopathology not covered in this chapter (substance abuse, posttraumatic stress, eating disorders) may owe their explanation to other considerations in this complex field, such as dosage effects on genes in synthetic or metabolic pathways of sex-specific hormones.

References 1. Rutter M, Caspi A, Moffitt TE. Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. J Child Psychol Psychiatry 2003;44:1092–115. 2. Gardner W, Pajer KA, Kelleher KJ, et al. Child sex differences in primary care clinicians’ mental health care of children and adolescents. Arch Pediatr Adolesc Med 2002;156:454–59. 3. Froehlich TE, Lanphear BP, Epstein JN, et al. Prevalence, recognition, and treatment of Attention-Deficit/Hyperactivity Disorder in a national sample of US children. Arch Pediatr Adolesc Med 2007;161:857–64. 4. Biederman J, Kwon A, Aleardi M, et al. Absence of gender effects on attention deficit hyperactivity disorder: findings in nonreferred subjects. Am J Psychiatry 2005;162:1083–89. 5. Biederman J, Faraone SV. The Massachusetts General Hospital studies of gender influences on attention-deficit/hyperactivity disorder in youth and relatives. Psychiatr Clin North Am 2004;27:225–32. 6. Starr E, Berument SK, Pickles A, et al. A family genetic study of autism associated with profound mental retardation. J Autism Dev Disord 2001;31:89–96. 7. Knickmeyer RC, Baron-Cohen S. Fetal testosterone and sex differences in typical social development and in autism. J Child Neurol 2006;21:825–45. 8. Baron-Cohen S, Knickmeyer RC, Belmonte MK. Sex differences in the brain: implications for explaining autism. Science 2005;310:819–23. 9. Gilmore JH, Lin W, Prastawa MW, et al. Regional gray matter growth, sexual dimorphism, and cerebral asymmetry in the neonatal brain. J Neurosci 2007;27:1255–60.

10. Lenroot RK, Gogtay N, Greenstein DK, et al. Sexual dimorphism of brain developmental trajectories during childhood and adolescence. Neuroimage 2007;36:1065–73. 11. Davies W, Wilkinson LS. It is not all hormones: alternative explanations for sexual differentiation of the brain. Brain Res 2006;1126:36–45. 12. Skuse DH. X-linked genes and mental functioning. Hum Mol Genet 2005;14(Review Issue 1):R27–32. 13. Gauthier J, Joober R, Dube MP, et al. Autism spectrum disorders associated with X chromosome markers in FrenchCanadian males. Mol Psychiatry 2006;11:206–13. 14. Marco EJ, Skuse DH. Autism-lessons from the X chromosome. Cogn Affective Neurosci 2006;1:183–93. 15. Skuse DH. Rethinking the nature of genetic vulnerability to autistic spectrum disorders. Trends Genet 2007;23:387–95. 16. Talebizadeh Z, Bittel DC, Veatch OJ, et al. Brief report: non-random X chromosome inactivation in females with autism. J Autism Dev Disord 2005;35:675–81. 17. Xu J, Disteche CM. Sex differences in brain expression of X- and Y-linked genes. Brain Res 2006;1126:50–55. 18. Nguyen DK, Disteche CM. High expression of the mammalian X chromosome in brain. Brain Res 2006;1126:46–49. 19. Skuse DH. Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism. Pediatr Res 2000;47:9–16. 20. Skuse DH, James RS, Bishop DV, et al. Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature 1997;387:705–8. 21. Romeo RD. Puberty: a period of both organizational and activational effects of steroid hormones on neurobehavioural development. J Neuroendocrinol 2003;15:1185–92. 22. Romeo RD, McEwen BS. Stress and the adolescent brain. Ann N Y Acad Sci 2006;1094:202–14. 23. Sisk CL, Zehr JL. Pubertal hormones organize the adolescent brain and behavior. Front Neuroendocrinol 2005;26:163–74. 24. Andersen SL. Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 2003;27:3–18. 25. McCormick CM, Mathews IZ. HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors. Pharmacol Biochem Behav 2007;86:220–33. 26. Kajantie E, Phillips DI. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 2006;31:151–78. 27. Sweeting H, West P. Sex differences in health at ages 11, 13 and 15. Soc Sci Med 2003;56:31–39. 28. Alonso J, Angermeyer MC, Bernert S, et al. ESEMeD/MHEDEA 2000 Investigators, European Study of the Epidemiology of Mental Disorders (ESEMeD) Project. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl 2004;420:21–27. 29. Marcus SM, Young EA, Kerber KB, et al. Gender differences in depression: findings from the STAR*D study. J Affect Disord 2005;87:141–50. 30. Miller G. Poor countries, added perils for women. Science 2005;308:1576.

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31. Schuster TL, Kessler RC, Aseltine RH Jr. Supportive interactions, negative interactions, and depressed mood. Am J Community Psychol 1990;18:423–38. 32. Williams K. Has the future of marriage arrived? A contemporary examination of gender, marriage, and psychological well-being. J Health Soc Behav 2003;44:470–87. 33. Angst J, Gamma A, Gastpar M, et al. Depression Research in European Society Study. Gender differences in depression. Epidemiological findings from the European DEPRES I and II studies. Eur Arch Psychiatry Clin Neurosci 2002;252:201–9. 34. Wyman RJ. Experimental analysis of nature-nurture interactions. J Exp Zoolog A Comp Exp Biol 2005;303:415–21. 35. Thompson MP, Kingree JB, Desai S. Gender differences in long-term health consequences of physical abuse of children: data from a nationally representative survey. Am J Public Health 2004;94:599–604. 36. Marin R, Guerra B, Alonso R, et al. Estrogen activates classical and alternative mechanisms to orchestrate neuroprotection. Curr Neurovasc Res 2005;2:287–301. 37. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 2005;4:141–94. 38. De Bellis MD, Keshavan MS, Beers SR, et al. Sex differences in brain maturation during childhood and adolescence. Cereb Cortex 2001;11:552–57. 39. Cohen LS, Soares CN, Vitonis AF, et al. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry 2006;63:385–90. 40. Parry BL, Fernando Martínez L, Maurer EL, et al. Sleep, rhythms and women’s mood. Part II. Menopause. Sleep Med Rev 2006;10:197–208. 41. Kravitz HM, Janssen I, Lotrich FE, et al. Sex steroid hormone gene polymorphisms and depressive symptoms in women at midlife. Am J Med 2006;119(9 Suppl 1):S87–93. 42. Crow TJ, Paez P, Chance SA. Callosal misconnectivity and the sex difference in psychosis. Int Rev Psychiatry 2007;19:449–57. 43. Forton JT, Kwiatkowski DP. Searching for the regulators of human gene expression. Bioessays 2006;28:968–72. 44. Thorup A, Petersen L, Jeppesen P, et al. Gender differences in young adults with first-episode schizophrenia spectrum disorders at baseline in the Danish OPUS study. J Nerv Ment Dis 2007;195:396–405. 45. Preston NJ, Orr KG, Date R, et al. Gender differences in premorbid adjustment of patients with first episode psychosis. Schizophr Res 2002;55:285–90.

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46. Grossman LS, Harrow M, Rosen C, et al. Sex differences in outcome and recovery for schizophrenia and other psychotic and nonpsychotic disorders. Psychiatr Serv 2006;57:844–50. 47. Usall J, Suarez D, Haro JM, et al. Gender differences in response to antipsychotic treatment in outpatients with schizophrenia. Psychiatry Res 2007;153:225–31. 48. Hebert LE, Scherr PA, McCann JL, et al. Is the risk of developing Alzheimer’s Disease greater for women than for men?. Am J Epidemiol 2001;153(2):132–36. 49. Andersen K, Launer LJ, Dewey ME, et al. Gender differences in the incidence of AD and vascular dementia: the EURODEM Studies. EURODEM Incidence Research Group. Neurology 1999;53:1992–97. 50. Barnes LL, Wilson RS, Bienias JL, et al. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 2005;62:685–91. 51. Kravitz HM, Meyer PM, Seeman TE, et al. Cognitive functioning and sex steroid hormone gene polymorphisms in women at midlife. Am J Med 2006;119(9 Suppl 1):S94–S102. 52. Yaffe K, Barnes D, Lindquist K, et al. Health ABC Investigators. Endogenous sex hormone levels and risk of cognitive decline in an older biracial cohort. Neurobiol Aging 2007;28:171–78. 53. Członkowska A, Ciesielska A, Gromadzka G, et al. Gender differences in neurological disease: role of estrogens and cytokines. Endocrine 2006;29:243–56. 54. Balistreri CR, Grimaldi MP, Vasto S, et al. Association between the polymorphism of CCR5 and Alzheimer’s disease: results of a study performed on male and female patients from Northern Italy. Ann N Y Acad Sci 2006;1089:454–61. 55. Candore G, Balistreri CR, Grimaldi MP, et al. Age-related inflammatory diseases: role of genetics and gender in the pathophysiology of Alzheimer’s disease. Ann N Y Acad Sci 2006;1089:472–86. 56. Martorell L, Costas J, Valero J, et al. Analyses of variants located in estrogen metabolism genes (ESR1, ESR2, COMT and APOE) and schizophrenia. Schizophr Res 2007; 100(1–3):308–15. 57. Sowers MR, Jannausch ML, McConnell DS, et al. Endogenous estradiol and its association with estrogen receptor gene polymorphisms. Am J Med 2006;119(9 Suppl 1):S16–22. 58. Rosa A, Picchioni MM, Kalidindi S, et al. Differential methy­ lation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins. Am J Med Genet B Neuropsychiatr Genet 2007;147B(4):459–62.

C hapter

13

Hormone Replacement Therapy and Cognitive Function Mary Sano1, Diane Jacobs2, and Katya Gaynor3 1

Director, Alzheimer Disease Research Center; Professor, Department of Psychiatry, Mount Sinai School of Medicine; Director of Research and Development; James J Peters VAMC, New York; NY, USA 2 Consulting Neuropsychologist, San Diego, CA, USA 3 Research Coordinator, Mount Sinai School of Medicine, Department of Psychiatry, New York, NY, USA

Laboratory studies

Introduction

Gonadal hormones have been under study for their effect on CNS function for more than 50 years, with the early focus on estrogen receptors in hypothalamic areas with presumed roles in homeostatic functions, such as growth, circadian cycle, and appetite. Studies demonstrating that fluctuation of dendritic spine growth in the CA1 region of the dorsal hippocampus, an area in the brain known for its role in memory consolidation, was dependent on ovarian hor­ mones provided further support for this connection between hormones and cognition.1 Furthermore, behavioral animal studies using a hippocampal learning task have indicated enhancement of spatial memory, with hormonal regimens. Several important observations include the following: hor­ mones do not enhance all aspects of cognition; there may be interactions between environmental stimuli and cogni­ tive effects; and overall cognitive effects are not large.2 For example, several studies demonstrate that estrogenic effects can be mitigated by stress3 or by environmental enrich­ ment.4 The type of learning may also be subject to differen­ tial effects with estrogen. Some rodent studies have shown that while estrogen may improve acquisition,5,6 it may have no effect – or may even have a detrimental effect – on pre­ viously acquired knowledge.7,8 This highlights the fact that cognition is multiply determined, an important observation when trying to translate these findings into clinical practice. The possible roles of estrogenic effect have expanded with the understanding of the estrogen receptor. While ini­ tial thinking reflected a single receptor transcription factor acting in the nucleus to mediate hormonal effects, a sec­ ond receptor was identified, and the receptors are currently designated as ER and ER.9,10 Studies of knock-out mice have suggested the possibility that ER, rather than ER, contributes to cognitive effects of estrogen. The availability

Hormone replacement therapy describes the use of exo­ genous hormones, specifically estrogen and progestins, to replace the endogenous sources that are depleted, usu­ ally due to age or surgical intervention. The term hormone replacement therapy (HRT) typically refers to the general replacement of estrogen and/or progesterone. It is now well understood that among women with an intact uterus the estrogen regimen must be supplemented with progesterone to avoid hyperplasia. The term estrogen replacement therapy (ERT) reflects the use of estrogen alone as the primary hor­ mone that requires replacement, and it is the therapy used in surgical menopause with hysterectomy, wherein the addi­ tion of progesterone is not necessary. Despite the sometimes interchangeable use of these terms, these two hormone regi­ mens, as well as the many agents used to replace estrogen and progesterone, may have different effects on cognition. The primary indication for this therapy is the treat­ ment of menopausal symptoms including hot flushes, night sweats, vaginal dryness, and osteoporosis, and the effec­ tiveness on these symptoms is well established in repeated studies. The transition through the menopause starts years before menstruation cessation. Symptoms during this time include mood swings, hot flushes, and loss of sexual drive. Other symptoms and medical conditions that increase with aging, such as cardiovascular disease and cognitive decline, are less clearly associated with the menopause. This review will examine the data describing cognitive function during the adult life with a focus on cognitive changes in adult­ hood and aging through the menopause. The effect of hor­ mone replacement on these functions will be examined. While animal and laboratory studies have been used to understand hormonal activity, the focus will be on clinical conditions and results from human clinical trials. Principles of Gender-Specific Medicine

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Copyright 2010 20 , Elsevier Inc. All rights reserved.

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of selective estrogen receptor modulators (SERMs)11–13 has permitted delineation of the roles of specific receptors and selective ER agonists have been shown to increase levels in vivo in the hippocampus of PSD-95, synaptophysin, and the AMPA-receptor subunit GluR1. These proteins play a key role in synaptic function. ER agonists also induced morphological changes in hippocampal neurons, includ­ ing an increased density of mushroom-type spines. Most importantly, estradiol or ER agonists improved perform­ ance in a variety of hippocampal-dependent memory tasks. Thus, these current results13 provide strong support for a role of ER in memory. These effects were absent in ER knockout mice and after treatment with an ER agonist. There is evidence of another receptor spanning the plasma membrane which may mediate nongenomic path­ ways linked to G proteins and tyrosine kinase pathways. ERs may also act directly via CREB and AP1 to initiate transcription and also interact with membrane receptors to regulate transcription. Thus, some effects of estrogen may be rapid and short-lived. There is some evidence that rapid enhancement of cognition may be associated with these membrane estrogen receptors through mitogenactivated protein kinase pathways in specific neural sites.14 For example, consolidation in memory tasks is enhanced when estrogen is given before or immediately after training, but the benefit is not obvious when the task is delayed for several hours. These findings are robust and are observed across a variety of behavioral tasks, but it is not clear how they translate to overall cognition. Hormone replacement therapy for women with an intact uterus includes the administration of progesterone-like compounds to counter the proliferative effect of estrogen on the uterine epithelium. Endogenous progesterone produces multiple effects in the brain through three principle mecha­ nisms: regulation of gene expression, modulation of neuro­ transmitter systems, and activation of signaling cascades (see Brinton for a review15). While there is evidence that progesterone provides neural protection in various animal models, it is not clear that synthetic progestins (commonly used in clinical applications) share these properties.

Menopause, Hormones, and Cognition It is unclear to what extent cognitive loss is associated with the menopausal transition. The strongest evidence for a link between menopause and cognition comes from studies of women undergoing surgical menopause. Dramatic changes in levels of ovarian hormones that follow surgical menopause may have a direct effect on cognitive functioning.16 Small well-controlled studies of women pre- and 3 months postoophorectomy demonstrate significant declines on measures of attention, abstract reasoning, clerical speed and accu­ racy, and immediate paragraph recall. However, cognitive

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p­ erformance of women post-oophorectomy who received postoperative hormone replacement therapy was unchanged, and women who underwent hysterectomy with sparing of ovaries also showed no such change in postoperative cogni­ tive performance. In a placebo-controlled study, hormone replacement protected against significant post-oophorectomy decline on a measure of verbal paired-associate learning in women.17 Pharmacologic suppression of ovarian function with GnRH agonists also produced memory impairment which was reversed by administration of estradiol.18 Evidence of cognitive effects associated with natural menopause has been less compelling than that observed fol­ lowing surgical menopause. Although cognitive complaints are common among women during and after the menopau­ sal transition (with over 40% of women between the ages of 48–55 complaining of forgetfulness19), neuro­psychological investigations typically fail to demonstrate an objective defi­ cit related to the menopause. A birth cohort study of women found weak evidence of an adverse effect of natural meno­ pause on cognitive function, but this finding was related to premenopausal cognitive functioning.20 In this cohort there was no association between cognition and vasomotor or psychological symptoms of the menopause, and there was no evidence of an effect from hormone therapy use. One conclusion is that genetic factors may influence cognitive changes through lifelong hormonal mechanisms. Cross-sec­ tional studies, however, have failed to find an association between reproductive period and cognitive performance.21 The Study of Women’s Health Across the Nation (SWAN) examined the association of cognitive performance with menopausal stage and hormone levels in 1657 women and found no relationship.22 Additional long­itudinal results dem­ onstrate some deterioration on cognitive tests at the earliest menopausal stages, with a return of function at later stages. These results suggest that while cognition may change with age, it may not be dependent on hormone levels. Alternately, the hormonal fluctuations characteristic of the early stages may underlie the temporary cognitive complaint. The longterm impact of this is not yet well understood.

Menopause and Dementia Dementia, defined by profound loss of memory and other cognitive functions sufficient to interfere with social and occupational functioning, is a serious and growing medical problem. Alzheimer’s disease (AD) is the most common cause of dementia, followed by cerebrovascular disease/ stroke. Some evidence suggests that there may be greater age-adjusted incidence of AD among women compared to men, although contradictory data are also evident (for a review see the chapter by Amatniek et al. in this volume). The interest in women’s health and an awareness of the aging of society stimulated many research initiatives to explore the relationship of hormones and dementia. Early

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evidence from epidemiological investigations suggested that postmenopausal hormone replacement therapy (HRT) may play a role in attenuating the devastation of AD and memory loss in aging. Although initial case-control studies yielded conflicting results, subsequent large-scale prospective cohort studies consistently showed a lower risk of developing AD among women who had used HRT during the postmeno­ pausal period.23–25 A meta-analysis26 combining the results of two cohort and 10 case-control studies yielded an overall risk-ratio of 0.66 (95% CI, 0.53–0.82); the current or past use of HRT (most commonly oral conjugated equine estrogen) was associated with 34% lower likelihood of developing AD.

Clinical trials Women’s Health Initiative Memory Study (WHIMS) While epidemiological studies have suggested a role for hor­ mone replacement therapy in the prevention of Alzheimer’s disease, findings from clinical trials have been disappoint­ ing. WHIMS was nested within the Women’s Health Initiative placebo-controlled trial of combination hormone therapy with 0.625 mg daily of conjugated equine estrogens (CEE) and 2.5 mg of medroxyprogesterone acetate (MPA) for women with a uterus or CEE alone for those who had had a hysterectomy.27 This substudy recruited 4532 women aged 65 or older and who were not demented at baseline – although about 6% did appear to have cognitive impairment. Annual assessments consisted of a structured mental status exam, the Modified Mini Mental State Exam (3MSE).28 At follow-up those who scored below a pre-set cut point on this exam were referred for more detailed neuropsychological assessment and for a clinician evaluation of dementia. The primary outcome measures of the WHIMS trial were inci­ dent dementia and mild cognitive impairment (MCI) defined by the following criteria: poor performance (10th percentile or lower) in at least one area of cognitive function, some functional impairment, decline from baseline functioning, absence of dementia, and no evidence of a psychiatric dis­ order or medical condition that could account for the decline in cognitive function. Change in the mental status exam score was also examined. Results from WHIMS revealed a two-fold increased risk of dementia for women in the estro­ gen plus progestin group.29 This increased risk translated into an additional 23 cases of dementia per 10 000 women per year. Alzheimer’s disease was the most common cause of dementia in both the HRT and placebo groups, although the specific effect for AD was not significant. Treatment groups did not differ in their risk of developing mild cogni­ tive impairment, however, there was a significant difference in mental status scores with women in the estrogen plus pro­ gestin group, demonstrating smaller average increases in total score compared with women who received placebo.30

There was also an increase in the number of women in the HRT group who demonstrated a clinically significant decline (defined as 2 SDs below average change) on mental status testing compared with the placebo group.30 The parallel WHIMS trial of 2947 women who had pre­ viously undergone hysterectomy and were assigned to CEE (i.e., estrogen-alone) or placebo did not reveal a significant effect of treatment group on incidence of dementia or inci­ dent MCI, although a pre-planned analysis of the data pooled from both studies found an increased risk of dementia for the active drug groups compared to the placebo groups (HR, 1.76; 95%CI, 1.19–2.60; p  0.005).31 This result remained significant after excluding participants with baseline mental status scores below the screening cut point. Women assigned to CEE, however, were about 40% more likely to be diag­ nosed with either MCI or probable dementia at some point during the trial. Also, the effects of CEE on the mental status exam were similar to those observed with CEE  MPA in that the treated group scored significantly lower compared to women assigned to placebo across the 5.4 years of followup, and women assigned to CEE were significantly more likely to experience a clinically significant decline on mental status testing.32 The most dramatic declines were observed among women who performed poorly at the start of the study, suggesting that hormone therapy may have acceler­ ated an extant disease process (e.g., cerebrovascular disease, neuropathologic changes) in these women. A Cochrane review33 of 16 trials with a total of 10 114 women, including the WHIMS data, concluded that ‘There is good evidence that both ERT and HRT do not prevent cognitive decline in older postmenopausal women when given as short-term or longer term (up to five years) ther­ apy.’ The authors acknowledge the possible implication that combined hormone therapy (estrogen and progesterone) is associated with a statistically significant decline in perform­ ance on verbal memory tests. Recently published data from the WHI cohort examined the effect of treatment on volumetric MRI conducted at 1.5 to 3 years post treatment. Findings indicate that frontal lobe, hippocampal, and total brain volumes were lower in those assigned to the treatment group.34

Effects of HRT in Alzheimer’s Disease Early studies of estrogen in patients with Alzheimer’s dis­ ease (AD) suggested a benefit – although most were open label studies comparing pre-post treatment response meas­ ured by clinical impression over brief intervals of several weeks (e.g. Fillit35). There have been several randomized clinical trials of CEE in women already diagnosed with mild to moderate AD.36–39 In each of these trials, CEE failed to improve cognition or slow the rate of cognitive decline among women with AD. Duration of follow-up ranged from 4 to 12 months. Furthermore, there was some evidence of deleterious cognitive effects. Based upon these

C h a p t e r 1 3    Hormone Replacement Therapy and Cognitive Function l

findings, use of CEE to treat AD in postmenopausal women is not recommended. In several small placebo-controlled studies, Asthana and colleagues found that transdermal 17-estradiol improved attention and memory functioning in postmenopau­ sal women with AD.39,40 As these studies had very small sample sizes (12 and 20 participants) and the duration of treatment was short (8 weeks), the therapeutic potential of transdermal 17-estradiol awaits the completion of larger multi-center studies with longer treatment durations.

Effects of HRT in the Early Post Menopause In the Study of Women’s Health Across the Nation (SWAN),22 which recruited 16 065 women between the ages of 42 and 52, forgetfulness was endorsed by 42% of perimenopausal women, 40% of postmenopausal women, and 30% of premenopausal women. While cognitive com­ plaint occurs in the early stages of menopause, there have been very few trials examining the effect of estrogen in this early stage of natural menopause. The COGENT trial (Cognitive Complaints in Early Menopause) aimed to examine the effects of HRT on cognitive function and qual­ ity of life (QOL) in recently postmenopausal women with subjective cognitive complaints.41 Study recruitment was stopped due to poor enrollment following the publication of WHIMS results. Yet 158 subjects completed this 4–month randomized trial of CEE (625 mg) and MPA compared to placebo. Despite the small sample size and relatively short duration, there were negative effects on short- and long-term verbal memory which approached significance. Neither the cognitive complaint nor the presence of vasomotor symp­ toms affected this association. Though no overall effect was apparent in QOL, the presence of vasomotor symptoms was associated with a benefit on this measure. While the longterm effect of HRT on cognition was not assessed in this study, these findings suggest that even short-term use may have immediate detrimental effects on memory.

Estrogenic Agents Other than CEE: Effects on Cognition There are few studies that have used forms of estrogen other than CEE. The Cochrane Review identified only nine studies in which the estrogenic agent was other than CEE and three of these studies were in women who had undergone surgical menopause.33 Dunkin and colleagues reported on 17 women randomly assigned to a transdermal estrogen preparation composed of 17-estradiol with a release rate of 0.1 mg E2/ day or placebo for 10 weeks and found no effect on any of the four cognitive factors assessed (verbal and nonverbal mem­ ory, attention, and executive function).42 Almeida et al. rand­ omized 115 non-demented women to treatment with estradiol (2 mg per day/po) or placebo for a total period of 20 weeks. There were no differences in intent-to-treat analysis on any of

145

the outcomes, including measures of cognition, depression, or quality of life.43 Another study using estradiol patches (deliv­ ering a mean of 0.1 mg estradiol/day percutaneously or pla­ cebo) found improvement in only one of four memory tests.44 Other short-term studies have also been unable to detect a beneficial effect of transdermal estradiol compared to pla­ cebo; in some, but not all, hormone levels in the treated group were related to memory scores. A longer study using ultra low doses of estradiol administered via a weekly transdermal patch that delivers estradiol, 0.014 mg/d (n  208), or placebo (n  209) followed women for up to 2 years. There were no significant differences on cognition between groups, although the absolute values suggested better performance in the pla­ cebo group on many of the cognitive test scores.45 A small trial (n  57), comparing the use of a low dose (0.25 mg/dl) of micronized 17-estradiol with oral micro­ nized progesterone (given for 2–weeks every 6 months) or placebo in older postmenopausal women, examined cog­ nitive differences over 3 years. There were no differences in measures of memory, language, mood, and executive function.46 Le Blanc examined the relationships between menopau­ sal symptoms, cognitive symptoms, and estrogen replace­ ment. Participants were individuals in the late menopausal transition or in early postmenopause. Most were in the early 5th decade. HRT consisted of estradiol (2 mg tablets) or an identical-appearing placebo. HRT increased levels of estro­ gen and improved menopausal symptoms but was not asso­ ciated with any change in cognitive test scores.47 The WEST study compared the effects of oral 17-estradiol (1 mg) daily to matching placebo in postmenopausal women with a history of TIA or stroke. It revealed no overall effect but did find a hint of benefit in those who demonstrated the best cognitive performance at baseline.48 Taken together, results from placebo-controlled trials of estradiol in postmenopausal women do not support a ben­ eficial effect for brief or more extended intervals. Several of these studies included cycling forms of progestin administra­ tion. While these trials were too small to draw conclusions, they did not demonstrate persistent evidence of detrimental effects on cognition. Dehydroepiandrosterone (DHEA), another steroid hor­ mone circulating in the human body, has been used in tri­ als in aging populations. Perimenopausal women have only approximately 50% of peak DHEA levels, and that amount declines to approximately 20% once an individual reaches 70. It is thought that DHEA can be converted to different metabolites by different brain regions and may replace agerelated hormonal loss. In a placebo-controlled trial of DHEA (50 mg/day) in elders, no benefit was seen on cognitive tests of language, memory, or executive dysfunction.49 This is consistent with an earlier review of randomized trials con­ ducted by Cochrane.50 This review was only able to identify three trials and no evidence of cognitive benefit. One study described a significant impairment on a visual memory

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recall test (p 0.01) compared to placebo under a stressor condition, but no difference in the absence of a stressor. The reviewers concluded ‘when compared to placebo the data does not support a beneficial effect of DHEA supplemen­ tation on cognitive function of non demented middle-aged or elderly people. There is no consistent evidence from the controlled trials that DHEA produces any adverse effects.’50

Cognitive Effects of Selective Estrogen Receptor Molecules (SERMS) SERMs are agents that focus on a subset of estrogen recep­ tors which are developed to target specific symptoms. Agents focusing on osteoporosis, such as raloxefine, or on blockade of estrogen-sensitive receptors in the breast, such as tamoxifen, have also been studied for their effects on cog­ nition. Raloxefine was examined in the MORE study which randomized postmenopausal women to receive a daily dose of 60 mg or 120 mg of raloxefine or placebo. Dementia was defined as a positive clinical report of symptoms and/ or diagnosis. In addition, those who scored in the lowest 10th percentile on cognitive screening were evaluated by a dementia expert. After 3 years, among the 5386 women enrolled, 181 (3.4%) had mild cognitive impairment and 52 (1.0%) had dementia, 36 with Alzheimer’s disease. The risk of mild cognitive impairment and Alzheimer’s disease was lower among those taking 120 mg of raloxifine compared to placebo; however, no effect was seen at the lower dose.51 Tamoxifen, an estrogen receptor blocker, has been reported to increase memory complaints. Several studies examining cognitive function have demonstrated cognitive impairment in neuropsychological testing as well as mem­ ory complaints. One study found that chemotherapy patients treated with tamoxifen with high- or low-dose chemother­ apy appeared to have between 3.5–and 8.2–times higher risk of cognitive impairment in comparison to controls.52 While cognitive deficits have been found in comparison to control or to the pre-treatment baseline, the deficits are not correlated with cognitive complaint.53 Some studies have suggested that use of tamoxifen is possibly related to worse verbal functioning in postmenopausal women54 and process­ ing speed in comparison to healthy controls in premeno­ pausal women.55 It is difficult to determine the appropriate comparison for assessing the effects of tamoxifen due to the fact that there may be an impact of the underlying condition for which it is being used (i.e. breast cancer). These con­ ditions may have direct effects, or indirect effects through other treatments or psychological responses to the disease.

Conclusion The promise from years of epidemiological studies and laboratory models that hormone replacement may provide cognitive benefit to aging women has been replaced by

significant disappointment. Current findings not only cast doubt on the putative beneficial effects of hormone therapy on cognition, but they also raise the possibility of a nega­ tive effect on cognition by this frequently used treatment. Another striking finding from the recent clinical trials and ongoing large-scale longitudinal studies is the lack of asso­ ciation between cognitive complaint, cognitive deficit, and endogenous hormone levels.

Questions for future research These findings raise questions about individual risk and responsiveness to hormonal fluctuations. Questions also remain regarding the cognitive efficacy of different estrogen preparations, the role of progesterone, the impact of age, and the timing and duration of therapy on cognitive out­ comes. Several important studies are ongoing and will soon report results to address these questions. Results from the PREPARE study, which randomized non-demented women with a family history of dementia to CEE or placebo, will be presented within the year.56 This study examined incident dementia and cognitive loss, and though it terminated treat­ ment when the WHIMS results were reported, annual assess­ ments were continued. This will tell us if the brief exposure can reproduce the benefit seen in observational studies. Another important question is whether earlier initiation of treatment and use of non CEE can benefit cognition. KEEPS is a study of cognitive and affective outcomes. It is a multi-center clinical trial which will investigate the potential benefits of menopausal hormone therapies admin­ istered to perimenopausal women.57 The primary outcome measures are performance on tests of verbal memory and attention/executive function assessed every 3 months. This three-armed study will compare CEE, transdermal estra­ diol (both of these using cyclic oral micronized progestin for uterine protection), and placebo. This study will address several features, including benefits in younger women, the use of transdermal and CEE estrogen, and the use of a pro­ gesterone with potentially minimal side effects. Finally, there is an important observational study, the SWAN study (a longitudinal cohort of women who have been carefully characterized from the premenopausal stage through the postmenopausal interval), that will continue to report results.58 These data will provide needed information about the natural history of cognitive changes in a very large nationally representative sample of women. These continu­ ing efforts will be critical to understanding how to maximize cognitive function within the context of women’s health.

Acknowledgment The authors’ work was supported by Federal Grants AG15922 and AG005138.

C h a p t e r 1 3    Hormone Replacement Therapy and Cognitive Function l

References   1. Woolley CS, McEwen BS. Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci 1992;12:2549–54.   2. Luine VN. Sex steroids and cognitive function. J Neuroendocrinol 2008;20:866–72.   3. Englemann M, Ebner K, Landgraf R, et al. Effects of morris water maze testing on the neuroendocrine stress response and intrahypothalamic release of vasopressin and oxytocin in the rat. Horm Behav 2006;50:496–501.   4. Gresack JE, Frick KM. Environmental enrichment reduces the mnemonic and neural benefits of estrogen. Neuroscience 2004;128:459–71.   5. Luine V, Rodriguez M. Effects of estradiol on radial arm maze performance of young and aged rats. Behav Neural Biol 1994;62:230–36.   6. Daniel JM, Fader AJ, Spencer AL, et al. Estrogen enhances performance of female rats during acquisition of a radial arm maze task. Horm Behav 1997;32:217–25.   7. Luine V, Richards ST, Wu VY, et al. Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters. Horm Behav 1998;34:149–62.   8. Fader AJ, Johnson PE, Dohanich GP. Estrogen improves working but not reference memory and prevents amnesic effects of scopolamine of a radial-arm maze. Pharmacol Biochem Behav 1999;62:711–17.   9. McEwen BS, Alves SE. Estrogen actions in the central nerv­ ous system. Endocr Rev 1999;20:279–307. 10. Luine V. Neuroendocrinology of memory and cognition. In: A Lajtha, ed. Handbook of Neurochemistry and Molecular Neurobiology, 3rd edn (Jeff D Blaustein, Volume Editor: Behavioral Neurochemistry and Neuroendocrinology.) Berlin: Springer; 2006:775–800. 11. Rissman EF, Heck AL, Leonard JE, et al. Disruption of estro­ gen receptor b gene impairs spatial learning in female mice. Proc Natl Acad Sci USA 2002;99:3996–4001. 12. Rhodes ME, Frye CA. ER beta-selective SERMs produce mnemonic enhancing effects in the inhibitory avoidance and water maze tasks. Neurobiol Learn Mem 2006;85:183–91. 13. Liu F, Day M, Muniz LC, et al. Activation of estrogen receptor beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci 2008;11:334–43. 14. Bryant DN, Sheldahl LC, Marriott LK, et al. Multiple path­ ways transmit neuroprotective effects of gonadal steroids. Endocr 2006;29:199–207. 15. Brinton RD, Thompson RF, Foy MR, et al. Progesterone recep­ tors: form and function in brain. Frontiers Neuroendocrinol 2008;29:313–39. 16. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrin 1988;13:345–57. 17. Phillips SM, Sherwin BB. Effects of estrogen on memory func­ tion in surgically menopausal women. Psychoneuroendocrin 1992;17:485–95. 18. Sherwin BB, Tulandi T. ‘Add-back’ estrogen reverses cogni­ tive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. J Clin Endocrinol Metab 1996;81(7):2545–49.

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19. Gold EB, Sternfeld B, Kelsey JL, et al. Relation of demo­ graphic and lifestyle factors to symptoms in a multi-racial/eth­ nic population of women 40-55 years of age. Am J Epidemiol 2000;152(5):463–73. 20. Kok HS, Kuh D, Cooper R, et al. Cognitive function across the life course and the menopausal transition in a British birth cohort. Menopause 2006;13(1):19–27. 21. Low LF, Anstey KJ, Jorm AF, et al. Reproductive period and cognitive function in a representative sample of natu­ rally postmenopausal women aged 60–64 years. Climacteric 2005;8(4):380–89. 22. Luetters C, Huang MH, Seeman T, et al. Menopause transition stage and endogenous estradiol and follicle-stimulating hor­ mone levels are not related to cognitive performance: crosssectional results from the study of women’s health across the nation (SWAN). J Womens Health 2007;16(3):331–44. 23. Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996;348:429–32. 24. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal study of aging. Neurology 1997;48:1517–21. 25. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replace­ ment therapy and incidence of Alzheimer disease in older women: the Cache county study. JAMA 2002;288(17):2123–29. 26. LeBlanc ES, Janowsky J, Chan BK, et al. Hormone replace­ ment therapy and cognition: systematic review and metaanalysis. JAMA 2001;285(11):1489–99. 27. Shumaker SA, Reboussin BA, Espeland MA, et al. The Women’s Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the pro­ gression of dementia. Control Clin Trials 1998;19:604–21. 28. Teng EL, Chui H. The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987;48:314–18. 29. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289(20):2651–62. 30. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estro­ gen plus progestin on global cognitive function in postmeno­ pausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289(20):2663–72. 31. Shumaker SA, Legault C, Kuller L, et al. Women’s Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impair­ ment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;291(24):2947–58. 32. Espeland MA, Rapp SR, Shumaker SA, et al. Women’s Health Initiative Memory Study. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004; 291(24):2959–68. 33. Lethaby A, Hogervorst E, Richards M, et al. Hormone replacement therapy for cognitive function in postmenopau­ sal women. Cochrane Database Syst Rev 2008;1, CD003122. 34. Resnick SM, Espeland MA, Jaramillo SA, et al. Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study. Neurology 2009;72(2):135–42.

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35. Fillit H, Weinreb H, Cholst I, et al. Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer’s type. Psychoneuroendocrinology 1986;11(3):337–45. 36. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000;54:295–301. 37. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replace­ ment therapy for treatment of mild to moderate Alzheimer disease. JAMA 2000;283:1007–15. 38. Wang PN, Liao SQ, Liu RS, et al. Effects of estrogen on cog­ nition, mood, and cerebral blood flow in AD: a controlled study. Neurology 2000;54:2061–66. 39. Asthana S, Baker LD, Craft S, et al. High-dose estradiol improves cognition for women with AD: results of a rand­ omized study. Neurology 2001;57(4):605–12. 40. Asthana S, Craft S, Baker LD, et al. Cognitive and neuroendo­ crine response to transdermal estrogen in postmenopausal women with Alzheimer’s disease: results of a placebo-controlled, doubleblind, pilot study. Psychoneuroendocrinology 1999;24(6):657–77. 41. Maki PM, Gast MJ, Vieweg AJ, et al. Hormone therapy in menopausal women with cognitive complaints. A rand­ omized, double-blind trial. Neurology 2007;69:1322–30. 42. Dunkin J, Rasgon N, Wagner K, et al. Reproductive events modify the effects of estrogen replacement therapy on cognition in healthy postmenopausal women. Psychoneuroendocrinology 2005;30(3):284–96. 43. Almeida OP, Lautenschlager NT, Vasikaran S, et al. A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life. Neurobiol Aging 2006;27:141–49. 44. Wolf OT, Kudielka BM, Hellhammer DH, et al. Two weeks of transdermal estradiol treatment in postmeno­ pausal elderly women and its effect on memory and mood. Psychoneuroendocrinology 1999;24:727–41. 45. Yaffe K, Vittinghoff E, Ensrud KE, et al. Effects of ultra-lowdose transdermal estradiol on cognition and health-related quality of life. Arch Neurol 2006;63(7):945–50. 46. Pefanco MA, Kenny AM, Kaplan RF, et al. The effect of 3-year treatment with 0.25 mg/day of micronized 17betaestradiol on cognitive function in older postmenopausal women. J Am Geriatr Soc 2007;55(3):426–31. 47. LeBlanc ES, Neiss MB, Carello PE, et al. Hot flashes and estrogen therapy do not influence cognition in early meno­ pausal women. Menopause 2007;14(2):191–202.

48. Viscoli CM, Brass LM, Kernan WN, et al. Estrogen ther­ apy and risk of cognitive decline: results from the Women’s Estrogen for Stroke Trial (WEST). Am J Obstet Gynecol 2005;192(2):387–93. 49. Kritz-Silverstein D, von Mühlen D, Laughlin GA, et al. Effects of dehydroepiandrosterone supplementation on cog­ nitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 2008;56(7):1292–98. 50. Grimley Evans J, Malouf R, Huppert F, et al. Dehydroe­ piandrosterone (DHEA) supplementation for cognitive func­ tion in healthy elderly people. Cochrane Database Syst Rev 2006;4, CD006221. 51. Yaffe K, Krueger K, Cummings SR, et al. Effect of raloxifene on prevention of dementia and cognitive impair­ ment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry 2005;162(4):683–90. 52. van Dam FS, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998;90(3):210–18. 53. Castellon SA, Ganz PA, Bower JE, et al. Neurocognitive performance in breast cancer survivors exposed to adju­ vant chemotherapy and tamoxifen. J Clin Exp Neuropsychol 2004;26(7):955–69. 54. Schilder CM, Eggens PC, Seynaeve C, et al. Neuropsychological functioning in postmenopausal breast cancer patients treated with tamoxifen or exemestane after AC-chemotherapy: crosssectional findings from the neuropsychological TEAM-side study. Acta Oncol 2009;48(1):76–85. 55. Palmer JL, Trotter T, Joy AA, et al. Cognitive effects of Tamoxifen in pre-menopausal women with breast cancer com­ pared to healthy controls. J Cancer Surviv 2008;2(4):275–82. 56. Sano M, Jacobs D, Andrews H, et al. A multi-center, rand­ omized, double blind placebo-controlled trial of estrogens to prevent Alzheimer’s disease and loss of memory in women: design and baseline characteristics. Clin Trials 2008;5(5): 523–33. 57. Crenshaw P. Kronos Early Estrogen Prevention Study (KEEPS). Metaregister of Current Controlled Clinical Trials. NCT0062331. 58. SWAN Study of Women’s Health Across the Nation. www. edc.gsph.pitt.edu/swan/.

Section 3

Cardiovascular Disease

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Introduction

Paula A. Johnson At the time of the first edition of this volume, the knowl­ edge of sex and gender differences in cardiovascular disease (CVD) was already far beyond other fields. Even still, there was still much to learn. Since 2004, there has been significant advancement in the field, but as in 2004, there is still much that is unknown. Since the publication of the first edition, the Women’s Ischemic Syndrome Evaluation (WISE) study has elucidated several aspects of how ischemic heart disease differs in women,1 the entity of acute reversible cardiomyo­ pathy or Tksubo’s cardiomyopathy, seen almost exclusively in women, has been named, and we have learned that there continues to be a disparity in the utilization of some advanced procedures in women. The 2001 Institute of Medicine Report, Exploring the Biological Contributions to Human Health: Does Sex Matter?, led to a increase in the study of sex dif­ ferences in health and disease.2 We have passed the 15-year mark of the NIH Revitalization Act of 1993, which estab­ lished guidelines for the inclusion of women and minorities in clinical studies funded by the National Institutes of Health. But, it is also the case that there is no mandate for reporting sex-specific results and results by sex–race groups. Studies have shown that through the work of the American Heart Association, the NIH and many other organ­ izations dedicating resources to the improvement of aware­ ness of CVD in women, a majority of women now correctly identify heart disease as the leading cause of mortality in the United States.3 Centers addressing the unique factors of heart disease in women have sprung up around the country. We have come a long way but there is still a very long way to go! This section on cardiovascular disease will survey four areas that will highlight the differences in normal physiology,

the aspects of risk that differ between women and men, take a deep dive into what we now know about hyperlipidemia in women and lastly, how stress impacts CVD in women as compared with men. Drs Legato and Leghe have updated their chapter on the sex differences in normal myocardial anatomy and physiology. This chapter lays the foundation for understanding how sex is important in the pathophysi­ ology of cardiovascular disease. Drs Bassuk and Manson have updated their chapter on how risk factors for CVD dif­ fer in women and men. Drs Sharma, Nagy, and Blumenthal present an in-depth discussion of the impact of dyslipidemia in women and men. Drs Anderson and Chesney cover the increasingly important area of differences in women and men with regard to the role of stress and emotion. Lastly, new to the section are Drs Balaram and Blasberg, who addresses the role of sex and gender in cardiothoracic surgery. All together, the section covers the range of sex differences, in normal function to risk to the invasive treatment of CVD.

References 1. Merz NB, Bonow RO, Sopko G, et al. Endorsed by the American College of Cardiology Foundation, Women’s Ischemic Syndrome Evaluation: Current Status and Future Research Direc­tions. Report of the National Heart, Lung and Blood Institute Workshop: October 2–4, 2002: Executive Summary. Circulation 2004;109:805–7. 2. National Institute of Medicine. Exploring the Biological Contri­ butions to Human Health: Does Sex Matter? Washington, DC: National Academies Press; 2001. 3. Christian AH, Rosamond W, White AR, et al. Nine-year trends and racial and ethnic disparities in women’s awareness of heart disease and stroke: an American Heart Association national study. J Womens Health (Larchmt) 2007;16:68–81.

Chapter

14

Gender and the Heart: Sex-Specific Differences in the Normal Myocardial Anatomy and Physiology Marianne J. Legato1, and Jaswinder K. Leghe2 1 Professor Emerita of Clinical Medicine, Columbia University College of Medicine, New York, NY; Adjunct Professor of Medicine, Johns Hopkins, Department of Medicine, Baltimore, USA 2 Clinical Instructor, NYU School of Medicine, Department of Medicine, New York, NY, USA

differences in their unique experiences with common diseases of the cardiovascular system.

Introduction Nowhere in the literature of gender-specific medicine are the data more extensive than in the area of the cardiovascular system. Research on women began in this discipline in the late 1980s, with the stunning observation in 1987 of Steingart’s group1 that women with symptoms suggestive of coronary artery disease were treated less aggressively than men. That paper was followed in the same year by a second from the same investigators describing sex bias in the decision to recommend patients for coronary artery bypass surgery.2 The response of the cardiology community to the challenge of gender bias in clinical care was immediate and effective. Basic scientists and clinicians alike began an extensive and sustained effort to look directly and specifically at the female patient. The effort has not been only that of the scientific community, but proved to be of great interest to the lay public: four years after Steingart’s papers, we published the first book for the lay public about women’s unique experience of coronary artery disease, which received the Blakeslee Award of the American Heart Association.3 Over the past two decades, The National Institute of Heart, Lung, and Blood of the National Institutes of Health, the American Heart Association, and other cardiovascular subspecialty groups have developed effective and innovative educational programs for the professional and lay public as well as supporting a tremendous variety of research in sex-specific cardiology. The harvest of new and vitally important data that has resulted is a paradigm of the usefulness of utilizing gender as a significant variable in scientific investigation. This chapter will review the differences between men and women’s normal cardiac physiology and describe some Principles of Gender-Specific Medicine

The vasculature Coronary Arteries As a consequence of their smaller body size compared with that of men, women’s hearts are generally smaller than that of their male counterparts. Contrary to popular assumption, though, there is wide variability in the size of coronary arteries; the Coronary Artery Surgery Study (CASS) reported that the coronaries are not always smaller in women than in men and that most are entirely suitable for bypass grafting.4 The investigators commented, however, that small body size and the size of correspondingly smaller coronary arteries were the strongest predictors of perioperative mortality after bypass grafting; mortality after CABG was 1.9% in men in the period studied (1975–80) compared with 4.5% for women. Clearly, however, body size was an important consideration: if patient size were considered, the difference in mortality was not statistically significant. Investigators from the NHLBI PTCA Registry reported that only height was inversely related to patient mortality during angioplasty and commented: ‘although female gender is clearly a risk factor for mortality, it is not easily explained by body size or other variables examined.’5 However, in an important paper, Kuchner et al., interested in the data showing that outcome for women with coronary artery disease is worse than in men, carefully examined coronary artery size normalized for LV mass in 100 male and 100 female subjects without cardiac disease and found that cross-sectional area of the 151

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coronaries was larger in men6 (p 0.001; p 0.01 when data were normalized for body surface area). These authors believe that such a measurement should be made in normal hearts because heart disease impacts coronary artery size: coronary artery disease (CAD) significantly narrows luminal size while left ventricular hypertrophy (LVH) is accompanied by larger than normal arteries. Interestingly enough, when the authors calculated optimal size of coronary arteries using the law of minimum viscous energy loss for the transport of blood within the coronary circulation, women’s coronaries were smaller than theoretically expected while men’s tended to be larger than expected (see Figure 2 in Kucher et al.6). These authors pointed out that Roberts and Roberts’ often quoted study examined the three major epicardial coronaries post mortem in 98 patients who had had cardiac events during life showed no difference in crosssectional size.7 The fact that these arteries were examined after death and thus were not perfused may have introduced some error. In contrast, Dodge et al., who used angiographic data albeit from in very small sample of 10 patients, found that women had smaller epicardial arteries than men even after normalization for body surface area.8 O’Connor and colleagues commented that small vessel size was a predictor of increased risk of in-hospital mortality in 1325 patients undergoing CABG in both sexes, and found that sex was an important predictor of coronary size: within each quartile of body-size measure, women had smaller vessels than men.9 The diameter of intact, living coronary arteries is impacted by age and gender; Wellman et al. studied isolated pressurized coronary arteries from rats to assess the role of sex and circulating estrogen on coronary avascular function: myogenic tone was greater in isolated arteries from estrogen-deficient male or ovariectomized rats compared to those from normal female rats or ovariectomized rats receiving estrogen replacement.10 Removal of vascular endothelium or inhibition of nitric oxide (NO) synthase abolished the phenomenon, and tamoxifen increased the pressure-induced constrictions of coronary arteries from female and ovariectomized/supplemented rats. In a six year study of over 35 000 asymptomatic subjects 30–90 years of age, coronary artery calcification increased with age for both men and women, but it was uncommon for men 40 years of age and women 50 years of age to have electron beam tomography- (EBT-) detected coronary calcification. Across all age groups calcification was higher in men than in women. Men had calcium scores equal to those of women who were 15 years older than themselves, reflecting the earlier onset of coronary artery atherosclerosis in males.11

Vascular Function Vascular function is different in the two sexes, in part due to hormone-dependent gender differences. Premenopausal women have lower blood pressure than same-aged men; it rises after the menopause.12,13 Long-term estrogen administration improves vasodilation in men13 but does not lower

blood pressure in postmenopausal women; Reckelhoff suggests that the higher blood pressure of these individuals is due to the impact of unopposed testosterone on the vasculature.14 Estrogen titers in men are lower than those of women, but are physiologically relevant; aromatase inhibitors disrupt normal vascular relaxation in males. Conversion of testosterone to estrogen by aromatase inhibitors is essential to physiologic vascular function in men.15

The myocardium There are clearly differences in cardiac chamber size between the sexes, which are largely but not completely explained by differences in body size and become established at puberty. The Framingham study described greater LV mass in normal adult males compared with females, even after correction for body surface area.16 DeSimone et al. surveyed echocardiographic LV mass in normal weight normotensive subjects 4 months to 70 years of age; there was no significant difference (mean 6%) in LV mass before age 12, but at all older ages, LV mass was 25–38% greater in men than in women.17 This increase in LV mass began at puberty and was achieved by an increase in both chamber dimension and wall thickness in males. The impact of testosterone on left ventricular mass has not been assessed, but in animal models, differences in cardiac size disappear with orchiectomy and were restored by testosterone replacement.18 Interestingly, DeSimone’s group reported no significant difference in chamber wall thickness between the sexes. They concluded that most of the gender-specific differences in LV mass in adults paralleled differences in body size and were related to what they termed a ‘greater ‘physiological’ hypertrophy in men than in women.’ In their study of preadolescent children, Goble and colleagues established that lean body mass was a strong predictor (while the amount of body fat was a weak predictor), of LV mass.

The myofiber Most investigators believe that the number of cardiac myocytes (myofibers) is fixed early in life19 and that once myofibrils begin to appear in the developing cell, its capacity to divide is over. Nevertheless, Anversa’s group reviewed recent work which showed that at least under certain circumstances, the differentiated myocyte is capable of mitosis and that in cardiac decompensation, myocyte apoptosis plays a critical role in the structure of the failing heart.20 Whether or not the increase in LV mass that occurs at puberty is achieved by myocyte hypertrophy or by replication of myocytes has not been studied to our knowledge. Even whether male myocytes are larger than female myocytes in the normal heart has not been established; certainly, the techniques to determine this are available and the data would be of considerable interest because of its potential relevance to the possible therapeutic use

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of testosterone in augmenting the capacity of the failing myocardium. There are sex-related differences in the expression of myosin isotypes in the heart21 and in collagen and elastin content in the thoracic aorta of hypertensive male and female rats.22 Rosenkranz-Weiss et al. studied genderspecific differences in mRNAs for functional and structural proteins in rat myocardium and found that there were sexspecific differences in the post-pubertal period for virtually all the major proteins of the heart: female rats had demonstrably higher mRNAs for the contractile proteins alphaand beta-myosin heavy chain (MHC) than age-matched males (p 0.001).23 Messenger RNA for sarcomeric actin was 79% higher in females (p 0.001), than it was for cytoskeletal actin (p 0.01). These differences were not apparent at birth. The findings may be more related to the ratio of total ventricular weight to body weight; it was 19.5% greater in adult females than in males (p 0.001), whereas in neonates the ratio was not different as a function of sex. In contrast, mRNA for collagen type I or cytoskeletal actin in fibroblasts isolated from neonatal rat myocardium was not different in the sexes, although DNA synthesis in the cells was 328% higher in adult females (p 0.01) and even more pronounced (900%) in the neonate (p 0.001). Whether or not this is, as the authors suggested, connected to a greater ability to regenerate the interstitial compartment of the heart or, conversely, to produce more scar tissue in the myocardium in the female is unknown. Even more interesting would be to assess the effect of menopause and its associated lower level of estrogen on myocardial composition at the cellular level. The difference in contractile proteins after puberty may well be at least in part a consequence of hormonal regulation; there are myocardial receptors for both estrogen and testosterone in myocytes, whereas only receptors for androgens have been identified in interstitial cells.24 An important study from Yang et al. reports that hormonal regulation alone may not be responsible for sex-specific differences in the function of the heart and circulation.25 They point out that in spite of nearly identical genome sequences, thousands of genes showed sexual dimorphism in liver, adipose, brain, and muscle tissue. The authors postulate that the initiating events of sexual differentiation trigger differential expression in many mediator genes that further regulate the sexually dimorphic expression of downstream genes.

Contractile properties of the normal heart Cardiac contractility is greater in the premenopausal female than in age-matched males; in the postmenopausal female, hormone therapy maintains this advantage and if it is withdrawn, contractility decreases.26 Capasso et al., defining the contractile properties of left ventricular papillary muscles in the rat, found that there were sex-specific characteristics in

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the adult: while there was no difference in peak isometric tension developed, the males took longer to develop maximal force and relaxed more slowly.27 Interestingly, perturbations like an increase in external calcium and exposure to verapamil and/or norepinephrine did not affect these gender-specific contractile properties. These data were confirmed by the work of Wang et al., who showed that in rat papillary muscle, an increase in extracellular calcium did not affect the inotropic response differently in males and females.28 However, under the same conditions, female atrial muscle showed a significantly greater inotropic response than that of males.

Aging and myocardial characteristics Mallat et al. assessed the impact of myocyte apoptosis in the aging heart and found no significant impact of the process: over an age range of 21–93 years, the percent of myocyte death ranged from 0 to 0.04% of heart cells.29 However, apoptosis was significantly (p 0.01) higher (three-fold) in men compared with women. Augmenting this information is the work of Olivett et al., who showed with morphometric methods that aging was associated in men with an average loss of nearly a gram of myocardium a year, accounting for the loss of approximately 64 million cells and involved both ventricular chambers equally.30 Compensatory increase in myocyte cell volume kept ventricular mass relatively constant: myocyte cell volume increased 158 m3/year in the LV and 167 m3/year in the RV. In contrast, aging in women, unlike the case for men, did not produce either myocyte cell loss or reactive hypertrophy. Myocardial mass is better preserved in aging women than in aging men.31 As women age, LV mass increases. DeSimone’s group reported better LV function, larger LV chambers, and a trend toward greater LV mass in females. This was associated with a sex-specific increase in atrial natriuretic factor and decreased plasma renin activity in females as they aged, changes that were not seen in men. Thus, an increase in LV volume load may be responsible for the observed increase in LV mass of older relative to younger women.32 The increase in LV mass in women with aging may be directly and importantly related to an increase in body mass index (BMI) with advancing age, which is not the case for men. The Framingham experience with 318 individuals (mean age 57  9 years) without known heart disease showed that all volumetric and unidimensional measurements of LV size were greater in men than in women (p 0.001) and remained greater after adjustment for height (p 0.02).33 Correlation of measurements with BSA, however, showed that volumetric measures were greater in men than in women, but that there were increased linear dimensions in women: end-diastolic dimension indexed to BSA, for example was greater in women (p 0.001) than in men. Importantly, and consistent with the observations of other

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investigators, global left ventricular ejection fraction was the same for both sexes. Gardin et al. examined how sex, age, and disease affected LV mass and function in a large (5201 men and women) study of the free living elderly in a somewhat older population than the Framingham group: all were older than 65.34 In patients with clinical coronary artery disease (CAD), LV mass increased with age and was significantly greater in men than in women. In those without clinically apparent myocardial disease weight-adjusted LV mass increased minimally with increasing age. The decrease in diastolic compliance of the heart as women age may be related to a difference in the sexspecific difference in the connective tissue content of the myocardium that becomes evident at puberty.23

Congestive heart failure Investigators from the Framingham study have studied myocyte death in congestive heart failure and noted a significant impact of gender on the process.35 Necrosis increased seven-fold in the hearts of patients in failure; it was twofold higher, however, in men than in women (13-fold in women and 27-fold in men). Apoptosis was also increased almost three-fold in men with CHF: (35-fold in women and 85-fold in men). Congestive heart failure occurs later in the course of heart disease in women compared with men. This same group has speculated that the difference in lifespan between women and men might be related to a relatively more intact myocardium with aging.14 Luchner and colleagues, interested in the generally observed phenomenon that middle-aged women are less susceptible to congestive heart failure, more responsive to treatment and have a less malignant course and better survival than do same-aged men, studied gender-specific differences in cardiac remodeling in heart failure in men and women with a mean age of about 52 years.36 They found that men with moderate or severe LV dysfunction have an increase in both LV mass and cardiac natriuretic peptides, which is greater than that observed in women. In women, these parameters increase only with severe dysfunction. In general, males with LV dysfunction had a slightly lower ejection fraction, a marked increase in LV mass, higher renin and lower cardiac diuretic proteins (ANP and BNP) than females. The work suggested that men adapt to hemodynamic overload with more LV dilation and hypertrophy than women; this may contribute to the observed better survival of women with congestive heart failure. Several aspects of the molecular biology of the myocyte present intriguing possibilities for the relatively longer lives of women compared with men. For example, the different susceptibility of males compared with females to myocardial decompensation with stress might be partially explained by the sexual dimorphism of the creatine kinase/

phosphocreatine (CK/PCr) system which is involved in the anaerobic synthesis of adenosine triphosphate (ATP). Female rats showed a larger variety of these enzymes at any weight.37 This apparently increased potential for energy generation might be related to the longer life expectancy of women. Another factor that might be a significant factor in women’s increased longevity is the observed ability of estrogen and progesterone to regulate the production of heat-shock proteins (HSPs), a family of endogenous protective proteins that protect the heart.38 Another interesting possible explanation for the higher risk for cardiovascular disease in men than in same-aged women (at least until the age of 60) is the hypothesis that the activation of the serine/threonin protein kinase called Akt (also known as protein kinase B) is greater in female than in male mammalian hearts.39 In adult premenopausal women, the Akt content of myocyte nuclei is higher than in those of same-aged men. The phytoestrogen genistein increased the content still further. There is currently a flurry of interest in this pivotally important molecule, which is essential to the signaling pathways in the cell: it acts as a transducer of many functions that depend on the activation of phosphatidylinositol 3-kinase (PI3 kinase).40 Akt reduces cytopathic damage associated with myocardial injury, inhibits apoptosis in cultured myocytes and mitigates ischemia-reperfusion injury in vivo.41,42 It apparently achieves this by stimulating a variety of anabolic processes, including glucose uptake, glycogen production, and the synthesis of translational proteins.43 Regitz-Zagrosek and her colleagues have suggested that estrogen receptors are involved in the development of heart failure: they found a 1.8-fold increase in ER mRNA and protein in end-stage human dilated cardiomyopathy compared with controls.44 In normal hearts, the hormone receptor was co-localized with beta-catenin at the intercalated disc in normal hearts, but these workers found this not to be the case in diseased hearts. This loss of estrogen receptor and beta-catenin at the disc may have a role in the development and progression of heart failure. Dixon and Drobic point out that there may be an important role of increased sympathetic activity in heart failure.45 The linkage between norepinephrine and the trophic cytokines of transforming growth factor-beta family is not clearly defined, but TGF-1 is a known stimulator of cardiac growth and for collagen secretion by fibroblasts. The authors make a plea for further investigation of the mech­ anism of the role of sympathetic hormones in congestive heart failure, particularly with regard to whether male myocardium differs from the female in the release or the impact of TGF- in the diseased heart. Brower and colleagues have shown that ovarian hormones protect the heart challenged by volume overload from adverse ventricular remodeling.46 The role of the sarcoplasmic reticulum in controlling the duration and intensity as well as the resolution of the contractile event is well understood. Calcium handling deficits are important components of myocardial decompensation,

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but may not be the same in males and females. Dash et al. have explored the molecular events involved in SR calcium handling in human failing hearts, and suggested that males seemed to ‘endure a selective additional insult to SR calciumhandling’ than females, i.e., there is a reduction in Ser16PLB phosporylation in failing male hearts that was not altered in male donor hearts.47 This was not the case for females. An interesting study of transgenic mice (which overexpressed a superinhibitor of SR calcium ATPase affinity for calcium, revealed that males and females both developed depressed contractile function, left ventricular remodeling, and hypertrophy.48 Death occurred by 6 months in males, but females had normal systolic function until up to 12 months of age. Marelli and colleagues reported a novel therapy for dysfunctional or infarcted myocardium by supplying it with new plenipotential cells almost two decades ago.49 Subsequently, a large body of experimental data has accumulated to suggest that such a maneuver could augment myocardial function in the failing or infarcted heart. For example, Anversa and Nadal-Ginard50 have shown that multipotential cardiac stem cells may be able to replenish the heart damaged by myocardial infarction. The work in this field opens another door to possible augmentation of myocardial capacity by stem cells after injury; our current techniques of improving myocardial function after damage are restricted to unloading the heart and/or increasing the work capacity of existing myocytes. In a review of cell-based cardiac repair, Murry and his colleagues pointed out several caveats about the clinical effectiveness of this modality:51 There are still issues of feasibility, safety, and efficacy and, most important, we really do not have a complete understanding of how these autologous implants work in the body. It may be, for example, that the improved function reported by many investigators is not actually accompanied by true regeneration of myocardium; the impact may be due to cytokines and growth factors released by the new cells. Macia and Boyden point out that using stem cells to foster myocardial repair may be complicated by evidence that such therapy is proarrhythmic; these are excitable cells that would form gap junctions with each other and with the surviving cells in the damaged heart.52 Such cells retain intrinsic pacemaker function and may provide areas of slowed conduction in the heart that set up a potential for the production of arrhythmias. In an important and novel study, Bergmann and his colleagues used carbon dating to measure cardiomyoctye renewal in human hearts.53 The data revealed that cardiomyocytes are renewed at a rate of about 1% a year at the age of 25, but by 75, the renewal rate has diminished to about 0.45%. Thus, by age 50, 55% of cardiomyocytes of the myocardium present at birth remain, while 45% are generated at an older age. Non cardiomyocytes are replenished much more rapidly in the heart, i.e. they have a median annual turnover of 18% and a median age of 4 years. Whether new cardiomyocytes are generated from the duplication of existing, fully differentiated cells or from stem cells cannot be determined by the

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carbon dating method. A method to accelerate or promote the rate of myocardial cell proliferation is an attractive alternative to the use of autologous stem cells and obviously depends on the future development of such strategies.

Myocardial hypertropy Data from the Framingham study confirmed that hypertension seemed to be less of a risk factor for coronary events, congestive heart failure, and sudden death in women than in men with similar levels of blood pressure.54 Whether or not this is due to gender-specific differences in LV structure and function is still unclear: hypertensive premenopausal women have enhanced cardiac function compared with men.55 The difference tends to disappear after menopause. In contrast, in a study of young adults with normal or marginally elevated blood pressure (systolic pressures below 160 mmHg and/or diastolic blood pressure less than 100 mg/Hg), Hinderliter et al. found that there were no difference in systolic or diastolic function.56 In a study of whether left ventricular hypertrophy, a well-demonstrated risk factor for morbidity and mortality, has a different prognosis for men and women, Liao et al. studied 436 black patients with echocardiographically determined LVH who were free of angiographically determined CAD.57 The RR for death all-cause mortality was 2.09 for men and 4.87 for women; cardiac mortality RR was 1.3 for men and 7.5 for women. Thus, either fatal endpoint was strikingly higher in females. Devereux’s group, looking at gender and diastolic function in hypertension, showed that men had slower early diastolic left ventricular filling than did women, implying a gender difference in diastolic function in LV hypertrophy.58 The molecular mechanisms involved in adaptation to pressure overload may differ as a function of sex: in a study of Wistar rats stressed by ascending aortic stenosis, although the magnitude of LV hypertrophy and systolic wall stress were similar in both genders, male hearts demonstrated a depressed contractile reserve, a greater expression of beta-myosin heavy chain and ANF mRNA, and depressed sarcoplasmic reticulum Ca2ATPase MRNA levels compared to those of females.59 Regitz-Zagrosek and her colleagues point out that there are sex differences in left ventricular hypertrophy in pressure overloaded hearts, and postulate that differences in estrogen receptor-mediated effects are responsible for those differences.60 In another interesting study, a gender-specific response of rat myocardial fibroblasts grown in tissue culture to hypoxia was observed: female cells were resistant to hypoxia-induced inhibition of DNA synthesis while male cells were susceptible.61 Estrogen seemed to be a significant factor in the difference in response: female cells hypoxia and estrogen combined led to an inhibition of DNA synthesis, whereas in male cells, estrogen only partially reversed the hypoxia-induced inhibition of DNA synthesis.

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It is clear that there are sex differences in the adaptation of the heart to hypertension: the Framingham study showed that women with isolated hypertension developed concentric LV hypertrophy (an increase LV wall thickness and mass without chamber enlargement) in contrast to men, whose increased LV mass by an increase in chamber size without an increase in wall thickness.62 There are also sexspecific differences in left ventricular systolic function in hypertensive patients: in a study of 944 men and women with untreated hypertension, LV function was superior in women: LV ejection fraction was 2–3% higher (p 0.02), midwall fractional shortening was 0.5% higher, and stresscorrected LV midwall fractional shortening 2% higher (p 0.004) in women compared with men.63 Aortic stenosis (AS) produces virtually the same results in left ventricular morphology as is the case for hypertension. Carroll et al. compared ventricular geometry in older men and women with AS and showed that women developed concentric hypertrophy and better contractile properties than men.64 Women’s dP/dt was better, they generated more systolic pressure and had a higher cardiac index than men. Men, on the other hand, developed a higher mean pulmonary artery pressure and a subnormal ejection performance that was three times worse than that of women. Clearly, the response of the left ventricular to pressure overload produces better contractile function in females than in males. Other cardiovascular responses to a demand for increased work were sex-specific and varied as a function of the type of demand. For example, Wagner and Horvath studied the response to cold exposure and discovered that women did not change their heart rate, while that of men slowed and thereby stroke volume was increased.65 Challenged by supine exercise, men increased their ejection fraction more than women, while end-diastolic volume index was higher in women.66 These differences were not explained by differences in exercise capacity. Some animal data, at least, do not support the idea that the gender-specific response of the heart to a demand for increased work is the consequence of hormones: Malhotra et al., studying the impact of sex hormones on the development of cardiac hypertrophy in rats, did not find that gonadectomy modified the gender-specific adaptive characteristics of the myocardium.67 There are sex differences in inherited and acquired abnormalities of the myocardium: some familial hypertrophic cardiomyopathies are more severe in males than in females.68 Women with aortic stenosis have more myocardial hypertrophy and better contractile function than men with this disorder.69 The response of the myocardium is modified by the hormonal milieu: female gender confers protection in animals who are reperfused after ischemic injury.63 In fact, testosterone impairs cardiac function in a mouse model of myocardial infarction in both males and females, while estrogen improves it.70

Hormones and the heart The sex-specific differences in the heart have prompted a widely held hypothesis that the hormonal milieu of men and women modulates not only the functional characteristics of the cardiovascular system, but is the reason premenopausal women are relatively less likely to develop coronary artery disease (CAD). CAD occurs a decade later in women, and the incidence of myocardial infarction in men and women is comparable only after the age of 60. Extensive investigation of the actions of estrogen on tissues and organs have established that it is a growth and regulatory hormone that is essential for optimal function. It is now well established that estrogen has relatively immediate (non-genomic) effects that are the consequence of its action at the cell membrane as well as more delayed (genomic) effects. The latter involve interaction with estrogen receptors at the level of the cell nucleus which sets off a cascade of events which have an impact on transcription and increase protein production in the cell. Although the precise details of how estrogen exerts its actions in the body are not completely understood, it is clear that it involves complex interactions not only between the hormone and its receptors, but involves estrogen-receptor associated proteins and its genomic impact depends, of course, on the regions of the cell controlled by specific target genes. Among the things we know about estrogen are the following: Estrogen regulates vasomotricity by stimulating production of the vasodilators nitrous oxide71 (this compound relaxes the smooth muscle in the arterial wall) and prostacyclin. Estrogen also protects against vascular injury: it reendothelializes injured vessels72 and inhibits apoptosis of cultured human endothelial cells.73 It also inhibits both the migration74 and proliferation75 of smooth muscle cells in vitro. There are estrogen receptors in the smooth muscle cells of the coronary arteries76 and in endothelial cells.77 Thus, estrogen can increase nitrous oxide production by endothelial cells, inhibit their apoptosis78 and promote their angiogenic activity.79 Importantly, while estrogen has an ability to prevent plaque formation in the arteries of oophorectomized monkeys fed an atherogenic diet,80 it had no effect on established plaque. The impact of estrogen on serum lipids is well established: it is one of the few interventions that raises high-density lipoprotein cholesterol (HDL-C) as well as lowering total cholesterol (TC), low-density lipoprotein (LDL-C) and lipoprotein a (Lp[a]). The hormone also has a role as an antioxidant in vivo: in postmenopausal women, exogenous estrogen decreased the oxidation of LDL cholesterol.81 Estrogen and its important regulatory functions are not isolated to women. Smith et al., for example, reported the case of a man who had a mutation in his estrogenreceptor gene; not only did he have impaired fertility; he

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was severely osteoporotic.82 (Estrogens are antiresorptive agents in bone.) The 2002 data from several randomized prospective clinical trials including the Women’s Health Initiative have reversed the prevailing opinion about the efficacy of using hormonal replacement therapy (HRT) for the prevention and/or the amelioration of coronary artery disease (CAD). Whereas observational studies overwhelmingly indicated that women profited from HRT, with a 40–50% lower incidence of CAD in users compared with non-users, recent randomized prospective studies have shown just the opposite: at least in older women (mean age 64–67), HRT not only has no demonstrable benefit in terms of preventing and/or ameliorating CAD, it presents an unacceptable risk of actual worsening of existing disease. It is conceivable that in women of this age, in whom the incidence of clinically significant CAD is equal to that of men, the coronaries already have significant plaque. Estrogen has no impact on established plaque and, in fact, may actually have helped destabilize existing plaque in some instances, accounting for the early harm noted in a subset of the study population. For a review of the factors that may reconcile the data from earlier, observational studies on the association of estrogen therapy with a markedly lowered incidence of coronary artery disease and those from the more recent, randomized studies showing not only early harm in a subset of the populations studied, but a failure to prevent and/or ameliorate the progression of coronary artery disease once established, see reference.83 The action of endogenous hormones may not be identical to that of exogenous preparations, and there is a large body of information suggesting that estrogen is essential for optimal functioning of the cardiovascular system. In spite of the recent data, investigators remain convinced that endogenous hormones play an important and unique role in the relative protection premenopausal women have from CAD. The activity of the renin–angiotensin system in males and females is different and is complexly impacted by estrogen. Women have higher levels of angiotensin than men, possibly due to an estrogen response component of its gene promoter.84 Both HT and oral contraceptives increase angiotensinogen in the circulation.85,86 The impact of estrogen on angiotensin synthesis in the liver is almost exclusively the result of oral preparations; transdermal estrogen did not produce this effect.68,69,87 Plasma renin levels are actually depressed in women compared with men, as is angiotensinconverting enzyme activity.88 The same is true of estrogen’s action on the AT-1 receptor,89 implying that overall, estrogen suppresses the conversion of angiotensin into renin and the intensity of action in females. These characteristics of the R–A system may help explain the progression of congestive heart failure in men and women and this may be one facet of estrogen’s protective effect on the cardiovascular

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system in the premenopausal patient. It also has important implications for postmenopausal HT therapy, particularly with regard to the choice of route of administration.

Electrophysiology and gender There are well described electrophysiologic differences in men and women. It has been known for almost a century that women have a faster resting heart rate than men.90 The difference is apparent in children as young as 5 years, and is not changed even by sleep.91 This is not due to differences in autonomic tone, but may be related to a difference in exercise capacity between the sexes, which Burke et al. found was the only predictor of heart rate.92 More recent data confirm this: Taneja et al. studied 354 normal patients and found that the sinus cycle length was longer in men, as was QRS duration and HV interval.93 Sinus node recovery time was longer in men, but AERP and VERP were not different between the sexes. At puberty, the rate-corrected QT (QTc) of the electrocardiogram shortens in males while that of women remains the same.82 After 50 years of age, the difference gradually disappears.94 Hormones may impact the duration of the QT interval: Burke showed that the QT interval was shorter in the luteal than in the follicular phase of the menstrual cycle84 in the presence of complete autonomic blockade. There are differences in autonomic nervous system activity in men and women that influence cardiac rates and rhythms. In general in humans, women have a preponderance of vagal compared with sympathetic responsiveness,95–97 while men suggest a preponderance of sympathetic control of cardiac function.98 In general, men show a greater rise of systolic blood pressure to a number of cardiovascular stressors.99 These include hypoglycemia,100 changes in blood oxygen content,101 and mental stress.102 Hormones also modify the electrical characteristics of the heart (for a comprehensive review see Pham and Rosen103). Hara et al. showed that dihydrotestosterone shortened the action potential duration (APD) of ooporectomized rabbits at cycle lengths greater than 500 msec, while estrogen prolonged it at cycle lengths longer than 100 msec, almost completely as a consequence of a prolongation of the late portion of phase 3.104 If the investigators added an antiarrhythmic drug, E4031, that prolongs repolarization by blocking the potassium channel, Ikr had no impact on the APD of rabbits exposed to DHT, but significantly increased the APD and promoted early after-depolarizations in estradiol-treated animals. This work supports our current hypothesis that the susceptibility of women to drugs that prolong the QTc is related to an intrinsic functional difference in or different density of the potassium channels in the female heart compared with that of the male. Recent work by Pham et al. demonstrated that hormones also modulate

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I Ca,L density in females but not in males and they hypothesized that the greater dispersion of these channels might also contribute to gender differences in repolarization and the relatively greater susceptibility of women to torsades de pointes.105 Ebert et al. reviewed the molecular basis for the susceptibility of women to drug-induced cardiac arrhythmias and ascribed it to the longer QT of women which reflects a relative prolongation of early repolarization.106 They pointed out that the increased tendency of women to develop torsade de pointes in response to antiarrhythmic drugs is not related to serum drug levels or to other associated factors like low magnesium levels, hypothyroidism or digoxin intoxication. The longer repolarization time of women may be the basis for the higher incidence in women of syncope and torsade in patients with complete heart block and marked bradycardia.107 Women are more susceptible to ectopic beats and arrhythmias as a function of hormonal shifts: many report an increased incidence of arrhythmias and premature beats during the luteal phase of their cycle. The arrhythmias of the perimenopausal period often respond to low dose oral contraceptives or transdermal estrogen. On the other hand, Kounis et al. reported an increased incidence of supraventricular tachycardias during pregnancy in women with anomalous AV conduction of the Wolff–Parkinson–White type.108 They attributed this to a number of factors, including increased blood volume and cardiac output, but suggested that increased estrogen concentrations might potentiate vulnerability. Estrogen increases the number of beta-adrenergic receptors in the myocardium109 and Romhilt reported that high estrogen oral contraceptives increased ventricular ectopy in women without intrinsic heart disease.110 There are sex-specific triggers for right ventricular outflow tract ventricular tachycardia: for men, exercise was more often the precipitating cause whereas for women, 59% reported that hormonal fluxes were associated with the arrhythmias.111 In fact, 41% of women felt that hormonal shifts were the only recognizable precipitating factor for their ectopic rhythms.

References   1. Tobin JN, Wassertheil-Smoller S, Wexler JP, et al. Sex bias in considering coronary bypass surgery. Ann Intern Med 1987;107:19–25.   2. Steingart RM, Packer M, Hamm P, et al. Sex differences in the management of coronary artery disease. N Engl J Med 1991;325:226–30.   3. Legato MJ, Colman C. The Female Heart: The Truth About Women and Coronary Artery Disease. New York, NY: Prentice Hall; 1991, 252.   4. Fisher LD, Kennedy JW, Davis KB, et al. Association of sex, physical size and operative mortality after coronary artery bypass in the Coronary Artery Surgery Study (CASS). J Thorac Cardiovasc Surg 1982;84:334–41.

  5. Kent KM, Kelsey SF, James M, et al. Percutaneous transluminal coronary angioplasty in women: 1985–1986 National Heart, Lung and Blood Institute-PTCA Registry. In: NK Wenger, L Speroff, B Packard, eds. Cardiovascular Health and Disease in Women. Greenwich, CT: Le Jacq Communications; 1993:115, (ch. 19).   6. Kucher N, Lipp E, Schwerzmann M, et al. Gender differences in coronary artery size per 100 g of left ventricular mass in a population without cardiac disease. Swiss Med Wkly 2001;131:610–15.   7. Roberts CS, Roberts WC. Cross-sectional area of the proximal portion of the three major epicardial coronary arteries in 98 necropsy patients with different coronary events: relationship to heart weight, age and sex. Circulation 1980; 62:953–59.   8. Dodge JT Jr, Brown BG, Bolson EL, et al. Lumen diameter of normal human coronary arteries: influences of age, sex, anatomic variation and left ventricular hypertrophy or dilatation. Circulation 1992;86:232–46.   9. O’Connor NJ, Morton JR, Birkmeyer JD, et al. Effect of coronary artery diameter in patients undergoing coronary bypass surgery. Northern New England Cardiovascular Disease Study Group. Circulation 1996;93(4):652–55. 10. Wellman GC, Bonev AD, Nelson MT, et al. Gender differences in coronary artery diameter involve estrogen, nitric oxide and Ca2 dependent K channels. Circulation Res 1996;79:1024–30. 11. Hoff JA, Chomka EV, Krainik AJ, et al. Age and gender distributions of coronary artery calcium detected by electron beam tomography in 35,246 adults. Am J Cardiol 2001;87(12):1335–39. 12. Dubey RK, Oparil S, Imthum B, Jackson EK. Sex hormones and hypertension. Cardiovasc Res 53:688–708. 13. Sader KMA, Celermajer DS. Endothelial function, vascular reactivity and gender differences in the cardiovascular system. Cardiovasc Res 2002;53:597–604. 14. Reckelhoff JR. Gender differences in the regulation of blood pressure. Hypertension 2001;37:1199–208. 15. Mendelsohn ME, Rosano GMC. Hormonal regulation of normal vascular tone in males. Circ Res 93:1142–5. 16. Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322:1561–66. 17. DeSimone G, Devereux RB, Daniels SR, et al. Gender differences in left ventricular growth. Hypertension 1995;26:979–83. 18. Koenig H, Goldstone A, Lu CY. Testosterone-mediated sexual dimorphism of the rodent heart. Ventricular lysosomes, mitochondria and cell growth as modulated by androgens. Circ Res 1982;50:782–87. 19. Zak R. Development and proliferative capacity of cardiac muscle cells. Circ Res 1974;35:17–26. 20. Anversa P, Leri A, Kajstura J, et al. Myocyte growth and cardiac repair. J Mol Cell Cardiol 2002;34(2):91–105. 21. Schaible TF, Malhotra A, Ciambrone G, et al. The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats. Circ Res 1984; 54:38–49. 22. Wolinsky H. Effects of hypertension and its reversal on the thoracic aorta of male and female rats. Circ Res 1971;28:622–37.

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23. Rosenkranz-Weiss P, Tomek RJ, Mathew J, et al. Gender-specific differences in expression of mRNA’s for functional and structural proteins in rat ventricular myocardium. J Mol Cell Cardiol 1994;26:261–70. 24. McGill HC Jr, Sheridan PJ. Nuclear uptake of sex steroid hormones in the cardiovascular system of the baboon. Circ Res 1981;48:238–44. 25. Yang X, Schadt EE, Want S, et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 2006:995–1003. 26. Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:15611–16. 27. Capasso JM, Remily RM, Smith RH, et al. Sex differences in myocardial contractility in the rat. Basic Res Cardiol 1983;78(2):156–71. 28. Wang SN, Wyeth RP, Kennedy RH. Effects of gender on the sensitivity of rat cardiac muscle to extracellular Ca2. Eur J Pharmacol 1998;361(1):73–77. 29. Mallat Z, Fornes P, Costagliola R, et al. Age and gender effects on cardiomyocyte apoptosis in the normal human heart. J Gerontol Med Sci 2001;56a(11):m719–23. 30. Olivett G, Giordano G, Corradi D. Gender differences and aging: effects on the human heart. J Am Coll Cardiol 1995;26(4):1068–79. 31. Olivetti G, Giordano G, Corradi D. Gender differences and aging effects on the human heart. J Am Coll Cardiol 26:1067–79. 32. DeSimone G, Devereux RB, Roman MJ, et al. Gender differences in left ventricular anatomy, blood viscosity and volume regulatory hormones in normal adults. Am J Cardiol 1991;68(17):1704–8. 33. Salton CJ, Chuang ML, O’Donnell CJ, et al. Gender differences and normal left ventricular anatomy in an adult population free of hypertension. J Am Coll Cardiol 2002; 39:1055–60. 34. Gardin JM, Siscovick D, Anton-Culver H, et al. Sex, age and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly. The Cardiovascular Health Study. Circulation 1995;91(6):1739–48. 35. Guerra S, Leri A, Wang X, et al. Myocyte death in the failing human heart is gender dependent. Circ Res 1999;85(9):856–66. 36. Luchner A, Brockel U, Muscholl M. Gender-specific differences of cardiac remodeling in subjects with left ventricular dysfunction: a population-based study. Cardiovasc Res 2002;53:720–27. 37. Ramierez OC, Jimenez E. Sex differences in rat heart: different patterns of catalytically active creatine kinase isoenzymes. Arch Inst Cardiol Mex 2000;70(5):438–47. 38. Knowlton AA, Sun L. Heat-shock factor-1, steroid hormones and regulation of heart-shock protein expression in the heart. Am J Physiol Heart Circ Physiol 2001;280(1):H455–64. 39. Camper-Kirby D, Welch S, Walter A, et al. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res 2001;88:1020–27. 40. Kandel ES, Hay N. The regulation and activities of the multi­ functional serine/threonine kinase Akt/PKB. Exp Cell Res 1999;253(1):210–29.

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41. Matusi T, Li L, delMonte F, et al. Adenoviral gene transfer of activated phosphatidylinositol 3kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 1999;1000:2373–79. 42. Fujio Y, Nguyen T, Wencker D, et al. Akt promotes survival of cardiomyocytes in vitro and protects against ischemiareperfusion injury in mouse heart. Circ Res 2000;101:660–67. 43. Sugden PH, Clerk A. Akt like a woman. Gender differences in susceptibility to cardiovascular disease. Circ Res 2001;88:975–77. 44. Mahmoodzadeh S, Eder S, Nordmeyer J, et al. Estrogen receptor alpha up-regulation and redistribution in human heart failure. FASEB J 20:926–34. 45. Dixon IMC, Brobic V. Gender dependency in the pathogenesis of cardiac hypertrophy. Effect of norepinephrine on transforming growth factor-beta release in female heart. Hypertension 2004;44:1–2. 46. Brower GL, Gardner JD, Janicki JS. Gender mediated cardiac protection from adverse ventricular remodeling is abolished by ovariectomy. Mol Cell Biochem 2003;251:89–95. 47. Dash R, Frank KF, Carr AN, et al. Gender influences on sarco­plasmic reticulum Ca2-handling in failing human myocardium. J Mol Cell Cardiol 2001;33:1345–53. 48. Haghighi K, Schmidt AG, Hoit BD. Superinhibition of sarco­ plasmic reticulum function by phospholamban induces cardiac contractile failure. J Biol Chem 2001;276(26):24145–51. 49. Marelli D, Desrosiers C, El-Alfy M, et al. Cell transplant­ ation for myocardial repair: an experimental approach. Cell Transplant 1992;1:383–90. 50. Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodelling. Nature 2002;415(6868):240–43. 51. Murry CE, Field LJ, Measche P. Cell-based cardiac repair. Reflections at the 10-year point. Circulation 2005;112:3174–83. 52. Macia E, Boyden PA. Stem cell therapy is proarrhythmic. Circulation 2009;119:1814–23. 53. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science April 3, 2009;324:98–101. 54. Kannel WB, Doyle JT, Ostfeld AM, et al. Optimal resources for primary prevention of atherosclerotic diseases: Atherosclerosis Study Group. Circulation 1984;70:155A–205A. 55. Garavaglia GE, Messerli FH, Schmieder RE, et al. Sex differences in cardiac adaptation to essential hypertension. Eur Heart J 1989;10:1110–14. 56. Hinderliter AL, Light KC, Willis PW IV. Gender differences in left ventricular structure and function in young adults with normal or marginally elevated blood pressure. Am J Hypertens 1992;5:32–36. 57. Liao Y, Cooper RS, Mensah GA, et al. Left ventricular hypertrophy has a greater impact on survival in women than in men. Circulation 1995;92(4):805–10. 58. Bella JN, Palmieri V, Kitzman DW, et al. Gender difference in diastolic function in hypertension (the HyperGEN study). Am J Cardiol 2002;89(9):1052–56. 59. Weinberg EO, Thienelt CD, Katz SE. Gender differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol 1999;34(1):264–73. 60. Nordmeyer J, Eder S, Mahmoodzadeh S, et al. Upregulation of myocardial estrogen receptors in human aortic stenosis. Circulation 2004;110:3270–75.

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s e c t i o n 3     Cardiovascular Disease l

61. Griffin M, Lee HW, Zhao L. Gender-related differences in proliferative response of cardiac fibroblasts to hypoxia: effects of estrogen. Mol Cell Biochem 2000;215(1–2):21–30. 62. Krumholz HM, Larson M, Levy D. Sex differences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol 1993;72(3):310–13. 63. Gerdts E, Zabalgiotia M, Bjornstad H, et al. Gender differences in systolic left ventricular function in hypertensive patients with electrocardiographic left ventricular hypertrophy (the LIFE study). Am J Cardiol 2001;87(8):980–83. 64. Carroll JD, Carroll EP, Feldman T, et al. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 1992;86:1099–107. 65. Wagner JA, Horvath SM. Cardiovascular reactions to cold exposure differ with age and gender. J Appl Physiol 1985;58:187–92. 66. Hanley PC, Zinsmeister AR, Clemens IP, et al. Gender related differences in cardiac response to supine exercise assessed by radionuclide angiography. J Am Coll Cardiol 1989;13:624–29. 67. Malhotra A, Buttrick P, Scheuer J. Effects of sex hormones on development of physiological and pathological cardiac hypertrophy in male and female rats. Am J Physiol 1990;259(3 Pt 2):H866–71. 68. Gesuterfer-Lowrance AAT, Christe M, Conner DA, et al. A mouse model of familial hypertrophic cardiomyopathy. Science 1996;272:731–34. 69. Douglas PS, Katz SE, Weinberg EO, et al. Hypertrophic remodeling: gender differences in the early response to LV pressure overload. J Am Coll Cardiol 1998;32:1118–25. 70. Cavasin MA, Sankey SS, Yu AL, et al. Estrogen and testosterone have opposing effects of chronic cardiac remodeling and function in mice. Am J Physiol Heart Circ Physiol 2003;284:H1560–69. 71. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340:1801–11. 72. Krasinski K, Spyridopoulos I, Asahara T, et al. Estradiol accelerates functional endothelial recovery after arterial injury. Circulation 1997;95:1768–72. 73. Spyridopoulos I, Sullivan AB, Kearney M, et al. Estrogenreceptor-mediated inhibition of human endothelial cell apoptosis: estradiol as a survival factor. Circulation 1997;95:1505–14. 74. Kolodgie FD, Jacob A, Wilson PS, et al. Estradiol attenuates directed migration of vascular smooth muscle cells in vitro. Am J Pathol 1996;148:969–76. 75. Bhalla RC, Toth KF, Bhatty RA, et al. Estrogen reduces proliferation and agonist-induced calcium increase in coronary artery smooth muscle cells. Am J Physiol 1997;272:H1996–2003. 76. Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 1994;89:1943–50. 77. Venkov CD, Rankin AB, Vaughan DE. Identification of authentic estrogen receptor in cultured endothelial cells: a potential mechanism for steroid hormone regulation of endothelial function. Circulation 1996;94:727–33. 78. Spyridopoulos I, Sullivan AB, Kearney M, et al. Estrogenreceptor-mediated inhibition of human endothelial cell apoptosis: estradiol as a survival factor. Circulation 1997;95: 1505–14.

79. Morales DE, McGowan KA, Grant DS, et al. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 1995;91:755–63. 80. Clarkson TB, Anthony MS, Klein KP. Hormone replacement therapy and coronary artery atherosclerosis: the monkey model. Br J Obstet Gynaecol 1996;103(Suppl 13):53–57. 81. Sack MN, Rader DJ, Cannon RO III. Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet 1994;343:269–70. 82. Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331:1056–61. 83. Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis and vascular function. Cardiovasc Res 2002;53:605–19. 84. Feldmer M, Kaling M, Takahashi S, et al. Glucocorticoid-and estrogen-responsive elements in the 5flanking region of the rat angiotensinogen gene. J Hypertens 1991;9:1005–12. 85. Hassager C, Riis BJ, Strom V, et al. The long-term effect of oral and percutaneous estradiol on plasma renin substrate and blood pressure. Circulation 1987;76:753–58. 86. Schunkert H, Danswer AH, Hense HW, et al. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation 1997;95:39–45. 87. De Lignieres B, Basdevant A, Thomas G, et al. Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metabol 1986;62:536–41. 88. Proudler AJ, Ahmed AI, Crook D, et al. Hormone replacement therapy and serum angiotensin-converting enzyme activity in post-menopausal women. J Hypertens 1999;17:405–11. 89. Nickenig G, Baumer AT, Grohe C, et al. Estrogen modulates AT1 receptor gene expression in vitro and in vivo. Circulation 1998;97:2197–201. 90. Bazett H. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353–70. 91. Larsen JA, Kadish AH. Effects of gender on cardiac arrhythmias. J Cardiovasc Electrophysiol 1998;9:655–64. 92. Burke J, Goldberger J, Ehlert FA, et al. Gender differences in heart rate before and after autonomic blockade: evidence against an intrinsic gender effect. Am J Med 1996; 100:537–43. 93. Taneja T, Mahnert BW, Passman R, et al. Effects of sex and age on electrocardiographic and cardiac electrophysiological properties in adults. Pacing Clin Electrophysiol 2001;24:16–21. 94. Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1991;8:690–95. 95. Madden K, Savard GK. Effects of mental state on heart rate and blood pressure variability in men and women. Clin Physiol 1995;15:557–69. 96. Ramaekers D, Ector H, Aubert AE, et al. Heart rate variability and heart rate in healthy volunteers. Is the female autonomic nervous system cardioprotective? Eur Heart J 1998; 19:1334–41. 97. Yamasaki Y, Kodama M, Matsuhisa M, et al. Diurnal heart rate variability in healthy subjects: effects of aging and sex difference. Am J Physiol 1996;271:H303–10.

C h a p t e r 1 4     Gender and the Heart l

  98. Ryan SM, Goldberger AL, Picus SM, et al. Gender and agerelated differences in heart rate dynamics: are women more complex than men? J Am Coll Cardiol 1994;24:1700–7.   99. Stoney CM, Davis MC, Matthews KA. Sex differences in physiological responses to stress and in coronary heart disease: a causal link? Psychophysiology 1987;24:127–31. 100. Davis SN, Shavers C, Costa F. Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds. Am J Physiol Endocrinol Metab 2000;279:E1054–63. 101. Jones PP, Davy KP, Seals DR. Influence of gender on the sympathetic neural adjustments to alterations in systemic oxygen levels in humans. Clin Physiol 1999;19:153–60. 102. Cooke JP, Creager MA, Osmundson PJ, et al. Sex differences in control of cutaneous blood flow. Circulation 1990;82:1607–15. 103. Pham RV, Rosen MR. Sex, hormones and repolarization. Cardiovasc Res 2002;53:740–51. 104. Hara M, Danilo P Jr, Rosen MR. Effects of gonadal steroids on ventricular repolarization and on the response to E4031. J Pharmacol Exp Ther 1998;285:1068–72. 105. Pham TV, Robinson RB, Danilo P Jr, et al. Effects of gonadal steroids on gender-related differences in transmural

106.

107.

108.

109.

110.

111.

161

dispersion of L-type calcium current. Cardiovasc Res 2002; 53:752–62. Ebert SN, Ziao-Ke L, Woosley RL. Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health 1998; 7:547–57. Kurita T, Ohe T, Marui N, et al. Bradycardia-induced abnormal QT prolongation in patients with complete atrioventricular block with torsades de pointes. Am J Cardiol 1992;69:628–33. Kounis NG, Zavras GM, Papadaki PJ, et al. Pregnancyinduced increase of supraventricular arrhythmias in Wolff– Parkinson–White syndrome. Clin Cardiol 1994;18:137–40. Klangkalya B, Chan A. The effects of ovarian hormones on beta-adrenergic and muscarinic receptors in rat heart. Life Sci 1988;42:2307–14. Romhilt DW, Chaffin C, Choi SC, et al. Arrhythmias on ambulatory electrocardiographic monitoring in women without apparent heart disease. Am J Cardiol 1984;54:582–86. Marchlinski FE, Megan P, Deely MP, et al. Sex-specific triggers for right ventricular outflow tract tachycardia. Am Heart J 2000;139:1009–13.

C hapter

15

Gender-Specific Aspects of Selected Coronary Heart Disease Risk Factors: A Summary of the Epidemiologic Evidence Shari S. Bassuk1, and JoAnn E. Manson2 1

Epidemiologist, Brigham and Women’s Hospital, Division of Preventive Medicine, Boston, MA, USA Professor of Medicine and the Elizabeth F. Brigham Professor of Women’s Health, Harvard Medical School, Brigham and Women’s Hospital, Division of Preventive Medicine, Boston, MA, USA 2

Until recently, coronary heart disease (CHD) was widely perceived to be less of a public health problem for women than for men. Although the incidence of CHD in women trails that in men by 10 years for total CHD and by 20 years for more serious clinical events such as myocardial infarction (MI) and sudden cardiac death, CHD nevertheless becomes the leading killer of US men by 45 years of age and of women by 65 years of age.1 In fact, once women develop overt CHD, they have a worse prognosis than men; case-fatality rates are higher for women following both MI and myocardial revascularization procedures, with 23% of heart attacks in women but only 18% of heart attacks in men followed by death within one year.1 Moreover, in 64% of women but only 50% of men who died suddenly from CHD, there were no previous symptoms of this disease.1 These gender differences are not entirely accounted for by differences in age or the fact that women tend to have more advanced disease at time of diagnosis. Finally, secular declines in heart disease mortality at younger ages have been less pronounced among women than among men. Among men aged 35–54 years, such mortality declined on average by 6.2% in the 1980s, 2.3% in the 1990s, and 0.5% per year from 2000 to 2002.1 Among similarly aged women, the average annual rate during these periods fell by 5.4% and 1.2% and then increased by 1.5%, respectively,1 a trend that may have resulted in part from a greater delay time from MI symptoms to diagnosis and less aggressive management. Boosting prevention and treatment efforts

Principles of Gender-Specific Medicine

among women is necessary to forestall potentially widening gender disparities in coronary outcomes. Many of the risk factors for CHD and strategies for preventing disease in men are also important for women. However, the magnitude of their effects may differ depending on sex. For example, the correlation of some major risk factors such as cigarette smoking, hypertension, and ­hypercholesterolemia with CHD is comparable in both sexes, but diabetes is a far more potent coronary risk factor among women than among men. Other exposures – most notably postmenopausal hormone therapy – are unique to women. In this chapter, we review the literature on selected risk factors for CHD among women.

Cigarette smoking Gender differences in rates of smoking – the leading preventable cause of death in the United States – have diminished in recent decades. From 1965 to 2005, smoking prevalence among US men declined from 52% to 24%, while that among women dropped from 34% to 18%.2,3 In epidemiologic studies, smoking is associated with at least a two-fold increase in CHD incidence and a 70% increase in CHD mortality. These risks are similar in women and men, or somewhat stronger in women.4 Among 117 000 female nurses aged 30–55 followed for 12 years in the Nurses’ Health Study, the age-adjusted relative risks (RR)

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C h a p t e r 1 5     Gender-Specific Aspects of Selected Coronary Heart Disease Risk Factors l

associated with current smoking were 4.13 for fatal CHD, 3.88 for nonfatal MI, and 3.93 for total CHD.5 There appears to be no safe exposure level; smoking only 1–4 cigarettes/ day (vs. none) doubled the risk for total CHD. The harmful effect of smoking persists in older populations; among more than 1 million adults aged 65 and older ­followed for 6 years in the American Cancer Society’s Cancer Prevention Study II, female and male smokers were 70% and 50% more likely to die from CHD, respectively, than their never-smoking counterparts.6 Environmental (secondhand) tobacco smoke is also a coronary risk factor.7 In a 10-year follow-up of 32 000 ­nonsmoking Nurses’ Health Study participants, occasional and regular exposure to environmental tobacco smoke, as compared with no exposure, predicted a 58% and 91% increase in risk for total CHD, respectively, after adjustment for potential confounders.8 Case-control studies have generally found that CHD risk returns to the level of never smokers within 5 years, regardless of how much or how long a person smokes.9–11 In contrast, cohort studies generally report longer intervals between smoking cessation and the waning of excess CHD risk;12–15 in some cohorts, CHD mortality of former heavy smokers remained 20–40% above that of nonsmokers 10 years after quitting. The reason for the divergence in case-control and cohort results is not known, but cohort studies that assess smoking only at baseline may be biased by exposure misclassification related to recidivism (resumption of smoking among former smokers). In the Nurses’ Health Study, which updated smoking status every 2 years, one-third of the excess CHD risk among former smokers disappeared within 2 years of smoking cessation, and the remaining excess risk dissipated over the following 10–14 years.5 In the most recent analysis of this cohort, approximately 60% of the CHD mortality risk associated with smoking was gone within 5 years of smoking cessation, and no excess risk was observed after 20 years.16 Smoking may lead to CHD via short-term effects – including coronary artery spasm, carboxyhemoglobinemia, arrhythmias, increased platelet aggregation and thrombosis – and long-term effects, such as those related to reduced high-density lipoprotein (HDL) cholesterol levels, endothelial damage, increased inflammation, and other metabolic changes that promote atherogenesis.17 Although smoking leads to an acute rise in blood pressure, its long-term effect on hypertension is not clear.

High blood pressure National survey data indicate that 29% of US women and men have hypertension, defined as a measured systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more, or current use of blood pressure medication.18 The prevalence of hypertension rises markedly with age. In early to middle adulthood, hypertension is less

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common in women than men, but because the age-related increase is more prominent in women, the reverse is true in later life. For white women in their 30s, 40s, 50s, 60s, and 70s or older, the prevalences of hypertension are 5%, 20%, 40%, 58%, and 79%, respectively; the corresponding figures for men are 12%, 24%, 36%, 56%, and 63%. For balck women in their 30s, 40s, 50s, 60s, and 70s or older, the prevalences are 14%, 45%, 61%, 84%, and 83%, respectively, and for their male counterparts, 18%, 34%, 57%, 74%, and 83%. The prevalence of hypertension rose by a relative 18% from 1988 to 2004, with greater increases for women than for men. Hypertension is an independent predictor of cardiovascular disease (CVD) incidence and mortality in both genders.19,20 Indeed, there is a direct, graded association between blood pressure and CVD risk, which is apparent down to a systolic pressure of 115 mm Hg and diastolic of 75 mm Hg.21 Using data from the Women’s Health Study, a 6-year follow-up of 39 000 middle-aged women, and the Physician’s Health Study, a 13-year follow-up of 22 000 middle-aged men, Glynn et al.22 developed gender-specific predictive models for cardiovascular risk associated with systolic and diastolic pressure. Endpoints included MI, stroke, coronary revascularization, and cardiovascular death. In both genders, systolic and diastolic blood pressure, considered separately, each predicted event rates. However, when both blood pressure types were modeled together, only systolic pressure predicted cardiovascular outcomes in women: a 10 mm Hg higher level of systolic pressure was associated with a 30% increased risk of CVD. In men, a 10 mm Hg higher level of systolic pressure was associated with a 14% increased risk of CVD, and a 10 mm Hg higher level of diastolic pressure was associated with a 17% increased risk of CVD. In both genders, systolic pressure had a slightly stronger effect on stroke than on MI, but the difference was not significant. Isolated systolic hypertension, a marker of loss of largeartery elasticity, is more common in women than in men, affecting an estimated 37% of US women aged 55 and older.23 In a meta-analysis of eight trials that enrolled more than 15 000 patients with this condition – the majority were women aged 60 – for a median of 3.8 years, antihypertensive treatment led to a 30% reduction in stroke incidence, a 23% reduction in CHD incidence, and an 18% reduction in cardiovascular mortality.24 The benefits were similar in both genders. A meta-analysis of pharmacologic interventions – primarily beta blockers and thiazide diuretics – in the treatment of all types of severe hypertension also showed comparable risk reductions in major cardiovascular events among treated women (RR, 0.74) and men (RR, 0.78).25

Dyslipidemia In most populations, serum total cholesterol increases with increasing age. In men, this increase usually plateaus at age

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45 to 50, whereas in women, the increase continues sharply until age 60 or 65.26 In the National Health and Nutrition Examination Survey of 1999–2002, mean total cholesterol level for women aged 20–29 years was 183 mg per deciliter (dl), rising to 223 mg/dl at age 60–69 years.27 Mean lowdensity lipoprotein (LDL) cholesterol was 107 mg/dl at age 20–29 and 133 mg/dl at age 60–69 years. At least part of this increase is thought to result from declining estrogen levels, which results in downregulation of hepatic LDL receptors.28,29 Encouragingly, national data show that mean LDL cholesterol levels in women aged 50 and older have steadily declined since 1976, likely due to the increasing use of cholesterol-lowering medications.27 Much of the seminal research on dyslipidemia and CHD has involved middle-aged men, among whom a 2–3% increase in the risk of CHD has been associated with every 1% increase in serum total cholesterol level.30 In a meta-analysis of observational cohort studies of some 86 000 women, high levels of total and LDL cholesterol also strongly predicted CHD mortality in women under age 65.31,32 In this age group, the relative risk for CHD mortality comparing women with total cholesterol levels greater than 240 mg/dl to those with levels less than 200 mg/dl was 2.44; women with LDL cholesterol levels exceeding 160 mg/dl had a risk 3.27 times greater than did those with LDL cholesterol levels less than 140 mg/dl. Among women aged 65 and older, however, high levels of total and LDL cholesterol were not as strongly associated with CHD mortality; the corresponding relative risks were a significant 1.12 and a nonsignificant 1.13, respectively. On the other hand, HDL cholesterol level was associated with CHD mortality in both younger and older women. Compared to those with HDL cholesterol levels exceeding 60 mg/dl, women with levels less than 50 mg/dl experienced roughly a doubling of risk of CHD mortality; the relative risks were 2.13 among women under age 65 and 1.75 among women aged 65 and older. The corresponding relative risks in men were 2.31 and 1.09, respectively. These data suggest that, in elderly populations, HDL cholesterol appears to be a stronger predictor of CHD in women than in men,31 although this sex differential has not been found in all studies.33,34 The importance of the ratio of total cholesterol to HDL cholesterol as a cardiovascular risk factor in the elderly is underscored by a prospective study of 3904 communitydwelling persons aged 71 years.33 During 4.4 years of follow-up, a high ratio was strongly predictive of an increased risk of CHD mortality in both sexes, although a statistically significant ‘dose-response’ pattern was observed only among women. In the Framingham Heart Study, the 16-year incidence of coronary events among individuals aged 50–90 years increased monotonically with the ratio of total cholesterol to HDL cholesterol in both sexes but more steeply in women than in men.35 Some observational studies suggest that triglycerides may be a particularly important coronary risk factor in

women, especially in the presence of low HDL cholesterol levels (below 40 mg/dl).36,37 A 1998 meta-analysis of 17 prospective studies of plasma triglyceride levels and incident CVD (with 16 studies representing 2445 events among 46 413 white men followed for an average of 8.4 years, and five studies representing 439 events among 10 864 white women followed for an average of 11.4 years) found that hypertriglyceridemia was associated with significant risk increases of 37% and 14% in women and men, respectively, after adjustment for HDL cholesterol and other risk factors.38 However, a 2007 meta-analysis of 29 prospective studies involving 10 158 incident CHD events among more than 262 000 participants found that the association between triglyceride level and CHD risk did not significantly vary by gender; the overall relative risk comparing the top vs. bottom tertile was 1.72.39 In a recent report from the Women’s Health Study, which followed 26 509 women aged 45 and older for 11.4 years, nonfasting triglyceride levels were strongly associated with incident cardiovascular events, independent of traditional cardiac risk factors, levels of other lipids, and markers of insulin resistance (RR for increasing tertiles: 1 [referent], 1.44, and 1.98); by contrast, fasting triglyceride levels showed little independent relationship.40 A meta-analysis of 18 prospective studies involving predominantly male subjects found top tertile plasma lipoprotein(a) [Lp(a)] values to be associated with a significant 70% increase in CHD risk as compared to values in the bottom tertile.41 More recently, the Women’s Health Study found that women in the highest quintile of Lp(a) were 1.47 times more likely to develop cardiovascular events than women in the lowest quintile.42 The association resulted almost entirely from a threshold effect among women with the highest Lp(a) levels (i.e., 90th percentile) and was strongest among women with high LDL cholesterol levels. These threshold and interaction effects do not support routine measurement of Lp(a) for cardiovascular risk stratification in women. Data from primary and secondary prevention trials of lipid-lowering therapy suggest substantial benefit of treatment in both genders. Taken in the aggregate, these studies show a similar and significant reduction in the incidence of major coronary events among treated women and men. In a meta-analysis of data from 90 056 participants (24% women) in 14 randomized trials of statins, women and men were 17% and 22% less likely, respectively, to have a major vascular event per millimole per liter of LDL cholesterol reduction.43

Obesity Excess body fat is often measured by body mass index (BMI) – weight in kilograms divided by the square of height in meters. The World Health Organization and the United

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States’ National Institutes of Health define underweight as BMI  18.5, normal weight as BMI 18.5– 25, overweight as BMI 25– 30, and obesity as BMI 30 kg/m2. Using these commonly accepted cutpoints, obesity prevalence doubled from 1980 to 2004 among US adults. In 2004, 62% of US women were overweight or obese, 33% were obese, and 7% were extremely obese (BMI 40);44,45 for men, these percentages were 71%, 31%, and 3%.45 A major CHD risk factor,46,47 obesity raises coronary risk partly through effects on traditional risk factors such as hypertension, hypercholesterolemia, and hyperglycemia,48–50 as well as novel risk factors such as atherogenic dyslipidemia (high triglycerides, apolipoprotein B, small low-density lipoprotein particles, and low HDL cholesterol), insulin resistance, and elevations in thrombotic and inflammatory markers, including fibrinogen, plasminogen activator inhibitor-1, interleukin-6 (IL-6), tumor necrosis factor- (TNF-), and C-reactive protein.51 Adipocytes produce hormones such as leptin, resistin, adiponectin, and retinol binding protein-4, which may regulate lipid and glucose metabolism and insulin action; cytokines such as TNF- and IL-6; and free fatty acids.52,53 Independent of its effect on risk factors, obesity also appears to have a residual impact on risk of CHD itself, a relation most apparent in long-term prospective studies of midlife populations. In such studies, the association between excess weight and CHD appears linear, so that even persons in the upper range of normal weight are at elevated risk compared with their leaner counterparts. In the Nurses’ Health Study, after controlling for age, smoking, menopausal status, postmenopausal hormone use, and parental history of MI, the RRs for CHD were 1.19, 1.46, 2.06, and 3.56 for women with BMI 21–22.9, 23–24.9, 25–28.9, and 29, compared with women with BMI less than 21.54 Nearly two-fifths (37%) of CHD incidence in this cohort was attributable to excess weight, defined as BMI of 21 or more. Weight gain between age 18 and midlife also predicted coronary risk. Compared with stable-weight women, women who gained 5–7.9 kg were 25% more likely to develop CHD, and those who gained 20 kg or more were 2.65 times more likely to do so. More than one-quarter (27%) of CHD incidence in this cohort could be explained by weight gains of 5 kg or more. The distribution of body fat also affects coronary risk. Adipose tissue in the waist, abdomen, and upper body is more metabolically active than that in the hip, thigh, or buttocks, and abdominal fat predicts dyslipidemia, hypertension, type 2 diabetes, and CHD. The heightened sensitivity of abdominal adipocytes to lipolytic agents and the subsequent direct delivery of free fatty acids and glycerol to the liver, thus inducing insulin resistance, are possible explanations for these associations.55 A waist circumference of 35 inches (89 cm) or more in women or 40 inches (101.5 cm) or more in men, or a waist-to-hip ratio greater than 0.80 in women or greater than 0.95 in men, is associated with a substantially increased cardiovascular risk.56

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In clinical trials among overweight or obese individuals, modest weight loss improves cardiovascular risk factors.57–61 In the observational Framingham Heart Study, a 5 lb (2.25 kg) weight loss over 16 years lowered the sum of five risk factors (highest quintile of systolic blood pressure, triglycerides, blood glucose, and serum total cholesterol, plus lowest quintile of HDL cholesterol) by 40% in women and by 48% in men; conversely, a 5 lb weight gain was associated with a 37% increase in this sum in women and a 20% increase in men.62 The 11-year Swedish Obese Subjects Study reported that ‘rates of recovery’ from hypertension, dyslipidemia, and diabetes were significantly higher,63 and total mortality was significantly lower,64 among 2010 bariatric-surgery patients, who maintained an average loss of 14–25% of body weight, than among 2037 matched obese control subjects, whose weight remained stable. Most estimates of the association between obesity and CHD are derived from studies of white populations of European ancestry. Although additional studies in diverse groups are needed, available data do not indicate that the biological relation between adiposity and CHD varies importantly across racial/ethnic lines. However, to the extent that there are racial/ethnic differences in the reliability of BMI as a measure of adiposity, studies that utilize more direct measures of adiposity will be useful for refining estimates of the health impact of overweight and obesity in various populations. For example, Asian women and men generally have a higher percentage of body fat than their white counterparts with the same BMI,65 and they are also more likely than whites to develop hypertension and type 2 diabetes for any 1-unit increase in BMI in the range 18.5 to 30.66 Thus, while supporting the use of current BMI cutpoints for defining overweight and obesity, the World Health Organization also suggests additional trigger points for public health action in some Asian populations, with BMI of 23 or more and 27.5 or more indicative of increased risk and high risk, respectively.65

Physical activity To reduce CVD risk, authorities have long recommended that adults engage in at least 30 minutes of moderate-intensity physical activity on most days of the week or vigorous-intensity physical activity for 20 minutes 3 days per week.67,68 Yet only 28% of US women and 31% of men exercise enough to meet this guideline, and 41% of women and 39% of men perform no leisure-time physical activity at all.69 Epidemiologic data strongly support the prescription of 30 minutes/day of moderate-intensity physical activity for sedentary women and older men. In a 3-year ­ followup of 73 000 postmenopausal women participating in the Women’s Health Initiative (WHI) Observational Study, brisk walking for at least 2.5 hours per week (i.e., a ­ half-hour

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five times per week) predicted a 30% reduction in cardiovascular events.70 After controlling for total exercise energy expenditure, brisk walking and more vigorous exercise were associated with similar risk reductions, and the results did not vary substantially by race, age, or baseline BMI. In an 8-year follow-up of 72 000 Nurses’ Health Study participants, 3 hours per week of brisk walking had the same protective effect as 1.5 hours per week of vigorous exercise; women engaging in either form of exercise had a 30–40% lower risk of MI than their sedentary peers.71 In a 7-year follow-up of 39 000 women aged 45 or older in the Women’s Health Study, walking at least one hour per week was associated with a 50% reduction in CHD risk in individuals reporting no vigorous physical activity.72 In the 10year Zutphen Elderly Study, men aged 64–84 who walked or cycled at least three times per week for 20 minutes had a 31% reduction in CHD death compared with less active men.73 In the Honolulu Heart Program, men aged 71–93 who walked 1.5 miles per day had half the CHD risk of those who walked less than one-quarter of a mile per day over 4 years of follow-up.74 Cardiovascular benefits of moderate-intensity exercise have also been observed in middle-aged men, although the associations are somewhat weaker than those for women and older men, perhaps because of generally higher physical activity levels for middle-aged men.75 In the Health Professionals Follow-up Study, which followed 44 000 men aged 40–75 for 12 years, 30 minutes or more per day of brisk walking was associated with an 18% reduction in CHD incidence among men who engaged in less than 1 hour of weekly vigorous exercise.76 Most studies of men have found that vigorous exercise leads to even greater risk reductions than moderate-intensity exercise. In the Health Professionals Follow-up Study, each 1 metabolic equivalent increase in exercise intensity was associated with a significant 4% reduction in CHD risk independently of total energy expenditure. Becoming physically active even in late adulthood appears to lower cardiovascular risk.77,78 In the Study of Osteoporotic Fractures, which assessed changes in physical activity over 6 years among 7553 women aged 65 and older, women who increased their physical activity were 36% less likely to die of cardiovascular causes during the subsequent 7 years than were women who stayed sedentary.77 Resistance exercise may also help reduce CHD risk. In the Health Professionals Follow-up Study, men who trained with weights for at least 30 minutes per week were 23% less likely to develop CHD during an 8-year period than those who did not train with weights.76 It is likely that similar findings would be observed in women. Aerobic and resistance exercise also have non-cardiovascular benefits, including preservation of bone density and musculoskeletal function.79 Yet only 17.5% of US women and 22% of men perform strength training at least twice per week80 as recommended by current guidelines.79,81

Physical activity prevents CVD in part through favorable effects on body weight, insulin sensitivity, glycemic control, blood pressure, lipids, endothelial function, hemostasis, and inflammatory defense systems.82 In the Women’s Health Study, these variables explained 59% of the inverse association between physical activity and incident CVD observed over an 11-year period.83 Habitual moderateintensity activity is as effective as more vigorous activity in lowering blood pressure and improving insulin sensitivity.82 In contrast, strong dose-response associations between exercise intensity and blood lipids – triglycerides and HDLcholesterol – have been reported.82

Type 2 diabetes The incidence of type 2 diabetes is increasing sharply in the United States: the condition now affects almost 8% of adults. Moreover, an estimated 40% of adults have impaired fasting glucose levels or impaired glucose tolerance.84 Type 2 diabetes is a particularly potent coronary risk factor in women, increasing their risk of developing or dying from CHD by three- to seven-fold, as compared with a two- to three-fold risk increase in men.85,86 In contrast to recent secular declines in CHD mortality in US men and women without diabetes and in men with diabetes, there has been no such decline in women with diabetes.87 Hu and colleagues88,89 compared the impact of type 2 diabetes and previous CHD on subsequent risk of fatal CHD during 20 years’ follow-up in the Nurses’ Health Study. With women with no history of diabetes or CHD at baseline as the referent, the age-adjusted RRs for fatal CHD were 8.7 for women with a history of diabetes and no CHD, 10.6 for women with a history of CHD and no diabetes, and 25.8 for women with both conditions. In a parallel 10-year analysis among men in the Health Professionals Follow-up Study, the corresponding RRs were 3.8 for men with diabetes only, 7.9 for those with previous MI only, and 13.4 for those with both conditions. Women with type 2 diabetes experienced sharply rising risks of fatal CHD as diabetes duration increased (5, 6–10, 11–15, 16–25, 25 years); with nondiabetic women as the referent, the RRs were 2.75, 3.63, 5.51, 6.38, and 11.9, respectively.88 A monotonically increasing trend, albeit less steep, was also found in men.89 Gender differences in the relation between type 2 diabetes and CHD may result from a particularly harmful effect of diabetes on cardiovascular risk factors in women.85,90 Adverse cardiovascular profiles are more common among diabetic women than among their male counterparts.91 For example, in the Second National Health and Nutrition Examination Survey, although the prevalence of hypertension and hypercholesterolemia was similar or higher in men than in women among persons with normal glucose tolerance, these conditions were more prevalent among women (51.9% for

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hypertension and 43.7% for ­hypercholesterolemia) than men (42.9% and 37.4%, respectively) with type 2 diabetes.92 Also, the decrease in HDL cholesterol associated with diabetes was more evident in women than in men, and elevated fasting triglycerides (250 mg/dl) were more common in diabetic women than in diabetic men (22.2% vs. 13.9%). Among persons with diabetes, obesity was more than twice as prevalent in women (46.6%) than men (20.9%), whereas among persons with normal glucose tolerance, mean BMI was somewhat higher in men (25.5 kg/m2) than women (24.4 kg/m2). Abdominal obesity, assessed by subscapular-to-triceps skinfold ratio, was more common in both diabetic men and women as compared with their nondiabetic counterparts, but the difference was greater for women (24.4%) than for men (15.6%). In addition, type 2 diabetes may be associated with greater endothelial dysfunction93 and inflammation94,95 in women than in men. Moreover, diabetes has been associated with elevated androgen in women (but lower androgen in men),96 which may predispose to coronary risk.97 There is a direct, graded relationship between degree of hyperglycemia and cardiovascular events in persons with diabetes; in one meta-analysis, an increase of 1% in hemoglobin A1c predicted an 18% increase in the risk of cardiovascular events.98 (Hyperglycemia is also associated with higher CVD incidence in persons without diabetes; in one meta-analysis this relation was stronger in studies that included women than in male-only cohorts.99) However, findings from clinical trials examining the role of intensive glycemic control in reducing CVD risk in patients with diabetes have been equivocal or null,100–103 and one has even suggested increased mortality.102 Current cardiovascular risk reduction guidelines for patients with diabetes rely primarily on the modification of other risk factors.104,105 Because obesity, smoking, hypertension, and dyslipidemia act synergistically with diabetes to increase CHD risk,106 controlling these factors yields greater absolute reductions in the risk of coronary events in diabetic than in nondiabetic populations. Aspirin also has an important role in risk reduction among many patients with diabetes.107

Aspirin Although aspirin is effective in the treatment of acute MI and in the secondary prevention of CVD among both women and men,108 there had until recently been few data to inform guidelines for aspirin use for primary prevention in women. Such guidelines had been based on results from clinical trials in men, which suggest that aspirin reduces incidence of first MI by one-third while having little effect on stroke.109 Recent results from the only large primary prevention trial of aspirin in women suggest a nearly opposite pattern. The Women’s Health Study trial evaluated the benefits and risks of low-dose aspirin (100 mg on alternate days) in the

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primary prevention of major cardiovascular events (MI, stroke, and cardiovascular death) among 39 000 initially healthy women aged 45 and older followed for 10 years and found that aspirin was associated with a statistically nonsignificant 9% reduction in such events.110 Aspirin lowered the risk of total stroke by 17% and the risk of ischemic stroke by 24% but had no benefit on MI or cardiovascular death. As expected, aspirin increased bleeding risks. Gastrointestinal hemorrhages requiring transfusion were 40% more common with aspirin, and there was also a nonsignificant 24% increase in hemorrhagic stroke risk. However, age may be a key determinant of a woman’s cardiovascular response to aspirin therapy. Among Women’s Health Study participants aged 65 and older, aspirin was associated with a statistically significant 26% reduction in risk of major cardiovascular events, with a significant benefit on both ischemic stroke (RR, 0.70) and MI (RR, 0.66). In contrast, for younger participants, aspirin appeared to provide little or no cardiovascular protection. The Women’s Health Study findings imply that women aged 65 and older are likely to experience a net benefit from preventive low-dose aspirin therapy and should be considered for such therapy unless contraindicated (e.g., by a history of gastrointestinal bleeding or aspirin allergy). For women under age 65, the clinical implications of the Women’s Health Study findings are less clear. It is not known whether subgroups of younger women at elevated CVD risk may benefit from aspirin or whether higher doses are needed for heart protection. We recommend against the routine use of aspirin in women under age 65 for coronary protection unless they are at elevated risk by virtue of a high Framingham Risk Score or the presence of diabetes (10-year risk 20%), a position also taken by the American Heart Association.111 Guidelines released in 2009 by the US Preventive Services Task Force encourage the use of aspirin for stroke prevention in women aged 55–79.112

Postmenopausal hormone therapy Many observational studies suggest that estrogen use leads to a 35–50% reduction in CHD incidence among postmenopausal women.113 Randomized trials also show favorable effects of exogenous oral estrogen on levels of LDL cholesterol, HDL cholesterol, lipoprotein(a), fibrinogen, and plasminogen activator inhibitor-1; LDL oxidation; and endothelial function. However, oral estrogen therapy also has unfavorable effects, including raising triglyceride and C-reactive protein levels and promoting coagulation via factor VII, prothrombin fragments 1 and 2, and fibrinopeptide A elevations.114 In randomized trials of clinical events, hormone therapy has not proven effective in preventing CHD in ­postmenopausal women as a whole. In the WHI hormone

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therapy trials among 27 000 postmenopausal women aged 50–79 (mean age, 63), women with a uterus who were assigned to 5.6 years of estrogen–progestin therapy were 24% more likely to develop CHD than their counterparts assigned to placebo,115 while women with hysterectomy assigned to 7.1 years of estrogen alone were equally likely to develop CHD as their counterparts assigned to placebo.116 However, a closer look at available data from animal,117 imaging,118,119 and observational studies,120 as well as the WHI121 and other clinical trials,122 suggests that timing of initiation of hormone therapy may influence its association with CHD. The results suggest that hormone therapy may have a beneficial or neutral effect on the heart if started in early menopause, when arteries are still likely to be relatively healthy, but a harmful effect if started in late menopause, when advanced atherosclerosis may be present.123 For example, although there was no relation between estrogen-only therapy and CHD in the overall WHI study population, such therapy was associated with a CHD risk reduction of 37% among women aged 50–59.121 By contrast, a risk reduction of only 8% was observed among those aged 60–69, and a risk increase of 11% was found among those aged 70–79. Because there were few cases of MI or coronary death (the primary definition of CHD in the WHI), especially in the younger women, these intra- and inter-age group differences were not statistically significant. However, when coronary revascularization was added to the CHD definition, estrogen-only therapy was associated with a significant 45% reduction in CHD among the youngest women.116 Age did not have a similar effect in the estrogen-progestin arm, but CHD risks increased with years since menopause.121 Estrogen–progestin was associated with an 11% risk reduction for women less than 10 years beyond menopause but was associated with a 22% increase in risk for women 10–19 years from menopause, and a 71% increase in risk for women 20 or more years from menopause (only the latter was statistically significant). In the observational Nurses’ Health Study, women who chose to start hormone therapy within 4 years of menopause experienced a lower CHD risk than did nonusers, whereas those who began hormone therapy 10 or more years after menopause appeared to receive little coronary benefit.120 Because observational studies generally include a high percentage of women who begin hormone therapy in early menopause while clinical trials to date have included a high percentage of women many years past menopause, these findings account at least in part for the apparent discrepancy in the results of the two types of studies. Although no woman should ever be given hormone therapy for CHD prevention, recently menopausal women and their clinicians can be reassured about cardiac risks when considering short-term use of hormone therapy for relief of hot flashes and night sweats severe enough to disrupt sleep and quality of life.123,124 Vasomotor symptom relief must be weighed against other treatment effects, but CHD

is ­ generally not of major concern for recently menopausal women in good cardiovascular health.

Alcohol Low-to-moderate consumption may confer CHD ­protection in women and men, while heavy alcohol use increases risk.125 In the Nurses’ Health Study, women who consumed 10–15 g per day of alcohol (the equivalent of one drink, i.e., 12 ounces (355 ml) of beer, 5 ounces (148 ml) of wine, or 1.5 ounces (44 ml) of spirits) experienced a 40% reduction in CHD risk as compared with nondrinkers over a 4-year period;126 an inverse relation was also found after 14 years.127 Other investigators have also reported coronary risk reductions of 30% to 50% among moderate drinkers as compared with nondrinkers.128–134 Although red wine might be expected to confer greater coronary protection than other alcoholic beverages because of the antioxidant value of its phenolic substances or bioflavonoids, the epidemiologic evidence does not support this.135 Experimental and observational data suggest that ,50% of the CHD risk reduction attributable to alcohol use results from increases in HDL cholesterol.135 Alcohol has also been linked to decreased fibrinogen,136 and tissue-type plasminogen activator,137,138 reduced platelet activation and aggregation,139 and improved insulin sensitivity.140 In the Nurses’ Health Study and Health Professionals Follow-up Study, levels of HDL cholesterol, fibrinogen, and hemoglobin A1c accounted for 75% of the observed relation between drinking frequency and MI in women and nearly 100% of the relation in men.134 Moderate alcohol use is also associated with a reduced risk for ischemic stroke, but its anti-clotting effects translate into an increased risk for hemorrhagic stroke.141 Moderate alcohol use has also been linked to an increased risk for breast cancer,142 and, at higher levels, colorectal143 and esophageal144 cancers. In addition, women are more susceptible to alcoholic liver disease145 and to ethanol-induced cardiomyopathy146 than are men, likely due to gender differences in alcohol metabolism and absorption.147 For these reasons, alcohol use guidelines148,149 are gender specific – women who drink should consume no more than one drink per day, whereas men who drink should consume no more than two drinks per day. Women and men who do not drink should not take up the habit to prevent CHD.

Psychosocial factors Depression Two meta-analyses of prospective cohort studies published from 1990 to 2000 of the relation between depression and CHD incidence each reported a significant relative

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risk of 1.64;150,151 one of these meta-analyses examined symptom severity and found that clinical depression (RR, 2.69) was a stronger predictor than depressed mood (RR, 1.49).150 Recent observational studies continue to support a link between depressive symptoms and CHD risk.152,153 For example, the INTERHEART study compared 12 461 acute MI cases with 14 637 controls in 54 countries on traditional and psychosocial risk factors, including depression, stress (see below), and locus of control.154 The strength of the relation between depression and MI (RR, 1.55) was comparable to those for other major risk factors and was similar for women (RR, 1.60) and men (RR, 1.53). Depression and the combined index of psychosocial factors accounted for 9% and 33% of MI cases, respectively. To date, the largest cohort study of depressive symptoms and subsequent CVD in women is the WHI Observational Study.155 Among 73 000 women without CVD at baseline, a high level of depressive symptoms – women with diagnosed clinical depression were excluded from the WHI – significantly predicted cardiovascular mortality (RR, 1.50) and total mortality (RR, 1.32), though not CHD incidence, over 4 years of follow-up, after adjustment for traditional risk factors. In the 10-year National Health and Nutrition Examination I Follow-up Study among 8000 US adults, depressive symptoms were significantly associated with nonfatal CHD (RR, 1.73) but not fatal CHD in women, as well as nonfatal CHD (RR, 1.71) and fatal CHD (RR, 2.34) in men.156

Anxiety Among 3369 women in the WHI Observational Study, a history of panic attacks was associated with a more than four-fold increase in CHD incidence during 5 years of follow-up.157 In a 12-year follow-up of 72 000 Nurses’ Health Study participants, phobic anxiety was associated with a marginally significant increased risk of sudden cardiac death (RR, 1.59) and fatal CHD (RR, 1.31) but not nonfatal MI.158 Similar relations have been observed in men.159–161

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Relatively few cohort studies have examined chronic non-work stress as a CVD risk factor. Among 73 000 Japanese adults followed for 8 years, women who reported high levels of (nonspecific) daily life stress were significantly more likely to die from MI (RR, 2.28), CHD (RR, 2.58), or CVD (RR, 1.64) than were their low-stress counterparts. Men with moderate daily life stress had significantly higher rates of fatal MI (RR, 1.74) than did men with low stress, although no significant associations were observed for other cardiovascular endpoints.165 Data from the Nurses’ Health Study show a strong relation between caregiving – a specific chronic stressor – and incident CHD over 4 years of follow-up. Women who reported caring for an ill spouse for 9 or more hours per week were nearly twice as likely to develop CHD,166 and those caring for children for 21 or more hours per week or grandchildren for 9 or more hours per week were 60% more likely to do so, than women without caregiving responsibilities.167 It is unclear whether interventions to treat mood disorders or manage stress can reduce coronary events. Secondary prevention trials have yielded disappointing results. The Enhancing Recovery in Coronary Heart Disease (ENRICHD) Study, designed to assess the effect of treatment for depression and social support with cognitive behavioral therapy and selective serotonin reuptake inhibitors on morbidity and mortality in patients after MI, found no effect on event-free survival.168 There are no trials in primary prevention settings. Although the mechanisms linking depression, anxiety, and stress to CHD are not well understood, they likely include direct biologic pathways, including dysregulation of the hypothalamic–pituitary–adrenocortical axis and the autonomic nervous system, with adverse effects on heart rate, blood pressure, and visceral obesity; hemostatic and endothelial dysfunction; and inflammatory activation.153 Psychosocial factors may also raise CHD risk indirectly through behavioral pathways – i.e., by adversely affecting lifestyle factors or medication adherence.153

Chronic Psychosocial Stress Taken in aggregate, epidemiologic evidence to date suggests that chronic work stress may increase CHD risk more for men than women, whereas chronic non-work stress may be more salient for women than men.162 In the INTERHEART study, chronic stress at home or work was associated with an increased risk for MI in women (RR, 1.74) and men (RR, 2.32). However, when stressor types were considered separately, a significant gender interaction emerged for work stress; this variable predicted MI in men only. In the Nurses’ Health Study, job strain was not predictive of CHD risk,163 although job insecurity was associated with a 2-year increase in coronary risk that did not persist with longer follow-up.164 More research is needed to clarify the relation between work stress and CHD in women.

Conclusion Compelling data from epidemiologic studies and randomized clinical trials indicate that CHD is largely preventable. Despite this, there are alarming trends in the prevalence of some cardiovascular risk factors among US women. Smoking rates are declining more slowly for women than for men; the prevalence of obesity, diabetes, and hypertension is increasing; and more than 70% of women do not engage in adequate leisure-time physical activity. While researchers have made great strides in identifying a large number of lifestyle, biochemical, and genetic factors potentially associated with CHD, the process of disease prevention must move beyond understanding disease mechanisms

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and identifying risk factors toward establishing intervention strategies that definitively reduce risk. It is also important to note that CHD should not be viewed as a categorical event but rather as a progressive disease process. As the availability and use of noninvasive tools to detect asymptomatic CHD become more widespread, the division between primary and secondary prevention strategies may become less distinct. Because first cardiovascular events are more often fatal in women than in men, especially careful consideration should be given to individual risk factor management before the onset of overt clinical disease in women.

References 1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics – 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119:480–86. 2. Hennekens CH. Risk factors for coronary heart disease in women. Cardiol Clin 1998;16:1–8. 3. Centers for Disease Control and Prevention. Tobacco use among adults – United States, 2005. MMWR 2005;55:1145–48. 4. Bolego C, Poli A, Paoletti R. Smoking and gender. Cardiovasc Res 2002;53:568–76. 5. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and time course of decreased risks of coronary heart disease in middle-aged women. Arch Intern Med 1994;154:169–75. 6. Thun MJ, Apicella LF, Henley SJ. Smoking vs. other risk factors as the cause of smoking-attributable deaths: confounding in the courtroom. JAMA 2000;284:706–12. 7. US Department of Health and Human Services. The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Washington, DC: US Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2006. 8. Kawachi I, Colditz GA, Speizer FE, et al. A prospective study of passive smoking and coronary heart disease. Circulation 1997;95:2374–79. 9. Rosenberg L, Kaufman DW, Helmrich SP, et al. The risk of myocardial infarction after quitting smoking in men under 55 years of age. N Engl J Med 1985;313:1511–14. 10. Rosenberg L, Palmer JR, Shapiro S. Decline in the risk of myocardial infarction among women who stop smoking. N Engl J Med 1990;322:213–17. 11. Dobson AJ, Alexander HM, Heller RF, Lloyd DM. How soon after quitting smoking does risk of heart attack decline? J Clin Epidemiol 1991;44:1247–53. 12. Hammond EC, Horn D. Smoking and death rates: report on forty-four months of follow-up of 187,783 men. II. Death rates by cause. JAMA 1958;166:1294–308. 13. Hammond EC, Garfinkel L. Coronary heart disease, stroke, and aortic aneurysm. Arch Environ Health 1969;19:167–82. 14. Rogot E, Murray JL. Smoking and causes of death among US veterans: 16 years of observation. Publ Health Rep 1980;95:213–22.

15. Doll R, Peto R. Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J 1976;2:1525–36. 16. Kenfield SA, Stampfer MJ, Rosner BA, et al. Smoking and smoking cessation in relation to mortality in women. JAMA 2008;299:2037–47. 17. US Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2004. 18. Cutler JA, Sorlie PD, Wolz M, et al. Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988–1994 and 1999–2004. Hypertension 2008;52:818–27. 19. Lawes CM, Bennett DA, Lewington S, et al. Blood pressure and coronary heart disease: a review of the evidence. Semin Vasc Med 2002;2:355–68. 20. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. 21. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345:1291–97. 22. Glynn RJ, L’Italien GJ, Sesso HD, et al. Development of predictive models for long-term cardiovascular risk associated with systolic and diastolic blood pressure. Hypertension 2002;39:105–10. 23. Martins D, Nelson K, Pan D, et al. The effect of gender on age-related blood pressure changes and the prevalence of isolated systolic hypertension among older adults: data from NHANES III. J Gend Specif Med 2001;4:10–13, 20. 24. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: metaanalysis of outcome trials. Lancet 2000;355:865–72. 25. Gueyffier F, Boutitie F, Boissel JP, et al. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann Intern Med 1997;126:761–67. 26. Jousilahti P, Vartiainen E, Tuomilehto J, et al. Twentyyear dynamics of serum cholesterol levels in the middleaged population of eastern Finland. Ann Intern Med 1996; 125:713–22. 27. Carroll MD, Lacher DA, Sorlie PD, et al. Trends in serum lipids and lipoproteins of adults, 1960–2002. JAMA 2005;294:1773–81. 28. Welty FK. Who should receive hormone replacement therapy? J Thromb Thrombolysis 1996;3:13–21. 29. Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 1993;98:83–90. 30. LaRosa JC, Hunninghake D, Bush D, et al. The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. A joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute. The Task Force on Cholesterol Issues, American Heart Association. Circulation 1990;81:1721–33.

C h a p t e r 1 5     Gender-Specific Aspects of Selected Coronary Heart Disease Risk Factors l

31. Manolio TA, Pearson TA, Wenger NK, et al. Cholesterol and heart disease in older persons and women. Review of an NHLBI workshop. Ann Epidemiol 1992;2:161–76. 32. Walsh JM, Grady D. Treatment of hyperlipidemia in women. JAMA 1995;274:1152–58. 33. Corti MC, Guralnik JM, Salive ME, et al. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA 1995;274:539–44. 34. Zimetbaum P, Frishman WH, Ooi WL, et al. Plasma lipids and lipoproteins and the incidence of cardiovascular disease in the very elderly. The Bronx Aging Study. Arterioscler Thromb 1992;12:416–23. 35. Kannel WB, Wilson PW. Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995;155:57–61. 36. LaRosa JC. Triglycerides and coronary risk in women and the elderly. Arch Intern Med 1997;157:961–68. 37. Castelli WP. The triglyceride issue: a view from Framingham. Am Heart J 1986;112:432–37. 38. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998;81: 7B–12B. 39. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450–58. 40. Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309–16. 41. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000;102:1082–85. 42. Suk Danik J, Rifai N, Buring JE, et al. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA 2006;296:1363–70. 43. Cholesterol Treatment Trialists’ Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective metaanalysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. 44. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 2004;291:2847–50. 45. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006;295:1549–55. 46. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2006;113:898–918. 47. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2006;113:e873–923.

171

48. Garrison RJ, Kannel WB. A new approach for estimating healthy body weights. Int J Obes Relat Metab Disord 1993;17:417–23. 49. Huang Z, Willett WC, Manson JE, et al. Body weight, weight change, and risk for hypertension in women. Ann Intern Med 1998;128:81–88. 50. Ashton WD, Nanchahal K, Wood DA. Body mass index and metabolic risk factors for coronary heart disease in women. Eur Heart J 2001;22:46–55. 51. Grundy SM. What is the contribution of obesity to the metabolic syndrome? Endocrinol Metab Clin North Am 2004;33:267–82. 52. Rajala MW, Scherer PE. Minireview: The adipocyte – at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 2003;144:3765–73. 53. Graham TE, Yang Q, Bluher M, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 2006;354:2552–63. 54. Willett WC, Manson JE, Stampfer MJ, et al. Weight, weight change, and coronary heart disease in women. Risk within the ‘normal’ weight range. JAMA 1995;273:461–65. 55. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881–87. 56. National Heart Lung and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults – The Evidence Report. Washington DC: NIH Publication Number 98-4083, 1998. 57. Stefanick ML. Physical activity and weight loss. In: JE Manson, JE Buring, PM Ridker, JM Gaziano, eds. Clinical Trials in Heart Disease: A Companion Guide to Braunwald’s Heart Disease. Philadelphia: WB Saunders; 2004:315–32. 58. Neter JE, Stam BE, Kok FJ, et al. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2003;42:878–84. 59. Esposito K, Pontillo A, Di Palo C, et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 2003;289: 1799–804. 60. Tchernof A, Nolan A, Sites CK, et al. Weight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation 2002;105:564–69. 61. Van Gaal LF, Wauters MA, De Leeuw IH. The beneficial effects of modest weight loss on cardiovascular risk factors. Int J Obes Relat Metab Disord 1997;21(Suppl 1):S5–S9. 62. Wilson PW, Kannel WB, Silbershatz H, et al. Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999;159:1104–1109. 63. Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–2693. 64. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741–752. 65. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157–163. 66. Stevens J, Truesdale KP, Katz EG, et al. Impact of body mass index on incident hypertension and diabetes in Chinese Asians, American Whites, and American Blacks: the People’s Republic of China Study and the Atherosclerosis Risk in Communities Study. Am J Epidemiol 2008;167:1365–1374.

172

s e c t i o n 3     Cardiovascular Disease l

67. US Department of Health and Human Services. Physical Activity and Health: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion; 1996. 68. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation 2007;116:1081–1093. 69. Barnes PM. Physical activity among adults: United States, 2000 and 2005. www.cdc.gov/nchs/products/pubs/pubd/hestats/physicalactivity/physicalactivity.htm 2007. Accessed May 14, 2009. 70. Manson JE, Greenland P, LaCroix AZ, et al. Walking compared with vigorous exercise for the prevention of cardiovascular events in women. N Engl J Med 2002;347:716–725. 71. Manson JE, Hu FB, Rich-Edwards JW, et al. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. N Engl J Med 1999;341:650–658. 72. Lee IM, Rexrode KM, Cook NR, et al. Physical activity and coronary heart disease in women: is ‘no pain, no gain’ passé? JAMA 2001;285:1447–1454. 73. Bijnen FC, Caspersen CJ, Feskens EJ, et al. Physical activity and 10-year mortality from cardiovascular diseases and all causes: the Zutphen Elderly Study. Arch Intern Med 1998;158:1499–1505. 74. Hakim AA, Curb JD, Petrovitch H, et al. Effects of walking on coronary heart disease in elderly men: the Honolulu Heart Program. Circulation 1999;100:9–13. 75. Lee IM. No pain, no gain? Thoughts on the Caerphilly study. Br J Sports Med 2004;38:4–5. 76. Tanasescu M, Leitzmann MF, Rimm EB, et al. Exercise type and intensity in relation to coronary heart disease in men. JAMA 2002;288:1994–2000. 77. Gregg EW, Cauley JA, Stone K, et al. Relationship of changes in physical activity and mortality among older women. JAMA 2003;289:2379–2386. 78. Wannamethee SG, Shaper AG, Walker M. Changes in physical activity, mortality, and incidence of coronary heart disease in older men. Lancet 1998;351:1603–1608. 79. Williams MA, Haskell WL, Ades PA, et al. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116:572–584. 80. Centers for Disease Control and Prevention. Trends in strength training – United States, 1998–2004. MMWR 2006;55:769–772. 81. American College of Sports Medicine. ASCM’s Guidelines for Exercise Testing and Preparation, 7th edn. Philadelphia, PA: Lippincott Williams and Wilkins; 2006. 82. Bassuk SS, Manson JE. Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease. J Appl Physiol 2005;99: 1193–1204. 83. Mora S, Cook N, Buring JE, et al. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation 2007;116:2110–2118.

84. Centers for Disease Control and Prevention. Prevalence of diabetes and impaired fasting glucose in adults – United States, 1999–2000. MMWR 2003;52:833–837. 85. Manson JE, Spelsberg A. Risk modification in the diabetic patient. In: JE Manson, PM Ridker, JM Gaziano, CH Hennekens, eds. Prevention of Myocardial Infarction. New York, NY: Oxford University Press; 1996:241–273. 86. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;332:73–78. 87. Gregg EW, Gu Q, Cheng YJ, et al. Mortality trends in men and women with diabetes, 1971 to 2000. Ann Intern Med 2007;147:149–155. 88. Hu FB, Stampfer MJ, Solomon CG, et al. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. Arch Intern Med 2001;161:1717–1723. 89. Cho E, Rimm EB, Stampfer M, et al. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in men. J Am Coll Cardiol 2002;40:954–960. 90. Mosca L, Manson JE, Sutherland SE, et al. Cardiovascular disease in women: a statement for healthcare professionals from the American Heart Association. Writing Group. Circulation 1997;96:2468–2482. 91. Barrett-Connor E, Giardina EG, Gitt AK, et al. Women and heart disease: the role of diabetes and hyperglycemia. Arch Intern Med 2004;164:934–942. 92. Cowie CC, Harris MI. Physical and metabolic characteristics of persons with diabetes. Diabetes in America, 2nd edn. NIH Publication No. 95-1468: Bethesda, MD: National Institutes of Health, 1995:117–164. 93. Steinberg HO, Paradisi G, Cronin J, et al. Type II diabetes abrogates sex differences in endothelial function in premenopausal women. Circulation 2000;101:2040–2046. 94. de Rekeneire N, Peila R, Ding J, et al. Diabetes, hyperglycemia, and inflammation in older individuals: the Health, Aging and Body Composition Study. Diabetes Care 2006;29:1902–1908. 95. Thorand B, Baumert J, Kolb H, et al. Sex differences in the prediction of type 2 diabetes by inflammatory markers: results from the MONICA/KORA Augsburg case-cohort study, 1984–2002. Diabetes Care 2007;30:854–860. 96. Ding EL, Song Y, Malik VS, et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006;295:1288–1299. 97. Shaw LJ, Bairey Merz CN, Azziz R, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health–National Heart, Lung, and Blood Institute sponsored Women’s Ischemia Syndrome Evaluation. J Clin Endocrinol Metabol 2008;93:1276–1284. 98. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421–431. 99. Levitan EB, Song Y, Ford ES, et al. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A metaanalysis of prospective studies. Arch Intern Med 2004;164: 2147–2155.

C h a p t e r 1 5     Gender-Specific Aspects of Selected Coronary Heart Disease Risk Factors l

100. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986. 101. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352:837–853. 102. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–2559. 103. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–2572. 104. American Diabetes Association. Standards of medical care in diabetes – 2008. Diabetes Care 2008;31(Suppl 1):S12–S54. 105. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007;30:162–172. 106. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 1991;151:1141–1147. 107. American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care 2004;27(Suppl 1):S72–S73. 108. Antithrombotic Trialists’ Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. 109. Hayden M, Pignone M, Phillips C, et al. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2002;136:161–172. 110. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293–1304. 111. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115:1481–1501. 112. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US Preventive Services Task Force recommendation statement. Ann Intern Med 2009;150:396–404. 113. Grodstein F, Stampfer M. The epidemiology of postmenopausal hormone therapy and cardiovascular disease. In: SZ Goldhaber, PM Ridker, eds. Thrombosis and Thromboembolism. New York, NY: Marcel Dekker; 2002:67–78. 114. Chae CU, Manson JE. Postmenopausal hormone therapy. In: JE Manson, JE Buring, PM Ridker, JM Gaziano, eds. Clinical Trials in Heart Disease. Philadelphia: WB Saunders; 2004:349–363. 115. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–534. 116. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med 2006;166:357–365.

173

117. Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res 2002;53:605–619. 118. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939–953. 119. Hodis HN, Mack WJ, Azen SP, et al. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. N Engl J Med 2003;349:535–545. 120. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health (Larchmt) 2006;15:35–44. 121. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465–1477. 122. Salpeter SR, Walsh JM, Greyber E, et al. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med 2006;21:363–366. 123. Manson JE, Bassuk SS. Invited commentary: hormone therapy and risk of coronary heart disease – why renew the focus on the early years of menopause? Am J Epidemiol 2007;166:511–517. 124. Manson JE, Bassuk SS. Hot Flashes, Hormones and Your Health. New York, NY: McGraw–Hill; 2007. 125. Di Castelnuovo A, Rotondo S, Iacoviello L, et al. Metaanalysis of wine and beer consumption in relation to vascular risk. Circulation 2002;105:2836–2844. 126. Stampfer MJ, Colditz GA, Willett WC, et al. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 1988;319:267–273. 127. Stampfer MJ, Hu FB, Manson JE, et al. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 2000;343:16–22. 128. Rosenberg L, Slone D, Shapiro S, et al. Alcoholic beverages and myocardial infarction in young women. Am J Public Health 1981;71:82–85. 129. Gordon T, Kannel WB. Drinking habits and cardiovascular disease: the Framingham Study. Am Heart J 1983;105:667–673. 130. Scragg R, Stewart A, Jackson R, et al. Alcohol and exercise in myocardial infarction and sudden coronary death in men and women. Am J Epidemiol 1987;126:77–85. 131. Rehm JT, Bondy SJ, Sempos CT, et al. Alcohol consumption and coronary heart disease morbidity and mortality. Am J Epidemiol 1997;146:495–501. 132. Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med 1997;337:1705–1714. 133. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–952. 134. Mukamal KJ, Jensen MK, Gronbaek M, et al. Drinking frequency, mediating biomarkers, and risk of myocardial infarction in women and men. Circulation 2005;112:1406–1413. 135. Sesso HD, Gaziano JM. Alcohol intake and cardiovascular morbidity and mortality. Curr Opin Nephrol Hypertens 1999;8:353–357.

174

s e c t i o n 3     Cardiovascular Disease l

136. Dimmitt SB, Rakic V, Puddey IB, et al. The effects of alcohol on coagulation and fibrinolytic factors: a controlled trial. Blood Coagul Fibrinolysis 1998;9:39–45. 137. Ridker PM, Vaughan DE, Stampfer MJ, et al. Association of moderate alcohol consumption and plasma concentration of endogenous tissue-type plasminogen activator. JAMA 1994;272:929–933. 138. Rimm EB, Williams P, Fosher K, et al. Moderate alcohol intake and lower risk of coronary heart disease: metaanalysis of effects on lipids and haemostatic factors. BMJ 1999;319:1523–1528. 139. Mukamal KJ, Massaro JM, Ault KA, et al. Alcohol consumption and platelet activation and aggregation among women and men: the Framingham Offspring Study. Alcohol Clin Exp Res 2005;29:1906–1912. 140. Davies MJ, Baer DJ, Judd JT, et al. Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women: a randomized controlled trial. JAMA 2002;287:2559–2562. 141. Reynolds K, Lewis B, Nolen JD, et al. Alcohol consumption and risk of stroke: a meta-analysis. JAMA 2003;289:579–588. 142. Singletary KW, Gapstur SM. Alcohol and breast cancer: review of epidemiologic and experimental evidence and potential mechanisms. JAMA 2001;286:2143–2151. 143. Cho E, Smith-Warner SA, Ritz J, et al. Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med 2004;140:603–613. 144. Layke JC, Lopez PP. Esophageal cancer: a review and update. Am Fam Phys 2006;73:2187–2194. 145. Sherlock S. Alcoholic liver disease. Lancet 1995;345: 227–229. 146. Urbano-Marquez A, Estruch R, Fernandez-Sola J, et al. The greater risk of alcoholic cardiomyopathy and myopathy in women compared with men. JAMA 1995;274:149–154. 147. National Institute on Alcohol Abuse and Alcoholism. Are Women More Vulnerable to Alcohol’s Effects? Alcohol Alert No. 46. Rockville, MD: National Institute on Alcohol Abuse and Alcoholism; 1999. 148. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 2006;114:82–96. 149. US Department of Agriculture and US Department of Health and Human Services. Dietary Guidelines for Americans, 6th edn. Washington, DC: US Government Printing Office; 2005. 150. Rugulies R. Depression as a predictor for coronary heart disease. a review and meta-analysis. Am J Prev Med 2002;23:51–61. 151. Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom Med 2003;65:201–210. 152. Frasure-Smith N, Lesperance F. Recent evidence linking coronary heart disease and depression. Can J Psychiatry 2006;51:730–737. 153. Goldston K, Baillie AJ. Depression and coronary heart disease: a review of the epidemiological evidence, explanatory

mechanisms and management approaches. Clin Psychol Rev 2008;28:288–306. 154. Rosengren A, Hawken S, Ounpuu S, et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:953–962. 155. Wassertheil-Smoller S, Shumaker S, Ockene J, et al. Depression and cardiovascular sequelae in postmenopausal women. The Women’s Health Initiative (WHI). Arch Intern Med 2004;164:289–298. 156. Ferketich AK, Schwartzbaum JA, Frid DJ, et al. Depression as an antecedent to heart disease among women and men in the NHANES I study. National Health and Nutrition Examination Survey. Arch Intern Med 2000;160:1261–1268. 157. Smoller JW, Pollack MH, Wassertheil-Smoller S, et al. Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women’s Health Initiative Observational Study. Arch Gen Psychiatry 2007;64:1153–1160. 158. Albert CM, Chae CU, Rexrode KM, et al. Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 2005;111:480–487. 159. Haines AP, Imeson JD, Meade TW. Phobic anxiety and ischaemic heart disease. Br Med J (Clin Res Ed) 1987;295:297–299. 160. Kawachi I, Colditz GA, Ascherio A, et al. Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 1994;89:1992–1997. 161. Shen BJ, Avivi YE, Todaro JF, et al. Anxiety characteristics independently and prospectively predict myocardial infarction in men: the unique contribution of anxiety among psychologic factors. J Am Coll Cardiol 2008;51:113–119. 162. Everson-Rose SA, Lewis TT. Psychosocial factors and cardiovascular diseases. Annu Rev Public Health 2005;26:469–500. 163. Lee S, Colditz G, Berkman L, et al. A prospective study of job strain and coronary heart disease in US women. Int J Epidemiol 2002;31:1147–1153. 164. Lee S, Colditz GA, Berkman LF, et al. Prospective study of job insecurity and coronary heart disease in US women. Ann Epidemiol 2004;14:24–30. 165. Iso H, Date C, Yamamoto A. Perceived mental stress and mortality from cardiovascular disease among Japanese men and women: the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study). Circulation 2002;106:1229–1236. 166. Lee S, Colditz GA, Berkman LF, et al. Caregiving and risk of coronary heart disease in US women: a prospective study. Am J Prev Med 2003;24:113–119. 167. Lee S, Colditz G, Berkman L, et al. Caregiving to children and grandchildren and risk of coronary heart disease in women. Am J Public Health 2003;93:1939–1944. 168. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 2003;289:3106–3116.

Chapter

16

Dyslipidemia Management in Women and Men: Exploring Potential Gender Differences Kavita Sharma1, Christian D. Nagy2, and Roger S. Blumenthal3 1

The Johns Hopkins Hospital, Department of Internal Medicine, Baltimore, MD, USA Fellow, The Johns Hopkins Hospital, Department of Internal Medicine and Pediatrics, Divisions of Cardiology and Pediatric Cardiology, Baltimore, MD, USA 3 Professor of Medicine, The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA 2

Introduction

a CHD equivalent), metabolic syndrome, smoking, hypertension, dyslipidemia, and inflammation. Family history has been known to be a risk factor for CHD and there is a strong correlation between certain genetic markers and development of CHD. The prevalence of CHD in men and women combined with effective available treatment options, emphasize the importance for physicians and patients to recognize and adequately treat CHD risk factors.

Cardiovascular disease (CVD) is the leading cause of death in both men and women. Each year more than 250 000 women die of coronary heart disease (CHD).1 On average, women develop coronary atherosclerosis a decade later than men do, and on average they develop a myocardial infarction (MI) 10–15 years later than men do. The prior under-representation of women in clinical trials was associated with the general misconception that CHD was primarily a disease of men. While death rates from CVD are declining, more women die of CVD than their male counterparts, in part due to the delay in diagnosis and the older age at which women develop CVD.2 Although traditional risk factors for the development of CVD such as obesity, diabetes mellitus (DM), cigarette smoking, hypertension, dyslipidemia, and inflammation are similar in both genders, the impact of each individual risk factor and related interventions may differ dramatically by gender.3 Women also have inherent attributes that modify their CVD risk, such as menopausal status and the use of hormone therapy. This chapter first examines gender differences in CVD risk factors, then specifically focuses on dyslipidemia in women and the effects of estrogen on CVD risk, and finally addresses treatment guidelines for dyslipidemia.

Obesity and Body Fat Distribution Obesity (body mass index 30) and sedentary lifestyle have been linked to an increased risk for developing CHD. About 30–40% of adult women are estimated to be obese. The Nurses’ Health Study demonstrated that compared to their lean counterparts, overweight women with a body mass index (BMI) of 25–29 kg/m2 had a relative risk for CHD of 1.8, while obese women (BMI 29 kg/m2) had a relative risk for CHD of 3.3.4 The distribution of body fat, rather than absolute weight, appears to be more significant in determining cardiovascular risk.5,6 In particular, abdominal fat accumulation is an important predictor for the development of type 2 DM, hypertri­ glyceridemia, hypertension, and CVD. The waist-to-hip ratio and waist circumference have been independently associated with risk of CVD in women, and correlate with higher lowdensity lipoprotein cholesterol (LDL-C) and lower high-density lipoprotein cholesterol HDL-C values.7 A waist-to-hip ratio 0.88 and waist circumference 38 inches (96.5 cm) is predictive of an increased risk of CVD events among women.7 Of note, a waist circumference 35 inches (89 cm) in women is considered to be a key component of the metabolic syndrome in white women.

Risk factors for developing CVD associated with Dyslipidemia The major CVD risk factors include obesity and fat distribution, physical inactivity, diabetes mellitus (now considered

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Diabetes Mellitus DM is a well-established risk factor for the presence and severity of CHD in women and men; 10% of Americans 20 years of age have DM and 21% of Americans 60 years of age have DM. Type 2 DM is associated with obesity, increased abdominal body fat distribution, hypertension, atherogenic dyslipidemia, and insulin resistance, which are all known related factors for increased CHD risk. DM also promotes endothelial dysfunction and platelet abnormalities. DM substantially increases the mortality of myocardial infarction in women compared to men. In a contemporary meta-analysis, the relative risk of coronary death from DM was 2.58 (95% confidence interval (CI) 2.05–3.26) for women and 1.85 (95% CI 1.47–2.33) for men (p  0.045).8 In women with DM, the incidence of coronary artery disease (CAD) is almost three times that of non-diabetic women, compared to a two-fold increased incidence in men. The apparent hormonal protective effect due to higher circulating levels of endogenous estrogens on CHD risk in premenopausal women is offset by the presence of DM. Racial differences may affect the role of DM as a risk factor for developing CHD in women. The CHD incidence associated with a medical history of DM appears to be greater in African-American women, compared to American women of European descent. Compared to non-diabetic individuals, those with DM are prone to having adverse lipid profiles: total cholesterol (TC), LDL-C, and triglyceride (TG) levels are higher, while HDL-C levels are lower. These differences are more pronounced in women than men.9 In both men and women, insulin promotes lipoprotein lipase-mediated TG removal, resulting in hypertriglyceridemia. DM also results in increased endogenous hepatic very-low-density lipoprotein cholesterol (VLDL-C) secretion and downregulation of LDL-C receptors.10

Hypertension One in three American adults has high blood pressure (HBP). A higher percentage of men than women have HBP during young adulthood and early middle age. Once women reach menopause (55 years of age), a much higher percentage of women have HBP compared to men.12 HBP is 2–3 times more common in women taking oral contraceptives, especially in obese and older women, than in those not taking them. From 1988–1994 to 1999–2002, the prevalence of HBP increased but was particularly high among black women (44%) compared to white women (30%). A strong association between elevated blood pressure (systolic and diastolic) and risk of CHD has been established in epidemiologic studies in both genders. The 2004 overall US death rate (per year per 100 000 population) from HBP was 18.1. Death rates were 16 for white males, 51 for black males, 14.5 for white females, and 41 for black females.13 Although women suffer fewer cardiovascular events than men at the same age, the population risk attributable to hypertension is higher for women than men because of the increased incidence with age and superior longevity of women. Numerous risk factors and markers for development of hypertension have been identified, including age, ethnicity, family history of hypertension and genetic factors, lower education and socioeconomic status, greater weight, lower physical activity, psychosocial stressors, sleep apnea, and dietary factors (including dietary fats, higher sodium and lower potassium intake, and excessive alcohol consumption).

Dyslipidemia Lipid physiology, gender-specific implications of dyslipidemia, and the well-established association between elevated cholesterol and CVD risk are discussed in the following section.

Smoking Cigarette smoking leads to more deaths from CHD and stroke than any other cause. More than 50% of myocardial infarctions among middle-aged women are attributable to tobacco use. Female smokers are at a six- to nine-fold increased risk of developing myocardial infarction and stroke than non-smokers. While the incidence of smoking in women has overall declined, the incidence of smoking in younger women has remained stable or even increased in parts of the United States. This population appears to be particularly vulnerable to the effects of cigarette smoking, in a dose-related fashion.11 Accelerated atherosclerosis and a predilection to vascular thrombosis are responsible for most of the harmful cardiovascular effects of smoking. ‘Second-hand smoking’ also increases the risk of heart disease in women.

Dyslipidemia Lipid Physiology Overview Lipoproteins are classified based on their densities. In order of increasing density, they are named chylomicrons, verylow-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Apolipoproteins on the surface are critical to lipoprotein metabolism.14 There are three pathways of lipoprotein metabolism: exogenous, endogenous, and reverse cholesterol transport. The exogenous pathway involves dietary cholesterol and triglyceride (TG) absorption in the jejunum in the form of chylomicrons. The enzyme lipoprotein lipase in peripheral

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tissue hydrolyzes TG, releasing free fatty acids (FFAs), which in turn are available for uptake. In the endogenous pathway, the liver synthesizes VLDL, which is transported to the peripheral tissue. Very-low-density lipoprotein TG are hydrolyzed by lipoprotein lipase to FFAs. Very-lowdensity lipoprotein can also be converted to IDL or LDL. Reverse cholesterol transport involves HDL returning cholesterol from the peripheral tissue to the liver. In the liver, cholesterol is excreted as bile acids through the biliary system.14 Lipid-lowering medications work by affecting one or several lipoprotein metabolism pathways. Increased total cholesterol (TC), decreased HDL-C, and increased TG levels are risk factors for CHD in both men and women. Before the age of 20, men and women have similar lipid profiles; from ages 20 to 55 men tend to have higher total cholesterol levels, but after 55 years of age, women’s cholesterol levels often steadily increase and often exceed those of men.3 Women tend to have higher levels of HDL-C than men throughout their life; however these levels decline slowly after the menopause. It is hard to know how much of this decrease is due to a fall in endogenous estrogen levels, increasing weight, decreased physical activity, or a combination of these factors. Lipid levels in women are influenced by hormonal changes throughout life as outlined in more detail in the next section. Women, and predominantly those men older than 65 years, demonstrate a weaker association between elevated TC and LDL-C levels with CHD; however HDL-C levels are closely and inversely associated with CHD risk in women. Triglycerides (TG) are an independent predictor of CHD in older women.15 HDL-C and TG appear to be more closely related to CHD risk among women than men, whereas LDL-C appears to be a more potent predictor among men.

Low-Density Lipoprotein Cholesterol The NCEP published its third set of guidelines for detection, evaluation, and treatment of dyslipidemia in May 2001.16 Because elevated LDL-C contributes to the development of CHD and treatment of LDL-C significantly reduced CHD events, lowering LDL-C is the primary therapeutic goal set by the NCEP. Although the NCEP recommends that TC, LDL-C, HDL-C and TG should be routinely checked in asymptomatic adults, the NCEP treatment goals primarily focus on lowering LDL-C; when the TG level is 200 mg/dl, the non-HDL-C is a secondary target of therapy. According to the NCEP ATP III guidelines, persons are categorized into three risk categories: (1) established CHD and CHD risk equivalents; (2) multiple (two or more) risk factors; (3) zero to one risk factor. The major risk factors that modify LDL-C goals are summarized in Table 16.1.16 CHD risk equivalents are the noncoronary forms of clinical atherosclerotic disease, DM, end-stage renal disease, and

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Table 16.1  Major risk factors (exclusive of LDL cholesterol) that modify LDL goalsa Age (men 45 years; women 55 years) Cigarette smoking Hypertension (blood pressure 140/90 mmHg) or on antihypertension medications Low HDL cholesterol (40 mg/dl)b Family history of premature CHD (CHD in male first-degree relative 55 years; CHD in female first-degree relative 65 years) Source: The National Heart, Lung, and Blood Institute (NHLBI)National Institutes of Health. Executive summary of the third report of the National Cholesterol Education Program (NCEP), expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Clinical Guidelines/Evidence Reports. JAMA 2001;285(19):2486-97. a Diabetes is regarded as a coronary heart disease equivalent. LDL indicates low-density lipoprotein; HDL, high-density lipoprotein. b HDL cholesterol 60 mg/dl counts as a ‘negative’ risk factor; its presence removes one risk factor from the total count.

multiple (2) risk factors with a predicted 10-year risk for CHD 20% (based on Framingham risk score).16 All persons with CHD or CHD risk equivalents are considered high risk. The LDL-C goal in high risk patients is 100 mg/dl. For those with 2 risk factors and a 10-year risk for CHD of 10–20%, the recommended LDL-C goal is 130 mg/dl. In persons with 0 to 1 risk factors and a 10-year risk for CHD of 10%, the LDL-C goal is 160 mg/dl. In 2004 the NCEP published its modified ATP III guidelines on the basis of five major clinical trials with statin therapy measuring clinical endpoints.17–22 Risk stratification terminology was modified to state that a person with two risk factors but a Framingham risk 10% over the next decade was at ‘moderate’ risk and those with 2 risk factors and an FRS of 10–20% were at ‘moderately high’ risk.17 The modified guidelines for LDL-C goals and cutpoints for therapeutic lifestyle changes and drug therapy by risk categories are summarized in Table 16.2. The NCEP concluded in 2004 that, based on clinical trial support, if the baseline LDL-C is 100 mg/dl in a patient considered to be very high risk, initiation of LDL-lowering therapy to achieve an LDL-C level of 70 mg/dl is a therapeutic option that has clinical trial support.17 Factors contributing to a person being very high risk are: (1) the presence of established CHD; (2) multiple risk factors (especially DM); (3) severe and poorly controlled risk factors (especially continued cigarette smoking); (4) multiple risk factors for metabolic syndrome (especially high TG 200 mg/dl plus non-HDL-C 130 mg/dl with low HDL-C 40 mg/ dl); and (5) patients with acute coronary syndromes, on the basis of the PROVE IT-TIMI22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22) trial. For moderately high-risk persons, the recommended LDL-C goal is 130 mg/dl,

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Table 16.2  ATP III goals and cutpoints for therapeutic lifestyle changes and drug therapy in different risk categories Risk category

LDL-C goal

Initiate TLC

Consider drug therapy

High risk: CHD or CHD risk equivalents (10 year risk 20%) Moderately high risk: 2 risk factors (10 year risk 10–20%) Moderate risk: 2 risk factors (10 year risk 10%) Lower risk: 0–1 risk factor

100 mg/dl(optional goal: 70 mg/dl) 130 mg/dl

≥100 mg/dl ≥130 mg/dl

130 mg/dl

≥130 mg/dl

≥100 mg/dl (100  mg/dl consider drug options) ≥130 mg/dl (100–129 mg/dl consider drug options) ≥160 mg/dl

160 mg/dl

≥160 mg/dl

≥190 mg/dl (160–189 mg/dl LDL-lowering drug optional)

Adapted from Grundy et al., 2004.17

but an LDL-C goal of 100 mg/dl is a therapeutic option based on clinical evidence. The guidelines emphasize that when LDL-lowering drug therapy is used in persons with moderate to high risk, the intensity of treatment should be sufficient to achieve at least a 30–40% reduction in LDL-C levels.17

High-Density Lipoprotein Cholesterol High HDL-C protects against CHD, as HDL-C is responsible for transporting cholesterol from the periphery to the liver for catabolism.23 In the United States, the average white woman has a HDL-C of 55 mg/dl and the average white man has a HDL-C of 45 mg/dl.24 A 1 mg/dl increase in HDL-C has generally been associated with a 2% decrease in risk of CHD.14 The NCEP ATP III considers an HDL-C 60 mg/dl a negative risk factor, whereas HDL-C 40 mg/ dl is considered a positive risk factor for CHD.16 It is noteworthy that a HDL-C 60 mg/dl represents the 85th percentile for men vs. the 70th percentile in women; it seems probable that the level of HDL-C considered cardioprotective may need to be higher in women.25 A HDL-C of 70 mg/ dl is about the 85th percentile for white women, and this may be a more appropriate designated ‘negative risk factor’ than a HDL-C of 60 mg/dl in women.25

Triglycerides Elevated TG appear to be an independent risk factor for CHD, especially in women.26,27 The ATP III considers a normal TG 150 mg/d1, borderline high TG 150–199 mg/ dl, high TG 200–499 mg/dl, and very high TG 500 mg/dl or greater.16 High TG are associated with denser LDL particles, which are generally thought to be more atherogenic and, therefore, associated with an increased risk of CHD.14 High TG are also associated with DM and metabolic syndrome, which is presumably a prediabetic or insulin-resistant state. Patients with metabolic syndrome have insulin resistance, abdominal obesity, elevated blood pressure, low HDL-C, and high TG.16 In patients with TG 200 mg/dl, the therapeutic goal is to lower TG in addition to lowering LDL-C.16

A large meta-analysis found that after controlling for HDL-C, the relative risk (RR) for men with high TG was 1.14 (95% CI: 1.05–1.28), whereas for women the RR was 1.37 (95% CI: 1.13–1.66).26 Another study that followed 12 339 middle-aged individuals participating in the Atherosclerosis Risk in Communities (ARIC) study, found that elevated TG is associated with a greater RR in women (4.7) than in men (2.1). In this study, the TG-associated risk persisted in women, but not in men, after the analysis controlled for LDL-C, HDL-C, and lipoprotein (a).27

Non-High-Density Lipoprotein Cholesterol As TG levels increase, the calculation of LDL-C by the Friedewald equation (LDL-CC  TC – HDL-C – TG/5) becomes less accurate. The equation has little applicability if the TG level is 400 mg/dl. Because patients with elevated TG have high TG-rich lipoproteins, such as VLDL, measuring non-HDL more accurately accounts for all atherogenic lipoproteins (VLDL, IDL, LDL, and Lp[a]). Only TC and HDL-C have to be measured to calculate non-HDL, and these values can be measured quite accurately even when the patient is in a nonfasting state.28,29 Data from the Lipid Research Clinics Program followup study revealed that in the 2406 men and 2056 women followed for 19 years, HDL-C and non-HDL-C were stronger predictors of CHD death than was LDL-C.28 A 30 mg/dl increase in non-HDL-C was associated with a 19% increased risk of CHD in men and a 15% increased risk in women. In women there was no significant correlation between LDL-C level and mortality from CHD.28 Rather than focusing only on LDL-C, non-HDL-C may be a better method of assessing CHD risk in patients with: (1) DM who have elevated TG, (2) in patients with normal LDLC but high VLDL-C or IDL-C, and (3) perhaps in women. High-density lipoprotein cholesterol is the single best parameter for CHD prediction in women, but non-HDL-C was better than LDL-C at assessing risk.28 In patients with CHD or CHD equivalents, the nonHDL-C goal is 130 mg/dl. If a patient has two or more of the NCEP-specified risk factors, the target non-HDL-C

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is 160 mg/dl. A non-HDL-C of 190 mg/dl is adequate if the patient has zero to one risk factors for CHD.16 Although there is a consensus that non-HDL-C has a role in assessing risk in individuals with high TG, arguments against routine non-HDL-C use focus on the many trials proving LDL-C as being predictive of CHD and question whether TG correlates with another risk factor such as obesity.13 Regardless, it is important to focus on optimizing LDL-C, HDL-C, and TG to normalize one’s non-HDL-C.

Apolipoprotein B-100 and Lipoprotein(a) An increased level of apolipoprotein B-100 (apoB) is also associated with higher cardiac risk in women. Each of the atherogenic lipoprotein particles contains a single molecule of apoB and, therefore, the concentration of apoB reflects the total number of circulating atherogenic apoB-containing lipoproteins, including VLDL, IDL, and Lp(a).30 ApoB is a better predictor of the number of LDL particles than LDL-C. Smaller than average LDL particle size and LDL pattern B are associated with the development of premature CHD in younger women, even after LDL-C and other risk factors are taken into account; however, the association is not independent of HDL-C, triglycerides and body mass index. Lp(a) is associated with higher cardiac risk in women. Lp(a) consists of an LDL particle with its apo B-100 molecule linked by a disulfide bridge to apo(a). Apo(a) is a glyco­ protein homologous to plasminogen with a yet uncertain biological function. A prospective analysis of elevated Lp(a) in the Framingham Study revealed that Lp(a) was a strong, independent predictor of myocardial infarction in women.31 Among obese women and women with metabolic syndrome or DM, there are often associated adverse changes in the lipid profile. There is a greater prevalence of the dyslipidemic triad consisting of LDL phenotype B (predominance of small, dense LDL), lower HDL-C levels, and higher TG levels. Adverse lipoprotein changes associated with DM tend to be more pronounced in women than in men and may account for the worse prognostic impact of DM on cardiovascular health among women.

Hormonal effects on CVD risk Hormonal influences on lipoprotein levels in women are diverse. Prior to puberty, the average lipid profile is similar in girls and boys. Young women have lower LDL-C cholesterol and non-HDL-C but higher HDL-C than men of similar age. Gender differences in HDL-C levels and HDL particle size emerge at puberty with the rise in endogenous testosterone levels and concomitant HDL decline in males. Over their lifespan, women exhibit a higher average HDL-C level than men by about 10 mg/dl. A substantial proportion (20%) of women with CVD have HDL-C levels of 60 mg/dl,

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which is considered ‘protective’ against CVD development. Gender differences in HDL-C and CVD risk may reflect either a deleterious effect of testosterone in men or a protective effect of estrogen in premenopausal women, or both. In premenopausal women, lipid values vary throughout the menstrual cycle. Parous women tend to have lower HDL-C than nulliparous women. After menopause, TC levels increase, LDL-C tends to rise, and LDL particle distribution shifts toward smaller, denser particles. Postmenopausal women tend to have a greater postprandial rise of lipoprotein levels after a standardized fat meal than premenopausal women despite a similar post-heparin lipoprotein lipase activity. Beyond the effects on lipids, estrogen can have both positive and negative effects on the cardiovascular system.29 Estrogen facilitates nitric oxide-mediated vasodilation, and inhibits the response of blood vessels to injury and the development of atherosclerosis. However, estrogen increases inflammatory markers such as C-reactive protein (CRP) and have prothrombotic effects, increasing circulating levels of prothrombin and decreasing antithrombin III, and consequently contributing to an increased risk of venous thromboembolic events.

Hormone Replacement Therapy The protective effect of estrogen in premenopausal women against cardiovascular events stimulated interest in the use of hormone replacement therapy (HT) as a putative preventive measure against atherosclerotic heart disease. Initial observational studies documented decreased cardiac event rates in postmenopausal women receiving hormone replacement therapy and hypotheses generated advocating its use seemed reasonable.32 Oral postmenopausal hormone therapy (HT) decreases LDL-C and Lp(a) levels, increases HDL-C and tri­ glyceride levels, and is associated with improved glucose toler­ ance, and reductions in weight and waist circumference.33 While observational and laboratory-based studies have consistently shown that estrogen has net beneficial effects on the cardiovascular system, several randomized clinical trials conducted in women with existing CVD found no overall effect of HT on the risk of CHD events. Some of the most influential of these studies are the Nurses’ Health Study (NHS),32,34,35 Heart and Estrogen/Progestin Replacement Study (HERS),33,36 Women’s Angiographic Vitamin and Estrogen (WAVE) Trial,37 Estrogen in the Prevention of Atherosclerosis Trial (EPAT),38 and the Women’s Health Initiative (WHI) Clinical Trials of Hormone Therapy.39–41 The published WHI data of primary prevention indicates that conjugated equine estrogen  medroxyprogesterone acetate treatment in postmenopausal women does not provide any cardioprotective effects and may even result in early harm with an increased venous thrombosis and stroke. To reconcile the scientific findings that suggested cardiovascular benefits with estrogen use with the null findings from these trials, the ‘timing hypothesis’ was proposed: the

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benefits of HT in preventing atherosclerosis occur only if therapy is initiated before advanced atherosclerotic disease develops.42 This hypothesis predicts that HT is not bene­ ficial when given to older women, because the underlying biologic characteristics of the vessel wall and the vascular response to HT are altered in aged, more atherosclerotic vessels. The randomized trials of cardiovascular effects of HT reporting null to negative findings generally involved initiating HT in older women (64–67 years).

Dyslipidemia management Diet and Exercise The first strategy in treating dyslipidemia is lifestyle modification. Decreasing total fat intake to 25–35% of total calories, decreasing saturated fat intake to 7% of total calories, reducing cholesterol to 200 mg/day, and increasing soluble fiber to 10–25 g/day, all help to decrease cholesterol levels.16 Increasing physical activity level and weight loss (if overweight) also improve the lipid profile by reducing total cholesterol and LDL-C, increasing HDL-C, and decrease TG.43,44 One study found that although regular exercise and a low-fat diet (with 10% of calories from fat) do decrease cholesterol in both genders, the change was slightly greater in men than women.45 After 3 weeks, the 2685 men enrolled (age 20–88) had a greater decrease in body weight (5.5%

vs. 4.4%), TC (24.4% vs. 20.8%), and LDL-C (25.5% vs. 19.5%) than the 1902 women did (age 20–92).45

HMG-CoA Reductase Inhibitors When diet and exercise do not adequately treat dyslipidemia, medication is the next step. The most effective drugs for lowering LDL-C are HMG-CoA reductase inhibitors (statins); HMG-CoA reductase is involved in the rate-limiting step of cholesterol synthesis. By reversible competitive inhibition, statins decrease cholesterol synthesis in the liver and also promote upregulation of LDL cell surface receptors.46 Statins can decrease LDL-C by 18–55%, decrease TG by 7–30%, and increase HDL-C by 5–15%.16 With maximum titration of atorvastatin for example, 87% of women with known CHD and 80% of women without CHD but with hypercholesterolemia, can achieve the NCEP ATP III goal LDL-C levels.47 Statins have been proven beneficial in both primary and secondary prevention of CHD in both genders. The 2004 NCEP modifications to the ATP III risk categories and cutpoints for therapeutic lifestyle changes and drug therapy (summarized in Table 16.2) were based on five major clinical endpoint trials of statin therapy.18–22 A summary of some of the major primary prevention clinical trials to date of statin therapy is provided in Table 16.3 (WOSCOPS: West of Scotland Coronary Prevention Study,48 AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention

Table 16.3  HMG-CoA reductase inhibitors: primary prevention trials

No. patients

Women (%)

WOSCOPS, 199548 AFCAPS/ TexCAPS, 199849 PROSPER, 200219 ASCOT-LLA, 200221 HPS, 200318

6 595

0

6 605

15

5 804

52

10 305

19

20 536

25

MEGA, 200650 JUPITER, 200851

7 382

69

17 802

38

Study, year

Baseline cholesterol

Intervention

Primary endpoint

Relative risk reduction in primary endpoint (%)

LDL-C 192HDL-C 44TG 164 LDL-C 150HDL-C 36–40TG 158

Pravastatin 40 mg

MI, CHD death

31

Lovastatin 20–40 mg

MI, sudden cardiac death, unstable angina

37

Pravastatin 40 mg

15

Atorvastatin 10 mg

CHD death, nonfatal MI, fatal or nonfatal stroke MI, CHD death

Simvastatin 40 mg

All-cause mortality

24

Pravastatin 10–20 mg Rosuvastatin 20 mg

MI, CHD and sudden death, 33 angina, revascularization MI, stroke, cardiovascular 44 death, angina requiring hospitalization

LDL-C 147, HDL-C 50,TG 133 LDL-C 131HDL-C 50TG 146 LDL-C average 126 HDL-C N/ATG N/A LDL-C 157 HDL-C 58 TG 128 LDL-C 104 HDL-C 51 TG 138

36

Abbreviations: MI: myocardial infarction; CHD: coronary heart disease; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TG: triglyceride; WOSCOPS: West of Scotland Coronary Prevention Study; AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study; PROSPER: Prospective Study of Pravastatin in the Elderly at Risk; ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm; HPS: Heart Protection Study; MEGA: Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; JUPITER: Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin.

C h a p t e r 1 6     Dyslipidemia Management in Women and Men: Exploring Potential Gender Differences l

Study,49 PROSPER: Prospective Study of Pravastatin in the Elderly at Risk,19 ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm,21 HPS: Heart Protection Study,18 MEGA: Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese,50 JUPITER: Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin51). The trials that have examined statin therapy and secondary prevention specifically in women are discussed in further detail below. The Scandinavian Simvastatin Survival Study (4S) was a landmark secondary prevention trial in subjects with known hypercholesterolemia.52 The 4S was a double-blind, placebocontrolled trial of 4444 participants with CHD (827 women). Participants had a history of MI or angina pectoris and hypercholesterolemia. They received placebo or 20–40 mg of simvastatin per day with a goal TC 200 mg/dl and a mean follow-up of 5.4 years. The 4S trial revealed that cholesterol lowering could decrease the risk of major coronary events in women by 34%.52 Men and women had similar declines in major coronary events, atherosclerotic events, hospitalizations for CHD, cardiovascular events, and coronary revascularization. Women in the simvastatin arm of the trial did not have a lower overall death rate, although men in the simvastatin arm did have a significant decrease in mortality.52 The Cholesterol and Recurrent Events (CARE) trial was also a randomized trial focusing on secondary prevention, but unlike 4S, the subjects all had ‘average’ cholesterol levels. The 4159 patients (576 women) all had TC level of 240 mg/dl or less, LDL-C between 115 mg/dl and 174 mg/ dl, and a history of prior MI. Participants received placebo or 40 mg/day of pravastatin.53 Women receiving pravastatin had a 46% decline in coronary events, whereas men had a 20% decrease in events. The beneficial effect of drug treatment appeared slightly greater among women than men (P  0.05) though there was a slightly higher incidence of breast cancer in the group assigned to statin use;53 this finding was not seen in other pravastatin trials. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study was designed similarly to CARE but had different outcomes pertaining to gender and treatment.54 LIPID was a randomized, double-blind, placebo-controlled trial comparing 40 mg/day of pravastatin to placebo in 9014 subjects (1516 women). LIPID showed that with a median follow-up of 6.1 years, treatment with pravastatin could decrease CHD mortality, total mortality, and cardiac events in men. However, in LIPID there was a nonsignificant 11% reduction in CHD events in women, vs. a significant 26% decline in CHD events in men.54 This study was inadequately powered to look at differences based on gender. The Air ForceTexas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) was a primary prevention trial that included women as participants.49 A total of 6605 participants (997 women) with average cholesterol and LDLC but with below average HDL-C received 20–40 mg per

181

day of lovastatin or placebo for a mean of 5.2 years. For subjects on lovastatin, the relative risk of a first acute major coronary event decreased by 37% in women and by 46% in men. This trial supports the use of cholesterol-lowering medications in men and women for primary prevention in persons with low HDL-C, especially if they have one additional risk factor.49 However, to prevent an event in one woman, more than 80 women needed to be treated with lovastatin. The largest secondary prevention study of cholesterol reduction in women is the Heart Protection Study.18 This was a 6-year multicenter trial examining the effects of cholesterol reduction on major vascular events in patients with known CHD, other types of atherosclerotic vascular disease, or DM in 20 536 individuals (5082 women). One half of the participants received 40 mg of simvastatin and one half received placebo. This study revealed that lowering cholesterol with simvastatin 40 mg decreased the risk of MI and stroke by one third. Treatment with simvastatin prevented 70–100 vascular events per 1000 patients treated and prevented 20–30 deaths per 1000 patients treated. This study also showed that statin use decreases CHD risk to a comparable extent in both men and women. Of note, there was no significant reduction in total mortality in female subjects.18 In 2008, results of the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) were published.51 This trial enrolled apparently healthy men (age 50) and women (age 60) who had baseline LDL-C levels of 130 mg/dl, and highsensitivity C-reactive protein (hsCRP) levels of 2.0 mg/l, with no prior history of cardiovascular disease or diabetes. The trial population included 38% women and almost 30% ethnic minorities. The participants were randomized to receive either rosuvastatin 20 mg daily or placebo. The primary endpoint was a combination of nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization, revascularization, and cardiovascular death. The study was stopped early after a median follow-up period of 1.9 years due to a clear benefit seen in the rosuvastatin group compared to placebo. Rosuvastatin decreased the primary endpoint relative risk by 44% (hazard ratio for rosuvastatin compared to placebo was 0.56, 95% CI 0.46–0.69, p 0.001). The relative risk reduction was comparable in both men and women. JUPITER is the first trial to demonstrate the benefit of statin therapy in patients with no known cardiovascular disease and low or normal LDL-C levels, but with elevated hsCRP levels. According to the current ATP III guidelines, most patients enrolled in JUPITER would not qualify for statin therapy for primary prevention because their baseline LDL-C was so low. Although the relative risk reductions achieved with the use of statin therapy in JUPITER were significant, absolute differences in risk are clinically more important than relative reductions in risk in deciding whether to recommend drug therapy, since the absolute

182

s e c t i o n 3     Cardiovascular Disease l

benefits of treatment must outweigh the associated risks and costs. The number of patients with hard cardiac events in JUPITER was reduced from 1.8% (157 of 8901 subjects) in the placebo group to 0.9% (83 of 8901 subjects) in the treatment arm; the authors estimated that 95 subjects meeting the entry criteria would need to be treated for 2 years to prevent a coronary event, a stroke, or cardiovascular death. If the results were extrapolated over 5 years, the number needed to treat to prevent one event in their primary endpoint was 25. It should be noted that the primary endpoint included coronary revascularization and not just heart attack, stroke, and CVD death. If one added total mortality and the occurrence of future venous thromboembolic events to the endpoint, the number needed to treat drops to 18, which is much lower than any other primary prevention trial using statin therapy. hsCRP has been shown to improve the estimation of the risk for coronary events.55 JUPITER, however, did not compare subjects with and without hsCRP measurements, and also did not compare the use of hsCRP with other markers of cardiovascular risk. Thus, it provided only limited information about the role of hsCRP testing in clinical management. A prior primary prevention trial49 did not show a benefit of lovastatin in those with an hsCRP of 1.5 mg/l. This was the rationale cited by the authors for only looking at subjects with an elevated hsCRP. Of note, the observed event rate in JUPITER was about 2–3 times higher than predicted by the Framingham risk score and this also supports the idea that an elevated hsCRP identifies subjects at higher than expected CVD risk. Given the benefits of statin therapy in primary prevention seen in JUPITER, it is reasonable to measure hsCRP levels in asymptomatic individuals who have an intermediate level of risk, if the decision to initiate drug treatment might change depending on the hsCRP level. If persons already qualify for statin therapy, there is no need to measure an hsCRP. Nevertheless, those subjects who had their hs-CRP fall below 2 mg/l had the greatest relative risk reduction in JUPITER and in two other recent large trials using rosuvastatin. Statins can lead to elevated liver enzymes, myopathy, and, rarely, rhabdomyolysis.16 It is reasonable to periodically monitor liver enzymes and evaluate for muscle symptoms while a patient is being treated with a statin. The risk of adverse effects can be increased by the addition of gemfibrozil, erythromycin, antifungal medication, macrolide antibiotics, or immunosuppression agents.

Nicotinic Acid Nicotinic acid, a water-soluble B vitamin complex, is another treatment for dyslipidemia. Nicotinic acid lowers LDL-C by 15–25% and lowers TG by 20–50%. It is especially beneficial in individuals with a low HDL-C, as it can

increase HDL-C by 15–35%.16 Nicotinic acid may decrease the ability of the liver to synthesize apolipoprotein B-containing lipoproteins, and it may decrease transport of fatty acids by inhibiting lipolysis in adipose tissue.56,57 Although there have been no clinical trials of nicotinic acid with women enrolled as subjects, one secondary prevention trial with male subjects found that nicotinic acid decreased CHD mortality.58 Although statins are typically first-line therapy for a high LDL-C, nicotinic acid may have a role in individuals with a normal LDL-C but a low HDLC or high TG. Niacin is also available in combination with simvastatin and in a long-acting formulation. High-dose nicotinic acid may be a suboptimal therapy in patients with DM as it can worsen hyperglycemia or insulin resistance. Some patients have difficulty tolerating high dose niacin therapy as they may experience flushing, GI distress, gout, or hepatotoxicity.16

Fibrates Fibrates are primarily used in patients with elevated TG. They can decrease TG by 50%, decrease LDL-C by 5–20%, and increase HDL-C by 10–20%.16 By altering transcription of genes encoding for proteins that control lipoprotein metabolism, fibrates increase the catabolism of TG-rich particles, decrease production of VLDL, and increase the production of apolipoprotein A-1.59 Fibrates may be modestly more effective in improving lipid parameters in women than in men. One study found that gemfibrozil decreased TG, decreased LDL-C, and increased HDL-3 significantly more in women than in men.60 Fibrates have occasionally been associated with gallstones, dyspepsia, and myopathy. The risk of myopathy and rhabdomyolysis is greater when gemfibrozil is combined with a statin.61

Bile Acid Resins/Ezetimibe Bile acid resins work by binding cholesterol-rich bile acids in the gut interrupting the enterohepatic circulation and as such increasing their excretion.62 They can decrease LDLC by 15–30%. In patients with hypertriglyceridemia they may increase TG levels,16 In a study evaluating the effect of cholestyramine vs. placebo in men with hypercholesterolemia, cholestyramine use resulted in a decreased incidence of CHD.63 Bile acid resins are not prescribed as frequently as other therapies due to their unpleasant gastrointestinal side effects and altered absorption of other medications.16 A formulation known as colesevelam is less likely to alter the metabolism of other medications. Ezetimibe lowers LDL-C by about 15–20% and is easier to tolerate than a resin. Ezetimibe inhibits reabsorption of cholesterol through the proximal small intestine. Unfortunately, we still do not have clinical trial data showing that ezetimibe provides incremental benefit on top of standard statin therapy. A large-scale clinical trial trying to

C h a p t e r 1 6     Dyslipidemia Management in Women and Men: Exploring Potential Gender Differences l

prove the clinical usefulness of this compound will likely not be available until 2012 or beyond.64

Conclusion Coronary heart disease remains the leading cause of death in men and women. Dyslipidemia is a well-established risk factor for developing CHD and treating abnormal lipid levels prevents development and progression of disease. There are documented differences in disease onset and lipid profiles between the two genders. Women typically manifest CHD 10 years later than men. The onset of disease in women usually occurs after menopause. LDL-C remains the major target of therapy; however non-HDL-C, which takes into account all atherogenic lipoproteins, may be a better predictor of CHD than LDL-C, especially in women. Elevated TG also appear to be a significant independent CHD risk factor, especially in women. Despite a ‘protective’ effect of HDL-C on the cardiovascular system, a large percentage of women with a ‘high’ HDL-C level develop CHD. It has been suggested that the current practice of regarding an HDL-C level of 60 mg/dl as a ‘negative risk factor’ for CHD in women might be suboptimal, and rather an HDL-C level 70 mg/dl should be classified as a ‘negative risk factor’ for women.25 Despite differences in CHD onset and lipid profiles, men and women appear to respond similarly to common therapies for dyslipidemia. Although it is important to continue our efforts to understand gender differences in regards to CHD, it is also important that physicians utilize the data derived from clinical trials to treat patients appropriately. Current data support the appropriate use of lipid-lowering therapy to minimize the risk of CHD in both men and women.

Suggestions for further investigations Triglycerides, HDL cholesterol, and non-HDL cholesterol appear to have greater prognostic importance in women than they do in men. The reasons for this are unclear. Until JUPITER, the only primary prevention lipid-lowering clinical trial involving women is the AFCAPS/ TexCAPS trial, which found 13 events in the placebo group and seven in the statin group over 5 years of treatment. There is a need for more cost-effective data on lipid lowering in women who are asymptomatic. In JUPITER there was comparable relative risk reduction with rosuva­ statin in both women and in men, but gender differences in cost-effectiveness have not been reported to date. Meta-analyses of lipid-lowering trials in women still have not shown a decrease in total mortality, while metaanalyses of the data in men show a statistically significant reduction in total deaths.

l

l

l

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References   1. Rosamond W, Flegal K, Furie K, et al. Heart Disease and Stroke Statistics 2008 Update. A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; [Epub ahead of print] (Accessed November 1, 2008.)   2. Mosca L, Appel LJ, Benjamin EJ, et al. American Heart Association. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 2004;109:672–93.   3. Foody JM, Pordon C. Women and coronary artery disease. In: JM Foody, ed. Preventative Cardiology: Strategies for the Prevention and Treatment of Coronary Artery Disease. Totowa, NJ: Humana Press; 2001:193–220.   4. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women [see comments]. JAMA 1991;265:1861–67.   5. Kaplan NM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. [Review]. Arch Intern Med 1989;149:1514–20.   6. Thompson CJ, Ryu JE, Craven TE, et al. Central adipose distribution is related to coronary atherosclerosis. Arterioscler Thromb 1991;11:327–33.   7. Soler JT, Folsom AR, Kushi LH, et al. Association of body fat distribution with plasma lipids, lipoproteins, apolipoproteins AI and B in postmenopausal women. J Clin Epidemiol 1988;41:1075–81.   8. Lee WL, Cheung AM, Cape D, et al. Impact of diabetes on coronary artery disease in women and men: a meta-analysis of prospective studies. Diabetes Care 2000;23:962–68.   9. Walden CE, Knopp RH, Wahl PW, et al. Sex differences in the effect of diabetes mellitus on lipoprotein triglyceride and cholesterol concentrations. N Engl J Med 1984;311:953–59. 10. Ginsberg HN. Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis. [Review]. Diabetes Care 1991;14:839–55. 11. Pinilla J, Gonzalez B, Barber P, et al. Smoking in young adolescents: an approach with multilevel discrete choice models. J Epidemiol Community Health 2002;56:227–32. 12. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Health, United States. With Chartbook on Trends in the Health of Americans. Hyattsville, MD: National Center for Health Statistics; 2006, Available at: www.cdc. gov/nchs/hus.htm. (Accessed 1 November 2008.). 13. National Center for Health Statistics, Centers for Disease Control and Prevention. Compressed mortality file: underlying cause of death, 1979 to 2004. Atlanta, GA: Centers for Disease Control and Prevention. Available at: wonder.cdc. gov/mortSQL.html. (Accessed 1 November 2008.) 14. O’Brien T, Nguyen TT. Subspecialty clinics: endocrinology. Lipids and lipoproteins in women. Mayo Clin Proc 1997;72:235–44. 15. Miller VT. Lipids, lipoproteins, women and cardiovascular disease. Atherosclerosis 1994;108(Suppl):S73–82. 16. The National Heart, Lung, and Blood Institute (NHLBI)National Institutes of Health. Executive summary of the third report of the National Cholesterol Education Program (NCEP), expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Clinical Guidelines/Evidence Reports. JAMA 2001;285:2486–97.

184

s e c t i o n 3     Cardiovascular Disease l

17. Grundy SM, Cleeman JI, Merz CN, et al. Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–39. 18. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:7–22. 19. Shepherd J, Blauw GJ, Murphy MB, et al. PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. PROspective Study of Pravastatin in the Elderly at Risk. Lancet 2002;360:1623–30. 20. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs. usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998–3007. 21. Sever PS, Dahlof B, Poulter NR, et al. ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOTLLA): a multicentre randomized controlled trial. Lancet 2003;361:149–58. 22. Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–504. 23. Pieters MN, Shouten D, Van Berkel TJ. In vitro and in vivo evidence for the role of HDL in reverse cholesterol transport. Biochem Biophys Acta 1994;1225:125–34. 24. National Heart, Lung, and Blood Institute, Lipid Metabolism Branch, Division of Heart and Vascular Diseases. The Lipid Research Clinics Population Studies Data Book. The Prevalence Study: Aggregate Distribution of Lipids, Lipoproteins and Selected Variables in 11 North American Populations. Bethesda, MD: National Institutes of Health; 1980, 1-36. 25. Bittner V, Simm J, Fong J, et al. Acute ischemic heart disease: correlates of high HDL cholesterol among women with coronary heart disease. Am Heart J 2000;139:288–96. 26. Austin MA, Hokanson IE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998;81: 7B–12B. 27. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoprotein A-I and B, and HDL density subtractions. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108–13. 28. Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001;161:1413–19. 29. Grundy SM. Non-high-density lipoprotein cholesterol level as a potential risk predictor and therapy target. Editorial. Arch Intern Med 2001;161:1379–80.

30. Blaha MJ, Blumenthal RS, Brinton EA, et al. on behalf of the National Lipid Association Taskforce on Non-HDL Cholesterol. The importance of non-HDL cholesterol reporting in lipid management. J Clin Lipidology 2008;2:267–73. 31. Bostom AG, Gagnon DR, Cupples LA, et al. A prospective investigation of elevated lipoprotein(a) detected by electrophoresis and cardiovascular disease in women. The Framingham Heart Study. Circulation 1994;90:1688–95. 32. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335:453–61, [Erratum in: 335:1406.]. 33. Hulley S, Grady D, Bush T, et al. for the Heart and Estrogen/ progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–13. 34. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933–41. 35. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769–75. 36. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49–57, [Erratum in: 288:1064.]. 37. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a ran­ domized controlled trial. JAMA 2002;288:2432–40. 38. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939–53. 39. The Women’s Health Initiative Study Group. Control Clin Trials 1998;19:61–109. 40. Writing Group for the Women’s Health Initiative Investigators. JAMA 2002;288:321–33. 41. Women’s Health Initiative Steering Committee. JAMA 2004; 291:1701–12. 42. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005;308:1583–87. 43. LaRosa JE. Triglycerides and coronary risk in women and the elderly. Arch Intern Med 1997;157:961–68. 44. Stefanick MI, Wood PD. Physical activity, lipid and lipoprotein metabolism and lipid transport. In: C Bouchard, RI Shephard, T Stephens, eds. Physical Activity, Fitness and Health: International Proceedings and Consensus Statement. Champagne, IL: Human Kinetics Publishers; 1994:417–31. 45. Barnard JR. Effects of lifestyle modification on serum lipids. Arch Intern Med 1991;151:1389–94. 46. Ma PT, Gil G, Sudhof T, et al. Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low-density lipoprotein receptor in livers of hamsters and rabbits. Proc Natl Acad Sci U S A 1986;83:8370–74. 47. McPherson R, Angus C, Murray P, et al. Efficacy of Atorvastatin in achieving National Cholesterol Education Program low-density lipoprotein targets in women with severe dyslipidemia and cardiovascular disease or risk factors for cardiovascular disease. The Women’s Atorvastatin Trial on Cholesterol (WATCH). Am Heart J 2001;141:949–56.

C h a p t e r 1 6     Dyslipidemia Management in Women and Men: Exploring Potential Gender Differences l

48. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440–45. 49. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;20:1615–22. 50. Nakamura H, Arakawa K, Itakura H, et al. the MEGA Study Group). Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006;368:1155–63. 51. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein (JUPITER Trial). N Engl J Med 2008; 359:2195–207. 52. Miettinen TA, Pyomla K, Olsson AG, et al. Cholesterollowering therapy in women and elderly patients with MI or angina pectoris: Findings from the Scandinavian Simvastatin Survival Study (4S). Circulation 1997;96:4211–18. 53. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9. 54. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: Results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. N Engl J Med 1998;339:1349–57. 55. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to

56.

57.

58.

59.

60.

61.

62.

63.

64.

185

clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499–511. Tato F, Vega GL, Grundy SM. Effects of crystalline nicotinic acid-induced hepatic dysfunction on serum low-density lipoprotein cholesterol and lecithin cholesteryl acyl transferase. Am J Cardiol 1998;81:805–7. Gotto A, Powell H. Manual of Lipid Disorders: Reducing the Risk for Coronary Heart Disease, 2nd edn. Baltimore, MD: Williams & Wilkins; 1999. Canner PL, Gatewood LC, White C, et al. Fifteen-year mortality in coronary drug project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245–55. Staels B, Dallongville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088–93. Koskinen P, Kovanen P, Tuomilehto J, et al. Gemfibrozil also corrects dyslipidemia in postmenopausal women and smokers. Arch Intern Med 1992;152:90–96. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol 1998;81:368–69. Mosca L, Grundy SM, Judelson D, et al. Guide to preventive cardiology for women. J Am Coll Cardiol 1999;33: 1751–55. Lipid Research Clinics Primary Prevention Study. Reduction in the incidence of coronary heart disease. JAMA 1984;251: 351–64. Musunuru K, Blumenthal RS. The implications of the ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression trial: a return to the first principles. Clin Cardiol 2008;31:288–90.

C hapter

17

Gender Differences in the Role of Stress and Emotion in Cardiovascular Function and Disease David E. Anderson1, and Margaret A. Chesney2 1

National Institute on Aging, National Institutes of Health, Baltimore, MD, USA Professor of Medicine, University of Maryland School of Medicine, Center for Integrative Medicine, Baltimore, MD, USA

2

or so.3 Many have utilized laboratory animals because of the level of experimental control that permits cause and effect statements that cannot be obtained in studies with humans. Studies with humans have confirmed findings in laboratory animals, identified risk factors for cardiovascular disease, and investigated the effects of behavioral and psychological interventions in cardiovascular disease. Studies focusing on antecedents of atherosclerosis have tended to focus on sympathetic nervous system activation and supportive endocrine response. In addition to this pathway, however, a smaller but growing literature has linked inhibitory stresses that elicit vigilant attention to the environment in the absence of sympathetic arousal with the development of hypertension.

Clinicians have long believed that the mind and emotional state can play an important role in the development of and recovery from illness and chronic disease. Thus, Sir William Osler famously commented more than a century ago that ‘it is more important to know what kind of a patient has the disease than to know what kind of a disease the patient has.’ Since then, the convergence of psychosomatic medicine and behavioral science has generated a number of testable hypotheses about the role of stress and emotion in the development of diseases of regulation, including hypertension1 and cardiovascular disease.2 Subsequent research has revealed that gender must be considered in any evaluation of the role of psychological factors in the etiology and treatment of cardiovascular disorders. This chapter is presented in four sections. The first section describes implications for the pathogenesis of cardiovascular disorders derived from laboratory studies of gender differences in cardiovascular reactivity to challenging tasks. The second section summarizes the current state of knowledge concerning the role of emotional states in the development and treatment of cardiovascular disorders, including the emerging literature on the role of positive emotions in the prevention of these disorders. The third section reviews gender differences in the role of social class, employment, job strain, and social support in cardiovascular disease pathogenesis and progression. Finally, recent large-scale studies of psychosocial interventions in cardiovascular disease are reviewed, concluding with implications for the future of this field.

Cardiovascular Activity at Rest Autonomic nervous system influence on the heart and peripheral vasculature differ in men and women at rest. Spectral analysis of heart rate variability has shown that young men maintain more sympathetic and less parasympathetic tone on the heart than do women,4 and men maintain more sympathetic influence on skeletal muscle and blood pressure than women.4,5 Testosterone stimulates the renin– angiotensin system, increasing vasoconstrictor tone in men6 while estrogen stimulates nitric oxide in the endothelium, augmenting vasodilatation in women.7 After menopause, when estrogen levels are diminished, blood pressure levels of women increase to those comparable to men, and their incidence of hypertension and CHD becomes equivalent.8 Baroreflex sensitivity is also greater in normotensive men than normotensive women, at least before age 60,9 and this difference plays a role in postural reflexes. Orthostatic hypotension is greater in men than women,7,10 as is blood pressure elevation during prolonged sitting11 or standing.12

Cardiovascular effects of laboratory stress More than 1500 studies of cardiovascular reactivity to laboratory stressors have been published in the last half century Principles of Gender-Specific Medicine

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Cardiovascular Reactivity The sympathetically mediated cardiovascular response to challenge tends to be elicited more strongly in men than women,13 and in older women compared with younger women.14 For example, role-playing of arguments was found to decrease heart rate variability (HRV) more in young men than in young women, indicating a stronger autonomic response to quarrelsome interactions.15 This difference is at least partially mediated by biological factors, since men respond to administration of adrenergic agents with more intense vasoconstriction than women.10 At the same time, reactivity is modulated in women by greater circulating levels of oxytocin, which is preferentially released in females under stress.16 Oxytocin has been shown to facilitate social bonding between mothers and infants, as well as between adults,17 and appears to increase survival value in laboratory animals, since protection of the young may be more successful if females are affiliated with groups than if they are alone.18 Its release is enhanced by estrogen17 and inhibited by androgen.16 Oxytocin administration decreases blood pressure and increases pain threshold.19 As a result, female rats under stress have also been found to exhibit fewer signs of freezing than male rats20 and engage in more exploratory behavior.21 Men typically show greater cardiovascular reactivity than women in tasks such as mental arithmetic, video games, color naming, and anger recall,13,22,23 but interpretation of the experimental context is a significant determinant of the magnitude of response.24 As a result, some studies show no gender differences in reactivity.25–27 The importance of social context was illustrated in a study that included both an ‘achievement challenge’ (mental arithmetic) and a ‘social alienation’ task (verbal disagreements).28 Salivary cortisol of men increased during the ‘achievement challenge’ but not the ‘social alienation’ task, whereas the opposite pattern was observed in women. During tasks that require ‘active coping,’ total peripheral resistance increases more in men, while heart rate and cardiac output increase more in women.25,26,29,30

Social Mediators of Cardiovascular Reactivity For both men and women, the presence of a hostile experimenter amplifies cardiovascular reactivity to challenge,31–33 while the presence of a friend or supportive confederate tends to moderate the response.34–36 When men and women are asked to make a speech in front of a group, blood pressure increases, but the magnitude of the elevation is greater in men than women.36 This response can be attenuated by the presence of a supportive female audience, but a male audience does not have the same effect.37,38 During structured discussion by previously unacquainted men and women, disagreement is usually sufficient to elevate blood pressure in both.39 The magnitude of response is

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greater in women if the male partner is hostile and greater in men if the female partner is dominant. When husbands and wives disagree, blood pressure change is less than between strangers, unless the ability to persuade is tied to reward, in which case, hostile men (but not women) are more reactive.40 Disagreement leads wives to construe their husbands as less friendly, but does not affect husbands’ perceptions of their wives. In another study of older couples in long marriages, verbal conflict evoked increased circulating cortisol, adrenocorticotropic hormone, and norepinephrine (but not epinephrine) in wives, while husbands showed no such changes.41 Thus, daily interactions exert continuing influence on blood pressure and its homodynamic mediators as a function of the structure of social relationships. Time to recovery following cardiovascular arousal may be as important for cardiovascular pathogenesis as magnitude of response,42 but recovery depends on the conditions under which it occurs. For men, anger expression after harassment during mental arithmetic was found to accelerate recovery of pre-task heart rate, but recovery was faster in women if they suppressed anger under these conditions.43 Cardiovascular reactivity can be augmented or diminished by repeated exposure to stressors. Viewings of a Holocaust film on two successive days were associated with no gender-associated differences in heart rate response or negative affect on the first day, but greater tachycardia and more negative affect in women than men on the second day.44 Gender differences in associations between psychometrically-assessed social support and cardiovascular reactivity were also studied in men and women exposed to a computer-generated cognitive stressor task.45 No gender differences were observed in reactivity to the first exposure to the stressor, but on a second exposure, women’s cardiovascular response was attenuated by social support, while men’s response was amplified by the presence of others. These findings illustrate that gender-specific responses to social agents must be considered in interpretations of responses to even nonsocial stress.

Animal Models of Atherosclerosis Studies with animals have shown how experimental social stress can augment atherosclerosis, and again, gender differences appear to be important. Experimental studies with monkeys housed alone showed that heart rates were higher, and the extent of atherosclerosis greater, in monkeys housed in groups, even though no differences in plasma lipids were observed.46 In these studies, male monkeys maintained in social groups whose members were periodically changed showed more atherosclerosis if they maintained a dominant position in the hierarchy than if they were subordinated.47 The dominant monkeys were found to engage in more aggressive behavior towards other monkeys than the more submissive animals, and maintained a higher level of sympathetic nervous system arousal, as indicated by the finding

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that the atherosclerosis could be minimized by sustained beta-adrenergic blockade. By contrast, female monkeys maintained in periodically changing social groups developed more atherosclerosis if they were kept in subordinated status.48 The subordinated females were characterized by a modest impairment of ovarian function,49 which may be relevant to the finding that women with lower estradiol concentrations were more likely to have CHD confirmed by angiograpy.50 Taken together, these studies indicate that atherosclerosis in males with lower status is mediated by sustained sympathetic arousal accompanying the challenges of everyday life. Premenopausal females are subject to similar contingencies but may be somewhat protected until menopause by circulating estrogen.

Inhibited Breathing and Hypertension in Women The role of stress and emotion in the pathogenesis of chronic hypertension remains a subject of debate. The original psychosomatic hypothesis stated that hypertension is promoted by the repression of anger, and the mediating pathway was presumed to involve the sympathetic nervous system.1 Indeed, behavioral stress can evoke dramatic increases in blood pressure via sympathetically mediated effects on the heart and peripheral vasculature, and many patients with chronic hypertension show evidence of increased sympathetic nervous system activity. However, healthy kidneys respond to acute changes in blood pressure via adjustments of circulating fluid volume to return blood pressure to pre-stress levels. Thus, some retardation of renal excretory function must be involved in the development of chronic hypertension, and it has been shown that a deficit in renal function is most adverse under conditions of high sodium intake.51,52 Thus, the development of hypertension might be potentiated in genetically predisposed individuals53 by exposure to a high sodium diet in combination with environmental stressors that suppress renal excretory function. Hypertensive patients are characterized in general by a deficit in affect, compared with normotensive subjects, suggesting that emotional inhibition as a personality trait could be a factor in some kinds of hypertension.54–56 For example, one study reported that hypertensive patients with low plasma renin activity were characterized by a ‘repressive’ coping style, defined by high defensiveness but low anxiety, while those with high renin hypertension exhibited higher levels of anger and anxiety.57 Interestingly, low plasma renin activity is strongly associated with salt sensitivity of blood pressure.58 Many studies have shown that blood pressure of hypertensive patients can decrease when they are placed on a low salt diet, while blood pressure of normotensive subjects can increase in response to a high salt diet.59,60 Salt sensitivity increases with age, and has been reported to be more prevalent in older women than older men.61

Slow respiratory rate62 or increased plasma acidity63 at rest are both risk factors for salt sensitivity of blood pressure in normotensive humans. At rest, individual differences in breathing pattern are relatively stable,64 with slow rates being associated with higher end tidal CO2, and less emotionality, and faster rates with lower end tidal CO2 and more emotionality65,66 Slow-breathing women tend to report greater perceived stress over the past month than faster-breathing women, but this association is less significant in men.67 In addition to these personality differences, events that elicit sustained attention to the environment are accompanied by acute suppression of breathing with neurally mediated increases in cerebral blood flow and decreases in skeletal muscle blood flow.68 Hypoventilatory breathing increases PCO2 and plasma acidity acutely, and if sustained over time, can result in a decrease in renal excretion of sodium and circulating fluid volume.69 Episodes of breath holding during daytime seated rest have been observed in hypertensive patients,70 and individual differences in frequency of breath holding in seated women at rest have been found to covary with 24-hour blood pressure level.71 Variability in breathing rate, tidal volume, minute ventilation, and end tidal CO2 were also greater in women with higher than lower 24-hour blood pressure, and these associations were independent of age, weight, and body surface area. Older women in the Baltimore Longitudinal Study of Aging with high resting end tidal CO2 were found to have higher resting blood pressure than those with lower resting end tidal CO2.72 This association was strongest in women who rated themselves as low in trait anger.73 To date, no such associations have been observed in men. Sleep apnea is well documented as a risk factor for hypertension.74 Many hypertensive females show some form of disordered breathing in sleep, while less than half of hypertensive men exhibit a similar problem. While sleep apnea is usually considered to involve mechanical airway obstruction, its intermittency suggests the participation of central nervous system factors, as well, and a small percentage of sleep apnea cases are purely central in origin. To date, no studies of salt sensitivity in men or women with sleep apnea have been reported, but this would seem to be a fertile area for future investigation.

Emotional states and cardiovascular disease This section reviews gender differences in the association of emotional states with cardiovascular disease and mortality, both as predictors in previously healthy persons and in those with cardiovascular disorders. Until recently, research on emotions in cardiovascular disease has focused on negative

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emotions such as anger, depression, anxiety, loneliness, and hopelessness. In the last few years, investigators have also been studying associations between positive affect and cardiovascular disease risk. Given that emotions include private events, assessment must be indirect, and involve self-report questionnaires or inferences from behavioral observations. This problem is not unique to emotional states, but also presents a challenge to medical research and practice, since reports of many symptoms must rely on self-report of private experience. In addition, communication about emotions can be subject to social influences. For example, women are more likely than men to report anginal pain in the absence of clinical disease,75 though the causes of this difference remain to be clarified. Another issue is the fact that women tend to develop cardiovascular disease later in life, when they are more likely to have other co-morbid factors.76 Thus, it is not surprising that studies of the role of emotions in cardiovascular disease do not always present a coherent picture.77

Anger and Hostility in Cardiovascular Disease Early work on the role of anger in cardiovascular disease by Friedman and Rosenman resulted in the emergence of a standardized interview for detecting the Type A personality or behavior pattern, a composite of traits including loud and explosive speech, time urgency, and hostile and competitive behaviors.78 Subsequent work with this interview suggested that hostility79,80 and, more specifically, hostile interaction style, but not content,81 were toxic factors that predicted CHD. A cross-sectional study reported that men and women differ in the ways in which they express aspects of hostility.82 For men, direct challenges and overt expressions of anger toward the interviewer (e.g., ‘That’s a stupid question’) were characteristic of patients later found to have CHD. For women, more subtle, indirect manifestations of antagonistic behavior were found to be predictors. In this study, social dominance, as indicated by number of interruptions during the interview, was associated with CHD in men, but not in women. This finding is consistent with other research that concluded that men and women express anger differently. Men are more likely to express anger than women, and are more likely to be angry longer than men.83 Subsequent work on anger and cardiovascular disease was potentiated by the development of the Spielberger State-Trait Anger Inventory, which included scales for anger frequency (trait anger), and direction (expressed or anger-out, and suppressed or anger-in).84 High trait anger has been prospectively associated with increased carotid artery intima-media thickness in several studies,85,86 including one with women.87 Anger and hostility are overlapping, but not identical concepts.88 Hostility signals resentment, distrust, cynicism or suspicion.89 Hostile individuals have larger increases in catecholamines and cortisol in response to challenge and provocation than less hostile persons,90,91

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and may manifest diminished vagal modulation of cardiac function30 and increased platelet activity.92,93 The role of hostility in cardiovascular disease has also been investigated using the Jenkins Activity Survey and the Cook-Medley Hostility Scale. A meta-analysis of 45 questionnaire studies published in 1996 found hostility to be a significant risk factor for coronary heart disease (CHD) and all cause mortality.94 Since then, several large prospective studies using questionnaires have provided additional support for this view. In one, a strong, angry temperament (tendency toward quick, minimally provoked, or unprovoked anger) was associated with a two-fold increase in CHD in normotensive, middle-aged men and women over a 4-year interval.95 Another study of patients with pre-existing CHD found that disease progression of CHD was increased in those with high anger expression, and even more so in those with both anger expression and low social support.96 High hostility was associated with a three-fold increase in CHD of men over a 7-year period.97 Conversely, one prospective study found that anger expression by a highly educated sample was associated with a reduced risk of CHD and stroke.98

Depression in Cardiovascular Disease Major depression is a clinical syndrome characterized by a feeling of sadness, together with decreased activity and adverse functional changes. It can be assessed by well-standardized self-report instruments such as the Beck Depression Inventory,99 the Center for Epidemiologic Studies–Depression (CES–D) scale100 and the Diagnostic Interview Schedule.101 One in five women experiences an episode of major depression during their lifetime, compared with one man in ten.102 Several theories exist concerning this gender difference. One focuses on data showing that women have less education, earn less money, and are more likely to be unemployed than men.103 Another examines possible differences in life and marital satisfaction,104 citing the combined stresses of work and home responsibilities. A third postulates that women’s socialization may be more likely than men’s to reinforce low perceived mastery and learned helplessness.103 Hopelessness105–108 and ‘vital exhaustion’109–111 are related constructs that have shown promise in attempts to understand the causes of hypertension or cardiovascular disease. A number of biological pathways have been studied by which depression, hopelessness, or ‘vital exhaustion’ might contribute to the development of hypertension or cardiovascular disease. First of all, that depression is a form of ‘anger turned inward’ is supported by the finding that both anger and depression are associated with tonic increases in sympathoadrenal drive.112,113 In addition, depression has been associated with increased plasma cortisol and its biological precursors,114,115 and depressed individuals may also develop significant impairment in platelet function.116,117

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Each of these can contribute to atherogenesis. Depression has also been associated with reduced heart rate variability and impaired vagal control,118,119 which could contribute to cardiac arrhythmias. Depression has also been associated with unhealthy lifestyle behaviors, such as smoking and poor patient compliance.120 The evidence for a role of depression in the pathogenesis of hypertension and cardiovascular disease is mixed. The most extensive study found that a combination of depression and anxiety predicted the incidence of self-reported, treated, and incident hypertension in men and women over a 20-year interval, with the strongest association found in black women.121 However, another study with women found that depression at baseline did not predict the development of hypertension over a 9-year period.122 Among those who developed high blood pressure, self-report of depression was more likely to occur during the intervening period, as was evidence of other negative feelings. A meta-analysis of 54 prospective, observational studies documented a relationship between clinical depression and depressive symptoms and the etiology of CHD.123 Other studies have associated depressed mood with acute cardiovascular events,124 and an unfavorable adaptation to and prognosis following CHD.125 The relationship between depression and CHD is not universally reported,123 however, which could be due to the relative proportions of men and women studied. In one study, no association was found between depression and CHD outcome in elderly men, but a significant association of depressive symptoms with increased risk for both cardiac events and cardiac mortality was observed in elderly women.126 Among patients with CHD, the prevalence of major depression was found to be three times that of other persons, and, as in the population as a whole, women are more often clinically depressed than men.127 Women also show higher rates of depression than men during the days prior to cardiac surgery.128 Following a myocardial infarction, they experience higher rates of depression than men that are not attributable to differences in age or medical status.129 Depressed CHD patients of both genders are at three-fold increased risk for cardiac mortality, independent of age, cigarette smoking and disease severity.130 The hypothesis that women are more likely to report depressive symptoms in the absence of depressed behavior or are more likely than men to seek help for depression lack empirical support.131 When patients participate in cardiac rehabilitation, women benefit as much as men132 and cardiovascular mortality can be reduced by approximately 25%.133 However, women are less likely to be referred, less likely to enroll, and less likely to attend cardiac rehabilitation than men.134 This undoubtedly hinders efforts at secondary prevention of CHD. Finally, one large, 14-year study with older persons free of heart failure at baseline showed that depressed patients who were more likely to be unmarried, have functional disability, and have hypertension and diabetes, had a 50%

more chance of developing heart failure than those who were not depressed at baseline. This effect was significant in women, but not in men.135 Heart failure patients were more depressed than controls,136 and women with heart failure were more likely to be depressed than men with heart failure.137

Positive Affect and Cardiovascular Risk Evidence is accumulating that positive affect is related to a reduced risk of disease and a longer life expectancy.138,139 Even though women have a greater risk of stroke with increasing age than men,140 prospective studies have documented associations between positive affect and reduced risk of stroke, disability, and overall mortality in both men and women, black as well as white.140,141 These associations were independent of negative affect and of other risk factors. Such observations have generated interest in the biological factors that might account for the associations of positive affect with improved health status. In one series of studies,142–145 participants from the Whitehall II epidemiological cohort were asked to complete ratings of positive and negative affect on repeated occasions during days when other physiological monitoring occurred. Higher positive affect was found to be directly associated with greater heart rate variability146 and inversely related to heart rate143 in men, but not women. By contrast, positive affect was unrelated to variations in ambulatory blood pressure in both genders. These finding are consistent with those of epidemiological studies that show a stronger link between high heart rate and mortality in men than women.143 Ratings of positive affect were negatively correlated with salivary cortisol on both a working day and a leisure day, and with reduced fibrinogen responses to mental stress testing in the lab.142 The findings linking positive affect to lower cortisol levels were replicated during a 3-year follow-up.144 A subsequent study with the same population confirmed the association between positive affect and low cortisol, and also found that positive affect in women was inversely associated with two measures of chronic inflammation, C-reactive protein and interleukin-6.145 These associations were independent of age, gender, body mass index, smoking, and a host of other variables, including negative affect. However, neither biomarker was related to positive affect in men. The Whitehall research also supports previous reports that larger social support networks are associated with reduced morbidity and mortality, including from cardiovascular disease.147,148 Those who reported higher levels of positive affect reported receiving more emotional and practical support than those who reported lower levels of positive affect.149 Positive affect was also associated with feelings of optimism and adaptive strategies for coping with stress. Conversely, negative affect was independently related to dysfunctional social relationships, greater

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e­ xposure to chronic stress, pessimism, depression, and avoidant coping. While men who were not in paid employment reported more positive affect, the opposite was true for women.149 Social support, positive affect, and better sleep were also found to go hand in hand, especially in men, because women reported more psychological distress, more exposure to neighborhood crime, and more sleep problems than men, even though they did not report less social support, or more negative social interactions, social isolation, or financial stress than men.150 These complex findings underline that possible gender differences in selfreported emotional states must be considered in evaluation of these findings.

Psychosocial risk factors in cardiovascular disease This section reviews gender differences in the role of social class, employment, job strain, and social support in cardiovascular disease pathogenesis and progression. The literature reviewed here consists largely of epidemiological studies that provide evidence of associations between sociobehavioral factors and current or consequent cardiovascular disease risk. Such studies often have statistical power due to large sample sizes, but cannot provide evidence or cause and effect. Nevertheless, the consistency of findings across a range of studies with different populations in different cultures indicates that strong societal forces are at work in the pathogenesis of cardiovascular disease, and that these forces affect men and women in different ways.

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higher brackets. In another,157 increased cigarette smoking,156 lower activity levels, and higher body mass index, and greater waist–hip ratios were linked to chest pain in low SES women.158 In addition, lower SES includes greater exposure to environmental stressors that produce more negative and less positive affect.159 Low SES environments lead to greater depletion of resources, including those that are material (tangible and financial reserves, such as lack of home ownership) and social (marriage, family, and employment). The depletion of resources and diminishing reserve capacities can foster loss spirals.159 Extensive research in various populations supports this framework linking poverty, diminishing resources, psychological adaptation, and most importantly, behavioral adaptations that increase risk. An example of this is seen in the associations between poverty, depression, adverse health behaviors, and risk of type 2 diabetes in black women.160 A recent longitudinal study of 401 initially healthy women confirmed two separate pathways linking low SES to the metabolic syndrome, one direct, and another indirect, mediated by high negative emotions.161 In a recent discussion of the importance of SES as a predictor of cardiovascular outcomes in women in the Women’s Ischemia Syndrome Evaluation (WISE) the authors concluded that economic disadvantage prominently affects cardiovascular disease outcomes for women with chest pain symptoms. ‘These results further support a profound intertwining between poverty and poor health. Cardiovascular disease management strategies should focus on policies that track unmet healthcare needs and worsening clinical status for low-income women [p. 1082].’162 The model proposed here points to the importance of addressing psychosocial factors as part of the unmet healthcare needs and problematic clinical status.

Socioeconomic Status Low socioeconomic status (SES), whether assessed via education, occupation, or income, has been consistently associated with increased rates of hypertension,151 CHD,152,153 and stroke in both men and women in industrialized countries.154 The gradient of these associations is steeper in women than in men. In fact, individual socioeconomic trajectory (i.e. changes in earning power) over a 10-year period was found to predict changes in blood pressure over that interval more strongly even than SES at baseline.155 Socioeconomic inequalities in mortality rate are increasing due to continuing reductions in death rates, including those for heart disease and stroke, among the most educated white and black men and white women, but are not being reduced in black women with less than a 12th-grade education.156 These gradients between SES, hypertension, cardiovascular disease, and stroke can be accounted for in part by an unhealthy lifestyle. Low socioeconomic status was associated in one study with a more atherogenic diet, less physical exercise, and more smoking than in those in

Employment and Job Strain Employment, itself, is associated with reduced risk of mortality from CHD in both men and women, compared with those who are unemployed, independent of education and income.163 In addition, job insecurity has been associated with increased risk of hypertension, independent of demographic and behavioral risk factors, and the association was stronger in men than women.164 One study reported that a combination of employment and family responsibility increased risk for CHD in women.165 In that study, conflicts between work and family roles predicted CHD, regardless of whether the women felt they had sacrificed career advancement for family involvement, or felt that family members had suffered as a result of their career involvement. Both men and women with lower socioeconomic status jobs are more likely to work under high strain; that is, jobs in which perceived demand is high relative to perceived control.166 High job strain has been associated with elevated

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daytime blood pressure in both genders.167–169 However, the magnitude of this effect depends not only on the nature of the work, but also on available support. Men show smaller blood pressure elevations in high strain jobs when they receive support from co-workers, while women show smaller blood pressure increases when they receive support from their supervisors.170 Both men and women tend to go to women for social support. Thus, women may be more susceptible to social stress, as well as support, from co-workers on the job. Whether high job strain leads to chronic hypertension remains to be clarified.171–173 Little evidence exists that job strain, defined in terms of demand/control, is a risk factor for coronary artery disease.174,175 Some support for job strain as a risk factor for CHD has been obtained in a study of English civil servants over an 11-year period that focused on the effort–reward ratio in the work.176

Family and Social Support When men come home from work in the evening, their blood pressure tends to fall.177 One study with men and women managers found, however, that the women were less likely to show decreases in blood pressure at the end of the workday.178 These effects were attributed to women’s total load at work and home, which was greater than men’s. Another factor that determines whether blood pressure falls when a worker comes home is whether someone else lives there.177 The decrease is greatest in parents with children, intermediate in couples without children, and non-significant in single workers who live alone. Blood pressure of ambulatory men and women tends to be lower when they are with their spouse than when they are with others or alone.179 Blood pressure of men and women falls during sleep, but less in men if they are depressed.180 Ambulatory monitoring studies have also found that blood pressure varies with reported anxiety during the day in women, but not in men.180 Lack of social support and social isolation has also been found to be a risk factor for CHD in both men and women, though the findings have been more pronounced in men.181 Mortality from CHD was enhanced among divorced men and widowers in several studies conducted in European countries.182–185 A positive association was observed whether the study examined some aspect of the size and nature of the social network, or the type of support received. Risk of nonfatal myocardial infarction was also found to be increased in female clerical workers who reported having a non-supportive boss.186 Once CHD has become manifest, lack of social ties is an independent risk factor for a subsequent major cardiac event and/or mortality after myocardial infarction.187,188 In this regard, a large Swedish study reported that, following myocardial infarction, marital stress was related to worse prognosis in women than work stress.189 On the other hand, social support has been reported to enhance emotional wellbeing and recovery after coronary artery bypass surgery

in men.190,191 In general, this literature suggests that socially-integrated individuals (those who are married and have strong community ties) have reduced risk for premature mortality,192 and that socially isolated individuals have a three-fold greater chance of adverse cardiac events after myocardial infarction.193

Chronic Psychosocial Stress As discussed previously, chronic stressors can emerge from a number of sources. These include poverty, job strain, family difficulties, and low social support or isolation. There are gender differences in the nature of these stressors and their associations to cardiovascular health, such that occupational stressors may be more influential for men,194 while caregiving and marital stress may be more strongly associated with CHD in women.189,195 The INTERHEART study was a global case-control study of acute MI in 52 countries that found nine modifiable risk factors to explain greater than 90% of acute MI in women and men, younger and older persons, across all major ethnic groups.196 Of the more than 27 000 participants, about a 25% were women. A ‘psychosocial factors’ measure that combined presence of depression, perceived ability to control life circumstances, stress at work and at home, financial stress, and major life events, was found significantly related to acute MI with an population attributable risk (PAR) of 33% for the overall sample, and 40% for women and 25% for men.196 A more detailed analysis of these data reported PAR and odds ratios for each of the components in the psychosocial factor ‘index’.197 Specifically, more cases than controls reported permanent stress at work, permanent stress at home, permanent stress at work or home, severe financial stress, stressful life events, and depression. The only gender difference in the global sample was that work stress was not associated with acute MI in women. The conclusion drawn from the INTERHEART study is that risk of CHD associated with general psychosocial stress, while less than that associated with smoking, is comparable to that of abdominal obesity and hypertension.196

Psychosocial interventions with cardiac patients Finally, in this section, gender differences in recent studies of psychosocial interventions in cardiovascular disease are reviewed. Among the existing intervention studies, two large-scale clinical trials to prevent the recurrence of cardiac events have received much attention. The five-year Montreal Heart Attack Readjustment Trial (M-HART) was conducted with 903 men and 473 women.198 That intervention involved 6–7 hour visits by trained counselors to the patients’ homes over 7–8 months, where physical condition, medication regimen, emotional state, family concerns,

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and work or retirement issues were explored in individually tailored problem solving sessions.199 Effects of this intervention were compared with those in a usual care control group. No effect of the psychosocial intervention on cardiac mortality in men was observed, but surprisingly, women in the treatment group showed a marginally significantly increase in cardiac events after 1 year, and all-cause mortality after 1 and 5 years. Detailed analyses of these findings showed that only high anxious, non-defensive men benefited from the psychosocial intervention, while high anxious, defensive persons of both genders were found to have increased mortality.198 The Enhancing Recovery in Coronary Heart Disease Patients Study (ENRICHD) evaluated the effects of 6 months of group cognitive behavior therapy and psychotropic drugs on cardiac patients, with treatment initiated soon after myocardial infraction.200 That study found that both men and women became less depressed than those in the control group, and obtained more social support. Despite these changes, no differences in cardiac mortality over a 3-year follow-up period were observed, with 24% of each group having died.200 It is noteworthy that the trial participants were recruited shortly after the cardiac event, a recruitment period reported to be characteristic of trials that showed no benefit for psychosocial intervention over usual care.201 A more recent meta-analysis of the literature reviewed not only those, but also 41 smaller studies of psychosocial or psychological treatment of heart disease, 23 of which included morality follow-up data.201 The main findings of the meta-analysis were that such treatments reduced recurrence of cardiac events and mortality over the first two years in men, but not women (though the fewer numbers of women studied could have resulted in a different outcome due to less statistical power). However, the beneficial effects of these psychosocial treatments were not observed if the treatment was initiated within the first two months after the myocardial infarction.201 Reductions in distress (but not depression) were critical to survival,201 a conclusion supported by the findings in another review, focusing on depression and outcomes of cardiovascular care.202 The meta-analysis concluded with the recommendation that gender-specific treatments tailored to the special needs of older women need to be developed, focusing on their older age and greater probability of social isolation.201,203,204 In addition, future studies might benefit from the inclusion of interventions to enhance positive affect, and training in coping skills that will leave men and women with new adaptive strategies for managing psychosocial stress characteristic of today’s world.205

Conclusion In summary, this chapter has reviewed gender differences in the role of stress and emotion in the development and

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treatment of cardiovascular disease. The main conclusions are as follows. First, gender differences are routinely observed in cardiovascular activity at rest and reactivity to laboratory stressors, including the fact that subtle aspects of the social situation in which the study is conducted have a major impact on individual response. Such studies are relevant to the hypothesis that cardiovascular disease is augmented by repeated exposure to perceived stressors. In addition, stress-induced respiratory suppression has been found to be a risk factor for hypertension, especially in women. Second, gender differences in the experience and expression of anger and depression have been documented in relation to cardiovascular disease. Men are more likely than women to express anger and women more likely than men to be depressed. In addition, studies have shown that positive emotional states are more than merely the converse of negative emotional states, and may be independently linked to the prevention of cardiovascular disease. Third, gender-specific gradients are observed in the association of socioeconomic status with cardiovascular disease, with the most severe gradients being observed in poorly educated women. Differential positive effects of social support from bosses and co-workers on women and men, respectively, in the job setting have been documented, and recurrence of cardiovascular disease is more closely linked to work stress in men and to marital stress in women. Finally, a few large-scale trials have reported limited effectiveness of psychosocial interventions following myocardial infarction, and concluded that future research should design genderspecific interventions to address the special needs of men and women. All in all, this literature extends our understanding of the profoundly important role of social and cultural factors in both the development and treatment of cardiovascular diseases as they differentially affect men and women.

Suggestions for further investigations Are the associations between emotional states and cardiovascular disease causal, or are both consequences of other factors? How significant are the gender differences in stressinduced breathing suppression for hypertension? To what extent are gender differences in depression biological and to what extent cultural?

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Acknowledgment This research was supported in part by the Intramural Research Program of that National Institutes of Health, National Institute on Aging.

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References 1. Alexander F. Emotional factors in essential hypertension. Psychosom Med 1939;1:173–79. 2. Friedman M, Rosenman RH. Association of specific overt behavior pattern and blood and cardiovascular findings. JAMA 1959;169:1286–96. 3. Linden W, Gerin W, Davidson K. Cardiovascular reactivity: status quo and a research agenda for the new millennium. Psychosom Med 2003;65:5–8. 4. Reckelhoff JF. Gender differences in the regulation of blood pressure. Hypertension 2001;37:1199–208. 5. Sanada M, Higashi Y, Nakagawa K, et al. Estrogen replacement therapy in postmenopausal women augments reactive hyperemia in the forearm by reducing angiotensin converting enzyme activity. Atherosclerosis 2001;158:391–97. 6. Evans JM, Ziegler MG, Patwardhan AR, et al. Gender differences in autonomic cardiovascular regulation: spectral, hormonal, and hemodynamic indexes. J Appl Physiol 2001;91:2611–18. 7. Barnett SR, Morin RJ, Kiely DK, et al. Effects of age and gender on autonomic control of blood pressure dynamics. Hypertension 1999;33:1195–200. 8. Whelton PK, He J, Klag MJ. Blood pressure in westernized populations. In: JD Swales, ed. Textbook of Hypertension. Oxford: Blackwell Scientific; 1994:11–21. 9. Laitinen T, Hartikainen J, Vanninen E, et al. Age and gender dependency of baroreflex sensitivity in healthy subjects. J Appl Physiol 1998;84:576–83. 10. Ludwig DA, Vernikos J, Wade CD, et al. Blood pressure changes during orthostatic stress: evidence of gender differences in neuroeffector distribution. Aviat Space Environ Med 2001;10:892–98. 11. Gotshall RW, Tsai PF, Frey MA. Gender-based differences in the cardiovascular response to standing. Aviat Space Environ Med 1991;62:855–59. 12. Gotshall RW, Aten LA, Yumikura S. Difference in the cardiovascular response to prolonged sitting in men and women. Can J Appl Physiol 1994;19:215–25. 13. Lawler KA, Wilcox ZC, Anderson SF. Gender differences in patterns of dynamic cardiovascular regulation. Psychosom Med 1995;57:357–65. 14. Steptoe A, Fieldman G, Evans O, et al. Cardiovascular risk and responsivity to mental stress: the influence of age, gender and risk factors. J Cardiovasc Risk 1996;3:83–93. 15. D’Antono B, Moskowitz DS, Miners C, et al. Gender and communal trait differences in the relations between social behavior, affect arousal, and cardiac autonomic control. J Behav Med 2005;28:267–79. 16. Jezova D, Jurankova E, Mosnarova A, et al. Neuroendocrine response during stress with relation to gender differences. Acta Neurobiol Exp (Warsz) 1996;56:779–85. 17. Uvnas-Moberg K. Antistress pattern induced by oxytocin. News Physiol Sci 1998;13:22–25. 18. Taylor SE, Klein LC, Lewis BP, et al. Biobehavioral responses to stress in females: tend-and-befriend, not fight-or-flight. Psychol Rev 2000;107:411–29. 19. Petersson M, Alster P, Lundeberg T, et al. Oxytocin increases nociceptive thresholds in a long-term perspective in female and male rats. Neurosci Lett 1996;212:87–90.

20. Klein LC, Popke EJ, Grunberg NE. Sex differences in effects of opioid blockade on stress-induced freezing behavior. Pharmacol Biochem Behav 1998;61:413–17. 21. Gray JA, Lalljee B. Sex differences in emotional behaviour in the rat: correlation between open-field defecation and active avoidance. Animal Behavior 1974;22:856–61. 22. Light KC, Turner JR, Hinderliter AL, et al. Race and gender comparisons: I. Hemodynamic responses to a series of stressors. Health Psychol 1993;12:354–65. 23. Vogele C, Jarvis A, Cheeseman K. Anger suppression, reactivity, and hypertension risk: gender makes a difference. Ann Behav Med 1997;19:61–69. 24. Davis MC, Matthews KA. Do gender-relevant characteristics determine cardiovascular reactivity? Match versus mismatch of traits and situation. J Pers Soc Psychol 1996;71:527–35. 25. Girdler SS, Turner JR, Sherwood A, et al. Gender differences in blood pressure control during a variety of behavioral stressors. Psychosom Med 1990;52:571–91. 26. Girdler SS, Light KC. Hemodynamic stress responses in men and women examined as a function of female menstrual cycle phase. Int J Psychophysiol 1994;17:233–48. 27. Jones PP, Spraul M, Matt KS, et al. Gender does not influence sympathetic neural reactivity to stress in healthy humans. Am J Physiol 1996;270:H350–57. 28. Stroud LR, Salovey P, Epel ES. Sex differences in stress responses: social rejection versus achievement stress. Biol Psychiatry 2002;52:318–27. 29. Allen MT, Stoney CM, Owens JF, et al. Hemodynamic adjustments to laboratory stress: the influence of gender and personality. Psychosom Med 1993;55:505–17. 30. Earle TL, Linden W, Weinberg J. Differential effects of harassment on cardiovascular and salivary cortisol stress reactivity and recovery in women and men. J Psychosom Res 1999;46:125–41. 31. Sloan RP, Bagiella E, Shapiro PA, et al. Hostility, gender, and cardiac autonomic control. Psychosom Med 2001;63:434–40. 32. Suarez EC, Williams RB Jr. The relationships between dimensions of hostility and cardiovascular reactivity as a function of task characteristics. Psychosom Med 1990;52:558–70. 33. Sheffield D. Task-induced cardiovascular activity and the presence of a supportive and undermining other. Psychol Health 1996;11:583–91. 34. Kamarck TW, Manuck SB, Jennings JR. Social support reduces cardiovascular reactivity to psychological challenge: a laboratory model. Psychosom Med 1990;52:42–58. 35. Gerin W, Pieper C, Levy R, et al. Social support in social interaction: a moderator of cardiovascular reactivity. Psychosom Med 1992;54:324–36. 36. Lepore SJ. Problems and prospects for the social supportreactivity hypothesis. Ann Behav Med 1998;20:257–69. 37. Glynn LM, Christenfeld N, Gerin W. Gender, social support, and cardiovascular responses to stress. Psychosom Med 1999;61:234–42. 38. Uno D, Uchino BN, Smith TW. Relationship quality moderates the effect of social support given by close friends on cardiovascular reactivity in women. Int J Behav Med 2002;9:243–62. 39. Newton TL, Bane CM, Flores A, et al. Dominance, gender, and cardiovascular reactivity during social interaction. Psychophysiology 1999;36:245–52.

C h a p t e r 1 7     Gender Differences in the Role of Stress and Emotion in Cardiovascular Function and Disease l

40. Smith TW, Gallo LC. Hostility and cardiovascular reactivity during marital interaction. Psychosom Med 1999;61: 436–45. 41. Kiecolt-Glaser JK, Glaser R, Cacioppo JT, et al. Marital conflict in older adults: endocrinological and immunological correlates. Psychosom Med 1997;59:339–49. 42. Brosschot JF, Thayer JF. Anger inhibition, cardiovascular recovery, and vagal function: a model of the link between hostility and cardiovascular disease. Ann Behav Med 1998;20:326–32. 43. Lai JY, Linden W. Gender, anger expression style, and opportunity for anger release determine cardiovascular reaction to and recovery from anger provocation. Psychosom Med 1992;54:297–310. 44. Schmaus BJ, Laubmeier KK, Boquiren VM, et al. Gender and stress: differential psychophysiological reactivity to stress reexposure in the laboratory. Int J Psychophysiol 2008;69(2):101–8. 45. Hughes B. Social support in ordinary life and laboratory measures of cardiovascular reactivity: gender differences in habituation-sensitization. Ann Behav Med 2007;34(2):166–76. 46. Kaplan JR, Adams MR, Clarkson TB, et al. Psychosocial factors, sex differences, and atherosclerosis: lessons from animal models. Psycholosom Med 1996;58(6):598–611. 47. Manuck SB, Kaplan JR, Clarkson TB. An animal model of coronary-prone behavior. In: MA Chesney, RH Roseman, eds. Anger and Hostility in Cardiovascular and Behavioral Disorders. New York, NY: Hemisphere; 1985:187–201. 48. Adams MR, Kaplan JR, Koritnik DR. Psychosocial influence on ovarian endocrine and ovulatory function in Macaca fasicularis. Physiol Behav 1985;58:598–611. 49. Shively CA, Clarkson TB. Social status and coronary artery atherosclerosis in female monkeys. Arterioscler Thromb 1994;14:721–26. 50. Hanke H, Hanke S, Ickrath O, et al. Estradiol concentrations in premenopausal women and coronary heart disease. Coron Artery Dis 1997;8:511–15. 51. Bianch C, Ferrari P. Animal models for arterial hypertension. In Genest J, Kuchel O, Hamet P, Cantin M. Hypertension. New York, NY: McGraw–Hill, 534–555. 52. Anderson DE. Behavior analysis and the search for the origins of hypertension. J Exp Anal Behav 1994;61:255–61. 53. Deng AY. Genetic basis of polygenic hypertension. Hum Mol Genet 2007;16:R195–R202. 54. Jula A, Salminen JK, Saarijarvi S. Alexithymia: a facet of essential hypertension. Hypertension 1999;33:1057–61. 55. Mann SJ, James GD. Defensiveness and essential hypertension. Psychosom Res 1998;45:139–48. 56. Winkleby MA, Ragland DR, Syme SL. Self-reported stressors and hypertension: evidence of an inverse association. Am J Epidemiol 1988;127:124–34. 57. Perini C, Smith DH, Neutel JM, et al. A repressive coping style protecting from emotional distress in low-renin essential hypertensives. J Hypertens 1994;12(5):601–7. 58. Laragh J. Laragh’s lessons in pathophysiology and clinical pearls for treating hypertension. Am J Hypertens 2001;14:84–89. 59. He FJ, MacGregor GA. Salt, blood pressure, and cardiovascular disease. Curr Opin Cardiol 2007;22(4):298–305.

195

60. Muntzel M, Drueke T. A comprehensive review of the salt and blood pressure relationship. Am J Hypertens 1992;5:1S–42S. 61. Nestel PJ, Clifton PM, Noakes M, et al. Enhanced blood pressure response to dietary salt in elderly women, especially those with small waist: hip ratio. J Hypertens 1993;11:1387–94. 62. Anderson DE, Parsons BA, McNeely JD, et al. Salt sensitivity of blood pressure is associated with resting respiratory rate: results of a clinical feeding trial in women. J Am Soc Hypertens 2007;1(4):256–63. 63. Sharma AM, Cetto C, Schorr U, et al. Renal acid-base excretion in normotensive salt-sensitive humans. Hypertension 1993;22:884–90. 64. Benchetrit G, Shea SA, Dinh TP, et al. Individuality of breathing patterns in adults assessed over time. Respir Physiol 1989;75:199–209. 65. Schaefer KE. Respiratory pattern and respiratory response to CO2. J Appl Physiol 1958;13:1–14. 66. Grossman P. Respiration, stress and cardiovascular function. Psychophysiology 1983;20:284–99. 67. Anderson DE, Chesney MA. Gender-specific association of perceived stress and inhibited breathing pattern. Int J Behav Med 2002;9:216–27. 68. Pardo JV, Fox PT, Raichle ME. Localization of a human system for sustained attention by positron emission tomography. Nature 1991;349:61–64. 69. Honig A. Peripheral arterial chemoreceptors and reflex control of sodium and water homeostasis. Am J Physiol Resp Integ Comp Physiol 1989;26:R1282–R302. 70. Novak V, Novak P, de Champlain J, et al. Altered cardiorespiratory transfer in hypertension. Hypertens 1994;23:104–13. 71. Anderson DE, Metzler JD, Chesney MA, et al. Breathing variability at rest is positively associated with 24-hr blood pressure level. Am J Hypertens 2008;12:1324–29. 72. Anderson DE, Parsons DJ, Scuteri A. End tidal CO2 is an independent determinant of systolic blood pressure in women. J Hypertens 1999;17:1073–80. 73. Scuteri A, Parsons D, Chesney MA, et al. Anger inhibition potentiates the association of high end-tidal CO2 with blood pressure in women. Psychosom Med 2001;63:470–75. 74. Silverberg DS, Oksenberg A, Iaina A. Sleep related breathing disorders are common contributing factors to the production of essential hypertension but are neglected, underdiagnosed, and undertreated. Am J Hypertens 1997;10:1319–25. 75. Kudenchuk PJ, Maynard C, Martin JS, et al. Comparison of presentation, treatment, and outcome of acute myocardial infarction in men versus women (the Myocardial Infarction Triage and Intervention Registry). Am J Cardiol 1996;78:9–14. 76. American Heart Association. 2000 Heart and Stroke Statistical Manual of Mental Disorders. Dallas, TX: American Heart Association; 1999. 77. Jorgensen RS, Johnson BT, Kolodziej ME, et al. Elevated blood pressure and personality: a meta-analytic review. Psychol Bull 1996;120:293–320. 78. Rosenman RH, Brand RJ, Jenkins D, et al. Coronary heart disease in Western Collaborative Group Study. Final followup experience of 8½ years. JAMA 1975;233:872–77. 79. Chesney MA, Hecker MHL, Black GW. Coronary-prone components of type A behavior in the WCGS: a new

196

80.

81.

82.

83. 84.

85.

86.

87.

88.

89.

90. 91.

92.

93.

94.

95.

96.

s e c t i o n 3     Cardiovascular Disease l

methodology. In: BK Houston, CR Snyder, eds. Type A Behavior Pattern: Research, Theory and Intervention. New York, NY: John Wiley; 1988:168–88. Hecker MH, Chesney MA, Black GW, et al. Coronaryprone behaviors in the Western Collaborative Group Study. Psychosom Med 1988;50:153–64. Dembroski TM, MacDougall JM, Costa PT, et al. Components of hostility as predictors of sudden death and myocardial infarction in the Multiple Risk Factor Intervention Trial. Psychosom Med 1989;51:514–22. Siegman AW, Townsend ST, Civelek AC, et al. Antagonistic behavior, dominance, hostility, and coronary heart disease. Psychosom Med 2000;62:248–57. Thomas SP. Women and Anger. New York, NY: Springer; 1993. Spielberger CD, Johnson EH, Russell SF, et al. The experience and expression of anger: construction and validation of an anger expression scale. In: MA Chesney, RH Rosenman, eds. Anger and Hostility in Cardiovascular and Behavioral Disorders. New York, NY: Hemisphere; 1985:5–30. Matsumoto Y, Uyama O, Shimizu S, et al. Do anger and aggression affect carotid atherosclerosis? Stroke 1993;24:983–86. Julkunen J, Salonen R, Kaplan GA, et al. Hostility and the progression of carotid atherosclerosis. Psychosom Med 1994;56:519–25. Barnett PA, Spence JD, Manuck SB, et al. Psychological stress and the progression of carotid artery disease. J Hypertens 1997;15:49–55. Megargee EI. The dynamic of aggression and their application to cardiovascular disorders. In: MA Chesney, RH Rosenman, eds. Anger and Hostility in Cardiovascular and Behavioral DisordersVol. 31–58. New York, NY: Hemisphere; 1985. Miller TQ, Smith TW, Turner CW, et al. A meta-analytic review of research on hostility and physical health. Psychol Bull 1996;119:322–48. Pope ML, Smith TW. Cortisol excretion in high and low cynically hostile men. Psychosom Med 1991;53:386–92. Suarez EC, Williams CS, Kuhn CM, et al. Biobehavioral basis of coronary-prone behavior in middle-age men. Part II: Serum cholesterol, the Type A behavior pattern, and hostility as interactive modulators of physiological reactivity. Psychosom Med 1991;53:528–37. Markovitz JH, Matthews KA, Kiss J, et al. Effects of hostility on platelet reactivity to psychological stress in coronary heart disease patients and in healthy controls. Psychosom Med 1996;58:143–49. Markovitz JH. Hostility is associated with increase platelet activation in coronary heart disease. Psychosom Med 1998;60:586–91. Miller TQ, Smith TW, Turner CW, et al. A meta-analytic review of research on hostility and physical health. Psychol Bull 1996;119:322–48. Williams JE, Nieto FJ, Sanford CP, et al. Effects of an angry temperament on coronary heart disease risk: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 2001;154:230–35. Angerer P, Siebert U, Kothny W, et al. Impact of social support, cynical hostility and anger expression on progression of coronary atherosclerosis. J Am Coll Cardiol 2000;36:1781–88.

  97. Kawachi I, Sparrow D, Spiro A III, et al. A prospective study of anger and coronary heart disease. The Normative Aging Study. Circulation 1996;94:2090–95.   98. Eng PM, Fitzmaurice G, Kubzansky LD, et al. Anger expression and risk of stroke and coronary heart disease among male health professionals. Psychosom Med 2003;65:100–10.   99. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–71. 100. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Measurement 1977;1:385–401. 101. Robins LN, Helzer JE, Croughan J, et al. The NIMH. Diagnostic Interview Schedule: version III: Public Health Service; 1981, (publication no. (HHS) ADM-T-42-3). 102. Blazer DG, Kessler RC, McGonagle KA, et al. The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry 1994;151:979–86. 103. Nolen-Hoeksema S, Larson J, Grayson C. Explaining the gender difference in depressive symptoms. J Pers Soc Psychol 1999;77:1061–72. 104. Weissman MM. Advances in psychiatric epidemiology: rates and risks for major depression. Am J Public Health 1987;77:445–51. 105. Bruhn JG, Paredes A, Adsett CA, et al. Psychological predictors of sudden death in myocardial infarction. J Psychosom Res 1974;18:187–91. 106. Everson SA, Kaplan GA, Goldberg DE, et al. Hypertension incidence is predicted by high levels of hopelessness in Finnish men. Hypertension 2000;35:561–67. 107. Anda R, Williamson D, Jones D, et al. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 1993;4:285–94. 108. Everson SA, Kaplan GA, Goldberg DE, et al. Hopelessness and 4-year progression of carotid atherosclerosis. The Kuopio Ischemic Heart Disease Risk Factor Study. Arterioscler Thromb Vasc Biol 1997;17:1490–95. 109. Appels A, Mulder P. Excess fatigue as a precursor of myocardial infarction. Eur Heart J 1988;9:758–64. 110. Kop WJ, Appels AP, Mendes de Leon CF, et al. Vital exhaustion predicts new cardiac events after successful coronary angioplasty. Psychosom Med 1994;56:281–87. 111. Pignalberi C, Patti G, Chimenti C, et al. Role of different determinants of psychological distress in acute coronary syndromes. J Am Coll Cardiol 1998;32:613–19. 112. Atanackovic D, Brunner-Weinzierl MC, Kröger H, et al. Acute psychological stress simultaneously alters hormone levels, recruitment of lymphocyte subsets, and production of reactive oxygen species. Immunol Invest 2002;31:73–91. 113. Veith RC, Lewis N, Linares OA, et al. Sympathetic nervous system activity in major depression. Basal and desipramineinduced alterations in plasma norepinephrine kinetics. Arch Gen Psychiatry 1994;51:411–22. 114. Nemeroff CB, Widerlov E, Bissette G, et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984;226:1342–44. 115. Gold PW, Loriaux DL, Roy A, et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N Engl J Med 1986;314:1329–35.

C h a p t e r 1 7     Gender Differences in the Role of Stress and Emotion in Cardiovascular Function and Disease l

116. Musselman DL, Tomer A, Manatunga AK, et al. Exaggerated platelet reactivity in major depression. Am J Psychiatry 1996;153:1313–17. 117. Laghrissi-Thode F, Wagner WR, Pollock BG, et al. Elevated platelet factor 4 and beta-thromboglobulin plasma levels in depressed patients with ischemic heart disease. Biol Psychiatry 1997;42:290–95. 118. Carney RM, Freedland KE, Eisen SA, et al. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychol 1995;14:88–90. 119. Watkins LL, Grossman P, Krishnan R, et al. Anxiety and vagal control of heart rate. Psychosom Med 1998;60: 498–502. 120. Orth-Gomér K, Chesney MA. Social Stress/Strain and Heart Disease in Women. In: D Julian, N Wenger, eds. Women and Heart Disease. London: Martin Dunitz; 1997:407–20. 121. Jonas BS, Lando JF. Negative affect as a prospective risk factor for hypertension. Psychosom Med 2000;62: 188–96. 122. Raikkonen K, Matthews KA, Kuller LH. Trajectory of psychological risk and incident hypertension in middle-aged women. Hypertension 2001;38:798–802. 123. Nicolson A, Kuper H, Hemingway H. Depression as a aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146,538 participants in 54 observational studies. Eur Heart J 2006;27:2763–74. 124. Steptoe A, Strike PC, Perkins-Porras L, et al. Acute depressed mood as a trigger of acute coronary syndromes. Biol Psychiatry 2006;60:837–42. 125. van Melle JP, de Jonge P, Spijkerman TA, et al. Prognostic association of depression following mycoardial infaction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 2004;66:814–22. 126. Mendes de Leon CF, Krumholz HM, Seeman TS, et al. Depression and risk of coronary heart disease in elderly men and women: New Haven EPESE, 1982–1991. Established Populations for the Epidemiologic Studies of the Elderly. Arch Intern Med 1998;158:2341–48. 127. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 1999;99:2192–217. 128. Czajkowski SM, Terrin M, Lindquist R, et al. Comparison of preoperative characteristics of men and women undergoing coronary artery bypass grafting. Am J Cardiol 1997;79:1017–24. 129. Burker EJ, Blumenthal JA, Feldman M, et al. Depression in male and female patients undergoing cardiac surgery. Br J Clin Psychol 1995;34(Pt 1):119–28. 130. Frasure-Smith N, Lesperance F, Juneau M, et al. Gender, depression, and one-year prognosis after myocardial infarction. Psychosom Med 1999;61:26–37. 131. Nolen-Hoeksema S. Sex Differences in Depression. Stanford, CA: Stanford University Press; 1990. 132. O’Farrell P, Murray J, Huston P, et al. Sex differences in cardiac rehabilitation. Can J Cardiol 2000;16:319–25. 133. Wenger NK, Froelicher ES, Smith LK, et al. Cardiac rehabilitation as secondary prevention. Agency for Health Care Policy and Research and National Heart, Lung, and Blood Institute. Clin Pract Guidel Quick Ref Guide Clin 1995:1–23.

197

134. Grace SL, Abbey SE, Shnek ZM, et al. Cardiac rehabilitation I: review of psychosocial factors. Gen Hosp Psychiatry 2002;24:121–26. 135. Williams JE, Nieto FJ, Sanford CP, et al. The association between trait anger and incident stroke risk: the Atherosclerosis Risk in Communities (ARIC) Study. Stroke 2002;33:13–19. 136. Havranek EP, Ware MG, Lowes BD. Prevalence of depression in congestive heart failure. Am J Cardiol 1999;84(348–50):A349. 137. Freedland KE, Rich MW, Skala JA, et al. Prevalence of depression in hospitalized patients with congestive heart failure. Psychosom Med 2003;65:119–28. 138. Chesney MA, Darbes L, Hoerster K, et al. Positive emotions: the other hemisphere of behavioral medicine. Int J Behav Med 2005;12:50–58. 139. Pressman SD, Cohen S. Does positive affect influence health? Psychol Bull 2005;131:925–71. 140. Ostir GV, Markides KS, Peek MK, et al. The association between emotional well-being and the incidence of stroke in older adults. Psychosom Med 2001;63:210–15. 141. Ostir GV, Markides KS, Black SA, et al. Emotional wellbeing predicts subsequent functional independence and survival. J Am Geriatr Soc 2000;48:473–78. 142. Steptoe A, Wardle J, Marmot M. Positive affect and healthrelated neuroendocrine, cardiovascular, and inflammatory processes. PNAS 2005;102:6508–12. 143. Kannel WB, Kannel C, Paffenbarger RS, et al. Heart rate and cardiovascular mortality: The Framingham Study. Am Heart J 1987;113:1489–94. 144. Steptoe A, Wardle J. Positive affect and biological function in everyday life. Nuerobio Aging 2005;26(Suppl 1):108–12. 145. Steptoe A, O’Donnell K, Badrick E, et al. Neuroendocrine and inflammatory factors associated with positive affect in healthy men and women: The Whitehall II Study. Am J Epidemiol 2007;167:96–102. 146. Bhattacharyya MR, Whitehead DL, Rakhit R, et al. Depressed mood, positive affect and heart rate variability in patients with suspected coronary heart disease. Psychosom Med 2008;70:1020–27. 147. Berkman LF, Glass TA. Social integration, social networks, social support and health. In: LF Berkman, I Kawachi, eds. Social Epidemiology. New York, NY: Oxford University Press; 2000:137–73. 148. Cohen S, Syme SL, eds. Social Support and Health. Orlando, FL: Academic Press; 2000. 149. Steptoe A, O’Donnell K, Marmot M, et al. Positive affect and psychosocial processes related to health. Br J Psychol 2008;99:211–27. 150. Steptoe A, O’Donnell K, Marmot M, et al. Positive affect, psychological well-being and good sleep. J Psychosom Res 2008;64:409–15. 151. Colhoun HM, Hemingway H, Poulter NR. Socio-economic status and blood pressure: an overview analysis. J Hum Hypertens 1998;12:91–110. 152. Kaplan GA, Keil JE. Socioeconnomic factors and cardiovascular disease: a review of the literature. Circulation 1993;88:1973–98. 153. Kubzansky LD, Kawachi I. Going to the heart of the matter: do negative emotions cause coronary heart disease? J Psychosom Res 2000;48:323–37.

198

s e c t i o n 3     Cardiovascular Disease l

154. Cox AM, McKewitt C, Rudd AG, et al. Socioeconomic status and stroke. Lancet 2006;5:181–88. 155. Matthews KA, Kiefe CI, Lewis CE, et al. Socioeconomic trajectories and incident hypertension in a biracial cohort of young adults. Hypertension 2002;39:772–76. 156. Jamal A, Ward E, Anderson RN, et al. Widening of socioeconomic inequalities in US death rates, 1993–2001. PLoS One 2008;3:1–8. 157. Lindquist TL, Beilin LJ, Knuiman M. Effects of lifestyle, coping and work-related stress on blood pressure in office workers. Clin Exp Pharmacol Physiol 1995;22:580–82. 158. Rutledge T, Reis SE, Olson M, et al. Socioeconomic status variables predict cardiovascular disease risk factors and prospective mortality risk among women with chest pain. The WISE Study. Behav Modif 2003;27:54–67. 159. Gallo LC, Bogart LM, Vranceanu AM, et al. Socioeconomic status, resources, psychological experiences, and emotional responses: a test of the reserve capacity model. J Pers Soc Psychol 2005;88:386–99. 160. deGroot M, Auslander W, Williams JH, et al. Depression and poverty among African American women at Risk for Type 2 diabetes. Ann Behav Med 2003;25:172–81. 161. Matthews KA, Räikkönen K, Gallo L, et al. Association between socioeconomic status and metabolic syndrome in women: testing the reserve capacity model. Health Psychol 2008;27:576–83. 162. Shaw LJ, Bairey-Merz CN, Bittner V, et al. Importance of socioeconomic status as a predictor of cardiovasular outcome and costs of care in women with suspected myocardial ischemia. Results from the National Institutes of Health, National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrom Evaluation (WISE). J Womens Health 2008;17:1081–92. 163. Sorlie PD, Rogot E. Mortality by employment status in the National Longitudinal Mortality Study. Am J Epidemiol 1990;132:983–92. 164. Levenstein S, Smith MW, Kaplan GA. Psychosocial predictors of hypertension in men and women. Arch Intern Med 2001;161:1341–46. 165. Dixon JP, Dixon JK, Spinner JC. Tensions between career and interpersonal commitments as a risk factor for cardiovascular disease among women. Women Health 1991;17:33–57. 166. Karasek R, Baker D, Marxer F, et al. Job decision latitude, job demands, and cardiovascular disease: a prospective study of Swedish men. Am J Public Health 1981;71: 694–705. 167. Schnall PL, Landsbergis PA, Pickering TG, et al. Perceived job stress, job strain, and hypertension. Am J Public Health 1994;84:320–21. 168. Pickering TG, Schwartz JE, James GD. Ambulatory blood pressure monitoring for evaluating the relationships between lifestyle, hypertension and cardiovascular risk. Clin Exp Pharmacol Physiol 1995;22:226–31. 169. Blumenthal JA, Thyrum ET, Siegel WC. Contribution of job strain, job status and marital status to laboratory and ambulatory blood pressure in patients with mild hypertension. J Psychosom Res 1995;39:133–44. 170. Karlin WA, Brondolo E, Schwartz J. Workplace social support and ambulatory cardiovascular activity in new york city traffic agents. Psychosom Med 2003;65:167–76.

171. Schnall PL, Schwartz JE, Landsbergis PA, et al. A longitudinal study of job strain and ambulatory blood pressure: results from a three-year follow-up. Psychosom Med 1998;60:697–706. 172. Albright CL, Winkleby MA, Ragland DR, et al. Job strain and prevalence of hypertension in a biracial population of urban bus drivers. Am J Public Health 1992;82:984–89. 173. Beilin LJ. Stress, coping, lifestyle and hypertension: a paradigm for research, prevention and non-pharmacological management of hypertension. Clin Exp Hypertens 1997;19:739–52. 174. Hlatky MA, Lam LC, Lee KL, et al. Job strain and the prevalence and outcome of coronary artery disease. Circulation 1995;92:327–33. 175. Yoshimasu K, Liu Y, Kodama H, et al. Job strain, Type A behavior pattern, and the prevalence of coronary atherosclerosis in Japanese working men. J Psychosom Res 2000;49:77–83. 176. Kuper H, Singh-Manoux A, Siegrist J, et al. When reciprocity fails: effort-reward imbalance in relation to coronary heart disease and health functioning within the Whitehall II study. Occup Environ Med 2002;59:777–84. 177. Steptoe A, Lundwall K, Cropley M. Gender, family structure and cardiovascular activity during the working day and evening. Soc Sci Med 2000;50:531–39. 178. Frankenhauser M, Lundberg U, Augustson H, et al. Stress on and off the job as related to occupational status in whitecollar workers. J Organizational Behav 1989;10:321–46. 179. Gump BB, Polk DE, Kamarck TW, et al. Partner interactions are associated with reduced blood pressure in the natural environment: ambulatory monitoring evidence from a healthy, multiethnic adult sample. Psychosom Med 2001;63:423–33. 180. Kario K, Shimada K. Differential effects of amlodipine on ambulatory blood pressure in elderly hypertensive patients with different nocturnal reductions in blood pressure. Am J Hypertens 1997;10:261–68. 181. Berkman LF, Vaccarino V, Seeman T. Gender differences on cardiovascular morbidity and mortality: the contribution of social networks and support. Ann Behav Med 1993; 15:112. 182. Koskenvuo M, Kaprio J, Kesaniemi A, et al. Differences in mortality from ischemic heart disease by marital status and social class. J Chronic Dis 1980;33:95–106. 183. Koskenvuo M, Kaprio J, Romo M, et al. Incidence and prognosis of ischaemic heart disease with respect to marital status and social class. A national record linkage study. J Epidemiol Commun Health 1981;35:192–96. 184. Mendes de Leon CF, Appels AW, Otten FW, et al. Risk of mortality and coronary heart disease by marital status in middle-aged men in The Netherlands. Int J Epidemiol 1992;21:460–66. 185. Orth-Gomer K, Rosengren A, Wilhelmsen L. Lack of social support and incidence of coronary heart disease in middleaged Swedish men. Psychosom Med 1993;55:37–43. 186. Eaker ED. Psychosocial factors in the epidemiology of coronary heart disease in women. Psychiatr Clin North Am 1989;12:167–73. 187. Wiklund I, Oden A, Sanne H, et al. Prognostic importance of somatic and psychosocial variables after a first myocardial infarction. Am J Epidemiol 1988;128:786–95.

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188. Case RB, Moss AJ, Case N, et al. Living alone after myocardial infarction: impact on prognosis. JAMA 1992;267:515–19. 189. Orth-Gomer K, Wamala SP, Horsten M, et al. Marital stress worsens prognosis in women with coronary heart disease: The Stockholm Female Coronary Risk Study. JAMA 2000;284:3008–14. 190. Kulik JA, Mahler HI. Emotional support as a moderator of adjustment and compliance after coronary artery bypass surgery: a longitudinal study. J Behav Med 1993;16:45–63. 191. Fontana AF, Kerns RD, Rosenberg RL, et al. Support, stress, and recovery from coronary heart disease: a longitudinal causal model. Health Psychol 1989;8:175–93. 192. House JS, Landis KR, Umberson D. Social relationships and health. Science 1988;241:540–45. 193. Berkman LF, Leo-Summers L, Horwitz RI. Emotional support and survival after myocardial infarction: a prospective, population-based study of the elderly. Ann Intern Med 1992;117:1003–9. 194. Kuper H, Marmot M. Job strain, job demands, decision latitude, and risk of coronary heart disease in the Whitehall II study. J Epidemiol Commun Health 2003;57:147–53. 195. Everson-Rose SA, Lewis TT. Psychosocial factors and cardiovascular disease. Annu Rev Public Health 2005;26:469–500. 196. Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with mycardial infarction in 52 countries (the INTERHEART STUDY): case-control study. Lancet 2004;364:937–52. 197. Rosengren A, Hawken S, Ôunpuu S, et al. Associationof psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART STUDY): case-control study. Lancet 2004;364:953–62.

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198. Frasure-Smith N, Lesperance F, Gravel G, et al. Long-term survival differences among low-anxious, high-anxious and repressive copers enrolled in the Montreal heart attack readjustment trial. Psychosom Med 2002;64:571–79. 199. Cossette S, Frasure-Smith N, Lesperance F. Clinical implications of a reduction in psychological distress on cardiac prognosis in patients participating in a psychosocial intervention program. Psychosom Med 2001;63:257–66. 200. Writing group for the ENRICHD Investigators. Effects of treating depression and low percevied social support on clinical events after myocardial infarction: the enhancing recovery in coronary heart disease patients (ERRICHD) randomized trial. JAMA 2003;289:3106–16. 201. Linden W, Phillips MJ, Leclerc J. Psychological treatment of cardiac patients: a meta-analysis. Eur Heart J 2007;28:2972–84. 202. Thombs BD, de Jonge P, Coyne JC, et al. Depression screening and patient outcomes in cardiovascular care: a systemat review. JAMA 2008;300:2161–71. 203. Claesson M, Birgander LS, Lindahl B, et al. Women’s hearts-stress management for women with ischemic heart disease: explanatory analyses of a randomized controlled trial. J Cardiopulm Rehabil 2005;25:93–102. 204. Lundberg U. Work and stress in women. In: K Orth-Gomer, MA Chesney, NK Wenger, eds. Women, Stress and Heart Disease. Mahwah, NJ: Lawrence Erlbaum; 1998:41–56. 205. Chesney MA. New behavioral risk factors for coronary heart disease: implications for intervention. In: K Orth-Gomér, N Schneiderman, eds. Behavioral Medicine Approaches to Cardiovascular Disease Prevention. Hillsdale, NJ: Lawrence Erlbaum; 1996:169–82.

C hap te r

18

The Role of Sex and Gender in Cardiothoracic Surgery Sandhya K. Balaram1, and Justin D. Blasberg2 1

Attending Surgeon, St Luke’s–Roosevelt Hospital Center, Division of Cardiothoracic Surgery; Assistant Professor of Clinical Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA 2 Resident, St Luke’s–Roosevelt Hospital Center, Department of Surgery, New York, NY, USA

Introduction

causation, risk factors, and modifiable predictors have not been completely clarified by available data, a number of evidence-based differences have been described. Female sex has generally been accepted as an independent predictor of early mortality in the perioperative period.2,7,16,28–31 In fact, many studies have shown this increased perioperative mortality to be on the order of 2–3% higher.7,10,28,32,33 Women have been shown to be at risk for a greater number of postoperative complications.7,16,17,22,29,34 However, in some reviews with long-term outcome data, female sex carries with it a protective effect outside of the immediate perioperative period.7,35,36 Although some of this effect may be seen as a result of expected increased longevity for women, the onset of disease at a later age seems to support this survival advantage overall. A review of differences in the biologic manifestations of disease, risk factors, and surgical outcomes reveals that gender in itself is a specific variable that must be considered in patients undergoing coronary bypass surgery.

Examination of factors that may contribute to gender disparities among patients with cardiac disease has been based on a large volume of both prospective and retrospectively collected surgical data from local and national registries. Prospective, randomized controlled trials have clearly proven that coronary artery bypass surgery (CABG) is a safe and effective method of treatment of coronary artery atherosclerosis.1–6 Surgical outcomes for this specific procedure have been intensely studied, categorized, and documented. As a result, a number of trends have been documented over the past several years. For example, a review of early coronary revascularization studies shows that fewer numbers of women underwent CABG; typically 30% of bypass patients were women.2,7–15 This was followed by a consistent finding of increased postoperative mortality when compared with men, suggesting that women had a physiologic predisposition to complications and poor outcome after surgical intervention.9,16–18 The reasons for these outcomes in coronary surgery in women became widely studied in the early 1990s, as the importance of sex differences became more widely recognized. Sex differences are based on unique biological and hormonal factors in the etiology of the disease that lead to differences in risk factors, survival, and prognosis. Risk factors have been shown to play a crucial role for both men and women and their importance has been paramount in determining why sex differences exist in the outcomes of cardiothoracic surgery.2,7,12,19–27 The risk profiles of men and women who undergo CABG vary widely.2,7,12,14,19–24,26,27 Furthermore, a given risk factor can have variable impact on outcomes between these two groups. Although definitive conclusions regarding

Principles of Gender-Specific Medicine

Gender and biology Biologic and hormonal differences play a role in not only the onset and progression of a given disease, but also in how the body reacts to the disease and subsequent treatment. Specific differences in the underlying substrate are partially responsible for the variation observed in cardiac surgery outcomes. These differences include age at presentation, location of disease, and the nature of coronary disease. Molecular studies, animal models, and clinical trials highlight the hormonal and metabolic differences that influence formation of coronary artery disease. The majority of these studies focus on the role of estrogen, androgens, and

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Copyright 2010 20 , Elsevier Inc. All rights reserved.

C h a p t e r 1 8     The Role of Sex and Gender in Cardiothoracic Surgery l

40 35 30

Percent

25 20 15 10 Female

5

Male

0 1989–90 1991

1992

1993

1994

1995

1996

1997

1998

Year

Figure 18.1  Graph demonstrating increase in percentage of male or female patients older than 70 years undergoing CABG. In 1998, approximately 35% of the female patients are elderly compared to less than 25% of men. This mirrors current trends. Reproduced with permission from Abramov, Tamariz, Sever, et al. 2000. Copyright (2000) Elsevier

cholesterol levels in the gender-specific development of coronary disease. One clear gender difference is the age of presentation with coronary disease. Life-table statistics show that average lifespan for women is longer than that for men.37 Currently, women in the United States are expected to live to age 77.79 years while the average life expectancy for men is 72.26 years.37 Women with coronary artery disease present at an advanced age compared to their male counterparts.18,35,37,38 In fact, increasing numbers of female patients are now presenting after age 70.7,39 While male CABG patients still outnumber women by a wide margin, some studies suggest that the majority of patients over the age of 70 undergoing surgery are female and those below 70 are primarily male7 (see Figure 18.1). The nature of coronary disease in younger females appears to be more virulent than that in older women: both percutaneous intervention and surgery carry a significantly higher mortality among young women.40,41 In specific studies, women age 55 and below have been shown to experience increased mortality rates up to 1.7% after myocardial infarction, 4.3% after percutaneous intervention, and 3.4% after CABG.15,41,42 (The precise reason for these relative poor outcomes is not as yet determined. It may be that this group has numerous risk factors placing them at a higher risk compared with men of the same age or they may lack specific protective factors that older women carry.) Estrogen has been thought to play a key role as a protective cardiovascular factor prior to menopause. Original studies looked at coronary artery disease progression following estrogen supplementation. These studies suggested that specific concentrations of hormone replacement might be beneficial to reducing cardiac risk, and this effect is mediated through specific estrogen receptors. In animal studies, estradiol supplementation was found to augment

201

coronary vasodilation in response to acetylcholine (which binds to estrogen receptors). This was presumed to be due to an estrogen-specific effect directly on the diseased coronary endothelium that may prevent the formation of atherosclerosis or injury.43,44 Other studies emphasized the importance of the endothelium and vascular tone. Estrogen has been shown to have a variety of effects on vascular tone, including vasodilation via endothelial production of nitrous oxide, reduction in mechanisms of vascular injury, delayed arterial disease formation, and reduced vascular smooth muscle proliferation. These effects are mediated through two known estrogen receptors, ER and ER.44–46 Manipulation of these receptors may decrease arterial disease through novel estrogen-receptor based therapies to limit vascular injury, increase vasodilation, and reduce the development of fatty streaks. These theories have been tested in animal models via exogenous estrogens to reduce the incidence of arterial disease.44–47 However, while the delayed onset of atherosclerosis has an established relationship to a premenopausal state in women, exogenous estrogen supplementation has not proven to reduce cardiovascular disease as once presumed. Recent prospective randomized studies such as the Heart and Estrogen/Progestin Replacement Studies (HERS) and Women’s Heath Initiative, have disproved prior investigation that estrogen supplementation following menopause is cardioprotective.47–49 Speculation about why these results differ in numerous animal models is not clear. Insight into the biochemical pathways responsible for postmenopausal coronary disease remains complex. The unexpected findings of the Women’s Heath Initiative have led researchers to question the role of estrogen supplementation in the prevention of arterial disease. Mouse studies have shown that lesion progression is significantly reduced following exogenous 17-estradiol supplementation in an ovary intact/follicle-depleted model compared to the ovariectomized counterpart, leading researchers to conclude that the development and lack of progression of atherosclerotic lesions was influenced specifically by exogenous estradiol, but only under specific endocrine conditions.50 Another study used a knock-out mouse model with apolipoprotein E deficiency and the development of rapid and proliferative arterial streaking was observed. Following removal of endogenous steroid hormones via castration, endothelial streak development continued to expand even more rapidly. Supplementation with estradiol (E2) was associated with regression of advancing arterial disease as predicted; however, this was only observed at very high concentrations similar to those found in vivo during gestation. The specific mechanism of this effect is still not clear, however. The authors postulate that estrogen may have a direct effect on endothelial cell injury, including modulation of arterial vasodilation, as well as an indirect effect on decreasing serum cholesterol levels.51 The role of estrogen on the immune system and inflammation, specifically its effects on pro-inflammatory

s e ct i o n 3     Cardiovascular Disease l

lymphocytes and cytokines such as interleukins and nitrous oxide, has also been explored without clear relationships to explain its inflammatory reducing effects. Why estrogen supplementation seems to offer cardiac protection in the animal model without translating into clinical practice is still unknown. However, this work has expanded our understanding that hormones play very specific roles in vascular injury and inflammatory processes, likely via their own receptors. Further inflammatory modulation may offer novel therapeutic options. As in women, the development of arterial disease in men is partially steroid-mediated, and estrogen absence reduces or even eliminates its protective effect over time. Clearly, in the mouse model, animals without specific estrogen receptors develop arterial disease, and are unable to effectively process and eliminate their cholesterol load.52 These mice developed early, larger, and more advanced atheromatous lesions.51 Removal of testosterone decreases the rate of atheromatous lesion development. This suggests that the role of atherosclerosis formation is mediated through estrogen receptors, and testosterone in the male counterpart has significant physiologic effects on atheroma formation.51 Androgens may also be important in determining the onset of coronary artery disease in men.52 Macrophages, which play a critical role in atherosclerosis formation and inflammation, are known to replicate in the presence of androgens. These specialized cells exhibit a large upregulation of genes in response to androgen exposure. These are genes related to lipoprotein processing, cell-surface adhesion, extracellular signaling, coagulation, fibrinolysis, and transport protein genes.52 A difference in the processing of cholesterol may also play an important role in coronary disease in men. Male hamsters fed a hypercholesterolemic diet were found to have higher LDL and total cholesterol levels, lower HDL levels, and larger atherosclerotic lesion size.53 Their female counterparts had larger LDL particle size, percentage of LDL in the particles assessed, as well as increased rate of LDL oxidation; all parameters associated with smaller atherosclerotic plaque size. Female estradiol levels were noted to be significantly higher than in their male counterpart, which was postulated to be a common factor to explain this difference.54 This has not, however, been substantiated across models. For instance, in another mouse model, no difference was found between male and female mice fed cholesterol-rich diets in terms of the formation of aortic atheromatous lesions.53 In addition to metabolic and hormonal factors, other specific biological differences between the sexes are found in the location and nature of the coronary disease. The location of the coronary atherosclerosis most frequently involves the left anterior descending artery in both sexes.55 However, men have been shown to have a higher incidence of diffuse three-vessel disease (Figure 18.2).55 Furthermore, men have been shown to have a significant increase in the

60 Patients (%)

202

50

Men

40

68(35%)*

30 20

294(54%)*

Women 161(30%) 55(29%)

69(36%)

88(16%)

10 0

1–VD

2–VD

3–VD

Coronary artery disease

Figure 18.2  Prevalence of one-, two-, and three-vessel coronary artery disease among men and women. *p  0.0001. Reproduced with permission from Kyriakidis, Petropoulakis, Androulakis, et al., 1995. Copyright (1995) Elsevier

severity and location of coronary stenoses when compared to women.55 Women have been shown to have smaller left anterior descending and left main coronary arteries as measured by intravascular ultrasound, suggesting an effect of sex on coronary dimensions.56 Many female patients are diabetic, and often present with diffuse, small vessel coronary disease. Other studies claim that both sexes have similar plaque burden, and that differences in body surface area may account for any discrepancy.25,57 In summary, the sensitive relationships between estrogen and testosterone, the inflammatory subunits of the immune system, and the endothelial response to oxidative damage and plaque formation are complex. In women, estrogen serves a cardioprotective effect, which results in the delayed presentation of coronary artery disease presumably due to reduced early disease formation. Studies show that women may benefit from the elevated estrogen levels premenopausally, perhaps accounting for the development of coronary disease at an older age. Estrogen receptors likely play an important role in atherogenesis.54,58 Likewise, androgens may also promote the formation of disease at specific concentrations in vivo.52 To date, the role of exogenous estrogen replacement in the postmenopausal woman is still unclear.

Gender and risk factors A key element of surgical outcomes involves the presence of preoperative risk factors, or co-morbid conditions, that influence the patient’s ability to respond to and recover from cardiac surgery. Gender plays a role in the in the presence, frequency, severity, and variety of risk factors as shown in multiple retrospective studies.3,7,15,18,19,38,41,52,59,60 Furthermore, the marked difference in male and female risk profiles has been suggested to account for observed differences in outcome. In examination of all high-risk patients, risk factors appear to be more important than gender in terms of outcomes.2 However, in most risk stratification models, female sex has been accepted as an independent predictor of higher mortality and morbidity after cardiac surgery.2,7,16,28,32,61

C h a p t e r 1 8     The Role of Sex and Gender in Cardiothoracic Surgery l

Abramov found female sex to be an independent risk factor for perioperative myocardial infarction, the need for IABP following CABG, and for increased risk of postoperative stroke.7 After adjustment for older age at presentation, a higher incidence of diabetes, and the presence of valvular disease, female sex was still found to be an independent predictor of increased mortality of 3.81% compared to 2.43% for men.32 Guru and colleagues shared this conclusion, adding that female sex also conferred an increased risk for cardiac readmission after the first year of surgery with up to a 50% increased risk.28,62 One clear risk factor for any surgery is age. In general, women present for CABG surgery at a later age, increasing their risk of surgery and complications.32 The average age at presentation for men is 63.3 years and for women is 66.4 years.32 Perhaps as a result of their advanced age, women often present with more severe medical co-morbidities at the time of surgery when compared to men.14,32 The exact reason for this is not known. It may be that their coronary disease is a direct result of corresponding co-morbid conditions; they are more likely to carry a diagnosis of diabetes, hypercholesteremia, hypertension, and cerebrovascular disease.32,63 The prevalence of diabetes and hypertension as specific co-morbidities in women is reproducible across studies.16,31,33,36,38,41,60,63,64 The urgent or emergent nature of surgical procedures in women also adds a key element of risk to cardiac procedures, increasing mortality several-fold. In terms of presentation, women clearly have required more urgent, rather than elective, cardiac surgery, thereby increasing their risk dramatically for a given procedure.32 In the past, this need for urgent revascularization led to the use of fewer arterial grafts for women.32 The role of gender (how women are responded to according to their sex) is unclear in the more emergent presentation of women. For example, women may be less likely to be responded to with earlier symptoms, making it more likely that they will present later in their course with a need for more emergent intervention. A review of multiple retrospective studies shows that other risk factors are specific to gender (Table 18.1). For example, male groups have an overwhelming percentage of patients who are current or previous tobacco users in comparison to women. These numbers often range from 51 to 60%.2 Men have previous myocardial infarctions, previous coronary interventions, and abnormal renal function.69 An important risk factor in cardiac surgery is cardiac function, and men more frequently carry a diagnosis of congestive heart failure (CHF), as defined by an ejection fraction (EF) less than 35%, when compared to women.32 These differ from those risk factors commonly attributed to women: average age above 70, the need for an urgent or emergent operation, diabetes mellitus, Class 3 or 4 angina, hypertension, and the presence of peripheral vascular disease (Table 18.1).2,7,17,32,65,69 Men often present with extensive three vessel disease, or more diffuse disease, in comparison to women.64

203

Table 18.1  Common risk factors by gender Female preoperative risk factors

Male preoperative risk factors

• Older age at presentation • Angina class 3 or 4 • Urgent surgical interventions • Preoperative IABG usage • Congestive heart failure • Previous percutaneous trans­ luminal coronary angioplasty • Diabetes • Hypertension • Peripheral vascular disease • Smaller body surface area • Lower hematocrit

• Ejection fraction less than 35% • Three-vessel disease • Repeat operations • Recent or significant history of smoking • Renal failure • COPD

Sources: From references 2,7,8,12,14–16,28,32,36,65,66,67,68

Although some of the risk factors between sexes may be similar, the weight of each can vary.2,12,70–72 Comparison of operative mortality for certain groups of risk factors shows a difference in outcome between men and women, i.e. risk factors affect each sex differently.36 For example, one of the most important factors related to late survival by univariate analysis is peripheral vascular disease ( PVD) or stroke, which decreases male survival overall to approximately 50% at 10 years. Poor cardiac function (EF 20%) decreases 10-year survival in men to 54%.64 Women have shown decreased survival when challenged by preoperative myocardial infarction or stroke, as well as the absence of a left internal mammary artery graft.64 Recent studies suggest that risk factors for short- and long-term survival are different, and may be affected by gender. Short-term mortality is affected by female sex and hemodynamic instability, but long-term mortality is more affected by systemic processes, such as renal function, intrinsic lung disease, diabetes, a previous episode of heart failure, the presence of peripheral vascular disease, and left main disease.61 Body surface area is another risk factor that differs between men and women but has been shown to play an important role in terms of differences in outcome. Females have a smaller body surface area and smaller coronary arteries; angiographic studies of coronary anatomy show women on average have a 10–15% smaller mid-left anterior descending artery diameter (2.01 mm vs. 1.8 mm).73 This makes the technical aspects of a coronary anastomosis more difficult than average sized vessels (2 cm diameter) and has been one of the principal noted causes of reduced graft patency.73 Multiple studies have associated this anatomic relationship as an independent risk factor of death from heart failure. Body surface area and coronary artery luminal diameter have also been shown to be a powerful determinant of mortality for men, but to a lesser extent.12,60

204

s e ct i o n 3     Cardiovascular Disease l

Female Male

Operative mortality (%)

5.0%

4.0%

3.0%

2.0%

1.0% 1 17 55 00 00 03 42 93 81 05 .70 2.1 2.0 3.2 2.0 2.3 1.9 2.1 1.8 1.8 5– 0– 3– 2– 3– 1– 7– 5– 1– 5 0 0 4 9 8 1 0 0 2.0 2.0 2.3 1.9 2.1 1.8 2.1 1.8 1.7

–1

0 .00

1

BSA (Square meters)

Figure 18.3  Operative mortality for men and women of equal body surface area (BSA) demonstrating a significant increase in mortality for both genders at a smaller BSA and marked improvement for men as BSA rises. Reproduced with permission from Edwards, Carey, Grover, Bero, and Hartz, 1998. Copyright (1998) Elsevier

This relationship has also been directly linked to higher perioperative mortality in women and patients with smaller body surface area.2,11,17,73 (Figure 18.3). Smaller body surface area and coronary artery size have also been associated with an increased risk of hospital mortality and related adverse events. One study has found that these characteristics increased the risk of in-hospital mortality up to 3.4 to 10.5 times the risk of controls.17,25,73 Men generally have a larger body surface area, which has been correlated directly with decreased hospital mortality.25 By one study’s estimation, the presence of a body surface area 1.6 was associated with a five times higher mortality than for a patient with a body surface area 2.0, irrespective of gender.73 This association between body size and outcomes has been also studied with regard to transfusion rates.74 Transfusions are known to be an independent predictor of both increased hospital mortality and intensive care unit length of stay. Smaller body surface area is associated with intraoperative hemodilution, often necessary in cardiopulmonary bypass, and may subsequently prompt transfusion.74,75 This is especially prevalent in females or those with smaller body surface area. Extrapolated from these data, it has been determined that men with smaller body surface area and women were more likely to receive transfusions, and thus were at higher risk for prolonged ICU length of stay and postoperative mortality.74,75 Conversely, larger body surface area for men has also been found to have a protective effect, similar to other studies, and does not prolong postoperative complications. However, others disagree, finding that body size irrespective of gender does not

increase operative mortality, but may contribute to complications such as low-output cardiac syndrome in the postoperative period.74,75 These gender-based risks are not specific to the Western population. Across the world, gender has been found to influence hospital mortality and adverse coronary events after coronary artery bypass surgery. Patients in Europe and Asia have gender-specific risk factors for poor outcome. Women typically present at an older age, have a higher mean body mass index, are more likely to suffer from hypertension and diabetes, and are also more likely to have unfavorable lipid profiles. Men are more likely to present as smokers, have worse cardiac performance preoperatively, are more likely to suffer postoperative myocardial infarctions, and have overall worse performance status compared to their female counterparts.29,76 Gender-specific risk factors are more intimately tied to the development of coronary artery disease than perhaps regional or environmental influences. Some data have suggested that there is an element of referral bias that leads to female patients being referred later for surgical intervention, and that this delay leads them to present with more co-morbidities and perhaps in more emergency settings. Khan first reported on 2297 patients undergoing isolated coronary artery bypass and found females presented with more advanced New York Heart Association (NYHA) functional class and older age, which were attributed as the causes for higher operative mortality associated with CABG. In this review, women were referred for CABG later in the course of their disease in comparison

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to their male counterparts; this referral bias may have ultimately increased risk for perioperative death.77 Krumholz found similar results in an analysis of 2473 patients post myocardial infarction. Gender was not a factor in referral for coronary catheterization, but females were less likely then men to be referred for CABG.78 Another retrospective review by Ayanian on 80,000 patients determined that women who were hospitalized for coronary artery disease, in general, underwent fewer diagnostic and therapeutic procedures than men. This included both coronary revascularization and CABG.79 More current data suggest that a referral bias to CABG is most likely not the most likely cause of increased perioperative mortality in women but that specific co-morbidities associated with female sex result in delayed presentation and a need for urgent intervention. Aldea reported on 1743 patients undergoing primary CABG and found that although women were older and more frequently required urgent or emergency interventions, an increased risk of perioperative mortality was due to this more acute and unstable presentation, and not a referral delay.80 Christakis also attributed increased perioperative risk to gender-specific risk factors such as body surface area and gender-specific co-morbidities, but did not find a referral bias for CABG in 7025 patients requiring intervention.65 Additional studies also have demonstrated that once women present with myocardial infarction or the need for urgent coronary imaging, referral to revascularization and CABG occurs with equal frequency between men and women.2,9,81,82 The true role of sex as a risk factor remains controversial. While the research shows that certain predictors are statistically significant in men versus women, a recent analysis attempted to stratify and analyze data comparing men to women matched by propensity scores.33 These scores can be compared as equal risk factors for mortality. A valid match was only possible for a very small percentage of patients due to the much larger cohort of males presenting with coronary disease. In this analysis, gender was not found to be a predictor of postoperative mortality or multiple complications, which highlights the confusion in attributing particular outcomes to gender as separate from the risk factor profile. While men and women can be compared based on presenting risk factors and co-morbidities, for the most part their profiles are so different that extrapolating data from this type of comparison may not be truly representative of real life situations.33

Gender and surgical outcomes Multiple studies confirm that women have a higher operative mortality after CABG than men (Table 18.2).2,7,12,28,41,83 A combination of age, more co-morbidity, and the necessity of urgent or emergent procedures, all contribute to this

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Table 18.2  Summary of 30-day CABG mortality studies Author 7

Abramov Aldea16 Blankstein32 Carey8 Christakis65 Doenst67 Edwards2 Hammar10 Humphries15 Koch33 O’Connor12 Ramstrom68 Vaccarino41 Woods69

No.

Year

Mortality (men vs. women)

4 823 1 743 15 440 1 335 7 025 1 567 34 4913 3 933 25 212 15 597 3 055 220 15 178 5 324

2002 1999 2005 1995 1995 2006 1998 1997 2007 2003 1993 1993 2002 2003

2.7% vs. 1.8% (p  0.09) 1.5% vs. 1.0% (p  0.33) 4.24% vs. 2.23% (p  0.0001) 6.3% vs. 3.1% (p  0.011) 3.5% vs. 1.8% (p  0.0001) 7% vs. 4% (p  0.026) 4.52% vs. 2.61% (p  0.001) 3.0% vs. 1.7% (p  0.01) 3.6% vs. 2.0% (p  0.001) 2.4% vs. 1.4% (p  0.01) 7.1% vs. 3.3% (p  0.001) 5.6% vs. 2.4% (p  0.001) 5.3% vs. 2.9% (p  0.001) 3.16% vs. 1.95% (p  0.007)

increased mortality. At present, the accepted mortality for women after CABG is 3.4% and after combined valve/ CABG procedures is 7.3%.84 Although age is a clear factor in this mortality rate, it does not explain the entire difference. It does not explain why younger women actually have a higher increase in mortality than their older cohort.31,41 Specific risk factors also contribute to this mortality, such as diabetes mellitus, body surface area, and use of IMA grafts.2,32 When examining specific postoperative complications, gender also affects the types of morbidity that occur after surgery. For example, in an analysis of evenly matched cardiac patients, women had higher incidence of postoperative Q-wave myocardial infarctions, prolonged inotropic support, and prolonged ventilatory requirements.33,41,65,83 Other complications that directly increase mortality and have been shown to be specific for women include postoperative MI, deep sternal wound infection, postoperative sepsis/ endocarditis, gastrointestinal complications, and respiratory failure.36,85 Specific associated risk factors for deep sternal wound infection include diabetes, obesity, prolonged intubation, and re-exploration for bleeding. In men, specific independent risk factors have been associated with worse outcome. These include: advanced age, history of peripheral vascular disease and heart failure, previous bypass grafts, major perioperative blood transfusion, and abnormal left ventricular function.36,69,86 Stroke is a devastating complication after cardiac surgery and data support an equal distribution of this complication between men and women.10,16,33,66 Certain predictors of stroke are the same between sexes: advanced age, recent myocardial infarction, smoking, peripheral vascular ­disease, postoperative sepsis, and respiratory failure.86 In the early postoperative period of 24 hours, there is no difference in risk between sexes. However, a recent study looking at stroke occurring after 24 hours postoperatively until discharge showed an increased incidence in female patients.86

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25 Women (n = 381) Men (n = 1619) P = 0.03

% Cumulative mortality

20

15

10

5

0 0

1

2

3

4

5

Years of follow-up

Figure 18.4  Five-year mortality after CABG demonstrating the significant increase in mortality for women as compared to men. Reproduced with permission from Herlitz, Brandrup-Wognsen, Karlson, et al. 2000. Copyright (2000) Elsevier

In the long term, there is no specific survival advantage between the sexes in non-diabetic patients.8 However, when considering all patients over a follow-up period of 10 years, survival for men is 65% and for women is 56%.8,28 Men endure an earlier onset of coronary disease, and thus their 10-year survival statistics may reflect their younger age at presentation. Women, again based on age and co-morbidity, do not have a favorable long-term outcome over men. Overall, when attributing a gender role to CABG outcome, the more common co-morbidities which are specific to sex are a better predictor of outcome than attributing outcome to a specific sex itself.7 In some studies, men have shown better 5-year survival when compared to women (Figure 18.4).87 Systemic diseases such as renal failure, diabetes, and diffuse atherosclersosis in the form of peripheral vascular disease play a causative role in long-term mortality for these patients. It is likely this effect is true across sexes. After the initial postoperative period, the adjusted mortality rates are equal between men and women.87 These results are similar to other reports showing 5-year mortality with equal survival for both sexes.9,36,88 Studies that claim gender plays no role in mortality consistently find that mortality is increased in the face of poor ventricular performance, congestive heart failure, and peripheral vascular disease.7,20 Men specifically have worse outcome in the presence of increased age, class IV NYHA symptoms, small vessel size, small body size (BSA 1.8 m2), and absence of left internal thoracic artery graft. They often present with worse left ventricular function and more extensive angiographic evidence of coronary disease. However, these qualities were not found to be statistically

significant predictors of increased mortality. The previously mentioned phenomenon of increased risk of postoperative myocardial infarction and anginal symptoms in females was also not supported by this particular study; sex was not found to be an independent predictor of operative mortality.20 In 1998, the largest sex-based study of CABG patients was published reporting on 344 913 patients from 1994– 1996 in the Society of Thoracic Surgery (STS) database.2 Operative mortality was statistically greater in women than men (4.5% vs. 2.6%). Dividing the groups into low and medium risk subsets showed that these males had a lower mortality compared to their female counterparts. However, gender was not found to play a role in postoperative mortality when considering only high-risk patients. The risk profiles of these patients were clearly different: men were likely to have a smoking history, cardiomegaly, COPD, a prior history of MI, higher NYHA classification, elective procedures, triple vessel disease, and an ejection fraction of less than 30%. Women were more likely to be older, diabetic, obese, hypercholesterolemic, and require dialysis. They were more likely to have had a recent myocardial infarction and present for emergent operation, suffer from congestive heart failure, and present in cardiogenic shock. They were also less likely to receive left internal thoracic artery grafts during surgery. The study concludes that it is not gender itself that increases or decreases postoperative risk, but rather the risk profiles associated with each sex, which alter expected surgical outcome.2,7,16,32 The findings from this and similar studies have led to formal practice guidelines for women undergoing CABG surgery (Table 18.3). In summary, women are at risk for increased shortterm mortality, have higher transfusion requirements, and

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Table 18.3  Society of Thoracic Surgery Gender-Specific Practice Guidelines for Women, 2005 Use internal mammary artery for bypass Maintain blood glucose 100–150 mg/dl Maintain intraoperative hematocrit above 22% Follow off-pump CABG indications when appropriate Account for body size when administering anesthetic and sedative drugs Maintain euthryroid state during surgery Do not use hormone replacement therapy for postmenopausal women undergoing CABG

a prolonged postoperative recovery in terms of respiratory recovery and inotropic support. However, after 30 days, the female mortality profile is more favorable. Women often present with a different spectrum of preoperative risk factors, and thus do not have similar short- or long-term outcomes. In reviewing all available data, it appears that men have a lower operative mortality, perhaps due to younger age and fewer co-morbidities, as well as a larger BSA. Their long-term survival is likely multifactorial in nature.

Gender and recovery after cabg The previous sections have focused on differences in pathology, risk factors, and outcomes after cardiac surgery. After the acute hospitalization is complete and the 30-day mortality mark has passed, does gender have a specific impact on daily life? During the recovery process, physical and mental differences have been documented that are specific to each sex. Women, perhaps as a result of their advanced age, are more likely to have lower physical function and more depression symptoms prior to surgery.31,41 This remains true after surgery as well. Postoperatively, men have shown better functional improvement after CABG.89 Whereas men benefit after surgery from improvements in both physical function and depression, women have shown a significant decline in both physical and mental health.31,33,84,90–92 Women consistently report lower health status indices after cardiac procedures and often do not report subjective significant improvement.8 Women reported clearly lower social support and more depression; this may be a result of significant household responsibilities that are unable to be met postoperatively and result in both less activity and loss of purpose.31,41,93 Rates of readmission after surgery are significantly higher (20.5% vs. 11%) for women as compared to men.31,41 This readmission rate has been supported by other studies as well.28,31 Common reasons for readmission include recurrent angina and congestive heart failure.28,31 Sternal wound infection is another specific reason for admission

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which is more common in women than men.28 Arrhythmias are a less common reason for readmission and are more common in men.31 Acute ischemia is an infrequent cause of readmission and similar between sexes.31 The question remains as to whether female gender itself contributes to slower recovery and readmission or is partially reflective of an older, sicker population. One relatively recent innovation in cardiac surgery has involved the advent of rapid recovery protocols to standardize postoperative care. This has been used to decrease hospital stays and improve outcomes among most surgical programs for routine, elective CABG patients and is often termed ‘fast track recovery.’ Ott and colleagues examined this method applied to 517 consecutive patients and found that only 30% of women were able to be discharged by postoperative day 5 as compared to 44% of men (p  0.01). The overall length of stay was significantly higher for women (7.2%  7.1% vs. 5.8 %  5.2%) (p  0.05).38 This increased length of stay for women has been supported in other studies as well.16,69 One clear reason for this difference is that the risk scores for women are significantly higher: women were older with more acute myocardial infarctions, obesity, diabetes, hypertension, and peripheral vascular disease when compared to men.38 Interestingly, this study showed no difference in complications or mortality at 30 days despite these differences in risk factors. Decreased cardiopulmonary bypass time and decreased operative time did not seem to benefit women in terms of postoperative length of stay, likely due to their older, more acute status.38 Recurrent angina is more frequent in female patients as well.83 In one study, this finding was as high as 15.2%  4.0 % in females vs. 8.5%  2.0% in males at 5 years.7 Historically, men experience greater relief of angina than women.11,88,89 This difference in recurrent angina has been documented in the percutaneous coronary intervention literature as well.40 For surgical patients, this may be a result of fewer bypass grafts performed in women in addition to the decreased number of internal mammary conduits in women versus men.3,7,16,28,36,83 Women have more small vessel disease and it is possible that their angina is not fully treated by either percutaneous intervention or bypass procedures. Graft occlusion and progression of coronary disease may also contribute to these symptoms. However, women are less likely to have repeat revascularization procedures during similar time intervals (0.6%  0.3 vs. 4.1%  0.8%).7 The likelihood of women being treated with surgery for recurrent disease after percutaneous intervention is also significantly lower than for their male counterparts.40,83 The reasons for such a difference are multifactorial and may be due to referral bias, diffuse disease often present in diabetic women, and the advanced age of women who present for reoperative revascularization. Congestive heart failure after surgery is also significantly higher for women, especially as a reason for readmission.83

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This is despite the fact that women in general have better left ventricular function prior to surgery. One reason for this finding may be that women with significant left ventricular hypertrophy, common in those with hypertension, may have difficulty in dealing with volume shifts and transient ischemia that is common in coronary artery surgery.94 Diastolic dysfunction also may play a relevant role in these readmissions.

Gender and valve surgery Overall, valve surgery and combined CABG/valve surgery carry a higher morbidity and mortality than isolated CABG alone. Although the majority of literature on gender differences for cardiac surgery involves CABG risks and outcomes, the role of gender in valve surgery has also been reviewed. Gender itself plays a role in the incidence of valve disease. Although men and women present with an equal incidence of aortic and mixed valvular disease, mitral disease is more common in females.84 Specifically, women are more likely to have mitral disease as a result of rheumatic fever when compared to men (35.7% vs. 16.3%).95 Valve surgery outcomes data support that women have a higher in-hospital mortality compared to men.84,95,96 Female sex is considered an independent risk factor in the setting of combined procedures and mitral valve repairs. Over the years, valve and CABG/valve mortality has improved for men, dropping from 6.9% in 1990 to 0.9% in 2000. Women do not show a similar benefit from improvements in technology, techniques, and cardiac protection that have facilitated cardiac surgery during these years.97 Mitral valve surgery shows a significant gender effect. Women are more commonly seen for reoperative mitral vale surgery (comprising 76% of one study population).98 In reoperative patients who undergo mitral valve replacement, female sex is a significant risk factor affecting shortterm survival of less than five years. Sex has not proven to play a role in mid-term survival.98 In addition, mitral valve regurgitation (MR) as an independent entity following CABG occurs more commonly in women.99 This can have a significant effect on long-term outcomes and readmissions after CABG. In one study, there was a 10% rate of 3–4 MR after CABG surgery in a population of patients who had either no or 1–2 MR preoperatively. In this study, women comprised 42% of the patients. Other risk factors were present in this patient group, such as renal insufficiency, prior CABG, and dilated LV size, but female sex in itself was found to be an independent predictor of MR.99 Gender-based retrospective studies for valve disease include female sex as a risk factor but also include age, emergency status, reoperation, combined CABG/valve surgery, and endocarditis as all relevant and clear risk factors for

mortality.84,100 Women have higher mortality rates postvalve surgery under the age of 60, with the mortality difference becoming insignificant by age 60.96 Combined valve/CABG is known to have a higher mortality than CABG alone, and female mortality rates range from 4 to 10%.84 Women, who comprise less than onethird of most study groups, are often older and carry more co-morbidities, including diabetes, congestive heart failure, stroke, and the need for urgent surgery. Females have been shown to be at higher risk for postoperative stroke by 19%.67 A review of long-term outcomes shows that women are more likely to have improved longevity after isolated valve and CABG/valve surgery, even when accounting for age and comorbidities.97 There is no clear advantage for men in terms of long-term survival, even though women persistently have higher preoperative risk factors.67 Other systemic factors seem to play a much more important role in longterm survival: poor left ventricular performance, peripheral vascular disease, diabetes, COPD, renal failure, and age.67

Gender and off-pump surgery One technical advancement over the past 10 years that has emerged as a possible method to level the sex mortality difference after CABG is the use of off-pump coronary bypass surgery (opCAB). The cardiopulmonary bypass circuit has multiple adverse affects on the body, including platelet dysfunction, coagulopathy, hemodilution, hypothermia, and activation of multiple immune and inflammatory responses.101 The passage of blood components throughout the extracorporeal circuit activates a number of host-defense mechanisms and promotes a systemic inflammatory type response in the body including activation of neutrophils, release of cytokines, and activation of inflammatory cascades and complement.101 Furthermore, in women, smaller BSA and on-pump hemodilutional anemia may be major factors contributing to the increased postoperative mortality in this population.102,103 With the technical advancement of cardiac stabilizers and improvements in bypass techniques off pump, adverse effects of cardiopulmonary bypass may be avoided. At present, approximately 20% of surgeries in the United States are performed off pump.19 It has evolved into a strategic tool for surgeons to use, particularly in certain high-risk groups. A large amount of data released regarding off-pump coronary bypass have shown variable decreases in rates of cerebrovascular accidents, bleeding, and renal failure.104,105 In terms of sex, CABG outcomes data have revealed that off-pump surgery seems to disproportionately favor women for significant improvements in mortality.104–107 Some studies have shown that complication rates such as infection, ARDS, shock, renal failure, neurologic and cardiac problems are less frequent than for on-pump surgery in matched samples.106

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Decreased transfusion rates and lower length of stay are other benefits.105 This has translated in some studies to a 42–73% higher mortality for on-pump surgery in women.104,106,108 However, not all studies have found that off-pump coronary surgery has improved mortality in terms of sex as a statistically significant variable.107,109 Off- pump surgery has not translated into a similar survival advantage for men. The incidence of death in a recent study by Puskas et al. demonstrating data in over 11 000 patients from 1997 to 2005 has shown that off-pump CABG was able to decrease observed mortality in women from 4.07% to 1.52%. The difference in male patients was less dramatic, with a decrease from 1.8% to 1.3%.105 The use of opCAB has helped decrease operative mortality for women to a risk that is similar to men, despite their increased risk factors. The complete reasons for this are not entirely clear, but opCAB surgery will continue to be an important tool to improve patient outcomes in the field of coronary revascularization.105

Conclusion Gender is an extremely complex issue in cardiothoracic surgery that influences presentation, biology, functional outcomes, and mortality. Knowledge of the importance of sex and gender has grown dramatically over the past 20 years, and has encompassed all aspects of surgical evaluation and treatments. The potential for improved quality of life and increased survival after cardiac surgery has been proven in both sexes and remain the most important indications for surgery. As innovative new procedures continue to evolve, including minimally invasive options such as opCAB and percutaneous therapies, more patients will be able to benefit from treatments that take into account both their gender and risk profiles in order to obtain optimal outcomes.

References 1. European Coronary Surgery Study Group. Long-term results of prospective randomised study of coronary artery bypass surgery in stable angina pectoris. European Coronary Surgery Study Group. Lancet 1982;2:1173–1180. 2. Edwards FH, Carey JS, Grover FL, et al. Impact of gender on coronary bypass operative mortality. Ann Thorac Surg 1998;66(1):125–131. 3. Edwards FH, Ferraris VA, Shahian DM, et al. Gender-specific practice guidelines for coronary artery bypass surgery: perioperative management. Ann Thorac Surg 2005;79(6):2189–2194. 4. Malenka DJ, Leavitt BJ, Hearne MJ, et al. Comparing longterm survival of patients with multivessel coronary disease after CABG or PCI: analysis of BARI-like patients in northern New England. Circulation 2005;112(9 Suppl):I371–376. 5. Peduzzi P, Kamina A, Detre K. Twenty-two-year follow-up in the VA Cooperative Study of Coronary Artery Bypass Surgery for Stable Angina. Am J Cardiol 1998;81(12):1393–1399.

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6. Seung KB, Park DW, Kim YH, et al. Stents versus coronaryartery bypass grafting for left main coronary artery disease. N Engl J Med 2008;358(17):1781–1792. 7. Abramov D, Tamariz MG, Sever JY, et al. The influence of gender on the outcome of coronary artery bypass surgery. Ann Thorac Surg 2000;70(3):800–805, discussion 806. 8. Carey JS, Cukingnan RA, Singer LK. Health status after myocardial revascularization: inferior results in women. Ann Thorac Surg 1995;59(1):112–117. 9. Davis KB, Chaitman B, Ryan T, et al. Comparison of 15-year survival for men and women after initial medical or surgical treatment for coronary artery disease: a CASS registry study. Coronary Artery Surgery Study. J Am Coll Cardiol 1995;25(5):1000–1009. 10. Hammar N, Sandberg E, Larsen FF, et al. Comparison of early and late mortality in men and women after isolated coronary artery bypass graft surgery in Stockholm, Sweden, 1980 to 1989. J Am Coll Cardiol 1997;29(3):659–664. 11. Johnson WD, Kayser KL, Pedraza PM. Angina pectoris and coronary bypass surgery: patterns of prevalence and recurrence in 3105 consecutive patients followed up to 11 years. Am Heart J 1984;108(5):1190–1197. 12. O’Connor GT, Morton JR, Diehl MJ, et al. Differences between men and women in hospital mortality associated with coronary artery bypass graft surgery. The Northern New England Cardiovascular Disease Study Group. Circulation 1993;88(5 Pt 1):2104–2110. 13. Bundy JK, Gonzalez VR, Barnard BM, et al. Gender risk differences for surgical site infections among a primary coronary artery bypass graft surgery cohort: 1995–1998. Am J Infect Control 2006;34(3):114–121. 14. Capdeville M, Chamogeogarkis T, Lee JH. Effect of gender on outcomes of beating heart operations. Ann Thorac Surg 2001;72(3):S1022–1025. 15. Humphries KH, Gao M, Pu A, et al. Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004). J Am Coll Cardiol 2007;49(14):1552–1558. 16. Aldea GS, Gaudiani JM, Shapira OM, et al. Effect of gender on postoperative outcomes and hospital stays after coronary artery bypass grafting. Ann Thorac Surg 1999;67 (4):1097–1103. 17. Fisher LD, Kennedy JW, Davis KB, et al. Association of sex, physical size, and operative mortality after coronary artery bypass in the Coronary Artery Surgery Study (CASS). J Thorac Cardiovasc Surg 1982;84(3):334–341. 18. Haskell WL, Alderman EL, Fair JM, et al. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP). Circulation 1994;89(3):975–990. 19. Edwards FH, Grover FL, Shroyer AL, et al. The Society of Thoracic Surgeons National Cardiac Surgery Database: current risk assessment. Ann Thorac Surg 1997;63(3):903–908. 20. Mickleborough LL, Takagi Y, Maruyama H, et al. Is sex a factor in determining operative risk for aortocoronary bypass graft surgery? Circulation 1995;92(9 Suppl):II80–184. 21. Hannan EL, Wu C, Bennett EV, et al. Risk stratification of in-hospital mortality for coronary artery bypass graft surgery. J Am Coll Cardiol 2006;47(3):661–668.

210

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22. Kim C, Redberg RF, Pavlic T, et al. A systematic review of gender differences in mortality after coronary artery bypass graft surgery and percutaneous coronary interventions. Clin Cardiol 2007;30(10):491–495. 23. Nashef SA, Roques F, Hammill BG, et al. Validation of European System for Cardiac Operative Risk Evaluation (EuroSCORE) in North American cardiac surgery. Eur J Cardiothorac Surg 2002;22(1):101–105. 24. Nashef SA, Roques F, Michel P, et al. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16(1):9–13. 25. Perrotta S, Nilsson F, Brandrup-Wognsen G, et al. Body mass index and outcome after coronary artery bypass surgery. J Cardiovasc Surg (Torino) 2007;48(2):239–245. 26. Pilote L, Dasgupta K, Guru V, et al. A comprehensive view of sex-specific issues related to cardiovascular disease. CMAJ 2007;176(6):S1–S44. 27. Tan ES, van der Meer J, Jan de Kam P, et al. Worse clinical outcome but similar graft patency in women versus men one year after coronary artery bypass graft surgery owing to an excess of exposed risk factors in women. CABADAS. Research Group of the Interuniversity Cardiology Institute of The Netherlands. Coronary Artery Bypass graft occlusion by Aspirin, Dipyridamole and Acenocoumarol/phenoprocoumon Study. J Am Coll Cardiol 1999;34(6):1760–1768. 28. Guru V, Fremes SE, Austin PC, et al. Gender differences in outcomes after hospital discharge from coronary artery bypass grafting. Circulation 2006;113(4):507–516. 29. Mandegar MH, Marzban M, Lebaschi AH, et al. Gender influence on hospital mortality after coronary artery bypass surgery. Asian Cardiovasc Thorac Ann 2008;16(3):231–235. 30. Stewart RD, Blair JL, Emond CE, et al. Gender and functional outcome after coronary artery bypass. Surgery 1999;126(2):184–190. 31. Vaccarino V, Lin ZQ, Kasl SV, et al. Gender differences in recovery after coronary artery bypass surgery. J Am Coll Cardiol 2003;41(2):307–314. 32. Blankstein R, Ward RP, Arnsdorf M, et al. Female gender is an independent predictor of operative mortality after coronary artery bypass graft surgery: contemporary analysis of 31 Midwestern hospitals. Circulation 2005;112(9 Suppl):I323–327. 33. Koch CG, Khandwala F, Nussmeier N, et al. Gender and outcomes after coronary artery bypass grafting: a propensity-matched comparison. J Thorac Cardiovasc Surg 2003;126(6):2032–2043. 34. Fox AA, Nussmeier NA. Does gender influence the likelihood or types of complications following cardiac surgery? Semin Cardiothorac Vasc Anesth 2004;8(4):283–295. 35. Gottlieb S, Harpaz D, Shotan A, et al. Sex differences in management and outcome after acute myocardial infarction in the 1990s: a prospective observational communitybased study. Israeli Thrombolytic Survey Group. Circulation 2000;102(20):2484–2490. 36. Toumpoulis IK, Anagnostopoulos CE, Balaram SK, et al. Assessment of independent predictors for long-term mortality between women and men after coronary artery bypass grafting: are women different from men? J Thorac Cardiovasc Surg 2006;131(2):343–351. 37. Arias E, Curtin LR, Wei R, et al. U.S. decennial life tables for 1999–2001, United States life tables. Natl Vital Stat Rep 2008;57(1):1–36.

38. Ott RA, Gutfinger DE, Alimadadian H, et al. Conventional coronary artery bypass grafting: why women take longer to recover. J Cardiovasc Surg (Torino) 2001;42(3):311–315. 39. Unlu Y, Sonmez B. Influence of cardiovascular risk factors on the outcome of coronary artery bypass surgery. Surg Today 2003;33(7):491–497. 40. Bell MR, Grill DE, Garratt KN, et al. Long-term outcome of women compared with men after successful coronary angioplasty. Circulation 1995;91(12):2876–2881. 41. Vaccarino V, Abramson JL, Veledar E, et al. Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women. Circulation 2002;105(10):1176–1181. 42. Adabag AS, Therneau TM, Gersh BJ, et al. Sudden death after myocardial infarction. JAMA 2008;300(17):2022–29. 43. Williams JK, Delansorne R, Paris J. Estrogens, progestins, and coronary artery reactivity in atherosclerotic monkeys. J Steroid Biochem Mol Biol 1998;65(1–6):219–224. 44. Tse J, Martin-McNaulty B, Halks-Miller M, et al. Accelerated atherosclerosis and premature calcified cartilaginous metaplasia in the aorta of diabetic male Apo E knockout mice can be prevented by chronic treatment with 17 beta-estradiol. Atherosclerosis 1999;144(2):303–313. 45. Mendelsohn ME. Mechanisms of estrogen action in the cardio­vascular system. J Steroid Biochem Mol Biol 2000;74(5): 337–343. 46. Mendelsohn ME. Nongenomic, ER-mediated activation of endothelial nitric oxide synthase: how does it work? What does it mean? Circ Res 2000;87(11):956–960. 47. Bruck B, Brehme U, Gugel N, et al. Gender-specific differences in the effects of testosterone and estrogen on the development of atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 1997;17(10):2192–2199. 48. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280(7):605–613. 49. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321–333. 50. Mayer LP, Dyer CA, Eastgard RL, et al. Atherosclerotic lesion development in a novel ovary-intact mouse model of perimenopause. Arterioscler Thromb Vasc Biol 2005;25(9):1910–1916. 51. Villablanca A, Lubahn D, Shelby L, et al. Susceptibility to early atherosclerosis in male mice is mediated by estrogen receptor alpha. Arterioscler Thromb Vasc Biol 2004;24(6):1055–1061. 52. Ng MK, Quinn CM, McCrohon JA, et al. Androgens upregulate atherosclerosis-related genes in macrophages from males but not females: molecular insights into gender differences in atherosclerosis. J Am Coll Cardiol 2003;42(7):1306–1313. 53. Johnston TP, Coker JW, Paigen BJ, et al. Sex does not seem to influence the formation of aortic lesions in the P-407induced mouse model of hyperlipidemia and atherosclerosis. J Cardiovasc Pharmacol 2002;39(3):404–411. 54. Wilson TA, Nicolosi RJ, Lawton CW, et al. Gender differences in response to a hypercholesterolemic diet in hamsters: effects on plasma lipoprotein cholesterol concentrations and early aortic atherosclerosis. Atherosclerosis 1999;146(1):83–91.

C h a p t e r 1 8     The Role of Sex and Gender in Cardiothoracic Surgery l

55. Kyriakidis M, Petropoulakis P, Androulakis A, et al. Sex differences in the anatomy of coronary artery disease. J Clin Epidemiol 1995;48(6):723–730. 56. Sheifer SE, Canos MR, Weinfurt KP, et al. Sex differences in coronary artery size assessed by intravascular ultrasound. Am Heart J 2000;139(4):649–653. 57. Kornowski R, Lansky AJ, Mintz GS, et al. Comparison of men versus women in cross-sectional area luminal narrowing, quantity of plaque, presence of calcium in plaque, and lumen location in coronary arteries by intravascular ultrasound in patients with stable angina pectoris. Am J Cardiol 1997;79(12):1601–1605. 58. Finking G, Krauss N, Romer S, et al. 17beta-estradiol, gender independently, reduces atheroma development but not neointimal proliferation after balloon injury in the rabbit aorta. Atherosclerosis 2001;154(1):39–49. 59. Murabito JM, Evans JC, Larson MG, et al. Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation. Circulation 1993;88(6):2548–2555. 60. Patel S, Smith JM, Engel AM. Gender differences in outcomes after off-pump coronary artery bypass graft surgery. Am Surg 2006;72(4):310–313. 61. Mehta RH, Honeycutt E, Shaw LK. Clinical and angiographic correlates of short- and long-term mortality in patients undergoing coronary artery bypass grafting. Am J Cardiol 2007;100(10):1538–1542. 62. Stewart RD, Campos CT, Jennings B, et al. Predictors of 30day hospital readmission after coronary artery bypass. Ann Thorac Surg 2000;70(1):169–174. 63. Ritchison A, Smith JM, Engel AM. Gender differences in diabetic patients following coronary artery bypass graft surgery. J Card Surg 2007;22(5):401–405. 64. Mickleborough LL, Carson S, Ivanov J. Gender differences in quality of distal vessels: effect on results of coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;126(4):950–958. 65. Christakis GT, Weisel RD, Buth KJ, et al. Is body size the cause for poor outcomes of coronary artery bypass operations in women? J Thorac Cardiovasc Surg 1995;110(5):1344–1356, discussion 1356-1358. 66. Koch CG, Higgins TL, Capdeville M, et al. The risk of coronary artery surgery in women: a matched comparison using preoperative severity of illness scoring. J Cardiothorac Vasc Anesth 1996;10(7):839–843. 67. Doenst T, Ivanov J, Borger MA, et al. Sex-specific long-term outcomes after combined valve and coronary artery surgery. Ann Thorac Surg 2006;81(5):1632–1636. 68. Ramstrom J, Lund O, Cadavid E, et al. Multiarterial coronary artery bypass grafting with special reference to small vessel disease and results in women. Eur Heart J 1993;14(5):634–639. 69. Woods SE, Noble G, Smith JM, et al. The influence of gender in patients undergoing coronary artery bypass graft surgery: an eight-year prospective hospitalized cohort study. J Am Coll Surg 2003;196(3):428–434. 70. Thomas JL, Braus PA. Coronary artery disease in women. A historical perspective. Arch Intern Med 1998;158(4):333–337. 71. Zindrou D, Taylor KM, Bagger JP. Excess coronary artery bypass graft mortality among women with hypothyroidism. Ann Thorac Surg 2002;74(6):2121–2125.

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72. Zitser-Gurevich Y, Simchen E, Galai N, et al. Effect of perioperative complications on excess mortality among women after coronary artery bypass: the Israeli Coronary Artery Bypass Graft Study (ISCAB). J Thorac Cardiovasc Surg 2002;123(3):517–524. 73. O’Connor NJ, Morton JR, Birkmeyer JD, et al. Effect of coronary artery diameter in patients undergoing coronary bypass surgery. Northern New England Cardiovascular Disease Study Group. Circulation 1996;93(4):652–655. 74. Ranucci M, Pazzaglia A, Bianchini C, et al. Body size, gender, and transfusions as determinants of outcome after coronary operations. Ann Thorac Surg 2008;85(2):481–486. 75. Rogers MA, Blumberg N, Heal JM, et al. Increased risk of infection and mortality in women after cardiac surgery related to allogeneic blood transfusion. J Womens Health (Larchmt) 2007;16(10):1412–1420. 76. Srichaiveth B, Ruengsakulrach P, Visudharom K, et al. Impact of gender on treatment and clinical outcomes in acute ST elevation myocardial infarction patients in Thailand. J Med Assoc Thai 2007;90(Suppl 1):65–73. 77. Khan SS, Nessim S, Gray R, et al. Increased mortality of women in coronary artery bypass surgery: evidence for referral bias. Ann Intern Med 1990;112(8):561–567. 78. Krumholz HM, Douglas PS, Lauer MS, et al. Selection of patients for coronary angiography and coronary revascularization early after myocardial infarction: is there evidence for a gender bias? Ann Intern Med 1992;116(10):785–790. 79. Ayanian JZ, Epstein AM. Differences in the use of procedures between men and women hospitalized for coronary, heart disease. N Engl J Med 1991;325:221–225. 80. Aldea GS, Gaudiani JA, Shapira OM, et al. Comparison of risk profile and outcomes in patients undergoing surgical and catheter-based revascularization. J Card Surg 1998;13(2):81– 89, discussion 90–92. 81. Robertson T, Kennard ED, Mehta S, et al. Influence of gender on in-hospital clinical and angiographic outcomes and on oneyear follow-up in the New Approaches to Coronary Intervention (NACI) registry. Am J Cardiol 1997;80(10A):26K–39K. 82. Kelsey SF, James M, Holubkov AL, et al. Results of percutaneous transluminal coronary angioplasty in women. 1985– 1986 National Heart, Lung, and Blood Institute’s Coronary Angioplasty Registry. Circulation 1993;87(3):720–727. 83. Jacobs AK, Kelsey SF, Brooks MM, et al. Better outcome for women compared with men undergoing coronary revascularization: a report from the bypass angioplasty revascularization investigation (BARI). Circulation 1998;98(13):1279–1285. 84. Ibrahim MF, Paparella D, Ivanov J, et al. Gender-related differences in morbidity and mortality during combined valve and coronary surgery. J Thorac Cardiovasc Surg 2003;126(4):959–964. 85. Salehi Omran A, Karimi A, Ahmadi SH, et al. Superficial and deep sternal wound infection after more than 9000 coronary artery bypass graft (CABG): incidence, risk factors and mortality. BMC Infect Dis 2007;7:112. 86. Toumpoulis IK, Anagnostopoulos CE, Chamogeorgakis TP, et al. Impact of early and delayed stroke on in-hospital and long-term mortality after isolated coronary artery bypass grafting. Am J Cardiol 2008;102(4):411–417. 87. Herlitz J, Brandrup-Wognsen G, Karlson BW, et al. Mortality, risk indicators of death, mode of death and symptoms of angina

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pectoris during 5 years after coronary artery bypass grafting in men and women. J Intern Med 2000;247(4):500–506. Loop FD, Golding LR, MacMillan JP, et al. Coronary artery surgery in women compared with men: analyses of risks and long-term results. J Am Coll Cardiol 1983;1(2 Pt 1):383–390. Stanton BA, Jenkins CD, Savageau JA, et al. Functional benefits following coronary artery bypass graft surgery. Ann Thorac Surg 1984;37(4):286–290. Koch CG, Nussmeier NA. Gender and cardiac surgery. Anesthesiol Clin North America 2003;21(3):675–689. Koch CG, Khandwala F, Cywinski JB, et al. Health-related quality of life after coronary artery bypass grafting: a gender analysis using the Duke Activity Status Index. J Thorac Cardiovasc Surg 2004;128(2):284–295. Lindquist R, Dupuis G, Terrin ML, et al. Comparison of health-related quality-of-life outcomes of men and women after coronary artery bypass surgery through 1 year: findings from the POST CABG Biobehavioral Study. Am Heart J 2003;146(6):1038–1044. Sjoland H, Caidahl K, Karlson BW, et al. Limitation of physical activity, dyspnea and chest pain before and two years after coronary artery bypass grafting in relation to sex. Int J Cardiol 1997;61(2):123–133. Greenberg MA, Mueller HS. Why the excess mortality in women after PTCA? Circulation 1993;87(3):1030–1032. Martinez-Selles M, Garcia-Fernandez MA, Moreno M, et al. [Influence of gender on the etiology of mitral regurgitation]. Rev Esp Cardiol 2006;59(12):1335–1338. Song HK, Grab JD, O’Brien SM, et al. Gender differences in mortality after mitral valve operation: evidence for higher mortality in perimenopausal women. Ann Thorac Surg 2008;85(6):2040–44, discussion 2045. Kulik A, Lam BK, Rubens FD, et al. Gender differences in the long-term outcomes after valve replacement surgery. Heart 2009;95(4):318–326. Akay TH, Gultekin B, Ozkan S, et al. Mitral valve replacements in redo patients with previous mitral valve procedures: mid-term results and risk factors for survival. J Card Surg 2008;23(5):415–421.

  99. Campwala SZ, Bansal RC, Wang N, et al. Mitral regurgitation progression following isolated coronary artery bypass surgery: frequency, risk factors, and potential prevention strategies. Eur J Cardiothorac Surg 2006;29(3):348–353. 100. Rankin JS, Hammill BG, Ferguson TB, Jr et al. Determinants of operative mortality in valvular heart surgery. J Thorac Cardiovasc Surg 2006;131(3):547–557. 101. Gleen P, Gravlee RFF, Kurusz M, et al. Cardiopulmonary Bypass Principles and Practice, 2nd edn. Baltimore, MD: Lipincott Williams and Wilkins; 2000. 102. DeFoe GR, Ross CS, Olmstead EM, et al. Lowest hematocrit on bypass and adverse outcomes associated with coronary artery bypass grafting. Northern New England Cardiovascular Disease Study Group. Ann Thorac Surg 2001;71(3):769–776. 103. Habib RH, Zacharias A, Schwann TA, et al. Adverse effects of low hematocrit during cardiopulmonary bypass in the adult: should current practice be changed? J Thorac Cardiovasc Surg 2003;125(6):1438–1450. 104. Mack MJ, Brown P, Houser F, et al. On-pump versus offpump coronary artery bypass surgery in a matched sample of women: a comparison of outcomes. Circulation 2004;110 (11 Suppl 1):II1–II6. 105. Puskas JD, Kilgo PD, Kutner M, et al. Off-pump techniques disproportionately benefit women and narrow the gender disparity in outcomes after coronary artery bypass surgery. Circulation 2007;116(11 Suppl):I192–I199. 106. Brown PP, Mack MJ, Simon AW, et al. Outcomes experience with off-pump coronary artery bypass surgery in women. Ann Thorac Surg 2002;74(6):2113–2119, discussion 2120. 107. Petro KR, Dullum MK, Garcia JM, et al. Minimally invasive coronary revascularization in women: a safe approach for a high-risk group. Heart Surg Forum 2000;3(1):41–46. 108. Lawton JS, Brister SJ, Petro KR, et al. Surgical revascularization in women: unique intraoperative factors and considerations. J Thorac Cardiovasc Surg 2003;126(4):936–938. 109. Bernet F, Baykut D, Reineke D, et al. Impact of female gender on the early outcome in off-pump coronary artery bypass surgery. Eur J Med Res 2006;11(3):114–118.

Section 4

Pulmonology

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Introduction

Marilyn K. Glassberg Eight years ago, the Institute of Medicine (IOM) published their groundbreaking report “Exploring Contributions to Human Health – Does Sex Matter?”. Not surprisingly, the pulmonary section was very small and did not include most of the topics in the prior edition or current edition of Principles of Gender-Specific Medicine. Nothing was intentionally omitted. The information was not known. In response to this failure of the IOM report, three books were published to discuss sex and gender issues in pulmonary medicine. The first was Clinics in Chest Medicine on Sex, Gender, and Respiratory Health and Disease, which I co-edited with Susan Murin and Idelle Weisman in the summer of 2004. We selected 15 reviews by 30 authors from around the world with the goal that the book would stimulate research and attention to the impact of sex and gender on respiratory health and disease. The second book was the Encyclopedia of Women’s Health, an attempt to be an all encompassing index, which included a small pulmonary disease section. The third book, which I read eagerly, was the previous edition of this text in 2004, when my colleague David Trawick indicated that “significant discoveries related to sex and genders in pulmonary medicine are occurring at an accelerated rate.” Now, five years later, his statement, for the most part, could not have been more correct. Differences between sexes and pulmonary diseases are now well documented and recognized as more than clinical observations. We are able to understand some of the science behind the effects of sex and gender on rare diseases as well as more common diseases to which women are more susceptible. The pulmonology section in this edition, which consists of nine reviews by 15 authors, is not meant to be all encompassing. Realizing that it would be impossible to cover all the topics that support the concept that sex does matter in women’s lung health, I chose nine topics and recognize a few oversights, including nontuberculous mycobacterium (NTM). Unfortunately, there is a minimal amount of data on the increased prevalence of NTM in women, and, to our knowledge, there are no ongoing studies on sex and gender differences in the development and course of NTM disease. The first three chapters concern respiratory diseases common to both men and women. First, Drs Lim and Kobzik assess the role of estrogens on the course of asthma and the impact of hormone replacement therapy on the clinical course. Next, Drs Murin, Bilello, Moores, and Holley update their prior chapter and examine gender issues and venous thromboembolism, focusing on female-specific risk factors for thrombosis such as pregnancy and hormone use. In the next chapter Dr Shafazand discusses how sleep and its associated disorders differ in women and men. The following five chapters highlight diseases where recent data underscore the increased susceptibility of women. Dr Chapman provides a review of the evolving

epidemiology of chronic obstructive pulmonary disease and differences in symptom patterns and response to treatments between the sexes. Next, Drs Toonkel and Powell review the influence of smoking on the increasing incidence of lung cancer in women and advocate for public policy initiatives to help prevent and reduce smoking prevalence in girls and women. Next, Dr Shure discusses pulmonary hypertension, where despite the fact that most research studies continue to be conducted in men, women develop the disease at a higher rate. Finally, Dr Aliniazee and I focus on autoimmune diseases, particularly scleroderma, and the current hypotheses explaining the higher incidence of the disease in women, including microchimerism. Our second chapter highlights two rare diseases that occur predominantly in women, benign metastasizing leiomyoma and lymphangioleiomyomatosis (LAM). The final chapter deals with sepsis, and Drs Bauman and Han provide an extensive review of the divergent course and outcome of sepsis in women. The latter is an example of a relatively new area of research that will have tremendous clinical impact in the future. Special thanks go to all of the contributing authors and their staffs for preparing this pulmonary section. I thank Dr Aliniazee for his devotion and attention to careful editing of every entry and each revision, and I appreciate and acknowledge the patience of the editor-in-chief, Marianne Legato. This issue is dedicated to my family, friends, and colleagues for their support of my devotion to women’s lung health. I will be forever grateful to Dr Maria ValdesDapena, who showed me my first case of LAM as a second year medical student in Pathology and suggested that more research be directed to sex and gender differences in disease. I also thank Dr Bruce Krieger, who referred me my first case of LAM. I hope that research on the effects of sex and gender in pulmonary diseases will continue at an accelerated rate and will foster change in future management.

Bibliography Franco S, Glassberg MK. Lung cancerEncyclopedia of Women’s Health. New York, NY: Kluwer Academic; 2004. Glassberg MK, Franco S. Chronic obstructive pulmonary diseaseEncyclopedia of Women’s Health. New York, NY: Kluwer Academic; 2004. Glassberg MK, Lange R. Lung transplantationEncyclopedia of Women’s Health. New York, NY: Kluwer Academic; 2004. Glassberg MK, Oberstein E. AsthmaEncyclopedia of Women’s Health. New York, NY: Kluwer Academic; 2004. Glassberg MK, Oberstein E. Lung diseases in pregnancyEncyclopedia of Women’s Health. New York, NY: Kluwer Academic; 2004. Glassberg MK, Murin S, Weisman I. Sex, gender, and respiratory health and diseaseClinics in Chest Medicine. Philadelphia, PA: WB Saunders; 2004. Trawick DR. Pulmonology. In: M Legato, ed. Gender-Specific Medicine. Burlington, MA: Academic Press; 2004.

Chapter

19

Gender Differences in Asthma Robert H. Lim1, and Lester Kobzik2 1 Research Associate, Harvard School of Public Health, Department of Environmental Health, and Instructor in Pediatrics Children’s Hospital Boston, Division of Respiratory Diseases, Boston, MA, USA 2 Harvard School of Public Health, Department of Environmental Health, and Brigham & Women’s Hospital, Department of Pathology, Boston, MA, USA

Introduction

There are important gender differences in asthma. A core observation in many epidemiologic studies is that asthma prevalence differs depending on sex and age. In the pre-pubertal population, asthma is more common in boys compared to girls. After puberty, the gender ratio shifts to favor females.4–8. The magnitude of this gender difference is perhaps best described as modest (post-pubertal male vs. female odds ratio 0.8,5 or 44.4d% of males with current asthma were diagnosed at 18 years or older vs. 63.9% for females9). However, given the large number of asthmatics (e.g. approximately 10% of the population), these percentage shifts have considerable impact. The basis for these gender effects remains incompletely understood, but significant progress has been made. A clearer understanding of the mechanisms behind this phenomenon will allow for better care of asthmatic patients. This chapter will first review the clinical and epidemiologic data concerning gender differences in asthma, and then will examine the literature regarding potential mechanisms. The potential etiologies examined include developmental differences, estrogens, progesterone, and androgens.

Asthma is a major public health problem. Data from 2005 reveal approximately 32.6 million people had been diagnosed with asthma at some point in their lifetime (11.2%),1 and approximately 20 million people had current asthma.2 The prevalence has also been rising dramatically in the past two decades, with some leveling off in the past few years. It remains a very common cause of substantial morbidity and occasional mortality. The diagnosis is usually made on the basis of symptom history, clinical exam, and pulmonary function testing. On spirometry, asthmatics generally have decreased FEV1, FEF25–75, and FEV1/FVC ratio, indicating obstructive lung disease consistent with the bronchoconstriction that characterizes the disease. Common factors that lead to asthma exacerbations include upper respiratory infections, allergen exposure, exercise, stress, and menses. The defining pathology of this chronic disease of the airways is allergic inflammation. The inflammatory response involves abundant eosinophils, as well as multiple other cell types including mast cells, lymphocytes, and neutrophils. These cells can accumulate in the airway wall and lumen, allowing detection either by biopsy or by lavage techniques. The inflammatory process is skewed towards Th2, similar to other allergic responses.3 A Th2 cytokine response is characterized by increased levels of specific cytokines, including interleukin (IL)-4, 5, and 13. This type of immune response is typically associated with allergy or parasitic infection. The inflammation leads to airway remodeling, with thickening of the airway wall and hypertrophy/hyperplasia of the airway smooth muscle layer. These changes are linked to the clinical symptoms associated with asthma: recurrent cough, wheeze, chest tightness, bronchial hyperresponsiveness, and dyspnea. However, the precise relationship of the many pathogenic cells and mediators to specific signs or symptoms is complex and remains the subject of active research.

Principles of Gender-Specific Medicine

Clinical and epidemiological studies Boys, Girls, Puberty, and Asthma The epidemiologic data regarding gender differences in asthma prevalence are remarkably uniform both before and after puberty. Almost all studies agree that asthma is more common in pre-pubescent boys than girls, and more common in post-pubescent girls than boys.4–11 This gender difference is well illustrated in a large study from New Zealand.6 This analysis included 1022 study members from the Dunedin Multidisciplinary Health and Development Research Study.

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The study focused on a representative birth cohort who were initially assessed at age 3 and ­ periodically thereafter until the age of 26. For the key feature of age at onset, males were much more likely than females to develop wheeze before the age of 10. In contrast, females were more likely than males to first develop wheeze between the ages of 10 and 26. In another large study, using the European Community Respiratory Health Survey data, de Marco et al. demonstrated similar findings.11 This study evaluated data on asthmatics from 16 different European nations. Compared to males, females had a lower risk of developing asthma during the ages of 0–10 years (agespecific female:male rate ratio 1), a similar risk from 10–15 years old (rate ratio 1), and a greater risk from 15 years old and up (rate ratio 1). These findings are summarized in Figure 19.1. They also showed that the findings were similar between the numerous individual European countries, reducing the likelihood of a localized, environmentally related effect. Not only are adolescent females more likely to develop asthma, but they are also more likely to be symptomatic than age-matched asthmatic males. For example, Tollefsen et al.10 demonstrated that females (13–19 years old) were more likely to have current asthma or wheeze at baseline than similar age males. More females who were asymptomatic at baseline reported current asthma and wheeze. Adolescent/adult females also suffer other manifestations of increased morbidity from asthma. Women with asthma are more likely to be hospitalized for exacerbations than their male counterparts.12–14 A large study, by Schatz et al. (1286 patients from 2 to 54 years old), found that female asthmatics had higher rates of hospitalization,12 as illustrated in Figure 19.2. Note that for the age range of 2–9 years old, the ratio of female to male inpatients is less than one; in contrast, from 19 years old and up, the ratio is greater than one. Thus, males are more likely to

be ­ hospitalized than females prior to puberty, but this is reversed after puberty. Some have argued that the increased hospitalizations may be due to the higher prevalence among females (reviewed by Almqvist et al.15). However, one study that took prevalence into account demonstrated that females were still more likely to be hospitalized than males post puberty.16 Other studies have used different clinical outcomes and have demonstrated similar results. Post-pubertal females had increased emergency department (ED) visits and oral steroid usage compared to males.16 These findings were similar to those of Sinclair et al.17 Post-pubertal females have increased ED usage, as well as increased risk of relapse following exacerbation. This was

Figure 19.1  Female-to-male age-specific ratios for development of asthma. Bars represent 95% confidence intervals. Dashed line drawn at a ratio of 1. Prior to 15 years of age the ratio favors males (ratio 1), but after 15 years of age, it favors females (ratio 1). Adapted from de Marco et al., 200011

Asthma inpatient ratio (female:male)

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 2–5

6–9

10–14 15–19

20–29

30–39

40–49

50–54

Age groups (yr)

Figure 19.2  Ratio of female to male inpatients for asthma by age group. Dashed lines represent 95% confidence intervals. Dotted line is drawn at a ratio of 1. Starting with the 20–29 years age group, females are more likely to be hospitalized than males. Adapted from Schatz et al., 200612

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demonstrated in a study by Rowe et al. when analyzing 18– 55-year-old patients enrolled from 20 different Canadian emergency rooms. Relapse was defined as any urgent visit to an ED, clinic, or physician office for worsening asthma following initial treatment in an ED.18 The relative risk for relapse in females compared to males was 1.57 (1.18–1.8). In addition to clinical outcomes, objective measures of asthma severity have also shown differences between sexes. A recent study examining 1041 children initially from 5 to 12 years of age and followed prospectively for 8.6 years (1.8 years) demonstrated that post-pubertal females had more severe disease as measured by response to methacholine.19 Bronchoreactivity is assessed by determining the concentration of methacholine at which the FEV1 decreases by 20% from baseline (PC20). Following puberty, females had significantly lower PC20s than did their male counterparts. Thus, by multiple measures, asthma is worse in females than males after puberty. These epidemiologic findings clearly demonstrate a gender difference in the manifestations of asthma. The main point is that, before puberty, asthma prevalence and severity is greater in males compared to females. After puberty, the opposite is true. The epidemiologic observations are consistent, but the underlying etiologies have not been fully elucidated and remain controversial. We will next consider the epidemiologic studies that suggest a role for sex hormones in the observed gender differences.

Menstruation, Menopause, HRT and Asthma Hormonal changes occur during puberty, it is not surprising that investigators have turned their attention to hormonal shifts as potential causes for gender differences in asthma. In order to examine the possible role of hormones, investigators have also looked at other times when hormonal flux is present: menstruation, menopause, and HRT. These studies produced variable and sometimes conflicting results. Perimenstrual asthma (PMA) is a well-known, but poorly understood, phenomenon, which describes a subset of asthmatic women who have changes in their symptoms during menses.20–22 It has also been shown that ­ irregular menstruation is associated with asthma symptoms.23,24 This implies that the hormonal shifts that occur perimenstruation are exacerbating symptoms. Efforts to identify specific hormones have led to mixed results. Rubio et al.25 demonstrated that 80% of women with asthma had abnormal levels of estradiol, progesterone, or cortisol during menstruation; most frequently, asthmatics had decreases in progesterone. In a study looking at exercise-induced asthma severity during menstruation, the most significant drops in post-exercise FEV1 (an indication of decreased airflow due to bronchoconstriction) occurred when serum progesterone levels were highest.26 These studies imply that progesterone may be pro-asthmatic. However, another study found ­normal hormone levels in similar groups,27 contradicting

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this implication. Although it is clear that there is a worsening of symptoms with some asthmatics during menses, the role, if any, for individual hormones remains unclear. Studies of menopausal women provide additional evidence, and some potential for confusion, about the role of female sex hormones in gender differences in asthma. In one large study comprising 1274 women from 45 to 56 years old, investigators studied the effect of menopause on lung function and asthma symptoms. They showed that menopause was associated with decreased lung function, more respiratory symptoms, and increased asthma risk,28 implying that female sex hormones were protective against asthma. However, a different study showed that postmenopausal women who never used HRT had a significantly lower risk of asthma as compared to premenopausal women, and that any HRT use increased their asthma risk.29 These data suggest that the female hormones in HRT, primarily estrogen, were actually ‘pro-asthmatic.’ The latter finding is, per se, more consistent with the increased prevalence and severity of asthma in females after puberty and acquisition of adult-like hormonal status. Interestingly several studies have shown that the risk for asthma related to HRT was significantly greater in lean women (BMI  25) versus obese women.28,30 Hence, it is possible that the contradictory effects of female sex hormones in some studies arise because BMI was not considered. The effects on respiratory health may also depend on the stage of the transition to menopause. During the menopausal transition, endogenous estrogens first increase, then decrease. Another possible limitation is the interaction of multiple hormones, in final effects. This complexity may hamper the ability of epidemiologic data to identify specific, causal hormones. Because the results from these menopausal/HRT studies are not entirely consistent, the role of female sex hormones observed in asthma remains unclear.

Mechanisms Developmental Differences Although most investigators interpret the available human data as hormones cause observed gender differences in asthma, another potential mechanism is the role of differential lung development between the sexes. The pattern of lung growth differs significantly in male vs. female children. Boys’ lung parenchyma growth tends to outstrip large airway growth. Girls’ have the opposite pattern, their large airways tend to grow faster than their parenchyma.31,32 This causes boys to have relatively more narrow airways compared to their female peers. This is known as dysanaptic growth. It has also been shown that infant females have proportionally larger airways relative to lung size than males.33 This relative airway narrowing in males has been mentioned as a possible mechanism for the increased

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prevalence and severity of asthma symptoms seen in prepubertal boys compared to girls.11 As children approach adulthood, the male’s lungs and conducting airway become larger than their female counterparts’ conducting airways,34 which parallels the post-pubertal switch seen in epidemiologic studies. Thus, one hypothesis has appealing simplicity: pre-pubertal males are more likely to wheeze because developmentally their airway diameter is smaller compared to their female counterparts, and post-puberty, the opposite is true. However, it should be noted that while this developmental difference might contribute to the gender effects seen in the pre/post-pubertal period, it cannot easily explain changes in asthma related to menses, menopause, and HRT. The developmental postulate also does not easily explain the increased first onset of asthma in females, a process that involves allergic immune responses as well as airway pathophysiology. One appealing aspect of this theory is that it makes testable predictions. For example, individuals with similar airway size should show similar prevalence and severity of asthma, a postulate that might be tested by comparing prevalence across gender after normalizing for age-related size changes in airways. Moreover, it is probably unwise to be too quick to dismiss the related clinical wisdom that children ‘outgrow their asthma.’ Hence, the role of developmental differences is uncertain but needs further investigation.

Animal Models Experimental data has reproduced some of the observed gender differences seen in human asthma. Using standard protocols of systemic sensitization with ovalbumin (OVA) and airway challenge, multiple investigators have found that female mice exhibit greater allergic lung disease as compared to males, with increased OVA specific IgG1 and IgE, increased Th2 cytokines, and increased peripheral blood eosinophilia.35–38 While these studies implicate female sex hormones, they do not allow identification of a role for specific hormones. Further animal studies have attempted to delineate specific roles for individual female sex hormones by isolating their effects using transgenic, ovariectomized, male, and hormone-supplemented rodents. Estrogen and Asthma Evidence which indicates that estrogen plays a prominent role in sex differences in asthma includes: (1) it is the major female sex hormone; (2) it is the primary constituent in HRT, which worsens asthma; (3) polymorphisms in the estrogen receptor are associated with bronchial hyperreactivity and a more rapid decline in lung function.39 Estrogen acts via estrogen receptors alpha and beta (ER, ER). Once bound, the receptor–ligand complex dimerizes, and binds to the estrogen receptor response elements (ERE), which then facilitates activity of numerous transcription factors and co-factors. The estrogen receptors are expressed

in lung tissue,40,41 and also on inflammatory cells such as mast cells,42 macrophages, lymphocytes, and monocytes.43 Further, estrogens are known to enhance antigen presentation, dendritic cell differentiation, T cell cytokine release, and T cell homing.44 The stage is clearly set for estrogen to affect allergic asthma. Surgical manipulation provides specific data implicating estrogen. Ligeiro de Oliveira et al. demonstrated that ovariectomized (OVX) rats (7 days prior to ovalbumin (OVA) sensitization) developed less allergic airway inflammation than sham-operated controls, following OVA-induced asthma. This indicates that female sex hormones play a pro-allergic role. More importantly, replacement of estradiol re-established airway inflammation in the OVX rats, and treatment of intact rats with tamoxifen (estrogen receptor antagonist) attenuated development of airway inflammation.45 The same group also showed that bone marrow cells of OVX rats treated with estradiol released more IL-4 (a major Th2 cytokine implicated in asthma pathogenesis) compared to untreated OVX rats. Cultured bronchoalveolar lavage (BAL) cells of OVX rats treated with estradiol showed increased IL-10, IL-1beta and TNF-alpha. Estradiol treatment also increased mast cell degranulation,46 a key step in allergic reactions. These results provide strong evidence that, at least within an experimental rodent model, estrogen can act as a pro-inflammatory/pro-asthmatic agent. Extrapolating to humans, the implication is that estrogen could account for the increase in asthma prevalence following increases in estrogens that accompany puberty in females. However, further exploration of available experimental data reveals that estrogen can also have protective effects. Riffo-Vasquez47 recapitulated the findings in the above studies using mice. However, they found that if the ovaries were removed 8 days post sensitization, there was no difference in airway inflammation versus sham-operated OVA exposed controls. When these mice were treated with estradiol (a form of estrogen), airway inflammation was attenuated. These data indicate that estrogen may have different effects depending on timing of administration. There are several mechanisms by which estrogens can affect inflammation, including changes in cytokine production, mast cell activation, and antigen presentation by antigen-presenting cells (APC). In addition to the Ligeiro de Oliveira et al.45 and Riffo-Vasquez et al.47 studies above, studies of other (non-asthma) disease models have shown Th2 skewing following estrogen exposure. In experimental autoimmune encephalitis (EAE), estrogen exposure has been shown to increase splenic T cell IL-10 (a proTh2 cytokine) production and ameliorate EAE (a process thought to be driven by excess Th1 immune dysfunction).48 In another study, OVX rats were treated with phytoestrogens and estrogen, resulting in significant ­ polarization of lymphocytes to a Th2 phenotype.49 Estrogens however can also be pro-Th1 under some circumstances. When

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o­ rchiectomized male mice were given estradiol, their ConA stimulated thymocytes and splenocytes all had increased levels of IFN-gamma mRNA.50 A molecular explanation for this duality exists. In the 5’-flanking sequence of IFN-gamma, there is an estrogen-response element (ERE). Exposure to estrogens can induce transcription of IFN-gamma, and increase activity of the IFN-gamma promoter.51 Estrogens can also induce activation and degranulation of mast cells, which releases mediators that contribute to the bronchspasm and wheeze of asthma. Exposure of a human mast cell line (HMC-1) and bone marrow derived mast cells to physiologic levels of estrogen induced release of beta-hexosaminidase, a marker for the granules that contain allergic mediators in mast cells.52 Its release indicates mast cell degranulation. More to the point, estrogen also enhanced IgE-induced degranulation and potentiated leukotriene C4 (LTC4, a potent bronchoconstrictor) production. Tamoxifen, an estrogen receptor antagonist, inhibited these effects. These effects were not observed in cells without ER.53 It is also likely that this action was mediated via a non-genomic mechanism (i.e. not via ERE, but rather through rapid signaling from membrane to cytoplasm), as the time to action was so rapid (on the order on minutes, not hours). In a recent pediatric study, Johnston et al. showed that montelukast, a leukotriene receptor antagonist, was more effective at preventing fall season asthma exacerbations in 10–14-year-old girls compared to their younger counterparts.54 Extrapolating from the in vitro study, this may be because pubertal asthmatic females have higher levels of estrogen-mediated mast cell degranulation and production of LTC4, which in turn enhance inflammation and an allergic/asthmatic phenotype. A third mechanism by which estrogen may affect allergic inflammation is by altering the behavior of antigen presenting cells. Specifically estrogen exposure can modulate the function of dendritic cells (DCs). DCs are potent antigen presenting cells and play a key role in allergy/asthma. Liu et al.55 showed that estrogen treatment inhibited antigen presentation based on cell proliferation studies. Estrogen also decreased the percentage of IFN-gamma producing DCs. In co-culture experiments of CD4T cells with estrogen-treated DCs, there was an increased percentage of T cells producing IL-4 and IL-10. Overall these results would indicate that estrogen may skew DCs to a more Th2 phenotype. The link between estrogen and harmful Th2 skewing is also implicated in female risk for autoimmune disease, as discussed in detail elsewhere in this volume. As noted earlier, the appealing simplicity of estrogen’s pro-allergic capabilities is not the whole story. In contrast to its ability to increase asthmatic inflammation, estrogen also can act to downregulate the airway hyperresponsiveness (AHR) – at least in rodent models. AHR describes the increase in airway resistance in response to exposure to increasing concentrations of a known ­ bronchoconstrictor,

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such as methacholine. Males of the BALB/c mouse strain are more sensitive than are females of this strain to inhaled methacholine, showing greater changes in Penh (a surrogate for airway resistance) and lower PC300, the provocative concentration causing a 300% increase in baseline Penh.37 In a study by Carey et al., ER deficient mice were used to demonstrate estrogen’s role in AHR.56 At baseline, these mice had increased response to methacholine compared to wild-type mice, suggesting that functional ER acts to decrease AHR. ER deficient mice did not exhibit increased response to methacholine, suggesting that ER does not significantly affect AHR. As ER deficient mice have increased circulating levels of estrogen, which could potentially act in a non-genomic fashion, the group also performed ovariectomies (OVX) on a subset of these mice and their wild-type controls. The results were similar. ER deficient OVX mice had increased airway responsiveness to methacholine as compared to wild-type OVX mice. When made allergic, the findings were similar. Allergic ER deficient mice had increased airway responsiveness compared to allergic wild-type mice, indicating that estrogen acts to decrease AHR.56 ER deficiency did not protect against airway inflammation as measured by BAL total cell counts and eosinophilia. This implies that, in this case, estrogen is not required for allergic airway inflammation. Another study demonstrated that ER does not likely play a role in airway inflammation. In that study administration of an ER agonist did not affect allergic airway inflammation in experimental asthma.57 Two mechanisms for this estrogen effect on AHR have been proposed. They include: decreased acetylcholine-induced airway reactivity by increased epithelial acetylcholinesterase activity58 and relaxation of tracheal smooth muscle cells by opening of BKCa (large conductance, calcium activated potassium channels) through activation via the nitric oxide-cGMP-protein kinase G pathway.59 These experimental data show that estrogens can affect both airway inflammation and AHR. In a recent paper, the pro-inflammatory effects of estrogen were separated from its effects on AHR. Matsubara et al.60 used a novel murine model to further characterize how estrogens can suppress AHR, and also identified a novel possible mechanism. Using a ‘lung exposure only’ protocol (standard asthma induction protocols include systemic sensitization with allergen/adjuvant and lung exposure), Matsubara et al. demonstrated that estrogen is protective against in vivo AHR. Only male mice developed in vivo AHR following their exposure protocol. Estradiol suppressed the AHR in a dose-dependent manner, and this suppression was reversed with an estrogen receptor antagonist. They also showed that OVX mice, but not sham-operated females, developed AHR which was reversed with estradiol, and estrogen receptor antagonists in non-OVX females induced AHR. All of this data provide a robust demonstration that estrogens are protective in this experimental model. This model did not generate a significant cellular response and there were no

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differences in BAL or cytokine parameters between groups, allowing for isolated analysis of estrogens effect on AHR. This study also addressed in more detail the mechanism by which estrogen may be acting. Even when given to males as little as one hour prior to assay of airway responsiveness, estrogen suppressed AHR. Similarly, when an estrogen receptor antagonist was given to females one hour prior to assay, AHR was enhanced. This data, along with the lack of potentially confounding influence of airway inflammation in this mouse asthma model, allowed the investigators to focus on direct effects of estrogens on airway contractility. Matsubara et al. further show that an NK-1 receptor antagonist (Sendide) had similar effects, with inhibition of AHR, supporting the study’s conclusion that, at least in this model, estrogens suppress AHR via an NK-1 dependent pathway. The mechanistic link to neurokinin biology is supported by the precedent of estrogen regulation of smooth muscle contractility in the uterus via effects on neurokinin receptor desensitization.61 In endothelial biology, estrogen also modulates smooth muscle contractility by enhancing activity of endothelial nitric oxide synthase (eNOS) whose product, nitric oxide, is vasodilatory and atheroprotective in females.62 The expression of eNOS in airway epithelium63 may allow similar effects on bronchial smooth muscle. This is supported by the fact that estrogen can activate eNOS in human airway epithelial cells.64 It is noteworthy that eNOSdeficient mice have been reported to manifest AHR.65 In summary, estrogens play a prominent role in the observed gender differences in asthma. However, based on the conflicting results in the literature, that role remains unclear. Some studies have demonstrated a protective effect on a key feature (AHR), while others show a detrimental effect (enhanced allergic inflammation). There are several likely sources for this complexity. Estrogen’s effects on experimental asthma may differ depending on the timing/dose and animal model used. It also affects the asthma phenotype in two distinct and contradictory ways (i.e. proinflammatory, anti-AHR). Finally, in biologic systems, estrogen does not act alone. Other sex hormones such as progesterone and androgens may contribute to, or counteract its action. Progesterone and Asthma Progesterone is another major female sex hormone that may alter asthma phenotype. Its levels, like those of estrogen, change during menses, menopause, pregnancy, and puberty. However, its role has not been as extensively studied as estrogen. Moreover, it should be noted that aside from the luteal phase during menstruation, levels are similar in men and women.66 Progesterone can have both genomic and non-genomic actions. The genomic actions are mediated via progesterone receptors A and B (PRA and PRB). Progesterone’s non-genomic actions are thought to operate

via membrane specific G-protein coupled receptors.67 PRs have been demonstrated on several cells types involved in asthma/allergy including mast cells,42 macrophages,68 and lymphocytes.69 Several animal studies have examined the role of progesterone in experimental asthma. Hellings et al. demonstrated that exogenous progesterone increased both airway eosinophilia and AHR in a mouse model of chronic asthma.70 Male mice were used in this study to remove confounding effects of endogenous female sex hormones and cyclic variations. These male mice were given repeated doses of oral medroxyprogesterone shortly before and during allergen (OVA) challenge. The asthmatic mice treated with progesterone showed increased AHR (measured by Penh), increased airway eosinophilia, and increased inflammatory infiltrate on histopathologic slides as compared to untreated asthmatic mice. In addition, the BAL fluid also showed increased IL-5 and decreased IFN-gamma. Progesterone’s pro-inflammatory effect was only observed in chronic asthma, as hormone treatment alone did not cause airway inflammation.70 It should be noted that while the effects seen in this study were likely due to progesterone, increased levels were not confirmed by serum testing. Another study using female mice showed similar proallergic effects of progesterone.71 In that study, a progesterone releasing pellet was implanted in OVX mice, asthma was induced with house dust mite allergen (HDMA), and during induction the mice were exposed to environmental tobacco smoke. Results showed that lung cells collected from asthmatic progesterone-treated females had higher levels of Con A stimulated IL-4 production versus asthmatic non-progesterone treated females. Asthmatic progesterone-treated mice also had significantly higher levels of BAL total protein and serum IgE compared to asthmatic non-treated mice. However, no difference was seen in BAL eosinophilia in these groups. Progesterone alone (in the absence of asthma) did not have any effect on airway inflammation. Hence, these two distinct studies, which used two different types of allergen-induced asthma, both found that progesterone can augment allergic inflammation. Like the estrogen findings, the progesterone experimental data are not entirely consistent. In a previously mentioned study by de Oliveira et al.,46 progesterone reduced BAL total cell counts and eosinophilia following asthma induction, suggesting that it was protective against airway inflammation. It also decreased IL-4 release by bone marrow cells from asthmatic mice. Interestingly, cells cultured from BAL released more IL-10 from progesterone-treated rats compared to non-treated. These contradictory results, as compared to the prior two mentioned studies, are likely related to the method of progesterone delivery. In this study, progesterone was given once, but in the prior two studies, it was chronically administered. A short ‘spike’ of progesterone may have different effects on experimental asthma compared to sustained high levels. Similar to estrogen, it is

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likely that the dose and timing can impact progesterone’s effects. The mechanism by which progesterone acts to affect asthma is likely via alterations in the Th1/Th2 axis. Circumstantial evidence for this can be seen in the pregnancy literature. Progesterone is often called the ‘pregnancy hormone.’ It maintains the maternal Th1/Th2 balance skewed toward Th2, which helps to prevent the mother from rejecting the fetus via Th1-dominant immune responses. Multiple studies have illustrated that progesterone shifts the differentiation of naïve T-helper cells toward the Th2 lineage. Progesterone can induce a Th1 lineage to produce IL-472 and can stimulate peripheral mononuclear blood cells to increase IL-4 and IL-13 production.73 Miyaura and Iwata74 demonstrated that physiologic concentrations of progesterone can directly affect T cell differentiation in the absence of other cells types, and that it suppressed Th1 development, and enhanced Th2 development. Hence, these data support the possibility that by causing Th2 skewing, progesterone may act to increase asthma severity in females, especially as levels rise during menses, and pregnancy. Progesterone causes Th2 skewing via progesteroneinduced blocking factor (PIBF). When exposed to progesterone, lymphocytes that express progesterone receptor (PR) synthesize PIBF.75 This substance then alters the cytokine profile of activated lymphocytes, making them more Th2-like with increased IL-4, IL-10, IFN-gamma production and decreased IL-12 (reviewed by Druckmann and Druckmann76). Like the prototypical Th2 cytokines IL-4 and IL-13, PIBF acts by causing phosphorylation of STAT6 via the JAK/STAT pathway. Its actions may be mediated through a type of IL-4 receptor.77 A similar process may be occurring in non-pregnant females, which could worsen asthma symptoms. Androgens and Asthma In addition to female sex hormones, androgens may also play a role in asthma and gender differences. Adrenarche, which precedes puberty, is characterized by adrenal gland maturation and rising levels of androgens in males and females. This is accompanied by growth of pubic hair, changes in sebaceous gland function, and other secondary sex characteristics. Androgen levels continue to rise until the third decade of life, at which point they begin decreasing. Although the levels rise in both sexes, androgen levels are higher in males than females (reviewed by Hiort78). Just as female hormones may be responsible for the increase in female asthma seen post-puberty, androgens could be postulated to mediate a decrease in males post-puberty. Scant human or experimental data are available to specifically address the role of androgens in asthma. However, there is some information from studies of atopic dermatitis (also an allergicTh2mediated process). One study showed that men with atopic

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dermatitis had significantly lower dehydroepiandrosterone (DHEA) levels compared to normal controls,79 implying that the androgen DHEA may be protective. Experimental data using rodent models has also indicated an anti-asthmatic role for androgens. DHEA treatment of mice with house dust mite-induced asthma caused decreased total cell counts and percent eosinophils on BAL compared to asthmatic mice that were not treated. Serum IL-4 and IL-5 levels were also decreased.80,81 Testosterone, another androgen that increases in pubertal males, also has anti-inflammatory properties. Castrated asthmatic mice had increased total cell counts and percent eosinophils on BAL and increased IL-4 mRNA compared to sham-operated male mice.36 The mechanism by which these androgens act has not been fully elucidated. Based on the in vivo models, they seem to act by promoting shift of the Th1/Th2 balance toward Th1, however some in vitro studies have shown an opposite effect. Du et al. demonstrated that antigen primed (keyhole limpet hemocyanin, KLH) splenocytes, when cultured in the presence of KLH and DHEA, had significantly increased IL-4 production compared to those cultured without DHEA.82 This suggests that DHEA is Th2 skewing. However the dose of DHEA used was higher than those found in human serum, making it less likely that this represented a physiologic system. The current state of knowledge about sex hormones is frustrating and incomplete. For estrogen, the bulk of data seems to point toward a pro-inflammatory role, but with a separate anti-AHR effect. It is not strictly ‘pro’ or ‘antiasthmatic.’ Although the data are mixed for progesterone, given its experimental Th2 skewing effects, it is predominantly ‘pro-asthmatic’. It is difficult to ascribe the pubertal change in asthma gender frequencies to progesterone, as levels are usually similar in men and women. However, it could account for changes in asthma symptoms seen in perimenstrual asthma. Androgens, based on in vivo experimental data and human data, have a protective effect and may well contribute to the decrease in asthma seen in pubertal boys. This synthesis glosses over important gaps in knowledge, especially given limitations in how well rodent models apply to human disease and in the paucity of experimental data addressing the likely combined/interactive effects of these hormones.

Conclusion It is clear that gender is an important determinant for asthma. Males have increased disease burden prior to puberty, but after puberty, females are more affected. Moreover, the severity of disease in women is greater than men. Despite many clinical and experimental studies, the cause of the observed gender differences has yet to be fully elucidated. Current studies have offered some clues, but the data have many contradictions and gaps. The cause of these

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gender effects is probably due to hormonal changes, though developmental differences (i.e. dysanaptic lung growth) may also contribute to a lesser extent. Further prospective epidemiologic and animal studies are required to conclusively determine the role of sex hormones in asthma. The key points of our review are summarized below: Before puberty, asthma is more common in boys than girls After puberty, asthma is more common and severe in girls than boys Hormonal flux can change asthma symptoms Animal and in vitro data indicate that: Estrogen is pro-inflammatory, but decreases airway hyperreactivity Progesterone is likely pro-asthmatic, while androgens are likely anti-asthmatic Estrogen, progesterone, and androgens may act by altering Th1/Th2 axis Specific medications may work better for females than males Clinicians should account for gender differences when giving anticipatory advice

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Despite a lack of satisfactory clarity, clinicians should be aware of these differences when treating their patients and when giving anticipatory guidance. Patients should be warned that with menopause, HRT, fertility treatment, menses, or menarche, that their typical asthma symptoms may change in frequency or severity. With severe asthmatics some caution should be taken when altering maintenance medications at these times. It is reasonable to speculate that females may also benefit more from specific types of medications. As estrogens enhance mast cell degranulation, mast cell stabilizers such a cromolyn may be more efficacious in females, or in gender-specific situations, e.g., perimenstrual asthma (another question that needs direct investigation). Women may also benefit more from leukotriene receptor antagonists than men. There are also implications for oral contraception. Low estrogen preparations may be less likely to change respiratory symptoms in asthmatics. Similar to questions of mechanism, there are numerous clinical and therapeutic questions ready for the interested investigator. Ultimately, awareness of gender differences will improve clinical management of asthmatics.

References 1. Akinbami L. Asthma Prevalence, Health Care Use and Mortality: United States, 2003–2005. 2006 (Available from: www.cdc.gov/nchs/products/pubs/pubd/hestats/ashtma0305/asthma03-05.htm#fig1/  . (Accessed August 2008.) 2. Moorman JE, Rudd RA, Johnson CA, et al. National surveillance for asthma – United States, 1980–2004. MMWR Surveill Summ 2007;56(8):1–54. 3. Holgate ST. Pathogenesis of asthma. Clin Exp Allergy 2008;38(6):872–97.

4. Abramson M, Kutin JJ, Raven J, et al. Risk factors for asthma among young adults in Melbourne, Australia. Respirology 1996;1(4):291–97. 5. Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. BMJ 1996;312(7040):1195–99. 6. Mandhane PJ, Greene JM, Cowan JO, et al. Sex differences in factors associated with childhood- and adolescent-onset wheeze. Am J Respir Crit Care Med 2005;172(1):45–54. 7. Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003;349(15):1414–22. 8. Sennhauser FH, Kuhni CE. Prevalence of respiratory symptoms in Swiss children: is bronchial asthma really more prevalent in boys? Pediatr Pulmonol 1995;19(3):161–66. 9. Rhodes L, Moorman JE, Redd SC. Sex differences in asthma prevalence and other disease characteristics in eight states. J Asthma 2005;42(9):777–82. 10. Tollefsen E, Langhammer A, Romundstad P, et al. Female gender is associated with higher incidence and more stable respiratory symptoms during adolescence. Respir Med 2007;101(5):896–902. 11. de Marco R, Locatelli F, Sunyer J, et al. Differences in incidence of reported asthma related to age in men and women: a retrospective analysis of the data of the European Respiratory Health Survey. Am J Respir Crit Care Med 2000;162(1):68–74. 12. Schatz M, Clark S, Camargo CA Jr. Sex differences in the presentation and course of asthma hospitalizations. Chest 2006;129(1):50–55. 13. Prescott E, Lange P, Vestbo J. Effect of gender on hospital admissions for asthma and prevalence of self-reported asthma: a prospective study based on a sample of the general population. Copenhagen City Heart Study Group. Thorax 1997;52(3):287–89. 14. Chen Y, Stewart P, Johansen H, et al. Sex difference in hospitalization due to asthma in relation to age. J Clin Epidemiol 2003;56(2):180–87. 15. Almqvist C, Worm M, Leynaert B. Impact of gender on asthma in childhood and adolescence: a GA2LEN review. Allergy 2008;63(1):47–57. 16. Schatz M, Camargo CA Jr. The relationship of sex to asthma prevalence, health care utilization, and medications in a large managed care organization. Ann Allergy Asthma Immunol 2003;91(6):553–58. 17. Sinclair AH, Tolsma DD. Gender differences in asthma experience and disease care in a managed care organization. J Asthma 2006;43(5):363–67. 18. Rowe BH, Villa-Roel C, Sivilotti ML, et al. Relapse after emergency department discharge for acute asthma. Acad Emerg Med 2008;15:709–17. 19. Tantisira KG, Colvin R, Tonascia J, et al. Airway responsiveness in mild to moderate childhood asthma: gender influences on the natural history. Am J Respir Crit Care Med 2008;178:325–31. 20. Eliasson O, Scherzer HH, DeGraff AC Jr. Morbidity in asthma in relation to the menstrual cycle. J Allergy Clin Immunol 1986;77(1 Pt 1):87–94. 21. Redmond AM, James AW, Nolan SH, et al. Premenstrual asthma: emphasis on drug therapy options. J Asthma 2004;41(7):687–93.

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22. Vrieze A, Postma DS, Kerstjens HA. Perimenstrual asthma: a syndrome without known cause or cure. J Allergy Clin Immunol 2003;112(2):271–82. 23. Real FG, Svanes C, Omenaas ER, et al. Menstrual irregularity and asthma and lung function. J Allergy Clin Immunol 2007;120(3):557–64. 24. Svanes C, Real FG, Gislason T, et al. Association of asthma and hay fever with irregular menstruation. Thorax 2005;60(6):445–50. 25. Rubio RL, Gago Rodriguez B, Almirall Collazo JJ, et al. Comparative study of progesterone, estradiol, and cortisol concentrations in asthmatic and non-asthmatic women. Allergol Immunopathol (Madr) 1988;16(4):263–66. 26. Stanford KI, Mickleborough TD, Ray S, et al. Influence of menstrual cycle phase on pulmonary function in asthmatic athletes. Eur J Appl Physiol 2006;96(6):703–10. 27. Tan KS, McFarlane LC, Lipworth BJ. Beta2-adrenoceptor regulation and function in female asthmatic patients receiving the oral combined contraceptive pill. Chest 1998;113(2):278–82. 28. Real FG, Svanes C, Omenaas ER, et al. Lung function, respiratory symptoms, and the menopausal transition. J Allergy Clin Immunol 2008;121(1):72–80, e3. 29. Troisi RJ, Speizer FE, Willett WC, et al. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma: a prospective cohort study. Am J Respir Crit Care Med 1995;152(4 Pt 1):1183–88. 30. Jarvis D, Leynaert B. The association of asthma, atopy and lung function with hormone replacement therapy and surgical cessation of menstruation in a population-based sample of English women. Allergy 2008;63(1):95–102. 31. Hoffstein V. Relationship between lung volume, maximal expiratory flow, forced expiratory volume in one second, and tracheal area in normal men and women. Am Rev Respir Dis 1986;134(5):956–61. 32. Boezen HM, Jansen DF, Postma DS. Sex and gender differences in lung development and their clinical significance. Clin Chest Med 2004;25(2):237–45. 33. Tepper RS, Morgan WJ, Cota K, et al. Physiologic growth and development of the lung during the first year of life. Am Rev Respir Dis 1986;134(3):513–19. 34. Martin TR, Castile RG, Fredberg JJ, et al. Airway size is related to sex but not lung size in normal adults. J Appl Physiol 1987;63(5):2042–47. 35. Corteling R, Trifilieff A. Gender comparison in a murine model of allergen-driven airway inflammation and the response to budesonide treatment. BMC Pharmacol 2004;4:4. 36. Hayashi T, Adachi Y, Hasegawa K, et al. Less sensitivity for late airway inflammation in males than females in BALB/c mice. Scand J Immunol 2003;57(6):562–67. 37. Melgert BN, Postma DS, Kuipers I, et al. Female mice are more susceptible to the development of allergic airway inflammation than male mice. Clin Exp Allergy 2005;35(11):1496–503. 38. Seymour BW, Friebertshauser KE, Peake JL, et al. Gender differences in the allergic response of mice neonatally exposed to environmental tobacco smoke. Dev Immunol 2002;9(1):47–54. 39. Dijkstra A, Howard TD, Vonk JM, et al. Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma. J Allergy Clin Immunol 2006;117(3):604–11. 40. Fasco MJ, Hurteau GJ, Spivack SD. Gender-dependent expression of alpha and beta estrogen receptors in human

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nontumor and tumor lung tissue. Mol Cell Endocrinol 2002; 188(1–2):125–40. 41. Mollerup S, Jorgensen K, Berge G, et al. Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. Lung Cancer 2002;37(2):153–59. 42. Zhao XJ, McKerr G, Dong Z, et al. Expression of oestrogen and progesterone receptors by mast cells alone, but not lymphocytes, macrophages or other immune cells in human upper airways. Thorax 2001;56(3):205–11. 43. Phiel KL, Henderson RA, Adelman SJ, et al. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett 2005;97(1):107–13. 44. Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy 2004;3(1):97–104. 45. Ligeiro de Oliveira AP, Oliveira-Filho RM, da Silva ZL, et al. Regulation of allergic lung inflammation in rats: interaction between estradiol and corticosterone. Neuroimmunomodulation 2004;11(1):20–27. 46. de Oliveira AP, Domingos HV, Cavriani G, et al. Cellular recruitment and cytokine generation in a rat model of allergic lung inflammation are differentially modulated by progesterone and estradiol. Am J Physiol Cell Physiol 2007;293(3):C1120–28. 47. Riffo-Vasquez Y, Ligeiro de Oliveira AP, Page CP, et al. Role of sex hormones in allergic inflammation in mice. Clin Exp Allergy 2007;37(3):459–70. 48. Kim S, Liva SM, Dalal MA, et al. Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology 1999;52(6):1230–38. 49. Gallo D, Battaglia A, Mantuano E, et al. 17beta-estradiol and soy phytochemicals selectively induce a type 2 polarization in mesenteric lymph nodes of ovariectomized rats. Menopause 2008;15:718–25. 50. Karpuzoglu-Sahin E, Zhi-Jun Y, Lengi A, et al. Effects of long-term estrogen treatment on IFN-gamma, IL-2 and IL-4 gene expression and protein synthesis in spleen and thymus of normal C57BL/6 mice. Cytokine 2001;14(4):208–17. 51. Fox HS, Bond BL, Parslow TG. Estrogen regulates the IFNgamma promoter. J Immunol 1991;146(12):4362–67. 52. Narita S, Goldblum RM, Watson CS, et al. Environmental estrogens induce mast cell degranulation and enhance IgEmediated release of allergic mediators. Environ Health Perspect 2007;15(1):48–52. 53. Zaitsu M, Narita S, Lambert KC, et al. Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Mol Immunol 2007;44(8):1977–85. 54. Johnston NW, Mandhane PJ, Dai J, et al. Attenuation of the September epidemic of asthma exacerbations in children: a randomized, controlled trial of montelukast added to usual therapy. Pediatrics 2007;120(3):e702–12. 55. Liu HY, Buenafe AC, Matejuk A, et al. Estrogen inhibition of EAE involves effects on dendritic cell function. J Neurosci Res 2002;70(2):238–48. 56. Carey MA, Card JW, Bradbury JA, et al. Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice. Am J Respir Crit Care Med 2007;175(2):126–35. 57. Catley MC, Birrell MA, Hardaker EL, et al. Estrogen receptor beta: expression profile and possible anti-inflammatory role in disease. J Pharmacol Exp Ther 2008;326(1):83–88.

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58. Degano B, Prevost MC, Berger P, et al. Estradiol decreases the acetylcholine-elicited airway reactivity in ovariectomized rats through an increase in epithelial acetylcholinesterase activity. Am J Respir Crit Care Med 2001;164(10 Pt 1):1849–54. 59. Dimitropoulou C, White RE, Ownby DR, et al. Estrogen reduces carbachol-induced constriction of asthmatic airways by stimulating large-conductance voltage and calciumdependent potassium channels. Am J Respir Cell Mol Biol 2005;32(3):239–47. 60. Matsubara S, Swasey CH, Loader JE, et al. Estrogen determines gender differences in airway responsiveness after allergen exposure. Am J Respir Cell Mol Biol 2007;38:501–8. 61. Crane LH, Williams MJ, Nimmo AJ, et al. Estrogen-dependent regulation of neurokinin 3 receptor-mediated uterine contractility in the rat. Biol Reprod 2002;67(5):1480–87. 62. Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev 2002;23(5):665–86. 63. Shaul PW, North AJ, Wu LC, et al. Endothelial nitric oxide synthase is expressed in cultured human bronchiolar epithelium. J Clin Invest 1994;94(6):2231–36. 64. Kirsch EA, Yuhanna IS, Chen Z, et al. Estrogen acutely stimulates endothelial nitric oxide synthase in H441 human airway epithelial cells. Am J Respir Cell Mol Biol 1999;20(4):658–66. 65. Feletou M, Lonchampt M, Coge F, et al. Regulation of murine airway responsiveness by endothelial nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 2001;281(1):L258–67. 66. Oettel M, Mukhopadhyay AK. Progesterone: the forgotten hormone in men? Aging Male 2004;7(3):236–57. 67. Arck P, Hansen PJ, Mulac Jericevic B, et al. Progesterone during pregnancy: endocrine-immune cross talk in mammalian species and the role of stress. Am J Reprod Immunol 2007;58(3):268–79. 68. Khan KN, Masuzaki H, Fujishita A, et al. Estrogen and progesterone receptor expression in macrophages and regulation of hepatocyte growth factor by ovarian steroids in women with endometriosis. Hum Reprod 2005;20(7):2004–13. 69. Polgar B, Kispal G, Lachmann M, et al. Molecular cloning and immunologic characterization of a novel cDNA coding for progesterone-induced blocking factor. J Immunol 2003;171(11):5956–63. 70. Hellings PW, Vandekerckhove P, Claeys R, et al. Progesterone increases airway eosinophilia and hyper-responsiveness in a murine model of allergic asthma. Clin Exp Allergy 2003;33(10):1457–63.

71. Mitchell VL, Gershwin LJ. Progesterone and environmental tobacco smoke act synergistically to exacerbate the development of allergic asthma in a mouse model. Clin Exp Allergy 2007;37(2):276–86. 72. Piccinni MP, Giudizi MG, Biagiotti R, et al. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 1995;155(1):128–33. 73. Hamano N, Terada N, Maesako K, et al. Effect of female hormones on the production of IL-4 and IL-13 from peripheral blood mononuclear cells. Acta Otolaryngol (Suppl) 1998; 537:27–31. 74. Miyaura H, Iwata M. Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 2002;168(3):1087–94. 75. Szekeres-Bartho J, Autran B, Debre P, et al. Immunoregulatory effects of a suppressor factor from healthy pregnant women’s lymphocytes after progesterone induction. Cell Immunol 1989;122(2):281–94. 76. Druckmann R, Druckmann MA. Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol 2005;97(5):389–96. 77. Kozma N, Halasz M, Polgar B, et al. Progesterone-induced blocking factor activates STAT6 via binding to a novel IL-4 receptor. J Immunol 2006;176(2):819–26. 78. Hiort O. Androgens and puberty. Best Pract Res Clin Endocrinol Metab 2002;16(1):31–41. 79. Tabata N, Tagami H, Terui T. Dehydroepiandrosterone may be one of the regulators of cytokine production in atopic dermatitis. Arch Dermatol Res 1997;289(7):410–14. 80. Yu CK, Yang BC, Lei HY, et al. Attenuation of house dust mite Dermatophagoides farinae-induced airway allergic responses in mice by dehydroepiandrosterone is correlated with down-regulation of TH2 response. Clin Exp Allergy 1999;29(3):414–22. 81. Yu CK, Liu YH, Chen CL. Dehydroepiandrosterone attenuates allergic airway inflammation in Dermatophagoides farinae-sensitized mice. J Microbiol Immunol Infect 2002;35(3):199–202. 82. Du C, Guan Q, Khalil MW, et al. Stimulation of Th2 response by high doses of dehydroepiandrosterone in KLH-primed splenocytes. Exp Biol Med (Maywood) 2001; 226(11):1051–60.

Chapter

20

Gender Issues in Venous Thromboembolism Susan Murin1, Kathryn Bilello2, Lisa Moores3, and Aaron Holley4 1

Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, and Vice-Chair for Clinical Affairs, University of California Davis School of Medicine, Department of Internal Medicine, Sacramento, CA, USA 2 Central California Faculty Medical Group and Associate Clinical Professor of Medicine, University of California San Francisco– Fresno Program, Fresno, CA, USA 3 Assistant Dean for Clinical Sciences, Professor of Medicine, The Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, MD, USA 4 Walter Reed Army Medical Center, Division of Pulmonary/Critical Care and Sleep Medicine, Department of Internal Medicine, Washington, DC, USA

Venous thromboembolism: epidemiology and risk factors

that determine whether a given individual presents with PE or DVT, or both, are not well understood. Recurrent disease is likely to manifest in the same manner (DVT or PE) as an initial event.6 Patients who initially present with PE are much more likely to die from PE in the subsequent year than are patients who initially present with DVT.10 A wide variety of clinical conditions and circumstances are recognized as risk factors for VTE (Table 20.1). These range from medical disorders, such as malignancy and congestive heart failure, to immobility from a variety of causes (the postoperative state, stroke, prolonged travel), to a variety of inherited and acquired conditions leading to a prothrombotic state (thrombophilia). The clinical importance of a thrombophilic disorder depends not just on the magnitude of thrombotic risk it conveys but also on its prevalence in the population. Deficiencies of the endogenous anticoagulants antithrombin (AT), protein C, and protein S have been recognized for decades but are relatively rare disorders. The discovery, over the last decade, of several highly prevalent, monogenic forms of thrombophilia, in particular the factor V Leiden (FVL) mutation and the Prothrombin 20210A variant, have led to a marked increase in the proportion of cases of thromboembolism for which a heritable predisposing condition can be identified. A genetic abnormality predisposing to thrombosis can now be identified in over one-third of unselected patients with thromboembolism, and in the majority of patients with familial thrombosis.11,12 While each of these conditions increases the relative risk of thrombosis, many, and for some types of thrombophilia the great majority, of affected individuals will not suffer a thrombotic event in their lifetime.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are closely related disorders commonly considered to be different parts of the spectrum of a single disease process, venous thromboembolism (VTE). A variety of factors, including difficulties with clinical diagnosis, variation in the composition of populations, and low autopsy rates, make accurate determination of the incidence of VTE difficult. Based upon a number of epidemiological studies of varying design the current best estimate of the cumulative incidence of diagnosed or fatal VTE is 0.71–1.17 cases per 1000 adult population per year.1 Extrapolating this to the current United States (US) population leads to an estimate of approximately 250 000 such cases in the United States each year. Because underdiagnosis of VTE is a wellrecognized problem, some authorities have proposed that the total annual incidence, including undiagnosed non-fatal cases, may be as high as 600 000 cases per year.2 Evidence of DVT of the lower extremities can be found in a majority of patients with PE.3 Approximately half of patients with DVT have evidence of PE, though PE is symptomatic in only a minority of these cases.4 In most clinical studies of VTE, DVT is diagnosed approximately twice as often as PE,5–7 but in series with a high proportion of autopsy diagnosed cases, PE is diagnosed more often than DVT.8,9 This discrepancy is likely attributable to a combination of underdiagnosis of PE during life, and overdiagnosis of PE at autopsy due to detection of clinically irrelevant pulmonary emboli in patients dying of other causes. The factors Principles of Gender-Specific Medicine

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l

Table 20.1  Risk factors for venous thromboembolism Immobilization  Age  40 years  Surgery within 3 months  Stroke or paralysis  Trauma/fracture  Prior venous thromboembolism  Malignancy  Congestive heart failure  Myocardial infarction  Central venous catheter  Diabetes mellitus with hyperosmolarity  Obesity  Chronic renal failure  Nephrotic syndrome  Inflammatory bowel disease  Collagen vascular disease  Race (black  white  Hispanic  Asian) *Pregnancy and parturition *Oral contraceptive use *Hormone replacement therapy *Estrogen-antagonist therapy  Thrombophilic conditions   Factor V Leiden   Prothrombin 20210A allele   Protein C deficiency   Protein S deficiency   Antithrombin deficiency   Dysfibrogenemia   Antiphospholipid antibodies (including lupus anticoagulant)   Hyperviscosity syndromes   Elevated levels of Factors VIII, IX, and XI   Disorders of plasminogen and plasminogen activation *Risk factors specific to female sex.

Likelihood of venous thrombosis, %

100 Antithrombin deficiency

90

Protein C deficiency

80

Protein S deficiency Activated protein C resistance

70

No thrombophilia

60 50 40 30 20 10 0 20

30

40

50

60

Age, y

Figure 20.1  Point estimates of thrombosis-free survival for patients with various forms of heritable thrombophilia, or no known thrombophilia. Reproduced from Crowther and Kelton, 2003.11 Copyright © (2003) American College of Physicians

Multiple defects are often present in patients with the most profound thrombotic tendency. Figure 20.1 shows estimates of the thrombosis-free survival for patients with the major inherited thrombophilic states. Other factors, including pregnancy and hormone therapies, remain important co-determinants of thrombotic risk for individuals with any of these conditions, as discussed further later in this chapter. The most common acquired form of thrombophilia is that associated with the presence of antiphospholipid antibodies. Antiphospholipid antibodies are a heterogeneous group of autoantibodies directed at phospholipids and proteinphospholipid complexes, and they include anticardiolipin antibodies and lupus anticoagulants. Defining the prevalence of antiphospholipid antibodies in the population has been problematic because of methodologic issues (with both epidemiological and laboratory methods) and because the production of such antibodies may be intermittent.13 Approximately 1% of healthy young people have such antibodies, but the prevalence rises with age and co-morbidity. Nearly a third of patients with lupus will develop antiphospholipid antibodies at some point in their disease.13 Antiphospholipid antibodies are recognized as risk factors for both venous and arterial thrombosis, as well as for other vascular disorders and for multiple complications of pregnancy. An anticardiolipin antibody above the 95th percentile was found to carry a fivefold relative risk of VTE in a nested case-control study within the Physicians Health Study.14 Persistently elevated levels of anticardiolipin antibody also predict an increased risk of recurrent VTE.15 A prospective, population-based study found no association between anticardiolipin antibodies and VTE occurrence among healthy individuals without any evidence of autoimmune disease, suggesting the significance of these antibodies may vary in different patient populations.16 Age has a marked effect on the incidence of VTE. VTE is very rare before adulthood, and uncommon before age 40. The incidence of VTE rises dramatically after the age of 408,17 (as shown in Figure 20.2). In the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, the risk of VTE among those greater than 85 years of age was 15 times that of those aged 45–54.18 Race also influences the incidence of VTE. In an epidemiological study done in California using hospital discharge data White et al. found an annual incidence of VTE of only 6/100 000 adult population for Asian-Pacific Islanders, 14/100 000 among Hispanics, 23/100 000 among whites, and 29/100 000 among African Americans.19 The LITE study confirmed the higher risk among blacks, who had an age-adjusted hazard ratio for VTE of 1.6 compared with whites.18 In a study of PE mortality based upon death certificate data, Lilienfeld found a consistently higher risk of fatal PE among blacks compared with whites.17 Others have confirmed the lower risk of VTE among Hispanics and Asians.20 This variation of incidence among different ethnic groups is likely due, in part, to differences in the prevalence of heritable risk factors for thrombosis between these groups.

C h a p t e r 2 0     Gender Issues in Venous Thromboembolism l

Annual Incidence per 100 000

1200 1000

All Venous Thromboembolism PE ± DVT DVT Alone

800 600 400 200 0 0–14 20–24 30–34 40–44 50–54 60–64 70–74 80–84 15–19 25–29 35–39 45–49 55–59 65–69 75–79 ≥85

Age group, y

Figure 20.2  Annual incidence of all venous thromboembolism, deep venous thrombosis alone, and pulmonary embolism with or without deep venous thrombosis among Olmstead County, MN, residents, 1966–1990, by age. Reproduced with permission from Silverstein et al., 1998.8 Copyright © (1998) American Medical Association. All rights reserved

Studies have been conflicting in their assessment of the role of gender as a risk factor for VTE. In the Worcester DVT Study the incidence of VTE was no different for men and women.5 Male gender was associated with an age-adjusted hazard ratio of 1.4 in the LITE Study.18 A population-based study in Olmstead County, Minnesota found that the incidence of VTE was slightly higher among females than males before age 45.8 Overall, males had a higher age-adjusted incidence rate than females, though this difference was small (overall male:female ratio 1.2 : 1). In a very large epidemiological study focusing on VTE in the elderly, Kniffin and colleagues found a slightly higher rate of DVT but lower incidence rate of PE, for women compared with men.21 In the California Patient Discharge Data Set the ratio of new cases of VTE among women to those among men was 1.2, but this was largely due to an increased incidence among very elderly women.19 In a large cohort of patients undergoing general and vascular surgery female gender was found to be associated with a slightly increased risk of postoperative thrombosis, with an odds ratio of 1.3.22 A systematic review of published literature focusing specifically on DVT, and including several of the above-mentioned studies, found no systematic differences in incidence between the genders.23 Male:female incidence ratios varied from 0.8–1.3 in the seven, high-quality studies reporting gender as a variable. Given the lack of consistency in the data on gender and VTE incidence, and the small differences observed in either direction, it appears that gender per se does not appreciably affect the overall incidence of VTE. Gender is associated with differing risk factors for VTE, as discussed below, but the lack of an overall gender effect on VTE incidence suggests that these gender-specific risk factors offset one another. In contrast to the lack of a clear and consistent effect of gender on the incidence of VTE, there is increasing evidence

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that gender does affect the natural history of VTE. Numerous studies have shown a significantly increased risk of VTE recurrence for men compared to women. A meta-analysis examining the relationship between gender and VTE recurrence confirmed that male gender is associated with a relative risk of 1.6 for recurrence after treatment for an episode of VTE; in the subset of randomized studies the relative risk was lower at 1.3 but still significantly elevated.24 The increased risk associated with male gender was seen across all event types, provoked and unprovoked events, and deep vein thrombosis (DVT) and PE. The reasons for the lower rate of recurrence among women are not clear. One obvious potential explanation is that VTE in women is more likely to occur in association with removable provoking factors, such as pregnancy, oral contraceptive pill (OCP) use, or hormone replacement therapy. Support for this hypothesis was provided by a study that found no difference in rates of recurrence between women with hormone-related VTE and men.25 However, other studies have concluded that events occurring in conjunction with exogenous hormonal factors do not account for all of the observed gender difference.24 The relationship between gender and VTE recurrence may be race-specific. In the only study that examined the effect of gender by race, White et al. found that the lower recurrence rate seen for women was driven by a lower rate for white women; women of Hispanic and black race had recurrence rates that were comparable to men.6 This study used administrative data and could not account for hormonal factors. An important indirect effect of gender on VTE is caused by the relationship between gender and specific clinical risk factors for VTE. Pregnancy, OCPs, hormone replacement therapy, and estrogen-antagonist therapies increase VTE risk, and these exposures are unique (pregnancy and OCPs) or nearly unique (estrogen agonist and antagonist therapies) to the female gender. In contrast, trauma is a well-recognized VTE risk factor that occurs more commonly among males than females. The remainder of this chapter focuses upon genderspecific risk factors for VTE among women, as well as on special considerations in the diagnostic and therapeutic approaches to VTE in the pregnant patient.

Hormonal therapy and VTE Oral Contraceptive Medications The Evidence OCPs (oral contraceptive pills) were introduced in the late 1950s, and achieved widespread use by the early 1960s.26 In 1998, the World Health Organization (WHO) estimated that 100 million women were using an OCP worldwide.27 The complications associated with their use, even if rare, have the potential to significantly impact public health.

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Since the time of their original use, OCPs have gone through numerous changes in composition. Original doses of estrogen were as high as 150 g of ethinylestradiol, which is a synthetic, slightly altered version of naturally occurring estradiol that is still used in OCPs today. Currently, estrogen doses in most OCPs range from 30 to 50 g, with newer brands having as little as 15–20 g. In addition, biphasic and triphasic pills vary the estrogen dose throughout each month.26 The progesterone component has also evolved over time, but in structure rather than dose. Several generations currently exist, with those considered first generation no longer in use. Most current brands contain a second or third generation progesterone, while a few recently marketed pills use novel forms that are considered fourth generation.26 A possible association between OCPs and VTE was recognized in 1961 when a young nurse developed a severe PE shortly after initiating an OCP containing 100 mg estrogen (mestranol) with norethynodrel added as a progestogen.26 The existence and magnitude of an OCP-mediated increase in VTE risk was a topic of investigation and debate for years thereafter. Early trials that established risk involved first generation OCPs no longer in use, and are therefore less relevant to current practice. These trials have been reviewed elsewhere.26,28–36 Assessment of the relationship between OCP use and VTE has been complicated by two factors: (1) the difficulties inherent in studying rare events and (2) the changes in OCP formulations with time. There are no large, prospective, randomized trials examining the relationship between OCPs and VTE. Given the low absolute rate of thromboembolic events in young women, estimated at 1 in 10 000, this type of study is not feasible.26,34 A randomized controlled trial designed to look at cardiovascular outcomes in women using different OCP formulations would need to enroll several hundred thousand women, and given the change in formulations over time, prospective studies would have little impact on current practice when data collection and analysis was finally complete.30 Most studies of OCPs and their association with VTE utilize case-control and retrospective cohort designs. Several groups have summarized the existing evidence in an attempt to better define the relationship.26,34,37–41 A meta-analysis looking at all published studies through 1996 reported pooled risk ratios of 3 for case-control studies, 4.8 for retrospective cohort studies, 2.4 for prospective cohort studies, and 1.1 for the single randomized controlled trial (which evaluated women using first generation OCPs). Although the authors confirmed a likely association between OCPs and VTE, they cautioned that the reported risks from many studies are likely exaggerated given that the studies with the strongest methodology reported overall risk ratios less than three. In addition, several of these welldesigned studies were conducted with older formulations which contained higher doses of estrogen, and therefore might overestimate current risks.40 Gomes et al. reviewed all studies evaluating VTE risk between 1966 and 2003.37 They compared odds and risk

ratios for VTE in OCP users, without using meta-analytic techniques. Associated risk ranged from non-significant to 22.1 depending on the age range studied, the composition of the OCP, the method of VTE confirmation (clinical vs. objective), and the outcomes assessed. For most studies, risk fell between two and ten times that seen in nonusers.37 Others conducting similar reviews have found an overall risk for VTE in OCP users to be of a similar range and magnitude.34,38,39  These authors also concluded that the risk for VTE is highest during the first year of use, only to fall off in subsequent years.37 Others have reached similar conclusions, with estimates of first year risk increased by a factor of ten in those with hereditary thrombophilia.38 Upon discontinuation, VTE rates will return to baseline within approximately three months.37 Biologic Plausibility OCPs are believed to exert their effect on the risk of thrombosis by causing alterations in endogenous coagulation and fibrinolytic systems.28 OCP use is associated with increases in prothrombin, factors VII, VIII, and X, and fibrinogen levels and decreases in factor V levels. These effects may be more pronounced in users of third generation pills.34,42 Estrogens also cause a dose-dependent activation of the endogenous fibrinolytic system.43 Changes in the levels of plasminogen, tissue plasminogen activator, and plasminplasminogen complexes among estrogen users have been described and indicate an overall increase in fibrinolytic activity, though other studies have shown conflicting results.34 The balance of these changes in factor levels are consistent with an overall pro-coagulant effect, though the changes are small, the levels remain in the normal range, and the contribution of this mechanism to OCP-associated thrombosis is unclear.34,43 More recent data suggests that OCPs, and perhaps the progestin component in particular, may have profound effects on the anticoagulant system.43 OCPs induce an acquired resistance to the endogenous anticoagulant, activated protein C (APC).44 In a blinded, randomized, crossover trial, Rosing and colleagues45 demonstrated that APC resistance increased during treatment with OCPs. In some users, the level of APC resistance associated with the use of OCPs approaches that seen in non-users heterozygous for the FVL mutation, a heritable abnormality of the Factor V molecule that makes it resistant to APC’s anticoagulant effect and is associates with a five-fold increase in the risk of thromboembolism.31 Several studies have found that compared with second generation pills, third generation products cause a highly significant additional increase in APC resistance.45,46 This has been postulated as the basis for the apparent increased risk of thrombotic events with third, as compared with second, generation pills.43 Of note, there has been debate about the accuracy of the thrombin generation test used to establish APC resistance in the Rosing study,38  and other studies have not confirmed the difference in APC resistance between second and third

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generation products.47 In fact, despite the increase in laboratory evidence of APC resistance, none of the women in Rosing’s study actually developed clinical VTE.45 Differences in clinical outcomes when using second or third generation products will be discussed in more detail below. The newer progestins (also discussed below) are thought to cause an even greater degree of APC resistance.48,49 It should be noted that there is considerable individual variability in the effects of OCPs upon clotting parameters50 and Bloemenkamp and colleagues were able to demonstrate more pronounced effects of OCPs on levels of clotting factors in women who had prior OCP-associated DVT, suggesting an interaction between environmental (OCP use) and host factors upon the development of thrombotic events. The potential role of the FVL mutation and other heritable forms of thrombophilia in contributing to OCPinduced thrombosis is discussed below. Age It is well known that age is an important risk factor for VTE. The associated annual risk is approximately 1 in 100 000 in those less than 20 years old, and increases by a factor of ten every 10–25 years thereafter to reach 1 in 1000 in those older than 75.37 Even though most females on OCPs are of a reproductive age, roughly 20 through 50, even small differences within this range may be significant. VTE risk has been estimated to increase by approximately 50 percent each decade going from age 20–24 to 40–44.51 Stated another way, the incidence rate ratio is 2.6 when comparing females over the age of 30 to those below.52 Estrogen Dose and Method of Delivery Estrogen appears to have a dose-dependent effect upon thromboembolism risk. Most OCPs in use today contain 30 g ethinylestradiol or less, which is associated with a decrease in risk when compared to higher doses (50– 150 g). Newer brands contain as little as 15–20 g, but it is unclear whether this additional drop will have a clinical impact on VTE.26 Combination contraceptives are also delivered in the form of a vaginal ring, and a transdermal patch. Although the vaginal ring is associated with lower serum levels of estrogen, few data are available on VTE rates with this form of therapy.38 Data on the transdermal patch are available and controversial.53 It has been associated with higher serum estrogen levels in the blood, but decreased prothrombotic activity thought to be due to the absence of the ‘liver first pass effect’ seen with oral administration. The VTE risk in comparison to low dose estrogen OCPs is equivocal to slightly lower.38 Progestin Perhaps a more important factor in determining OCPassociated VTE risk than estrogen dose is the type of progestin used. Studies published since 1995 not only confirmed

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the increased risk of VTE in women taking any OCP medications, but also suggested an unexpected increased risk in women using the newer third generation pills, especially those containing gestodene and desogestrel. As the WHO Collaborative, Boston Collaborative Drug Surveillance Program and the Transnational Research studies all suggested this phenomenon.31,33,54 British agencies in the mid-1990s recommended that all women stop using these formulations. This then triggered a lively debate in the medical community about potential bias and confounding in studies comparing third generation products to earlier formulations.33,55,56 Of 16 original publications directly comparing third generation to earlier generation OCPs,13 revealed an increased risk, while three concluded that there was no difference.34 Hennessy and colleagues performed a meta-analysis of studies comparing second and third generation preparations, and found a summary relative risk of 1.7.57 Finally, a well-designed metaanalysis of studies done between 1995 and 2000 revealed an overall odds ratio of 3.1 among first time users of third versus second generation OCPs. Interestingly, this study also found an overall odds ratio of 1.3 for studies funded by the pharmaceutical industry and 2.3 in other studies.58 Most authors now accept that there is a two- to three-fold increase in risk with third generation preparations.34,37–39 Table 20.2 summarizes the odds ratios for VTE for second and third generation OCP in a variety of studies. Three additional progestins are available in combination form: drospirenone (DRSP), cyproterone acetate (CYP), and chlormadinone acetate (CA). Data on all three are limited, and the first two are available only in Europe. Studies of changes in coagulation parameters and initial observational data indicate VTE risk is not different from second generation Table 20.2  Odds ratio for venous thromboembolism associated with the use of low estrogen dose oral contraceptives Odds ratio (95% CI) First author, year

Any OCP

2nd generation

3rd generation

Bloemenkamp, 1995 WHO, 1995 Jick, 1995 Spitzer, 1996 Lewis, 1996 Grodstein, 1996 Lidegaard, 1998 Bloemenkamp, 1999 Lidegaard, 2002

—

3.8 (1.7–8.4) 8.7 (3.9–19.3)

— 5.9 (3.7–9.8) 4.0 (3.1–5.3) 4.4 (3.4–5.8) 2.2 (0.8–5.9) — 3.2 (2.3–4.5)

3.6 (1.7–8.4) — 3.2 (2.3–4.3) — — 1.8 (1.1–2.9) —

—

2.9 (2.2–3.8) 4.0 (3.2–4.9)

8.7 (3.9–19.3) — 4.8 (3.4–6.7) — — 3.2 (2.3–4.4) —

Point estimates of thrombosis-free survival for patients with various forms of heritable thrombophilia, or no known thrombophilia. Reproduced by permission of Wolters Kluwer Health from Battaglioli and Martinelli, 2007.39 Copyright©(2007) Lippincott Williams & Wilkins; www.lww.com

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progestins or controls with DRSP and CA respectively. CYP has been linked to an elevated risk for VTE in comparison with second generation products, and is no longer recommended for contraceptive use.38 FVL and Other Heritable Thrombophilias Not surprisingly, inherited disorders of coagulation are important risk factors for the development of OCP-related VTE. The FVL mutation, prothrombin 20210A-allele, and inherited deficiencies of antithrombin (AT), protein C, and protein S are most important.32 The APC resistance conferred by the FVL mutation appears to be additive with that caused by OCPs, resulting in a 20–30-fold increased risk of developing VTE compared with non-users of OCPs who lack the mutation. Patients with deficiencies of AT, protein S, and protein C likely carry a six- to eight-fold increased risk.28,59 Although the prothrombin gene mutation appears to be a mild risk factor for thrombosis in most young people, it appears to play a greater role in combination with OCPs, with a relative risk of 16 compared with non-carrier, nonOCP users.28 A recent cohort study showed that risk is further increased when more than one of the above defects is present in the same patient.60 Given the increased risk of VTE among women with thrombophilia who use OCPs, the screening of all women for common disorders prior to prescription has been suggested. With the extremely low prevalence of protein C and protein S in the population and the complexity of testing for these disorders, this is clearly not practical. The high prevalence of the FVL mutation in the general population, and the ease with which one can test for it, make screening more feasible. Estimates of the number of patients this would involve and the associated costs vary widely, anywhere from $5000 to $440 000 per prevented thrombus.61 Others have argued that regardless of cost, comprehensive screening would prevent only a very small number of fatal pulmonary emboli while potentially denying effective contraception to a large number of women.62 Some have advocated doing careful personal and family histories to identify a subgroup of potential OCP users for which screening might have increased utility. While some studies have shown a statistical association with VTE and family history,52 others have found that family history alone lacks sensitivity and would not improve the yield over general screening.63,64 In a cohort of 324 women considering starting OCP therapy, 34 (10%) were found to have a positive family history of VTE. Only three of these women were found to have an underlying thrombophilia. On the other hand, 19% of the entire cohort was found to have an underlying disorder, only three of whom would have been identified by a positive family history.64 Although some gynecologic practices today likely do screen all of their women beginning OCP treatment,65 at this time such an approach cannot be recommended and is not considered standard of care.

Others One study found that tobacco use of greater than ten cigarettes per day in OCP users further increased VTE risk,66 but this association has not been confirmed by others.38,52 It appears that obesity further increases the likelihood of clotting.52 Summary OCP use is associated with a general two- to three-fold increase in the risk of developing VTE when compared with non-use. Women who use third generation drugs containing gestodene or desogestrel as the progestin component have a slightly greater risk than women using second generation preparations. Women who appear to be at highest risk are those with an underlying inherited predisposition to thrombosis, particularly the FVL mutation and AT deficiency. Despite the marked increase in relative risk of thrombosis that occurs with OCP use in individuals with these conditions, the absolute risk of thrombosis remains low. Routine screening for heritable forms of thrombophilia before prescribing OCPs is not currently recommended. Family history of VTE has not yet proven to be reliable in defining a subgroup of patients to screen. Occurrence of an episode of VTE while taking OCPs should lead to cessation of therapy and no further use of these medications. If the event occurs in the setting of a known precipitant, such as recent surgery or immobilization, then the decision regarding further use should be individualized. At a minimum, the medications should be temporarily discontinued with any further surgeries. Some authorities recommend that patients who develop idiopathic VTE while using OCPs should be investigated for heritable thrombophilia, though it is not yet clear how this will affect therapy or if it should prompt family screening, and there is not universal agreement on this point. Obesity and smoking pose additional risk for VTE among users of OCPs. Fortunately, the absolute risk of developing VTE while on OCPs is low, allowing the majority of women to safely benefit from this convenient and effective form of contraception.

Hormone Replacement Therapy The Evidence The term hormone replacement therapy (HRT) refers to a variety of estrogen or combined estrogen/progestin formulations prescribed to millions of women for proven benefits of menopausal symptom relief and osteoporosis prevention. Given the clear association between OCP use and VTE, and the similarities in the constituent hormones of HRT and OCPs, concern for an increased risk of VTE among users of HRT was raised. Early studies on this topic were equivocal. In 1997 Douketis and colleagues40 reviewed the existing literature and concluded that an association might exist, but that further data were needed. This was based primarily

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on six case-controlled studies, all of which suffered from methodological problems, and only two of which revealed an increased risk of non-fatal VTE. Since the review by Douketis, several large-scale RCTs have evaluated thrombotic outcomes in HRT.67,68 Although important differences between studies exist, almost universally they point to an association between HRT and VTE. Additional observational data published since 1996 also supports this relationship.67 Two of the more notable RCTs have received particular attention, the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI).69,70 HERS was a randomized trial of the effect of HRT as a secondary prevention in women with heart disease. DVT and PE, recorded as secondary outcomes, occurred in 2.5% of the treatment group, as opposed to 0.9% of the placebo group, for a hazard ratio of 2.89 (95% CI 1.50–5.58). In addition, two of the PEs in the hormone group were fatal. In 2002, Hulley and colleagues reported follow-up data from the HERS study. The HERS II reported on noncardiovascular events occurring during the original 4 years of the randomized trial, as well as an additional 3 years of open label follow-up (93% of the women from the original study agreed to participate). Over the entire 7-year period, the intention-to treat hazard ratio (HR) for all venous thromboembolic events was 2.08 (95% CI 1.28–3.40). When adjusted for actual adherence to medication, the HR increased to 3.04 (95% CI 1.46–6.31). As in other studies, the authors found that the risk of a venous thromboembolic event was greatest early on in use. Although there was no statistical trend when analyzed by year of observation, the HR decreased after the second year of use, and the relative risk of any venous thromboembolic event during HERS was 2.66 (95% CI 1.41–5.04) as compared with 1.40 (95% CI 0.64–3.05) during HERS II.71 The WHI, published in July of 2002, was a large, prospective, double-blinded RCT examining the major health benefits and risks of HRT in more than 16 000 postmenopausal women.70 The study was terminated early because of an increase in invasive breast cancer cases and an overall global health index suggesting harms that exceeded benefits. Women taking HRT experienced a twofold greater rate of both DVT and PE, as well as all VTE events. These investigators also found a decreasing risk of VTE with time. Although few women with a prior VTE event were enrolled, those who were had an even greater risk of recurrent events (HR 4.90, [95% CI 0.58–41.06] as compared with an HR of 2.06 [95% CI 1.54–2.76] in those without a prior history). A subsequent nested, case-control examination of the same data revealed additional factors that affected outcomes.72 Again, similar to what was seen in studies of VTE and OCPs, risk appeared to increase with age, weight, and the presence of FVL. The hazard ratio for women aged 60–69 years old on HRT was 4.28 (95% CI, 2.38–7.72), and increased to 7.46 (95% CI, 4.32–14.38) for women

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70–79 years old as compared with those 50–59 years old taking placebo. Women with body mass index (BMI) 25–30 and 30 had HRs of 3.80 (95% CI, 2.08–6.94) and 5.61 (95% CI, 3.12–10.11) respectively, compared with women of normal weight taking placebo. Although multiple genetic variants were examined, only FVL was found to be associated with an elevated VTE risk, HR 6.69 (95% CI, 3.09– 14.49), in comparison to those without the mutation who were taking placebo. Recent meta-analyses and review articles have generally confirmed the results from the HERS and the WHI.67,68 In a meta-analysis published in 2008, data from both RCTs and observational studies were included. Combining seven case-control and one cohort study, the pooled estimate for VTE in oral estrogen users was 2.5 (95% CI, 1.9–3.4). The pooled estimate when considering only the nine RCTs published between 1995 and 2007 was 2.1 (95% CI, 1.4–3.1).67 Researchers have sought to clarify differences in risk based on route of administration, the type of estrogen being used, and whether or not the estrogen is given concomitantly with a progestin. In the 2008 meta-analysis mentioned above, the pooled HR for transdermal estrogen use was 1.2 (95% CI, 0.9–1.7), again suggesting less pro-coagulant effect with the estrogen patch.67 This has led to debate, with some authors advocating that post-menopausal women receiving HRT should receive this form of therapy, especially in the presence of additional thrombotic risk factors.53,73 It is important to note that the pooled ratio cited above comes from observational data, and no randomized trials for transdermal estrogen have been conducted. There are also different forms of estrogen used in HRT. Both the WHI and HERS used conjugated equine estrogen (CEE) for HRT, while esterified estrogen (EE) is also given for relief of menopause symptoms. A case control study performed in 2004 found no elevation in VTE risk with this form of estrogen.74 In a 2007 review, data from this case control study, the WEST trial (17-estradiol administered alone), and the different arms of HERS and the WHI were combined.68 There was no increase in VTE risk when estrogen that was not CEE was used alone (see Table 20.3). Again, it should be noted that no RCT data exist, and that this topic requires further study. Lastly, Hodis and Mack addressed the issue of concomitant progestin exposure, which is common practice in post-menopausal females with an intact uterus in order to reduce the risk for endometrial cancer. Comparing the same trials cited in the previous paragraph, they found an elevation in VTE risk with medroxy-progesterone acetate (MPA) regardless of the type of estrogen used.68 When comparing pooled odds ratios from observational studies alone, the authors of the 2008 meta-analysis did not find a statistically significant difference between use of estrogen plus a progestin versus estrogen use alone.67 In summary, the elevated risk for VTE with HRT has been well established with RCTs. The decision to use this

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l

Table 20.3  Absolute and relative risks of VTE, DVT, and PE in RCTs of hormone replacement therapy and other medications Absolute risk events per 10 000 women per year Trial and outcome

RR (95% CI)

Placebo

NR 1.60(0.91–2.86) 3.01 (1.15–9.27)

NR 8 23

1.44 (1.06–1.95) 1.37 (0.94–1.99) 1.49 (0.89–2.49)

25 16 8

NR NR NR

NR 20 13

2.06(1.57–2.70) 1.95(1.43–2.67) 2.13(1.45–3.11)

17 13 8

2.7 (1.4–5.0) 2.8 (1.3–6.0) 2.8 (0.9–8.7)

23 16 7

1.32(0.99–1.75) 1.47(1.06–2.06) 1.37(0.90–2.07)

22 15 10

0.8 (0.2–3.4) 0.5 (0.0–5.8) 1.0 (0.1–7.1)

44 22 22

a

NSABP VTE DVT PE RUTHa VTE DVT PE FIELDBb VTE DVTc PEd WHI-EPa VTE DVT PE HERSa VTE DVT PE WHI-Ea VTE DVT PE WESTa VTE DVT PE

No. of additional cases per 10 000 women per year of therapy

Therapy Tamoxifcn NR 13 69 Raloxifene 36 23 13 Fenofibrate NR 27 22 CEE  MPA 35 26 18 CEE  MPA 62 44 19 CEE alone 30 23 14 17-estradiol alone 32 11 21

— 5 46 11 7 5 — 7 9 18 13 10 39 28 12 8 8 4 12 11 1

RR, relative risk; NSABP, National Surgical Adjuvant Breast and Bowel Project; RUTH, Raloxifene Use for the Heart; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes; WHI-EP, Women’s Health Initiative estrogen  progestin trial; HERS, Heart and Estrogen/progestin Replacement Study; WHI-E, Women’s Health Initiative estrogen trial; WEST, Women’s Estrogen for Stroke Trial; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolus; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate; NR, not reported. Reproduced by permission of Wolters Kluwer Health from Hodis and Mack, 2007.68 Copyright © (2007) The North American Menopause Society a For references, see citations in the original publication. b Cohort comprised 37% (n  3 657) women. c Increased risk of deep vein thrombosis, P  0.074. d Increased risk of pulmonary embolism, P  0.022.

therapy must be based on individualized patient characteristics, with thrombotic risk taken into account. If HRT is given, transdermal administration could be considered for patients with genetic risk, older age, or obesity. Limitations in the available data do not allow us to assume risk is negligible when estrogen is used alone or in forms other than the CEE product. Biologic Explanation The effects of HRT on the coagulation system appear to be similar to those of OCPs, with evidence for increased

markers of coagulation, Factor VII levels, and APC resistance and a decrease in antithrombin levels.29 Investigators have compared the hemostatic variables during treatment with HRT and placebo.75 There were no differences between the groups at baseline, but after HRT initiation of HRT there was a highly significant decrease in the concentrations of all clotting inhibitors except free protein S, a decrease in Factor VIIa, and an increase in prothrombin fragments and D-dimer levels that was not seen in the placebo group. These changes were more pronounced in the women who eventually developed recurrent VTE, suggesting

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that some women are ‘high responders’ in terms of estrogen’s effects on coagulation.75 APC resistance appears to be increased in HRT users. The degree of change appears to vary based on the type of estrogen being used and the method of delivery.76,77 These data are in line with the elevated risk for VTE in patients with FVL who use HRT.77,78 Other Hormones Two selective estrogen receptor modulators are currently used with some frequency. Tamoxifen is used primarily for the prevention and adjuvant treatment of breast cancer, although there are reports of its use in fibroproliferative disorders, such as retroperitoneal fibrosis. Raloxifene, which has also been investigated in breast cancer prevention, has been approved for the prevention of osteoporosis as well.32 Although these agents have antiestrogenic properties, they are also partial agonists at selected receptors. In 2008, Adomaityte et al. published a meta-analysis summarizing the relationship between raloxifene for HRT and VTE occurrence. They found nine RCTs suitable for analysis, although it is important to note that VTE was not the primary outcome assessed for any study and that all were funded by the pharmaceutical industry. Pooled odds ratios showed a relative increase of 62% for overall VTE (OR 1.62, 95% CI 1.25–2.09), 54% for DVT (OR 1.54, 95% CI 1.13–2.11) and 91% for PE alone (OR 1.91 95% CI 1.05–3.47).79 Data from breast cancer prevention trials show similar results for tamoxifen. RCT data universally show roughly twice the risk for VTE in users as compared with placebo, and an increase in VTE risk with advanced age, tobacco use, and obesity.80,81 As with standard HRT, deciding when to use tamoxifen is complicated and requires an appropriate analysis of risks and benefits. Given that existing trials included younger women selected for breast cancer prevention, it is difficult to apply the tamoxifen data to older females concerned with osteoporosis, heart disease, and menopause symptoms.82,83 Table 20.3 shows absolute and relative risk for VTE in major RCTs of HRT and estrogen-reception modulation therapies.

Conclusion All forms of hormonal therapy commonly used by women today have been associated with an increased risk of VTE. The risk is highest in the first 6–12 months of therapy. There are subgroups of women who are at particularly high risk, such as those with underlying thrombophilias, a prior history of VTE, and those who are older, obese, or currently using tobacco. These risks must be kept in mind and balanced with the potential benefits when prescribing any of these medications.

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Pregnancy and VTE Pregnancy has long been recognized as a risk factor for thromboembolic disease. It is estimated that pregnancy confers a three- to five-fold increase in VTE risk compared to the non-pregnant state.84,85 PE is a leading cause of maternal death in the industrialized world.86–89 In the US’s Center for Disease Control and Prevention’s (CDC) Pregnancy-Related Mortality Surveillance System, from 1991 to 1999, PE was the most common cause of pregnancy-related mortality, accounting for 20% of maternal deaths,87 and it was the most common cause of maternal mortality in a review of maternal deaths in the United Kingdom.88 In a population-based cohort study using 30 years of data (from 1966 to 1995) the overall incidence of VTE was 200 per 100 000 woman-years. In contrast, incidence in non-pregnant women of childbearing age was 48 per 100 000 woman-years. Incidence of VTE was five times higher among postpartum women than pregnant women.90 An analysis of 21 year diagnostic trends for pregnancy-associated VTE using the National Hospital Discharge Survey data (an extensive database representing the entire population of the United States) demonstrated an upward trend in the rate of pregnancy-associated DVT from 1979 to 1999.91 Whether this increase was due to increased DVT prevalence versus increased disease recognition was unclear. Compared with non-pregnant women, women who were pregnant had a 2.33-fold greater rate of diagnosed DVT. Older age, being black, and delivery by cesarean section were associated with higher rates of DVT. A similarly designed study using data from the Nationwide Inpatient Sample from 2000–2001 showed increased risk of VTE among older women and black women.92 Pregnancy poses several risks for the development of venous thrombosis. Venous stasis occurs from hormonally induced increases in venous distensibility and capacity as well as vena caval compression by the enlarging gravid uterus.93–95 Hypercoagulability results from increased levels of fibrinogen and several clotting factors (II, VII, VIII, IX, X, XII) as well as decreased levels of inhibitors of coagulation such as protein S.96–98 Acquired activated protein C resistance99 and reduced fibrinolysis100 have both been described in normal pregnancy. This hypercoagulable state persists throughout pregnancy and for up to 6 weeks postpartum. Antepartum, VTE events are distributed evenly among the three trimesters.101,102 An additional factor responsible for increased VTE risk in the peripartum period is vascular injury resulting from childbirth and especially delivery by caesarean section. No doubt this contributes to the elevated risk of VTE seen in the postpartum period relative to antepartum.90,103 Caesarean section is associated with a further increase in the incidence of VTE compared with vaginal delivery.91,104 Other risk factors for VTE during pregnancy include obesity, smoking, maternal age, parity, prolonged bed rest, infection, prior history of VTE, and thrombophilia.91,92,105,106

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Thrombophilia and Pregnancy-related VTE Thrombophilia is an important additional risk factor for thrombosis during pregnancy, with some form of hereditary or acquired form of thrombophilia contributing to more than half of all maternal thromboembolic events.105,107 Moreover, thrombophilia is associated with increased prevalence of multiple adverse pregnancy outcomes – to include miscarriage, intra-uterine growth restriction, preeclampsia, abruption and intra-uterine death,105,108which are thought to result from thrombosis of the uteroplacental circulation.109 Several case-control and cohort studies have linked thrombotic complications of pregnancy to multiple thrombophilic disorders including FVL and prothrombin G20210A mutations, protein C and protein S deficiencies, antithrombin deficiency and antiphospholipid antibody syndrome.15,110–120 Early studies of VTE incidence in pregnant and post-partum women with thrombophilia demonstrated a high frequency of thromboembolic events, ranging from 47% in postpartum antithrombin-deficient women to 14% in postpartum women with protein S deficiency.116 However, these studies, of women who had already suffered a thrombotic event, were flawed by selection bias. Friederich and colleagues116 partially circumvented this obstacle by determining the frequency of VTE during pregnancy among asymptomatic female family members of patients with a history of VTE and known deficiency of antithrombin, protein C, or protein S. The risk for VTE was increased eight-fold in factor-deficient women compared with non-deficient women in this cohort; however, the absolute risk of VTE was only 4.1% (7 of 169 pregnancies), a much lower frequency than that previously reported. It likely still overestimates risk, given that the study population was drawn from symptomatic kindreds, who have higher event rates than individuals without a family history of thrombosis. In a prospective analysis of unselected women without a history of VTE with a singleton pregnancy who were FVL carriers, there were no thromboembolic events among 134 carriers.121 Meta-analysis of FVL mutation and pregnancy-related VTE showed that FVL mutation was associated with a 4.5-fold increased risk of VTE among women enrolled in cohort studies and an 8.6-fold increased risk among those enrolled in case-control studies.122 In a case-control study of 119 women with pregnancy-related VTE, Gerhardt and associates117 evaluated the prevalence of inherited thrombophilia. The odds ratio for VTE was 9.3 for women with FVL, and 15.2 for women with the G20210A prothrombin-gene mutation. The presence of combined FVL and G20210A prothrombin-gene mutation conveyed a markedly higher risk, as reflected by an odds ratio of 107. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (associated with hyperhomocysteinemia) was not associated with an elevated risk of VTE. In a similarly designed study of 119 women with a first episode of VTE during pregnancy or the puerperium114 the odds ratio for VTE was 9.1 among women with any thrombophilia,

10.6 for carriers of FVL, 2.9 for carriers of the G20210A prothrombin gene mutation and 13.1 for antithrombin, protein C or protein S deficiency (considered as a group). A recently published systematic review of thrombophilias in pregnancy found all heritable thrombophilias with the exception of the MTHFR C677T mutation to be significantly associated with an increased risk of VTE.123 The risk was highest for homozygous FVL with a relative risk of 34.4 compared with pregnant women without thrombophilia. Not surprisingly the presence of multiple thrombophilic defects such as combined heterozygous FVL and prothrombin gene mutation are associated with a higher risk of VTE than single defects.124,125 It is important to emphasize that while relative risks are increased, absolute risks for pregnancy-related thrombosis are, for most forms of thrombophilia, low; antithrombin deficiency, particularly the quantitative (Type I) deficiency, is the exception. Absolute risks have been calculated at approximately 1 in 500 for individuals heterozygous for FVL, 1 in 200 for those heterozygous for prothrombin 20210A, 1 in 100 for those with protein C deficiency, and 1 in 2.8 and 1 in 42 for those with quantitative and qualitative forms of antithrombin deficiency, respectively.117,126 While most investigations of the pregnancy-related risks associated with antiphospholipid antibodies have focused on the well-recognized association with pregnancy loss, increased risk of intra- or postpartum thromboembolism is another complication associated with such antibodies.118,127 The literature does not support general screening of pregnant women for thrombophilia and it cannot be recommended. Screening should be considered for pregnant women with a personal or family history of VTE as well as those women with pregnancy complications, such as recurrent miscarriage, intra-uterine growth restriction, severe preeclampsia, placental abruption, and intra-uterine fetal death that suggest an increased likelihood of thrombophilia.128

Clinical Presentation and Diagnosis of VTE in the Pregnant Patient The clinical manifestations of VTE and the appropriate diagnostic approach to suspected VTE do not differ substantially for the pregnant and non-pregnant patient. While comprehensive discussion of the manifestations and diagnostic evaluation of VTE are beyond the scope of this chapter, issues uniquely relevant to VTE in pregnancy are discussed below. The reader is directed to several reviews94,95,129–131 for discussion of issues common to the pregnant and non-pregnant patient. The typical signs and symptoms of VTE, leg swelling and pain, dyspnea, and chest pain, are common during pregnancy and are usually caused by processes other than VTE. Not surprisingly, the prevalence of VTE in clinically suspected cases is significantly lower in pregnant women when compared to the non-pregnant population. For example, in the non-pregnant population, one in four patients

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with suspected DVT will prove to have DVT132 and one in four patients with suspected PE will prove to have PE.133 In contrast, in a study of pregnant women presenting with clinically suspected DVT, the diagnosis was confirmed in less than 10% of cases.134 Likewise, the prevalence of PE was less than 5% in a study of 120 consecutive pregnant women presenting with suspected PE.135 DVT appears to occur more frequently in the antepartum period, whereas PE is diagnosed more commonly in the postpartum period, especially after cesarean delivery.136 Among pregnant women DVT disproportionately affects the left leg (approximately 90% cases, compared with 55% of cases in non-pregnant patients), possibly due to compression of the left iliac vein by the right iliac artery as they cross.137 The evaluation of patients with suspected VTE involves assessment of pretest clinical suspicion of VTE followed by objective confirmation with diagnostic tests. Diagnosis of VTE in pregnancy is problematic because of concerns about the performance of tests that expose the fetus to radiation, as well as by the paucity of studies offering evidence-based guidelines to direct the diagnostic work up of VTE during pregnancy. Consequently, the clinician is often left to apply diagnostic algorithms that have not been validated in the pregnant population. In spite of these obstacles, definitive diagnosis (or exclusion) of suspected VTE is imperative not only because missing the diagnosis of VTE can result in fatal PE, but because misdiagnosis subjects the pregnant patient and fetus to the risks of anticoagulation and influences future decisions regarding VTE prophylaxis. Fetal risks of radiological procedures used in the evaluation of VTE have been examined.138 Ionizing radiation carries risks of both teratogenicity and oncogenicity. However, cumulative radiation dose absorbed by the fetus in the work-up of VTE falls below 5 rad, a level that has not been associated with a significant risk of fetal injury in most studies.138 In fact, the combination of chest radiograph, ventilation-perfusion lung scan, and pulmonary angiogram on average exposes the fetus to less than 0.5 rad. Estimated mean fetal radiation dose with helical CT pulmonary angiography (CTA) is less than that with ventilation-perfusion (V/Q) lung scanning during all trimesters (3–131 Gy vs. 640–800 Gy, respectively).139,140 Interestingly, a UK survey of 161 healthcare professionals (predominantly radiologists and related specialists) showed that only slightly greater than half (58%) knew that V/Q scintigraphy exposes the fetus to a higher radiation dose than CTA, suggesting that healthcare professionals need further education regarding radiation dosemetry.140 The risk of childhood cancer after in utero radiation exposure is increased slightly; however, the absolute incidence of cancer in the first 10 years of life remains low at approximately 0.2 %.141 In a review of pregnancy outcomes of 120 women who underwent V/Q scanning during pregnancy there was no increase in adverse pregnancy events, and in follow-up of more than 90% of

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offspring after a mean age of 120 months, there was no increase in malignancies or developmental abnormalities.135 Magnetic resonance imaging (MRI) during pregnancy has been less well studied. MRI appears to be safe to the fetus in the short-term, but long-term risk is unknown.142 Diagnosis of suspected DVT during pregnancy should begin with compression ultrasonography (CUS). A negative ultrasound result coupled with non-high clinical suspicion probably requires no further evaluation, although some experts recommend serial CUS (over subsequent 7 days) to exclude propagation of calf vein thrombosis.94 If clinical suspicion is high or results are equivocal, then management options would include definitive diagnosis with venography or magnetic resonance venography (MRV) vs. serial CUS (with treatment withheld for serial negative CUS). While withholding anticoagulation in the setting of serially negative impedence plethysmography (IPG) was shown to be safe in 139 pregnant patients with suspected DVT and initial negative IPGs134 this study has not been repeated using CUS. However, a retrospective review of 162 pregnant or postpartum women who had CUS performed for suspicion of DVT showed that none of the available patients with negative studies108 had a VTE event within 3 months of the scan.143 If isolated iliac vein thrombosis is suspected (back pain with swelling of the entire leg), then MRV or venography are recommended as CUS is insensitive for the diagnosis of iliac vein thrombosis.94,95,144 Studies (in non-pregnant patients) have demonstrated the value of adding D-dimer measurement to other tests in diagnostic algorithms designed to minimize invasive testing for both DVT and PE.145–147 The merit of D-dimer testing rests with its high negative predictive value (up to 97 % as a stand-alone test). D-dimer levels increase as pregnancy progresses as well as in complicated pregnancies, which may limit its usefulness as a diagnostic tool in this population. In a prospective study of 50 women seeking to become pregnant, D-dimer concentrations (as measured by latex agglutination) increased with each trimester such that only 22% of women in the second trimester and none (of 23) in the third trimester had a normal D-dimer concentration (500 ng/ml).148 In contrast, D-dimer measured by red blood cell agglutination (SimpliRed assay) may be useful in evaluating VTE in pregnancy. In a prospective study of 149 consecutive pregnant women with suspected DVT, the SimpliRed assay was negative in 100, 76, and 49% of women with negative CUS in the first, second, and third trimesters, respectively.149 To date there are no management studies incorporating D-dimer measurement into the clinical work-up of pregnant patients with suspected VTE. V/Q scanning has long been the cornerstone of the diagnostic approach to the patient with suspected PE. Chan and associates published a retrospective review of V/Q scan findings and outcome in 120 consecutive pregnant women with suspected PE referred for lung scanning.135 The distribution of scan patterns was markedly different from that

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reported in the non-pregnant population. Of the 113 scans performed in women who were not on anticoagulation prior to testing, 73.5% were interpreted as normal, 24.8% as nondiagnostic, and 1.8% as high probability. In contrast, in the non-pregnant population, normal scans are found in 27–36% of patients, non-diagnostic scans in 47–59% of patients, and high probability scans in 8–14% of patients.132,149 The high percentage of normal scans probably reflects the relative youth of the pregnant population, with fewer co-morbid lung conditions present to cause abnormal perfusion scans. The lower percentage of high probability scans likely reflects the lower prevalence of PE in pregnant patients presenting with clinical suspicion of PE. Only two women underwent pulmonary angiography, and one was positive in a patient with a non-diagnostic scan. A total of 104 cases (80 with normal scans and 24 with non-diagnostic scans) were not anticoagulated, and no VTE events were reported over a mean 20.6 months of follow-up. The authors concluded that a normal lung scan safely excludes VTE, as is the case among nonpregnant patients. As a result of the ready availability of CT angiography as well as publication of high quality management studies demonstrating the safety of withholding anticoagulation in patients with a negative CTA, CTA has supplanted V/Q scanning as the imaging study of choice for evaluation of PE in the non-pregnant population.150,151 For similar reasons, CTA is also the preferred diagnostic test in the work-up of PE in pregnancy despite the lack of prospective studies in the pregnant population. The lower fetal radiation dose given with CTA is another advantage of CTA over V/Q scanning. Because DVT and PE are closely related disorders and their management usually identical, some experts recommend CUS (which avoids fetal radiation exposure) as the initial test in the evaluation of suspected PE during pregnancy.95 Patients with CUS indicative of DVT are treated, while those with negative CUS findings require further testing. Ultimately, patients with non-definitive CTA findings and those where discordance exists between pretest clinical probability of VTE and study result may require invasive pulmonary angiography.

Treatment of VTE During Pregnancy Selection of an anticoagulant during pregnancy necessarily includes consideration of potential adverse effects to the fetus. Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and the heparinoid danaparoid sodium do not cross the placenta and therefore do not cause fetal bleeding or birth defects, although bleeding at the uteroplacental junction can occur.127,152 Danaparoid is the recommended agent for treatment of heparin-induced thrombocytopenia (HIT) during pregnancy. The pentasaccharide fondiparinux does not cross the placenta, but minimal evidence exists regarding its safe use in pregnancy.153 Its use should be reserved for those pregnant women with

heparin-induced thrombocytopenia (HIT) who cannot receive danaparoid. The safe use of UFH and LMWH during pregnancy has been well established.154–156 In contrast, coumarin derivatives do cross the placenta and can cause an embryopathy as well as fetal hemorrhage.128 For these reasons, coumarins should be avoided during pregnancy. While efficacy has been demonstrated for adjusted dose UFH (given subcutaneously every 12 hours in doses adjusted to achieve a therapeutic activated partial thromboplastin time), LMWH is favored by most experts as the anticoagulant of choice during pregnancy,94,157 though the substantial cost of the medication may be a deterrent in some practice settings. Advantages of LMWH include fixed weight-based dosing without need for monitoring APTT, lower incidence of heparin-induced thrombocytopenia, and lower incidence of heparin-induced osteoporosis.128 Given the long duration of anticoagulant treatment (until at least 6 weeks after delivery), development of osteoporosis is a justifiable concern. Dahlman noted a 2.2% incidence of vertebral fracture in a study of 184 women receiving prophylactic dose UFH during pregnancy.158 In contrast, a recently published prospective study of 120 pregnant women randomized to thromboprophylaxis with either UFH or LMWH showed minimal clinically significant bone loss with either agent.159 As the pregnancy advances and weight is gained, the LMWH dose must be adjusted. This may be done by changing the dose according to the increased weight or by performing weekly anti-Factor Xa levels and targeting dose to a level of approximately 0.5–1.2 U/ml.128 Treatment of VTE should last at least 3–6 months. If the event occurred early in pregnancy, after conclusion of treatment, VTE prophylaxis with LMWH or UFH should be maintained until at least 6 weeks postpartum. After delivery, warfarin may be substituted for heparin. Neither warfarin nor the heparins are secreted in breast milk. To minimize risk of bleeding during delivery, it is recommended that UFH or LMWH be discontinued 24 h prior to elective induction of labor. If spontaneous labor occurs in a woman taking UFH or LMWH, protamine may be administered if bleeding risk is felt to be significant. However, clinical series have not shown significant bleeding complications with LMWH.156,160 To minimize risk of epidural hematoma, epidural and spinal anesthesia should be delayed at least 12 hours after a prophylactic dose of LMWH and 24 hours after a therapeutic dose of LMWH.161

Management of Pregnant Women with Thrombophilia or History of Prior VTE Individuals with a known thrombophilic condition or with a history of prior VTE are known to be at increased risk of pregnancy-related VTE. Given the effectiveness of prophylactic anticoagulant therapy in reducing the incidence VTE, the issue of prophylaxis of selected pregnant women is an important one. Decisions regarding VTE prophylaxis during

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pregnancy are complex and must take into account all factors that collectively influence the individual’s risk for VTE recurrence. Idiopathic VTE or VTE associated with a permanent clinical risk factor is associated with a higher rate of recurrence than VTE associated with transient risk factors, such as prior surgery.162 The type of thrombophilia also affects the risk of thrombosis. Antithrombin deficiency, homozygosity for FVL or prothrombin gene mutations, combinations of different thrombophilias, and antiphospholipid syndrome are all associated with greater thrombogenic potential than the lesser thrombophilias. Finally, other individual risk factors, such as morbid obesity, and situational risk factors, such as the need for prolonged bed rest, must be considered. LMWH is the preferred agent for VTE prophylaxis during pregnancy given its advantages over UFH. If UFH is selected for VTE prophylaxis it is important to note that higher doses than the standard 5000 U q12 h are recommended.153 Estimates of risk for thromboembolism during pregnancy among women with a history of VTE vary significantly, from zero to 13%.128 A prospective study by Brill-Edwards and associates added significantly to our knowledge about recurrence risk, and thus management, of pregnant women with a history of prior VTE.163 A series of 125 pregnant women with a single previous episode of VTE were prospectively evaluated for antepartum VTE recurrence. Women with known thrombophilia or VTE within 3 months of study enrollment were excluded. Antithrombotic treatment was withheld in all patients until 24 hrs after delivery at which time treatment with UFH and warfarin was started, with anticoagulation continued for 4–6 weeks postpartum. A total of 95 of the women were screened for thrombophilia after completion of the trial. Only 3 of 125 women (2.4%) had an antepartum recurrence of VTE. None of the 44 women without thrombophilia and whose previous thrombosis was associated with a temporary risk factor had a recurrence. In contrast, 3 of 51 women (5.9%) with abnormal thrombophilia testing and/or a previous episode of idiopathic thrombosis had a recurrence. In a retrospective cohort study of 159 women with at least one pregnancy after VTE (293 pregnancies in total), the probability of antepartum VTE in those not given prophylaxis was 6.2%, while that for postpartum VTE was 6.5%.164 The presence of thromobophilia or of temporary risk factors did not appear to influence the risk of recurrent VTE associated with pregnancy. Finally, in a similarly designed study of 88 women with a single episode of VTE and subsequent pregnancy (155 pregnancies), the rate of VTE in those not given prophylaxis was 5.8% during pregnancy and 8.3% postpartum.165 In this study presence of thrombophilia was not associated with an increased risk of recurrent VTE associated with pregnancy, whereas previous unprovoked VTE or VTE associated with prior pregnancy or estrogen use was associated with a higher risk of recurrent VTE. Based on the available data, the most recent American College of Chest Physician guidelines suggest

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antepartum clinical surveillance alone is adequate for pregnant women whose prior VTE occurred in the setting of a non-pregnancy or non-estrogen-related temporary risk factor. For all other pregnant women with a prior history of VTE, antepartum clinical surveillance or heparin administration is recommended according to designated risk category. For all women with a prior history of VTE some form of anticoagulant prophylaxis or treatment is recommended for at least 6 weeks postpartum.153 It remains unanswered whether women with asymptomatic thrombophilia require antepartum prophylaxis. While pregnancy-related risk of VTE has been examined (refer to the appropriate section above), there is a lack of trials evaluating the role of VTE prophylaxis in pregnant women with thrombophilia but no prior VTE. Accordingly, with the exception of antithrombin deficiency (where antepartum prophylaxis is recommended), the clinician is advised to perform an individualized risk assessment to determine whether antepartum prophylaxis is indicated.153 A strategy of risk assessment and heparin prophylaxis was prospectively evaluated in 810 women with the findings of a low incidence of symptomatic VTE (five events total for a rate of 0.6%) and few clinically important adverse events (1.1% rate of serious bleeding possibly related to dalteparin).166 As with pregnant women with prior history of VTE, it is also recommended that pregnant women with asymptomatic thrombophilia receive postpartum anticoagulants. Because of the association between adverse pregnancy outcomes and thrombophilia123,167 guidelines suggest that women with recurrent pregnancy loss, history of intra-­uterine death, severe or recurrent preeclampsia or intra-uterine growth retardation should be screened for underlying thrombophilia.168 Multiple studies have demonstrated improved fetal survival in pregnant women with antiphospholipid antibodies (APLAs) treated with aspirin and heparin,169–171 and it is recommended that patients with APLAs and a history of pregnancy complications be treated with antepartum aspirin plus either UFH (prophylactic or intermediate doses) or LMWH (prophylactic dose).128,153 The data evaluating antithrombotic therapy in women with inherited thrombophila (without APLAs) and recurrent pregnancy loss is less convincing.123 A Cochrane Review examining this question found only two studies that met inclusion criteria and concluded the evidence was too limited to recommend the use of anticoagulants in this setting.172 Accordingly, evidence-based guidelines are unable to make firm recommendations for the use of antithrombotic agents in women with inherited thrombophilia and adverse pregnancy outcomes.153

Summary Pregnancy poses several risks for the development of VTE. While the prevalence of VTE is low in pregnant women presenting with clinically suspected VTE, aggressive pursuit of a definitive diagnosis is essential to avoid the potentially

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fatal complication of PE, a leading cause of maternal death. Diagnosis will necessarily incorporate algorithms and technologies untested in the pregnant population, so that application of sound clinical judgment is essential. Studies highlighting the increased risk of both VTE and adverse outcomes of pregnancy in women with thrombophilia have multiplied, enhancing our understanding of the relation between thrombophilia and thrombotic risk during pregnancy. However, much remains to be learned, especially regarding selection of populations at greatest risk for VTE or recurrent pregnancy loss. Evidence-based guidelines, such as those published by the Eighth ACCP Consensus Conference on Antithrombotic Therapy, are presently our best resource for managing thrombotic complications of pregnancy.

Conclusion VTE causes substantial morbidity and mortality. The incidence of VTE does not appear to vary significantly by gender, as evidenced by a lack of consistency in the magnitude and even direction of effect of gender in a variety of epidemiological studies of varying design. Gender does appear to affect VTE recurrence, with men having a higher rate of recurrent VTE than women. The main influence of gender upon VTE is the relationship between female gender and several well-recognized clinical risk factors for VTE: OCP use, hormone replacement therapy, estrogen receptor modulator therapy, and pregnancy. The fact that women of ­ childbearing age do not appear to have a substantially greater incidence of VTE compared to age-matched men may reflect an offsetting of these female-specific risk factors by other risk factors that are more common in men, such as trauma. Hormonal therapies are associated with a two- to threefold increase in VTE incidence. Risk is higher with some formulations than others, during initial use, and among women who are obese, smoke, or have one of several forms of heritable thrombophilia. The pregnant state is associated with a three- to five-fold increase in VTE risk, and thromboembolism is a major cause of peripartum death. Heritable forms of thrombophilia are also important co-determinants of VTE risk in pregnancy. The mechanisms through which pregnancy and hormonal therapies increase VTE risk have not been definitively established, but hormonal effects upon levels of coagulation and anticoagulation factors likely play a role. Venous compression and venous injury also contribute to increased risk in the pregnant state. Approaches to diagnosis of VTE in the pregnant woman are largely the same as in the non-pregnant patient, but special treatment considerations do apply. Warfarin is embryopathic, particularly between the 6th and 12th weeks of pregnancy, and should be avoided in favor or heparin or low-molecular weight heparin when treatment of the pregnant woman is necessary. Guidelines have been published

to assist the clinician in decision-making about prophylaxis of pregnant women at increased risk of pregnancy-related or post-partum VTE.

References 1. White RH. The epidemiology of venous thromboembolism. Circulation 2003;107(23 Suppl 1):I4–I8. 2. Dalen JE. Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis. Chest 2002;122:1440–1456. 3. Hull R, Hirsh J. Long-term anticoagulant therapy in patients with venous thrombosis. Arch Intern Med 1983;143:2061–2063. 4. Meignan M, Rosso J, Gauthier H et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med 2000;160:159–164. 5. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151:933–938. 6. White RH, Dager WE, Zhou H, et al. Racial and gender differences in the incidence of recurrent venous thromboembolism. Thromb Haemost 2006;96:267–273. 7. Cushman M, Tsai A. Incidence rates, case fatality, and recurrence rates of deep vein thrombosis and pulmonary embolism: the longitudinal investigation of thromboembolism etiology (LITE) [Abstract]. Thromb Haemost 2001;86(Suppl 1). 8. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585–593. 9. Hansson PO, Welin L, Tibblin G, et al. Deep vein thrombosis and pulmonary embolism in the general population. ‘The Study of Men Born in 1913’. Arch Intern Med 1997;157:1665–1670. 10. Douketis JD, Kearon C, Bates S, et al. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998;279:458–462. 11. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med 2003;138:128–134. 12. Murin S, Marelich GP, Arroliga AC, et al. Hereditary thrombophilia and venous thromboembolism. Am J Respir Crit Care Med 1998(5 Pt 1):1369–1373. 13. Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 2000;15:145–151. 14. Ginsberg JS, Brill-Edwards P, Johnston M, et al. Relationship of antiphospholipid antibodies to pregnancy loss in patients with systemic lupus erythematosus: a cross-sectional study. Blood 1992;15(80):975–980. 15. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998;104:332–383. 16. Runchey SS, Folsom AR, Tsai MY, et al. Anticardiolipin antibodies as a risk factor for venous thromboembolism

C h a p t e r 2 0     Gender Issues in Venous Thromboembolism l

17. 18.

19.

20.

21.

22.

23.

24.

25.

26.

27. 28.

29.

30.

31.

32.

33. 34.

35.

in a population-based prospective study. Br J Haematol 2002;119:1005–1010. Lilienfeld DE. Decreasing mortality from pulmonary embolism in the United States, 1979–1996. Int J Epidemiol 2000;29:465–469. Tsai AW, Cushman M, Rosamond WD, et al. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002;162:1182–1189. White RH, Zhou H, Romano PS. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998;128:737–740. Klatsky AL, Armstrong MA, Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in AsianAmericans. Am J Cardiol 2000;85:1334–1337. Kniffin WD Jr., Baron JA, Barrett J, et al. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994;154:861–866. Rogers SO Jr, Kilaru RK, Hosokawa P, et al. Multivariable predictors of postoperative venous thromboembolic events after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg 2007;204:1211–1221. Fowkes FJ, Price JF, Fowkes FG. Incidence of diagnosed deep vein thrombosis in the general population: systematic review. Eur J Vasc Endovasc Surg 2003;25:1–5. McRae S, Tran H, Schulman S, et al. Effect of patient’s sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 2006;368:371–378. Cushman M, Glynn RJ, Goldhaber SZ, et al. Hormonal factors and risk of recurrent venous thrombosis: the prevention of recurrent venous thromboembolism trial. J Thromb Haemost 2006;4:2199–2203. Rosendaal FR, Van Hylckama Vlieg A, Tanis BC, et al. Estrogens, progestogens and thrombosis. J Thromb Haemost 2003;1:1371–1380. WHO. Cardiovascular Disease and Steroid Hormone Contra­ ception. Geneva: World Health Organization; 1998. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis, arteriosclerosis, thrombosis, and vascular biology. 2002:22:201–10. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Oral contraceptives, hormone replacement therapy and thrombosis. Thromb Haemost 2001;86:112–123. Westhoff CL. Oral contraceptives and thrombosis: an overview of study methods and recent results. Am J Obstet Gynecol 1998;179(3 Pt 2):S38–S42. Weiss G. Risk of venous thromboembolism with thirdgeneration oral contraceptives: a review. Am J Obstet Gynecol 1999;180(2 Pt 2):295–301. Waselenko JK, Nace MC, Alving B. Women with thrombophilia: assessing the risks for thrombosis with oral contraceptives or hormone replacement therapy. Semin Thromb Hemost 1998;24(Suppl 1):33–39. Walker AM. Newer oral contraceptives and the risk of venous thromboembolism. Contraception 1998;57:169–181. Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001;344:1527–1535. Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983–987.

239

36. Farmer RD, Lawrenson RA, Todd JC, et al. A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives. Br J Clin Pharmacol 2000;49:580–590. 37. Gomes MP, Deitcher SR. Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review. Arch Intern Med 2004;164:1965–1976. 38. Martinez F, Avecilla A. Combined hormonal contraception and venous thromboembolism. Eur J Contracept Reprod Health Care 2007;12:97–106. 39. Battaglioli T, Martinelli I. Hormone therapy and thromboembolic disease. Curr Opin Hematol 2007;14:488–493. 40. Douketis JD, Ginsberg JS, Holbrook A, et al. A reevaluation of the risk for venous thromboembolism with the use of oral contraceptives and hormone replacement therapy. Arch Intern Med 1997;157:1522–1530. 41. Koster T, Small RA, Rosendaal FR, et al. Oral contraceptives and venous thromboembolism: a quantitative discussion of the uncertainties. J Intern Med 1995;238:31–37. 42. Mammen EF. Oral contraceptive pills and hormonal replacement therapy and thromboembolic disease. Hematol/Oncol Clin North Am 2000:1045–1059, vii-viii. 43. Levi M, Middeldorp S, Buller HR. Oral contraceptives and hormonal replacement therapy cause an imbalance in coagulation and fibrinolysis which may explain the increased risk of venous thromboembolism. Cardiovasc Res 1999;41: 21–24. 44. Jespersen J. Plasma resistance to activated protein C: an important link between venous thromboembolism and combined oral contraceptives – a short review. Eur J Contracept Reprod Health Care 1996;1:3–11. 45. Rosing J, Middeldorp S, Curvers J, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999;354:2036–2040. 46. Kemmeren JM, Algra A, Meijers JC, et al. Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor V Leiden mutation: a randomized trial. Blood 2004;103:927–933. 47. Winkler UH. Hemostatic effects of third- and second-generation oral contraceptives: absence of a causal mechanism for a difference in risk of venous thromboembolism. Contraception 2000;62(2 Suppl):11S–20S, discussion 37S–38S. 48. Alhenc-Gelas M, Plu-Bureau G, Guillonneau S, et al. Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives. J Thromb Haemost 2004;2:1594–1600. 49. van Vliet HA, Frolich M, Christella M, et al. Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens. Human Reprod 2005;20:563–568. 50. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, et al. Hemostatic effects of oral contraceptives in women who developed deep-vein thrombosis while using oral contraceptives. Thromb Haemost 1998;80:382–387. 51. Petitti DB. Clinical practice. Combination estrogen-progestin oral contraceptives. N Engl J Med 2003;349:1443–1450. 52. Spannagl M, Heinemann L, DoMinh T, et al. Comparison of incidence/risk of venous thromboembolism (VTE) among

240

53.

54.

55.

56.

57.

58.

59.

60.

61. 62.

63.

64.

65.

66.

67.

68.

s e c t i o n 4     Pulmonology l

selected clinical and hereditary risk markers: a communitybased cohort study. Thromb J 2005;3:1–10. Schaudig K, Thomssen C. Hormonal therapy with patch or pill: how much does it matter?. Thromb Haemost 2007;97: 503–504. Lawrenson R, Farmer R. Venous thromboembolism and combined oral contraceptives: does the type of progestogen make a difference?. Contraception 2000;62(2 Suppl):21S–28S. Heinemann LA, Lewis MA, Assmann A, et al. Case-control studies on venous thromboembolism: bias due to design? A methodological study on venous thromboembolism and steroid hormone use. Contraception 2002;65:207–214. Bloemenkamp KW, Rosendaal FR, Buller HR, et al. Risk of venous thrombosis with use of current low-dose oral contraceptives is not explained by diagnostic suspicion and referral bias. Arch Intern Med 1999;159:65–70. Hennessy S, Berlin JA, Kinman JL, et al. Risk of venous thromboembolism from oral contraceptives containing gestodene and desogestrel versus levonorgestrel: a meta-analysis and formal sensitivity analysis. Contraception 2001;64:125–133. Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis.. BMJ 2001;323:131–134. Pabinger I, Schneider B. Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natural Inhibitors. Thromb Haemost 1994;71:548–552. van Vlijmen EF, Brouwer JL, Veeger NJ, et al. Oral contraceptives and the absolute risk of venous thromboembolism in women with single or multiple thrombophilic defects: results from a retrospective family cohort study. Arch Intern Med 2007;167:282–289. Aznar J, Gilabert J. Oral contraceptive users and screening of factor V Leiden. Thromb Haemost 1999;81:845–846. Vandenbroucke JP, van der Meer FJ, Helmerhorst FM, et al. Factor V Leiden: should we screen oral contraceptive users and pregnant women?. BMJ 1996;313:1127–1130. Aznar J, Mira Y, Vaya A, et al. Is family history sufficient to identify women with risk of venous thromboembolism before commencing the contraceptive pill? Clin Appl Thromb Hemost 2002;8:139–141. Cosmi B, Legnani C, Bernardi F, et al. Value of family history in identifying women at risk of venous thromboembolism during oral contraception: observational study. BMJ 2001; 322:1024–1025. Girolami A, Spiezia L, Girolami B, et al. Tentative guidelines and practical suggestions to avoid venous thromboembolism during oral contraceptive therapy. Clin Appl Thromb Hemost 2002;8:97–102. Nightingale AL, Lawrenson RA, Simpson EL, et al. The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives. Eur J Contracept Reprod Health Care 2000;5:265–274. Canonico M, Plu-Bureau G, Lowe GD, et al. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008;336:1227–1231. Hodis HN, Mack WJ. Postmenopausal hormone therapy in clinical perspective. Menopause 2007;14:944–957.

69. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–613. 70. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. 71. Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58–66. 72. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004:1573–1580. 73. Roberts H. Type of hormone replacement therapy and risk of venous thromboembolism. BMJ 2008;336:1203–1204. 74. Smith NL, Heckbert SR, Lemaitre RN, et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA 2004;292:1581–1587. 75. Hoibraaten E, Qvigstad E, Andersen TO, et al. The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism – results from a randomized, double-blind, clinical trial. Thromb Haemost 2001;85:775–781. 76. Smith NL, Heckbert SR, Doggen CJ, et al. The differential association of conjugated equine estrogen and esterified estrogen with activated protein C resistance in postmenopausal women. J Thromb Haemost 2006;4:1701–1706. 77. Nicolaides AN, Breddin HK, Carpenter P, et al. Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence. Int Angiol 2005;24:1–26. 78. Smith NL, Heckbert SR, Lemaitre RN, et al. Conjugated equine estrogen, esterified estrogen, prothrombotic variants, and the risk of venous thrombosis in postmenopausal women. Arterioscler Thromb Vasc Biol 2006;26:2807–2812. 79. Adomaityte J, Farooq M, Qayyum R. Effect of raloxifene therapy on venous thromboembolism in postmenopausal women. A meta-analysis. Thromb Haemost 2008;99:338–342. 80. Decensi A, Maisonneuve P, Rotmensz N, et al. Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation 2005;111:650–656. 81. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen prophylaxis for breast cancer – 96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 2007;99:272–282. 82. Veronesi U, Maisonneuve P, Decensi A. Tamoxifen: an enduring star. J Natl Cancer Inst 2007;21(99):258–260. 83. Goldhaber SZ. Tamoxifen: preventing breast cancer and placing the risk of deep vein thrombosis in perspective. Circulation 2005;111:539–541. 84. Treffers PE, Huidekoper BL, Weenink GH, et al. Epidemiological observations of thrombo-embolic disease during pregnancy and in the puerperium, in 56,022 women. Int J Gynaecol Obstet 1983;21:327–331. 85. Heit JA, Silverstein MD, Mohr DN, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001;86:452–463.

C h a p t e r 2 0     Gender Issues in Venous Thromboembolism l

  86. Atrash HK, Rowley D, Hogue CJ. Maternal and perinatal mortality. Curr Opin Obstet Gynecol 1992;4:61–71.   87. Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance – United States, 1991–1999. MMWR Surveill Summ 2003;52:1–8.   88. de Swiet M. Maternal mortality: confidential enquiries into maternal deaths in the United Kingdom. Am J Obstet Gynecol 2000;182:760–766.   89. Berg CJ, Atrash HK, Koonin LM, et al. Pregnancy-related mortality in the United States, 1987–1990. Obstet Gynecol 1996;88:161–167.   90. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697–706.   91. Stein PD, Hull RD, Kayali F, et al. Venous thromboembolism in pregnancy: 21-year trends. Am J Med 2004;117: 121–125.   92. James AH, Jamison MG, Brancazio LR, et al. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006;194:1311–1315.   93. Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Engl J Med 1996;335:108–114.   94. Bates SM, Ginsberg JS. How we manage venous thromboembolism during pregnancy. Blood 2002;100:3470–3478.   95. Chan WS, Ginsberg JS. Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy. Thromb Res 2002;107:85–91.   96. Stirling Y, Woolf L, North WR, et al. Haemostasis in normal pregnancy. Thromb Haemost 1984;52:176–182.   97. Woodhams BJ, Candotti G, Shaw R, et al. Changes in coagulation and fibrinolysis during pregnancy: evidence of activation of coagulation preceding spontaneous abortion. Thromb Res 1989;55:99–107.   98. Faught W, Garner P, Jones G, et al. Changes in protein C and protein S levels in normal pregnancy. Am J Obstet Gynecol 1995;172:147–150.   99. Clark P, Brennand J, Conkie JA, et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998;79:1166–1170. 100. Wright JG, Cooper P, Astedt B, et al. Fibrinolysis during normal human pregnancy: complex inter-relationships between plasma levels of tissue plasminogen activator and inhibitors and the euglobulin clot lysis time. Br J Haematol 1988;69:253–258. 101. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999;54:265–271. 102. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol 2005;193:216–219. 103. Simpson EL, Lawrenson RA, Nightingale AL, et al. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. Br J Obstet Gynaecol 2001;108:56–60. 104. Andres RL, Miles A. Venous thromboembolism and pregnancy. Obstet Gynecol Clin North Am 2001;28:613–630. 105. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999;353:1258–1265.

241

106. Larsen TB, Sorensen HT, Gislum M, et al. Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study. Thromb Res 2007;120:505–509. 107. Brenner BR, Nowak-Gottl U, Kosch A, et al. Diagnostic studies for thrombophilia in women on hormonal therapy and during pregnancy, and in children. Arch Pathol Lab Med 2002;126:1296–1303. 108. Sibai BM. Thrombophilias and adverse outcomes of pregnancy – what should a clinician do? N Engl J Med 1999;340:50–52. 109. Many A, Schreiber L, Rosner S, et al. Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia. Obstet Gynecol 2001;98:1041–1044. 110. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348:913–916. 111. Ridker PM, Miletich JP, Buring JE, et al. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998;128:1000–1003. 112. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;7(340):9–13. 113. Martinelli I, Taioli E, Cetin I, et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000;343:1015–1018. 114. Martinelli I, De Stefano V, Taioli E, et al. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium. Thromb Haemost 2002;87:791–795. 115. Many A, Elad R, Yaron Y, et al. Third-trimester unexplained intrauterine fetal death is associated with inherited thrombophilia. Obstet Gynecol 2002;99:684–687. 116. Friederich PW, Sanson BJ, Simioni P, et al. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis. Ann Intern Med 1996;125:955–960. 117. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–380. 118. Ogunyemi D, Cuellar F, Ku W, et al. Association between inherited thrombophilias, antiphospholipid antibodies, and lipoprotein A levels and venous thromboembolism in pregnancy. Am J Perinatol 2003;20:17–24. 119. Lockwood CJ. Inherited thrombophilias in pregnant patients: detection and treatment paradigm. Obstet Gynecol 2002;99:333–341. 120. Saade GR, McLintock C. Inherited thrombophilia and stillbirth. Semin Perinatol 2002;26:51–69. 121. Dizon-Townson D, Miller C, Sibai B, et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol 2005;106:517–524. 122. Biron-Andreani C, Schved JF, Daures JP. Factor V Leiden mutation and pregnancy-related venous thromboembolism: what is the exact risk? Results from a meta-analysis. Thromb Haemost 2006;96:14–18. 123. Robertson L, Wu O, Langhorne P, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006;132:171–196. 124. Samama MM, Rached RA, Horellou MH, et al. Pregnancyassociated venous thromboembolism (VTE) in combined

242

125.

126.

127.

128. 129. 130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

s e c t i o n 4     Pulmonology l

heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone. Br J Haematol 2003;123:327–334. Folkeringa N, Brouwer JL, Korteweg FJ, et al. High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects. Br J Haematol 2007;138: 110–116. McColl MD, Ellison J, Reid F, et al. Prothrombin 20210 G→A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy. BJOG 2000;107(4):565–569. Long AA, Ginsberg JS, Brill-Edwards P, et al. The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus: a cross-sectional study. Thromb Haemost 1991;66:520–524. Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001;119(1 Suppl):122S–131S. Hyers TM. Venous thromboembolism. Am J Respir Crit Care Med 1999;159:1–14. Tapson VF, Carroll BA, Davidson BL, et al. The diagnostic approach to acute venous thromboembolism. Clinical practice guideline. Am Thorac Soc Am J Respir Crit Care Med 1999;160:1043–1066. Greer IA. The acute management of venous thromboembolism in pregnancy. Curr Opin Obstet Gynecol 2001;13: 569–575. Wells PS, Hirsh J, Anderson DR, et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet 1995;345: 1326–1330. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263:2753–2759. Hull RD, Raskob GE, Carter CJ. Serial impedance plethysmography in pregnant patients with clinically suspected deep-vein thrombosis. Clinical validity of negative findings. Ann Intern Med 1990;12:663–667. Chan WS, Ray JG, Murray S, et al. Suspected pulmonary embolism in pregnancy: clinical presentation, results of lung scanning, and subsequent maternal and pediatric outcomes. Arch Intern Med 2002;162:1170–1175. Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999;94:730–734. Ginsberg JS, Brill-Edwards P, Burrows RF, et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost 1992;67:519–520. Ginsberg JS, Hirsh J, Rainbow AJ, et al. Risks to the fetus of radiologic procedures used in the diagnosis of maternal venous thromboembolic disease. Thromb Haemost 1989;61:189–196. Winer-Muram HT, Boone JM, Brown HL, et al. Pulmonary embolism in pregnant patients: fetal radiation dose with helical CT. Radiology 2002:487–492. Groves M, Yates SJ, Win T, et al. CT pulmonary angiography versus ventilation-perfusion scintigraphy in pregnancy: implications from a UK survey of doctors’ knowledge of radiation exposure. Radiology 2006;240:765–770. Doll R, Wakeford R. Risk of childhood cancer from fetal irradiation. Br J Radiol 1997;70:130–139.

142. Kanal E. Pregnancy and the safety of magnetic resonance imaging. Magn Reson Imaging Clin North Am 1994; 2:309–317. 143. Le Gal G, Prins AM, Righini M, et al. Diagnostic value of a negative single complete compression ultrasound of the lower limbs to exclude the diagnosis of deep venous thrombosis in pregnant or postpartum women: a retrospective hospital-based study. Thromb Res 2006;118:691–697. 144. Fraser DG, Moody AR, Morgan PS, et al. Diagnosis of lower-limb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging. Ann Intern Med 2002;136:89–98. 145. Perrier A, Desmarais S, Miron MJ, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999;353:190–195. 146. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med 2001;135:98–107. 147. Perrier A, Bounameaux H. Cost-effective diagnosis of deep vein thrombosis and pulmonary embolism. Thromb Haemost 2001;86:475–487. 148. Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005;51:825–829. 149. Chan WS, Chunilal S, Lee A, et al. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med 2007;147:165–170. 150. Hull RD, Raskob GE, Coates G, et al. A new noninvasive management strategy for patients with suspected pulmonary embolism. Arch Intern Med 1989:2549–2555. 151. Moores LK, Jackson WL Jr., Shorr AF, et al. Meta-analysis: outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography. Ann Intern Med 2004;141:866–874. 152. van Belle A, Buller HR, Huisman MV, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006;295:172–179. 153. Bates SM, Greer IA, Pabinger I, et al. Venous Thromboembolism, Thrombophilia, Antithrombotic Therapy, and Pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 Suppl):844S–886S. 154. Ginsberg JS, Kowalchuk G, Hirsh J, et al. Heparin therapy during pregnancy. Risks to the fetus and mother. Arch Intern Med 1989;149:2233–2236. 155. Sanson BJ, Lensing AW, Prins MH, et al. Safety of lowmolecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999;81:668–672. 156. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401–407. 157. Adam JD, Michael JP, Serdar HU, et al. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol 2007;197:457, e1–e21.

C h a p t e r 2 0     Gender Issues in Venous Thromboembolism l

158. Dahlman TC. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 1993;168:1265–1270. 159. Casele H, Haney EI, James A, et al. Bone density changes in women who receive thromboprophylaxis in pregnancy. Am J Obstet Gynecol 2006;195:1109–1113. 160. Dulitzki M, Pauzner R, Langevitz P, et al. Low-molecular-weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies. Obstet Gynecol 1996;87:380–383. 161. Horlocker TT, Wedel DJ. Spinal and epidural blockade and perioperative low molecular weight heparin: smooth sailing on the Titanic. Anesth Analg 1998;86:1153–1156. 162. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;25(340):901–907. 163. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this pregnancy study group. N Engl J Med 2000;343:1439–1444. 164. Pabinger I, Grafenhofer H, Kaider A, et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005;3:949–954. 165. De Stefano V, Martinelli I, Rossi E, et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 2006;135:386–391.

243

166. Bauersachs RM, Dudenhausen J, Faridi A, et al. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007;98:1237–1245. 167. Kist WJ, Janssen NG, Kalk JJ, et al. Thrombophilias and adverse pregnancy outcome – a confounded problem! Thromb Haemost 2008;99:77–85. 168. Duhl AJ, Paidas MJ, Ural SH, et al. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol 2007;197:457, e1-21. 169. Rai R, Cohen H, Dave M, et al. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997;314:253–257. 170. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996;174:1584–1589. 171. Empson M, Lassere M, Craig J, et al. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database of Syst Rev (Online) 2005(2), CD002859. 172. Di Nisio M, Peters L, Middeldorp S. Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome. Cochrane Database of Syst Rev (Online) 2005(2), CD004734.

C hapter

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Sleep in Women: Gender Differences in Health and Disease Shirin Shafazand Assistant Professor of Medicine, University of Miami Miller School of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Miami, FL, USA

Introduction

getting a good night’s sleep only a few nights a month or less. Not surprisingly, given their social and/or familial responsibilities, working mothers (72%) and single working women (68%) were more likely to experience sleep problems like insomnia.14 These sleep disturbances are not without consequences; in the NSF survey, women who experienced daytime sleepiness were more likely to report high stress (80%), drive drowsy at least once per month (27%), spend less time with friends and family (39%), be too tired for sex (33%), and be late for work (20%). Recently, studies recognize that men and women experience sleep and sleep disorders differently. They differ in the prevalence of certain sleep disorders and may have varying presentations and responses to therapies. This chapter serves to both review the existing literature on gender differences in sleep and highlight the considerable gaps in knowledge.

Sleep occupies one-third of our lives and has considerable impact on our physical and emotional health. A significant body of literature points to the role sleep quality and duration plays in normal metabolism, immune function, mood, and cognitive functioning. Sleep-disordered breathing (SDB), in particular, has been associated with increased risk of stroke, hypertension, atrial fibrillation, coronary artery disease, and worsening diabetes.1–12 The majority of our knowledge about sleep disorders comes from studies where subjects were predominately or exclusively male. Yet in large epidemiological surveys, women consistently report more sleep problems than men.13–15 This may reflect a true genetic predisposition or more likely is a reflection of the influence of social and psychological parameters on baseline biological differences. A 2007 Sleep in America poll conducted by the National Sleep Foundation (NSF) surveying 1003 American women aged 18–64, found that 60% of women only get a good night’s sleep a few nights per week or less; 67% experienced sleep problems at least a few nights each week, with 46% experiencing sleep problems every night.14 Studies of sleep in women, whether in health or disease, are affected by the distinct hormonal changes that occur throughout a woman’s life cycle, including puberty, menses, pregnancy, and menopause. Differences exist not only between the sexes but within cohorts of women as they transition through these biologically determined milestones. Additionally, socioeconomic status, workplace, and familial roles influence observed gender differences. In the NSF 2007 poll, 30% of pregnant women and 42% of post-partum women reported rarely or never getting a good night’s sleep, compared to 15% among all women; 25% of perimenopausal women and 30% of postmenopausal women reported Principles of Gender-Specific Medicine

Normal sleep and gender differences Sleep is a reversible behavioral state of perpetual disengagement from and unresponsiveness to the environment.16 However, sleep is not a passive state. During sleep the brain undergoes cyclic changes between the two main sleep states, rapid eye movement (REM) and non-REM sleep comprised of three stages (N1, N2, N3). Stage N3, slow wave sleep (SWS), is regarded as the deeper more refreshing part of sleep, while REM may play a role in learning and memory consolidation. The duration, architecture, and timing of sleep in humans changes with age. Older adults have decreased sleep efficiency (the amount of sleep relative to the amount 244

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of time spent in bed) with more frequent arousals regardless of the presence of sleep disorders. The circadian timing of sleep–wake cycles also change, as older adults sleep earlier in the evening and wake up earlier in the morning.17 There is a reduction in SWS with aging and women preserve SWS better than men.18 Despite subjective reports of inadequate sleep time and insomnia throughout the life cycle,19 women, especially young adults, have better objective sleep quality (higher sleep efficiency, shorter time to sleep onset) compared with age-matched men.20 This suggests that women may be more susceptible to clinical symptoms of sleep deprivation or they are more likely to report these symptoms.

Gender-specific conditions that impact sleep Gender differences in sleep are influenced by specific hormonal and physical changes in women that may increase the risk for sleep disturbances.

Menstrual Cycle The menstrual cycle of healthy women is characterized by cyclic changes in the production of gondal steroids (estradiol and progesterone), pituitary hormones (LH, FSH, prolactin, growth hormone), melatonin, cortisol, and fluctuations in body temperature. Sleep studies across the menstrual cycle have been21 limited by small sample sizes, heterogenous cycle lengths, lack of ovulation timing controls, and oral contraceptive use. An additional confounding variable is the use of a sleep lab environment for studies instead of a home environment. Nevertheless, data from survey studies suggest that subjective sleep quality is worse (longer initial sleep latency, lower sleep efficiency) during the premenstrual week and the first few days of menstruation (luteal phase).17,21 The NSF 2007 poll found that 25–35% of menstruating women complained of sleep disturbances during menses or immediately before menses.14 Despite subjective reports of poor sleep quality around the time of menstruation, objective overnight measures of sleep have yielded mixed results. It appears in healthy young women with no menstrual complaints there is little evidence of major sleep architecture differences across the menstrual cycle (SWS, REM sleep, sleep latency).22,23 The occurrence of higher frequency EEG waves, sleep spindles, may increase slightly during the luteal phase but the clinical significance of this change is uncertain.22,24 Women with primary dysmenorrhea report more subjective fatigue and worse sleep quality than controls. One report correlated these subjective findings of sleep disruptions

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with overnight sleep studies showing lower sleep efficiency and less REM.25 Women with premenstrual mood disorders including premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) report insomnia, hypersomnia, fatigue, or disturbing dreams during the luteal phase.17,26,27 Few polysomnography (PSG) studies address these disorders objectively and are limited by small sample size and lack of standard definitions for PMS or PMDD, thus complicating conclusions and generalizations. In one of the larger studies of sleep and PMS, Parry et al.28 report on 14 women with PMDD and 9 normal controls. No major differences in PSG-measured sleep variables were noted. Based on available research, laboratory studies have found no evidence of increased sleep disturbance in women who are symptomatic during their luteal phase compared with their own asymptomatic follicular phase. Due to the limited nature of these studies much is yet unknown about PMS/PMDD and sleep.

Pregnancy Sleep during pregnancy is affected by hormonal changes and disrupted by the physical changes of pregnancy including abdominal distention, fetal movement, increased urinary frequency, back and joint pain, heartburn, leg cramps, and nasal congestion.29 PSG reveals decreased SWS, more frequent awakenings, increased total sleep time and time spent awake after sleep onset.30,31 While REM may be decreased or remain stable, changes in sleep may occur as early as 11–12 weeks gestation and can last up to 3 months post partum.32,33 The incidence of specific sleep disorders including sleepdisordered breathing (SDB) and restless legs syndrome (RLS) may also increase during pregnancy. SDB may range from mild nasal congestion and snoring to severe obstructive sleep apnea OSA. Guilleminault et al. found a significant increase in chronic loud snoring reported by a bed partner, from 4% prior to pregnancy to 12% at 6 months’ gestation.34 OSA during pregnancy has been associated with intra-uterine fetal growth retardation, impaired placental function, and pregnancy-induced hypertension.35,36 Nasal continuous positive airway pressure (CPAP) helps reduce sleep-induced hypertension and improve OSA symptoms with no known risks of therapy.37,38 RLS is different from the leg cramps that can increase in frequency during pregnancy. The former is characterized by an unpleasant sensation. Women with RLS complain of burning, creeping, and a sensation of insects crawling up their legs that prevents them from falling asleep due to an uncontrollable urge to get up and move the legs to relieve the symptoms. In a longitudinal study of 30 women, the incidence of RLS increased from 0% pre-pregnancy, peaked to 23% by the third trimester, and decreased to 3% post partum.39 The symptoms can be very severe and discourage some women from future

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pregnancies.17 RLS in pregnancy is associated with iron deficiency and folate deficiency anemias.39 Iron and folate supplements to treat anemia, prenatal vitamins, and avoiding caffeine during pregnancy may help prevent RLS.21 More studies are needed, however, to determine the best management strategies for relieving RLS in pregnant women. Dopaminergic therapy, while effective in the general population with RLS, is not approved for use in pregnancy.

Menopause Fluctuations in hormonal levels associated with physical and psychological changes affect sleep pattern during menopause. Epidemiological studies have found that 40–57% of women complain about difficulty falling asleep or maintaining sleep during the menopause transition.40,41 Hot flashes, mood disorders (anxiety and depression), and an increase in the incidence of primary sleep disorders (OSA and RLS) contribute to insomnia. Despite considerable complaints of insomnia, in the absence of a diagnosis of a primary sleep disorder, PSG may fail to demonstrate clearly significant changes. Brief increases in cortical arousals have been noted in symptomatic menopausal women but the timing of these events to temperature, hormonal or symptom fluctuations is not well defined.17 Postmenopausal women had longer total sleep time, increased SWS, and better sleep quality than their premenopausal states.41 Hormone replacement therapy (HRT) may alleviate many of the symptoms leading to sleep disruption during menopause. Several studies show that estrogens reduce complaints of hot flashes and sleep problems.42,43 There can be a decrease in the PSG intensity but not frequency of cortical arousals.21 In a randomized controlled trial, health-related quality of life, physical and psychological symptoms of menopause were measured in 3721 postmenopausal women receiving a combination of estrogen and progesterone or placebo for one year. After one year small but significant improvements were observed in three of nine components of the women’s health questionnaire for those taking combined HRT: vasomotor symptoms (p 0.001), sexual functioning (p 0.001), and sleep problems (p 0.001).44 Additionally, observational studies have shown that the prevalence of OSA in women on HRT is decreased compared with women not receiving HRT.41,45 Although HRT may offer relief of menopausal sleep symptoms, its use should be carefully weighed against the associated risk of increased cardiac events, venous thromboembolism, and breast cancer.

Gender differences in sleep disorders Sleep Disordered Breathing SDB is increasingly recognized as an important cause of morbidity and mortality. Several well-designed cohort

studies have shown that OSA is independently associated with an increased likelihood of hypertension, stroke, heart failure, cardiac arrhythmias, worsening diabetes, daytime sleepiness, motor vehicle accidents, and decreased quality of life.1–12 Historically, OSA was described as a disease of men with most clinical (sleep lab) studies reporting the male:female prevalence ratio to range from 10 to 60:1,46 while more recent studies report a prevalence ratio of 2 to 4:1.47–50 In 1993, the prevalence of symptomatic undiagnosed OSA was reported as 4% in men and 2% in middle aged women.51 One reason for this long-standing underestimation of prevalence and the discrepancy noted between general population surveys and clinic reports may be that men and women differ in their symptomatic presentations. Typical OSA symptoms include daytime sleepiness, snoring, and witnessed apneas. Women with OSA are more likely to present with atypical initial symptoms of insomnia, fatigue, clinical depression or hypothyroidism at the time of diagnosis.52 They are less likely to have apneas witnessed by bed partners and more likely to report restless legs, nightmares, palpitations, and hallucinations.52–54 Prior to the OSA diagnosis, female patients were two times more likely to be treated for depression than male patients.55 Physicians are less likely to recognize OSA in women because of their atypical presentation and therefore make fewer sleep study referrals, underdiagnose OSA, and pursue alternative diagnoses. Health care utilization in the years prior to OSA diagnosis differs between the sexes. In one study, the 5-year total health care costs were 1.3 times higher in women compared to men with OSA, after correcting for BMI and AHI (p  0.0001).56 Men and women who were eventually diagnosed with OSA had undergone significantly more consultations with specialists compared to controls. Compared with men with OSA, women with OSA had more visits to a variety of specialists including otolaryngologists, ophthalmologists, pulmonologists, and gastroenterologists. Women with OSA reported significantly lower perceived health status and were almost three times more likely to be prescribed anxiolytics, antidepressants, asthma medication, and anti­ psychotics in the 5 years prior to OSA diagnosis. PSG findings of OSA also differ between the two sexes. Compared with men, women with OSA are more likely to have partial (hypopneas) than complete obstructions (apneas), and the respiratory disturbances have shorter mean and maximum durations.57 The average apnea hypopnea index (AHI, one measure of OSA severity, representing the number of apneas and hypopneas observed per hour of sleep) of women with OSA is lower than men.48,57 Women are less likely to have positional OSA (increased respiratory events in supine position) and have a higher body mass index (BMI) at any given AHI.58,59 Women are more likely to have REM-related OSA.60,61 Upper airway resistance syndrome (UARS) with its attendant respiratory-related arousals, may be a milder variant of OSA and is more frequently seen in

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women. Guilleminault et al.62 studied 334 women and 100 men with UARS. Most women with UARS had an AHI 5 and were not obese. The most common presenting symptom was tiredness or fatigue in 83% of cases and sleepiness in only 13% of cases, insomnia was a frequent complaint; 43% of premenopausal women studied had amenorrhea or dysmenorrhea with 41% of patients reporting depression. Once again, atypical symptom presentation may delay accurate diagnosis. The differences in anatomy of the upper airway and ventilatory drive may play a role in the gender-related differences noted in OSA. In the normal state, men have larger soft palates, a larger tongue size, and a longer pharynx.63–65 Neck soft tissue volume is also greater in men than in women.65 Men have more narrowing of the oropharyngeal space in the supine position compared with women,63,64,66 despite a greater upper airway diameter when awake and upright. When compared to normal subjects, male OSA patients are known to have certain craniofacial abnormalities that predispose them to increased airway narrowing and collapse during sleep. Small posteriorly placed mandible (retrognathia), an enlarged tongue, a large soft palate, a narrow posterior airway space (PAS), and an inferiorly positioned hyoid bone (the mandibular plane-hyoid bone distance-MP-H) are the most frequently reported abnormalities.14 Guilleminault et al.67 found that women with OSA have a longer soft palate, a longer MP-H, and a smaller PAS than control women. When OSA women were compared to OSA men, they had shorter soft palates than men but the MPH distance was similarly abnormal in both men and women. Although men and women differ in their craniofacial measurements, the differences noted do not sufficiently explain the male predominance of OSA. Obesity is a strong risk factor for OSA and contributes to the prevalence of OSA in men. Compared with men, women have a higher BMI at each level of AHI measured. Obesity is greater in younger compared to older OSA patients, particularly in women where obesity is more marked in premenopausal than postmenopausal women.47 The distribution of total body fat, however, is probably a more important risk factor where greater upper body obesity increases the upper airway resistive load. In one study of OSA patients, despite similar BMI and waist circumference, men had greater upper body obesity, demonstrated by a smaller hip circumference and greater subscapular skinfold thickness.68 Gender-related differences in the control of ventilation may play a role in explaining the observed differences in the prevalence of OSA. Men have increased ventilatory response to hypoxia and hypercapnia during wakefulness.69–72 Hyper­ capnic ventilatory response, however, is decreased during sleep in both men and women,70 resulting in a slight increase of PCO2 during sleep. Arousal from sleep will, therefore, induce a greater ventilatory instability in men compared with women, resulting in hyperventilation, hypocapnia, and central apnea or hypopnea. Women are also less likely than men to develop apneas during NREM sleep.73 It has been

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suggested that this difference in chemoresponsiveness makes men more vulnerable to airway collapse in the presence of hypocapnia.74 This may underlie the gender differences in prevalence and severity of OSA. Continuous positive airway pressure (CPAP) is the predominant treatment for OSA. While it has been shown to be effective in maintaining upper airway patency, its clinical effectiveness is dependent on consistency of use. Compliance to therapy is variable from 46% to 89% depending on the definition of compliance.16,75 The optimal duration of CPAP use is not well defined with improvements in subjective sleepiness reported with an average of 4 hours per night and objective measures of sleepiness requiring 6 hours to show improvement.76 The evidence supporting gender differences in CPAP compliance is limited and conflicting with women more likely to be adherent in some studies and men in others.77–79 Studies have not examined gender differences in short-term and long-term response to CPAP therapy. Most of the studies reporting improvements in functioning, sleepiness, mood, and cardiovascular outcomes are conducted in male populations or include only a small number of women, making comparative and gender-specific conclusions difficult. Additionally, most studies evaluate severe OSA whereas women in general are more likely to have mild to moderate disease or symptomatic UARS. Upper airway surgery, encompassing a broad range of procedures with increasing complexity, is appropriate therapy for a subset of patients with OSA, in isolation and/or in conjunction with continued CPAP therapy. There is minimal data about potential gender differences in the outcomes of upper airway surgery. Mandibular advancement devices are a second line treatment for OSA, particularly in patients with mild forms of disease. While the literature is limited, there is some suggestion that women have better overall treatment success, especially with milder disease (defined by AHI). Men who have supine dependent OSA were also more likely to show improvement using oral appliances.57,80 In summary, men and women differ in the prevalence of OSA. However, this difference is not quite as large as once perceived and the gap may become even less with the increase in obesity noted in the general population. Women may have an atypical presentation and are more likely to report insomnia or depression rather than daytime sleepiness and snoring. PSG findings suggest some differences as well. Healthcare utilization prior to the diagnosis of OSA is heavier in women when compared to men with similar OSA severity. More research is needed to determine women’s adherence to and clinical responsiveness to standard treatment modalities.

Insomnia Insomnia is the most common sleep complaint, with a lifetime prevalence of 30% in the general adult population.57 Acute or transient insomnia should be distinguished from chronic insomnia where patients report difficulty initiating or

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maintaining sleep, early morning awakenings or non-restorative sleep lasting a minimum of one month, associated with social, emotional, and physical dysfunction. The prevalence of chronic symptomatic insomnia in the general population is less at between 9% and 15%.57 Johnson et al.81 found that in 1014 adolescents randomly selected from an urban popu­ lation, there was no risk difference in rates of insomnia between boys and girls prior to puberty; with the onset of menses an almost three-fold increase in risk of insomnia was noted in girls. A meta-analysis combining data from 29 worldwide studies, representing over 1.2 million participants, demonstrated a 41% (range 28–55%) greater risk of insomnia in women compared with men.19 The risk ratio increased with age, with women over the age of 65 having the highest risk of insomnia (risk ratio 1.73, 95% confidence interval, 1.65–1.83). Unfortunately, the reasons for the strong preponderance of insomnia in women have not been clearly determined. Certain risk factors and co-morbidities that have been associated with insomnia are also found more commonly in women, but it is unclear whether there is an underlying gender difference in the prevalence of ‘pure’ or primary/psychosocial insomnia. Anxiety and depression are disorders of affect that are more common in women and are associated with insomnia.16 This association is likely bi-directional with depression leading to insomnia and poor sleep quality predating a depressive episode. The impact of hormonal fluctuations in menstrual and postmenopausal women and the increased subjective reports of insomnia have been discussed previously in this chapter. The 2003 NSF Sleep in America poll showed that older individuals who report bodily pain were also more likely to report difficulty falling asleep (OR 1.89, 95% CI 1.28–2.78), have frequent awakenings (OR 2.68, 95% CI 2.06–3.49), wake up early (OR 1.88, 95% CI 1.32– 2.66), and wake up unrefreshed (OR 2.11, 95% CI 1.54– 2.90).82 Chronic pain disorders are more commonly reported in women and have been linked to insomnia. Poor sleep quality in turn enhances pain perception, even in healthy individuals. Currently there are very few data addressing potential differences between the sexes in their response to various insomnia therapies. In general, the literature demonstrates the effectiveness of a variety of pharmacological and behavior therapies in the management of insomnia and other co-morbid psychiatric and medical conditions.83 Future research is needed to determine whether specific subsets of cognitive and pharmacological measures are more effective for women.

Other Sleep Disorders RLS affects 10% of US adults16 and population studies indicate a slight female predominance.84,85 This may be due to gender differences in the prevalence of common RLS risk factors. Primary RLS (in the absence of known risk factors) may have a genetic predisposition but it is unclear whether there is any gender differentiation. Established risk factors

for developing RLS including iron deficiency, psychiatric disorders, and their medication side effects, may be more common in women. As previously mentioned, pregnancy is a known risk factor. The pathophysiology of RLS is an area of active research. Women with an initial predisposition to insomnia may experience more sleep disruption with RLS. Other sleep disorders including narcolepsy and REM behavior disorders are more common in men while sleeprelated eating disorders occur mostly in women.16 Women are more likely to experience and admit to tiredness than men.86 Irrespective of primary sleep disorders, this tiredness may be a reflection of women’s roles and responsibilities as they balance the demands of home, family, childcare, work, and relationships. More women than men reported sleep problems on four or more nights (20% vs. 14%). A general survey of 8000 British men and women aged 16–74 demonstrated a strong association between disadvantaged socioeconomic circumstances and sleep problems (difficulties falling asleep or maintaining sleep). Low education, household income, living in public housing, and unemployment were all independently associated with reported sleep problems.87 Divorced and widowed participants reported the worst sleep in both sexes. Interestingly, gender differences in sleep problems were halved following adjustment for socioeconomic characteristics, suggesting that in part the differences noted between men and women are related to the more disadvantaged socioeconomic circumstances of most women.

Conclusions While men and women are similar in many aspects of normal and disordered sleep, they do experience sleep differently. The prevalence of sleep-disordered breathing is increased in men while insomnia is more frequently reported in women. Women with OSA are more likely to report fatigue or insomnia rather than typical symptoms of daytime sleepiness or snoring. Women experience subjective sleep disturbances throughout the life cycle that is related to hormonal fluctuations experienced during the menstrual cycle, pregnancy, and menopause. The study of gender differences in sleep goes beyond physiological and psychological differences to include sociological insights. Social roles and responsibilities in addition to socioeconomic circumstances have a significant impact on sleep; women differ from men in many of these roles. Much research is still needed to fully elucidate gender differences in sleep physiology, risk factors, long-term health outcomes, and response to therapies.

References 1. Baldwin CM, Griffith KA, Nieto FJ, et al. The association of sleep-disordered breathing and sleep symptoms with quality of life in the Sleep Heart Health Study. Sleep 2001;24(1):96–105.

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2. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004;110(4):364–367. 3. Newman AB, Nieto FJ, Guidry U, et al. Relation of sleepdisordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001;154(1):50–59. 4. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342(19):1378–1384. 5. Punjabi NM, Shahar E, Redline S, et al. Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 2004;160(6):521–530. 6. Sassani A, Findley LJ, Kryger M, et al. Reducing motorvehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep 2004;27(3):453–458. 7. Svatikova A, Wolk R, Gami AS, et al. Interactions between obstructive sleep apnea and the metabolic syndrome. Curr Diab Rep 2005;5(1):53–58. 8. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353(19):2034–2041. 9. Young T, Blustein J, Finn L, et al. Sleep-disordered breathing and motor vehicle accidents in a population-based sample of employed adults. Sleep 1997;20(8):608–613. 10. Young T, Finn L. Epidemiological insights into the public health burden of sleep disordered breathing: sex differences in survival among sleep clinic patients. Thorax 1998;53(Suppl 3):S16–S19. 11. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31(8):1071–1078. 12. Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997;157(15):1746–1752. 13. Akerstedt T, Knutsson A, Westerholm P, et al. Sleep disturbances, work stress and work hours: a cross-sectional study. J Psychosom Res 2002;53(3):741–748. 14. Ferguson KA, Ono T, Lowe AA, et al. The relationship between obesity and craniofacial structure in obstructive sleep apnea. Chest 1995;108(2):375–381. 15. Lindberg E, Janson C, Gislason T, et al. Sleep disturbances in a young adult population: can gender differences be explained by differences in psychological status? Sleep 1997;20(6):381–387. 16. Collop NA, Adkins D, Phillips BA. Gender differences in sleep and sleep-disordered breathing. Clin Chest Med 2004; 25(2):257–268. 17. Lee KA, Baker FC, Newton KM, et al. The influence of reproductive status and age on women’s sleep. J Womens Health (Larchmt) 2008;17(7):1209–1214. 18. Reynolds CF III, Kupfer DJ, Taska LS, et al. Sleep of healthy seniors: a revisit. Sleep 1985;8(1):20–29. 19. Zhang B, Wing YK. Sex differences in insomnia: a metaanalysis. Sleep 2006;29(1):85–93. 20. Goel N, Kim H, Lao RP. Gender differences in polysomnographic sleep in young healthy sleepers. Chronobiol Int 2005; 22(5):905–915. 21. Moline ML, Broch L, Zak R. Sleep in women across the life cycle from adulthood through menopause. Med Clin North Am 2004;88(3):705–736, ix. 22. Driver HS, Dijk DJ, Werth E, et al. Sleep and the sleep electroencephalogram across the menstrual cycle in young healthy women. J Clin Endocrinol Metab 1996;81(2):728–735.

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23. Kravitz HM, Janssen I, Santoro N, et al. Relationship of day-to-day reproductive hormone levels to sleep in midlife women. Arch Intern Med 2005;165(20):2370–2376. 24. Ishizuka Y, Pollak CP, Shirakawa S, et al. Sleep spindle frequency changes during the menstrual cycle. J Sleep Res 1994; 3(1):26–29. 25. Baker FC, Driver HS, Rogers GG, et al. High nocturnal body temperatures and disturbed sleep in women with primary dysmenorrhea. Am J Physiol 1999;277(6 Pt 1):E1013–E10121. 26. Baker FC, Driver HS. Circadian rhythms, sleep, and the menstrual cycle. Sleep Med 2007;8(6):613–622. 27. Baker FC, Kahan TL, Trinder J, et al. Sleep quality and the sleep electroencephalogram in women with severe premenstrual syndrome. Sleep 2007;30(10):1283–1291. 28. Parry BL, Mostofi N, LeVeau B, et al. Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and normal control subjects. Psychiatry Res 1999;85(2):127–143. 29. Baratte-Beebe KR, Lee K. Sources of midsleep awakenings in childbearing women. Clin Nurs Res 1999;8(4):386–97. 30. Pien GW, Schwab RJ. Sleep disorders during pregnancy. Sleep 2004;27(7):1405–1417. 31. Santiago JR, Nolledo MS, Kinzler W, et al. Sleep and sleep disorders in pregnancy. Ann Intern Med 2001;134(5):396–408. 32. Lee KA, Zaffke ME. Longitudinal changes in fatigue and energy during pregnancy and the postpartum period. J Obstet Gynecol Neonatal Nurs 1999;28(2):183–191. 33. Lee KA, Zaffke ME, McEnany G. Parity and sleep patterns during and after pregnancy. Obstet Gynecol 2000;95(1):14–18. 34. Guilleminault C, Querra-Salva M, Chowdhuri S, et al. Normal pregnancy, daytime sleeping, snoring and blood pressure. Sleep Med 2000;1(4):289–297. 35. Franklin KA, Holmgren PA, Jonsson F, et al. Snoring, pregnancy-induced hypertension, and growth retardation of the fetus. Chest 2000;117(1):137–141. 36. Poyares D, Guilleminault C, Hachul H, et al. Pre-eclampsia and nasal CPAP: part 2. Hypertension during pregnancy, chronic snoring, and early nasal CPAP intervention. Sleep Med 2007;9(1):15–21. 37. Blyton DM, Sullivan CE, Edwards N. Reduced nocturnal cardiac output associated with preeclampsia is minimized with the use of nocturnal nasal CPAP. Sleep 2004;27(1):79–84. 38. Edwards N, Blyton DM, Kirjavainen T, et al. Nasal continuous positive airway pressure reduces sleep-induced blood pressure increments in preeclampsia. Am J Respir Crit Care Med 2000;162(1):252–257. 39. Lee KA, Zaffke ME, Baratte-Beebe K. Restless legs syndrome and sleep disturbance during pregnancy: the role of folate and iron. J Womens Health Gend Based Med 2001;10(4):335–341. 40. Ohayon MM. Severe hot flashes are associated with chronic insomnia. Arch Intern Med 2006;166(12):1262–1268. 41. Young T, Finn L, Austin D, et al. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2003;167(9):1181–1185. 42. Polo-Kantola P, Erkkola R, Helenius H, et al. When does estrogen replacement therapy improve sleep quality? Am J Obstet Gynecol 1998;178(5):1002–1009. 43. Polo-Kantola P, Erkkola R, Irjala K, et al. Effect of short-term transdermal estrogen replacement therapy on sleep: a random­ ized, double-blind crossover trial in postmenopausal women. Fertil Steril 1999;71(5):873–880.

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44. Welton AJ, Vickers MR, Kim J, et al. Health related quality of life after combined hormone replacement therapy: randomised controlled trial. BMJ 2008;337:a1190. 45. Shahar E, Redline S, Young T, et al. Hormone replacement therapy and sleep-disordered breathing. Am J Respir Crit Care Med 2003;167(9):1186–1192. 46. Chaudhary BA, Speir WA Jr. Sleep apnea syndromes. South Med J 1982;75(1):39–45. 47. Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleepdisordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163(3 Pt 1):608–613. 48. Kapsimalis F, Kryger MH. Gender and obstructive sleep apnea syndrome, part 1: Clinical features. Sleep 2002;25(4):412–419. 49. Kripke DF, Ancoli-Israel S, Klauber MR, et al. Prevalence of sleep-disordered breathing in ages 40–64 years: a populationbased survey. Sleep 1997;20(1):65–76. 50. Young T, Evans L, Finn L, et al. Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep 1997;20(9):705–706. 51. Young T, Palta M, Dempsey J, et al. The occurrence of sleepdisordered breathing among middle-aged adults. N Engl J Med 1993;328(17):1230–1235. 52. Shepertycky MR, Banno K, Kryger MH. Differences between men and women in the clinical presentation of patients diagnosed with obstructive sleep apnea syndrome. Sleep 2005;28(3):309–314. 53. Baldwin CM, Kapur VK, Holberg CJ, et al. Associations between gender and measures of daytime somnolence in the Sleep Heart Health Study. Sleep 2004;27(2):305–311. 54. Valipour A, Lothaller H, Rauscher H, et al. Gender-related differences in symptoms of patients with suspected breathing disorders in sleep: a clinical population study using the sleep disorders questionnaire. Sleep 2007;30(3):312–319. 55. Smith R, Ronald J, Delaive K, et al. What are obstructive sleep apnea patients being treated for prior to this diagnosis? Chest 2002;121(1):164–172. 56. Greenberg-Dotan S, Reuveni H, Simon-Tuval T, et al. Gender differences in morbidity and health care utilization among adult obstructive sleep apnea patients. Sleep 2007;30(9):1173–1180. 57. Phillips BA, Collop NA, Drake C, Consens F, Vgontzas AN, Weaver TE. Sleep disorders and medical conditions in women. Proceedings of the Women & Sleep Workshop, National Sleep Foundation, Washington, DC, March 5–6, 2007. J Women’s Health (Larchmt) 2008;17(7):1191–1199. 58. Exar EN, Collop NA. The upper airway resistance syndrome. Chest 1999;115(4):1127–39. 59. Leech JA, Onal E, Dulberg C, et al. A comparison of men and women with occlusive sleep apnea syndrome. Chest 1988;94(5):983–988. 60. O’Connor C, Thornley KS, Hanly PJ. Gender differences in the polysomnographic features of obstructive sleep apnea. Am J Respir Crit Care Med 2000;161(5):1465–1472. 61. Ware JC, McBrayer RH, Scott JA. Influence of sex and age on duration and frequency of sleep apnea events. Sleep 2000;23(2):165–170. 62. Guilleminault C, Stoohs R, Kim YD, et al. Upper airway sleep-disordered breathing in women. Ann Intern Med 1995; 122(7):493–501. 63. Brooks LJ, Strohl KP. Size and mechanical properties of the pharynx in healthy men and women. Am Rev Respir Dis 1992;146(6):1394–1397.

64. Mohsenin V. Gender differences in the expression of sleepdisordered breathing: role of upper airway dimensions. Chest 2001;120(5):1442–1447. 65. Whittle AT, Marshall I, Mortimore IL, et al. Neck soft tissue and fat distribution: comparison between normal men and women by magnetic resonance imaging. Thorax 1999;54(4):323–328. 66. Martin SE, Mathur R, Marshall I, et al. The effect of age, sex, obesity and posture on upper airway size. Eur Respir J 1997;10(9):2087–2090. 67. Guilleminault C, Quera-Salva MA, Partinen M, et al. Women and the obstructive sleep apnea syndrome. Chest 1988;93(1):104–9. 68. Millman RP, Carlisle CC, McGarvey ST, et al. Body fat distribution and sleep apnea severity in women. Chest 1995; 107(2):362–366. 69. Douglas NJ, White DP, Weil JV, et al. Hypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis 1982;125(3):286–289. 70. Douglas NJ, White DP, Weil JV, et al. Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 1982;126(5):758–762. 71. White DP, Douglas NJ, Pickett CK, et al. Hypoxic ventilatory response during sleep in normal premenopausal women. Am Rev Respir Dis 1982;126(3):530–533. 72. White DP, Douglas NJ, Pickett CK, et al. Sexual influence on the control of breathing. J Appl Physiol 1983;54(4):874–879. 73. Jordan AS, Eckert DJ, Catcheside PG, et al. Ventilatory response to brief arousal from non-rapid eye movement sleep is greater in men than in women. Am J Respir Crit Care Med 2003;168(12):1512–1519. 74. Zhou XS, Shahabuddin S, Zahn BR, et al. Effect of gender on the development of hypocapnic apnea/hypopnea during NREM sleep. J Appl Physiol 2000;89(1):192–199. 75. Hoffstein V, Viner S, Mateika S, et al. Treatment of obstructive sleep apnea with nasal continuous positive airway pressure. Patient compliance, perception of benefits, and side effects. Am Rev Respir Dis 1992;145(4 Pt 1):841–845. 76. Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 2007;30(6):711–719. 77. Lewis KE, Seale L, Bartle IE, et al. Early predictors of CPAP use for the treatment of obstructive sleep apnea. Sleep 2004;27(1):134–138. 78. Pelletier-Fleury N, Rakotonanahary D, Fleury B. The age and other factors in the evaluation of compliance with nasal continuous positive airway pressure for obstructive sleep apnea syndrome. A Cox’s proportional hazard analysis. Sleep Med 2001;2(3):225–232. 79. Sin DD, Mayers I, Man GC, et al. Long-term compliance rates to continuous positive airway pressure in obstructive sleep apnea: a population-based study. Chest 2002;121(2):430–435. 80. Marklund M, Stenlund H, Franklin KA. Mandibular advancement devices in 630 men and women with obstructive sleep apnea and snoring: tolerability and predictors of treatment success. Chest 2004;125(4):1270–1278. 81. Johnson EO, Roth T, Schultz L, et al. Epidemiology of DSM-IV insomnia in adolescence: lifetime prevalence, chronicity, and an emergent gender difference. Pediatrics 2006;117(2):e247–e256. 82. Foley D, Ancoli-Israel S, Britz P, et al. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res 2004;56(5):497–502.

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83. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4(5):487–504. 84. Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med 2004;5(3): 237–246.

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85. Nichols DA, Allen RP, Grauke JH, et al. Restless legs syndrome symptoms in primary care: a prevalence study. Arch Intern Med 2003;163(19):2323–2329. 86. Dzaja A, Arber S, Hislop J, et al. Women’s sleep in health and disease. J Psychiatr Res 2005;39(1):55–76. 87. Arber S, Bote M, Meadows R. Gender and socio-economic patterning of self-reported sleep problems in Britain. Soc Sci Med 2009;68(2):281–289.

C hapter

22

Are Women More Susceptible to Chronic Obstructive Pulmonary Disease? Kenneth R. Chapman Director, Asthma and Airway Centre, University Health Network, Toronto Western Hospital; Professor of Medicine, University of Toronto; GSK-CIHR Research Chair in Respiratory Health Care Delivery; Toronto, Ontario, Canada

Introduction

campaigns that encouraged women to identify cigarette smoking as a mark of their equality with men.1 Such campaigns were highly successful; in the early 1920s women consumed less than 10% of the tobacco consumed in the United States but by the mid-1960s women accounted for at least one-third of tobacco being smoked. By the middle of the twentieth century, approximately half of all adults smoked tobacco regularly. In the mid-1960s, the pivotal report of the United States Surgeon General announced the link between tobacco smoking and the development of lung cancer, a watershed announcement leading to the slow but inevitable decline in tobacco consumption so that only about one in five adults in North America now smokes regularly. Women are now just as likely to smoke as men. Although the decline in overall tobacco consumption has led to decreased mortality from coronary artery disease and stroke, two tobacco-linked causes of mortality, the same decline has not been seen for COPD. Indeed, mortality has continued to rise for COPD, a complex phenomenon that is thought to reflect the gradual aging of the population in many nations, the rise of tobacco consumption in the developing world and the permanence of the tobacco-induced COPD injury.2 By the year 2020, COPD is projected to be the third most common cause of death on the planet.3 One might expect from this gradual shift towards gender parity in tobacco consumption that women now develop COPD as commonly as men. However, epidemiologic data suggests that women may be more susceptible than men to the adverse effects of tobacco smoking and are developing COPD more often and at an earlier age. For ­ example, Figure 22.1 shows data for COPD hospitalizations in Canada from the mid-1980s to 2000 with projections to 2015.4;5 Early in the recording period, men were being hospitalized for COPD care approximately twice as often

Through much of the twentieth century, chronic obstructive pulmonary disease (COPD) was regarded as a disease of aging men, a perspective that reflected the tobacco smoking patterns of Western nations through the early and middle portions of that century. More men than women smoked and physicians noted that men were more commonly employed outside the house than women and were therefore more likely to be exposed to significant occupational respiratory irritants. These patterns of tobacco consumption and employment have shifted dramatically and in many parts of the world, women are just as likely to smoke tobacco regularly as men. In part because of this markedly changed behavior, COPD has become much more common amongst women. Indeed, in North America COPD is now diagnosed more commonly in women than men while a careful review of the epidemiologic data suggests that women may be more susceptible to the development of COPD than men. It is less clear that women exhibit different manifestation of the disease or that they respond differently to therapy; these matters remain the subject of ongoing clinical research.

Evolving epidemiology Early in the twentieth century, the mass manufacturing of cigarettes encouraged the widespread adoption of tobacco consumption in the form of cigarettes. Initially, the growth in tobacco consumption excluded women. In North America, it was considered scandalous for women to smoke tobacco in public. These conventional attitudes were targeted shrewdly by the tobacco industry with marketing Principles of Gender-Specific Medicine

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Copyright 2010, Elsevier Inc. All rights reserved.

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253

Number of individuals

80 000 Women - Projected

70 000

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40 000 30 000 20 000

13

11

09

07

05

03

01

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15 20

20

20

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20

20

20

95

93

91

89

87

97

19

19

19

19

19

19

19

19

85

10 000

Year

Figure 22.1  Current and projected hospitalization rates for COPD care in Canada, by gender. Source: Canadian Institute for Health Information. Respiratory Disease in Canada, 2001

as women. By the turn of the millennium, women had achieved parity in their need for COPD hospitalization. The projected trend estimates that women will require hospital­ization for COPD care twice as often as men will by the year 2015. COPD mortality trends in Canada (see Figure 22.2) ­ parallel the hospitalization data; by the year 2015, women will be more than twice as likely to lose their lives to COPD as men. Even now, a review of published mortality data shows that Canadian women are more likely to lose their lives to COPD than to breast cancer. There is a growing body of evidence that women are more susceptible to the development of COPD than men. For example, in the Copenhagen City Heart Study, 13 897 men and women were recruited for long-term follow-up of cardiopulmonary health with lung function measured for between 7 and 16 years.6 The investigators were able to calculate rates of excess FEV1 decline in smokers expressed as milliliters per pack-year (ml/pack-year) of tobacco consumption. For the men, they found the excess decline in lung function attributable to smoking was 6.3 ml/pack-year but for women was significantly higher at 7.4 ml/pack-year. In a comparable study of 4814 individuals, the Glostrup Population Study arrived at similar conclusions, calculating an excess rate of FEV1 decline of 8.4 ml/pack-year for men and 10.5 ml/pack-year for women. A cross-sectional study by Carter and colleagues has also reported that for a given amount of tobacco smoking, women are at greater risk of developing COPD.6 Moreover, women seem to account for a preponderance of patients with COPD against a background of little or no tobacco consumption. Silverman and colleagues have reported that amongst 84 patients with COPD in the absence or near-absence of tobacco smoking, 71% were women.7 Female first-degree relatives of these patients who smoked were far more likely to have significant impairment in FEV1 as compared to male first-degree relatives who smoked. Tobacco smoking is not the only significant environmental factor in the development of COPD. In many parts of

the developing world, women are exposed to the smoke of cooking and heating fires in poorly ventilated dwellings. This long-term exposure to the smoke of biomass fuels is a significant factor in the development of COPD in large parts of South America, Africa and South Asia.8 Physicians who practice in the developed world and care for immigrant patients must remember that non-tobacco exposure may lead to COPD that is nearly indistinguishable from the COPD seen in the usual tobacco-consuming patient.9 Women have a greater risk of developing COPD compared to men because of hormonal influences, or, the most likely explanation, differences in airway size and length between men and women. We understand that airway resistance varies to the fourth power of airway radius so that similar degrees of narrowing have greater impact on airflow in smaller than large airways. This hypothesis is consistent with a number of well-known clinical patterns. For example, women account for a preponderance of patients with adult asthma (refer to Chapter 19 on Gender Differences in Asthma). In most studies of asthma, the ratio of women to men is approximately 60:40. This is true only for adult asthma, however. Amongst children, boys are more likely to have asthma than girls, the difference is also likely to be explained by different patterns of lung growth between the sexes. In the first Lung Health Study, methacholine hyperreactivity was greater amongst women participants than men participants, a finding that could be explained by smaller airway caliber baseline amongst women than men.10

Diagnostic errors Any epidemiologic data concerning COPD must be interpreted cautiously. Although the diagnosis of this common and potentially lethal disorder should be relatively simple with a spirometric measure of lung function, spirometry is seldom used in clinical practice and the typical patient with

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14 000 Men - Actual

Number of Individuals

12 000 10 000 8000

Women - Actual Men - Projected Women - Projected

6000 4000 2000 0 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2015 1987

Year

Figure 22.2  Current and projected mortality rates for COPD in Canada, by gender. Source: Canadian Institute for Health Information. Respiratory Disease in Canada, 2001

COPD is diagnosed only when lung function has fallen below 50% of the predicted normal value. This diagnostic delay or ‘underdiagnosis’ may be explained by the gradual nature of the lung function loss, adaptation to symptoms that appear gradually, and some ‘excess’ capacity that allows early lung function to occur silently. A gradual loss of lung function over many years as the consequence of tobacco smoking is often a clinically silent process. Maximal exercise remains possible even with loss of lung function to 70% of the age-related normal value. For the average sedentary individual, a loss of lung function to well below this value will fail to provoke breathlessness during usual daily activities. If exercise provokes breathlessness outside the norm for an individual, he or she may regard the symptoms as being simply the consequence of aging or a lack of exercise conditioning. Persistent cough with sputum production is often regarded by the smoker as a ‘normal’ smoker’s cough. Episodic exacerbations may be dealt with by short-term prescriptions for antibiotic while the underlying cause of the event goes unsuspected by primary care physicians. In the past, the diagnosis of COPD was further delayed by ‘definitions’ such as ‘chronic bronchitis’ and ‘emphysema’ that were difficult to apply clinically.11;12 Chronic bronchitis was characterized as a persistent and productive cough that could not be explained by another pulmonary process and emphysema was defined in pathologic terms. The definitions neither lent themselves to clinical application nor mentioned measuring airflow, a standard objective measure that is at the heart of the modern COPD definition. The Global Initiative for Obstructive Lung Disease in its GOLD guidelines defines COPD as airflow limitation that is not completely reversible and that arises from long-term exposure to a noxious substance. In numerical terms, airflow limitation is defined as an FEV1/FVC less than 70% after the administration of inhaled ­bronchodilator.

Using this definition, the BOLD initiative has attempted to determine the true prevalence of COPD around the world using spirometry to screen at-risk populations.13 In Latin America, spirometric screening of adults 40 years and older revealed crude COPD prevalence rates ranging from a low of 7.8% in Mexico City to a high of 19.7% in Montevideo.14 The mean prevalence of previously undiag­ nosed COPD was 12.7%, ranging from 6.9% in Mexico City to 18.2% in Montevideo.15 (False positive diagnosis was also seen; among 237 subjects with a prior COPD diagnosis, only 36% had post-bronchodilator FEV1/FVC 0.7, while 64 had normal spirometry). As has often been suggested previously, the investigators attributed the underdiagnosis of COPD to be inadequate use of spirometry by primary care physicians.16 Women may be particularly disadvantaged by the suboptimal use of spirometry to detect and quantify airflow obstruction. Chapman and colleagues surveyed primary care physicians throughout North America, presenting 192 physicians with one of two clinical scenarios in which a middle-aged or older tobacco smoker presented with the gradual onset of breathlessness with exertion.17 The two scenarios differ in one significant way: in one scenario the hypothetical patient was a man and in the other the patient was a woman. The investigators reconfirmed the finding that spirometry was seldom requested by physicians in their investigation of such a problem. Only 22% of physicians would have requested a measure of lung function while 80% would have requested a chest x-ray. Cardiovascular studies such as electrocardiogram or a stress test were more likely to be requested than spirometry. COPD was much more likely to be considered the provisional diagnosis when the hypothetical patient was a man than when the hypothetical patient was a woman (58% vs. 42%). The study also showed that this gender bias could be corrected. As a second stage of the investigation, researchers presented

C h a p t e r 2 2    Are Women More Susceptible to Chronic Obstructive Pulmonary Disease? l

p­ hysicians with spirometry that showed moderate or greater airflow obstruction and no significant response to inhaled bronchodilator. The likelihood of a COPD diagnosis rose and the difference between genders narrowed, with provisional diagnosis of COPD at 74% for men and 66% for women. With further objective information – an obstructive spirometry that was unchanged by an oral steroid trial – the difference between the sexes disappeared, with a provisional diagnosis of COPD of 85% vs. 79% in the male versus female scenario respectively. Although these data were generated in North America, the study and its findings have been replicated in a large European population.18 In another large European survey, women were more likely that men to receive smoking cessation counseling but were less likely to have lung function measured with a spirometer.19

Clinical manifestations There have been relatively few studies comparing the clinical manifestations and clinical course of COPD between men and women. There appear to be differences between the sexes but these differences are subtle. If an attempt is made to match men and women by objective measures of disease severity such as FEV1, women appear to be more greatly impaired than men with comparable disease severity. Health-related quality of life tends to be lower in women and they are more likely to suffer depression.20,21 Similar findings have been reported in asthma such that women appear to report symptoms more frequently than men with a comparable degree of disease severity measured in objective terms22 (refer to Gender Differences in Asthma). Investigators have also compared COPD arising from long-term exposure to biomass fuels to COPD arising from tobacco smoking, the former exposure more likely to affect women. Although there may be subtle differences in pathology and radiographic distribution of abnormalities between the two types of exposure,23 for all practical clinical purposes the symptoms, complications, and clinical course are the same regardless of the irritant exposure responsible.24 Despite having greater morbidity from COPD than men, women may not suffer from greater mortality. de Torres and colleagues compared men and women with COPD matched for severity either by the BODE index or by GOLD staging. Regardless of the criteria for matching, survival was better in women than men with COPD.25

Management Should COPD in women be treated differently between men and women? There have, until recently, been few reports of treatment results that differ between men and women.

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However, more and more such analyses are being conducted and subtle differences in responses to therapy have emerged. While the framework of management remains the same for men and women, small differences in monitoring and management have suggested themselves. Smoking cessation remains the single most important step to improve outcomes in COPD. Regrettably, sustained quitting is difficult for most patients despite its importance to their health. Various interventions have been devised to aid smokers in their cessation efforts, interventions that range from the simple advice of physicians, through a variety of behavioral strategies, nicotine replacement therapy, antidepressant therapy and, most specifically, an oral partial agonist of nicotinic receptors in the brain, varenicline.26 Combining interventions is typically more effective than using one intervention.27 In general, women have been less successful in smoking cessation efforts than men.28 It is unclear whether this difference is driven by social or biologic factors but women do have different reasons for smoking and responses to smoking cessation. One frequently noted social factor is the mildly anorectic effect of smoking, a property subtly advertised by the ‘Virginia Slims’ advertising of the 1960s.29–31 Smoking cessation is typically accompanied by a modest weight gain, often slightly more in women who quit than men. For some women, avoidance of this weight gain is given as a reason to forgo a cessation attempt or to end one. These different motives must be taken into account by those who counsel smokers to quit. Not all of these gender differences place women at a disadvantage; women are often motivated to quit smoking during pregnancy and may remain motivated to abstain after giving birth to spare their children exposure to secondhand tobacco smoke. Nicotine replacement therapy is the preferred adjunct to women who seek some adjunct in the smoking cessation effort during pregnancy. Most current guidelines for the management of COPD recommend an incremental approach to prescription therapy for COPD. For patients with few or no symptoms, intervention is limited to smoking cessation and the routinely recommended vaccination against influenza and pneumococcal pneumonia. Occasional episodes of breathlessness are treated on an as-needed basis with rapid-acting broncho­dilators. For patients with more severe disease and symptoms that interfere with daily activities, long-acting bronchodilators are employed. If a single agent bronchodilator such as tiotropium is insufficient to alleviate symptoms, additional long-acting agents may be used and the patient may inhale two bronchodilators such as tiotropium and formoterol. Finally, for patients who are most severely affected and particularly those who have exacerbations, an inhaled corticosteroid is added to the regimen. This incremental approach is in stark contrast to the secondary prevention strategies used in the management of coronary artery disease. In patients who survive a ­ myocardial infarction or unstable angina, routine secondary preventive measures

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would include ­ combination therapy with a statin, beta blocker, aspirin, and an ACE inhibitor unless a specific contraindication such as allergy prevents the use of one or more agent. The goal of using all these pharmacologic interventions simultaneously is the prevention of death or serious cardiac event in the patient already identified as being at risk. This reasoning has not been employed for the management of COPD patients although their risk is high. Several studies suggest that the one year mortality of patients discharged from hospital after the care of a COPD exacerbation is 20–25%.32–34 As outlined below, each of the incremental steps used for the management of COPD has been shown to reduce exacerbation risk and combination therapy with inhaled corticosteroid therapy and long-acting beta2 agonist has been shown to reduce the rate of lung function decline and all-cause mortality in treated COPD patients. Moreover, the individual components of the regimen have been shown to be at least additive and not redundant when given in combination. Early studies of COPD used short-term response to FEV1 as a primary outcome variable, an outcome variable poorly suited to the assessment of COPD treatments but one that continues to have undue prominence in clinical trials at the insistence of regulatory authorities. However, small shifts in FEV1 tend to be mirrored by parallel changes in other outcomes. For example, Petty and colleagues reported that the combination of inhaled ipratropium and albuterol was more effective at improving FEV1 over 3 hours than either agent given singly.35 More important was the observation that when these three regimens were compared over a 3–month period, patients receiving the combination had least need for oral corticosteroid in the treatment of exacerbations. The first of the long-acting bronchodilators studied in the treatment of COPD was salmeterol, the long-acting beta2 agonist inhaled in a dosage of 50 g twice daily.36 As expected, FEV1 responses for 12 hours after inhalation were better than FEV1 responses seen with ipratropium inhaled every 6 hours or placebo. Again, the secondary outcome of exacerbation rate was lowest in the most effective bronchodilator regimen. Studies with formoterol in COPD have shown similar results.37 Tiotropium is the first inhaled anticholinergic bronchodilator permitting just once-daily administration. Its use is associated with bronchodilator benefits that are sustained over 24 hours and are associated with reduced exacerbation rate and hospitalizations for exacerbation.38,39 Combinations of inhaled beta2 agonists and inhaled anticholinergics tend to have additive effects such that patients are even less likely to have exacerbations with two complementary bronchodilators than with a ­ monotherapy.40,41 Other endpoints such as health status (quality of life), dyspnea scores, and exercise tolerance tend to parallel the FEV1 outcome. The role of inhaled corticosteroids in COPD remains controversial and concern over these agents likely remains the reason that incremental therapy has not given way to

immediate maximal combination therapy for secondary prevention in COPD. COPD has generally been regarded as a disease that is not responsive to corticosteroids. This has been based on the failure of oral or inhaled corticosteroids to produce short-term improvements in the spirometry of COPD patients as might be seen in asthma patients.42 This negative viewpoint was underscored by the reporting of four independent trials that compared the ability of inhaled corticosteroids to reduce the rate of FEV1 decline when compared to placebo in populations of patients with mild to moderate COPD.43–46 These trials of three or more years’ duration failed individually to show a slower rate of FEV1 decline in the corticosteroid-treated subjects although subsequent meta-analysis showed that patients inhaled budesonide, triamcinolone or fluticasone had a rate of FEV1 decline almost 10 ml per year slower than patients who inhaled placebo.47 The average annual rate of FEV1 decline in the healthy adult is approximately 30 ml per year so that a slowing of 10 ml per year is appreciable, particularly in the most severely obstructed patients with low baseline FEV1. The most significant outcome of these trials was the observation made in the ISOLDE trial that patients who inhaled fluticasone were significantly less likely to have an exacerbation than patients who inhaled placebo. This finding has been replicated and inhaled corticosteroids have found their way into guidelines for patients who suffer exacerbations. Reduced mortality is the obvious goal in the management of COPD and observational data suggested that this would be possible with available pharmacotherapy. Reviewing a primary care database, Soriano and ­colleagues reported lower mortality amongst COPD patients treated with the combination of salmeterol and fluticasone as compared to patients treated without either of these agents.48 (Mortality in those treated with either agent alone was intermediate between placebo-treated and combinationtreated patients.) This was a retrospective review of outcomes from therapies that were not assigned in random double-blind fashion. However, the landmark TORCH trial tested the hypothesis that the inhaled combination of salmeterol and fluticasone would reduce mortality as compared to placebo inhalation in COPD.49 The use of the combination was associated with a lower mortality as well as improved lung function, improved quality of life and fewer exacerbations. In a subsequent report, Celli and colleagues reported that rate of lung function decline was reduced by 17 ml/year in the combination therapy treated patients as compared to those who received placebo.50 The finding of reduced mortality has been replicated in a study comparing two years of therapy with either salmeterol/fluticasone or tiotropium.51 Although exacerbations rates were similar between the two treatment groups, mortality was lower in the patients treated with the combination. Enthusiasm for combination therapy incorporating an inhaled corticosteroid has been tempered by several factors.

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Some have expressed concern that in the TORCH trial, in both treatment arms in which fluticasone was a component of therapy, there was an increase rate of non-fatal pneumonia. This finding has been replicated in other COPD trials with inhaled corticosteroid therapy. With respect to gender differences, there is a concern about the potential for systemic impact of inhaled corticosteroids. Most trials of fluticasone or fluticasone in combination with salmeterol have used the relatively high dosage of 1000 g per day of fluticasone. Although the lower airway deposition and therefore the systemic impact of the fluticasone may be limited in the severely obstructed COPD patient, it has not allayed concerns completely. In the second Lung Health Study, the use of triamcinolone was accompanied by measurable adverse effects on skin but there was no clear effect on adrenal function or bone mineral density.52 Given the higher prevalence of osteoporosis in the COPD population and women’s increased tendency to suffer reduced bone mineral density, the decision to use or withhold inhaled corticosteroids could be made differently between men and women with the disease. In general, however, the response to inhaled therapies appears similar between men and women.53 Pulmonary rehabilitation improves health status and exercise tolerance in patients with COPD. Men may benefit somewhat more from extended exercise rehabilitation programs than women although the difference is modest.54 Attempts have been made to improve rehabilitation outcomes in men with the use of androgens but the results have been disappointing. Oxygen therapy is known to reduce mortality in patients with COPD who are persistently hypoxemic although the role of oxygen for the treatment of intermittent hypoxemia during sleep or with exercise remains controversial. Investigators have reported differences in survival between men and women with COPD treated with oxygen but no consistent trend is evident. Investigators in different countries have reported both better and worse survival amongst women as compared to men in the setting of long-term oxygen therapy for COPD.55 Surgical interventions for COPD include lung volume reduction surgery and ultimately lung transplantation. No consistent differences between the sexes have been reported.

Conclusions Until recently there has been little attempt to compare the manifestations of COPD between the sexes. In broad terms, the disease and its impact is similar between men and women but subtle differences have become apparent. At present, our knowledge should encourage us to consider COPD as a diagnosis seen as commonly amongst women as men. As we counsel smoking cessation, we must be aware of the different behavioral factors that may play a

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role in motivating smokers of either sex. In the long-term management of the disease, our treatment decisions may be influenced by different symptom patterns and co-morbid illnesses between men and women.

References 1. Chapman KR. Chronic obstructive pulmonary disease: are women more susceptible than men? Clin Chest Med 2004;25(2):331–41. 2. Chapman KR, Mannino DM, Soriano JB, et al. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J 2006;27(1):188–207. 3. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: global burden of disease study. Lancet 1997;349(9064):1498–504. 4. Canadian Institute for Health Information, Canadian Lung Association, Health Canada, Statistics Canada. Respiratory Disease in Canada. Bryanton V, Chen Y, Johanson H, et al., eds. H39-593/2001E. 2001. Ottawa, Health Canada. 5. Public Health Agency of Canada. Life and breath: respiratory disease in Canada. Ottawa: Public Health Agency of Canada; 2007. 6. Prescott E, Bjerg AM, Andersen PK, et al. Gender difference in smoking effects on lung function and risk of hospitalization for COPD: results from a danish longitudinal study. Eur Respir J 1997;10(4):822–27. 7. Silverman EK, Weiss ST, Drazen JM, et al. Gender-related differences in severe, early-onset chronic obstructive pulmonary disease. Am J Resp Crit Care Med 2000;162(6):2152–58. 8. Buist AS, Vollmer WM, McBurnie MA. Worldwide burden of COPD in high- and low-income countries. Part I. The burden of obstructive lung disease (BOLD) initiative. Int J Tuberc Lung Dis 2008;12(7):703–8. 9. Brehm JM, Celedon JC. Chronic obstructive pulmonary disease in hispanics. Am J Resp Crit Care Med 2008;177(5):473–78. 10. Kanner RE, Connett JE, Altose MD, et al. Gender difference in airway hyperresponsiveness in smokers with mild COPD: The lung health study. Am J Resp Crit Care Med 1994;150:956–61. 11. Chapman KR, Bowie DM, Goldstein RS, et al. Guidelines for the assessment and management of chronic obstructive pulmonary disease. Canadian Thoracic Society Workshop Group. Can Med Assoc J 1992;147:420–28. 12. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD and asthma. This official statement of the American Thoracic Society was adopted by the ATS board of directors, November 1986. Am Rev Respir Dis 1987;136:225–44. 13. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD study): a population-based prevalence study. Lancet 2007;370(9589):741–50. 14. Menezes AM, Perez-Padilla R, Jardim JR, et al. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study. Lancet 2005;366(9500):1875–81. 15. Talamo C, De Oca MM, Halbert R, et al. Diagnostic labeling of COPD in five Latin American cities. Chest 2007;131(1):60–67.

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16. Kesten S, Chapman KR. Physician perceptions and management of COPD. Chest 1993;104:254–58. 17. Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. Chest 2001;119(6):1691–95. 18. Miravitlles M, de la Rosa C, Naberan K, et al. [Attitudes toward the diagnosis of chronic obstructive pulmonary disease in primary care]. Arch Bronconeumol 2006;42(1):3–8. 19. Watson L, Vestbo J, Postma DS, et al. Gender differences in the management and experience of chronic obstructive pulmonary disease. Resp Med 2004;98(12):1207–13. 20. Chavannes NH, Huibers MJ, Schermer TR, et al. Associations of depressive symptoms with gender, body mass index and dyspnea in primary care COPD patients. Fam Pract 2005;22(6):604–7. 21. Katsura H, Yamada K, Wakabayashi R, et al. Gender-associated differences in dyspnoea and health-related quality of life in patients with chronic obstructive pulmonary disease. Respirology 2007;12(3):427–32. 22. Day A, Ernst P, Glick L, et al. Women and asthma: ­ lessons from a gender analysis of the asthma in Canada survey. J Asthma 2006;43(2):169–73. 23. Rivera RM, Cosio MG, Ghezzo H, et al. Comparison of lung morphology in COPD secondary to cigarette and biomass smoke. Int J Tuberc Lung Dis 2008;12(8):972–77. 24. Ramirez-Venegas A, Sansores RH, Perez-Padilla R, et al. Survival of patients with chronic obstructive pulmonary disease due to biomass smoke and tobacco. Am J Resp Crit Care Med 2006;173(4):393–97. 25. de Torres JP, Cote CG, Lopez MV, et al. Sex differences in mortality in patients with COPD. Eur Respir J 2009;33(3):528–35. 26. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs. placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006;296(1):56–63. 27. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340(9):685–91. 28. Gritz ER, Nielsen IR, Brooks LA. Smoking cessation and gender: the influence of physiological, psychological, and behavioral factors. J Am Med Womens Assoc 1996;51(1–2):35–42. 29. Berman BA, Gritz ER. Women and smoking: current trends and issues for the 1990s. J Subst Abuse 1991;3(2):221–38. 30. Gritz ER, Crane LA. Use of diet pills and amphetamines to lose weight among smoking and nonsmoking high school seniors. Health Psychol 1991;10(5):330–35. 31. Gritz ER, St Jeor ST, Bennett G, et al. National working conference on smoking and body weight. task force 3: implications with respect to intervention and prevention. Health Psychol 1992;11(Suppl):17–25. 32. Gunen H, Hacievliyagil SS, Kosar F, et al. Factors affecting survival of hospitalised patients with COPD. Eur Respir J 2005;26(2):234–41. 33. Holguin F, Folch E, Redd SC, et al. Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001. Chest 2005;128(4):2005–11. 34. Geelhoed EA, Brameld KJ, Holman CD, et al. Readmission and survival following hospitalization for chronic obstructive pulmonary disease: long-term trends. Intern Med J 2007;37(2):87–94.

35. Petty TL. The combination of ipratropium and albuterol is more effective than either agent alone. Chest 1995;107(Suppl.):S183–86. 36. Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999;115(4):957–65. 37. Dahl R, Greefhorst LAPM, Nowak D, et al. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Resp Crit Care Med 2001;164(5):778–84. 38. O’Donnell DE, Fluge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23(6):832–40. 39. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med 2005;143(5):317–26. 40. Chapman KR, Ringdal N, Backer V, et al. Salmeterol and fluticasone propionate (50/250 microg administered via combination diskus inhaler: as effective as when given via separate diskus inhalers. Can Resp J 1999;6(1):45–51. 41. van Noord JA, Aumann JL, Janssens E, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 2005;26(2):214–22. 42. Callaghan CM, Dittus RS, Katz BP. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease. Ann Intern Med 1991;114:216–23. 43. Pauwels RA, Löfdahl CG, Laitinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;340(25):1948–53. 44. Burge PS, Calverley PM, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320(7245):1297–303. 45. Vestbo J, Sorensen T, Lange P, et al. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999;353(9167):1819–23. 46. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343(26):1902–9. 47. van Grunsven PM, Van Schayck CP, Derenne JP, et al. Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis. Thorax 1999;54(1):7–14. 48. Soriano JB, Vestbo J, Pride NB, et al. Survival in COPD patients after regular use of fluticasone propionate and sal­ meterol in general practice. Eur Respir J 2002;20(4):819–25. 49. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356(8):775–89. 50. Celli B, Ferguson GT, Anderson JA, et al. Salmeterol/fluticasone propionate (SFC improves lung function and reduces the rate of decline over three years in the TORCH survival study. Proc Am Thorac Soc 2006;175:A763. 51. Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Resp Crit Care Med 2008;177(1):19–26.

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52. Tashkin DP, Murray HE, Skeans M, et al. Skin manifestations of inhaled corticosteroids in COPD patients: results from Lung Health Study II. Chest 2004;126(4):1123–33. 53. Vestbo J, Soriano JB, Anderson JA, et al. Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD. Respir Med 2004;98(11):1045–50.

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54. Foy CG, Rejeski WJ, Berry MJ, et al. Gender moderates the effects of exercise therapy on health-related quality of life among COPD patients. Chest 2001;119(1):70–76. 55. Miyamoto K, Aida A, Nishimura M, et al. Gender effect on prognosis of patients receiving long-term home oxygen therapy. Am J Resp Crit Care Med 1995;152(3):972–76.

C hapter

23

The Gender-Specific Aspects of Lung Cancer Rebecca L. Toonkel1, and Charles A. Powell2 1

Postdoctoral Research Fellow, Columbia University, Division of Pulmonary, Allergy, and Critical Care Medicine, New York, NY, USA 2 Associate Professor of Medicine, Columbia University, Division of Pulmonary, Allergy, and Critical Care Medicine, New York, NY, USA

Introduction

hand, the frequency of women smoking decreased 47% to the current level of 17%.9 It is not clear whether gender-related differences in lung cancer incidence and mortality are solely attributable to trends in cigarette smoking prevalence. Epidemiological and molecular studies suggest that gender-associated differences in tumor biology and lung cancer susceptibility may contribute to lung cancer mortality and incidence, independent of cigarette smoking.10 Because cigarette smoking status is clearly associated with susceptibility, it is a common source of confounding bias in these studies.

Lung cancer is the leading cause of cancer death among women.1 In the United States, lung cancer incidence in women is second only to breast cancer, accounts for approximately 12% of new cancer diagnoses each year, and will affect 1 in 17 women over her lifetime.2 Reflecting shifting patterns in smoking behavior, the incidence of lung cancer in men has stabilized in recent years, but continues to rise in women. Between 1990 and 2008, lung cancer incidence in men increased 12% (from 102 000 to 114 690 cases/year), while the incidence in women increased 82% (from 55 000 to 100 330). Thus, while women accounted for 35% of those diagnosed with lung cancer in 1990, 47% of patients diagnosed with lung cancer in 2008 were women.3,4 While lung cancer continues to be the leading cause of cancer death in men and women, lung cancer mortality rates have been declining in men since 1990, but have only recently plateaued in women. With 71 030 female deaths predicted in 2008, lung cancer will account for the death of more women than breast and all gynecological cancers combined.3,4 Because the current death rate for nonsmoking US women is similar to historical values from the 1930s,5 the more than 500% increase in female deaths since that time is likely largely directly attributable to an increase in the prevalence of smoking among women.6 Smoking accounts for approximately 90% of lung cancer deaths.7 The prevalence of cigarette smoking among both US men and women peaked in 1964 (50% in men and 32% in women) prior to the publication of the Surgeon General’s Report on smoking and health.8 Subsequently, smoking prevalence rates have steadily declined in both sexes, but to a greater degree in men. In 2007, 22% of men were current smokers, a reduction of 56% since 1964. On the other Principles of Gender-Specific Medicine

Are lung cancers in smokers and nonsmokers different? Worldwide, about 53% of women and 25% of men with lung cancer are never-smokers.11 Thus, among those with lung cancer, women are significantly more likely to be lifetime never-smokers than men.12–16 It is clear that different histologic subtypes of lung cancer predominate in smokers compared to nonsmokers. Compared to the histology of other common cancers of the breast, and colon, which are all adenocarcinoma, the histology of lung cancer is heterogenous. Lung cancer histology is comprised of two major classes: small cell and non-small cell lung carcinoma (NSCLC), which comprise 15% and 85% of lung cancer cases, respectively. Small cell carcinoma is rare in never-smokers and is associated with an overall 5-year survival of less than 10%. Non-small cell carcinoma is comprised of squamous cell carcinoma, large cell carcinoma, and adenocarcinoma subtypes. NSCLC treatment options and prognosis are guided by stage of cancer as determined by the TNM classification and 5-year survival ranges from 5% in Stage 4 260

Copyright 2010 2010, Elsevier Inc. All rights reserved.

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to 70% in Stage 1. Prognosis is also associated with histology, with the prognosis for adenocarcinoma being more favorable than that for squamous and large cell carcinoma. Adenocarcinoma is the most common histologic subtype in never-smokers,17–19 while small cell and squamous cell carcinoma are more common in current or former smokers. Thus smoking-associated prognosis differences may be influenced by the greater proportion of nonsmokers with adenocarcinoma12 and by the increasing frequency of the adenocarcinoma subtype bronchioloalveolar carcinoma in nonsmokers, which is associated with longer survival than other adenocarcinoma subtypes.20 The clinical differences in outcomes of smokers and nonsmokers are supported by molecular studies that indicate the molecular alterations of lung tumors from smokers and nonsmokers are different. For example, chromosomal copy number aberrations and loss of heterozygosity are associated with smoking status.21,22 Also, tumor cell DNA from smokers shows a global increase in promoter hypermethylation and a dose-dependent specific increase in methylation of the tumor suppressor genes APC and p16.23,24 P53 mutations are also more common in lung tumors from smokers with G:C–T:A transversions predominating as opposed to the G:C–A:T transitions that are more common in tumors from nonsmokers.25 Importantly, recent studies indicate that the gene expression profiles of lung adenocarcinomas from smokers differ from those in never-smokers,26,27 suggesting differential pathway activation in tumors caused by cigarette smoking compared with tumors caused by other environmental exposures. Mutations of the epithelial growth factor receptor (EGFR) are more common among tumors from nonsmokers,28–31 while Kras mutations predominate in tumors from smokers and G:C-T:A transversions are found exclusively in smokers.32–36 Because EGFR mutations occur more frequently in tumors from nonsmokers, these patients also have higher rates of response to targeted therapy with tyrosine kinase inhibitors such as gefitinib and erlotinib.29,37–41 While it is not clear that nonsmokers also have an improved response to standard adjuvant chemotherapy,42 studies have found a survival advantage for nonsmokers compared with smokers. In an analysis of 654 patients with adenocarcinoma, Nordquist et al. found a 5-year survival of 23% for never-smokers vs. 16% for current smokers (p  0.004).43 Another group examined data on 1405 patients with lung cancer and found smoking status to be an independent predictor of cancerspecific survival in multivariate analysis.44 Equally important, the survival of smokers with lung cancer may also be affected by poorer underlying lung function and a higher frequency of comorbidities such as cardiovascular disease. Taken together, these studies indicate that smoking status is associated with clinically important differences in tumor molecular features and with survival and suggest this may be an important bias in studies that examine gender related differences.

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Are lung cancers in men and women different? A number of important differences between lung cancers in men and women have been identified. While adenocarcinoma is the most frequent diagnosis in women, men are more likely to develop squamous or small cell carcinoma.12,13,15,45–47 Notably, bronchioloalveolar carcinoma also occurs more commonly in women.10,13,15,46 As noted above, these differences may be attributable in part to differences in smoking status.19 Women tend to be diagnosed with lung cancer at a younger age12–14,16,47–49 and at an earlier stage than men.12,13,47,49,50 However, men and women with adenocarcinoma present younger than those with squamous cell carcinoma, suggesting that diagnosis at a younger age in women may simply reflect the greater proportion of women with adenocarcinoma (and in turn, perhaps just a greater proportion of nonsmokers).14,16,48,51 Likewise, the increased frequency of bronchioloalveolar carcinoma, a slower growing and less aggressive subtype, may also contribute to diagnosis at an earlier stage in women. Alternatively, it is possible that women are diagnosed at younger ages and earlier stages because of differences at presentation. Men are more likely to complain of hemoptysis, weight loss, and chest pain, while women are more likely to be asymptomatic.15 Although this difference in presentation may be partially attributable to the increased frequency of centrally located squamous cell carcinomas in men vs. peripherally located adenocarcinoma in women, it is also possible that it is due to gender differences in reporting of symptoms and health care utilization.

Are women more susceptible to lung cancer? Lung cancer arises as the result of a complex interplay of environmental exposures (such as tobacco smoke, diet, cooking fumes, and occupational exposures) and individual susceptibilities (such as genetic, epigenetic, and hormonal factors). What is the evidence that there is an increased female susceptibility to lung cancer? Are female smokers more susceptible to lung cancer than male smokers, after controlling for the exposure (i.e., are women more susceptible to the same dose of tobacco carcinogens)? Are nonsmoking women more susceptible to lung cancer than nonsmoking men? Most studies suggest that women are more susceptible to the carcinogenic effects of cigarette smoke.14,50,52–54 In a study of 17 425 current and former smokers undergoing CT screening for lung cancer, Henschke and colleagues reported an odds ratio for lung cancer of 1.9 (95% CI 1.5–2.5) in women compared with men when controlled for both age and pack-years. Women were diagnosed with lung cancer at a median of 47 pack-years, while men were diagnosed at a median of 64 pack-years.46 In a well-designed, case control

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study of 1889 never-smokers and current smokers, Zang and Wynder reported odds ratios for lung cancer were 1.2–1.7fold higher for women than men both for never-smokers and for smokers. The odds ratios increased with increasing levels of exposure, again suggesting an increased susceptibility to the carcinogenic effects of smoke in women.10 Support for this hypothesis also comes from evidence that women may be more susceptible to the health effects of cigarette smoke generally. For example, a meta-analysis of studies on smoking induced morbidity and mortality showed a higher overall disease effect in women.55 A few studies suggest that women do not have an increased susceptibility to the carcinogenic effects of cigarette smoke.56–59 This is expected given the complexities in controlling for genderrelated differences in cigarette smoke exposure levels. In order to address susceptibility while controlling for gender differences in the exposure to cigarette smoke and its effect on lung cancer risk, investigators have compared incidence rates of lung cancer in nonsmoking men and women. Female nonsmokers appear to have an increased risk for lung cancer compared with nonsmoking males. Wakelee and colleagues examined lung cancer incidence in neversmoking men and women aged 40–79 in six large prospective cohorts and found that while the age-adjusted incidence rates for women in each cohort ranged from 14.4 to 20.8 per 100 000 person-years, rates for men were significantly lower at 4.8 to 13.7 per 100 000 person-years.60 Thun et al. however pooled data on never-smokers from 13 large cohort studies and detected no difference in incidence and death rates between males and females of European descent aged 40 and above.5 The pooled age-standardized incidence rates were 14.0 per 100 000 and 13.8 per 100 00 for men and women, respectively. Women may also have a higher incidence among those aged 40–59, a similar incidence among those aged 60–79, and a lower incidence among those older than 80 years (p  0.06). While both of these studies included three of the same cohorts, their different approaches (i.e. incidence vs. death rates, pooled vs. non-pooled data, and age-adjusted vs. age-standardized rates) may account for their disparate outcomes. Thus, further study will be needed to definitively answer the question of whether female nonsmokers are at an increased risk for lung cancer.

Potential mechanisms for a gender effect on lung cancer Epidemiologic studies show clear trends of increasing rates of lung cancer deaths in women and in the proportion of lung cancer cases occurring in never-smokers. Environmental exposures, molecular epidemiology, and hormonal influences may also contribute to gender differences in lung cancer.

Environmental Exposures While some studies have estimated that environmental tobacco smoke, or ‘second-hand’ smoke exposure results in an excess risk of 20% for lung cancer in never-smokers,61 others have found a more modest increase in lung cancer risk.62 While few have studied the differential exposure and effect of second-hand smoke on men and women, a pooled analysis of 14 studies in China detected an odds ratio for second-hand smoke-related lung cancer of 1.70 (95% CI: 1.32– 2.18) for nonsmoking women as opposed to 1.64 (95% CI: 1.29–2.07) for the population at large.63 Another study found an increased risk for lung cancer among Japanese women living with a smoking spouse, however no study has compared a similar incidence to the incidence of lung cancer in nonsmoking men living with a smoking spouse.64 In addition to environmental tobacco smoke, women worldwide are also exposed to higher levels of several environmental pollutants associated with lung cancer, such as cooking oil vapor and coal dust. Several studies have identified volatilization of cooking oil fumes from open woks and poorly ventilated kitchens as a risk factor for lung cancer in nonsmoking women in the developing world.63,65–70 In a case-control study of 672 Chinese women and 735 controls, cooking with rapeseed oil and stir-frying more than thirty dishes per week were identified as risk factors for lung cancer.71 In vitro studies have also shown mutagenic effects of heated rapeseed and soybean oils.72 While most studies suggest that environmental exposure to coal dust and lung cancer are linked,63,66,71,73–75 not all studies agree.76 If coal dust exposure is associated with lung cancer, then, as with cooking oil vapors, women in developing countries may be at a greater risk than men because of poorly ventilated indoor coal stoves. While women may have an increased risk of lung cancer related to exposures in the home, they have a decreased risk for lung cancer associated with occupational exposures such as asbestos, chromium, and arsenic.77,78 Other environmental exposures such as domestic radon,79,80 arsenic contamination of drinking water,81,82 and dietary factors83 have been implicated in lung cancer risk, but no clear gender associations have been identified. A novel exposure recently linked with lung cancer risk in women is infection with human papilloma virus serotypes 16 and 18 (HPV 16/18). Cheng et al. found that among female nonsmokers with lung cancer, the odds ratio for infection, as detected by PCR, was significantly higher in women than men.84 If validated, this intriguing finding may provide insights into the role of infection in lung carcinogenesis. Overall, current evidence suggests that second-hand smoke and cooking oil vapor exposures are important contributors to lung cancer risk in never-smoking women. Minimization of these exposures is a logical strategy to lower the incidence of lung cancer in never smoking women.

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Molecular Epidemiology In cigarette smokers, lung cancer arises as the consequence of cumulative genetic and epigenetic alterations to the bronchial epithelium that culminates in carcinoma in susceptible individuals. Within cigarette smoke are thousands of particulate compounds, of which at least 60 have been determined by the International Agency for Research on Cancer (IARC) to be carcinogenic in humans or laboratory animals.85 These carcinogens include polycyclic aromatic hydrocarbons (PAH) such as Benzo-[a]-pyrene (BaP), and nicotine derived nitrosamines such as NNK. The response to carcinogen exposure is mediated by enzyme systems that metabolize endogenous chemicals and xenobiotics. Although initially thought to be restricted to the liver, it is clear these enzymes are expressed and active in other organs, including the lung. The metabolism of environmental pollutants and drugs is divided into two reaction classes, phase I (functionalization) and phase II (conjugation). Inter-individual phenotypic heterogeneity is associated with allelic variants that exist within each gene family. PAH are metabolized by CYP1A1 and by CYP1B1. There are at least 12 variant alleles of CYP1A1, some of which are associated with increased enzyme inducibility and have been examined in lung cancer case-control studies. CYP1A1 induces the conversion of BaP to its toxic metabolite BaPdiol epoxide, which binds covalently to DNA to form DNA adducts, a validated biomarker of DNA damage and lung cancer risk. Polymorphisms in exon 7 of CYP1A1 have been associated with an increased risk for lung cancer86 and CYP1A1 expression has been shown to be higher in females and to be associated with increased DNA adduct levels.87 Other recent studies suggest that induction of CYP1A1 may be mediated by crosstalk between the estrogen and aryl hydroxylase receptors.88 Phase II enzyme detoxification conjugations occur with moieties such as glucoronide, mercapturic acid, acetate, methyl, sulphate, glycine, glutamine, thiocyanate, and glucoside, resulting in a hydrophilic product that is readily excretable.89 Phase II enzymes include glutathione S-transferases (GSTs), uridine diphosphate glucuronosyltransferases, sulphotransferases, epoxidases, acyltransferases, acetyltrans­ ferases, methyltransferases, and transaminases. The most frequently studied Phase II enzymes are the GSTs, which function to conjugate electrophilic compounds, such as BaP with glutathione. The GSTM1 class occurs in null form in 50% of the white population. Two studies have linked deletions of GSTM1 with lung cancer risk in nonsmoking women, especially those exposed to high levels of environmental tobacco smoke.90,91 In addition, the UDP-glucuronyltransferase enzymes (UDPs) have been implicated in lung cancer risk in women. Recent studies suggest that UDPs expression may be regulated by estrogen and that deletion polymorphisms in the UGT2B17 gene (the most potent hepatic enzyme against the tobacco

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carcinogen NNK) may be associated with lung cancer risk in women but not men.92,93 The role of susceptibility factors in lung carcinogenesis traditionally has been examined in case-control studies. However, data obtained from the case-control study design may be confounded by recall bias and by information bias due to the presence of lung cancer. The results may be obscured by the long time interval between exposure to mutagens and the development of lung cancer. To address these concerns, researchers have recently directed efforts to developing intermediate biomarkers of lung cancer for the determination of lung cancer susceptibility factors. These intermediate biomarkers include well-characterized molecular dosimeters of cigarette carcinogen exposure, such as PAH-DNA adducts. Studies have shown that elevated adduct levels and impaired DNA repair capacity are associated with an increased risk for lung cancer94 and gender differences in metabolism and DNA repair have been observed.95 In a study of 62 nonsmoking lung cancer patients and 20 controls, DNA adduct levels were found to be significantly higher in lung tissue from women than men.96 Similarly, lung DNA adduct levels per pack-year of smoke exposure are significantly higher in non-smoking women than men.87,97 Other genes potentially involved in lung cancer risk include the nicotinic acetylcholine receptor (nAchR) and the gastrin-releasing peptide receptor (GRPR). Recent results from three genome wide association studies of lung cancer risk identified common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 that were associated with nicotine dependence and/or lung cancer risk.98–100 Although there was a slight increased risk for women compared with men (p  0.06) in the IARC Central European cohort, there was no increased risk for women in the Iceland cohort. The gene encoding gastrinreleasing peptide receptor (GRPR), which is important in mediating signaling pathways important for lung cell growth, is located on the X-chromosome and is known to escape X-chromosome inactivation in females. Expression of GRPR is higher in women than in men and is upregulated in response to tobacco smoke, thus suggesting a role for gender associated gene expression differences that may be important in lung carcinogenesis.101 Tumor genetics may also play a role in female lung cancer susceptibility and prognosis. For example, loss of heterozygosity at chromosome 11p15 was found to occur more commonly in men and among smokers, and was associated with a poorer overall survival. However, because smoking exposure was not controlled for in this study, it is unclear if the observed effect of gender simply reflects a smaller number of female smokers.102 Alterations in tumor cell p53 expression and activity have also been linked to gender. Guinee et al. identified a higher frequency of p53 transversion mutations in lung cancer cells from female smokers103 and Mukhopadhyay and colleagues observed

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that estradiol promotes apoptosis in lung cancer lines via activation of p53.104 In conclusion, several lines of evidence suggest that the molecular epidemiology of lung cancer may be different in men and women and may help to explain the observed differences in lung cancer susceptibility and prognosis.

Hormones There is increasing evidence that estrogens play a critical role in lung cancer susceptibility and prognosis. Later menarche and shorter cycle lengths have been associated with an increased incidence of lung cancer65 while early menopause has been shown to be protective.105 Notably, in a study of 766 patients with small cell lung cancer, female gender was identified as an independent predictor of response and survival, but only for women under the age of 60, supporting a putative tumor suppressive effect of estrogen manifested as a shift towards increased lung cancer mortality among postmenopausal women.106 Estrogens bind two receptor subtypes with high affinity, ER and ER. Both receptors have been identified in normal lung tissue107–109 as well as resected lung tumor specimens.110–113 In vitro studies have demonstrated estrogen receptor expression and response by NSCLC cell lines as well as normal lung fibroblasts and bronchial epithelium.111,114 Estrogen metabolites have also been shown to have antiangiogenic and pro-apoptotic effects.104,115 The role of estrogen in lung cancer is complicated by the fact that its effect may be receptor-dependent, with ER promoting and ER inhibiting gene transcription.116 The effects of estradiol on lung cancer may not be limited to cells expressing the estrogen receptor. A second receptor, the type II estrogen binding site, binds to both estrogen and tamoxifen and inhibits cell growth in a dosedependent manner.117 Also, estrogens have been shown to mediate effects on the EGFR pathway. Stabile et al. showed that EGFR expression is downregulated in response to estrogen and is upregulated in response to the estrogen receptor antagonist fulvestrant. Using a murine xenograft model, treatment with combination gefitinib and fulvestrant suppressed tumor growth 60% as opposed to 49% and 32% for gefitinib or fulvestrant alone.118 Estrogen and progesterone receptors have also been identified in some resected human lung cancer specimens.110,119 While Canver et al. found positive immunostaining for estrogen receptors in 62 of 64 NSCLC specimens, another study found detectable staining in only 2 of 32 specimens.114,120 Positive tumor immunostaining for ER has been associated with improved survival in men.121 Recently, Niikawa et al. examined 59 frozen NSCLC specimens and found that 73% had higher intratumoral estradiol concentrations than surrounding non-neoplastic lung tissue. They also found that intratumoral estradiol concentration was positively correlated with tumor size.122 Another group

identified gender dependent expression patterns of intratumoral estrogen receptors by using RT-PCR to show estrogen receptor gene expression in 85% of specimens from women but only 15% of specimens from men.123 The role of HRT and effects on estrogen signaling may alter lung cancer risk. Adami et al. found a relative risk for lung cancer of 1.3 (95%CI: 0.9–1.7) for women receiving HRT.124 Taioli et al. also found an increased risk of adenocarcinoma in women receiving hormone replacement therapy (HRT), however, subgroup analyses revealed that this effect was limited only to smokers.105 Not all studies have identified an increased risk for lung cancer associated with HRT,125 and several demonstrate a protective effect.126–130 In a case-control study of 499 women with lung cancer and 519 controls, Schabath et al. found a 34% reduction in the overall risk of lung cancer associated with the use of HRT after controlling for age and smoking status.126 Similarly, Schwartz et al. found the duration of HRT use in postmenopausal women to be associated with a reduction in lung cancer risk (OR 0.88, 95% CI 0.78–1.00).127 Prospective trials will be needed to definitively address this issue.

Do women with lung cancer have a better prognosis than men? It has been suggested that while women may be more susceptible to lung cancer than men, they may also have a better prognosis. While men certainly have a higher death rate from lung cancer than women, it is unclear if this is due to inherent biologic differences between men and women or is simply a result of multiple potential confounders such as smoking prevalence, histology, stage at diagnosis, comorbid disease, and underlying lung function. For example, while many studies do show a survival advantage for women with lung cancer, they also show that women are more often never-smokers, present at an earlier stage, have better underlying lung function and fewer co-morbidities, and are less likely to require extensive surgical operations such as pneumonectomy.12,13,15 Despite these potential confounders, several studies suggest that women may have a better response to treatment and a better survival after surgical resection for NSCLC.12,13,15,47,49,131–133 A study of 2531 patients in the SWOG database treated for advanced NSCLC between 1974 and 1988 identified female gender as an independent predictor of survival134 and these results have been confirmed by others.16,135,136 While some have found female gender to be predictive of improved survival at all stages,47,51,137 others have found the effect to be limited.13,15,132 However, because women nonsmokers outnumber men and most studies do not control for smoking history, it is difficult to determine if the survival advantage is due to gender differences or smoking status.

C h a p t e r 2 3    The Gender-Specific Aspects of Lung Cancer l

Therefore, studies that adjust for total tobacco exposure are of particular interest. Henschke et al. found that female smokers with NSCLC identified by CT screening had a hazard ratio for death of 0.48 (95% CI: 0.25–0.89) compared with males after controlling for stage and packyears.46 Similarly, in a prospective study of 4618 patients treated for NSCLC at the Mayo Clinic, men were found to have a relative risk of death from lung cancer of 1.20 (95% CI: 1.11–1.30) after adjusting for age, stage, and pack-years smoked.138 A survival advantage for women has also been observed in SCLC. An analysis of 1745 patients with SCLC in the CALGB database identified female gender in multivariate analysis to be an independent predictor of treatment response and survival for both limited and extensive disease.139 Similar results were seen in a pooled analysis of three German multicenter trials where women were found to have a higher rate of complete remission (35% vs. 25%) and an improved two year survival (19% vs. 8%).106 Other studies also found that female gender predicted improved survival, but did not control for extent of disease.140,141 In summary, the data do seem to support a survival advantage for women with both SCLC and NSCLC.

Conclusions Cigarette smoking remains the leading cause of lung cancer death and of cancer death in women of the world. While it is not yet clear if women are more susceptible to lung cancer, current evidence does suggest that women with lung cancer have an improved prognosis compared to men with similar cigarette smoke exposure. Potential explanations for observed gender disparities in lung cancer include environmental exposures, molecular genetic factors, and hormonal differences. The gap between male and female smoking prevalence is narrowing and we are likely to see the incidence and death rates from lung cancer in women begin to approach those in men. As research continues to be directed towards understanding gender-specific aspects of lung cancer susceptibility and prognosis, advocacy for public policy initiatives will help prevent and reduce smoking prevalence in girls and women. Exposure to environmental pollutants can be remediated, which is a strategy that may be helpful in lowering the incidence of lung cancer in never smoking women in developing countries.

References 1. Ferlay J, International Agency for Research on Cancer. GLOBOCAN 2000 cancer incidence, mortality, and prevalence worldwide. [IARC cancerBase no 5]. Lyons: IARCPress; 2001: p. 1 CD-ROM. 2. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53(1):5–26.

265

3. Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA Cancer J Clin 1990;40(1):9–26. 4. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71–96. 5. Thun MJ, Hannan LM, Adams-Campbell LL, et al. Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies. PLoS Med. 2008;5(9):e185. 6. American Cancer Society. Cancer Facts and Figures – 1994. Atlanta, GA: American Cancer Society; 1994. 7. Peto R. Imperial Cancer Research Fund (Great Britain), World Health Organization. Mortality from smoking in Developed countries, 1950–2000: indirect estimates from national vital statistics. Oxford: Oxford University Press; 1994. 8. Garfinkel L. Trends in cigarette smoking in the United States. Prev Med 1997;26(4):447–450. 9. Cigarette smoking among adults – United States, 2007. MMWR 2008;14;57(45):1221–1226. 10. Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996;88(3–4):183–192. 11. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74–108. 12. Ferguson MK, Wang J, Hoffman PC, et al. Sex-associated differences in survival of patients undergoing resection for lung cancer. Ann Thorac Surg 2000;69(1):245–49, discussion 9–50. 13. Alexiou C, Patrick Onyeaka CV, Beggs D, et al. Do women live longer following lung resection for carcinoma? Eur J Cardiothorac Surg 2002;21(2):319–325. 14. McDuffie HH, Klaassen DJ, Dosman JA. Female–male differences in patients with primary lung cancer. Cancer 1987; 59(10):1825–1830. 15. de Perrot M, Licker M, Bouchardy C, et al. Sex differences in presentation, management, and prognosis of patients with non-small cell lung carcinoma. J Thorac Cardiovasc Surg 2000;119(1):21–26. 16. Radzikowska E, Glaz P, Roszkowski K. Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20,561 cases. Ann Oncol 2002;13(7):1087–1093. 17. Muscat JE, Wynder EL. Lung cancer pathology in smokers, ex-smokers and never smokers. Cancer Lett 1995;88(1):1–5. 18. Brownson RC, Loy TS, Ingram E, et al. Lung cancer in nonsmoking women. Histology and survival patterns. Cancer 1995;75(1):29–33. 19. Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol 2007;25(5):561–570. 20. Subramanian J, Velcheti V, Gao F, et al. Presentation and stage-specific outcomes of lifelong never-smokers with nonsmall cell lung cancer (NSCLC). J Oncol 2007;2(9):827–830. 21. Wong MP, Fung LF, Wang E, et al. Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers. Cancer 2003;97(5):1263–1270. 22. Powell CA, Bueno R, Borczuk AC, et al. Patterns of allelic loss differ in lung adenocarcinomas of smokers and nonsmokers. Lung Cancer 2003;39(1):23–29. 23. Toyooka S, Maruyama R, Toyooka KO, et al. Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int J Cancer 2003;103(2):153–160.

266

s e c t i o n 4     Pulmonology l

24. Toyooka S, Suzuki M, Tsuda T, et al. Dose effect of smoking on aberrant methylation in non-small cell lung cancers. Int J Cancer 2004;110(3):462–464. 25. Le Calvez F, Mukeria A, Hunt JD, et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res 2005;65(12):5076–5083. 26. Takeuchi T, Tomida S, Yatabe Y, et al. Expression profiledefined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. J Clin Oncol 2006;24(11):1679–88. 27. Powell CA, Spira A, Derti A, et al. Gene expression in lung adenocarcinomas of smokers and nonsmokers. Am J Respir Cell Mol Biol 2003;29(2):157–162. 28. Sonobe M, Manabe T, Wada H, et al. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 2005;93(3):355–363. 29. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101(36):13306–13311. 30. Pham D, Kris MG, Riely GJ, et al. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol 2006;24(11):1700–1704. 31. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97(5):339–346. 32. Slebos RJ, Hruban RH, Dalesio O, et al. Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst 1991;83(14):1024–1027. 33. Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res 2006;12(5):1647–1653. 34. Dutu T, Michiels S, Fouret P, et al. Differential expression of biomarkers in lung adenocarcinoma: a comparative study between smokers and never-smokers. Ann Oncol 2005;16(12):1906–1914. 35. Ahrendt SA, Decker PA, Alawi EA, et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 2001;92(6):1525–1530. 36. Gealy R, Zhang L, Siegfried JM, et al. Comparison of mutations in the p53 and K-ras genes in lung carcinomas from smoking and nonsmoking women. Cancer Epidemiol Biomarkers Prev 1999;8(4 Pt 1):297–302. 37. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497–1500. 38. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 2005;353(2):133–144. 39. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebocontrolled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366(9496):1527–1537. 40. Shepherd FA, Rodrigues Pereira J, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353(2):123–132.

41. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129–2139. 42. Toh CK, Wong EH, Lim WT, et al. The impact of smoking status on the behavior and survival outcome of patients with advanced non-small cell lung cancer: a retrospective analysis. Chest 2004;126(6):1750–1756. 43. Nordquist LT, Simon GR, Cantor A, et al. Improved survival in never-smokers vs. current smokers with primary adenocarcinoma of the lung. Chest 2004;126(2):347–351. 44. Yano T, Miura N, Takenaka T, et al. Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer 2008;113(5):1012–1018. 45. Wynder EL, Mabuchi K, Beattie EJ Jr. The epidemiology of lung cancer: recent trends. JAMA 1970;213(13):2221–2228. 46. Henschke CI, Yip R, Miettinen OS. Women’s susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. JAMA 2006;296(2):180–184. 47. Cerfolio RJ, Bryant AS, Scott E, et al. Women with pathologic stage I, II, and III non-small cell lung cancer have better survival than men. Chest 2006;130(6):1796–1802. 48. Ramalingam S, Pawlish K, Gadgeel S, et al. Lung cancer in young patients: analysis of a Surveillance, Epidemiology, and End Results database. J Clin Oncol 1998;16(2):651–657. 49. Minami H, Yoshimura M, Miyamoto Y, et al. Lung cancer in women: sex-associated differences in survival of patients undergoing resection for lung cancer. Chest 2000;118(6):1603–1609. 50. Henschke CI, Miettinen OS. Women’s susceptibility to tobacco carcinogens. Lung Cancer 2004;43(1):1–5. 51. Ferguson MK, Skosey C, Hoffman PC, et al. Sex-associated differences in presentation and survival in patients with lung cancer. J Clin Oncol 1990;8(8):1402–1407. 52. Risch HA, Howe GR, Jain M, et al. Are female smokers at higher risk for lung cancer than male smokers? A case-control analysis by histologic type. Am J Epidemiol 1993;138(5):281–293. 53. Brownson RC, Chang JC, Davis JR. Gender and histologic type variations in smoking-related risk of lung cancer. Epidemiology 1992;3(1):61–64. 54. Harris RE, Zang EA, Anderson JI, et al. Race and sex differences in lung cancer risk associated with cigarette smoking. Int J Epidemiol 1993;22(4):592–599. 55. Mucha L, Stephenson J, Morandi N, et al. Meta-analysis of disease risk associated with smoking, by gender and intensity of smoking. Gend Med 2006;3(4):279–291. 56. Doll R, Gray R, Hafner B, et al. Mortality in relation to smoking: 22 years’ observations on female British doctors. Br Med J 1980;280(6219):967–971. 57. Doll R, Peto R. Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J 1976;2(6051): 1525–1536. 58. Kreuzer M, Boffetta P, Whitley E, et al. Gender differences in lung cancer risk by smoking: a multicentre case-control study in Germany and Italy. Br J Cancer 2000;82(1):227–233. 59. Prescott E, Osler M, Hein HO, et al. Gender and smokingrelated risk of lung cancer. The Copenhagen Center for Prospective Population Studies. Epidemiology 1998;9(1):79–83. 60. Wakelee HA, Chang ET, Gomez SL, et al. Lung cancer incidence in never smokers. J Clin Oncol 2007; 25(5):472–478.

C h a p t e r 2 3    The Gender-Specific Aspects of Lung Cancer l

61. National Cancer Institute (US), California Environmental Protection Agency. Reproductive and Cancer Hazard Assessment Section, California Environmental Protection Agency. Air Toxicology and Epidemiology Section. Health effects of exposure to environmental tobacco smoke: the report of the California Environmental Protection Agency. Bethesda, MD: http://cancercontrol.cancer.gov/tcrb/monographs/ 10/m10_7.pdf/. 62. Vineis P, Airoldi L, Veglia F, et al. Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study. BMJ 2005;330(7486):277. 63. Zhao Y, Wang S, Aunan K, et al. Air pollution and lung cancer risks in China – a meta-analysis. Sci Total Environ 2006;366(2–3):500–513. 64. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan. BMJ (Clinical Research Ed) 1981;282(6259):183–185. 65. Gao YT, Blot WJ, Zheng W, et al. Lung cancer among Chinese women. Int J Cancer 1987;40(5):604–609. 66. Boffetta P, Nyberg F. Contribution of environmental factors to cancer risk. Br Med Bull 2003;68:71–94. 67. Yu IT, Chiu YL, Au JS, et al. Dose–response relationship between cooking fumes exposures and lung cancer among Chinese nonsmoking women. Cancer Res 2006;66(9):4961–4967. 68. Zhong L, Goldberg MS, Gao YT, et al. Lung cancer and indoor air pollution arising from Chinese-style cooking among nonsmoking women living in Shanghai, China. Epidemiology 1999;10(5):488–494. 69. Metayer C, Wang Z, Kleinerman RA, et al. Cooking oil fumes and risk of lung cancer in women in rural Gansu, China. Lung Cancer 2002;35(2):111–117. 70. Ko YC, Cheng LS, Lee CH, et al. Chinese food cooking and lung cancer in women nonsmokers. Am J Epidemiol 2000;151(2):140–147. 71. Wu-Williams AH, Dai XD, Blot W, et al. Lung cancer among women in north-east China. Br J Cancer 1990;62(6):982–987. 72. Qu YH, Xu GX, Zhou JZ, et al. Genotoxicity of heated cooking oil vapors. Mutat Res 1992;298(2):105–111. 73. Mumford JL, He XZ, Chapman RS, et al. Lung cancer and indoor air pollution in Xuan Wei, China. Science 1987;235(4785):217–220. 74. Kleinerman R, Wang Z, Lubin J, et al. Lung cancer and indoor air pollution in rural China. Ann Epidemiol 2000;10(7):469. 75. Kleinerman RA, Wang Z, Wang L, et al. Lung cancer and indoor exposure to coal and biomass in rural China. J Occup Environ Med 2002;44(4):338–344. 76. Ko YC, Lee CH, Chen MJ, et al. Risk factors for primary lung cancer among non-smoking women in Taiwan. Int J Epidemiol 1997;26(1):24–31. 77. Gottschall EB. Occupational and environmental thoracic malignancies. J Thorac Imaging 2002;17(3):189–197. 78. Neuberger JS, Field RW. Occupation and lung cancer in nonsmokers. Rev Environ Health 2003;18(4):251–267. 79. Krewski D, Lubin JH, Zielinski JM, et al. A combined analysis of North American case-control studies of residential radon and lung cancer. J Toxicol Environ Health A 2006;69(7):533–597. 80. Darby S, Hill D, Auvinen A, et al. Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. BMJ 2005;330(7485):223.

267

81. Chen CL, Hsu LI, Chiou HY, et al. Ingested arsenic, cigarette smoking, and lung cancer risk: a follow-up study in arseniasis-endemic areas in Taiwan. JAMA 2004;292(24): 2984–2990. 82. Ferreccio C, Gonzalez C, Milosavjlevic V, et al. Lung cancer and arsenic concentrations in drinking water in Chile. Epidemiology 2000;11(6):673–679. 83. Feskanich D, Ziegler RG, Michaud DS, et al. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. J Natl Cancer Inst 2000;92(22):1812–1823. 84. Cheng YW, Chiou HL, Sheu GT, et al. The association of human papillomavirus 16/18 infection with lung cancer among nonsmoking Taiwanese women. Cancer Res 2001; 61(7):2799–2803. 85. Hoffmann D, Hoffmann I, El-Bayoumy K. The less harmful cigarette: a controversial issue. a tribute to Ernst L. Wynder. Chem Res Toxicol 2001;14(7):767–790. 86. Le Marchand L, Guo C, Benhamou S, et al. Pooled analysis of the CYP1A1 exon 7 polymorphism and lung cancer (United States). Cancer Causes Control 2003;14(4):339–346. 87. Mollerup S, Ryberg D, Hewer A, et al. Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients. Cancer Res 1999;59(14):3317–3320. 88. Thomsen JS, Wang X, Hines RN, et al. Restoration of aryl hydrocarbon (Ah) responsiveness in MDA-MB-231 human breast cancer cells by transient expression of the estrogen receptor. Carcinogenesis 1994;15(5):933–937. 89. Williams RT. The metabolism of certain drugs and food chemicals in man. Ann N Y Acad Sci 1971;179:141–154. 90. Kiyohara C, Wakai K, Mikami H, et al. Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of environmental tobacco smoke and lung cancer: a casecontrol study in Japanese nonsmoking women. Int J Cancer 2003;107(1):139–144. 91. Bennett WP, Alavanja MC, Blomeke B, et al. Environmental tobacco smoke, genetic susceptibility, and risk of lung cancer in never-smoking women. J Natl Cancer Inst 1999;91 (23):2009–2014. 92. Gallagher CJ, Muscat JE, Hicks AN, et al. The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism: sex-specific association with urinary 4-(methylnitrosamino)-1-(3-pyridyl)1-butanol glucuronidation phenotype and risk for lung cancer. Cancer Epidemiol Biomarkers Prev 2007;16(4):823–828. 93. Lazarus P. Gender issues and the molecular epidemiology of lung cancer risk. Clin Lung Cancer 2008;9(3):140. 94. Wei Q, Cheng L, Amos CI, et al. Repair of tobacco carcinogeninduced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst 2000;92(21):1764–1772. 95. Schenkman JB, Frey I, Remmer H, et al. Sex differences in drug metabolism by rat liver microsomes. Mol Pharmacol 1967;3(6):516–525. 96. Cheng YW, Hsieh LL, Lin PP, et al. Gender difference in DNA adduct levels among nonsmoking lung cancer patients. Environ Mol Mutagen 2001;37(4):304–310. 97. Ryberg D, Hewer A, Phillips DH, et al. Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients. Cancer Res 1994;54(22):5801–5803. 98. Thorgeirsson TE, Geller F, Sulem P, et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 2008;452(7187):638–642.

268

s e c t i o n 4     Pulmonology l

  99. Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008;452(7187):633–637. 100. Amos CI, Wu X, Broderick P, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008;40(5):616–622. 101. Shriver SP, Bourdeau HA, Gubish CT, et al. Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer. J Natl Cancer Inst 2000;92(1):24–33. 102. Schreiber G, Fong KM, Peterson B, et al. Smoking, gender, and survival association with allele loss for the LOH11B lung cancer region on chromosome 11. Cancer Epidemiol Biomarkers Prev 1997;6(5):315–319. 103. Guinee DG Jr, Travis WD, Trivers GE, et al. Gender comparisons in human lung cancer: analysis of p53 mutations, anti-p53 serum antibodies and C-erbB-2 expression. Carcinogenesis 1995;16(5):993–1002. 104. Mukhopadhyay T, Roth JA. Induction of apoptosis in human lung cancer cells after wild-type p53 activation by methoxyestradiol. Oncogene 1997;14(3):379–384. 105. Taioli E, Wynder EL. Re: Endocrine factors and adenocarcinoma of the lung in women. J Natl Cancer Inst 1994; 86(11):869–870. 106. Wolf M, Holle R, Hans K, et al. Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival. Br J Cancer 1991;63(6):986–992. 107. Brandenberger AW, Tee MK, Lee JY, et al. Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ERbeta) mRNA in the midgestational human fetus. J Clin Endocrinol Metab 1997;82(10):3509–3512. 108. Enmark E, Pelto-Huikko M, Grandien K, et al. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 1997;82(12):4258–4265. 109. Kuiper GG, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997;138(3):863–870. 110. Cagle PT, Mody DR, Schwartz MR. Estrogen and progesterone receptors in bronchogenic carcinoma. Cancer Res 1990;50(20):6632–6635. 111. Stabile LP, Davis AL, Gubish CT, et al. Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res 2002;62(7):2141–2150. 112. Schwartz AG, Prysak GM, Murphy V, et al. Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sex. Clin Cancer Res 2005;11(20):7280–7287. 113. Beattie CW, Hansen NW, Thomas PA. Steroid receptors in human lung cancer. Cancer Res 1985;45(9):4206–4214. 114. Canver CC, Memoli VA, Vanderveer PL, et al. Sex hormone receptors in non-small-cell lung cancer in human beings. J Thorac Cardiovasc Surg 1994;108(1):153–157. 115. Fotsis T, Zhang Y, Pepper MS, et al. The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 1994;368(6468):237–239. 116. Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 1997;277(5331):1508–1510.

117. Caltagirone S, Ranelletti FO, Rinelli A, et al. Interaction with type II estrogen binding sites and antiproliferative activity of tamoxifen and quercetin in human non-small-cell lung cancer. Am J Respir Cell Mol Biol 1997;17(1):51–59. 118. Stabile LP, Lyker JS, Gubish CT, et al. Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects. Cancer Res 2005;65(4):1459–1470. 119. Omoto Y, Kobayashi Y, Nishida K, et al. Expression, function, and clinical implications of the estrogen receptor beta in human lung cancers. Biochem Biophys Res Commun 2001;285(2):340–347. 120. Radzikowska E, Langfort R, Giedronowicz D. Estrogen and progesterone receptors in non small cell lung cancer patients. Ann Thorac Cardiovasc Surg 2002;8(2):69–73. 121. Skov BG, Fischer BM, Pappot H. Oestrogen receptor beta over expression in males with non-small cell lung cancer is associated with better survival. Lung Cancer 2008;59(1):88–94. 122. Niikawa H, Suzuki T, Miki Y, et al. Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin Cancer Res 2008;14(14):4417–4426. 123. Fasco MJ, Hurteau GJ, Spivack SD. Gender-dependent expression of alpha and beta estrogen receptors in human nontumor and tumor lung tissue. Mol Cell Endocrinol 2002;188(1–2):125–140. 124. Adami HO, Persson I, Hoover R, et al. Risk of cancer in women receiving hormone replacement therapy. Int J Cancer 1989;44(5):833–839. 125. Blackman JA, Coogan PF, Rosenberg L, et al. Estrogen replacement therapy and risk of lung cancer. Pharmaco­ epidemiol Drug Saf 2002;11(7):561–567. 126. Schabath MB, Wu X, Vassilopoulou-Sellin R, et al. Hormone replacement therapy and lung cancer risk: a case-control analysis. Clin Cancer Res 2004;10(1 Pt 1): 113–123. 127. Schwartz AG, Wenzlaff AS, Prysak GM, et al. Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in women. J Clin Oncol 2007;25(36):5785–5792. 128. Ramnath N, Menezes RJ, Loewen G, et al. Hormone replacement therapy as a risk factor for non-small cell lung cancer: results of a case-control study. Oncology 2007; 73(5–6):305–310. 129. Kreuzer M, Gerken M, Heinrich J, et al. Hormonal factors and risk of lung cancer among women? Int J Epidemiol 2003; 32(2):263–271. 130. Chen KY, Hsiao CF, Chang GC, et al. Hormone replacement therapy and lung cancer risk in Chinese. Cancer 2007; 110(8):1768–1775. 131. O’Connell JP, Kris MG, Gralla RJ, et al. Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 1986;4 (11):1604–1614. 132. Mitsudomi T, Tateishi M, Oka T, et al. Longer survival after resection of non-small cell lung cancer in Japanese women. Ann Thorac Surg 1989;48(5):639–642. 133. Chang MY, Mentzer SJ, Colson YL, et al. Factors predicting poor survival after resection of stage IA non-small cell lung cancer. J Thorac Cardiovasc Surg 2007;134(4):850–856.

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134. Albain KS, Crowley JJ, LeBlanc M, et al. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9(9):1618–1626. 135. Ouellette D, Desbiens G, Emond C, et al. Lung cancer in women compared with men: stage, treatment, and survival. Ann Thorac Surg. 1998;66(4):1140–43, discussion 3–4. 136. Ederer F, Mersheimer WL. Sex differences in the survival of lung cancer patients. Cancer 1962;15:425–432. 137. Fu JB, Kau TY, Severson RK, et al. Lung cancer in women: analysis of the national Surveillance, Epidemiology, and End Results database. Chest 2005;127(3):768–777. 138. Visbal AL, Williams BA, Nichols FC III, et al. Gender differences in non-small-cell lung cancer survival: an analysis

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of 4,618 patients diagnosed between 1997 and 2002. Ann Thorac Surg 2004;78(1):209–15, discussion 15. 139. Spiegelman D, Maurer LH, Ware JH, et al. Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients. J Clin Oncol 1989;7(3):344–354. 140. Paesmans M, Sculier JP, Lecomte J, et al. Prognostic factors for patients with small cell lung carcinoma: analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer 2000;89(3):523–533. 141. Johnson BE, Steinberg SM, Phelps R, et al. Female patients with small cell lung cancer live longer than male patients. Am J Med 1988;85(2):194–196.

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24

Gender-Specific Considerations in Pulmonary Hypertension Deborah Shure Master FCCP, Consultant Medical Reviewer, Center for Devices and Radiological Health, Miami, FL, USA

Introduction

Very little is known about gender-specific issues in most diseases associated with pulmonary arterial hypertension. For most diseases, the issue has not been investigated although in some, gender trends in epidemiological variables or in treatment responses have been investigated and not detected. Because most of the little we do know is related to diseases in Group 1 of the Venice classification, they will be the focus of this chapter. In particular, IPAH and scleroderma will be reviewed because recognized gender issues are associated with these disorders.

Pulmonary arterial hypertension is defined by a mean pulmonary artery pressure greater than 25 mmHg at rest or greater than 30 mmHg with exercise with a pulmonary capillary wedge pressure less than 15 mmHg as measured by right heart catheterization.1 It can also be defined by a pulmonary artery systolic pressure of 40 mmHg as estimated by echocardiographic criteria. Elevations in pulmonary artery pressure occur in a wide variety of pulmonary, cardiac, and systemic diseases. Classification schemes for these diseases have changed over the years reflecting our changing understanding of pathophysiology, etiology, and therapy. The currently accepted classification was developed at the 2003 Third World Symposium on Pulmonary Arterial Hypertension and is often referred to as the Venice classification based on the symposium’s venue.2 The Venice classification reflects an organization based on etiology and similarities in therapeutic interventions. It divides diseases into five categories (Table 24.1). Group 1 consists of diseases that primarily involve the small pulmonary arteries and muscular arterioles. These diseases tend to have similar histological changes and many respond to the same treatments. Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is probably the best known of these diseases. Familial pulmonary arterial hypertension (FPAH), drug and toxin induced pulmonary arterial hypertension, and HIV-related pulmonary arterial hypertension all have similar pathology and clinical pictures to IPAH and respond similarly to drug therapy. This group also includes pulmonary arterial hypertension associated with collagen vascular diseases, most of which have overlapping pathological features with IPAH and also respond to some extent to the same drug therapies. Groups 2 through 5 categorize diseases associated with left heart disease, hypoxemic lung disease, chronic thromboembolic disease, and miscellaneous diseases. Principles of Gender-Specific Medicine

Idiopathic pulmonary arterial hypertension IPAH primarily involves remodeling of small pulmonary arteries and arterioles although changes can be seen to a lesser extent in the pulmonary venous system. The pathological changes consist of endothelial cell proliferation, often in a complex pattern termed a plexiform lesion, as well as smooth muscle cell (medial) hypertrophy, and some adventitial changes related to fibrosis and alterations in extracellular matrix.3 Identical pathological findings can be seen in FPAH, anorexigenic, toxin, and HIV-related pulmonary arterial hypertension. These changes result in narrowing of the small pulmonary arteries and arterioles. In addition, thrombotic occlusion of the microvasculature occurs, probably by thrombus formation in situ, possibly related to altered flow. This added occlusion leads to further microvascular narrowing of the microvasculature. Heightened vasoreactivity used to be viewed as a hallmark of the disease. Vasoreactivity has been variably defined in relation to percentage decreases in pulmonary artery pressure or pulmonary vascular resistance in response to a vasodilator drug, but the more recently accepted definition is at least 270

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a 10 mmHg drop in mean pulmonary artery pressure to a mean pressure of 40 mmHg.4 In general, the decrease in pulmonary artery pressure should not be accompanied by an adverse effect on cardiac output. It is now known that vasoreactivity is present in only 10–20% of patients with IPAH and could reflect a different genotype, a different phenotype, or an earlier disease stage. A recent study suggests that patients without the known gene associated with FPAH (BMPR2, see Pathogenesis) are more likely to be vasoreactive,5 supporting a genetic difference underlying the response. Vasoreactivity has implications for treatment choices (see Treatment), but does not appear to have prognostic significance. There is no recognized gender difference in vasoreactivity.

Epidemiology IPAH is a rare disease with a prevalence of 1–2 cases/million in the general population.5 FPAH accounts for approximately

Table 24.1  Venice Classification of pulmonary hypertension (abbreviated) Group 1: Pulmonary arterial hypertension – includes: • Idiopathic • Familial • Associated with collagen vascular disease, HIV, drugs, toxins, portal hypertension, congenital systemic-pulmonary shunts, other • Associated with significant venous or capillary involvement including pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis • Persistent pulmonary hypertension of the newborn Group 2: Pulmonary hypertension associated with left heart disease Group 3: Pulmonary hypertension associated with lung diseases or hypoxemia • • • • • •

Chronic obstructive pulmonary disease Interstitial lung disease Sleep disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities

Group 4: Pulmonary hypertension associated with chronic thrombotic or embolic disease • Thromboembolic obstruction of proximal pulmonary arteries • Thromboembolic obstruction of distal pulmonary arteries • Non-thrombotic pulmonary embolism (tumor, parasites, foreign material) Group 5: Miscellaneous • Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels Source: Simmonneau et al. (2004)2

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6% of cases6 although the prevalence may be underestimated. It is thought that some sporadic cases of IPAH may be familial, but misidentified because of the low penetrance of the gene. Based on registry information from a number of countries, there is a clear female predominance in IPAH, FPAH, and anorexigenic pulmonary arterial hypertension. Although ratios vary from country to country, the overall female to male ratio in IPAH is approximately 2 to 1.7,8 At least one genetic factor appears to be related to the female predominance of IPAH in that more girls than boys are born to women who have the gene identified with both familial and idiopathic pulmonary arterial hypertension6 (see Pathogenesis). Estrogen does not seem to explain the increased incidence since estrogens cause vasodilatation and diminish the vasoconstrictor response in pulmonary arteries9and estrogen-containing contraceptives have not been associated with an increased incidence of IPAH. Other gender differences have been observed in IPAH. The disease usually appears in the third and fourth decades of life, although 10% of patients in the United States registry are over age 60.7 In general, the onset of disease is usually later in men than women. It is not known if this difference is related to actual disease onset, clinical expression of disease, or disease recognition. Mortality differences have been noted related to gender. In particular, a two-fold increase in mortality has been noted in African American women10,11. The reasons for this increase in mortality are not known and may be multifactorial. There does not appear to be a difference in the response of African American women to treatment. Finally, Raynaud’s phenomenon and a variety of autoantibodies, including antinuclear antibodies and antithyroid antibodies, have been observed in about 30% of patients with IPAH and all are more common in women. These findings suggest a possible role for the immune system in the pathogenesis of IPAH, a role which has only recently been explored (see Scleroderma Pathogenesis). Diet drugs have been responsible for a number of pulmonary arterial hypertension outbreaks, which appear clinically and pathologically identical to IPAH. So-called anorexigenic pulmonary arterial hypertension was first reported in Europe in the 1960s related to a diet drug, aminorex fumarate.12 Several outbreaks and many sporadic cases have occurred world-wide related to amphetamine derivatives, particularly fluramine, dexfenfluramine, and phenteramine.13 These drugs are associated with a 20–fold increase in the risk of developing pulmonary arterial hypertension with greater than 3 months of use.13 While fenfluramine and dexfenfluramine were withdrawn from the market in the United States in 1997 because of heart valve toxicity, they continue to be available elsewhere and may be contained (unlabeled) in weight loss products purporting to be “natural” or “herbal.” In addition, anorexigenic agent use has been reported in over 11% of cases of secondary forms of pulmonary arterial hypertension,14 suggesting that these drugs may trigger or predispose to the development

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of other forms of pulmonary hypertension. Because women are the largest users of weight loss products, anorexigenrelated pulmonary arterial hypertension is a significant women’s issue. Other reported triggers of IPAH or a pathologically similar picture are cocaine, L-tryptophan, and toxic rapeseed oil.15,16 L-tryptophan has been used in many countries as a treatment for depression. Because depression tends to be more common in women, a higher incidence of IPAH in women could be related in part to its use. In addition, St John’s wort, which is sometimes used for depression or weight loss, and phenylpropanolamine, which is used for weight loss, have both been linked to unexpected increases in IPAH.17,18 Use of such preparations is more likely in women and may contribute to the increased incidence of IPAH in women. A pathological picture nearly identical to that of IPAH can occur in HIV infection with or without overt AIDS. While pathologically similar, the disease has a more rapid onset and a more rapidly fatal course than IPAH.19 The incidence of this form of pulmonary hypertension in HIV-infected people is estimated to be 0.5%20 although this figure may be under estimated.21 While HIV/AIDS is more common in men, a slightly increased female to male ratio (1.4:1) for HIV-related pulmonary arterial hypertension has been observed.21

Pathogenesis FPAH is known to be an autosomal dominant disorder with reduced penetrance and genetic anticipation (earlier onset in successive generations).6 The gene responsible for much of FPAH was identified in 2000 as the bone morphogenetic protein receptor type 2 gene (BMPR2).22–24 The gene is associated with over 50% of cases of familial IPAH, 25% of sporadic IPAH, and 6% of pulmonary hypertension associated with congenital heart disease.25 As noted before, women with this gene have more female offspring with FPAH than male offspring. Although the gene has not been found in other forms of pulmonary arterial hypertension such as those associated with collagen vascular diseases26 or HIV infection, only 10–20% of those who carry the gene develop pulmonary arterial hypertension. There is evidence that those who carry the gene may have abnormal increases in pulmonary artery pressure in response to exercise.27 Discovery of the BMPR2 gene has greatly expanded our knowledge of pathogenetic mechanisms in IPAH, FPAH, and associated forms of pulmonary arterial hypertension. With this knowledge, an increasingly complex picture of these diseases has emerged at the molecular level resulting in the identification of many potential targets for therapeutic interventions in the future.28 BMPR2 is expressed at high levels in normal pulmonary endothelial cells and at lower levels in pulmonary arterial smooth muscle cells and fibroblasts. In contrast, BMPR2 expression in the pulmonary vasculature is greatly reduced in patients with BMPR2 mutations.29 Its expression is also reduced in patients with

IPAH without BMPR2 mutations,29 suggesting that BMPR2 dysfunction may be responsible for other forms of pulmonary arterial hypertension even without a genetic basis for the dysfunction. Further support for this concept comes from the observation that the HIV-1 tat protein inhibits expression of BMPR2 transcripts which may be responsible for pulmonary arterial hypertension in HIV infection.30 Mechanistically, BMPR2, which acts through cell signaling pathways (Smad and MAPK), regulates endothelial cell apoptosis and smooth muscle cell proliferation. With BMPR2 mutations or lower levels of BMPR2 without known mutations, endothelial cell apoptosis is accelerated and vascular smooth muscle proliferation is enhanced. The effect on endothelial cell apoptosis may alter endothelial integrity exposing vascular smooth muscle cells to potentially toxic agents, which could in turn stimulate uncontrolled smooth muscle cell proliferation. In addition, apoptosis-resistant endothelial clones may develop and be responsible for the monoclonal plexiform lesions.31,32 The sources of injurious agents could be many, including viruses such as HIV and HHV-8,33 drugs, serum proteins, or autoantibodies for which there is increasing evidence.34 This picture corresponds to a larger picture of pulmonary arterial hypertension resulting from a response to injury leading to vascular remodeling with subsequent narrowing of vessels and expression of pulmonary hypertension (Figure 24.1). A complex interplay of genetic factors and injury triggers mediated through a number of molecular pathways may be responsible for the final pathological features. Evidence for such a scheme can be seen in the rat monocrotaline model of pulmonary arterial hypertension in which an intense inflammatory response to the toxin is seen first, followed by remodeling, and then measurable pulmonary arterial hypertension.

Injury triggers

Genetic background

BMPR2 Others Multiple pathways

Diet drugs Toxins HIV HHV-8

Prostacyclins, endothelin, no others

Figure 24.1  The pathogenesis of pulmonary arterial hypertension involves an interplay of vascular injury with a genetic predisposition and environmental triggers. Injury leads to remodeling with narrowing of the pulmonary microvasculature and development of high pulmonary pressures through a large number of molecular pathways.

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Along with our expanded knowledge of the genetics of IPAH has come an expanded knowledge of the many pathways involved in the disease. The most studied pathways for which therapeutic interventions exist include prostacylin, endothelin, and nitric oxide (NO), although many more targets have been identified and are under investigation. In general, most therapeutic agents in IPAH have antiproliferative properties as well as vasodilator properties. Given the pathogenetic model of vascular remodeling in response to injury, antiproliferative properties of therapeutic agents may be critical.

Diagnosis and Treatment The diagnosis of IPAH necessitates suspicion of the disease because the symptoms may be non-specific until the disease is advanced and overt right ventricular failure occurs. For much its course, patients complain only of fatigue and later of dyspnea, particularly with exertion. Delay in diagnosis has not been studied, but one may wonder based on other patterns of disease recognition by physicians, if the diagnosis of IPAH in women complaining of fatigue and dyspnea on exertion may tend to be delayed. Regardless of gender, it is essential to consider the disease in any one with unexplained dyspnea. The diagnosis is largely one of exclusion since there are no specific markers of IPAH. The chest radiograph and CT scan may be unremarkable until signs of right ventricular dilatation develop. Pulmonary function tests may be normal or show restrictive disease. Arterial blood gases may be normal at rest, but often show oxygen desaturation with exercise. An echocardiogram can provide a screen for the presence of pulmonary hypertension, but pulmonary hypertension can only be estimated if some degree of tricuspid regurgitation is present. In addition, echocardiograms can have significant false positive and false negative results in pulmonary hypertension35 so right heart catheterization is needed to establish the diagnosis and provide information on which to base initial treatment. The approach to diagnosis should further include exclusion of other conditions causing dyspnea and pulmonary hypertension such as chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea, collagen vascular diseases, HIV infection, and chronic thromboembolic disease. A complete history, physical examination, relevant laboratory studies, and lung imaging studies are all essential. Lung ventilation-perfusion scanning may be particularly helpful in diagnosing chronic thromboembolic pulmonary hypertension since the lung scan in IPAH is either normal or shows a diffuse salt and pepper pattern, while the lung scan in chronic thromboembolic disease shows segmental or lobar defects.36 Current therapy for IPAH and related forms of pulmonary arterial hypertension includes calcium channel blockers, prostacyclins (IV, subcutaneous, or inhaled), endothelin receptor antagonists, and phosphodiesterase-5 inhibitors

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which act as nitric oxide enhancers. Calcium channel blockers are an older form of therapy and have never been studied in randomized controlled trials unlike newer treatments. Substantial information exists, however, to suggest that they may benefit a small subset of patients who demonstrate enhanced vasoreactivity on vasodilator testing. Such testing can be done as part of the diagnostic right heart catheterization. Although only 10–20% of patients with IPAH will be vasoreactive and not all of these will tolerate calcium channel blockers, it is worth trying the treatment. The effect of the drugs should be reevaluated after 2–3 months because not all patients who demonstrate vasoreactivity in the laboratory have a long-term response. Patients who are not vasoreactive should not be tried empirically on calcium channel blockers because adverse hemodynamic reactions may occur. Treatment with drugs other than calcium channel blockers does not require demonstration of vasoreactivity for a positive effect. In general, intravenous epoprostenol is preferred for severely compromised patients because of its more rapid onset and its well established effectiveness on both hemodynamics and survival. Because the delivery system for intravenous epoprostenol is complex and has associated complications, less severe degrees of disease are treated with oral agents including endothelin receptor antagonists and phosphodiesterase inhibitors. There is also increasing interest in combination therapies. In addition, strong observational evidence supports the use of anticoagulation to prolong survival in all cases of IPAH. No gender differences have been observed in responses to these therapeutic agents.

Scleroderma Many autoimmune diseases occur more frequently in women although no genetic basis has as yet been discovered for this tendency. Some knowledge does exist with respect to sex differences in autoimmune diseases37 (refer to Chapter 26). Gender differences in immunity do not, however, provide a clear explanation of gender trends in the incidence of autoimmune diseases since not all disorders are more common in women. Some disorders are more common in men and others have no sex predominance.

Scleroderma and Pulmonary Hypertension Scleroderma can serve as a useful prototype of an autoimmune disease more common in women and associated with pulmonary arterial hypertension. Pulmonary arterial hypertension may develop from vascular destruction and hypoxemia related to extensive pulmonary fibrosis in the diffuse form of scleroderma or by small vessel involvement in the limited form. Estimates of the prevalence of pulmonary

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arterial hypertension in scleroderma vary, but at least 12% of patients will develop it34 and up to 60% show pathological evidence of pulmonary vascular disease.38

Pathogenesis No gender basis for the increased female to male ratio in scleroderma has been found. In fact, no single gene has as yet been identified, but a genetic basis has been assumed from familial clusters of the disease,39 the increased fatality with pulmonary hypertension associated with DRw52 and DRw6 HLA alleles,40 and the increased incidence of autoantibodies in family members.41 In addition, polymorphisms of the angiotensin-converting enzyme and nitric oxide synthetase genes are associated with increased risk of scleroderma; Oklahoma, but not Mississippi Choctaws have a greatly increased risk;42 and antitopoisomerase I antibodies, common in scleroderma, are linked to specific HLA alleles.43 In the absence of a known genetic basis for the increased incidence in women, environmental factors are of potential interest. Occupational silica exposure occurs more commonly in men and is associated with an increased incidence of scleroderma.44 L-tryptophan, more commonly used in women as noted previously, has been associated with a scleroderma-like disease45 as has a contaminated rapeseed oil exposure which also caused pulmonary arterial hypertension.46 Women exposed to a number of petroleumbased solvents have also been noted to have an increased incidence of scleroderma.47 On the other hand, oral contraceptives have not been associated with increased risk,48 suggesting that estrogens may not play a causal role. Microchimerism and pregnancy may offer the best current explanation of the female preponderance of this disease.49 According to this theory, fetal cells that enter the mother’s bloodstream may persist for years. Women who develop scleroderma appear to have greater numbers of these cells and an association with HLA DQA1*0501 expression. In women who develop scleroderma, the HLA typing of the fetal cells is more closely matched to the paternal HLA of the children. These findings have not been definitively confirmed, but offer the best explanation for the gender difference in scleroderma development to date. The development of microvascular disease resulting in pulmonary arterial hypertension in scleroderma may be related to the formation of autoantibodies. Endothelial cell apoptosis is thought to be a primary pathogenetic event in the formation of scleroderma skin lesions34,38 and autoantibodies to endothelial cells are found in scleroderma patients. The levels of these antibodies correlate with disease progression. In addition, vascular and perivascular inflammatory infiltrates are common in both scleroderma and IPAH with lymphocytes, mast cells, and immunoglobulin deposits,34 suggesting a role for immune cells. Further support for an immune role in the development of ­ pulmonary

a­ rterial hypertension is the association of pulmonary arterial hypertension with immune deficiency states such as HIV and latent HHV-8 infection. All these conditions are associated with CD4 defects including absolute deficiency of CD4 cells, a decreased CD4/DC8 ratio, or a decreased relative percentage of CD4  CD25 cells (the Treg subset).34 While definitive proof is lacking, autoimmunity and inflammation may underlie pulmonary vascular disease development in scleroderma and other collagen vascular diseases and may form the basis for new therapeutic approaches in the future.

Treatment Treatment of pulmonary arterial hypertension in association with scleroderma or other collagen vascular diseases is similar to that of IPAH. The currently approved drugs for treatment of IPAH have all been used for treatment of collagen vascular-related pulmonary arterial hypertension. No gender differences have been noted in the responses to treatment, but, in general, the therapeutic response is less than that of IPAH.

Summary Despite the higher incidence of many forms of pulmonary arterial hypertension in women, still little is known about the reasons for the predisposition or about potential therapeutic implications. Both FPAH and IPAH may have a genetic basis for the predisposition although environmental triggers, such as anorexigenic drugs, may further contribute to the incidence. Collagen vascular diseases, with scleroderma as the prototype, may have an increased incidence in women related to microchimerism and pregnancy. Further information is needed to explain the female predominance in all these settings. Such information may, in the end, have implications for disease treatment or prevention that have yet to be explored.

References   1. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12 Suppl):40S–47S.   2. Simmonneau G, Nazzareno G, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43 (12 Suppl S):5S–12S.   3. Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc 1985;60(1):16–25.   4. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension. Chest 2004;126 (Suppl):35S–62S.

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  5. Rosenzweig E, Morse J, Knowles J, et al. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant 2008;27:668–74.   6. Loyd JE, Butler MG, Foroud TM, et al. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 1995;152(1):93–97.   7. Rich S, Dantzker FR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107(2):216–23.   8. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet 2003;361(9368):1533–44.   9. Lahm T, Crisostomo PR, Markel TA, et al. The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: potential new clinical implications for an old hormone. Crit Care Med 2008;36(7):2174–83. 10. Lilienfeld DE, Rubin LJ. Mortality from primary pulmonary hypertension in the United States, 1979–1996. Chest 2000;117(3):796–800. 11. Davis KK, Lilienfeld DE, Doyle RL, et al. Increased mortality in African Americans with idiopathic pulmonary arterial hypertension. J Natl Med Assoc 2008;100(1):69–72. 12. Kay JM, Smith P, Heath D, et al. Aminorex and the pulmonary circulation. Thorax 1971;26(3):262–70. 13. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335(9):609–16. 14. Rich S, Rubin L, Walker AM, et al. Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest 2000;117(3):870–74. 15. Garcia-Dorado D, Miller DD, Garcia EJ, et al. An epidemic of pulmonary hypertension after toxic rapeseed oil ingestion in Spain. J Am Coll Cardiol 1983;1(5):1216–22. 16. Gomez-Sanchez MA, SaenzdelaCalzada C, Gomez-Pajuelo C, et al. Clinical and pathologic manifestations of pulmonary vascular disease in the toxic oil syndrome. J Am Coll Cardiol 1991;18(6):1539–45. 17. Barst RJ, Abenhaim L. Fatal pulmonary arterial hypertension associated with phenylpropanolamine exposure. Heart 2004;90(7):e42. 18. Walker AM, Langleben D, Korelitz JJ, et al. Temporal trends and drug exposures in pulmonary hypertension: an American experience. Am Heart J 2006;152(3):521–26. 19. Nunes H, Humb , Sitbon O, et al. Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2003;167(10):1433–39. 20. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008;177(1):108–13. 21. Reinsch N, Buhr C, Krings P, et al. Effect of gender and highly active antiretroviral therapy on HIV-related pulmonary arterial hypertension: results of the HIV-HEART Study. HIV Medicine 2008;9:550–56. 22. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67(3):737–44.

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23. Lane KB, Machado RD, Pauciulo MW. The International PPH Conortium et al. Heterozygous germline mutations in BMPR2, encoding a TGF- receptor, cause familial primary pulmonary hypertension. Nat Genet 2000;26(1):81–84. 24. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF- family. J Med Genet 2000;37(10):741–45. 25. Roberts KE, McElroy JJ, Wong WP, et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 2004;24(3):371–74. 26. Morse J, Barst R, Horn E, et al. Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic protein receptor 2 mutations. J Rheumatol 2002;29(11):2379–81. 27. Grunig E, Janssen B, Mereles D, et al. Abnormal pulmonary arterial pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 2000;102:1145–50. 28. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655–65. 29. Moreell NW. Pulmonary hypertension due to BMPR2 mutation. Proc Am Thorac Soc 2006;3:680–86. 30. Caldwell RL, Gadipatti R, Lane KB, et al. HIV-1 TAT represses transcription of the bone morphogenetic protein receptor-2 in U937 monocytic cells. J Leukoc Biol 2006;79:192–201. 31. Tuder RM, Radisavljevic Z, Shroyer KR, et al. Monoclonal endothelial cells in appetite suppressant-associated pulmonary hypertension. Am J Respir Crit Care Med 1998;158(6): 1999–2001. 32. Yeager ME, Halley GR, Golpon HA, et al. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 2001;88(1):E2–E11. 33. Cool CD, Kennedy D, Voelkel NF, et al. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997;28(4):434–42. 34. Nicolls MR, Taraseviciene-Stewart L, Rai PR, et al. Autoimm­ unity and pulmonary hypertension: a perspective. Eur Respir J 2005;26:1110–18. 35. Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardio­ graphic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003; 167(5):735–40. 36. Shure D. Chronic thromboembolic pulmonary hypertension: diagnosis and treatment. Semin Respir Med 1996;17:7–15. 37. Wizemann TM, Pardue M, eds. Exploring the Biological Contributions to Health: Does Sex Matter? Washington, DC: National Academy Press; 2001. 38. Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis 2002; 45(3):225–34. 39. Englert H, Small-McMahon J, Chambers P, et al. Familial risk estimation in systemic sclerosis. Aust N Z J Med 1999;29(1):36–41. 40. Langevitz P, Buskila D, Gladman DD, et al. Farewell VT, Lee P. HLA alleles in systemic sclerosis: associations with pulmonary hypertension and outcome. Br J Rheumatol 1992;31(9):609–13. 41. Feghali-Botswick C, Medsger TA Jr, Wright TM, et al. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003;48(7):1956–63.

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42. Arnett FC, Howard RF, Tan F, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum 1996;39(8):1362–70. 43. Tan FK, Stivers DN, Arnett FC, et al. HLA haplotypes and microsatellite polymorphisms in and around the major histocompatibility complex region in a Native American population with a high prevalence of scleroderma (systemic sclerosis). Tissue Antigens 1999;53(1):74–80. 44. Rodnan GP, Benedek TG, Medsger TA Jr, et al. The association of progressive systemic sclerosis (scleroderma) with coal miners’ pneumoconiosis and other forms of silicosis. Ann Intern Med 1967;66(2):323–34. 45. Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia–myalgia syndrome associated with tryptophan use. N Engl J Med 1990;323(6):357–65.

46. Tabuenca JM. Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet 1981;2(8246): 567–68. 47. Garabrant DH, Lacey JV, Laing TJ, et al. Scleroderma and solvent exposure among women. Am J Epidemiol 2003;157 (6):493–500. 48. Mayes MD. Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect 1999;107(Suppl. 5):743–48. 49. Nelson JL, Furst DE, Maloney S, et al. Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 1998;351(9102):559–62.

Chapter

25

Sex and Gender Differences in Pulmonary Manifestations of Autoimmune Disease Muddassir Aliniazee1, and Marilyn K. Glassberg2 1

University of Miami, Miller School of Medicine, Pulmonary and Critical Care Medicine, Miami, FL, USA Associate Professor, University of Miami Miller School of Medicine, Department of Medicine/Pulmonary and Critical Care Division, Director, Rare and Interstitial Lung Disease Program, Miami, FL, USA 2

Overview

increases with age regardless of sex. Elevated autoantibodies increase the risk for AD, but benefit the patient by providing protection against infections.1 The immune response signaling pathways may be different between the sexes. T-helper cell (Th) type 1, Th2, and Th17 proliferation relies on cytokines, such as interferon (IFN)-, interleukin (IL)-4, and IL-17. IFN- and IL-17 are proinflammatory cytokines, which affect Th1 and Th17 respectively. IL4 affects Th2 and activates B cells for autoantibody proliferation. These pathways mutually inhibit each other with cytokines and Th cells having multiple affects. Historically, Th1 cells were responsible for cell-mediated immunity, which promoted tissue damage; whereas Th2 cells correlated with an ­antibodymediated response, and were involved in the allergic response.9 Currently, Th17 is assumed to play a central role in tissue damage caused by chronic inflammation in AD.9 Th1 products cause contradictory responses in Th17 with TNF activating Th17, which results in chronic inflammation while IFN- indirectly inhibits inflammation via Th17. To date, AD in men reflect a Th1 type of reaction with proinflammatory agents, IFN- and IL-17, causing damage via macrophages and neutrophils.1,9–12 AD in women reflects

Although only 8% of the population develop autoimmune diseases (AD), 78% are women (Table 25.1).1 The pulmonary manifestations range from mild to life-threatening and the severity depends on the AD. In some AD, such as rheumatoid arthritis (RA), gender differences are well recognized. More men develop pulmonary disease in RA, which includes interstitial lung disease, rheumatoid nodules, and pleural effusions.2–8 In scleroderma, 40–80% of patients develop pulmonary complications that contribute to the high mortality rate. Sjögren’s syndrome has a low mortality rate and rarely involves the lungs. This chapter will focus on the literature available on sex hormone differences in the pulmonary manifestations of RA, scleroderma, and the association of Raynaud’s phenomenon.

Pathogenesis Women produce more autoantibodies than men and have a milder inflammatory response.1 The number of antibodies

Table 25.1  Examples of increased incidence of autoimmune disease in women Incidence

Autoimmune disease

Most commonly affected target organ

2:1

Dermatomyositis

Muscle

3:1

Rheumatoid arthritis

Joints, lunga

4:1

Systemic sclerosis

Collagen in skin

9:1

Systemic lupus erythematosus

Cell nuclei in skin and lung

9:1

Sjögren syndrome

Glands

Adapted from Fairweather et al., 2008,1 p.601 Note that in men, rheumatoid arthritis affects lung more commonly than in women.

a

Principles of Gender-Specific Medicine

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Copyright 2010 2010, Elsevier Inc. All rights reserved.

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a Th2-type immune response with increased numbers of autoantibodies1,13. As women age (50 years), chronic inflammation, fibrosis, elevated autoantibodies, and a Th2 response become the hallmarks of AD. Thus, the higher prevalence of AD in women may be explained by the primary TH2 immunological response and the dependence on IL-4, which provides anti-inflammatory effects by inhibiting the proinflammatory cytokine, IFN- and increasing anti-inflammatory products.14,15

Sex hormones and autoimmune disease Estrogen, progesterone, and testosterone are involved in the complicated immunological response found in AD.1,9,16,17 Estrogens can be proinflammatory or anti-inflammatory and can cause a bimodal effect on cytokines and cells.9,18 Estrogens can stimulate antibody production by B cells, likely through the inhibition of T cell suppression of B cells.9,16 Animal studies support the hypothesis that estradiol (E2) promotes AD when autoaggressive B cells are present. Chronically elevated E2, however, inhibits the initiation of an AD as long as the aggressive B cells are not present.7 This finding may explain why AD appears in women during their reproductive years as well as in the third and fourth decades of life. E2 at periovulatory to pregnancy levels stimulates Il-4, Il-10, and IFN- but inhibits TNF from CD4 T cells suggesting that E2 has a protective effect on the development of AD.1,9–11,16,18,19 Estrogen receptors (ERs), ER and ER, are implicated in AD and the inflammatory response.20 T cells in SLE patients showed lower mRNA expression of ER than in controls but amounts of ER expression remained the same as in normal controls. The ratio of ER to ER is therefore increased in SLE patients.9,21,22 These results suggest an inflammation-dependent upregulation of ER relative to ER. Hypoxia has also been reported to reduce ER whereas oxidative injury increases ER.23,24

Hamman–Rich-type syndrome exist.27 Necrobiotic nodules occur in about 20% of RA cases with pulmonary involvement.26 Central cavitation occurs in 50% of cases and calcification is rare.2 Nodules can also grow on the vocal cords. The annual incidence of pulmonary effusion in RA patients is 1.54% in men and 0.34% in women and pleurisy rates are 24% in men and 16% in women.5,6 RA patients with pleural effusion are typically over 35 years old, 80% are men, and about 80% have rheumatoid nodules.5–7,28–30 Rheumatoid factor seropositivity, subcutaneous nodules, severe articular destruction, coexisting Sjögren’s syndrome, and other systemic involvement predict pulmonary

Figure 25.1  Fifty-nine-year-old male with rheumatoid arthritis. Large left pleural effusion positive for rheumatoid factor is noted in the CT of the chest.

Rheumatoid arthritis Rheumatoid arthritis affects more women than men but RArelated pulmonary complications occur more often in men (3:1). Although RA is a chronic systemic autoimmune disease, diagnostic criteria do not focus on the extra-articular manifestations of the disease, even though they are associated with increased morbidity and mortality.25,26 Pulmonary symptoms usually develop within five years of the joint disease. In most cases, joint disease precedes pulmonary disease. In 20% of cases, however, pulmonary disease may precede articular involvement. The most common pulmonary parenchymal presentation associated with RA is interstitial lung disease. The symptoms are typically insidious but reports of rapidly fatal

Figure 25.2  Fifty-nine-year-old male with rheumatoid arthritis. Post thoracentesis, interstitial changes are noted in both lungs.

C h a p t e r 2 5     Sex and Gender Differences in Pulmonary Manifestations of Autoimmune Disease l

involvement. Pleuropulmonary complications, including interstitial lung disease, organizing pneumonia, chronic eosinophilic pneumonia, bronchiectasis, rheumatoid nodules, pulmonary vascular disease, or pleural disease, occur in RA in between 50 and 71%. Many patients remain asymptomatic throughout the course of the disease.27 There are no comparative studies to date on gender differences in clinical course or response to treatment between men and women.

Scleroderma Overview Scleroderma is a multisystem, chronic disease of unknown etiology in which collagen deposits in blood vessels, joints, and organs including the skin, lungs, kidneys, heart, and intestines. Limited scleroderma, including CREST syndrome, has prominent skin manifestations, rare lung involvement and causes no change in mortality. Diffuse scleroderma patients develop thickening of the skin, renal complications, and pulmonary fibrosis (PF) at an early age compared to non-scleroderma patients.31,32 Renal complications such as acute renal failure and malignant hypertension were leading causes of mortality in scleroderma until the development of ACE inhibitors. Pulmonary complications occur in 10% of scleroderma patients and have no proven therapies, making them the leading cause of mortality.33–35 Important risk factors of scleroderma are family history, black race, age between 30 and 50, and nulliparity.35–37 The average age at which patients are diagnosed with scleroderma is between 30 and 50.37–40 A poorer prognosis is associated with diffuse scleroderma, diagnosis at an early age, male gender, and multi-organ involvement.31,35–37

Laboratory The prevalence of autoantibodies associated with scleroderma, such as anti-centromere (ACA) and anti-­topoisomerase I (anti-TOPO), depend on the type of scleroderma, race, age, and gender.37,41,42 Limited scleroderma patients with positive ACA are typically elderly white women with a long history of Raynaud’s phenomenon and gastrointestinal complications.42 Anti-TOPO has clinical characteristics of diffuse skin involvement and PF.43 The ACA is associated with distinct HLA subtypes and limited scleroderma, pulmonary arterial hypertension (PAH), and digital ulcers. A meta-analysis of scleroderma patients showed a positive correlation between anti-TOPO, renal, cardiac, and pulmonary involvement and a higher mortality rate.44 Approximately 20% of ACA positive patients develop PAH, resulting in 50% of scleroderma-related mortality.42 Although few patients with diffuse scleroderma and antiTOPO succumb to severe pulmonary disease, most patients with anti-TOPO function normally with chronic but moderate PF. Anti-Th/To is a less common but moderately

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specific antibody for scleroderma. Limited scleroderma patients with positive anti-Th/To are usually white men and encounter more pulmonary disease than ACA-positive patients. The presence of anti-RNA polymerase III predisposes scleroderma patients to skin and renal complications but not to pulmonary involvement.

Chest Imaging Symptomatic patients may have normal chest x-rays up to 10% of the time, limiting their benefit as a definitive and early screening for scleroderma pulmonary involvement.34 On average, scleroderma patients with pulmonary involvement only showed 13% damage to the lungs and abnormalities were confined to the lower lung zones.45,46 Although pulmonary involvement in scleroderma is best visualized by HRCT, it lacks diagnostic value. HRCT scan cannot determine the etiology of abnormal findings or differentiate between scleroderma types and patients may require a biopsy. Frequently, HRCT findings integrated with PFTs determine the clinical significance without a biopsy.46

Epidemiology More women develop scleroderma according to current epidemiological data.37,39 Most studies also indicate that the United States has a higher prevalence and incidence of scleroderma than many other industrialized nations.37,47–50 Since 1950, scleroderma rates have increased in the United States.37,51–53 Current prevalence and incidence is 242 and 19.3 cases per million, respectively.37 In the United States there are 389.8 female to 84.1 male cases per million at a female-to-male prevalence ratio is 4.6:1.0 with and an incidence ratio of 3.2:1.0.37 The disparity between prevalence and incidence occurs because the sexes differ in the type of scleroderma they develop and the associated mortality rate. More women are diagnosed with limited scleroderma that carries a ­ betterprognosis. It has a 10-year survival rate of 92%, while more men are diagnosed with the poorer-prognosis diffuse scleroderma, which has a 10 year survival rate of 65%.40 The prognosis with scleroderma types means men have a higher mortality rate at an early age even though women are 4.6 times likelier to encounter this disease. Age-adjusted mortality rate studies in overall scleroderma show women had higher rates than men.54 Scleroderma mortality has decreased in the last 50 years, possibly because of new treatments, such as ACE inhibitors, for treatment of the vascular aspect of the disease.35,40,42,55,56 Varying estimates exist on the prevalence of PAH and scleroderma, but approximately 12% of scleroderma patients develop the complication.57

Scleroderma and Lung Cancer Although the data are derived as an incidental finding from studies not focused on gender differences and rate

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of malignancies in scleroderma, a metanalysis reveals an increased risk for women with scleroderma to develop a malignancy.17,58 A population-based cohort study, however, reported no sex difference in the rate of malignancies in scleroderma.59 Compared to non-scleroderma patients, scleroderma patients have a higher risk for malignancies in general with a dual diagnosis occurring at 6.2%.58,60 The risk increases with age and an older age at scleroderma diagnosis is a significant risk factor of malignancy.17,58,61 The risk of development of lung cancer increases by 16.5 times in scleroderma patients.60,62 Adenocarcinoma, subtype bronchoalveolar cell, the most common pathology, occurs 5–9 years after an scleroderma diagnosis.58,59,63,64 All forms of lung cancer present the largest relative risk for the development of cancer in scleroderma.58,59,63–66 Breast, bladder, and prostate cancers are also associated with increased relative risk.59 The second most common malignancy, breast cancer, devel­ ops within two years after a scleroderma diagnosis.58,64,67 Postulated reasons for the higher malignancy rates in scleroderma are a defect in immune surveillance, impaired clearance of carcinogens, increased epithelial hyperplasia, and familial susceptibility.58 Correlation between malignancies and scleroderma-related autoantibodies show inconclusive results.41,58,62,68 Whether or not estrogens play a role in the susceptibility of the development of lung cancer in women with scleroderma has not been investigated. Racial differences may also impact gender differences in scleroderma. In the United States there is higher prevalence of scleroderma than in other industrialized nations. Blacks constitute 12.8% of the population and have a higher prevalence and incidence of scleroderma than their age-adjusted white counterparts.54,69,70 Black patients also have a more aggressive form of the disease characterized by digital ulcers, poorer pulmonary function, development of PF, gastrointestinal tract complications and higher titers of autoantibodies. All of these lead to an increased mortality rate.32,54,71,72 Black patients, particularly women, have a higher ageadjusted mortality rate compared to white patients.54 Rare groups such as the Oklahoma Choctaw Indians also develop scleroderma in the United States.73 Family history is a significant predictor of scleroderma.32,74–76 The absolute risk remains low in familial clustering at 1.6% and less than 1% for patient offspring. When compared to the general population at 0.026%, scleroderma poses a 13–15 times greater relative risk for a firstdegree relative.35,77 HLA class II haplotype on chromosome 15q is also involved in the pathogenesis of scleroderma.35 The gene encodes for the fibrillin-1which regulates TGF, a major contributor to the sclerosis process.75,78,79 HLA alleles, DRw52 and DRw6 are associated with an increase in fatalities with PAH.80 Genetic studies in twins revealed that a family history is the strongest predictor of disease but genetic susceptibility is not sufficient to develop scleroderma.35,81

Scleroderma-related Lung Disease and Raynaud’s Phenomenon Most patients with scleroderma develop Raynaud’s phenomenon characterized by pale extremities and chronic tissue hypoxia that can lead to digital ulcers.25 Clinical criteria used to classify scleroderma by the American College of Rheumatology include sclerodermatous skin changes, skin manifestations, and visceral manifestations.25 Typical skin changes include tightness, thickening, and non-pitting induration.25 In Raynaud’s, collagen deposits in the skin destroy the reticular layer of the dermis affecting the elasticity, strength, and dermal structures of the skin.82 As the phenomenon progresses, collagen and ECM protein deposits compress dermal capillaries, which cause tissue hypoxia that results in skin atrophy, thinned epidermis, and muscle wasting.82 Typically, women have more severe decreased cutaneous blood flow compared to men and develop Raynaud’s phenomenon in a ratio of 4:1.83,84 Women with scleroderma who receive HRT containing only estrogen have double the rate of Raynaud’s phenomenon compared to control patients.17,83–85 When estrogen and progesterone are replaced, the occurrence of Raynaud’s phenomenon is decreased, demonstrating a possible protective benefit of progesterone.17,85

Exogenous Factors Associated with Gender Differences Environmental factors including occupational toxins, drugs, and others factors affect the development, severity, and prevalence of scleroderma. Men show higher rates of ­environmental-related scleroderma because they are exposed to more occupational toxins, including silica dust, organic and chlorinated solvents on a larger scale than women.86–89 After inhalation, toxins such as silica particles cause an immunological response in the lungs and blood vessels, causing fibrotic changes.90 In vitro studies show macrophages from patients with scleroderma release IL-1, IL-6, and TNF.91 These factors may activate fibroblasts to produce collagen and cause fibrosis.91 Other compounds, such as organic and chlorinated solvents, are volatile substances that penetrate the skin and denature protein causing cutaneous sclerosis.88,92,93 Scleroderma patients who also have exposure to environmental toxins show a more severe form of scleroderma.88 Radiotherapy, bleomycin, paclitaxel, docetaxel, and carboplatin chemotherapy for existing malignancies can promote the development of scleroderma or scleroderma-like transformations.58,61,94,95 Antineoplastic agents also increase the risk for scleroderma. Bleomycin related scleroderma shows inflammation and PF depending on the gender and sex hormones of the scleroderma patient. Bleomycin is shown to induce PF with greater pulmonary distress and a higher mortality rate in female rats.96 Increased amounts of collagen with fibrosis and inflammation markers are found

C h a p t e r 2 5     Sex and Gender Differences in Pulmonary Manifestations of Autoimmune Disease l

Figure 25.3  Ground glass opacities, traction bronchiectasis, and marked interstitial fibrosis noted in CT scan of chest from a 52-year-old black woman with scleroderma. Lung biopsy demonstrated nonspecific interstitial pneumonitis.

in the lungs of the female group versus the male group.96 An ovariectomized group treated with and without E2 replacement showed that E2-treated lung sections had greater inflammatory and fibrosing reaction to bleomycin.96

Sex Hormones and Scleroderma Several studies have examined the association of sex hormones and the clinical course of AD. Several studies have focused on the relationship between OCP use, reproductive history, hormone replacement therapy (HRT), estrogen antagonists, and the development of scleroderma. Studies examining patients’ menarche, reproductive history, OCP use, and menopausal age showed no correlation to scleroderma.17 Estrogen without progesterone given as HRT showed a small yet significant increase in risk for scleroderma.17 Because of the antihormonal effects of herbicides, pesticides, and their metabolites, other studies have explored their impact on scleroderma development. The pesticides that could potentially interrupt normal endocrine mechanisms, particularly estrogens, include polychlorinated biphenyls, DDT metabolites, and 2,3,7,8-tetrachlorodibezop-dioxin (TCDD).17 Results show an increase in scleroderma in self-reported cases of herbicide and pesticide exposure. These factors pose an occupational hazard to farming, which has an increased risk of systemic AD, including scleroderma.97 No studies to date have focused on gender differences and the development of scleroderma after exposure to herbicides or pesticides. Childbearing-aged women and postmenopausal women with scleroderma demonstrate no significant difference in

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circulating serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and E2.98 The prolactin levels, however, were significantly higher in the scleroderma patients than in the non-scleroderma control group. Using regression analysis, prolactin concentrations correlates to skin sclerosis, vascular, and lung involvement. In a small sample size study, scleroderma patients also had a higher rate of spontaneous abortions.98 Microchimerism can occur during pregnancy and may explain why some women develop scleroderma.99 The discovery of Fetal Y-chromosome sequences in maternal blood cells and in skin biopsies from women with scleroderma led to the hypothesis that fetal cells cross with maternal blood during pregnancy and may remain for several years.100,101 There is also an association of scleroderma with HLA allele DQA1*0502 expression. In women with scleroderma, the fetal cells show greater similarities to the paternal set of HLA alleles. The pathogenesis of scleroderma in some women may involve a fetal antimaternal graft-vs.-host reaction.100

Pulmonary Disease Pulmonary disease in scleroderma patients can present with mild respiratory symptoms including mild dyspnea on exertion, a non-productive cough with bibasilar crackles on chest auscultation, and hemoptysis. A major cause of mortality that accounts for 30–70% of scleroderma patients is PF.102,103 Scleroderma with PF predicts poor hospitalization outcomes by increasing hospital deaths by 2.63 times versus scleroderma patients without PF.104 In the nascent stage of PF, lymphocytes, plasma cells, macrophages, and eosinophils invade the alveoli and cause inflammation.82 As the inflammation subsides, vascular damage and fibrosis in the alveolar interstitium predominate. The fibrotic deposits produce distinct histological patterns. The most common pattern seen on biopsy is nonspecific interstitial pneumonitis (NSIP), which has moderate type 2 pneumocyte inflammation and an even distribution of fibrosis throughout the lungs.34,82 This pattern is differentiated from usual interstitial pneumonia (UIP), which has scattered fibrotic patches and can be seen in the lungs of patients with scleroderma.34,82,105 Although the etiology of PF in scleroderma is unknown, centrilobular fibrosis can also develop from fibrotic damage to the gastrointestinal tract, usually the esophagus, with the development of gastro­ esophageal reflux which may eventually result in aspiration pneumonia.42,106–109 Scleroderma can lead to PAH with pulmonary or tricuspid insufficiency murmurs, jugular venous distention, and pedal edema (refer to Chapter 24, Gender-Specific Considerations in Pulmonary Hypertension). A higher tricuspid gradient, older age, and presence of autoantibodies correlates with the development of lung disease,110,111 PAH occurs in 10–26% of scleroderma patients and reduces 1-year survival rate from 90% to about 60%.112–115 PAH accounts for 30% of all

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scleroderma-related deaths.33 Pharmacotherapy advances, such as calcium channel blockers, prostacyclins, endothelinreceptor antagonists, and phosphodiesterase inhibitors show improvements in short-term survival but long-term studies remain inconclusive.33,116,117

15.

16.

Conclusion The understanding of gender differences in the development of pulmonary disease in autoimmune disease is evolving. Women appear to have increased susceptibility to most AD, excluding RA. The available clinical data are minimal and support further research and clinical studies to define the role of hormones in the lung and their role in AD.

17.

18. 19.

20.

References   1. Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol 2008;173(3):600–9.   2. Walker WC, Wright V. Pulmonary lesions and rheumatoid arthritis. Medicine (Baltimore) 1968;47(6):501–20.   3. Saag KG, Kolluri S, Koehnke RK, et al. Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum 1996;39(10):1711–19.   4. Kelly CA. Rheumatoid arthritis: classical rheumatoid lung disease. Baillieres Clin Rheumatol 1993;7(1):1–16.   5. Jurik AG, Davidsen D, Graudal H, et al. Prevalence of pulmonary involvement in rheumatoid arthritis and its relationship to some characteristics of the patients. A radiological and clinical study. Scand J Rheumatol 1982;11(4):217–24.   6. Jurik AG, Graudal H. Pleurisy in rheumatoid arthritis. Scand J Rheumatol 1983;12(2):75–80.   7. Balbir-Gurman A, Yigla M, Nahir AM, et al. Rheumatoid pleural effusion. Semin Arthritis Rheum 2006;35(6):368–78.   8. Halla JT, Schrohenloher RE, Volanakis JE, et al. Immune complexes and other laboratory features of pleural effusions: a comparison of rheumatoid arthritis, systemic lupus erythematosus, and other diseases. Ann Intern Med 1980;92(6):748–52.   9. Straub RH. The complex role of estrogens in inflammation. Endocr Rev 2007;28(5):521–74. 10. Pappu BP, Angkasekwinai P, Dong C, et al. Regulatory mechanisms of helper T cell differentiation: new lessons learned from interleukin 17 family cytokines. Pharmacol Ther 2008; 117(3):374–84. 11. Sakazaki F, Ueno H, Nakamuro K, et al. 17beta-estradiol enhances expression of inflammatory cytokines and inducible nitric oxide synthase in mouse contact hypersensitivity. Int Immunopharmacol 2008;8(5):654–60. 12. Frisancho-Kiss S, Davis SE, Nyland JF, et al. Cutting edge: cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J Immunol 2007; 178(11):6710–14. 13. Beeson PB. Age and sex associations of 40 autoimmune diseases. Am J Med 1994;96:457–562. 14. Fairweather D, Frisancho-Kiss S, Yusung SA, et al. IL-12 protects against coxsackievirus B3-induced myocarditis by

21.

22.

23.

24.

25.

26.

27.

28.

29. 30. 31.

32.

33. 34.

increasing IFN-gamma and macrophage and neutrophil populations in the heart. J Immunol 2005;174(1):261–69. Frisancho-Kiss S, Nyland JF, Davis SE, et al. Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J Immunol 2006; 176(11):6411–15. Lang TJ. Estrogen as an immunomodulator. Clin Immunol 2004;113(3):224–30. Mayes MD. Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect 1999;107(Suppl 5):743–48. Calabrese EJ. Estrogen and related compounds: biphasic dose responses. Crit Rev Toxicol 2001;31(4-5):503–15. Sakazaki F, Ueno H, Nakamuro K, et al. 17beta-estradiol enhances contact hypersensitivity and IFN-gamma expression in inflamed skin of BALB/c mice. Toxicol Lett 2006;166(1):60–66. Heldring N, Pike A, Andersson S, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007;87(3):905–31. Rider V, Li X, Peterson G, et al. Differential expression of estrogen receptors in women with systemic lupus erythematosus. J Rheumatol 2006;33(6):1093–101. Schneider CP, Nickel EA, Samy TS, et al. The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis. Shock 2000;14(3):347–53. Stoner M, Saville B, Wormke M, et al. Hypoxia induces proteasome-dependent degradation of estrogen receptor alpha in ZR75 breast cancer cells. Mol Endocrinol 2002;16(10):2231–42. Tamir S, Izrael S, Vaya J, et al. The effect of oxidative stress on ERalpha and ERbeta expression. J Steroid Biochem Mol Biol 2002;81(4-5):327–32. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31(3):315–24. Yigla M, Simsolo C, Goralnik L, et al. The problem of empyematous pleural effusion in rheumatoid arthritis: report of two cases and review of the literature. Clin Rheumatol 2002;21(2):180–83. Schlesinger C, Koss MN. The organizing pneumonias: an update and review. Curr Opin Pulm Med 2005;11(5): 422–30. Faurschou P, Francis D, Faarup P, et al. Thoracoscopic, histological, and clinical findings in nine case of rheumatoid pleural effusion. Thorax 1985;40(5):371–75. Light RW. Pleural diseases. Dis Mon 1992;38(5):261–331. Walker WC, Wright V. Rheumatoid pleuritis. Ann Rheum Dis 1967;26(6):467–74. Altman RD, Medsger TA Jr, Bloch DA, et al. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum 1991;34(4):403–13. Kuwana M, Kaburaki J, Arnett FC, et al. Influence of ethnic background on clinical and serologic features in patients with systemic sclerosis and anti-DNA topoisomerase I antibody. Arthritis Rheum 1999;42(3):465–74. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 2007;66(7):940–44. Kaloudi O, Miniati I, Alari S, et al. Interstitial lung disease in systemic sclerosis. Intern Emerg Med 2007;2(4):250–55.

C h a p t e r 2 5     Sex and Gender Differences in Pulmonary Manifestations of Autoimmune Disease l

35. Allanore Y, Wipff J, Kahan A, et al. Genetic basis for systemic sclerosis. Joint Bone Spine 2007;74(6):577–83. 36. Lambe M, Bjornadal L, Neregard P, et al. Childbearing and the risk of scleroderma: a population-based study in Sweden. Am J Epidemiol 2004;159(2):162–66. 37. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48 (8):2246–55. 38. Villaverde-Hueso A, de la Paz MP, Martin-Arribas MC, et al. Prevalence of scleroderma in Spain: an approach for estimating rare disease prevalence using a disease model. Pharmacoepidemiol Drug Saf 2008;17(11):1100–7. 39. Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am 2003;29(2):239–54. 40. Al-Dhaher FF, Pope JE, Ouimet JM, et al. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum 2008 August 14. 41. Higuchi M, Horiuchi T, Ishibashi N, et al. Anticentromere antibody as a risk factor for cancer in patients with systemic sclerosis. Clin Rheumatol 2000;19(2):123–26. 42. Steen VD. The many faces of scleroderma. Rheum Dis Clin North Am 2008;34(1):1–15. 43. Medsger TA Jr, Silman AJ, Steen VD, et al. A disease severity scale for systemic sclerosis: development and testing. J Rheumatol 1999;26(10):2159–67. 44. Highland KB, Silver RM. New developments in scleroderma interstitial lung disease. Curr Opin Rheumatol 2005;17(6): 737–45. 45. Goh NS, Veeraraghavan S, Desai SR, et al. Bronchoalveolar lavage cellular profiles in patients with systemic sclerosisassociated interstitial lung disease are not predictive of disease progression. Arthritis Rheum 2007;56(6):2005–12. 46. Woodhead F, Wells AU, Desai SR, et al. Pulmonary complications of connective tissue diseases. Clin Chest Med 2008;29(1):149–64, vii. 47. Vonk MC, van Dijk AP, Heijdra YF, et al. Pulmonary hypertension: its diagnosis and management, a multidisciplinary approach. Neth J Med 2005;63(6):193–98. 48. Vonk MC, Broers BM, Heijdra YF, et al. Systemic sclerosis and its pulmonary complications in the Netherlands An epidemiological study. Ann Rheum Dis 2009;68(6):961–65, Epub 2008 May 29. 49. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23(5):581–90. 50. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15(2):202–5. 51. Maricq HR, Weinrich MC, Keil JE, et al. Prevalence of scleroderma spectrum disorders in the general population of South Carolina. Arthritis Rheum 1989;32(8):998–1006. 52. Michet CJ Jr, McKenna CH, Elveback LR, et al. Epidemio­ logy of systemic lupus erythematosus and other connective tissue diseases in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 1985;60(2):105–13. 53. Steen VD, Oddis CV, Conte CG, et al. Incidence of systemic sclerosis in Allegheny County, Pennsylvania. A twenty-

54.

55.

56. 57.

58. 59.

60. 61. 62.

63.

64.

65.

66.

67. 68.

69. 70.

71. 72.

73.

283

year study of hospital-diagnosed cases, 1963-1982. Arthritis Rheum 1997;40(3):441–45. Mendoza F, Derk CT. Systemic sclerosis mortality in the United States: 1999–2002 implications for patient care. J Clin Rheumatol 2007;13(4):187–92. Steen VD, Costantino JP, Shapiro AP, et al. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990;113(5):352–57. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med 2000;133(8):600–3. Nicolls MR, Taraseviciene-Stewart L, Rai PR, et al. Autoimm­ unity and pulmonary hypertension: a perspective. Eur Respir J 2005;26(6):1110–18. Wooten M. Systemic sclerosis and malignancy: a review of the literature. South Med J 2008;101(1):59–62. Hill CL, Nguyen AM, Roder D, et al. Risk of cancer in patients with scleroderma: a population based cohort study. Ann Rheum Dis 2003;62(8):728–31. Peters-Golden M, Wise RA, Hochberg M, et al. Incidence of lung cancer in systemic sclerosis. J Rheumatol 1985;12(6):1136–39. Pearson JE, Silman AJ. Risk of cancer in patients with scleroderma. Ann Rheum Dis 2003;62(8):697–99. Ciolkiewicz M, Domyslawska I, Ciolkiewicz A, et al. Coexis­ tence of systemic sclerosis, scleroderma-like syndromes and neoplastic diseases. Pol Arch Med Wewn 2008;118(3):119–26. Talbott JH, Barrocas M. Carcinoma of the lung in progressive systemic sclerosis: a tabular review of the literature and a detailed report of the roentgenographic changes in two cases. Semin Arthritis Rheum 1980;9(3):191–217. Rosenthal AK, McLaughlin JK, Gridley G, et al. Incidence of cancer among patients with systemic sclerosis. Cancer 1995;76(5):910–14. Derk CT, Rasheed M, Artlett CM, et al. A cohort study of cancer incidence in systemic sclerosis. J Rheumatol 2006;33(6): 1113–16. Bouros D, Hatzakis K, Labrakis H, et al. Association of malignancy with diseases causing interstitial pulmonary changes. Chest 2002;121(4):1278–89. Scope A, Sadetzki S, Sidi Y, et al. Breast cancer and scleroderma. Skinmed 2006;5(1):18–24. Weiner ES, Earnshaw WC, Senecal JL, et al. Clinical associations of anticentromere antibodies and antibodies to topoi­somerase I. A study of 355 patients. Arthritis Rheum 1988; 31(3):378–85. US Census Bureau. State & County QuickFacts. 2008; July 25. Krishnan E, Furst DE. Systemic sclerosis mortality in the United States: 1979–1998. Eur J Epidemiol 2005;20(10): 855–61. Gaubitz M. Epidemiology of connective tissue disorders. Rheumatology (Oxford) 2006;45(Suppl 3):iii3–iii4. Greidinger EL, Flaherty KT, White B, et al. AfricanAmerican race and antibodies to topoisomerase I are associated with increased severity of scleroderma lung disease. Chest 1998;114(3):801–807. Arnett FC, Howard RF, Tan F, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum 1996;39(8):1362–1370.

284

s e c t i o n 4     Pulmonology l

74. Maddison PJ, Stephens C, Briggs D, et al. Connective tissue disease and autoantibodies in the kindreds of 63 patients with systemic sclerosis. The United Kingdom Systemic Sclerosis Study Group. Medicine (Baltimore) 1993;72(2):103–112. 75. Agarwal SK, Tan FK, Arnett FC, et al. Genetics and genomic studies in scleroderma (systemic sclerosis). Rheum Dis Clin North Am 2008;34(1):17–40. 76. Mayes MD, Trojanowska M. Genetic factors in systemic sclerosis. Arthritis Res Ther 2007;9(Suppl 2):S5. 77. Agarwal SK, Tan FK, Arnett FC, et al. Genetics and genomic studies in scleroderma (systemic sclerosis). Rheum Dis Clin North Am 2008;34(1):17–40. 78. Tan FK, Stivers DN, Foster MW, et al. Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population. Arthritis Rheum 1998;41(10):1729–1737. 79. Kawaguchi Y, Tochimoto A, Ichikawa N, et al. Association of IL1A gene polymorphisms with susceptibility to and severity of systemic sclerosis in the Japanese population. Arthritis Rheum 2003;48(1):186–192. 80. Langevitz P, Buskila D, Gladman DD, et al. HLA alleles in systemic sclerosis: association with pulmonary hypertension and outcome. Br J Rheumatol 1992;31(9):609–613. 81. Feghali-Bostwick C, Medsger TA Jr, Wright TM, et al. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003;48(7):1956–1963. 82. Varga JA, Trojanowska M. Fibrosis in systemic sclerosis. Rheum Dis Clin North Am 2008;34(1):115–143. 83. Cooke JP, Creager MA, Osmundson PJ, et al. Sex differences in control of cutaneous blood flow. Circulation 1990;82(5):1607–1615. 84. Fraenkel L. Raynaud’s phenomenon: epidemiology and risk factors. Curr Rheumatol Rep 2002;4(2):123–128. 85. Fraenkel L, Zhang Y, Chaisson CE, et al. The association of estrogen replacement therapy and the Raynaud phenomenon in postmenopausal women. Ann Intern Med 1998;129(3):208–211. 86. Kettaneh A, Al MO, Tiev KP, et al. Occupational exposure to solvents and gender-related risk of systemic sclerosis: a meta-analysis of case-control studies. J Rheumatol 2007;34(1):97–103. 87. Smith V, Vanthuyne M, Vander CB, et al. Over-representation of construction-related occupations in male patients with systemic sclerosis. Ann Rheum Dis 2008;67(10):1448–1450. 88. Magnant J, de Monte M, Guilmot JL, et al. Relationship between occupational risk factors and severity markers of systemic sclerosis. J Rheumatol 2005;32(9):1713–1718. 89. Chifflot H, Fautrel B, Sordet C, et al. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum 2008;37(4):223–235. 90. Steenland K, Goldsmith DF. Silica exposure and autoimmune diseases. Am J Ind Med 1995;28(5):603–608. 91. Haustein UF, Herrmann K. Environmental scleroderma. Clin Dermatol 1994;12(3):467–473. 92. Goldman JA. Connective tissue disease in people exposed to organic chemical solvents: systemic sclerosis (scleroderma) in dry cleaning plant and aircraft industry workers. J Clin Rheumatol 1996;2(4):185–190.

  93. Nietert PJ, Sutherland SE, Silver RM, et al. Is occupational organic solvent exposure a risk factor for scleroderma? Arthritis Rheum 1998;41(6):1111–1118.   94. Ardern-Jones MR, Black MM. Widespread morphoea following radiotherapy for carcinoma of the breast. Clin Exp Dermatol 2003;28(2):160–162.   95. Bleasel NR, Stapleton KM, Commens C, et al. Radiationinduced localized scleroderma in breast cancer patients. Australas J Dermatol 1999;40(2):99–102.   96. Gharaee-Kermani M, Hatano K, Nozaki Y, et al. Genderbased differences in bleomycin-induced pulmonary fibrosis. Am J Pathol 2005;166(6):1593–1606.   97. Gold LS, Ward MH, Dosemeci M, et al. Systemic autoimmune disease mortality and occupational exposures. Arthritis Rheum 2007;56(10):3189–3201.   98. La Montagna G, Baruffo A, Pasquali D, et al. Assessment of pituitary gonadotropin release to gonadotropin releasing hormone/thyroid-stimulating hormone stimulation in women with systemic sclerosis. Rheumatology (Oxford) 2001;40(3): 310–314.   99. Nelson JL. Microchimerism and scleroderma. Curr Rheu­ matol Rep 1999;1(1):15–21. 100. Artlett CM, Smith JB, Jimenez SA, et al. Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med 1998;338(17):1186–1191. 101. Nelson JL, Furst DE, Maloney S, et al. Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 1998;351(9102):559–562. 102. Silver RM. Endothelin and scleroderma lung disease. Rheumatology (Oxford) 2008;47(Suppl 5):v25–v26. 103. Steen VD, Conte C, Owens GR, et al. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994;37(9): 1283–1289. 104. Chung L, Krishnan E, Chakravarty EF, et al. Hospitalizations and mortality in systemic sclerosis: results from the Nationwide Inpatient Sample. Rheumatology (Oxford) 2007; 46(12):1808–1813. 105. Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002;165(12):1581–1586. 106. Marie I, Dominique S, Levesque H, et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum 2001;45(4):346–354. 107. de Souza RB, Borges CT, Capelozzi VL, et al. Centrilobular fibrosis: an underrecognized pattern in systemic sclerosis. Respiration 2009;77(4):389–397, Epub 2008 September 18. 108. Marie I. [Gastrointestinal involvement in systemic sclerosis]. Presse Med 2006;35(12 Pt 2):1952–1965. 109. Ntoumazios SK, Voulgari PV, Potsis K, et al. Esophageal involvement in scleroderma: gastroesophageal reflux, the common problem. Semin Arthritis Rheum 2006;36(3):173–181. 110. Hesselstrand R, Ekman R, Eskilsson J, et al. Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992–2001. Rheumatology (Oxford) 2005;44(3):366–371. 111. Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial

C h a p t e r 2 5     Sex and Gender Differences in Pulmonary Manifestations of Autoimmune Disease l

hypertension: application of a registry approach. Ann Rheum Dis 2003;62(11):1088–1093. 112. Galie N, Manes A, Farahani KV, et al. Pulmonary arterial hypertension associated to connective tissue diseases. Lupus 2005;14(9):713–717. 113. Callejas-Rubio JL, Moreno-Escobar E, de la Fuente PM et al. Prevalence of exercise pulmonary arterial hypertension in scleroderma. J Rheumatol 2008;35(9):1812–1816. 114. Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemo­ dynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003;123(2): 344–350.

285

115. Stupi AM, Steen VD, Owens GR, et al. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 1986;29(4):515–524. 116. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114(13):1417–1431. 117. Robertson L, Pignone A, Kowal-Bielecka O, et al. Pulmonary arterial hypertension in systemic sclerosis: diagnostic pathway and therapeutic approach. Ann Rheum Dis 2005;64(6): 804–807.

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26

Benign metastasizing leiomyoma and lymphangioleiomyomatosis: lung diseases of women Muddassir Aliniazee1, and Marilyn K. Glassberg2 1

University of Miami, Miller School of Medicine, Pulmonary and Critical Care Medicine, Miami, FL, USA Associate Professor, University of Miami Miller School of Medicine, Department of Medicine/Pulmonary and Critical Care Division, Director, Rare and Interstitial Lung Disease Program, Miami, FL, USA 2

Introduction

on chest imaging, patients can present with mild pulmonary symptoms such as dyspnea on exertion and cough. The multiple, non-calcified, benign, smooth muscle pulmonary nodules of BML can mimic a malignancy. These nodules can present from 3 months to 20 years post hysterectomy4 with a mean time of 14.9 years.5 Depending on the tumor’s location and age, the size varies from a few millimeters to several centimeters.3,4 Overall, BML has a good prognosis with a median survival of 94 month5 with the primary cause of death attributed to common diseases.6

This chapter reviews two rare lung diseases in women, BML and LAM, are non-neoplastic diseases that behave in many ways like neoplastic disease. They can be aggressive and their primary clinical manifestation in the lung may in fact represent a metastatic process. Their etiologies remain incompletely understood. Medical therapies to date have been ineffective due to the lack of clinical trials. Pulmonary transplantation remains a viable option for these patients. Earlier Recognition of these diseases will lead to a better understanding of their pathogenesis and the development of newer treatments.

Pathogenesis In the literature, three hypotheses explain the pathogenesis of BML: metastatic uterine leiomyoma, metastatic uterine leiomyosarcoma, and multifocal leiomyoma growth.7 In the metastatic uterine leiomyoma hypothesis, uterine smooth muscle cells infiltrate the blood vessels and embolize in organs, creating new tumors.8 Although most women who develop BML undergo either a dilation and curettage, myomectomy or hysterectomy, the disease may also present as pulmonary nodules without a preceding surgery.7,9,10 In the second hypothesis, BML lung tumors are metastases of lowgrade, well-differentiated uterine leiomyosarcomas. Benign uterine leiomyomas and low-grade well-differentiated malignant uterine leiomyosarcomas should be differentiated by examining mitotic activity, the level of cellular atypia, and the degree of necrosis.9,11 Two primary problems occur in using this method: different standards exist in the number of mitotic figures needed to identify malignancies, and mitotic activity varies with hormone levels in a menstrual cycle.9,11 The third hypothesis is that multifocal leiomyomas grow systemically in response to sex hormones

Benign metastasizing leiomyoma Introduction Benign metastasizing leiomyoma (BML) is an extremely rare disease of unknown etiology that primarily affects women. Typically, the women are in their reproductive years and status post-hysterectomy for uterine leiomyomas. Since Steiner first described the disease in 1939, there have been approximately 100 reported cases of BML. Case reports provide sporadic and incomplete information on the natural history of the disease and there are no diagnostic or standard treatment protocols. The disease is not benign despite the hypothesis that BML originates from uterine leiomyomas, a common neoplasm that has a prevalence of 3–20%.1 Benign uterine smooth muscle cells spread hematogenously to the lung, the heart, lymph nodes, omentum, peritoneum, pelvic cavity, breast, bone, mediastinum, and nervous system.1–3 Although BML is usually diagnosed after an incidental finding Principles of Gender-Specific Medicine

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and can be positive for estrogen and progesterone receptors.2,3,5,7,9,11,12 In premenopausal women, the extrauterine leiomyomas can regress during hypo-estrogen states such as status post-oophorectomy, postpartum, or through hormonal manipulation.7,9,13 During the second and third trimesters of pregnancy, however, when hormone levels are elevated, nodules can regress and continue to regress post partum.7,8

Imaging BML is usually diagnosed from an incidental finding of pulmonary nodules on chest radiography.4 The extent of lung damage seen on the chest radiography shows little correlation to respiratory symptoms.4 Typically, the chest CT shows nodules that are smooth, well-circumscribed, multiple opacities scattered bilaterally throughout the lungs and range from 1 to 42 mm.3,4 The pulmonary nodules are usually noncalcified and do not enhance after IV contrast medium administration.4 Less common features include cavitary lung nodules, interstitial lung disease, and a miliary pattern.4,7 Chest CT scans may also show pericardial effusion, pleural effusion and mediastinal lymphadenopathy.4 Women who present with no symptoms but with a positive chest image for pulmonary nodules and a history of uterine leiomyomas should be evaluated for BML.4,7

Differential Diagnosis The differential diagnosis for BML includes primary or metastatic leiomyosarcomas, primary pulmonary ­leiomyomas, pulmonary hamartomas, and leiomyomatous hyperplasia. Primary pulmonary leiomyoma is a femalepredominant disease similar to BML but it produces solitary nodules that are expected to be sex-hormone receptor negative.14 Primary pulmonary leiomyosarcoma is malepredominant and similar to primary pulmonary leiomyoma but invades surrounding tissue with smooth muscle cells and shows increased cellularity, mitoses, and nuclear pleomorphism.10 Hamartomas produce calcified lung nodules in men and women, whereas BMLs are non-calcified nodules in women.9 Leiomyomatous hyperplasia causes a diffuse process in the lungs that can mimic early BML but does not develop as smooth muscle tumors with positive immunohistochemistry for uterine markers.9

Treatment No standard treatment protocol exists for BML but most regimens include surgical resection of the lung nodules and hormonal regulation. First, the pulmonary nodules are surgically extirpated via bronchoscopic or thoracic approach. Afterwards, the treatment regulates sex hormone levels through surgical and medical oophorectomies, in order to prevent neoplasm reoccurrences and regress existing neoplasms. Post-oophorectomy patients report gradual elimination

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of pulmonary nodules.15,16 Pulmonary metastases, however, have been reported post-oophorectomy.15 Current treatments antagonizing luteinizing hormonereleasing hormone, progesterone, and estrogen decrease growth of the nodules.12 Treatment response rates as reported in case reports is variable regardless of sex hormone receptor status.7 However, progesterone’s effectiveness in regression of pulmonary nodules improves if the neoplasm is progesterone receptor positive.9 Three theories exist about progesterone’s mechanism of action in causing BML nodule regression. First, progesterone acts on the hypothalamic-pituitary–gonadal axis to block its end products, and decrease ovarian production of estrogen. Second, progesterone increases the enzyme rate to inactivate and reduce estradiol effects by transforming it into its less active form, estrone. Third progesterone decreases aromatase activity by almost one-third and curtailing estrogen production.11 Historically progesterone was prescribed because of its effectiveness in the management of endometrial and breast cancers. Drugs directed at antagonizing estrogens have succeeded in treating some cases of BML.9,11,14,15 Initially, studies found an overexpression of aromatase-P450 in rapidly growing uterine leiomyomas and targeted this enzyme with the aromatase inhibitor, anastrozole, to block androgen conversion to estradiol in the gonads and peripheral tissue in treating premenopausal BML patients.3,11 Anastrozole in combination with a gonadotropin-releasing hormone agonist or a selective estrogen-receptor modulator improved BML patient outcomes.3,11 Drugs designed to alter extracellular matrix production and angiogenesis have also been used in the treatment of BML.17 In normal myometrium, TGF- induces extracellular matrix production and decreases degradative enzyme collagenase levels. In leiomyomas, the TGF- pathway is dysregulated.18,19 Administering gonadotropin-releasing hormone agonists to female patients with uterine leiomyomas decreased the mRNA expression of specific forms of TGF- and its receptors in the myometrium.18 The antifibrotic drug, pirfenidone, showed positive results by successfully decreasing the mRNA expression for collagen type I for both normal myometrium and leiomyoma tissue.19 Other drugs target the rich vasculature of uterine leiomyomas. RG13577, an antiangiogenic drug, was also effective in decreasing the size of leiomyomas.19

Conclusion BML is a rare sex-specific disease that affects young women with an unknown etiology. Important genderrelated variables, particularly estrogen, affect BML from the development of smooth muscle cell pulmonary nodules to treatment. Current studies are exploring treatments as alternatives to surgery and to drugs with greater efficacy for the management of patients with BML. Estrogen’s role in pulmonary disease remains unclear and additional research should elucidate its role in the lung.

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pulmonary cysts that can lead to multiple pneumothoraces, abdominal tumors, and chylous fluid from the lymphatic system. LAM is usually described in two forms: when it manifests concurrently with tuberous sclerosis complex (TSC), TSC-LAM and when it arises sporadically, S-LAM. Even though LAM is a rare pulmonary disease, studies beyond case reports exist. No consensus on standard protocol exists in approaching and treating patients with LAM. Currently clinical trials are examining potential treatments. LAM patients are usually women during their reproductive age who present with mild pulmonary symptoms, recurrent pneumothoraces or chylous pleural effusion. LAM’s worldwide prevalence is estimated at 250 000–300 000 cases and the incidence is 1–2.6 cases per 1 000 000 women with many cases going undiagnosed.20–22 Most women have the disease for 3–5 years and suffer approximately 2.2 pneumothoraces before LAM is diagnosed.23 The LAM Foundation estimates there to be 1000 women with S-LAM in USA.7 The average patient age at onset of symptoms and diagnosis is 38.9 and 41.0, respectively but LAM does occur in postmenopausal women taking HRT.24,25 TSCLAM is 5–10 times more common than S-LAM but analyzing multiple registries finds 85% S-LAM patients and 15% TSC-LAM.22 The theory is that TSC-LAM presents with milder symptoms or S-LAM has co-morbidities that are more serious. Patients previously diagnosed with tuberous sclerosis undergo routine screening for LAM because they are frequently asymptomatic for LAM.

Pathogenesis

Figure 26.1  (A) Posteroanterior chest radiograph of a 37year-old woman with BML. (B) Multiple bilateral nodules are visualized and more clearly seen in the CT scan of the chest. (C) Pathology-One of multiple, well-circumscribed pulmonary nodules in the lung biopsy. These nodules can be several millimeters to centimeters in size. There are benign appearing proliferating smooth muscle cells and dense connective tissue seen in the nodule.

Lymphangioleiomyomatosis Introduction Lymphangioleiomyomatosis (LAM) is a rare interstitial lung disease that occurs predominantly in women. LAM is characterized by an unorganized proliferation of atypical smooth muscle cells that infiltrate the lung. Clinically, LAM presents with a progressive increase in dyspnea on exertion,

There appears to be a genetic component in the development of TSC-LAM. TSC has two gene mutations to the hamartin (TSC1) and tuberin (TSC2) genes. Both of these genes encode for proteins that act as tumor growth suppressors. These proteins regulate cell growth, survival, and motility through the tyrosine kinase and G-coupled protein receptors.22 The mutations cause an excessive increase in protein translation leading to inappropriate cellular proliferation, migration, and infiltration of dysfunctional cells or dysfunctional cells regulating normal cells.22 The common TSC2 mutation in TSC and TSC-LAM has strengthened the idea that both diseases are on the same spectrum of disease.7 TSC-LAM has a ‘two hit’ theory where the ‘first hit’ is the mutation in the TSC genes (TSC1 or TSC2) within every cell. The ‘second hit’ occurs when an individual cell loses its heterozygous state and transforms into a homozygous for the abnormal TSC gene. When both of these ‘hits’ occur, the cell can exhibit the disease. Because every cell contains the ‘first hit,’ the development of the disease depends on the ‘second hit.’ TSC-LAM shows maternal inheritance of mothers to daughters, while S-LAM does not. Studies show estrogen may play an essential role in LAM and its progression by being involved in the signaling pathway.26 The disease never presents before menarche,

C h a p t e r 2 6     Benign metastasizing leiomyoma and lymphangioleiomyomatosis: lung diseases of women l

accelerates during pregnancy and subsides post oophorectomy.21 Postmenopausal women also present with LAM but while taking estrogen-based HRT.27 Estrogen and progesterone receptors are found in atypical smooth muscle cells, characteristic of the disease.28,29

Diagnosis Female LAM patients usually present during their reproductive years with emphysema, multiple pneumothoraces, or chylous pleural effusion. LAM is diagnosed after excluding Langerhans’ cell histiocytosis (LCH) and emphysema. The thoracic duct thickens and obstructs the lymphatic drainage resulting in chylous pleural effusion in 80% of the patients and ascites in about 30% of the patients.21 Lymph node involvement throughout the abdomen and pelvis may occur in almost 50% of the patients with renal angiolipomas.21 Visualization of the damage to the lungs its diagnostic value is limited with a chest x-ray (Figure 26.2A). High-resolution computed tomography (HRCT) findings of diffuse cystic lung disease are characteristic of LAM (Figure 26.2B). Chest radiography is commonly used to initially evaluate LAM patients.22 Although the disease is frequently asymptomatic, a chest x-ray can find mild reticular changes with hyperinflation or normal lungs.4,21 Pulmonary cysts coalesce to form a reticulated pattern. An HRCT scan has a higher diagnostic value and shows multiple thin-walled cysts dispersed throughout the lungs. Macroscopically, LAM lungs show honeycombing with cysts measuring 1 cm and filled with air and serosanguineous or chylous fluid.30 Microscopically, smooth muscle cells proliferate in the walls of enlarged airspaces, which occlude alveoli and cause air trapping. Ground-glass opacities on HRCT are believed to represent LAM cells.21 PFTs show an increased total lung capacity, residual volume but a decreased forced expiratory

Figure 26.2  CT without IV contrast enhancement, high­resolution images, show multiple small cystic changes in both lungs of a 43-year -old woman with lymphangioleiomyomatosis.

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volume (FEV1). Patients show signs of obstructive disease with a decreased FEV1 and FEV1/forced vital capacity (FVC) ratio, a restrictive disease or a combination of the two. Carbon monoxide diffusion is decreased and arterial blood gas analysis shows hypoxemia without hypercapnia.31 The diagnostic standard for LAM is open-lung biopsy with immunohistochemical staining for human melanoma black (HMB-45). All LAM cells are not HMB-45 positive, the epithelioid cells are positive while the faster-­proliferating spindle-shaped LAM cells are negative.26 Lung biopsy with HMB-45 staining is required only if the patient is being considered for lung transplantation.21

Treatment Estrogen’s exact role in LAM is uncertain, but antiestrogen therapies have been used to treat the disease with modest results.21,26,32 Tamoxifen treatment was discontinued when it was found to aggravate the disease in some women.7 Progesterone-based treatments were prescribed because of its antiestrogen effects but a retrospective analysis shows no decrease in the rate of FEV1 decline.33,34 Bilateral oophorectomies, radiotherapy of the ovaries and chemotherapy show no conclusive clinical improvements in patients.7 Lung transplants remain an important alternative for patients with end-stage tissue damage, even though LAM sometimes reoccurs.7,35 The choice of a single or double lung transplant depends on the transplant team.7,36 After a lung transplant, inhaled beta agonists are used for obstructive symptoms.23 Ongoing studies are evaluating the efficacy of sirolimus, an immunosuppressant, in treating LAM and TSC-LAM.

References 1. Marino JL, Eskenazi B, Warner M, et al. Uterine leiomyoma and menstrual cycle characteristics in a population-based cohort study. Hum Reprod 2004;19(10):2350–55. 2. Lee HJ, Choi J, Kim KR. Pulmonary benign metastasizing leiomyoma associated with intravenous leiomyomatosis of the uterus: clinical behavior and genomic changes supporting a transportation theory. Int J Gynecol Pathol 2008;27(3):340–45. 3. Nasu K, Tsuno A, Takai N, et al. A case of benign metasta­ sizing leiomyoma treated by surgical castration followed by an aromatase inhibitor, anastrozole. Arch Gynecol Obstet June 4, 2008. 4. Abramson S, Gilkeson RC, Goldstein JD, et al. Benign metastasizing leiomyoma: clinical, imaging, and pathologic correlation. AJR Am J Roentgenol 2001;176(6):1409–13. 5. Kayser K, Zink S, Schneider T, et al. Benign metastasizing leiomyoma of the uterus: documentation of clinical, immunohistochemical and lectin-histochemical data of ten cases. Virchows Arch 2000;437(3):284–92. 6. Pocock E, Craig JR, Bullock WK. Metastatic uterine leiomyomata. A case report. Cancer 1976;38(5):2096–100.

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7. Pitts S, Oberstein EM, Glassberg MK. Benign metastasizing leiomyoma and lymphangioleiomyomatosis: sex-specific diseases? Cli Chest Med 2004;25(2):343–60. 8. Horstmann JP, Pietra GG, Harman JA, et al. Spontaneous regression of pulmonary leiomyomas during pregnancy. Cancer 1977;39(1):314–21. 9. Wentling GK, Sevin BU, Geiger XJ, et al. Benign metastasizing leiomyoma responsive to megestrol: case report and review of the literature. Int J Gynecol Cancer 2005;15(6):1213–17. 10. Robboy SJ, Bentley RC, Butnor K, et al. Pathology and pathophysiology of uterine smooth-muscle tumors. Environ Health Perspect 2000;108(Suppl 5):779–84. 11. Rivera JA, Christopoulos S, Small D, et al. Hormonal manipulation of benign metastasizing leiomyomas: report of two cases and review of the literature. J Clin Endocrino Metab 2004;89(7):3183–88. 12. Rao AV, Wilson J, Sylvester K. Pulmonary benign metastasizing leiomyoma following hysterectomy: a clinicopathologic correlation. J Thorac Oncol 2008;3(6):674–76. 13. Gal AA, Brooks JS, Pietra GG. Leiomyomatous neoplasms of the lung: a clinical, histologic, and immunohistochemical study. Mod Pathol 1989;2(3):209–16. 14. Jautzke G, Muller-Ruchholtz E, Thalmann U. Immunohisto­ logical detection of estrogen and progesterone receptors in multiple and well differentiated leiomyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases. Pathol Res Prac 1996;192(3):215–23. 15. Abu-Rustum NR, Curtin JP, Burt M, Jones WB. Regression of uterine low-grade smooth-muscle tumors metastatic to the lung after oophorectomy. Obstet Gynecol 1997;89(5 Pt 2):850–52. 16. Banner AS, Carrington CB, Emory WB, et al. Efficacy of oophorectomy in lymphangioleiomyomatosis and benign metastasizing leiomyoma. N Engl J Med July 23, 1981;305(4):204–9. 17. Hyder SM, Stancel GM. Regulation of angiogenic growth factors in the female reproductive tract by estrogens and progestins. Mol Endocrinol 1999;13(6):806–11. 18. Kandioler D, Dekan G, End A, et al. Molecular genetic differentiation between primary lung cancers and lung metastases of other tumors. J Thorac Cardiovasc surg 1996;111(4):827–31. 19. Nowak RA. Novel therapeutic strategies for leiomyomas: targeting growth factors and their receptors. Environ Health Perspect 2000;108(Suppl 5):849–53. 20. McCormack FX, Moss J. S-LAM in a man? Am J Respir Crit Care Med 2007;176(1):3–5. 21. Hohman DW, Noghrehkar D, Ratnayake S. Lymphangioleiom yomatosis: a review. Eur J Inter Med 2008;19(5):319–24. 22. McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest 2008;133(2):507–16.

23. Almoosa KF, Ryu JH, Mendez J, et al. Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest 2006;129(5):1274–81. 24. Johnson SR, Tattersfield AE. Decline in lung function in ­lymph angioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 1999;160(2):628–33. 25. Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at ­enrollment. Am JRespir Crit Care Med 2006;173(1):105–11. 26. Glassberg MK, Elliot SJ, Fritz J, et al. Activation of the estrogen receptor contributes to the progression of pulmonary lymphangioleiomyomatosis via matrix metalloproteinaseinduced cell invasiveness. J Clin Endocrinol Metab 2008;93(5): 1625–33. 27. Taylor JR, Ryu J, Colby TV, et al. Lymphangioleiomyomatosis. Clinical course in 32 patients. N Engl J Med 1990;323(18): 1254–60. 28. Matsui K, Takeda K, Yu ZX, et al. Downregulation of estrogen and progesterone receptors in the abnormal smooth muscle cells in pulmonary lymphangioleiomyomatosis following therapy, An immunohistochemical study. Am J Respir Crit Care Med 2000;161(3 Pt 1):1002–9. 29. Ohori NP, Yousem SA, Sonmez-Alpan E, Colby TV. Estrogen and progesterone receptors in lymphangioleiomyomatosis, epithelioid hemangioendothelioma, and sclerosing hemangioma of the lung. Am J Clin Pathol 1991;96(4):529–35. 30. Abbott GF, Rosado-de-Christenson ML, Frazier AA, et al. From the archives of the AFIP: lymphangioleiomyomatosis: radiologic-pathologic correlation. Radiographics 2005;25(3):803–28. 31. Crausman RS, Jennings CA, Mortenson RL, et al. Lymphan gioleiomyomatosis: the pathophysiology of diminished exercise capacity. Am J Respir Crit Care Med 1996;153(4 Pt 1): 1368–76. 32. Eliasson AH, Phillips YY, Tenholder MF. Treatment of lymphangioleiomyomatosis. A meta-analysis. Chest 1989;96(6): 1352–55. 33. Oberstein EM, Gomez JP, Glassberg MK. [How lymphangioleiomyomatosis can be recognized and treated?]. Med Clín(Barc) 2002;119(10):382–85. 34. Taveira-Dasilva AM, Stylianou MP, Hedin CJ, et al. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest 2004;126(6):1867–74. 35. Boehler A, Speich R, Russi EW, et al. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 1996;335 (17):1275–80. 36. Nine JS, Yousem SA, Paradis IL, et al. Lymphangioleiomyo matosis: recurrence after lung transplantation. J Heart Lung Transplant 1994;13(4):714–19.

Chapter

27

Gender Differences in Susceptibility, Outcomes, and Pathophysiology of Sepsis Kristy A. Bauman1, and MeiLan K. Han2 1

Assistant Professor, University of Michigan, Division of Pulmonary and Critical Care Medicine, Ann Arbor, MI, USA Medical Director, Women’s Respiratory Health Program and Pulmonary Rehabilitation, University of Michigan, Division of Pulmonary and Critical Care, Ann Arbor, MI, USA 2

Introduction

hypotension persists despite adequate volume resuscitation and vasopressors are required to achieve adequate systemic blood pressure2 (Figure 27.1). This chapter will review the epidemiology and pathophysiology of sepsis, particularly as it applies to gender, and provide insights into potential mechanisms for gender differences.

Systemic inflammatory response syndrome (SIRS) is a clinical syndrome characterized by systemic inflammation and widespread tissue injury. SIRS is defined by several clinical variables including temperature 38°C or 35°C, heart rate 90 beats/min, respiratory rate 20 breaths/ min or PCO2  32 mmHg, and WBC  12 000 cells/mm3 or 4000 cells/mm3.1 SIRS can result from insults such as trauma, thermal injury, pancreatitis, autoimmune disorders, and surgery. When SIRS occurs as a result of infection, it is termed sepsis. Severe sepsis occurs when there is evidence of organ hypoperfusion or dysfunction including decreased urine output, altered mental status, and disseminated intravascular coagulation. Septic shock ensues if

Infection

Inflammation

Epidemiology of sepsis The incidence of sepsis in the United States has increased dramatically in the past thirty years with greater than 650 000 cases diagnosed annually.3,4 Risk factors that have been identified for developing sepsis include age greater than 65,

• Progressive inflammatory response • Uncontained infection/ secondary injury

• Immune supression: reduced infection containment • Endothelial damage: barrier dysfunction • Epithelial dysfunction: barrier dysfunction

Sucessful containment

Multiple organ failure hypoxia/ apoptosis

Irreversible changes Host death

Resolution Host recovery

Figure 27.1  Sepsis pathogenesis. Sepsis typically develops following infection or an inflammatory insult that is not contained and cleared by the host. The dysregulation of the inflammatory response leads to disruption and damage to the host immune system and several cell types. Endothelial and epithelial cells constitute an important barrier in the containment of infection and inflammation. Disruption of the endothelial and epithelial barrier could allow further dissemination of infection. Widespread cellular and immune dysfunction could then propagate resulting in organ failure, eventually resulting in an irrecoverable state. Reproduced with permission from Buras et al., 2005.114 Copyright (2005) Nature Publishing Group/Macmillan Publishers Principles of Gender-Specific Medicine

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Copyright 2010 20 , Elsevier Inc. All rights reserved.

s e c t i o n 4     Pulmonology

Population-adjusted incidence of sepsis (no./100 000)

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l

300

Men Women

200

100

0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 Year

Figure 27.2  Population-adjusted incidence of sepsis, according to sex, 1979–2000. Points represent the annual incidence rate, and I bars the standard error. Reproduced with permission from Martin et al., 2003.4 Copyright (2003) Massachusetts Medical Society

impaired immune function, bacteremia, and community acquired pneumonia.5–7 There is general agreement that male gender is also a risk factor for the development of sepsis. One of the first large epidemiologic studies to look at the epidemiology of sepsis was published in 2001.3 After reviewing all hospital discharge records from seven large states in 1995, women had lower age-specific sepsis incidence and mortality, although the mortality difference was largely explained by differences in age, co-morbidities, and site of infection. In a separate US study spanning over 22 years, sepsis was also reported to be more common among men than women with a mean annual relative risk of 1.28 for men4 (Figure 27.2). Analysis of data from four multicenter sepsis trials from the 1980s and 90s reported that 60–65% of sepsis patients were male.1 Other data also support these results. Men are more likely than women to develop sepsis after surgery, and to have an increased risk of infection.8 Multiple organ dysfunction syndrome (MODS) and posttraumatic sepsis are noted less commonly in females.9 In a study of over 500 trauma patients, men were shown to be more likely to develop severe infection with a 58% greater risk than women.10 An international epidemiologic study similarly reported that 62–65% of infected patients in an intensive care unit (ICU) were men.11 The influence of gender on the incidence of sepsis and infection in medical, surgical, and trauma patients is evident from large hospital and ICU-based studies. Overall, mortality rates from sepsis are alarmingly high, and even with adequate treatment have been reported to be between 20 and 50%.4,12 Mortality rates increase with disease severity. A study by Annane demonstrated mortality rates of 7, 16, 20, and 46%, respectively for SIRS, sepsis, severe sepsis, and septic shock.13 Fortunately, while the incidence of sepsis is increasing, hospital fatality rates due to sepsis are on the decline.4,12 Undisputed risk factors for mortality due to sepsis include comorbid medical conditions such as AIDS, hepatic failure, alcohol dependence, malignancy, and immune suppression.14–16

In addition to having a greater risk of developing sepsis, those over age 65 have an increased risk of death due to sepsis.4,12 Nosocomial infections are associated with a higher mortality rate than community acquired infections,17 although among nosocomial bloodstream infections, certain pathogens including Candida species and Pseudomonas aeruginosa for example, lead to extraordinarily high fatality rates.18 Many studies have reported conflicting data regarding the influence of gender on sepsis mortality. A prospective study of 52 surgical intensive care unit patients with severe sepsis or septic shock found a significant difference in mortality between male and female patients. Hospital mortality rate was 70% in male and 26% in female patients. This difference was not accounted for by difference in severity of organ failure as the multiple organ dysfunction score from day 1 to 28 was similar between genders19 In contrast to these reports, two large surgical ICU studies did not demonstrate an improved prognosis for females as compared to males. Wichmann et al. prospectively collected data on over 4000 surgical ICU admissions and concluded that although a diagnosis of severe sepsis was more likely in men, sepsisrelated mortality was not different between men and women.8 Eachempati et al. described 443 surgical patients with severe sepsis and also found no difference in mortality between women and men,20 except after age 80 when men fared better. The number of patients greater than 80 years of age was small.20 In a large study of over 500 mechanically ventilated patients in a medical intensive care unit, there were no gender differences in either mortality, total time on mechanical ventilation, need for tracheostomy, and medical ICU or hospital length of stay. About 22% of males and females included in the study had a diagnosis of sepsis as the indication for mechanical ventilation.21 Differences in sex hormones between males and females may account for the differential response to injury, inflammation, and sepsis seen in some studies. If this is the case, one would expect that the protective effects of being female would be more pronounced in premenopausal women and that postmenopausal women not receiving hormonal replacement therapy would be relatively less protected. Several studies address this issue by examining the effect of age and gender on outcomes of critical illness. A large study by Wohltmann et al. of 20 261 trauma patients noted that female gender was associated with a significant survival advantage in those below the age of 50.22 An additional supporting study demonstrated a reduction in sepsis and multiple organ failure in females compared to males, again only in those younger than 50.23 George et al. demonstrated that male blunt trauma patients less than 50 years old were found to have a 2.5 times higher risk of death than females; however, this risk was not found in males greater than 50 years old.24 Overall, these findings are consistent with the hypothesis that sex hormones may provide protection to women under 50 that is lost after menopause. There are other studies, however, which while demonstrating improved outcomes for women, do not support

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the hormonal hypothesis as an explanation. Adrie et al. reported on 1692 French ICU patients with severe sepsis in which hospital mortality rate and ICU mortality rate was significantly higher in men than in women.25 In this study, however, the lower risk of hospital mortality for women was actually detected only in patients over the age of 50. Perhaps the largest study to examine gender differences in trauma outcomes with a cohort of over 155 000 patents concluded that male patients who sustained blunt trauma had an increased risk of death compared with female patients for those over 50 years of age.24 Also arguing for improved outcomes in females but against the hormone hypothesis are data from sepsis in children where levels of sex hormones are low. Higher male fatality rates, largely due to sepsis, have been reported in children with burns.26 In a case-control study of children admitted to a hospital in the Netherlands, while the case fatality rate between genders was not significantly different, male children had higher Pediatric Risk of Mortality scores, fewer pediatric ICU-free days, and higher prevalence of shock.27 Finally, there are a group of studies which not only demonstrate poorer outcomes for women, but also suggest that pre-menopausal women may actually fare worse. In a cohort of patients with significant thermal injury, mortality rates among females were over twice that of males in those under the age of 60 and no difference was noted among those aged 60 and older;28 in a separate study of nearly 5000 burn patients, O’Keefe et al. found that female gender was actually an independent risk factor for mortality, particularly in those between the ages of 30 and 59.29 There are many possible explanations for the inconsistent results seen in these studies. These may include variable sample sizes, failure to control for confounding factors such as coexisting medical illnesses, differences in the type of injury sustained, patient care protocols, hormonal milieu of the female patient at the time of insult and preadmission use of oral contraceptives and estrogen replacement therapy. Thus while the available data suggest that risk of developing sepsis likely is lower for women, the data with respect toward outcomes is less clear. While clinical studies in humans are fraught with difficulties in controlling for heterogeneity, animal studies are not, and have provided significant insight into gender-based differences in inflammation and injury.

Experimental evidence of genderbased difference in sirs and sepsis Sex Hormones and the Immune Response to Stress In contrast to findings in humans, animal studies have consistently found advantages for females under stress-inducing conditions. Female animals have clearly been shown to tolerate sepsis better than males, with significantly improved survival rates.30 Differences in sex hormones have been suggested as the cause of gender-based differences in the

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incidence and outcomes of sepsis and the gender-specific responses to acute injury. Experimental models in mice and rats are commonly employed in order to define the role of sex hormones in post-injury and inflammation pathogenesis. Modulation of male sex hormones includes surgical removal of the testes or castration.31 At 2 weeks post-procedure, circulating androgen levels are markedly decreased. Other approaches involve androgen receptor antagonists such as flutamide which inhibits androgen uptake or nuclear binding of the activated androgen receptor to the nuclear response elements in the nucleus.32 Bucalutamide inhibits binding of androgen to its cytosolic receptor, yet has little effect on serum testosterone levels.33 Methods to modulate female sex hormones include surgical ovariectomy, the use of estrogen receptor antagonists, estrogen receptor agonists, and aromatase inhibitors such as anastrozole.34 Estrogen levels are highest in the rodents proestrus cycle and animals can be studied during this stage to determine high-level estrogen effects.34 Animal models of acute injury often employed include hemorrhagic shock models, thermal injury models, and models of sepsis such as cecal ligation and puncture.35 The insights gained through the use of animal models in defining gender-based differences in acute injury and sepsis are described below. Experimental evidence also suggests a significant protective role for female sex hormones in stress states. 17beta estradiol is the predominant circulating estrogen in female animals. 17-estradiol appears to stimulate humoral and cell-mediated immunity whereas the male hormone 5-dihydrotestosterone (DHT) negatively influences these responses.36–38 Studies have also demonstrated preserved immune function in models of trauma and hemorrhage for female rodents in the prostreus phase when estrogen levels peak as compared to male rodents.39,40 Ovariectomized females did not have preservation of immune function, and reacted similarly to males. Using the same model, administration of 17-estradiol to males or to the ovariectomized females preserved immune function.30,39 Gender also influences inflammatory cytokine production. In a hemorrhagic shock model, female rodents demonstrated preserved splenocyte-proliferative capacity and IL-3 secretion and maintained macrophage IL-1 secretion compared to males who experienced reduced expression of all pro-inflammatory cytokines and a reduced splenocyte-proliferative capacity.41 Using a cecal ligation and puncture model of sepsis, Erikoglu et al. demonstrated that male and female rats treated with estrogen and progesterone compared to untreated control rats had a reduction of lung and hepatic congestion and inflammation.42 The mechanisms through which sex hormones have their effects occur through two mechanisms: ‘genomic’ and ‘nongenomic’ (see Figure 27.3). Traditionally, estrogen has been thought to diffuse passively into cells and after binding to its receptor, act within the nucleus of the cells by binding to specific DNA response elements and regulating gene transcription. Multiple estrogen-regulated

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Estrogen

Rapid change in • vasomotor tone • cellular response to injury GPR30 Estrogen receptor

D Nongenomic effects

C

Kinases

e.g. ↓ vasoconstriction, ↑ vasodilation, ↓ pro-injury singnalling

Genomic effects

e.g. ↓ or ↑ production of proteins

Estrogen receptor

Estrogen Estrogen receptor

B

Estrogen receptor Transcription factor

A Genomic effects

Figure 27.3  Genomic and nongenomic effects of estrogen. (A), The genomic estrogen effects require estrogen to passively diffuse into the cell. After binding to its receptor, estrogen acts as a transcription factor. (B), Alternatively, the complex may induce or decrease the production of a specific protein in a more indirect manner through activation or inhibition of its transcription factor- (TNF-). These two mechanisms are referred to as the genomic mechanisms of estrogen. They rely on the increased or decreased production of proteins to mediate its effects. Therefore, these effects take longer to occur. In contrast, the nongenomic effects occur much more rapidly because they use existing proteins and signaling pathways. (C–D), The nongenomic effects may either be mediated by classic-type estrogen receptors (C) residing in the cell membrane such as estrogen receptor- or- by more nonclassic-type receptor proteins such as the G-protein-coupled receptor 30 (D). This results in modification in intracellular signaling pathways and kinases. Effects include upregulation of the PI-3K/Akt pathway and effects on mean arterial pressure kinases. Reproduced with permission from Lahm et al , 2008.46 Copyright (2008) Society of Critical Care Medicine and Lippincott Williams & Wilkins; www.lww.com

genes in trauma sepsis have been described. The gene products include heme-oxygenase, heat shock protein, and endothelin-1 among others.43–45 Estrogen may also act in a more indirect manner by using existing proteins to mediate its effects. These nongenomic effects may be mediated by estrogen receptors (ER) residing in the cell membrane including ER and ER or by a more nonclassic receptor protein such as the G-protein coupled receptor 30.46 These plasma membrane estrogen receptors are located on several immune cells including macrophages, leukocytes, and thymocytes.47 Suzuki et al. demonstrated that the beneficial effects of 17-estradiol on proinflammatory cytokine expression is mediated through ER in splenic macrophages, liver Kupfer cells and T cells, and through ER in alveolar macrophages.48 The mechanism by which 17estradiol acts through ER in splenic T cells is mediated through mitogen-activated protein kinase (MAPK), NF-B, and activator protein 1 (AP-1) signaling pathways.49 In a trauma hemorrhage model, hepatic injury was prevented via an ER-mediated reduction in NF-B, AP-1 activity, and inducible nitric oxide synthase (iNOS) expression. ER

induced downregulation of iNOS and offered significant protection from acute lung injury.48–50 This protective effect is mediated via downregulation of lung macrophage inhibitory factor which upregulates toll-like receptor 4 (TLR4).51 TLR4 plays a major role in the systemic inflammatory response in sepsis. Flutamide results in protective effects in the liver after hemorrhagic insult through downregulation of NF-B via an ER signaling pathway.52 Collectively, these data demonstrate that estrogen is immune-enhancing and protective against the widespread tissue injury that occurs in settings of acute injury or sepsis. This protection is mediated both through genomic mechanisms by alteration of gene expression and via non-genomic pathways through activation of estrogen receptors and MAPK signaling. While estrogen is immune enhancing and protective in animal models, testosterone, a predominantly male sex hormone, is deleterious and acts as an immune suppressant. In murine two-hit models with hemorrhagic shock or trauma as the first injury followed by sepsis as the second insult, survival was improved in males after testosterone receptor blockade.53 In another study, testosterone receptor blockade

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with flutamide led to improvement in both cardiac contractility and hepatocellular function after injury.54 Additionally, castration of male rodents prior to trauma and hemorrhage prevented the immune suppression which occurred in control male animals.55 Treatment of either castrated males or female rodents with DHT led to a reduction in splenic and macrophage inflammatory IL-1 and IL-3 cytokine production after injury.55–58 17-estradiol promotes Th1 cytokine expression by reducing IL-10 secretion. Alternatively, DHT inhibits Th1 cytokine expression, impairing cell-mediated immunity.56, 59 While experimental findings continue to expand our knowledge in animal models, attributing a sex hormonebased mechanism for gender-related differences in humans requires documentation of sex hormone levels. These levels should be studied at injury onset, post-injury, and during recovery. Several studies have shown that estrogen levels are elevated in response to stress from critical illness while testosterone levels are markedly low.19, 60–62 In the prospective study by Schroder et al., the testosterone levels were normal in women and low in men, but they had a higher mortality rate. Serum estradiol level in males and postmenopausal females was significantly elevated on day 1 of sepsis diagnosis and continued to be elevated at day 14. The values for premenopausal females were not reported.19 In another study of critically ill patients, high estrogen levels were observed in those with sepsis and septic shock, both males and females. LH and FSH levels were decreased in both sexes and testosterone levels were low in all male patients.61 Elevated estradiol levels have also been linked to adverse outcomes in critically ill patients. A prospective study in surgical and trauma intensive care units, the median estradiol concentration was significantly elevated in non-survivors regardless of sex. Estradiol concentration was a good predictor of poor outcome in men and in premenopausal women, however was a poor predictor in postmenopausal women.63 In a study of over 300 medical ICU patients with severe infection, mortality rate correlated with age, APACHE II score and 17–estradiol level in both males and females. Gender alone however did not predict mortality. Of the female patients studied, 70% were over 50 years old, suggesting that most were likely postmenopausal. The women had higher follicle stimulating hormone levels relative to males which is expected in the postmenopausal state.64 Why higher estradiol levels correlated with higher mortality is unclear given animal studies suggesting estradiol is protective. Estradiol may be produced as a compensatory response to injury and therefore may simply be a marker of injury severity. Another possibility is that estradiol at very high levels may actually have immunosuppressive effects, as estrogen has also been reported to suppress cell-mediated immunity in pregnancy.65 Difference in glucocorticoid production may also modulate gender differences in the stress response during sepsis. Female rats had higher levels of plasma adrenocroticotropin

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(ACTH) and corticosterone levels in response to a neurogenic stressor (mild electric foot shocks).66 This difference was abolished by ovariectomy suggesting the effect is likely modulated by sex hormones. However, in response to a systemic stressor, alcohol injection, the same investigators found no obvious effect of sex on corticosterone secretion. In a separate study, ovariectomized female rats had lower basal and stress-induced corticosterone levels than intact females, which was restored after administration of 17-estradiol.67 In a study of humans, ethinyl estradiol administered to men led to an acute increase in free plasma hydrocortisone suggesting estrogen may mediate the corticosteroid response to stress.68 Gender differences in prolactin production during stress may also modulate immune function. While lactation is the function most commonly associated with prolactin, it also stimulates the immune system by enhancing proliferation of lymphocytes and macrophages.69 Prolactin concentrations in response to stress are higher in women than men.70 Male mice subjected to hemorrhagic shock followed by fluid resuscitation were randomized to prolactin versus placebo prior to resuscitation. Prolactin-treated animals also maintained immune function as compared to placebo-treated animals.71

Gender Differences in Hemodynamic Response to Stress Gender influences cardiovascular physiology. Cardiovascular systems are involved in the inflammatory response of sepsis. The systemic inflammatory response has been demonstrated to lead to cardiac inflammation. Cytokines produced as part of the inflammatory response depress cardiac function.72 In a rat model of hemorrhagic shock, higher estrogen and prolactin levels were associated with better cardiovascular function.73 In a follow-up experiment, male rats received a dose of 17-estradiol during resuscitation and experienced higher intestinal, hepatic, and adrenal blood flow, and improved splanchnic oxygen delivery as compared to the placebo treated group.74 In male rodents, administration of 17-estradiol following trauma-hemorrhage also resulted in improved myocardial contractility, cardiac output, hepatocellular function, and reduced IL-6 secretion.39, 40 Acute injury leads to the production of inflammatory mediators including MAPK and NF-B. Wang et al. reported that males had higher levels of activated MAPK in isolated hearts after global ischemia and reperfusion.75 Additionally, Angele et al. has reported that castration attenuates the increase in activated MAPK caused by trauma-hemorrhage.76 Ovariectomized females also have impaired cardiac functional recovery after ischemia reperfusion injury when compared to intact females. In humans, better cardiac function has also been reported in women after burn injuries.77 Another potential mechanism for gender-related cardioprotective effects in sepsis is increased nitric oxide (NO) production. NO reduces neutrophil accumulation and causes vasodilation. Estrogen

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increases NO production through increased expression of nitric oxide synthase.78 Estrogen also decreases apoptosis in cardiac myocytes after global ischemia reperfusion injury.75 Cardioprotection may also result from estrogen induced down-regulation of 1-adrenoreceptors in the heart during ischemic insults. Physiological increases in circulating estrogen levels have also been demonstrated to acutely attenuate pulmonary artery vasoconstriction under normoxic and hypoxemic conditions.79 Lahm et al. demonstrated that administering 17-estradiol to rats attenuates phenylephrine- and hypoxiainduced vasoconstriction, a finding that has been confirmed by several other investigators in other animal models.80 Male rats are more prone to the development of pulmonary arterial remodeling and right ventricular hypertrophy when exposed to chronic hypoxemia.81 In humans, women have decreased incidence of high-altitude pulmonary edema82 and hormone replacement therapy may prevent the development of pulmonary hypertension in postmenopausal patients with systemic sclerosis.83 These effects are likely mediated through an increase in prostacyclin release and an increase in NO production through both genomic and nongenomic mechanisms. Downregulation of endothelin-1 (ET-1) gene expression by estrogen likely also contributes. ET-1 is a potent vasoconstrictor and mitogen. Estradiol replacement therapy prevents hypoxia-mediated increases in ET-1 expression.84 An additional mechanism that may mediate gender differences in vasodilation and sepsis is the hormone relaxin. Relaxin is a 6 kdA dimeric peptide hormone structurally related to the insulin family of peptides. Relaxin is most well known for the role it plays in preparing the birth canal for parturition including cervical softening and widening of the pubic symphysis. In women, relaxin is produced and secreted by the corpus luteum of the ovary and circulating in highest amounts during pregnancy.85 Breast tissue is also responsible for some amount of hormone production. While relaxin levels are highest during pregnancy and during the second phase of the menstrual cycle,86 relaxin is also detectable in men where the prostate is the primary source of production. Interestingly, the higher levels of relaxin in women as compared to men appear to be sustained into the postmenopausal period.87 The primary receptor for relaxin, LGR788 has been identified in several tissues and cells outside the female reproductive tract including the heart, kidney, and lung; the pleitropic effects of this hormone have more recently begun to be realized.89 Relaxin has demonstrated activity as a vasodilator in the kidney90 and other vascular beds.91 As with estrogen, these effects are believed to be mediated by increased NO synthesis.92 We know that acute renal failure in the ICU is associated with high mortality, with many of these patients experiencing acute renal failure in the setting of multi-system organ failure. The incidence of acute renal failure in ICU patients has been reported to be 13.0/100 000 in men and 9.1/100 000 in

women.93 Several studies also have reported increased risk of death for male patients as compared to female patients experiencing acute renal failure in the ICU. Men also have significantly greater functional and histologic renal injury from ischemia.94 It is possible that both estrogen and relaxin could be mediating these effects. Estradiol treatment of male rats with renal ischemia improves survival.95 In a hypoxic pulmonary hypertension model in the rat, relaxin administered subcutaneously resulted in reduced right ventricular pressures and ameliorated collagen accumulation in the main pulmonary arteries after ten days of hypoxia.96 In an ischemia reperfusion intestinal injury model in rats induced by splanchnic artery occlusion, relaxin infusion reduced the drop of blood pressure and mortality rate.97 Relaxin also reduced leukocyte infiltration and expression of endothelial cell adhesion molecules in the ileum. Free radical-mediated tissue injury also appeared to be attenuated resulting in a reduction in ileal cell apoptosis. Other protective effects of relaxin may also include its ability to bind and stimulate the glucocorticoid receptor that when activated translocates to the cell nucleus and inhibits NF-B and stimulates transcription of glucocorticoid response elements. In an animal model of acute pancreatitis, treatment with relaxin reduced serum amylase, lipase, C-reactive protein, and IL-6 as well as pancreatic and lung myeloperoxidase.98 Acinar and fat necrosis, hemorrhage, and neutrophil infiltrate were also reduced. Both chemical NO synthase inhibition by L-NAME (N-nitro-L-arginine methyl ester) and glucocorticoid receptor blockage by mifepristone decreased the efficiency of relaxin.

Gender Differences and Gene in Polymorphisms An additional focus of ongoing research is the relationship between gender and genetic polymorphisms. Polymorphisms occur when inter-individual differences in DNA sequences coding for one specific give rise to different functional and phenotypic traits. The IL-1 receptor­associated kinase (IRAK-1) has been shown to play a ­central role in TLR2- and TLR4-induced activation of NFB, regulating the transcription of many sepsis-associated proinflammatory mediators. There are two haplotypes for the IRAK-1 gene in whites. The variant haplotype consists of five intron single-nucleotide polymorphisms (SNPs) and three exon SNPs. Arcaroli et al. examined the functional significance of the IRAK-1 variant haplotype in modifying nuclear translocation of NF-B and its effects on outcomes from sepsis in 155 white patients. The IRAK-1 variant haplotype was associated with increased nuclear levels of NFB in LPS-stimulated peripheral neutrophils from patients with sepsis compared with that in patients with wild-type IRAK-1 haplotype.99 There was an increased incidence of shock, and higher 60-day mortality in patients with the IRAK-1 variant haplotype compared with wild type.

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The IRAK-1 variant haplotype is located on the X chromosome100 and therefore men are more likely than women to demonstrate the functional effects of the IRAK-1 variant haplotype. Homozygous women would have similar risks, although the frequency of homozygosity in women is significantly less. There were no adverse effects in the women studied suggesting that the effects of the IRAK-1 haplotype are not dominant.99 Research also demonstrates that gender may influence the phenotypic expression of specific genetic polymorphisms with respect to host response to inflammation and sepsis. Lipopolysaccharide (LPS) is a component of the Gram-negative bacterial envelope. It is an important mediator of sepsis. Data from a study by Hubacek et al. suggests that polymorphisms in the gene encoding for LPS binding protein may increase the risk of both sepsis and the risk of death due to sepsis in males but not in females.101 In an effort to better understand gender differences in the innate immune response and vascular reactivity, van Eijk et al. administered intravenous Escherichia coli LPS to healthy human volunteers. Overall, females displayed a more pronounced pro-inflammatory response with higher rise in C-reactive protein, leukocyte sequestration, TNF-, and LPS binding protein. In the absence of LPS, administration of norepinephrine induces vasoconstriction. Vascular sensitivity to norepinephrine was decreased after LPS administration in males, but did not change in females.102 Messer et al. reported an Ncol polymorphism of the human TNF- gene, labeled TNF-1and TNF-2, which results in altered TNF- production.103 In a prospective study of 201 patients with severe sepsis in surgical intensive care units, the role of the genomic marker TNF-Ncol polymorphism was evaluated with respect to gender. The genotype distribution of patients homozygous for TNF-1, and heterozygous or homozygous for TNF-2 was comparable between males and females. In women, no difference in survival rate was found between the different genotypes, while mortality rate was significantly increased in men homozygous for TNF-2. The overall survival rate was higher in women. Genetic polymorphisms have also been studied to examine gender differences in susceptibility to adult respiratory distress syndrome (ARDS). Sepsis is a risk factor for the development of organ damage in the lung, characterized by acute lung injury or ARDS. ARDS is acute lung inflammation and increased permeability resulting in severe hypoxemia and bilateral infiltrates on chest radiography in the absence of left heart failure.104 In ARDS, pulmonary surfactant is dysfunctional. Surfactant is synthesized by type II alveolar epithelial cells and lowers surface tension allowing for normal lung expansion.105 Polymorphisms of the surfactant protein-B gene were found to be associated with development of ARDS.106 In critically ill patients with risk factors for ARDS including sepsis and septic shock, women with a variant surfactant protein-B allele were at increased odds of ARDS development whereas men with the variant allele were not.107 These studies

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contribute to the increasing data that gender differences exist in disease susceptibility, severity, and outcome of critically ill patients. However, it is unlikely that a single gene can explain the highly variable individual susceptibility to complex syndromes such as sepsis and ARDS. Furthermore, exactly how gender modulates the expression of these polymorphisms is also not clear as it could be through sex steroid dependent or independent mechanisms.

Gender Differences in Health Care Access and Delivery Finally, some authors have suggested that differences in health care access and delivery and not biology may explain gender differences in outcomes of critical illness and sepsis. Overall, studies in the United States have found that patients receive only about half of the recommended level of health care.108,109 A multi-community study of greater than 6000 patients demonstrated that women received a higher proportion of recommended care than men, 56.6% vs. 52.3%.109 Women had higher scores than men for preventive care (57.8% vs. 50.1%) and chronic care (57.9% vs. 54.5%) but lower scores for acute care (51.9% vs. 58.4%). These differences were statistically significant. Women were less likely then men to undergo extensive evaluation and invasive treatment for cardiovascular disease.110,111 Additionally in a cohort of critically ill patients, men were more likely than women to receive multiple invasive procedures112 This bias toward less aggressive intensive care unit treatment has not been consistently demonstrated. For example, in a large cohort of intensive care unit patients with severe sepsis, no difference was found in the number of invasive procedures or the level of care as assessed by the nine equivalents of nursing manpower score between men and women.25 Differences in patient, family or physician attitudes with respect to gender and withdrawal of life-sustaining care are also a consideration in determining outcomes. In a study of surgical and medical ICU patients, Kollef et al. employed a multivariate analysis strategy and found that female gender is independently associated with increased mortality in surgical, not medical patients. Women in this study were more likely to have medical support withdrawn raising the possibility of bias or variability in the process of care related to gender.113 In contrast, Epstein et al. reported that in mechanically ventilated medical ICU patients, there was no gender difference in the number and timing of orders written to withhold or withdraw care between males and females21

Conclusion While it is clear that gender influences the incidence of sepsis in humans, gender differences in mortality have not been as consistently documented. Animal models clearly demonstrate

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that sex steroids modulate the host response to sepsis. The majority of evidence suggests that estrogen plays a protective role by stimulating humoral and cell-mediated immunity. Both estrogen and relaxin may reduce pulmonary artery pressures and improve hemodynamics. Relaxin may also improve splanchnic blood flow and stimulate the glucocorticoid receptor leading to decreased inflammation. Testosterone, on the other hand, acts as an immune suppressant. While this data is intriguing, the pathophysiology of sepsis, however, is complicated and depends on a balance between pro- and anti-inflammatory mediators which may explain why studies examining gender differences in sepsis outcomes have reported such varying results. More data are needed to clarify how gender differences in animal models translate to sepsis in humans and how this information can be used to improve outcomes.

References   1. Bone RC, Sprung CL, Sibbald WJ. Definitions for sepsis and organ failure. Crit Care Med 1992;20(6):724–26.   2. Levi M, ten Cate H, van der Poll T, et al. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993;270(8):975–79.   3. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29(7):1303–10.   4. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348(16):1546–54.   5. Jones GR, Lowes JA. The systemic inflammatory response syndrome as a predictor of bacteraemia and outcome from sepsis. Q J Med 1996;89(7):515–5122.   6. Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med 2006;34(1):15–21.   7. Dremsizov T, Clermont G, Kellum JA, et al. Severe sepsis in community-acquired pneumonia: when does it happen, and do systemic inflammatory response syndrome criteria help predict course?. Chest 2006;129(4):968–78.   8. Wichmann MW, Inthorn D, Andress HJ, et al. Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Intens Care Med 2000;26(2):167–72.   9. Oberholzer A, Keel M, Zellweger R, et al. Incidence of septic complications and multiple organ failure in severely injured patients is sex specific. J Trauma 2000;48(5):932–37. 10. Offner PJ, Moore EE, Biffl WL. Male gender is a risk factor for major infections after surgery. Arch Surg 1999;134(9):935–38, discussion 8-40. 11. Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intens Care Med 2002;28(2):108–21. 12. Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 2007;35(5):1244–50.

13. Annane D, Aegerter P, Jars-Guincestre MC, et al. Current epidemiology of septic shock: the CUB-Rea Network. Am J Respir Crit Care Med 2003;168(2):165–72. 14. Danai PA, Moss M, Mannino DM, et al. The epidemiology of sepsis in patients with malignancy. Chest 2006;129(6):1432–40. 15. O’Brien JM Jr., Ali NA, Aberegg SK, et al. Sepsis. Am J Med 2007;120(12):1012–22. 16. Knaus WA, Wagner DP, Draper EA, et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991;100(6):1619–36. 17. Shorr AF, Tabak YP, Killian AD, et al. Healthcare-associated bloodstream infection: A distinct entity? Insights from a large U.S. database. Crit Care Med 2006;34(10):2588–95. 18. Miller PJ, Wenzel RP. Etiologic organisms as independent predictors of death and morbidity associated with bloodstream infections. J Infect Dis 1987;156(3):471–77. 19. Schroder J, Kahlke V, Staubach KH, et al. Gender differences in human sepsis. Arch Surg 1998;133(11):1200–5. 20. Eachempati SR, Hydo L, Barie PS. Gender-based differences in outcome in patients with sepsis. Arch Surg 1999;134(12): 1342–47. 21. Epstein SK, Vuong V. Lack of influence of gender on outcomes of mechanically ventilated medical ICU patients. Chest 1999;116(3):732–39. 22. Wohltmann CD, Franklin GA, Boaz PW, et al. A multicenter evaluation of whether gender dimorphism affects survival after trauma. Am J Surg 2001;181(4):297–300. 23. Frink M, Hsieh YC, Hu S, et al. Mechanism of salutary effects of finasteride on post-traumatic immune/inflammatory response: upregulation of estradiol synthesis. Ann Surg 2007;246(5):836–43. 24. George RL, McGwin G Jr., Windham ST, et al. Age-related gender differential in outcome after blunt or penetrating trauma. Shock 2003;19(1):28–32. 25. Adrie C, Azoulay E, Francais A, et al. Influence of gender on the outcome of severe sepsis: a reappraisal. Chest 2007;132 (6):1786–93. 26. Barrow RE, Herndon DN. Incidence of mortality in boys and girls after severe thermal burns. Surg Gynecol Obstet 1990;170(4):295–98. 27. Maat M, Buysse CM, Emonts M, et al. Improved survival of children with sepsis and purpura: effects of age, gender, and era. Crit Care 2007;11(5):R112. 28. McGwin G Jr., George RL, Cross JM, et al. Gender differences in mortality following burn injury. Shock 2002;18(4):311–15. 29. O’Keefe GE, Hunt JL, Purdue GF. An evaluation of risk factors for mortality after burn trauma and the identification of gender-dependent differences in outcomes. J Am Coll Surg 2001;192(2):153–60. 30. Zellweger R, Wichmann MW, Ayala A, et al. Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med 1997;25(1):106–10. 31. Waynforth H. Experimental and Surgical Techniques in the Rat. London: Academic Press; 1980. 32. Wichmann MW, Angele MK, Ayala A, et al. Flutamide: a novel agent for restoring the depressed cell-mediated immunity following soft-tissue trauma and hemorrhagic shock. Shock 1997;8(4):242–48. 33. Kolvenbag GJ, Furr BJ. Relative potency of bicalutamide (Casodex) and flutamide (Eulexin). Urology 1999;54(1):194–97.

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34. Choudhry MA, Schwacha MG, Hubbard WJ, et al. Gender differences in acute response to trauma-hemorrhage. Shock 2005;24(Suppl. 1):101–6. 35. Deitch EA. Animal models of sepsis and shock: a review and lessons learned. Shock 1998;9(1):1–11. 36. Kovacs EJ, Messingham KA, Gregory MS. Estrogen regulation of immune responses after injury. Mol Cell Endocrinol 2002;193(1-2):129–35. 37. Yokoyama Y, Schwacha MG, Samy TS, et al. Gender dimorphism in immune responses following trauma and hemorrhage. Immunol Res 2002;26(1-3):63–76. 38. Ansar Ahmed S, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol 1985;121(3):531–51. 39. Knoferl MW, Jarrar D, Angele MK, et al. 17 beta-Estradiol normalizes immune responses in ovariectomized females after trauma-hemorrhage. Am J Physiol Cell Physiol 2001;281(4): C1138. 40. Mizushima Y, Wang P, Jarrar D, et al. Estradiol administration after trauma-hemorrhage improves cardiovascular and hepatocellular functions in male animals. Ann Surg 2000;232(5):679. 41. Wichmann MW, Zellweger R, DeMaso CM, et al. Enhanced immune responses in females, as opposed to decreased responses in males following haemorrhagic shock and resuscitation. Cytokine 1996;8(11):853–63. 42. Erikoglu M, Sahin M, Ozer S, et al. Effects of gender on the severity of sepsis. Surg Today 2005;35(6):467–72. 43. Szalay L, Shimizu T, Schwacha MG, et al. Mechanism of salutary effects of estradiol on organ function after traumahemorrhage: upregulation of heme oxygenase. Am J Physiol Heart Circ Physiol 2005;289(1):H92–98. 44. Szalay L, Shimizu T, Suzuki T, et al. Androstenediol administration after trauma-hemorrhage attenuates inflammatory response, reduces organ damage, and improves survival following sepsis. Am J Physiol Gastrointest Liver Physiol 2006;291(2):G260–66. 45. Ba ZF, Shimizu T, Szalay L, et al. Gender differences in small intestinal perfusion following trauma hemorrhage: the role of endothelin-1. Am J Physiol Gastrointest Liver Physiol 2005;288(5):G860–65. 46. Lahm T, Crisostomo PR, Markel TA, et al. The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: potential new clinical implications for an old hormone. Crit Care Med 2008;36(7):2174–83. 47. Olsen NJ, Kovacs WJ. Gonadal steroids and immunity. Endocr Rev 1996;17(4):369–84. 48. Suzuki T, Shimizu T, Yu HP, et al. Tissue compartmentspecific role of estrogen receptor subtypes in immune cell cytokine production following trauma-hemorrhage. J Appl Physiol 2007;102(1):163–68. 49. Suzuki T, Shimizu T, Yu HP, et al. Estrogen receptor-alpha predominantly mediates the salutary effects of 17beta-estradiol on splenic macrophages following trauma-hemorrhage. Am J Physiol Cell Physiol 2007;293(3):C978–84. 50. Yu HP, Hsieh YC, Suzuki T, et al. Salutary effects of estrogen receptor-beta agonist on lung injury after trauma-hemorrhage. Am J Physiol Lung Cell Mol Physiol 2006;290(5):L1004–9. 51. Hsieh YC, Frink M, Hsieh CH, et al. Downregulation of mig-ra­tion inhibitory factor is critical for estrogen-mediated

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

299

attenuation of lung tissue damage following traumahemorrhage. Am J Physiol Lung Cell Mol Physiol 2007;292(5):L1227–32. Shimizu T, Yu HP, Hsieh YC, et al. Flutamide attenuates pro-inflammatory cytokine production and hepatic injury following trauma-hemorrhage via estrogen receptor-related pathway. Ann Surg 2007;245(2):297–304. Angele MK, Wichmann MW, Ayala A, et al. Testosterone receptor blockade after hemorrhage in males: restoration of the depressed immune functions and improved survival following subsequent sepsis. Arch Surg 1997;132(11):1207–14. Remmers DE, Wang P, Cioffi WG, et al. Testosterone receptor blockade after trauma-hemorrhage improves cardiac and hepatic functions in males. Am J Physiol 1997;273(6 Pt 2):H2919–25. Wichmann MW, Zellweger R, DeMaso CM, et al. Mechanism of immunosuppression in males following trauma-hemorrhage. Critical role of testosterone. Arch Surg 1996;131(11):1186–91, discussion 91-2. Angele MK, Knoferl MW, Ayala A, et al. Testosterone and estrogen differently effect Th1 and Th2 cytokine release following trauma-haemorrhage. Cytokine 2001;7;16(1):22–30. Angele MK, Ayala A, Cioffi WG, et al. Testosterone: the culprit for producing splenocyte immune depression after trauma hemorrhage. Am J Physiol 1998;274(6 Pt 1):C1530–36. Angele MK, Ayala A, Monfils BA, et al. Testosterone and/ or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage. J Trauma 1998;44(1):78–85. Angele MK, Knoferl MW, Schwacha MG, et al. Sex steroids regulate pro- and anti-inflammatory cytokine release by macrophages after trauma-hemorrhage. Am J Physiol 1999;277(1 Pt 1):C35–42. Scheingraber S, Dobbert D, Schmiedel P, et al. Gender-specific differences in sex hormones and cytokines in patients undergoing major abdominal surgery. Surg Today 2005;35(10):846–54. Fourrier F, Jallot A, Leclerc L, et al. Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock. Circ Shock 1994;43(4):171–78. Christeff N, Carli A, Benassayag C, et al. Relationship between changes in serum estrone levels and outcome in human males with septic shock. Circ Shock 1992;36(4):249–55. Dossett LA, Swenson BR, Evans HL, et al. Serum estradiol concentration as a predictor of death in critically ill and injured adults. Surg Infect 2008;9(1):41–48. Angstwurm MW, Gaertner R, Schopohl J. Outcome in elderly patients with severe infection is influenced by sex hormones but not gender. Crit Care Med 2005;33(12):2786–93. Grossman C. Possible underlying mechanisms of sexual dimorphism in the immune response, fact and hypothesis. J Steroid Biochem 1989;34(1-6):241–51. Rivier C. Gender, sex steroids, corticotropin-releasing factor, nitric oxide, and the HPA response to stress. Pharmacol Biochem Behav 1999;64(4):739–51. Seale JV, Wood SA, Atkinson HC, et al. Gonadal steroid replacement reverses gonadectomy-induced changes in the corticosterone pulse profile and stress-induced hypothalamicpituitary-adrenal axis activity of male and female rats. J Neuroendocrinol 2004;16(12):989–98.

300

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68. Marks LJ, Friedman GR, Duncan FJ. Effect of estrogen administration on hydrocortisone metabolism in man. J Lab Clin Med 1961;57:47–53. 69. Bernton EW, Meltzer MS, Holaday JW. Suppression of macrophage activation and T-lymphocyte function in hypoprolactinemic mice. Science 1988;239(4838):401–4. 70. Motreja S, Subbakrishna DK, Subhash MN, et al. Gender but not stimulus parameters influence prolactin response to electroconvulsive therapy. Psychoneuroendocrinology 1997; 22(5):337–48. 71. Zellweger R, Wichmann MW, Ayala A, et al. Prolactin: a novel and safe immunomodulating hormone for the treatment of immunodepression following severe hemorrhage. J Surg Res 1996;63(1):53–58. 72. Kher A, Wang M, Tsai BM, et al. Sex differences in the myocardial inflammatory response to acute injury. Shock 2005;23(1):1–10. 73. Jarrar D, Wang P, Cioffi WG, et al. The female reproductive cycle is an important variable in the response to traumahemorrhage. Am J Physiol Heart Circ Physiol 2000;279(3): H1015–21. 74. Kuebler JF, Jarrar D, Toth B, et al. Estradiol administration improves splanchnic perfusion following trauma-hemorrhage and sepsis. Arch Surg 2002;137(1):74–79. 75. Wang M, Baker L, Tsai BM, et al. Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 2005;288(2):E321–26. 76. Angele MK, Nitsch S, Knoferl MW, et al. Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol. Am J Physiol Endocrinol Metab 2003;285(1):E189–96. 77. Horton JW, White DJ, Maass DL. Gender-related differences in myocardial inflammatory and contractile responses to major burn trauma. Am J Physiol Heart Circ Physiol 2004;286(1):H202–13. 78. Node K, Kitakaze M, Kosaka H, et al. Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels. Circulation 1997;96(6):1953–63. 79. Lahm T, Patel KM, Crisostomo PR, et al. Endogenous estrogen attenuates pulmonary artery vasoreactivity and acute hypoxic pulmonary vasoconstriction: the effects of sex and menstrual cycle. Am J Physiol Endocrinol Metab 2007;293(3):E865–71. 80. Lahm T, Crisostomo PR, Markel TA, et al. Exogenous estrogen rapidly attenuates pulmonary artery vasoreactivity and acute hypoxic pulmonary vasoconstriction. Shock 2008;30(6):660–67. 81. Stupfel M, Pesce VH, Gourlet V, et al. Sex-related factors in acute hypoxia survival in one strain of mice. Aviat Space Environ Med 1984;55(2):136–40. 82. Ergueta J, Spielvogel H, Cudkowicz L. Cardio-respiratory studies in chronic mountain sickness (Monge’s syndrome). Respiration 1971;28(6):485–517. 83. Beretta L, Caronni M, Origgi L, et al. Hormone replacement therapy may prevent the development of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Scand J Rheumatol 2006;35(6):468–71. 84. Earley S, Resta TC. Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression. Am J Physiol Lung Cell Mol Physiol 2002;283(1):L86–93.

  85. Ivell R, Einspanier A. Relaxin peptides are new global players. Trends Endocrinol Metab 2002;13(8):343–48.   86. Lippert TH, Armbruster FP, Seeger H, et al. Urinary excretion of relaxin after estradiol treatment of postmenopausal women. Clin Exp Obstet Gynecol 1996;23(2):65–69.   87. Giordano N, Papakostas P, Lucani B, et al. Serum relaxin in systemic sclerosis. J Rheumatol 2005;32(11):2164–66.   88. Hsu SY, Nakabayashi K, Nishi S, et al. Activation of orphan receptors by the hormone relaxin. Science 2002; 295(5555):671–74.   89. Bathgate RA, Samuel CS, Burazin TC, et al. Relaxin: new peptides, receptors and novel actions. Trends Endocrinol Metab 2003;14(5):207–13.   90. Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest 1999;103(4):525–33.   91. Bani-Sacchi T, Bigazzi M, Bani D, et al. Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br J Pharmacol 1995;116(1):1589–94.   92. Danielson LA, Kercher LJ, Conrad KP. Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am J Physiol Regul Integr Comp Physiol 2000;279(4):R1298–304.   93. Hutchens MP, Dunlap J, Hurn PD, et al. Renal ischemia: does sex matter?. Anesth Analg 2008;107(1):239–49.   94. Park KM, Kim JI, Ahn Y, et al. Testosterone is responsible for enhanced susceptibility of males to ischemic renal injury. J Biol Chem 2004;279(50):52282–92.   95. Muller V, Losonczy G, Heemann U, et al. Sexual dimorphism in renal ischemia-reperfusion injury in rats: possible role of endothelin. Kidney Int 2002;62(4):1364–71.   96. Tozzi CA, Poiani GJ, McHugh NA, et al. Recombinant human relaxin reduces hypoxic pulmonary hypertension in the rat. Pulm Pharmacol Ther 2005;18(5):346–53.   97. Masini E, Cuzzocrea S, Mazzon E, et al. Protective effects of relaxin in ischemia/reperfusion-induced intestinal injury due to splanchnic artery occlusion. Br J Pharmacol 2006;148(8): 1124–32.   98. Cosen-Binker LI, Binker MG, Cosen R, et al. Relaxin prevents the development of severe acute pancreatitis. World J Gastroenterol 2006;12(10):1558–68.   99. Arcaroli J, Silva E, Maloney JP, et al. Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis. Am J Respir Crit Care Med 2006;173(12):1335–41. 100. Ishida R, Emi M, Ezura Y, et al. Association of a haplotype (196Phe/532Ser) in the interleukin-1-receptor-associated kinase (IRAK1) gene with low radial bone mineral density in two independent populations. J Bone Miner Res 2003;18(3):419–23. 101. Hubacek JA, Stuber F, Frohlich D, et al. Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis. Crit Care Med 2001;29(3):557–61. 102. van Eijk LT, Dorresteijn MJ, Smits P, et al. Gender differences in the innate immune response and vascular reactivity following the administration of endotoxin to human volunteers. Crit Care Med 2007;35(6):1464–69.

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103. Messer G, Spengler U, Jung MC, et al. Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production. J Exp Med 1991;173(1): 209–19. 104. Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149(3 Pt 1):818–24. 105. Hallman M, Spragg R, Harrell JH, et al. Evidence of lung surfactant abnormality in respiratory failure: study of bronchoalveolar lavage phospholipids, surface activity, phospholipase activity, and plasma myoinositol. J Clin Invest 1982;70(3):673–83. 106. Lin Z, Pearson C, Chinchilli V, et al. Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS. Clin Genet 2000;58(3):181–91. 107. Gong MN, Wei Z, Xu LL, et al. Polymorphism in the surfactant protein-B gene, gender, and the risk of direct pulmonary injury and ARDS. Chest 2004;125(1):203–11.

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108. McGlynn EA, Asch SM, Adams J, et al. The quality of health care delivered to adults in the United States. N Engl J Med 2003;348(26):2635–45. 109. Asch SM, Kerr EA, Keesey J, et al. Who is at greatest risk for receiving poor-quality health care?. N Engl J Med 2006;354(11):1147–56. 110. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med 1991;325(4):221–25. 111. Vaccarino V, Rathore SS, Wenger NK, et al. Sex and racial differences in the management of acute myocardial infarction, 1994 through 2002. N Engl J Med 2005;353(7):671–82. 112. Valentin A, Jordan B, Lang T, et al. Gender-related differences in intensive care: a multiple-center cohort study of therapeutic interventions and outcome in critically ill patients. Crit Care Med 2003;31(7):1901–7. 113. Kollef MH, O’Brien JD, Silver P. The impact of gender on outcome from mechanical ventilation. Chest 1997;111(2):434–41. 114. Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat Rev Drug Discov 2005;4(10): 854–65.

Section 5

Gastroenterology

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Introduction Linda A. Lee

Effective management of gastrointestinal and hepatobiliary diseases in women requires an appreciation of the important effects of gender and sex on the epidemiology and clinical presentation of a multitude of gastrointestinal and liver diseases. Biological and gender differences explain why certain disorders affecting the digestive tract occur with increased propensity among women, why women experience unique symptoms, and should guide the management approach. Most obvious are those disorders affecting only women because of their association with female sex organs and pregnancy, like the HELLP syndrome, Crohn’s urogenital complications, or pelvic outlet obstruction and constipation in a multiparous woman. The impact of sex and gender on other disorders is less obvious, but extensive data exist demonstrating sex-based differences in central pain perception and regulation of the immune system. Central pain perception, like gastrointestinal motility and secretion, is increased by estrogen, and may account for the reduced response of analgesics in women.1 Hence, the increased prevalence of irritable bowel syndrome (IBS) and other chronic pain syndromes in women may in part be due to women reporting pain at lower thresholds.2 A genetic etiology for female predominant autoimmune diseases may be attributable to the genetic mosaicism of females as a result of X-chromosome inactivation.3 Skewing of X-chromosome inactivation, in which the X chromosome of one parent is favored over another, could lead to loss of expression of immune tolerance genes, a mechanism already linked to primary biliary cirrhosis, which affects women nine times more frequently than men.4 Genetics and other factors determine how drugs affect women, a particularly important topic in the management of female gastrointestinal disease. Women are more susceptible to adverse drug reactions, such as drug-induced hepatitis and NSAID toxicity.5 Increased susceptibility to drug reactions may in part be due to sex-based differences in genetic polymorphisms affecting CYP enzymes expression.6 Differences in pharmacologic response also may be related to women having more body fat than men, altering the volume of distribution of certain drugs. Studies on alosetron, used to treat IBS, have illustrated the increased efficacy in women of this drug may be related to sex-specific differences in regional cerebral serotonin metabolism.7 Gender and societal differences also impact gastrointestinal and liver diseases in many ways. Women with gastrointestinal symptoms report more embarrassment and shame, and often a lower healthcare quality of life than men.8 This may lead to more frequent clinical presentation of women with functional bowel disorders to healthcare

providers at least in the Western world. Gender differences in how women access healthcare should determine how disorders might best be managed. Women may feel more comfortable with female healthcare providers, particularly when it comes to colorectal cancer screening.9 Women are more likely to be counseled on preventative healthcare services when their primary care provider is female.10 Studies have documented the increased desire of women, particularly those with higher education, to be active participants in decision-making and to seek more information from their healthcare providers.11 In the chapters that follow, several important disorders demonstrating the impact of sex and gender on the digestive tract will be described. Emphasis is placed on the effect of female biology and gender on epidemiology and management of gastrointestinal disease to emphasize why a unique approach is necessary when treating women with gastrointestinal symptoms.

References 1. Craft RM, Mogil JS, Aloisi AM. Sex differences in pain and analgesia: the role of gonadal hormones. Eur J Pain 2004;8:397–411. 2. Greenspan JD, Craft RM, LeResche L, et al. Studying sex and gender differences in pain and analgesia: a consensus report. Pain 2007;132(Suppl 1):S26–45. 3. Migeon BR. Why females are mosaics, X-chromosome inactivation, and sex differences in disease. Gend Med 2007;4: 97–105. 4. Invernizzi P. The X chromosome in female-predominant autoimmune diseases. Ann N Y Acad Sci 2007;1110:57–64. 5. Anderson GD. Gender differences in pharmacological response. Int Rev Neurobiol 2008;83:1–10. 6. Anderson GD. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Women’s Health (Larchmt) 2005;14:19–29. 7. Nakai A, Diksic M, Kumakura Y, et al. The effects of the 5HT3 antagonist, alosetron, on brain serotonin synthesis in patients with irritable bowel syndrome. Neurogastroenterol Motil 2005;17:212–21. 8. Chang L, Toner BB, Fukudo S, et al. Gender, age, society, culture, and the patient’s perspective in the functional gastrointestinal disorders. Gastroenterology 2006;130:1435–46. 9. Farraye FA, Wong M, Hurwitz S, et al. Barriers to endoscopic colorectal cancer screening: are women different from men? Am J Gastroenterol 2004;99:341–49. 10. Henderson JT, Weisman CS. Physician gender effects on preventive screening and counseling: an analysis of male and female patients’ health care experiences. Med Care 2001;39:1281–92. 11. Ende J, Kazis L, Ash A, et al. Measuring patients’ desire for autonomy: decision making and information-seeking preferences among medical patients. J Gen Intern Med 1989;4:23–30.

Chapter

28

Inflammatory Bowel Disease in Women Melissa Munsell1, Marc Sonenshine2, and Mary L. Harris3 1

Clinical Fellow, The Johns Hopkins University School of Medicine, Department of Medicine and Gastroenterology, Baltimore, MD, USA 2 The Johns Hopkins University School of Medicine, Department of Internal Medicine, Baltimore, MD, USA 3 Medical Director, The Center for Inflammatory Bowel and Colorectal Diseases, Mercy Medical Center, Baltimore, MD, USA

Introduction

common in IBD, particularly iron deficiency. In a menstruating woman with simultaneous losses due to IBD, iron status must be closely monitored and replenished, frequently requiring oral and sometimes intravenous replenishment. Regulating menstruation with oral contraception may minimize symptoms as well as reduce intensity of bleeding. In patients with perianal and perineal disease, minimizing menses may reduce symptoms and associated complications, such as irritation of surrounding tissue.

Inflammatory bowel disease (IBD) affects both genders, but has unique implications in the management of women. Ulcerative colitis (UC) and Crohn’s disease (CD) have the potential to affect women across all ages, yet IBD has its greatest incidence in the second and third decades of life, coinciding with the reproductive years. Physicians treating female patients with IBD not only need to be well versed in the management of the disease itself, but also in special circumstances relating to women. These issues range from complications of IBD including menstrual irregularities, rectovaginal fistulas, and osteoporosis to issues of fertility and pregnancy, and also to overall sexual health.

Rectovaginal Fistulas The transmural inflammation of Crohn’s disease provokes fistulization. In women, enterovesical fistulas less commonly arise due to the interfering anatomic position of the uterus and adnexa, though symptoms of dysuria, pneumaturia, urinary frequency, and suprapubic pain are present in rare instances. Rather, transmural extension and fistula formation to the vagina from the rectosigmoid colon is more common. Rectovaginal fistulas are extremely distressing for women psychologically, physically, and socially. Rectovaginal fistulas (RVF) not only result from IBD, but can also complicate diverticulitis, perineal operative or obstetric trauma and bowel-related malignancies. When patients present with fecal-vaginal discharge or passage of flatus vaginally with a suspected RVF, diagnosis and determining the underlying cause is of extreme importance. Careful examination may require anesthesia, while multiple imaging modalities may assist, including water-soluble Gastrograffin enema, fistulography, pelvic magnetic resonance imaging (MRI), or proctoscopy. Historically, but less frequently used diagnostic tools include instilling methylene blue rectally and documenting dye on a previously impregnated vaginal tampon or vaginoscopy and rectal

Gynecologic complications Menstrual Abnormalities The majority of women with IBD (up to 60%) suffer from abnormal menses, including amenorrhea, dysmenorrhea, menorrhagia, and irregular menses.1 On average, less than 5% of healthy women suffer from either oligomenorrhea or polymenorrhea. In adolescents with IBD, the mean age of menarche is slightly higher than healthy girls.2 This likely results from a combination of factors, including chronic disease, potential for malnutrition, and medication effect. Not only do these patients suffer from irregular menses but women with active inflammatory disease often have increased abdominal pain during their premenstrual and menstrual periods. Commonly, gynecologists treat dysmenorrhea with non-steroidal anti-inflammatory agents, which may exacerbate IBD. Micronutrient deficiencies are

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Table 28.1  Classification of rectovaginal fistulas Simple

Complex

Low or mid-vaginal septum 2.5 cm in diameter Trauma or infection

High vaginal septum 2.5 cm in diameter Inflammatory bowel disease, radiation, or neoplasm Multiple failed repairs

Source: Tsang and Rothenberger (1997)3

insufflation with the vagina filled with water. Classification of a RVF incorporates the cause, location and size; in general, RVFs from inflammatory bowel disease are complex, regardless of the location or size (Table 28.1).3 Both medical and surgical management can play a role in the treatment of RVF. In Crohn’s disease, the goal is to treat the underlying disease to allow mucosal healing. In studies, the tumor necrosis factor inhibitor infliximab performs better than cyclosporine, azathioprine, and mycophenolate mofetil in CD-related RVF.4 In one study of infliximab and RVF, 33% had complete resolution of the fistula, 7% had partial healing, and 60% had no response.5 RVF are often managed with combination therapy using infliximab and metronidazole, which continues to be a mainstay of therapy in perianal and perineal disease. Ciprofloxacin may have a role, as well, and has been used in combination with other medical therapy in the treatment of perianal fistulas.6 If the RVF persists, the option of surgery remains, therefore it is important to have close consultation with surgical colleagues. Remission of disease activity is key to provide optimal surgical conditions to allow for suturing in healthy surrounding tissue. Finally, ulcerative colitis does not cause fistulizing disease. However, as a complication of colectomy with ileal pouch anal anastomosis (IPAA) for ulcerative colitis, a pouch to vagina fistula may occur, but may also reflect misdiagnosed Crohn’s disease.

Miscellaneous Gynecologic Issues Rarer gynecologic-related concerns occur with IBD pati­ ents, including granulomatous salpingitis and oophoritis. Occasionally, primary gynecologic conditions such as endo­ metriosis may be misdiagnosed as inflammatory bowel disease causing gastrointestinal symptoms.

Osteoporosis Though not only unique to women, screening for osteoporosis should begin within 6 months of diagnosis with IBD, and should occur yearly. Decreased bone mineral density in IBD is likely related to malnutrition and systemic inflammation though other factors such as corticosteroid use likely contribute.7–11 In IBD, the prevalence of

osteoporosis is 15%, though the prevalence of osteopenia is much higher at 50%.12 Though patients with both Crohn’s disease and ulcerative colitis are at risk for decreased bone density, those with CD carry greater risk.13 Studies have shown that osteopenia may be seen in newly diagnosed patients with IBD, prior to any steroid therapy.14 Age, body mass index, serum magnesium, and history of bowel resections appear to be more important predictors for low bone mineral density than steroid use.15,16 Calcium and vitamin D supplementation have been shown to maintain and increase bone mineral density.17,18 Vitamin D may also help regulate cytokine responses and dampen inflammatory responses.19 Biologic therapy with infliximab is associated with increased markers of bone formation without increasing bone resorption.20 Weight-bearing exercise should be encouraged while smoking should be avoided. Calcium and vitamin D supplementation should be given, and bisphosphonates may be necessary.

Fertility and pregnancy Genetics and Inheritance The majority of women with IBD are affected during their peak reproductive years.21 As expected, most patients with IBD are concerned with the risk of passing the disease to their offspring. No simple Mendelian model explains the pattern of inheritance for IBD. For Crohn’s disease, monozygotic twins have a 50% concordance rate, while dizygotic twins have a 3% rate. For ulcerative colitis, the rate in twins is much less, specifically 10% for monozygotic and 5% for dizygotic twins. The strongest risk factor for developing IBD is family history; specifically if one parent is affected, the child’s risk is anywhere from 2 to 13 times higher than the general population.22,23 If one parent has CD, a child has a 5% lifetime risk of developing either UC or CD. If one parent has UC, however, the lifetime risk of developing IBD is 1.6%.24 In Ashkenazi Jewish families, the risk is even higher for children who have a parent with CD (7.8%) or UC (4.5%). If both parents have IBD, the risk escalates to 35–50%.25 Genetic research may eventually guide physicians to predict inheritance and pathogenesis, specifically phenotypical manifestations such as stricturing versus fistulizing disease, response to medications, and extraintestinal manifestations. For instance, mutations in the recently discovered protein on the CARD15 gene (previously NOD2) are associated with ileal CD with earlier age of onset and stricturing disease in white patients.

Fertility With some exceptions, most studies have shown that both men and women with IBD have similar rates of fertility

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Table 28.2  Effect of IBD on fertility IBD/Treatment type

Male

Female

Active disease Sulfasalazine 5-aminosalicyclic acid Corticosteroids Mercaptopurine/azathioprine Biological agents Small/large bowel resection Ileal pouch anal anastomosis

No effect Reduces No effect Reduces No effect Possible Unlikely Reduces

Reduces No effect No effect No effect No effect Unlikely Unlikely Reduces

Source: Heetun et al. (2007)47

as the general population.26, 27 Though fertility is relatively unaffected, women with IBD have reduced birth rates compared to the general population. Patients may choose voluntary childlessness, but other factors, such as sexual dysfunction, may play a role. Sexual dysfunction may result from dyspareunia, decreased libido, and self-image concerns, particularly in those with an ostomy or perianal disease. Fear of incontinence may also contribute to sexual dysfunction.1 Both surgery and active disease, however, may result in reduced fertility. Prior to surgery, women with ulcerative colitis have fecundability ratios (ability to conceive per menstrual cycle with unprotected intercourse) similar to the general population. However, after surgery with IPAA, the fecundability ratio is decreased.28 This finding was confirmed in a separate study demonstrating a 38.6% infertility rate in UC patients after IPAA and in 13.3% of those patients without surgery.29 Reduced fertility also occurs in patients after proctocolectomy with ileostomy and in nonUC patients who undergo IPAA.30,31 Surgery in the pelvis likely leads to adhesions and possible damage to the reproductive organs. This risk of infertility needs to be discussed with the patient prior to surgery. If a woman is of childbearing age, an attempt should be made to delay surgery. If surgery is necessary, consideration should be given to subtotal colectomy with rectal stump and ileostomy with conversion to IPAA later in life. Similar to surgery, active Crohn’s disease makes conception more difficult, likely due to increased pelvic inflammation causing adhesions and scarring.27 Though certain medications used to treat IBD are contraindicated in pregnancy, no medication is known to decrease fertility in women. In men, however, sulfasalazine causes oligospermia, reduced sperm motility, and abnormal sperm morphology which are reversible within three months of discontinuation of the drug.32,33 If fertility is a concern in males, 5-aminosalicylic acid (5-ASA) drugs are preferred as these side effects do not occur. Infliximab may decrease sperm motility and the number of oval forms, potentially contributing to infertility34 (see Table 28.2). IPAA in males can rarely result in erectile dysfunction (2–4%) and retrograde ejaculation,

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though overall male sexual function is reported to improve after surgery.35,36

Pregnancy Outcomes Several, large, population-based studies have shown increased poor outcomes of pregnancy in IBD, including risk of preterm birth (before 37 weeks’ gestation), low birth weight (2500 g), and small for gestational age infants.37–41 Women with IBD do not appear to have an increased risk of miscarriage, stillbirth, or fetal demise compared to the general population.42 One population-based cohort study showed women with ulcerative colitis had a significantly higher rate of congenital malformations than controls (7.9% vs. 1.7%), though other outcomes were similar.40 More recently, a large community-based study showed women with IBD are more likely to have adverse outcomes with pregnancy with independent predictors of poor outcome including a diagnosis of IBD and surgery for IBD.43 Interestingly, in this study, disease activity did not predict adverse outcomes, contradictory to previous studies. The rate of stillbirth for patients suffering from active, nonfulminant UC is 18–40%, while those with severe or fulminant disease may reach 60%.44 Therefore, emphasis of treatment should be for remission prior to and throughout the pregnancy. A misconception exists that IBD patients should avoid medications during pregnancy to prevent harmful consequences to the fetus, but rather, those adverse events that do occur are likely to be related to disease activity. Smoking tobacco is an important, independent risk factor for low birth weight infants. Furthermore, smoking can exacerbate Crohn’s disease. Patients should be strongly encouraged to quit smoking.

Pregnancy Effects on IBD The course of both ulcerative colitis and Crohn’s disease correlates with disease activity at the time of conception.42 Studies show that those with inactive disease have the same rate of flare during pregnancy and the puerperium time as non-pregnant patients with quiescent disease.45 Relapses and flares are more likely to occur during the first trimester, possibly due to self-discontinuation of maintenance medications as opposed to some unique feature of the first trimester. Those with active disease at the onset of pregnancy have more difficulty controlling disease. In women with active ulcerative colitis at conception, disease activity worsens in 45%, remains unchanged in 24%, while the other 40% are able to achieve remission.46 In active Crohn’s disease, activity is improved in only 1/3 of cases.46 Of the 2/3 of cases that remain active, half have worse, more intense activity that often becomes chronically active (Table 28.3).47 Only rarely do the inaugural signs or symptoms of IBD appear during pregnancy. Typically, if this occurs, the disease is mild with good response to treatment.

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Table 28.3  Summary of effect of gestation on course of IBD At conception

Disease in remission Active disease

Patients in remission during pregnancy (%)

Patients with worsening/chronically active disease during pregnancy (%)

UC

CD

UC

CD

70–80% 30%

70% 33%

20–30% 50–70%

30% 67%

Source: Heetun et al. (2007)47

No good data exist regarding the optimal period of remission time before conception to prevent flares during pregnancy. Experts, however, recommend a 3 month disease quiescent interval prior to conception. Finally, pregnancy only minimally affects ulcerative colitis patients with an IPAA as one-third of patients have mild pouch dysfunction.48 Dysfunction described as increased defecation frequency and incontinence occurs during the third trimester due to increased uterine size and the resulting distorted anatomy. Typically, these problems are temporary and usually resolve completely after delivery.

Mode of Delivery Retrospective studies document a higher rate of cesarean sections (C-section) in women with IBD as compared to controls, with one review approximating 26% vs. 13%.49,50 With two exceptions, the decision for C-section should be based on obstetric necessity . In patients with a history of active perianal disease or IPAA, C-section should be considered. For CD patients without perianal disease or with inactive perianal disease, vaginal delivery does not increase the risk of postpartum perianal disease.51 One survey of patients reported a rate of perineal disease after an episiotomy in CD patients with no prior perineal disease history at 18%.52 On the contrary, with active perineal disease a vaginal delivery with or without episiotomy increases the risk of rectovaginal fistulas, extension of disease, and difficulty with wound healing. Overall, conservative physicians, assuming the woman has no strong desire for a vaginal delivery, often elect for C-section for CD patients who have ever had perineal involvement, active disease, or are at risk for requiring an episiotomy. Patients with IPAA may benefit from C-section, as well. Normal vaginal delivery does not damage the actual pouch, but anal sphincter damage can occur.53 One survey reviewed mode of delivery in 29 patients with 49 births, comparing vaginal delivery with C-section. The reason for vaginal delivery was patient preference while the Caesarean group was due to obstetric concerns, as well as patients desire to ‘protect the pouch’ and sphincter function. There were no differences in pouch function after delivery between the two groups, as determined by the mean fecal incontinence score.54 Follow-up occurred for only 57 months, and studies

on healthy individuals undergoing vaginal delivery have previously shown occult sphincter damage and injury to the innervation of pelvic floor. Damage to the anal sphincter occurring during pregnancy may be compounded by agerelated changes, therefore incontinence may not be immediately evident. Many physicians still recommend C-section for pouch protection, but the risks of C-section must also be considered.

Medications Many women (and physicians) fear using medications for IBD during pregnancy due to concern for adverse effects. Extensive research shows increased risk of poor outcomes is more likely to be related to disease activity, as the majority of medications used for the treatment of IBD appear to be safe (Table 28.4). Physicians may understand the critical goal of remission, but unfortunately this may not be effectively communicated to the patient. Frequently, pregnant women stop their medications prior to conception or once the pregnancy is known only to experience disease relapse. Ideally, disease activity should be controlled for 3 months prior to conception. Patients with difficult-to-control disease may require continuation of medical therapy throughout pregnancy.42 In making medication decisions, physicians can use the United States Food and Drug Administration (FDA) classification of medications as a guide (Table 28.5). Aminosalicylates Sulfasalazine has been used for decades in the treatment of inflammatory bowel disease and is safe in pregnancy (Class B). A large study showed no increase in fetal morbidity or mortality in 287 pregnancies in women with IBD taking sulfasalazine compared to matched controls not on sulfasalazine.55 There is less experience with 5-ASA medications, though all are categorized as category B, with the exception of olsalazine (category C). Multiple studies, however, have shown no increased teratogenic risk with mesalamine products.56–60 Sulfasalazine does impair folate absorption. Although no studies have shown an increased risk of neural tube defects, cardiovascular or genitourinary abnormalities, patients should take at least 2 mg of folic acid supplementation during pregnancy and prior to conception, if possible. Topical aminosalicylates also appear

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Table 28.4  Summary of FDA pregnancy category for common medications used in IBD A

B

C

D

X

Folate

Sulfasalazine Mesalazine Metronidazole Loperamide Cholestyramine Infliximab Adalimumab Pantoprazole Metoclopramide Ondansetron Propofol Meperidine Naloxone

Corticosteroids Cyclosporine Ciprofloxacin Diphenoxylate Tacrolimus Omeprazole Promethazine Fentanyl

Azathioprine 6-mercaptopurine Bismuth Midazolam

Methotrexate Thalidomide

Table 28.5  FDA pregnancy categories Category

Interpretation

A B

Controlled studies show no risk No evidence of risk in humans, OR animal studies are negative but there are no adequate human studies Risk cannot be ruled out: animal studies positive or lacking, human studies lacking Positive evidence of risk: can still use if benefit outweighs risk Contraindicated during pregnancy

C D X

to be safe in pregnancy.61 During later stages of pregnancy, patients tend to tolerate suppositories better than enemas. Antibiotics In the treatment of IBD, metronidazole (category B) and ciprofloxacin (category C) are the most commonly prescribed antibiotics. Though metronidazole is carcinogenic in mice and mutagenic in bacteria, most human studies show no increased risk of birth defects or cancer.62–64 One populationbased control study demonstrated that women exposed to metronidazole during the first trimester had slight, but insignificant, increased rates of infants with cleft lip/cleft palate.65 Given these findings and the potential for carcinogenicity, metronidazole use should be avoided in the first trimester if possible and duration of therapy should be limited. Fluoroquinolones, such as ciprofloxacin, affect growing cartilage, potentially causing arthropathies in children. Studies have not demonstrated an increased risk of congenital abnormalities.66,67 Similar to metronidazole, given the potential risk for teratogenicity, ciprofloxacin should be avoided in the first trimester and duration of therapy should be limited. Frequently ciprofloxacin and metronidazole are used to treat pouchitis. An alternative is amoxicillin/clavulanic acid (category B), which is safe in pregnancy.68–70 Rifaximin

is a new drug which is used for bacterial overgrowth and may have a role in the treatment of pouchitis. Rifaximin is category C and does have teratogenic risk in animals, but human data are lacking.70 Corticosteroids Corticosteroids (category C) are used in a variety of inflammatory conditions and are frequently used in IBD flares to induce remission. Overall, corticosteroids have been used commonly in pregnancy and appear to be safe. Case control studies have noted a small increased risk of oral clefts in women using corticosteroids in the first trimester.71,72 This was refuted by a prospective, controlled study of 311 women with no increased rate of oral cleft or other major anomalies in those on corticosteroids in the first trimester.73 Corticosteroids have rarely been associated with neonatal adrenal insufficiency and low birth weight.74 In addition, corticosteroid use may be associated with premature rupture of membranes.75 The risks of corticosteroid use will likely be outweighed by the need to control the mother’s IBD, if necessary. Budesonide is also FDA category C, and studies have not been performed in pregnant women. Animal models demonstrated teratogenicity and embryocidal effects.44 The high rate of first pass metabolism (80–90%), the relative safety of other steroids, as well as the lack of known complications, likely make budesonide safe in pregnancy. Immunomodulators Azathioprine/6-mercaptopurine The immunomodulators 6-mercaptopurine (6-MP) and the pro-drug azathioprine are classified as FDA category D. Both medications are known to cross the placenta and can be detected in cord blood, though the immature fetal liver is unable to metabolize the pro-drug azathioprine to 6-MP.76 Much of the data on pregnancy for these drugs comes from a non-IBD population in patients with solid organ transplantation.77 In the transplant population the rates of

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congenital anomalies ranged from 0 to 11.8% with no typical pattern of anomalies.78 One retrospective series evaluating 14 pregnant women on azathioprine reported no adverse outcomes.79 However, other retrospective studies have reported an increased incidence of fetal demise.80 In 155 IBD patients taking 6-MP during pregnancy compared to IBD controls, there was no increase in spontaneous abortion, major congenital anomalies, neoplasia, or fetal infections.81 In contrast, a Danish study reported an increased risk of congenital malformations, perinatal mortality, and preterm birth in women exposed to these immunomodulators in pregnancy.60 Of note, this included only 11 patients exposed to azathioprine or 6-MP, of which 6 had IBD. It is difficult to distinguish complications due to IBD flare or an actual side effect of the medication. Since a disease flare during pregnancy results in significant fetal risk, these medications are continued during conception and during pregnancy, particularly if one has had chronically active disease. If a patient remains in remission, cessation of the immunomodulator could be considered but must be discussed with the treating physician and patient. Not only women have been studied in the evaluation of immunomodulators in pregnancy; men have been studied also. One retrospective review of pregnancy outcomes in the partners of fathers taking 6-MP within 3 months of conception showed a higher incidence of pregnancy-related complications, specifically spontaneous abortions in the first trimester and congenital anomalies.80 The authors recommended discontinuing 6-MP at least 3 months prior to conception. The design of the review has significant limitations, but obviously creates concern for conception from a father being treated with 6-MP. Cyclosporine Cyclosporine (category C) does cross the placenta, but a meta-analysis of cyclosporine use in pregnancy showed no statistically significant increase in congenital malformations.82 In a case report, cyclosporine used for fulminant ulcerative colitis at 27 weeks of pregnancy was associated with no adverse outcomes.83 In patients with UC, typically cyclosporine is reserved for patients with refractory disease. It is no different in pregnancy; cyclosporine may be a better alternative than colectomy, which is associated with a high rate of fetal mortality.84 Maternal hypertension and nephrotoxicity can occur with cyclosporine use, and blood pressure and renal function should be closely monitored. Methotrexate Methotrexate, a folic acid antagonist, is pregnancy category X and should not be used in pregnancy, nor in women considering conception. Due to its metabolic action, rates of neural tube and craniofacial defects, as well as fetal loss, are extremely high. Methotrexate embryopathy is associated with intra-uterine growth retardation, decreased ossification

of the calvarium, low set ears, micrognathia, limb abnormalities, and possible mental retardation.85 Methotrexate embryopathy typically occurs when women are exposed to the drug at 6–8 weeks after conception, though increased fetal toxicity and mortality can be seen if the drug is taken at any stage of pregnancy.86 Both men and women should discontinue methotrexate at least 3–6 months prior to conception. Women of child-bearing age on methotrexate should use two forms of contraception. Thalidomide Thalidomide has been used in the treatment of IBD, particularly Crohn’s disease. Of course, thalidomide is category X and is contraindicated in pregnancy. It is highly teratoge­ nic and causes limb defects, central nervous system effects, and ab­normalities of many organ systems.86 Women of childbearing age on thalidomide should be on two forms of contraception, which should begin at least one month prior to starting thalidomide and be continued until one month after therapy is discontinued. Biologic Therapy Infliximab Biologic therapy, including infliximab and adalimumab, are the newest class of medications for treatment of inflammatory bowel disease. Infliximab (category B) appears to be low risk with no reports of maternal toxicity or teratogenicity in murine models. One case report describes multiple congenital anomalies and fetal death in a fetus exposed to infliximab; however, this was complicated by active Crohn’s disease in the mother treated with metronidazole, azathioprine, and 5-ASA.87 Other case reports show successful outcomes of pregnancy with infliximab use.88 The Infliximab Safety Database collects data retrospectively, with data available for 96 women receiving infliximab during pregnancy. Out of 96 pregnancies, there were 100 births with outcomes similar to the general population.89 The TREAT registry collects data prospectively on patients with CD. Of 5807 patients in the registry, 66 pregnancies were reported with 36 exposed to infliximab. There were no fetal malformations, and there were no significant differences in rates of miscarriage and neonatal complications compared to women not exposed to infliximab.90 Infliximab crosses the placenta, and high levels of the drug have been detected in newborns, though the clinical significance of this is unknown.91 This may have implications on the infant’s vaccination status. Potentially, the dosing interval could be adjusted in the third trimester to minimize infliximab levels in the infant. Men may be affected by infliximab with decreased sperm motility and number of oval forms, but fertility may remain unaffected.34 Adalimumab Similar to infliximab, adalimumab is pregnancy category B. Minimal data exist in humans but studies in monkeys did

C h a p t e r 2 8     Inflammatory Bowel Disease in Women l

not demonstrate increased risk to the fetus. Case reports have also demonstrated successful treatment of Crohn’s disease in pregnancy without adverse outcomes.92 Symptomatic Therapy In addition to medications indicated for treatment of Crohn’s disease and ulcerative colitis, many patients need medications for symptomatic relief, including antiemetics, antacids, antidiarrheals, antispasmodics, and nutritional supplements. This is a multitude of data for nausea and vomiting of pregnancy, and such data are extrapolated to the pregnant woman with IBD. Treatments for nausea during pregnancy include alteration of diet (avoiding spicy, fatty, or malodorous foods) and natural supplements, such as ginger. If these measures are not successful, then antiemetics may be indicated. The prokinetic metoclopramide (category B) has been used for nausea in pregnancy for years with relative safety with no reports of fetal abnormalities in humans.93 The serotonin antagonists, dolasetron, granisetron, and ondansetron are category B drugs. Ondanestron is used to treat hyperemesis gravidarum with no reported increased risk of fetal malformations.94 While there are no human studies on granisetron and dolasetron, supratherapeutic doses in animals appear to be safe.95 The phenothiazines (prochlorperazine and promethazine) are category C and are also used to treat nausea and vomiting of pregnancy. They have not been associated with increased risk of fetal malformations.96 Gastroesophageal reflux (GERD) is a common problem, particularly in pregnancy. Often mild symptoms can be successfully managed with lifestyle and dietary modifications. Most over-the-counter antacids containing magnesium, aluminum, or calcium are considered safe in pregnancy in normal doses. Antacids containing sodium bicarbonate should not be used in pregnancy as they can result in maternal or fetal metabolic alkalosis and fluid overload.95 Magnesium trisilicates should be avoided as fetal nephrolithiasis, hypotonia, and respiratory distress can occur.95 If excess amount of calcium carbonate are taken, the milk-alkali syndrome can result.97 H2-receptor antagonists are category B medications. Cimetidine and ranitidine are preferred over famotidine and nizatidine due to limited human safety data in the latter two.98 Proton pump inhibitors, with the exception of omeprazole, are category B medications. Omeprazole (category C) has not been found to be associated with major malformation in humans, but there was a dose-related increase in embryo and fetal mortality in animal studies.99 Omeprazole has been shown to be safe in many prospective database studies.100–102 Sucralfate, which is minimally absorbed, is safe and is category B. If diarrhea is due to active IBD, the goal is remission with treatment of the disease. However, diarrhea may be from other etiologies, such as coexistent irritable bowel syndrome (IBS). Dietary manipulation and stool bulking agents, such

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as psyllium, should be tried first, if possible. Cholestyramine is pregnancy category C and is often used in cholestasis of pregnancy.103 In diarrhea related to cholecystectomy or ileal resection, cholestyramine may be effective, but fat-soluble vitamin deficiency can occur. Loperamide (category B) and diphenoxylate with atropine (category C) are probably low risk but have potential links to fetal malformations in human reports.104 Due to the risk for fetal toxicity, loperamide and diphenoxylate atropine should be avoided in pregnancy.95 Bismuth subsalicylate (also found in Kaopectate) is category C and should not be taken in pregnancy. The salicylates may be absorbed leading to potential teratogenicity, low birthweight, perinatal mortality, and prolonged gestation and labor.105 Finally, with tincture of opium, the opiates cross the placenta creating fetal dependency and intra-uterine growth retardation, and therefore should not be used in pregnancy.106 Antispasmodics, often used for cramps and abdominal discomfort associated with IBS, are anticholinergics which have increased rate of fetal malformations and fetal tachycardia, and therefore they are often avoided in pregnancy.107 Acetaminophen is effective and safe for musculoskeletal and abdominal pains. Supplements Supplementation of vital vitamins like folate is paramount during pregnancy in IBD, as patients are often vitamin deficient. Recommendations for folic acid supplementation is high dose, 2 mg per day, particularly for patients taking sulfasalazine.. Patients with ileal disease may require repletion of cyanocobalamin (B12) and vitamins A, D, E, and K. No studies show harm in repletion. Often, due to anemia, iron repletion is also necessary.

Lactation In the United States, more than 60% of new mothers breastfeed. In women with IBD, however, the rate of breastfeeding is lower, at 44%.108 Fear of medication interactions, physician recommendation, or personal choice likely explain the decreased rate of breastfeeding in IBD.108 An increase in postpartum IBD flares has been reported in women who breastfeed, but this association is not seen once adjusting for medication cessation.108 Medications safe in pregnancy may not be recommended while a woman is breastfeeding. 5-ASA drugs can be used while breastfeeding, but rarely cause diarrhea in the infant, which is dose-dependent.109 With antibiotics, metroni­ dazole is not recommended in breastfeeding, while amoxicillin/clavulanic acid is safe. Data on fluoroquinolones are limited and safety is unknown with rifaximin. Prednisone can be used while breastfeeding, though data are lacking with budesonide. Essentially all immunomodulators are contraindicated or not recommended in breastfeeding, including

s e c t i o n 5     Gastroenterology

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l

azathioprine, 6-MP, methotrexate, and cyclosporine. There are no human data on thalidomide and lactation, but given its significant toxicity profile, it should not be used in breastfeeding. Currently, little information exists regarding biologic therapy and lactation. It is unknown if infliximab is excreted in breast milk and case reports describe breastfeeding while using infliximab without adverse effect.110 Use of infliximab and adalimumab (for which few data exist) in breastfeeding should be discussed between physician and patient. The balance between the benefits of breastfeeding, the risk of unknown medicine concentrations in breast milk with unknown infant absorption, and the risk discontinuation of medications must all be weighed before a decision on breastfeeding can be made (Table 28.6).

Diagnostic Testing Endoscopy Endoscopy may be necessary during pregnancy. The American Society for Gastrointestinal Endoscopy has developed clear indications for endoscopy in pregnancy, along with general principles to guide care.111 Indications for endoscopy include, but are not limited to, severe diarrhea with a negative evaluation, bleeding, refractory nausea, vomiting, and pain. If possible, procedures should be delayed until the second trimester. If there is a strong indication for

Table 28.6  Medications used during breastfeeding Safe to use while breastfeeding

Limited data, currently not recommended

Contraindicated

Sulfasalazine Mesalamine Corticosteroids (20 mg/day)

Cyclosporine 6-mercaptopurine Azathioprine

Methotrexate Metronidazole Ciprofloxacin

Infliximab Source: Sauk and Kane, 2005134

endoscopy, care should be taken to minimize procedure time and sedation. The goal of sedation, specifically in pregnant women, should be anxiolysis or moderate sedation, not deep sedation. Appropriate drug selection is important, as well. Meperidine (category B) is not associated with teratogenicity or poor fetal outcomes, and can be used judiciously for endoscopy.96,98 Fentanyl (category C) has a more rapid onset of action than meperidine, but was embryocidal in rats at high doses.112 It appears to be safe in humans as most anecdotal evidence and human studies show no neonatal toxicity, but single case reports have described respiratory depression, muscle rigidity, and opioid withdrawal in the newborn.113–118 Propofol, a category B medicine, can be used for sedation in pregnancy and is often preferred. It is recommended for use in the third trimester since studies in the first and second trimester are lacking.119–121 Midazolam, like all benzodiazepines, is a category D; however, midazolam has not been associated with cleft palate or neurobehavioral disorders like diazepam.122,123 Overall, esophagogastroduodenoscopy and flexible sigmoidoscopy are safe if performed for correct indications, but colonoscopy is less often indicated. Endoscopic retrograde cholangiopancreatography may be needed for biliary disease. Fetal monitoring is typically not necessary, but should be considered for the high-risk or late third-trimester patient.124 Finally, obstetric consultation should be obtained prior to endoscopy (Table 28.7). Diagnostic Imaging Complications can occur in IBD, including abscesses, fistulas, strictures, and bowel obstruction. Such complications often require radiological imaging for evaluation, which needs to be limited in pregnancy. The American College of Radiology states that ‘no single diagnostic radiologic procedure results in sufficient radiation to threaten the well-being of the fetus.’ Women and physicians, however, are hesitant to expose a fetus to any amount of radiation if unnecessary. In general, the risk of fetal anomalies, growth restriction,

Table 28.7  Summary of ASGE indications for and general principles guiding endoscopy in pregnancy Indications: GI and relating to IBD

General principles

1. Significant or continued bleeding 2. Severe/refractory nausea, vomiting, pain 3.  Dysphagia or odynophagia 4. Severe diarrhea with negative evaluation 5.  Suspicion for mass 6. Biliary pancreatitis, choledocholithiasis, or cholangitis 7. Biliary or pancreatic ductal injury

1.  Strong indication 2.  Defer to second trimester if able 3.  Lowest dose of safest sedation 4.  Minimize procedure time 5.  Position avoiding vena caval obstruction – pelvic tilt, left lateral 6.  Confirm fetal heart sounds before and after procedure 7.  Make obstetric support available 8. Contraindicated in obstetric complications – ruptured membranes, imminent delivery, eclampsia

Source: Qureshi et al., 2005111

C h a p t e r 2 8     Inflammatory Bowel Disease in Women l

carcinogenesis or abortion is not seen in a single radiological procedure less than 5 rad (0.05 Gy) and a cumulative total of 25 rad.125 Average fetal rad exposure in an abdominal x-ray is 200 mrad, a barium enema or small bowel series range from 700 to 1600 mrad, and computed tomography (CT) of the abdomen is 250 mrad.126 Furthermore, gestational age factors into exposure damage, as radiation-induced malformations are increased during the first trimester while organogenesis occurs and radiation-induced prenatal death is increased during the pre-implantation period. Therefore, postponing radiologic procedures until delivery or at most second trimester is beneficial. However, radiological imaging may be necessary, and after discussion with the patient, the ultimate risk is still low, but not nil. Alternative imaging may also be possible and preferable in pregnancy. Ultrasonography is safe in pregnancy and can help rule out abscess and need for further imaging. Magnetic resonance imaging (MRI) involves magnets and alterations in hydrogen particles, but no radiation. The primary safety concerns with MRI are the heating effects of radiofrequency pulses and acoustic noise to the fetus.127 When imaging is required (i.e. acute abdominal pain), MRI is the best imaging modality, as there are no documented fetal adverse effects to date (at 1.5 T and lower magnetic field strengths) and provides more detail than ultrasound. One small prospective study showed MRI in pregnancy was 95% sensitive in ruling out pathologic causes for abdominal pain. MRI is better than ultrasound due to its ability to produce multiple views – coronal, sagittal, and axial; its limits include cost but also timeliness. However, the National Radiologic Protection Board still recommends against MRI during first trimester and gadolinium as long-term data are still lacking.44,128,129 The acuity of the patient and need for diagnosis must be balanced with the radiological complications. X-ray and computed topography (CT) does put the fetus at risk for minimal and likely non-toxic radiologic exposure, but MRI and ultrasound are currently without any proven risk.

Self-image Chronic diseases often alter self-image and confidence, especially Crohn’s disease and ulcerative colitis. IBD patients often experience physical symptoms that are not socially acceptable. IBD directly (i.e. symptoms, extraintestinal manifestations) and indirectly (i.e. medication side effects and consequences of surgery) disrupts and affects body image.130 The distressing symptoms of IBD regularly affect daily living and subsequently self-assurance. Leaving the secure confines of a home and bathroom for even basic daily chores may be fraught with reservation because of fecal incontinence, urgency, and malodorous flatulence. Physicians often recommend carrying a change of clothing when going out, as well as locating the closest restroom, which may provide some security.

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All chronic disease states affect nutrition, but especi­ ally those related to the GI tract. Maximizing micro- and macronutrient absorption and reserve through vitamin supplementation as well as supplemental nutrition shakes to meet adequate caloric intake helps prevent ‘sickly’ and ‘frail’ appearances, not to mention the untoward effects of a deficiency that may lead to further debilitation, like fractures and profound anemia. The medications used to treat inflammatory bowel disease are not without risk and side effects. Steroids, especially, have many adverse effects that may alter body image and interpersonal relationships, such as weight gain with moon facies, acne, increased body hair, psychosis, insomnia, and drastic mood swings. Education on expectations and awareness of side effects, as well as frequent appointments to assess not only efficacy but also adverse effects creates a good relationship between physician and patient and allows for prompt changes if necessary.131 Extraintestinal manifestations of inflammatory bowel disease also complicate the psychosocial aspects of these chronic diseases. Pyoderma gangrenosum is a painful, ulcerative skin disorder that can be disfiguring and difficult to treat. Axial (ankylosing spondylitis) and peripheral arthritis occur with IBD causing discomfort and limiting mobility. Fistulas, whether enterocutaneous, enterovesical, rectovaginal, or perirectal, cause emotional distress. In addition to inducing remission of active disease with aggressive medical management and early surgical consultation, garments to conceal the altered body area may provide aesthetic advantages and prevent embarrassment. Referrals to counselors, psychiatrists, social workers, physical and occupational therapists provide outlets for discussions of concerns beyond what a physician can provide as well as resources to help overcome obstacles and limitations created by the disease.131 In their disease course, patients with IBD may undergo surgery with creation of a temporary or permanent ostomy. Some patients are extremely worried about mastering technical skills to care for a stoma. It is important to support patients through the initial anger, anxiety and stress that may coincide. Specifically for those not married or within a compassionate relationship, patients worry and agonize about desirability often to the point of sexual paralysis. In a study of just over 300 patients with ostomies, over half felt less attractive sexually, while a significantly smaller percentage of their partners had the same feelings, only 6% of husbands and 9% of wives. Reiterating and concentrating on the positive effects of the stoma as far as quality of life (decreased pain and increased control of life) while remaining sensitive and sympathetic of the profound changes eventually improves self-image. Resources such as stoma nurses and ostomy-related organizations may help patients to cope more effectively. Most surgeries for IBD do not require an ostomy, but even a surgical scar can create anguish for a patient; classically described by the young teenage female worried about wearing a bathing suit.132

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Communication between patients and their physicians regarding issues pertaining to aspects of their chronic diseases from a social perspective is often left out during a clinic visit due to tight constraints on physician time and lack of compensation. Recognition of such concern, appropriate education, and referrals for resources provide outlets to help relieve angst. The use of an IBD nurse advocate can help increase time spent with a health professional, allowing for ongoing communication, particularly providing social and psychological support. Finally, treatment of concurrent depression and anxiety via pharmacologic or counseling sessions can improve quality of life.133

11.

12.

13.

14.

CONCLUSIONS 15.

Ulcerative colitis and Crohn’s disease can be challenging to manage. The female patient may have unique complications of these diseases. As women with IBD are frequently affected during their reproductive years, physicians need to be prepared to treat the patient during pregnancy. Adverse outcomes in pregnancy are more likely to be due to disease activity, as opposed to medication effect. The goal is to achieve remission prior to conception and maintain remission throughout pregnancy.

16.

17.

18.

References 1. Weber A, Ziegler C, Belinson J, Mitchinson A, Widrich T, Fazio V. Gynecologic history of women with inflammatory bowel disease. Obstet Gynecol 1995;86(5):843–47. 2. Zacharias L, Rand WM, Wurtman RJ. A prospective study of sexual development and growth in American girls: the statistics of menarche. Obstet Gynecol Surv 1976;31(4):325–37. 3. Tsang CB, Rothenberger DA. Rectovaginal fistulas: therapeutic options. Surg Clin North Am 1997;77(1):95–114. 4. Levy C, Tremaine WJ. Management of internal fistulas in Crohn’s disease. Inflamm Bowel Dis 2002;8(2):106–11. 5. Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Sandborn WJ. Infliximab for Crohn’s disease in clinical practice at the mayo clinic: the first 100 patients. Am J Gastroenterol 2001;96(3):722–29. 6. Bressler B, Sands BE. Review article: medical therapy for fistulizing Crohn’s disease. Aliment Pharmacol Ther 2006;24(9):1283–93. 7. Silvennoinen JA, Karttunen TJ, Niemela SE, Manelius JJ, Lehtola JK. A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut 1995;37(1):71–76. 8. Abitbol V, Roux C, Chaussade S, et al. Metabolic bone assessment in patients with inflammatory bowel disease. Gastroenterology 1995;108(2):417–22. 9. Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut 1997;40(2):228–33. 10. Semeao EJ, Jawad AF, Stouffer NO, Zemel BS, Piccoli DA, Stallings VA. Risk factors for low bone mineral density in

19.

20.

21.

22.

23.

24.

25.

26.

children and young adults with Crohn’s disease. J Pediatr 1999;135(5):593–600. Ardizzone S, Bollani S, Bettica P, Bevilacqua M, Molteni P, Bianchi Porro G. Altered bone metabolism in inflammatory bowel disease: there is a difference between Crohn’s disease and ulcerative colitis. J Intern Med 2000;247(1):63–70. Bernstein CN, Blanchard JF, Metge C, Yogendran M. The association between corticosteroid use and development of fractures among IBD patients in a population-based database. Am J Gastroenterol 2003;98(8):1797–801. Jahnsen J, Falch JA, Aadland E, Mowinckel P. Bone mineral density is reduced in patients with Crohn’s disease but not in patients with ulcerative colitis: a population based study. Gut 1997;40(3):313–19. Lamb EJ, Wong T, Smith DJ, et al. Metabolic bone disease is present at diagnosis in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2002;16(11):1895–902. Habtezion A, Silverberg MS, Parkes R, Mikolainis S, Steinhart AH. Risk factors for low bone density in Crohn’s disease. Inflamm Bowel Dis 2002;8(2):87–92. Jong DJ, Corstens FHM, Mannaerts L, Rossum LGM, Naber AHJ. Corticosteroid-induced osteoporosis: does it occur in patients with Crohn’s disease?. Am J Gastroenterol 2002;97(8):2011–15. Vogelsang H, Ferenci P, Resch H, Kiss A, Gangl A. Prevention of bone mineral loss in patients with Crohn’s disease by longterm oral vitamin D supplementation. Eur J Gastroenterol Hepatol 1995;7(7):609–14. Siffledeen JS, Fedorak RN, Siminoski K, et al. Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease. Clin Gastroenterol Hepatol 2005;3(2):122–32. Leal JY, Romero T, Ortega P, Amaya D. Serum values of interleukin-10, gamma-interferon and vitamin A in female adolescents. Invest Clin 2007;48(3):317–26. Abreu MT, Geller JL, Vasiliauskas EA, et al. Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn’s disease. J Clin Gastroenterol 2006;40(1):55–63. Andres PG, Friedman LS. Epidemiology and the natural course of inflammatory bowel disease. Gastroenterol Clin North Am 1999;28(2):255–81, vii. Orholm M, Munkholm P, Langholz E, Nielsen OH, Sorensen TI, Binder V. Familial occurrence of inflammatory bowel disease. N Engl J Med 1991;324(2):84–88. Orholm M, Fonager K, Sorensen HT. Risk of ulcerative colitis and Crohn’s disease among offspring of patients with chronic inflammatory bowel disease. Am J Gastroenterol 1999;94(11):3236–38. Yang H, McElree C, Roth MP, Shanahan F, Targan SR, Rotter JI. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993;34(4):517–24. Bennett RA, Rubin PH, Present DH. Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease. Gastroenterology 1991;100(6):1638–43. Baird DD, Narendranathan M, Sandler RS. Increased risk of preterm birth for women with inflammatory bowel disease. Gastroenterology 1990;99(4):987–94.

CHAPTER 28 27. Hudson M, Flett G, Sinclair TS, Brunt PW, Templeton A, Mowat NA. Fertility and pregnancy in inflammatory bowel disease. Int J Gynaecol Obstet 1997;58(2):229–37. 28. Olsen KO, Joelsson M, Laurberg S, Oresland T. Fertility after ileal pouch-anal anastomosis in women with ulcerative colitis. Br J Surg 1999;86(4):493–95. 29. Johnson P, Richard C, Ravid A, et al. Female infertility after ileal pouch-anal anastomosis for ulcerative colitis. Dis Colon Rectum 2004;47(7):1119–26. 30. Wikland M, Jansson I, Asztely M, et al. Gynaecological problems related to anatomical changes after conventional proctocolectomy and ileostomy. Int J Colorectal Dis 1990;5(1):49–52. 31. Olsen KO, Juul S, Bulow S, et al. Female fecundity before and after operation for familial adenomatous polyposis. Br J Surg 2003;90(2):227–31. 32. Birnie GG, McLeod TI, Watkinson G. Incidence of sulphasalazine-induced male infertility. Gut 1981;22(6):452–55. 33. O’Morain C, Smethurst P, Dore CJ, Levi AJ. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 1984;25(10):1078–84. 34. Mahadevan U, Terdiman JP, Aron J, Jacobsohn S, Turek P. Infliximab and semen quality in men with inflammatory bowel disease. Inflamm Bowel Dis 2005;11(4):395–99. 35. Tiainen J, Matikainen M, Hiltunen KM. Ileal J-pouch–anal anastomosis, sexual dysfunction, and fertility. Scand J Gastroenterol 1999;34(2):185–88. 36. Gorgun E, Remzi FH, Montague DK, et al. Male sexual function improves after ileal pouch anal anastomosis. Colorectal Dis. 2005;7(6):545–50. 37. Fonager K, Sorensen HT, Olsen J, Dahlerup JF, Rasmussen SN. Pregnancy outcome for women with Crohn’s disease: a follow-up study based on linkage between national registries. Am J Gastroenterol 1998;93(12):2426–30. 38. Kornfeld D, Cnattingius S, Ekbom A. Pregnancy outcomes in women with inflammatory bowel disease – a population-based cohort study. Am J Obstet Gynecol 1997;177(4):942–46. 39. Norgard B, Fonager K, Sorensen HT, Olsen J. Birth outcomes of women with ulcerative colitis: a nationwide Danish cohort study. Am J Gastroenterol 2000;95(11):3165–70. 40. Dominitz JA, Young JC, Boyko EJ. Outcomes of infants born to mothers with inflammatory bowel disease: a populationbased cohort study. Am J Gastroenterol 2002;97(3):641–48. 41. Moser MA, Okun NB, Mayes DC, Bailey RJ. Crohn’s disease, pregnancy, and birth weight. Am J Gastroenterol 2000;95(4):1021–26. 42. Katz JA. Pregnancy and inflammatory bowel disease. Curr Opin Gastroenterol 2004;20(4):328–32. 43. Mahadevan U, Sandborn WJ, Li DK, Hakimian S, Kane S, Corley DA. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from northern California. Gastroenterology 2007;133(4):1106–12. 44. Steinlauf AF. Present DH. Medical management of the pregnant patient with inflammatory bowel disease. Gastroenterol Clin North Am 2004;33(2):361–85, xi. 45. Subhani JM, Hamiliton MI. Review article: the management of inflammatory bowel disease during pregnancy. Aliment Pharmacol Ther 1998;12(11):1039–53. 46. Friedman S, Regueiro MD. Pregnancy and nursing in inflammatory bowel disease. Gastroenterol Clin North Am 2002;31(1):265–73, xii.

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47. Heetun ZS, Byrnes C, Neary P, O’Morain C. Review article: reproduction in the patient with inflammatory bowel disease. Aliment Pharmacol Ther 2007;26(4):513–33. 48. Juhasz ES, Fozard B, Dozois RR, Ilstrup DM, Nelson H. Ileal pouch-anal anastomosis function following childbirth. an extended evaluation. Dis Colon Rectum 1995;38(2):159–65. 49. Nielsen OH, Andreasson B, Bondesen S, Jarnum S. Pregnancy in ulcerative colitis. Scand J Gastroenterol 1983;18(6):735–42. 50. Porter RJ, Stirrat GM. The effects of inflammatory bowel disease on pregnancy: a case-controlled retrospective analysis. Br J Obstet Gynaecol 1986;93(11):1124–31. 51. Ilnyckyji A, Blanchard JF, Rawsthorne P, Bernstein CN. Perianal Crohn’s disease and pregnancy: role of the mode of delivery. Am J Gastroenterol 1999;94(11):3274–78. 52. Brandt LJ, Estabrook SG, Reinus JF. Results of a survey to evaluate whether vaginal delivery and episiotomy lead to perineal involvement in women with Crohn’s disease. Am J Gastroenterol 1995;90(11):1918–22. 53. Hahnloser D, Pemberton JH, Wolff BG, et al. Pregnancy and delivery before and after ileal pouch-anal anastomosis for inflammatory bowel disease: immediate and long-term consequences and outcomes. Dis Colon Rectum 2004;47(7):1127–35. 54. Ravid A, Richard CS, Spencer LM, et al. Pregnancy, delivery, and pouch function after ileal pouch-anal anastomosis for ulcerative colitis. Dis Colon Rectum 2002;45(10):1283–88. 55. Mogadam M, Dobbins WO 3rd, Korelitz BI, Ahmed SW. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology 1981;80(1):72–76. 56. Habal FM, Hui G, Greenberg GR. Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: safety and clinical course. Gastroenterology 1993;105(4):1057–60. 57. Marteau P, Tennenbaum R, Elefant E, Lemann M, Cosnes J. Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules. Aliment Pharmacol Ther 1998;12(11):1101–8. 58. Trallori G, d’Albasio G, Bardazzi G, et al. 5-aminosalicylic acid in pregnancy: clinical report. Ital J Gastroenterol 1994;26(2):75–78. 59. Diav-Citrin O, Park YH, Veerasuntharam G, et al. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology 1998;114(1):23–28. 60. Norgard B, Fonager K, Pedersen L, Jacobsen BA, Sorensen HT. Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy: a Danish cohort study. Gut 2003;52(2):243–47. 61. Bell CM, Habal FM. Safety of topical 5-aminosalicylic acid in pregnancy. Am J Gastroenterol 1997;92(12):2201–2. 62. Beard CM, Noller KL, O’Fallon WM, Kurland LT, Dahlin DC. Cancer after exposure to metronidazole. Mayo Clin Proc 1988;63(2):147–53. 63. Falagas ME, Walker AM, Jick H, Ruthazer R, Griffith J, Snydman DR. Late incidence of cancer after metronidazole use: a matched metronidazole user/nonuser study. Clin Infect Dis 1998;26(2):384–88. 64. Caro-Paton T, Carvajal A, Martin de Diego I, Martin-Arias LH, Alvarez Requejo A, Rodriguez Pinilla E. Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol 1997;44(2):179–82.

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65. Czeizel AE, Rockenbauer M. A population based case-control teratologic study of oral metronidazole treatment during pregnancy. Br J Obstet Gynaecol 1998;105(3):322–27. 66. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother 1998;42(6):1336–39. 67. Larsen H, Nielsen GL, Schonheyder HC, Olesen C, Sorensen HT. Birth outcome following maternal use of fluoroquinolones. Int J Antimicrob Agents 2001;18(3):259–62. 68. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. Augmentin treatment during pregnancy and the prevalence of congenital abnormalities: a population-based case-control teratologic study. Eur J Obstet Gynecol Reprod Biol 2001;97(2):188–92. 69. Berkovitch M, Diav-Citrin O, Greenberg R, et al. First-trimester exposure to amoxycillin/clavulanic acid: a prospective, controlled study. Br J Clin Pharmacol 2004;58(3):298–302. 70. Mahadevan U. Fertility and pregnancy in the patient with inflammatory bowel disease. Gut 2006;55(8):1198–206. 71. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86(3):242–44. 72. Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts: a case-control study. Teratology 1998;58(1):2–5. 73. Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004;18(1):93–101. 74. Reinisch JM, Simon NG, Karow WG, Gandelman R. Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science 1978;202(4366):436–38. 75. Armenti VT, Moritz MJ, Cardonick EH, Davison JM. Immunosuppression in pregnancy: choices for infant and maternal health. Drugs 2002;62(16):2361–75. 76. Hou S. Pregnancy in renal transplant recipients. Adv Ren Replace Ther 2003;10(1):40–47. 77. Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke JF. National transplantation pregnancy registry– outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1994;57(4):502–6. 78. Polifka JE, Friedman JM. Teratogen update: azathioprine and 6-mercaptopurine. Teratology 2002;65(5):240–61. 79. Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJ, Clark ML. Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 1990;99(2):443–46. 80. Rajapakse RO, Korelitz BI, Zlatanic J, Baiocco PJ, Gleim GW. Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 2000;95(3):684–88. 81. Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology 2003;124(1):9–17. 82. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a metaanalysis. Transplantation 2001;71(8):1051–55. 83. Bertschinger P, Himmelmann A, Risti B, Follath F. Cyclosporine treatment of severe ulcerative colitis during pregnancy. Am J Gastroenterol 1995;90(2):330.

84. Anderson JB, Turner GM, Williamson RC. Fulminant ulcerative colitis in late pregnancy and the puerperium. J R Soc Med 1987;80(8):492–94. 85. Del Campo M, Kosaki K, Bennett FC, Jones KL. Developmental delay in fetal aminopterin/methotrexate syndrome. Teratology 1999;60(1):10–12. 86. Briggs GG, Freeman FR, Yaffe SJ. Drugs in Pregnancy and Lactation, seventh ed.. Philadelphia, PA: Lippincott, Williams, and Wilkins; 2005. 87. Srinivasan R. Infliximab treatment and pregnancy outcome in active Crohn’s disease. Am J Gastroenterol 2001;96(7):2274–75. 88. Burt MJ, Frizelle FA, Barbezat GO. Pregnancy and exposure to infliximab (anti-tumor necrosis factor-alpha monoclonal antibody). J Gastroenterol Hepatol 2003;18(4):465–66. 89. Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol 2004;99(12):2385–92. 90. Lichtenstein GR, Cohen RD, Feagan BG, et al. Safety of infliximab in Crohn’s disease: data from the 5000-patient TREAT registry. Gastroenterology 2004;126(Suppl):A54. 91. Vasiliauskas EA, Church JA, Silverman N, Barry M, Targan SR, Dubinsky MC. Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol 2006;4(10):1255–58. 92. Vesga L, Terdiman JP, Mahadevan U. Adalimumab use in pregnancy. Gut 2005;54(6):890. 93. Sorensen HT, Nielsen GL, Christensen K, Tage-Jensen U, Ekbom A, Baron J. Birth outcome following maternal use of metoclopramide. the Euromap study group. Br J Clin Pharmacol 2000;49(3):264–68. 94. Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG 2004;111(9):940–43. 95. Mahadevan U, Kane S. American gastroenterological association institute technical review on the use of gastrointestinal medications in pregnancy. Gastroenterology 2006;131(1):283–311. 96. US Department of Education and Welfare PHS, National Institutes of Health. The collaborativ study of the national institute of neurological diseases: the women and their pregnancies. DHEW Publication No (NIH) 1972:73–379. 97. McGuinness B, Logan JI. Milk alkali syndrome. Ulster Med J 2002;71(2):132–35. 98. Schwethelm B, Margolis LH, Miller C, Smith S. Risk status and pregnancy outcome among medicaid recipients. Am J Prev Med 1989;5(3):157–63. 99. Prilosec (package insert), AstraZeneca, Wilmington, DE, 2001. 100. Lalkin A, Loebstein R, Addis A, et al. The safety of omeprazole during pregnancy: a multicenter prospective controlled study. Am J Obstet Gynecol 1998;179(3 Pt 1):727–30. 101. Kallen BA. Use of omeprazole during pregnancy – no hazard demonstrated in 955 infants exposed during pregnancy. Eur J Obstet Gynecol Reprod Biol 2001;96(1):63–68. 102. Diav-Citrin O, Arnon J, Shechtman S, et al. The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study. Aliment Pharmacol Ther 2005;21(3):269–75.

CHAPTER 28 103. Jenkins JK, Boothby LA. Treatment of itching associated with intrahepatic cholestasis of pregnancy. Ann Pharmacother 2002;36(9):1462–65. 104. Lewis JH, Weingold AB. The use of gastrointestinal drugs during pregnancy and lactation. Am J Gastroenterol 1985;80(11):912–23. 105. Collins E. Maternal and fetal effects of acetaminophen and salicylates in pregnancy. Obstet Gynecol 1981;58(Suppl. 5):57S–62S. 106. Wagner CL, Katikaneni LD, Cox TH, Ryan RM. The impact of prenatal drug exposure on the neonate. Obstet Gynecol Clin North Am 1998;25(1):169–94. 107. McKeigue PM, Lamm SH, Linn S, Kutcher JS. Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994;50(1):27–37. 108. Kane S, Lemieux N. The role of breastfeeding in postpartum disease activity in women with inflammatory bowel disease. Am J Gastroenterol 2005;100(1):102–5. 109. Nelis GF. Diarrhoea due to 5-aminosalicylic acid in breast milk. Lancet 1989;1(8634):383. 110. Mahadevan U, Kane S, Sandborn WJ, et al. Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn’s disease. Aliment Pharmacol Ther 2005;21(6):733–38. 111. Qureshi WA, Rajan E, Adler DG, et al. ASGE guideline: Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc 2005;61(3):357–62. 112. Martin LV, Jurand A. The absence of teratogenic effects of some analgesics used in anaesthesia. additional evidence from a mouse model. Anaesthesia 1992;47(6):473–76. 113. Fernando R, Bonello E, Gill P, Urquhart J, Reynolds F, Morgan B. Neonatal welfare and placental transfer of fentanyl and bupivacaine during ambulatory combined spinal epidural analgesia for labour. Anaesthesia 1997;52(6):517–24. 114. Morley-Forster PK, Reid DW, Vandeberghe H. A comparison of patient-controlled analgesia fentanyl and alfentanil for labour analgesia. Can J Anaesth 2000;47(2):113–19. 115. Nelson KE, Rauch T, Terebuh V, D’Angelo R. A comparison of intrathecal fentanyl and sufentanil for labor analgesia. Anesthesiology 2002;96(5):1070–73. 116. Carrie LE, O’Sullivan GM, Seegobin R. Epidural fentanyl in labour. Anaesthesia 1981;36(10):965–69. 117. Lindemann R. Respiratory muscle rigidity in a preterm infant after use of fentanyl during caesarean section. Eur J Pediatr 1998;157(12):1012–13. 118. Regan J, Chambers F, Gorman W, MacSullivan R. Neonatal abstinence syndrome due to prolonged administration of fentanyl in pregnancy. BJOG 2000;107(4):570–72. 119. Abboud TK, Zhu J, Richardson M, PeresDaSilva E, Donovan M. Intravenous propofol vs thiamylal-isoflurane for caesarean

120.

121.

122.

123. 124.

125.

126.

127.

128.

129.

130.

131. 132.

133.

134.

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section, comparative maternal and neonatal effects. Acta Anaesthesiol Scand 1995;39(2):205–9. Cheng YJ, Wang YP, Fan SZ, Liu CC. Intravenous infusion of low dose propofol for conscious sedation in cesarean section before spinal anesthesia. Acta Anaesthesiol Sin 1997;35(2):79–84. Gregory MA, Gin T, Yau G, Leung RK, Chan K, Oh TE. Propofol infusion anaesthesia for caesarean section. Can J Anaesth 1990;37(5):514–20. Safra MJ, Oakley GP, Jr. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet 1975;2(7933):478–80. Czeizel A. Lack of evidence of teratogenicity of benzodiazepine drugs in hungary. Reprod Toxicol 1987;1(3):183–88. Katz JA. Endoscopy in the pregnant patient with inflammatory bowel disease. Gastrointest Endosc Clin N Am 2002;12(3):635–46. Patel SJ, Reede DL, Katz DS, Subramaniam R, Amorosa JK. Imaging the pregnant patient for nonobstetric conditions: algorithms and radiation dose considerations. Radiographics 2007;27(6):1705–22. Bentur Y. Ionizing and nonionizing radiation in pregnancy. In: G Koren, ed. Maternal-Fetal Toxicology, second ed.. New York: Marcel Dekker; 1994:515. De Wilde JP, Rivers AW, Price DL. A review of the current use of magnetic resonance imaging in pregnancy and safety implications for the fetus. Prog Biophys Mol Biol 2005;87(2–3):335–53. Birchard KR, Brown MA, Hyslop WB, Firat Z, Semelka RC. MRI of acute abdominal and pelvic pain in pregnant patients. AJR Am J Roentgenol 2005;184(2):452–58. Shoenut JP, Semelka RC, Silverman R, Yaffe CS, Micflikier AB. MRI in the diagnosis of Crohn’s disease in two pregnant women. J Clin Gastroenterol 1993;17(3):244–47. Trachter AB, Rogers AI, Leiblum SR. Inflammatory bowel disease in women: impact on relationship and sexual health. Inflamm Bowel Dis 2002;8(6):413–21. Giese LA, Terrell L. Sexual health issues in inflammatory bowel disease. Gastroenterol Nurs 1996;19(1):12–17. Notter J, Burnard P. Preparing for loop ileostomy surgery: women’s accounts from a qualitative study. Int J Nurs Stud 2006;43(2):147–59. Husain A, Triadafilopoulos G. Communicating with patients with inflammatory bowel disease. Inflamm Bowel Dis 2004;10(4):444–50, discussion 451. Sauk J, Kane S. The use of medications for inflammatory bowel disease during pregnancy and nursing. Expert Opin Pharmacother 2005;6(11):1833–39.

C hapter

29

Disorders of Defecation in Women Susan L. Gearhart1 1

Assistant Professor of Colorectal Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Introduction

Table 29.1A  Rome II criteria for the diagnosis of chronic functional constipation

Pelvic floor disorders are known to effect up to 42% of adult women. These disorders include urinary incontinence, fecal incontinence, pelvic organ prolapse, and obstructed defecation. Risk factors include increasing age, increasing parity, and more recently, obesity.1 It is estimated that by 2030 more than one-fifth of the US female population will be over 65 years of age. As the age of this population increases, the national burden of healthcare costs, lost productivity, and decreased quality of life will be substantial. In this chapter, the more common disorders of defecation, including constipation and fecal incontinence, will be discussed.

Two or more of the following for at least 12 weeks (not necessarily consecutive) in the preceding 12 months: 1. Straining during 25% of bowel movements 2. Hard stools for 25% of bowel movements 3. Sensation of incomplete evacuation for 25% of bowel movements 4. Sensation of anorectal blockage for 25% of bowel movements 5. Manual maneuvers to facilitate 25% of bowel movements 6. Fewer than three bowel movements per week

Table 29.1B  Criteria for the diagnosis of irritable bowel syndrome (IBS) – constipation predominant

Prevalence and etiology of constipation

Abdominal pain and two or more of the following for at least 12 weeks (not necessarily consecutive) in the preceding 12 months:

A precise definition of constipation is lacking in the literature. The most accepted definition presently is based upon the Rome II criteria for the diagnosis of chronic functional constipation (see Table 29.1A). In addition, chronic functional constipation should be a separate condition from irritable bowel syndrome – constipation predominant (see Table 29.1B). In the United States, constipation is one of the most common digestive complaints, accounting for over 2.5 million physician visits annually and over 20% of the population of Western countries are estimated to be affected.2,3 It is estimated that over 800 million dollars are spent on laxatives per year in the United States.4 The causes of constipation are variable and are listed in Table 29.2. Constipation can be classified into three categories: normaltransit, slow-transit, and outlet obstruction.

1. Eased pain after defecation 2. Change in frequency of bowel movements 3. Change is shape and appearance of feces Associated symptoms: 1. 2. 3. 4. 5. 6.

Current medical conditions and prescribed and over-thecounter medication use should be reviewed. Information regarding bowel habits at a young age may provide useful information into causation. Furthermore, a careful physical exam particularly of the anorectum, is essential to rule out any anorectal disorders that may exacerbate the patient’s symptoms. Digital exam should be performed while having the patient squeeze the anal sphincter muscles, relax, and

Evaluation of constipation The initial evaluation of a patient presenting with either longstanding or new-onset constipation is a detailed history. Principles of Gender-Specific Medicine

Fewer than three bowel movements per week Hard stools Straining Sense of incomplete evacuation Mucus discharge Abdominal bloating

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Copyright 2010 , Elsevier Inc. All rights reserved.

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Table 29.2  Medical conditions leading to symptoms of constipation l l l l l l l

Diabetes mellitus Hypothyroidism Hypopituitarism Porphyria CNS trauma Parkinson’s disease Brain and CNS tumors

then attempt to evacuate. All patients, and especially those who are of the age of 50 years or have had a recent change in bowel habits, need to be evaluated with colonoscopy as part of the initial work-up of constipation. The etiology of functional constipation can often be classified into five groups from which the best treatment can then be determined. These groups include: (1) diet/lifestyle/ medication-related causes; (2) pelvic floor dysfunction; (3) colonic inertia; (4) megacolon; (5) idiopathic functional constipation. There are several physiologic tests that can be performed which may provide insight into the etiology of the patient’s constipation and, therefore, the best method of treatment. These tests are described in detail below.

Colonic Transit Time (Sitzmarks Study) This study is accomplished by having the patient swallow 20 radiopaque discs and obtaining serial abdominal x-rays to ascertain the position of the discs within the colon. The patient is required to refrain from the use of any laxatives during this study. There are two methods to determine the colonic transit time: the modified Martelli and the modified Metcalf.5 The modified Martelli technique requires the patient to have a baseline abdominal x-ray, ingest the 20 discs and the repeat an x-ray at day 1 and day 5 following ingestion. If more then 20% of the markers still are present on the 5th day, it is presumed the patient has an abnormal study. Alternatively, if the modified Metcalf is utilized, 20 radiopaque markers are ingested on days 1, 2, and 3 of the study and abdominal x-rays are obtained on days 4 and 7. The transit time at different areas within the colon can then be determined by counting all the discs and multiplying this number with a known constant as previously described by Arhan et al.6 Generally, total transit time of more than 68 hours, right colon transit time of more than 32 hours, left colon transit time of more than 39 hours, and rectosigmoid transit time of more than 36 hours were considered abnormal. When interpreting colonic transit studies, it is important to be able to see all the films that have been taken and to be aware of the days the films were taken. The distribution of the sitzmark discs can help determine the etiology of the constipation. If the right colon contains most of the sitzmarks for an abnormally long period of time, the patient most likely has colonic inertia. If the sitzmarks are gathered together in

Figure 29.1  Defecography demonstrating abnormal descent of the rectum during straining.

the left colon and rectosigmoid colon, than pelvic floor dysfunction is the likely cause. If the colon transit study is normal then the patient has normal transit constipation.

Defecography Defecography is a dynamic radiographic study of anorectal function during a simulated defecation and is often done in conjunction with cystography (see Figure 29.1). The patient is required to swallow oral diluted barium to opacify the small bowel. Barium gel is injected into the rectum and vagina. Finally contrast is injected into the bladder. The patient is placed in the upright position on a commode and asked to evacuate the barium from her rectum and bladder with real time imaging from the start of straining to the completion of evacuation. This study is helpful in determining pelvic organ prolapse, non-relaxing puborectalis, internal rectal prolapse, enterocele, rectocele, and cystocele. If the patient has a mixed disorder of incontinence associated with constipation, this test may be difficult to perform.

Anorectal Physiology Testing The components of anorectal physiology include anal canal manometry during rest, squeeze and strain, detection of the rectoanal inhibitory reflex, rectal compliance and balloon expulsion testing, and surface electromyography (EMG). Abnormal resting pressure of the anorectum is present in disorders like internal and frank rectal prolapse. Lack of the rectoanal inhibitory reflex is seen in Hirschsprung’s disease. Lack of relaxation of the anal sphincter complex during defecation noted on EMG indicates non-relaxing puborectalis. The best method to determine non-relaxing

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s e c t i o n 5     Gastroenterology l

Table 29.3  Methods of evaluation and treatment for known subtypes of functional constipation Subtype of constipation

Frequency*

Evaluation/findings

Treatment

Dietary/lifestyle/medication/ Pelvic floor dysfunction

33% 43%

Behavior modification/patient education Biofeedback Rectocele repair Repair of descending perineum

Colonic inertia

11%

Megacolon

4%

None Abnormal anorectal physiology (neg. balloon expulsion, EMG) Defecography (rectocele, non-relaxing puborectalis) Colonic transit (delayed rectosigmoid transit) Abnormal Colonic transit (total colonic inertia) Consider defecography to rule out mixed disorder Abnormal anorectal physiology with neg. RAIR Normal studies

Idiopathic constipation *

9%

Total abdominal colectomy with ileorectal anastomosis

Rule out infectious etiologies Rectal myomectomy or fecal diversion Medical management

7

As described by Lacerda-Filho et al.

puborectalis (or spastic anorectum with a closed anus upon defecation) is needle EMGs; however, this in itself would be too irritating to the anal canal. When dietary modification and lifestyle changes fail to achieve any response and physiologic testing is normal, most patient will either be determined to have IBS associated constipation or normal transit functional constipation. Among patients who fail dietary and lifestyle modifications and undergo physiologic testing, the most common types of constipation identified are abnormal pelvic floor function and IBS associated constipation. The findings associated with each subtype and suggested treatments have been summarized in Table 29.3.

Treatment of constipation It is important to note, as emphasized in the study by Lacerda-Filho, that a careful history and evaluation reveals nearly 23% of patients suffer from functional constipation as a result of poor diet and lifestyle.7 This can be ascertained upon history and physical exam. These patients are nearly 100% responsive to re-education and additional physiologic testing was not necessary. All patients should be encouraged to add supplementary fiber to their diet on a regular basis, drink plenty of fluids, enroll in a daily exercise program, and avoid any medications that may worsen their symptoms. The treatment of constipation related to pelvic floor dysfunction and slow transit is described below.

Outlet Obstruction due to Non-relaxing Puborectalis Pelvic floor dysfunction can be found in up to 30% of patients with chronic constipation.7,8 The cause related to pelvic floor dysfunction is most commonly associated with non-relaxing

puborectalis. Other causes include descending perineum syndrome and rectocele. However, frequently the latter presents with symptoms of obstructed defecation and not chronic constipation. These patients need to evacuate daily but have to assist themselves manually or with enemas. The mainstay of therapy for patients with chronic constipation due to non-relaxing puborectalis is biofeedback or pelvic floor physical therapy. During this treatment, patients work with techniques to relax the pelvic floor through massage and attempts at balloon expulsion. The ability of the patient to relax is monitored throughout treatment with surface EMG which provides feedback to the patient on how well she is doing. The patients are also given a series of exercises that can be performed at home. The response to biofeedback can be followed by having patients chart their laxative use. Reported improvement has been shown to occur in up to 89% of patients.9,10 Other investigators have utilized validated patient quality of life surveys to evaluate response to biofeedback and have demonstrated a significant improvement in quality of life as a result of pelvic floor physical therapy.8

Outlet Obstruction Due to Descending Perineum or Rectocele The treatment of other causes of pelvic floor dysfunction such as rectocele or descending perineum syndrome should begin with pelvic floor physical therapy. Often an element of non-relaxing puborectalis may be present but difficult to ascertain secondary to abnormal anatomy. It is interesting to note that physical exam in up to 81% of elderly women will demonstrate a rectocele. However, only 50% of these patients will be symptomatic.11 In descending perineum syndrome, obstructed defecation occurs because of widening of the anal rectal angle seen on defecography. Furthermore, there is weakening of the perineal body and a

C h a p t e r 2 9     Disorders of Defecation in Women l

vertical orientation of the rectum. This is usually a consequence of chronic straining or weakening of the sacral or pudendal nerves during childbirth. Results from the surgical management of constipation have been variable and no good long-term studies have been performed. Surgery is performed for patients with constipation due to pelvic outlet obstruction, slow transit colonic inertia, and a combination of both. Surgery is indicated in patient with obstructed defecation and a rectocele that is greater than 4 cm in size as measured on defecography. Furthermore, it should be noted on defecography that the rectocele does not empty. It is recommended that non-operative management with dietary modification, biofeedback, and occasional enema use be tried prior to repair. If no alterations occur in the patient’s current dietary and defecatory habits prior to surgery, the rectocele will return. Surgery for pelvic floor dysfunction is really a repair of a pelvic floor hernia. If the repair undergoes continued strain it will fail. The surgical procedure for outlet obstruction secondary to rectocele includes a transvaginal approach. In this approach, the plane between the rectum and vagina is identified and the connective tissue defect in this septum is repaired by either careful plication of the tissues or placement of the patient’s own fascia lata or harvested skin (alloderm) to strengthen the repair. Success following transvaginal approach has been demonstrated to be 83–93%.12,13 Alternatively, a transanal approach may be performed. The newer method of the transanal approach is the Stapled Transanal Rectal Resection (STARR) procedure. In this procedure, a stapling device is used to eliminate redundant rectal mucosa and cause scarring of the rectum which will aid in support and prevent rectocele formation. A contraindication for the STARR procedure would be the presence of fecal incontinence since this may cause trauma or injury to the sphincter complex. Boccasanta and colleagues demonstrated that at 1 year of follow-up after the STARR procedure, 90% of patients were satisfied.14 It is the author’s preference to repair a rectocele using the transvaginal approach. This approach allows for closure of the hernia defect and repair with reinforcement if necessary. The transanal approach will only reduce the excess rectal mucosa but does not eliminate the hernia defect. This fact is supported by findings from the 2008 Cochrane Review, which concluded that transvaginal repair may have lower recurrence rates than the transanal repair.15

Slow Transit Constipation Surgery for slow transit constipation is indicated when patients have confirmed abnormal transit confined to their colon and normal pelvic floor physiology. All patients prior to surgery should undergo a trial of conservative management. With proper patient selection, anticipated success rates from total abdominal colectomy with ileorectal anastomosis should approach 90%. The most common complication

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from this procedure has been small bowel obstruction, with an incidence is some series of nearly 20%.16–18 It is not recommended that patients undergo an ileosigmoid anastomosis because this type of reconstruction is associated with a 50% conversion rate to ileorectal anastomosis.19 Other alternatives include preservation of the ileocecal valve with creation of a cecorectal anastomosis. Unfortunately, this procedure is associated with an increase in abdominal (cecal) bloating and recurrence of constipation.20 Finally, the ACE procedure (antegrade continent enema) was developed by Malone in 199021 as a treatment option for constipation resistant to conservative methods. In this procedure, the appendix is reversed and brought to the skin as a stoma through which a catheter can be inserted and the patient can then administer antegrade enemas to assist in evacuation. This procedure has been highly effective in young children with neurogenic problems but has been less successful in adults with chronic constipation.

Sacral Nerve Stimulation for Chronic Constipation The basis for the use of sacral nerve stimulation (SNS) in the treatment of chronic constipation is the finding that stimulation of the S3 nerve root resulted in an increase in pan-colonic antegrade propagating sequence which in turn increased patient’s bowel frequency and reduced laxative use. Temporary electrodes can be placed that stimulate the S3 nerve root. Once the electrode is proven to be beneficial, a permanent device can be implanted. The success of this procedure has been variable, from 42% to 94% at approximately 1 year follow-up.22–25 Turning off the stimulator in most patients was associated with immediate return of symptoms. However, the use of SNS for constipation is relatively new and long-term studies are needed to further assess the use of this technique.

Prevalence and etiology of fecal incontinence Fecal incontinence is defined as the involuntary passage of fecal material 10 ml for at least one month in an individual. The prevalence of this disorder ranges in the literature from 2% to 15% and fecal incontinence has a significant social and economic impact on the patient and society.26,27 The average cost per patient to treat incontinence is approximately $18 000. In addition, the cost of protective products per patient is $500 per year. The most common cause of fecal incontinence is anorectal trauma related to childbirth. An anatomical defect may occur in up to 32% of women following parturition regardless of visible damage to the perineum.28 Although the reported incidence of postpartum fecal incontinence is less

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than 10%, symptoms are believed to not occur till later in life.29 Furthermore, it is believed that pregnancy and prolonged delivery may cause stretch injuries to the pudendal nerve leading to reduced nerve conduction velocity which may adversely affect the coordinated control of the posterior pelvic floor. Aging is believed to contribute to the overall risk of incontinence as it leads to a gradual loss of anal squeeze and resting pressures due to the loss of elasticity of the sphincter muscle complex.30 Medical conditions known to contribute to the development of fecal incontinence are listed in Table 29.4.

Table 29.4  Medical conditions known to contribute to symptoms of fecal incontinence Neurological disorders l l l l l l

Dementia Brain tumor Stroke Multiple sclerosis Tabes dorsalis Cauda equina lesions

Skeletal muscle disorders

Evaluation of fecal incontinence Symptoms of fecal incontinence can be described as the following: (1) passive incontinence or unwanted loss of stool without patient awareness; (2) urge incontinence or unwanted loss of stool despite active attempts to inhibit defecation; and (3) post-defecation incontinence or unwanted loss of stool in the immediate time after a bowel movement with normal continence at other times. The abnormality associated with each type and the method of evaluation is listed in Table 29.5. The individual studies are described below.

Anorectal Anatomy Prior to a discussion on the individual studies useful in identifying causes and determining treatment of fecal incontinence, it is important to review the anatomy of the anal canal. The anal sphincter complex is the most sophisticated sphincter mechanism in the human body. Much has been learned about sphincter function recently. For instance, the fine control that provides you with the capability to determine the consistency of what is to pass through the anal canal (air, liquid, solid waste) is determined by temperature-sensing cells found within the anal canal. The sphincter anatomy is different when evaluating females vs. males. In females, there is loss of the normal external sphincter complex in the upper anal canal. This is not a loss secondary to childbirth but is present because the rectovaginal septum creates the upper canal. The neuroanatomy of the anal canal can be divided into autonomic and sympathetic. Autonomic stimulation provides either internal sphincter contraction or relaxation and this is involuntary. Voluntary contraction of the external sphincter is through the pudendal nerve and additional branches of S3 and S4. This contraction is short-acting.

Anal Ultrasound/MRI The use of either method of radiographic evaluation of the sphincter muscles is perhaps the most useful tool in defining the etiology of incontinence and determining the method of treatment. Both tools will demonstrate any disruption of the internal or external sphincter muscle (Figure 29.2).

Myasthenia gravis Myopathies, muscular dystrophy

l l

Miscellaneous l l l l

Hypothyroidism Irritable bowel syndrome Sedation Severe diarrhea

Table 29.5  Summary of the evaluation for subtypes of fecal incontinence Symptom classification

Anatomic abnormality

Method of evaluation

Passive incontinence

Internal sphincter  external sphincter

Urge incontinence

Rectal compliance External anal sphincter Anorectal disorder External anal sphincter

Anorectal physiology PNTML, anal ultrasound Sigmoidoscopy Compliance testing Sigmoidoscopy Defecography Anorectal physiology

Post-defecation incontinence

Anorectal Physiology Anorectal physiology includes four-channel manometry, sampling reflex or rectal anal inhibitory reflex (RAIR), balloon expulsion, pudendal nerve latency testing (PNTML), and surface electromyography (EMG). All tests can be performed together in a physiology lab with the patient in the left lateral decubitus position. For four-channel manometry a perfusion catheter is inserted into the rectum and slowly removed while pressure readings are recorded every centimeter with the patient at rest and during squeeze. The RAIR is demonstrated on manometry by the instillation of air into a balloon placed into the anus on the end of the manometry catheter. With rapid instillation, there is a reflex relaxation of the internal sphincter which is identified with a drop in resting pressure within the anal canal. Balloon expulsion

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(a)

(b)

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(c)

Figure 29.2  Anal ultrasound demonstrating the anal sphincter complex at the (a) lower anal canal, (b) mid-anal canal, and the (c) upper anal canal. The external sphincter abnormally absent in the mid-anal canal.

is performed using the same balloon and is a test for the patient’s ability to evacuate the balloon through the anal canal as well as the compliance of the rectum. Pudendal nerve function is tested with a specialized electrode placed into the anus and at the opening of the pudendal canal. A stimulus is applied to the nerve and this is followed by contraction of the external sphincter muscle. The use of surface EMG is helpful in demonstrating appropriate relaxation of the anal sphincter muscle during strain.

Treatment of fecal incontinence Successful treatment of fecal incontinence is best documented using a validated quality of life score and incontinence score. The reason for this is that some patients may do everything they want to do but always wear protective products. If only one score is used, the incontinence symptoms may either be ‘over-rated’ or ‘under-rated.’ The most common surveys include the Wexner Score, the Fecal Incontinence Severity Index, and the Fecal Incontinence Quality of Life Survey. Non-surgical options for the treatment of incontinence are lacking, especially for passive incontinence secondary to a sphincter defect. Optimization with the use of Imodium is worthwhile. The author recommends that if the patient uses Imodium, that it be used consistently either around mealtime or at bedtime. The role of biofeedback is to improve sensation and strengthen the external anal sphincter muscle by the use of pelvic floor exercises (Kegel exercises). For urge incontinence, the primary etiology is loss of rectal compliance. This may be due to radiation, rectal prolapse, scleroderma, inflammatory bowel disease, or other conditions the decrease the compliance of the rectum. Every effort should be made to provide rectal healing in order to eliminate this condition. Finally, post-defecatory incontinence is likely related to a pelvic floor disorder such as pelvic organ prolapse. Surgical correction of the prolapse will provide symptomatic relief. The following procedures are most commonly used for surgical correction of fecal incontinence.

Overlapping Sphincteroplasty The most common technique for repair of injured external anal sphincter is the overlapping sphincteroplasty. A transverse incision is made into the perineal body and the internal and external sphincter muscles in the anterior location are identified. The muscle fibers in the anterior position will be mostly scar tissue and can be divided. The muscle is mobilized bilaterally and then overlapped with a non-absorbable suture. Long-term (5-year) results from this procedure demonstrate an approximate success rate of 50–60%.31–34 Repeated sphincteroplasty can be performed with similar long-term success.35

Submucosal Injections Several different substances, including carbon beads (durasphere), collagen, silicone, non-animal stabilized hyaluronic acid (NASH-DX), and polytetrafluoroethylene, have all been described in the use of mild incontinence with varied success. The benefit of this procedure is the ease of application.

Dynamic Graciloplasty For this procedure, the gracilis muscle is used to provide reinforcement or replacement to the external anal sphincter. Once the gracilis muscle graft has healed a stimulator is placed to change the muscle fiber type to one that is fatigueresistant so that a sustained contraction could be provided. The patient would then just turn off the stimulator in order to evacuate. This procedure has been for the most part abandoned secondary to the high morbidity associated with it.

Artificial Bowel Sphincter (ABS) The idea of an artificial sphincter mechanism was borrowed from the urologist. This system is made up of a drainable reservoir, a pump, and a circular cuff (Figure 29.3). Success rates have been reported to approach 90%. However, the challenge has been infection, which is some series has led

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Pump Baloon reservoir

incontinence episodes have been reported in 75–100% of patients.37 Interestingly, the etiology of incontinence either with or without a sphincter defect does not affect the success rate of this product. SNS is durable, with sustainable results at 5 years.

References Cuff

Figure 29.3  The artificial bowel sphincter device in place.

Implantable pulse generator

Tined lead

Figure 29.4  Placement of the device for sacral nerve stimulation is at the S3 nerve root. Courtesy of Medtronic, Inc., Minnesota, MN

to an explantation rate of 37%.36 Therefore, the use of the ABS system is contraindicated in pelvic sepsis, Crohn’s disease, and radiation.

Fecal Diversion This is often considered the last resort after failure of all other possible treatments. A permanent stoma can free the incontinent patient of social isolation. However, if a diverting stoma is performed, it is important to inform the patient that some mucus leakage may still occur.

Sacral Nerve Stimulation (SNS) SNS was originally designed for urinary urge incontinence; however, when undertaking these studies it was noted that some patients also had fecal incontinence and the use of the neurostimulation device resulted in improvement of fecal incontinence as well (Figure 29.4). Presently this is the most promising product for the management of fecal incontinence. Success rates of at least a 50% reduction in

  1. Nygaard I, Barber M, Burgio K, et al. Prevalence of symptomatic pelvic floor disorders in US women. JAMA 2008;300(11):1311–16.   2. Wald A, Scarpignato C, Kamm MA, et al. The burden of constipation on quality of life: results of a multinational survey. Aliment Pharmacol Ther 2007;26:2227–36.   3. Irvine EJ, Ferrazzi S, Pare P, Pthompson WG, Rance L. Health-related quality of life in funcional GI disorders: focus on constipation and resource utilization. Am J Gastroenterol 2002;97:1986–93.   4. Lembo T, Camilleri M. Chronic constipation. N Engl J Med 2003;349:1360–8.   5. Metcalf AM, Phillips SF, Zinsmeister AR, MacCarty RL, Beart RW, Wolf BG. Simplified assessment of segmental colonic transit. Gastroenterology 1987;92:40–7.   6. Arhan P, Devroede G, Jehannin B, et al. Segmental colonic transit time. Dis Colon Rectum 1981;24:625–9.   7. Lacerda-Filho A, Lima M, Magalhaes M, Paiva R, CunhaMelo J. Chronic constipation – the role of clinical assessment and colorectal physiologic tests to obtain an etiologic diagnosis. Arq Gastroenterol 2008;45:50–7.   8. Lewicky-Gaupp C, Morgan D, Chey W, Muellerleile P, Fenner D. Successful physical therapy for constipation related to puborectalis dyssynergia improves symptoms severity and quality of life. Dis Colon Rectum 2007;51:1686–91.   9. Jorge JM, Habr-Gama A, Wexner SD. Biofeedback therapy in the colon and rectal practice. Appl Psychophysiol Biofeedback 2003;28:47–61. 10. Palsson OS, Heymen S, Whitehead WE. Biofeedback treatment for functional anorectal disorders: a comprehensive efficacy review. Appl Psychophysiol Biofeedback 2004;29: 153–74. 11. Rosato GO. Rectocele and perineal hernias. In: DE Beck, SD Wexner, eds. Fundamentals of Anorectal Surgery. London: WB Saunders; 1998:99–114. 12. Yamana T, Takahashi T, Iwadare J. Clincal and physiologic outcomes after transvaginal rectocele repair. Dis Colon Rectum 2006;49(5):661–7. 13. de Tayrac R, Picone O, Chauveaud-Lambling A, et al. A 2-year anatomical and functional assessment of transvaginal rectocele repair using a polypropylene mesh. Int Urogynecol J Pelvic Floor Dysfunt 2006;17(2):100–5. 14. Boccasanta P, Venturi M, Stuto A, et al. Stapled transanal rectal resection for outlet obstruction: a prospective multicenter trial. Dis Colon Rectum 2004;47(8):1285–96. 15. Maher C, Baessler K, Glazener CM, et al. Surgical management of pelvic organ prolapse in womenl a short version Cochrane review. Neurourol Urodyn 2008;27(1):3–12. 16. Pikarsky AJ, Singh JJ, Weiss EG, et al. Long-term follow up of patients undergoing colectomy for colonic inertia. Dis Colon Rectum 2001;4:179–83.

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17. Piccirillo MF, Reissman P, Carnavos R, et al. Colectomy as treatment for constipation in selected patients. Br J Surg 1995;82:898–901. 18. Kamm MA, Hawley PR, Lennard-Jones JE. Outcome of colectomy for severe idiopathic constipation. Gut 1988;29:969–73. 19. Pemberton JH, Rath DM, Ilstrup DM. Evaluation and surgical treatment of severe chronic constipation. Ann Surg 1991;214:403–13. 20. Fasth S, Hedlund H, Savaninger G, et al. Functional results after subtotal colectomy and caecorectal anastomosis. Acta Chir Scand 1983;149:623–7. 21. Malone PS, Ransley PG, Kiely EM. Preliminary report: the antegrade continence enema. Lancet 1990;336:1217–18. 22. Malouf AJ, Wiesel PH, Nicholls T, et al. Short-term effects of sacral nerve stimulation for idiopathic slow-transit constipation. World J Surg 2002;26:166–70. 23. Kenefick NJ, Nicholls RH, Cohen RJ, et al. Permanent sacral modulation for the treatment of idiopathic constipation. Br J Surg 2002;89:882–8. 24. Knenfick NJ. Sacral nerve neuromodulation for the treatment of lower bowel motility disorders. Ann R Coll Surg Engl 2006;88(7):617–23. 25. Holzer B, Rosen HR, Novi G, et al. Sacral nerve stimulation in patients with severe constipation. Dis Colon Rectum 2008;51:524–30. 26. Perry S, Shaw C, McGrother C, et al. Prevalence of fecal incontinence in adults aged 40 years or more living in the community. Gut 2002;50:480–4. 27. Roberts RO, Jacobsen SJ, Reilly WT, et al. Prevalence of combined fecal and urinary incontinence: a community-based study. J Am Geriatr Soc 1999;47:837–41.

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28. Richter HE, Fielding JR, Bradley CS, et al. Endoanal ultrasound findings and fecal incontinence symptoms in women with and without recognized anal sphincter tears. Obstet Gynecol 2006;108(6):1394–401. 29. Bharucha AE, Zinsmeister AR, Locke R, et al. Risk factors for fecal incontinence: a population-based study in women. Am J Gastroenterol 2006;101:1305–12. 30. Donnelly V, O’Connell PR, O’Herlihy C. The influence of estrogen replacement on fecal incontinence in post-menopausal women. Br. J Obstet Gynecol 1997;104:311–5. 31. Grey BR, Sheldon RR, Telford KJ, et al. Anterior anal sphincter repair can be of long-term benefit: a 12-year case cohort from a single surgeon. BMC Surg 2007;7(1):1–6. 32. Zorcolo L, Covotta L, Bartolo DC. Outcome of anterior sphincter repair for obstetric injury: comparison of early and late results. Dis Colon Rectum 2005;48:524–31. 33. Barisic GI, Krivokapic ZV, Markovic VA, et al. Outcome of overlapping anal sphincter repair after three months and after a mean of eighty months. Int J Colorectal Dis 2006;21:52–6. 34. Maslekar S, Gardiner AB, Duthie GS. Anterior anal sphincter repair for fecal incontinence: good long-term results are possible. Am Coll Surg 2007;204:40–6. 35. Vaizey CJ, Norton C, Thornton MJ, et al. Long-term results of repeat anal sphincter repair. Dis Colon Rectum 2004;47:858–63. 36. Wong WD, Congliosi SM, Spencer MP, et al. The safety and efficacy of the artificial bowel sphincter for fecal incontinence: results from a multicenter cohort study. Dis Colon Rectum 2002;45:1139–53. 37. Pinto R, Sands D. Surgery and sacral nerve stimulation for constipation and fecal incontinence. Gastrointest Endoscopy Clin North Am 2009;19:83–116.

C hapter

30

Idiopathic Gastroparesis: Gender Aspects Henry P. Parkman1 1

Associate Professor of Medicine and Physiology, Temple University, Department of Physiology, Philadelphia, PA, USA

Introduction

smooth muscle cells. ICCs are considered to be the responsible for generation of gastric slow wave activity. The electrical impulses are transmitted distally in an aboral fashion at a rate of 3 cycles/minute. This electrical activity triggers the muscle to contract producing peristaltic antral contractions. The antral contractions help in triturating the food into small particles allowing passage across the pylorus.

Gastrointestinal motility and functional motility disorders are common and are associated with persistent symptoms that can often result in a poor quality of life.1 GI motility and functional GI disorders are much more common in women than in men. Gastroparesis, in particular, is an increasingly recognized condition.2 This chapter will focus on gastric motility and gastroparesis and discuss gender effects on gastric motility.

Gender aspects of gastric motility Normal gastric emptying

In normal subjects, gastric emptying is affected by age, gender, menopausal status, and even phase of the menstrual cycle. Gastric emptying in premenopausal females is delayed compared to that in males.4–7 Some investigators,7,8 but not all,9,10 have reported that gastric emptying is slower during the luteal phase (days 18–20) of the menstrual cycle when there are elevated levels of estrogen and progesterone than in the follicular phase (days 8–10), when levels of these sex hormones are low. Postmenopausal women on sex hormone replacement therapy have slower gastric emptying of solids than men.9 These observations suggest that the female reproductive hormones, estrogen and progesterone, have inhibitory effects on gastric motility.7 The slower gastric emptying is thought to be due to reduced gastric smooth muscle contractility caused by the female reproductive hormones, particularly progesterone.11,12 Interestingly, nausea of pregnancy, which occurs predominately during the first trimester, when estradiol and progesterone are elevated, is associated with gastric dysrhythmias.13–15 However, delayed gastric emptying has also been reported during the follicular phase (first 10 days of the menstrual cycle),5,16 suggesting that gender differences exist that may not be related to levels of estrogen and

Normal gastric emptying reflects a coordinated activity of different regions of the stomach and the duodenum.3 Upon eating, postprandial receptive relaxation of the gastric fundus occurs allowing accommodation of food without significantly increasing gastric pressure. Rhythmic antral contractions then help triturate large food particles to a smaller size allowing emptying out of the stomach. Pyloric relaxation occurs which allows small food particles (chyme) to enter the duodenum. Any undigested and larger particles are later swept across the pylorus by a series of contractions known as the phase III migrating motor complex that occur in the fasting state in cycles of every 90 minutes. Gastric emptying is regulated by the influence of central nervous system predominantly through the vagal efferent pathways and enteric nervous system on gastric smooth muscle. Gastric emptying is controlled by gastric myoelectric and motor activity. The gastric myoelectrical activity originates from gastric pacemaker located at the junction of the proximal third and distal two-thirds of the gastric corpus along the greater curvature. The interstitial cells of Cajal (ICCs) are located in the myenteric plexus and are coupled to gastric Principles of Gender-Specific Medicine

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progesterone. Studies by Knight et al. have shown that gastric emptying of solid food in normal young women is slower than in aged-matched men, even in the first 10 days of the menstrual cycle when estrogen and progesterone levels are low.16 The slower gastric emptying as reflected by the higher gastric retention in women seen in this study was associated with normal proximal gastric emptying but a decreased rate of distal gastric emptying. Females had decreased antral contractility as recorded by dynamic antral scintigraphy and antroduodenal manometry. Thus, the delay in gastric emptying of solids in women appears to be primarily due to altered distal gastric motor function. One explanation may be that less vigorous antral contractions may contribute to slower breakdown of food particles and delay the rate of gastric emptying. Gender-related differences have also been reported to be present in the proximal stomach affecting motility and perception.17 The relaxation of the proximal stomach that occurs postprandially was prolonged in women compared to men as assessed using a gastric barostat. This was associated with an increase in the symptom of nausea in postprandially. These effects of gender on symptom production in small mechanistic studies have been extended by looking at the effect of gender on upper gastrointestinal symptoms in the com­munity.18 In this study by Camilleri et al., a telephone survey of 21 128 adults was conducted which asked questions about the presence of upper GI symptoms during the past 3 months. Interestingly, symptoms of early satiety and nausea are more common in females than in males, by nearly a 2:1 ratio. The symptom on nausea was present in 1.4% of males and 3.0% of females. The symptom of early satiety was present in 3.7% of males and 5.7% of females.18 The practical clinical practice corollary of these studies is that this suggests the need to compare females with symptoms of gastric dysfunction using gastric emptying parameters derived in normal women rather than to those derived in normal men. However, this is not done in most centers. Stanghellini et al. evaluated indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Sex-specific normal ranges were used where the normal ranges in females were slower than males.19 Interestingly, female sex, postprandial fullness, and vomiting were the only factors independently associated with gastric emptying in patients with functional dyspepsia. The exact mechanism of the female gender effect on gastrointestinal motility is unknown.20 As discussed above, most presume this is a hormonal effect from estrogen and progesterone. The mechanism through which sex hormones exert their effects on GI motility is unclear. Progesterone, a steroid compound, is thought to work though genomic effects. However, progesterone may act via genomic and nongenomic mechanisms to influence contractile elements of the gut. In animals, sex steroid receptors have been found throughout the GI tract. Studies in animals have shown that

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female sex hormones have an inhibitory effect on GI motility.11 Progesterone may also exert its inhibitory effect on GI motility by reducing plasma motilin levels.21 Progesterone also has effects on calcium channels, G proteins, and nuclear transcription.22 Xiao et al. showed that acute administration of progesterone produced a transient blocking of calcium release from storage sites.22 Studies by Pasricha et al. have shown that diabetes induces sex-dependent changes in neuronal nitric oxide synthase dimerization and function in the rat gastric antrum.23 nNOS expression, dimerization, and function are sex-dependent and furthermore that diabetes affects these processes differently in males and females. Female animals had more delayed gastric emptying than males–both in normal animals and those with diabetes. Estrogen has also been shown to have effects on gastrointestinal motility, although not as prominent as progesterone’s effects. Estrogen has been suggested to prime and enhance the inhibitory effects of progesterone.24 Previous studies have demonstrated that 17-estradiol administration delays gastric emptying for liquids in both male and female rats.

Gastroparesis Gastroparesis is a chronic motility disorder of the stomach characterized by delayed gastric emptying in the absence of a mechanical cause of obstruction. Gastroparesis can occur in many clinical settings with varied symptoms and severity of symptoms. Diabetic, postsurgical and idiopathic etiologies comprise the majority of cases. Diagnostic evaluation in patients with symptoms suggestive of gastroparesis generally consists of upper endoscopy and gastric emptying scintigraphy. Management of this condition can be particularly challenging. The American Gastroenterological Association have published a medical position statement and an accompanying review on gastroparesis25,26 and the American Neurogastroenterology and Motility Society has published a detailed review of the treatment of gastroparesis.27

Gastric motility abnormalities in gastroparesis As discussed above, gastric emptying is a coordinated activity of the proximal and distal stomach that is regulated by gastric myoelectric activity and gastric contractions. Abnormalities in any of these activities can result in the process of delayed emptying of the stomach and may lead to symptoms of gastroparesis. Delayed gastric emptying can result from abnormal antral contractility, abnormal gastric myoelectric activity, and pyloric tone.26 Antral hypomotility, both in the frequency and amplitude of contractions, has

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been well described in gastroparesis. Gastric dysrhythmias, especially postprandial gastric dysrhythmias as measured by electrogastrography, are well described in patients with gastroparesis.28

Etiology of Gastroparesis Gastroparesis was initially described as an infrequent complication of long-standing diabetes especially in association with other complications of diabetes such as neuropathy. In a recent series of 146 patients with gastroparesis, the three major categories of gastroparesis were idiopathic (36%), diabetic (29%), and postsurgical (13%).29

Idiopathic Gastroparesis Idiopathic gastroparesis refers to symptomatic disease with no detectable primary underlying abnormality for delayed gastric emptying. This may represent the most common form of gastroparesis.25,26,29 Symptoms may fluctuate, with episodes of pronounced symptoms interspersed with relatively asymptomatic periods. Most patients with idiopathic gastroparesis are women; typically young or middle aged.19 Symptoms of idiopathic gastroparesis overlap with those of functional dyspepsia and in some patients it may be difficult to provide a definitive distinction between the two. Abdominal pain/discomfort typically is the predominant symptom in functional dyspepsia, whereas nausea, vomiting, early satiety, and bloating predominate in idiopathic gastroparesis. Delayed gastric emptying can also be seen in patients with gastroesophageal reflux disease where reflux symptoms may predominate. The histologic basis of idiopathic gastroparesis is poorly understood. In one case, myenteric hypoganglionosis and reductions in numbers of interstitial cells of Cajal were observed.30 A subset of patients with idiopathic gastroparesis report sudden onset of symptoms after a viral prodrome, suggesting a potential viral etiology for their symptoms.31 In this patient subset, previously healthy subjects develop the sudden onset of nausea, vomiting, diarrhea, fever, and cramps suggestive of a systemic viral infection. However, instead of experiencing resolution of symptoms, these individuals note persistent nausea, vomiting, and early satiety. Viruses that have been implicated in these cases include cytomegalovirus, Epstein–Barr virus, and varicella zoster. These patients appear to have slow resolution of their symptoms over several years.31 In contrast, individuals with idiopathic gastroparesis without a viral trigger tend to show less improvement over time.

Clinical Presentation of Gastroparesis Symptoms of gastroparesis are variable and include early satiety, nausea, vomiting, bloating, and upper abdominal discomfort. In one series, of 146 patients with gastroparesis,

nausea was present in 92%, vomiting in 84%, abdominal bloating in 75%, and early satiety in 60%.29 Complications of gastroparesis may contribute to patient morbidity and include esophagitis, Mallory–Weiss tear, and vegetableladen bezoars.32 Symptoms of gastroparesis may simulate the symptoms related to other structural disorders of the stomach and proximal GI tract such as peptic ulcer disease, partial gastric or small bowel obstruction, gastric cancer, and pancreaticobiliary disorders.32 There also is an overlap between the symptoms of gastroparesis and functional dyspepsia. Indeed, idiopathic gastroparesis can be considered one of the causes of functional dyspepsia. Symptom correlation with delayed gastric emptying is variable for diabetic gastropathy, idiopathic gastroparesis, and functional dyspepsia. In recent studies, early satiety, postprandial fullness, and vomiting have been reported to predict delayed emptying in patients with functional dyspepsia.33 In patients with diabetes, abdominal fullness and bloating were found to predict delayed gastric emptying.34 In individuals with symptoms of gastroparesis who have normal rates of gastric emptying, other motor, myoelectric, or sensory abnormalities may be responsible for the symptoms. Abdominal discomfort or pain is present in 46%–89% of patients with gastroparesis but is usually not the predominant symptom, in contrast to its prominence in functional dyspepsia.29,35 Nevertheless, treatment of abdominal pain in gastroparesis can be challenging. Patients with functional dyspepsia exhibit increased sensitivity to gastric distention suggestive of afferent neural dysfunction as a contributing factor for the symptoms.36 Similarly, in diabetic patients with dyspeptic symptoms, gastric distention elicits exaggerated nausea, bloating, and abdominal discomfort, suggesting that sensory nerve dysfunction may participate in symptom genesis in some patients with gastroparesis.37

Evaluation of Patients with Suspected Gastroparesis A careful history and careful physical examination is an important part of the initial evaluation. Symptom onset and progression of the disease with understanding the periods of exacerbations are particularly important. History should include reviewing all the patient’s medications to help identify and eliminate drugs that can aggravate symptoms. Interestingly, in females, symptoms may worsen around the time of the menstrual cycle.38 Physical examination may reveal signs of dehydration or malnutrition in patients with long-standing, severe symptoms of gastroparesis. The presence of a succussion splash, detected by auscultation over the epigastrium while moving the patient side to side or rapidly palpating the epigastrium, indicates excessive fluid in the stomach from gastroparesis or mechanical gastric outlet obstruction.

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Initial laboratory studies should be performed to identify electrolyte abnormalities such as hypokalemia and metabolic alkalosis, renal insufficiency, anemia, pancreatitis, or thyroid dysfunction. In females with only several months of symptoms, a pregnancy test should be obtained. An abdominal obstruction series should be performed to evaluate for mechanical gastric outlet or small bowel obstruction. Most patients will need an upper endoscopy or a radiographic upper gastrointestinal series to exclude mechanical obstruction or ulcer disease. The presence of retained food in the stomach after overnight fasting without evidence of mechanical obstruction is suggestive of gastroparesis. Bezoars may be found in severe cases. Gastric Emptying Scintigraphy Gastric emptying scintigraphy of a solid-phase meal is considered the gold standard for diagnosis of gastroparesis as it quantifies the emptying of a physiologic caloric meal. Measurement of gastric emptying of solids is more sensitive for detection of gastroparesis as liquid emptying may remain normal even in the presence of advanced disease. Dual solid and liquid phase emptying scans may be useful in symptomatic patients after gastric surgery. For solid-phase testing, most centers use a 99mTc sulfur colloid-labeled egg sandwich as the test meal with standard imaging at 0, 1, 2, and 4 hours.39,40 The radiolabel should be cooked into the meal to ensure radioisotope binding to the solid phase. This prevents elution of the radiotracer into the liquid phase, which might produce an erroneous measurement of the faster liquid-phase gastric emptying. Scintigraphic assessment of emptying should be extended to at least 2 hours after meal ingestion.40 Even with extension of the scintigraphic study to this length, there may be significant day-to-day variability (up to 20%) in rates of gastric emptying. For shorter durations, the test is less reliable due to larger variations of normal gastric emptying. Extending scintigraphy to 4 hours has been advocated to improve the accuracy in determining the presence of gastroparesis.40 A 4-hour gastric emptying scintigraphy test using radiolabeled EggBeaters meal with jam, toast, and water is advocated by the Society of Nuclear Medicine and the American Neurogastroenterology and Motility Society.41 Emptying of solids typically exhibits a lag phase followed by a prolonged linear emptying phase. A variety of parameters can be calculated from the emptying profile of a radiolabeled meal such as half emptying time and duration of the lag phase. The simplest approach for interpreting a gastric emptying study is to report the percent retention at defined times after meal ingestion, usually 2 and 4 hours, with normal being 60% remaining in the stomach at 2 hours and 10% remaining at 4 hours. As noted above, some centers use gender-specific normal values for gastric emptying.19

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Treatment Treatment of gastroparesis involves diet manipulation with the use of small, more frequent meals low in fat and fiber and emphasizing soft foods and liquids. Medical treatment involves the use of prokinetic and antiemetic agents. This has been extensively reviewed by the American Neurogastroenterology and Motility Society.27

Conclusion Patients with gastroparesis are being increasingly recognized. Pertinent to this book, most patients are female. The reason for this is unknown. Management of gastroparesis can be particularly challenging. Symptoms do not necessarily correlate with gastric emptying, the marker of this disorder. Current management strategies are often suboptimal for adequately improving patient’s symptoms. Importantly, advances in the evaluation and treatment of this disorder are being made. Several new treatment modalities are being investigated in this disorder, which makes a favorable outlook for this condition.

References   1.  Parkman HP, Doma S. The importance of gastrointestinal motility disorders. Pract Gastroenterol 2006;30(9):23–40.   2.  Wang YR, Fisher RS, Parkman HP. Trends of gastroparesisrelated hospitalizations in the United States, 1995–2004. Am J Gastroenterol 2008;103(2):313–22.   3.  Camilleri M, Hasler W, Parkman HP, et al. Measurement of gastroduodenal motility in the GI laboratory. Gastroenterology 1998;115:747–62.   4.  Datz FL, Christian PE, Moore J. Gender-related differences in gastric emptying. J Nucl Med 1987;28:1204–7.   5.  Hutson WR, Roehrkasse RL, Wald A. Influence of gender and menopause on gastric emptying and motility. Gastroenterology 1989;93:934–40.   6.  Wedmann B, Schmidt G, Wegener M, et al. Effects of age and gender on fat-induced gallbladder contraction and gastric emptying of a caloric liquid meal: a sonographic study. Am J Gastroenterol 1991;86:1765–70.   7.  Gill RC, Murphey PD, Hooper HR, et al. Effect of the menstrual cycle on gastric emptying. Digestion 1987;36:168–74.   8.  Petring OU, Flachs H. Inter- and intrasubject variability of gastric emptying in healthy volunteers measured by scintigraphy and pracetamol absorption. Br J Clin Pharmacol 1990;29:703–8.   9.  Mones J, Carrio I, Calabuig R, et al. Influence of the menstrual cycle and of menopause on the gastric emptying rate of solids in female volunteers. Eur J Nucl Med 1993;20:600–2. 10. Horowitz M, Maddern GJ, Chatterton BE, et al. The normal menstrual cycle has no effect on gastric emptying. Br J Obstet Gynecol 1985;92:743–46. 11. Bruce LA, Behsudi FM, Danhof IE. Smooth muscle mechanical responses in vitro to bethanechol after progesterone in male rat. Am J Physiol 1978;235:E422–28.

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12. Kumar D. In vitro inhibitory effect of progesetone on extrauterine human smooth muscle. Am J Obstet Gynecol 1962;84:1300–4. 13. Koch KL, Stern RM, Vasey M, et al. Gastric dysrhythmias and nausea of pregnancy. Dig Dis Sci 1990;35:961–68. 14. Walsh JW, Hasler WL, Nugent CE, et al. Progesterone and estrogen are potential mediators of gastric slow-wave dysrhythmias in nausea of pregnancy. Am J Physiol 1996;270(3 Pt 1): G506–14. 15. Riezzo G, Pezzolla F, Darconza G, et al. Gastric myoelectrical activity in the first trimester of pregnancy: a cutaneous electrogastrographic study. Am J Gastroenterol 1992;87:702–7. 16. Knight LC, Parkman HP, Brown KL, et al. Delayed gastric emptying and decreased antral contractility in normal premenopausal women compared with men. Am J Gastroenterol 1997;92:968–75. 17. Mearadji B, Penning C, Vu MK, et al. Influence of gender on proximal gastric motor and sensory function. Am J Gastroenterol 2001;96:2066–73. 18. Camilleri M, Dubois D, Coulie B, et al. Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study. Clin Gastroenterol Hepatol 2005;3(6):543–52. 19. Stanghellini V, Tosetti C, Paternico A, et al. Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 1996;110:1036–42. 20. Heitkemper M, Jarrett M. Irritable bowel syndrome: Does gender matter? J Psychosomatic Res 2008:583–87. 21. Christofides ND, Ghatiei MA, Bloom SR, et al. Decreased plasma motilin concentrations in pregnancy. Br Med J (Clin Res Ed) 1982;285:1453–54. 22. Xiao ZL, Cao W, Biancani P, et al. Nongenomic effects of progesterone on the contraction of muscle cells from the guinea pig colon. Am J Physiol GI 2006;290:G1008–15. 23. Gangula PRR, Maner WL, Micci M-A, et al. Diabetes induced sex-dependent changes in neuronal nitric oxide synthase dimerization and function in the rat gastric antrum. Am J Physiol GI 2007;292:G725–33. 24. Davis M, Ryan JP. Influence of progesterone on guinea pig gallbladder motility in vitro. Dig Dis Sci 1986;31(5):513–18. 25. Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association medical position statement: diagnosis and treatment of gastroparesis. Gastroenterology 2004;127:1589–91. 26. Parkman HP, Hasler WL, Fisher RS. American Gastroentero­ logical Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 2004;127:1592–622. 27. Abell TL, Bernstein RK, Cutts T, et al. Treatment of gastroparesis: a multidisciplinary review. Neurogastroenterol Motil 2006;18(4):263–83.

28. Parkman HP, Hasler WL, Barnett JL, et al. Electrogastrography: a document prepared by the gastric section of the American Motility Society Clinical GI Motility Testing Task Force. Neurogastroenterol Motil 2003;75:89–102. 29. Soykan I, Sivri B, Sarosiek I, et al. Demography, clinical characteristics, psychological profiles, treatment and longterm follow-up of patients with gastroparesis. Dig Dis Sci 1998;43:2398–404. 30. Zarate N, Mearin F, Wang XY, et al. Severe idiopathic gastroparesis due to neuronal and interstitial cells of Cajal degeneration: pathological findings and management. Gut 2003;52:966–70. 31. Bityutskiy LP, Soykan I, McCallum RW. Viral gastroparesis: a subgroup of idiopathic gastroparesis – clinical characteristics and long-term outcomes. Am J Gastroenterol 1997;92:1501–6. 32. Parkman HP, Schwartz SS. Esophagitis and other gastrointestinal disorders associated with diabetic gastroparesis. Arch Intern Med 1987;147:1477–80. 33. Sarnelli G, Caenepeel P, Geypens B, et al. Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia. Am J Gastroenterol 2003;98:783–88. 34. Horowitz M, Harding PE, Maddox AF, et al. Gastric and oesophageal emptying in insulin-dependent diabetes mellitus. J Gastroenterol Hepatol 1986;1:97–113. 35. Hoogerwerf WA, Pasricha PJ, Kalloo AN, et al. Pain: the overlooked symptom in gastroparesis. Am J Gastroenterol 1999;94:1029–33. 36. Lemann M, Dederding JP, Flourie B, et al. Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia. Dig Dis Sci 1991;36:1249–54. 37. Samsom M, Salet GAM, Roelofs JMM, et al. Compliance of the proximal stomach and dyspeptic symptoms in patients with type 1 diabetes mellitus. Dig Dis Sci 1995;40:2037–42. 38. Heitkemper MM, Jarrett M. Pattern of gastrointestinal and somoatic symptoms acroos the menstrual cycle. Gastroente­ rology 1992;102:505–13. 39. Thomforde GM, Camilleri M, Phillips SF, et al. Evaluation of an inexpensive screening scintigraphic test of gastric emptying. J Nucl Med 1995;36:93–96. 40. Guo J-P, Maurer AH, Fisher RS, et al. Extending gastric emptying scintigraphy from two to four hours detects more patients with gastroparesis. Dig Dis Sci 2001;46:24–29. 41. Abell TL, Camilleri M, Donohoe K, et al. Consensus Recommendations for Gastric Emptying Scintigraphy. A Joint Report of the Society of Nuclear Medicine and the American Neurogastroenterology and Motility Society. Am J Gastroenterol 2008;103:753–63.

Chapter

31

Liver Disease in Women Karen Krok, and Ayman Koteish The Johns Hopkins University School of Medicine, Department of Gastroenterology and Hepatology, Baltimore, MD, USA

Introduction

Table 31.1  Liver diseases seen in pregnancy Liver disease

The cyclical hormonal changes that occur in women are often a reason to exclude females from clinical and basic research studies. However, these very hormones may play a role in the pathogenesis of diseases in women. For this reason, it is important to consider gender when evaluating a patient. In hepatology, gender and sex hormones play a role in the epidemiology of autoimmune diseases (autoimmune hepatitis and primary biliary cirrhosis), the effect of alcohol on the liver, the development of benign and malignant liver tumors, and of course on pregnancy-related liver diseases. In this chapter we will discuss the impact of female gender on the development and/or progression of specific liver diseases.

Coincidental to pregnancy Viral hepatitis Gallstones Drug-induced Budd–Chiari Unique to pregnancy Hyperemesis gravidarum Intrahepatic cholestasis of pregnancy HELLP syndrome Acute fatty liver of pregnancy Ovarian hyperstimulation syndrome

It is estimated that up to 3% of pregnancies are complicated by liver disorders.1 There are four different scenarios in which a pregnant patient may be referred to a hepatologist (Table 31.1):

1 Late 2 and 3 3 3 1

Ovarian Hyperstimulation Syndrome (OHSS) OHSS is a potentially fatal iatrogenic complication associated with ovulation-induction therapy. The basic pathophysiologic hallmark of OHSS is an increase in capillary permeability that results in the leakage or exudation of protein-rich fluid from the ovaries or peritoneal surface to the third space compartments. Vascular endothelial growth factor (VEGF) is considered responsible for this pathophysiologic process; in fact, VEGF levels correlate with the severity of OHSS.2 VEGF, also known as vascular permeability factor, is an angiogenic cytokine that increases the permeability of blood vessel walls, and induces changes in cellular actin fibers affecting the integrity of tight cell junctions; hence, its dysregulation directly affects fluid shifts across cellular junctions. VEGF also plays an important role in follicular growth, corpus luteum function, and ovarian angiogenesis. OHSS occurs when pharmacological doses of exogenous gonadotropins override the hypothalamic–pituitary–ovarian

Liver diseases unique to pregnancy Liver diseases coincidental to pregnancy Chronic liver disease and pregnancy Pregnancy after a liver transplant.

In general, liver diseases that may coincide with, but are unrelated to pregnancy usually do not result in significant maternal or fetal mortality. However, in the case of pregnancyspecific liver disease, it is essential to accurately determine the gestational age, and the timing of the disease onset.

Liver Diseases Unique to Pregnancy Liver diseases unique to pregnancy include ovarian hyperstimulation syndrome (OHSS), hyperemesis gravidarum Principles of Gender-Specific Medicine

1–3 1–3 1–3 Usually post partum

(HG), intrahepatic cholestasis of pregnancy (ICP), acute fatty liver of pregnancy (AFLP), hemolysis–elevated liver enzymes–low platelets (HELLP) syndrome, and hepatic hemorrhage or rupture.

Pregnancy and liver diseases

1. 2. 3. 4.

Trimester of occurrence

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Copyright 2010 20 , Elsevier Inc. All rights reserved.

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Table 31.2  Classification of ovarian hyperstimulation syndrome Grade

Size of follicles

Mild (I) Moderate (II)

5  5 cm 12  12 cm

Severe (III)

12  12 cm

Other symptoms and signs Elevated estradiol Abdominal pain, nausea, vomiting, diarrhea, sudden weight gain of at least 3 kg Ascites, effusions, electrolyte imbalance, hypovolemia, thromboembolic disease

feedback mechanism, leading to the recruitment of a large number of follicles. Hence, OHSS is classified into three grades depending on the size of the follicles and the severity of clinical findings (Table 31.2). The clinical signs and symptoms of OHSS constitute a continuum. Patients may complain of bloating, nausea, vomiting, diarrhea, shortness of breath (related to pleural effusions), rapid weight gain, and ascites. Thromboembolic events and adult respiratory distress syndrome also have been known to occur, which can be seen in ‘severe’ OHSS. This latter complication occurs in 0.5–1% of IVF cycles.3 Fortunately, the severe form of OHSS is rare, while mild-to-moderate forms of OHSS occur in 3–6% of ovulation induction cycles. Laboratory data may demonstrate renal failure, hemoconcentration, leukocytosis, hyponatremia, hyperkalemia, and elevated liver enzymes. OHSS-related death has occurred in eight patients in the literature, though there are no liverrelated deaths reported. Liver abnormalities associated with OHSS after IVF were first reported in 1988 and subsequently have been found to affect up to 30–40% of patients; females are found to develop a mild to moderate increase in their serum ALT and AST (no greater than 1000 IU/L).4,5 Significant cholestasis is rare. ALT and AST can remain elevated for up to 2 months, and have been associated with a lower pregnancy rate. In the literature, the only two reports of liver histology findings are from two autopsies obtained in OHSS patients. The first showed a normal lobular pattern by light microscopy, while the other was characterized by periportal macrovesicular steatosis (acinar zone 1), with an inflammatory infiltrate composed mainly of mononuclear cells and marked Kupffer cell hyperplasia.6,7 These changes are not specific to the liver manifestation in OHSS, and may be seen in a multitude of liver diseases. The etiology of the liver abnormalities in OHSS is unknown. Four theories have been proposed to explain the liver abnormalities in OHSS. In the first, it is thought to be related to elevated estrogen levels;8 this appears unlikely as one would expect more of a cholestatic picture and, more importantly, there is no correlation between OHSS-related

liver abnormalities and estrogen levels. The second theory revolves around the release of hepatotoxins from the overstimulated ovaries. The third hypothesizes that increased vascular permeability in the liver leads to hepatic edema, and hence an elevation in ALT and AST.9 In the final theory, it is believed that liver abnormalities are due to ischemic injury related to the development of microvascular (sinusoidal) thrombosis.10 Treatment for OHSS is largely supportive, and consists of: intravenous fluids to correct hypovolemia, paracentesis for symptomatic relief, and total parenteral nutrition as needed. Heparin (5000 units subcutaneously twice daily) is recommended to prevent the thromboembolic complications of OHSS. In the majority of cases, however, patients will fully recover after a short period of time. Hyperemesis Gravidarum (HG) HG is a severe form of morning sickness, where persistent vomiting is associated with weight loss exceeding 5% of prepregnancy body weight. Ketonuria, unrelated to other causes, may be present. Liver dysfunction can occur in women with HG and usually occurs within 1–3 weeks after the onset of severe vomiting. Moderate increases in the serum aminotransferases can occur in approximately 50% of hospitalized patients, usually with values in the low hundreds, and rarely as high as 1000 IU/l.11 The ALT is typically elevated to a greater extent than the AST. Hyperbilirubinemia can occur, but rarely exceeds 3–4 mg/dl.12 HG is not a liver disease per se, and the cause of the hepatic enzyme abnormalities is unknown. The degree of abnormality in the blood tests correlates with the severity of the vomiting; the highest elevations are seen in patients with the most severe or protracted vomiting. It is suspected that the liver abnormalities may be related to dehydration and relative malnutrition. Abnormal liver biochemical tests resolve promptly upon resolution of the vomiting; however, hyperemesis gravidarum, along with liver enzyme abnormalities, often recurs in subsequent pregnancies.12 Intrahepatic Cholestasis of Pregnancy (ICP) ICP is a disorder characterized by pruritus and mild jaundice that usually occurs in the second or third trimester of pregnancy and resolves shortly after delivery. Although it is associated with a very low maternal morbidity and mortality rate, ICP carries a significant risk to the fetus including an increased risk for premature birth, meconium-stained amniotic fluid, neonatal respiratory distress syndrome, and neonatal demise.13–15 Fetal mortality rates have varied from 11 to 20% depending on the study. Many theories have been proposed for the pathogenesis of ICP. One theory implies that estrogen may be a factor, as this hormone is increased throughout pregnancy. Supporting this theory is the fact that women with multiple gestations have an increased production of estrogen,

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and are at an increased risk for ICP.16 Hereditary factors also may be involved as women with a family and personal history of ICP have an increased risk for developing this disorder.17 A heterozygous mutation in the Multiple Drug Resistance-3 (MDR3) gene may be detected in up to 20% of women with ICP, and recently a larger family pedigree was studied which demonstrated evidence for linkage of the dominant form of ICP to heterozygosity for a MDR3 mutation.18 In addition, environmental factors appear to play a role as this disorder is found in less than 1% of pregnancies in the United States and Europe, but complicates up to 20% of pregnancies in Chile, and has a higher incidence during the winter months.19 Typically, jaundice develops after the 22nd week of pregnancy, but has been reported as early as the first trimester.20 Pruritus coexists with jaundice, and may be the only symptom of ICP in up to 50% of cases. Interestingly, pruritus often develops on the palms and soles of the feet, and then ascends throughout the remainder of the body. A key diagnostic feature is an elevation in serum bile acid levels, with an elevation in the chenodeoxycholic acid and cholic acid fraction by 10 to 100 times that of a healthy pregnant woman.21 Bilirubin rarely exceeds 6 mg/dl, alkaline phosphatase can be elevated up to four times the upper limit of normal, and transaminases may also be slightly elevated. A liver biopsy is not indicated for the diagnosis. Treatment is aimed at controlling the pruritus. Cholesty­ ramine, ursodeoxycholic acid, phenobarbital, and dexamethasone have been shown in small studies to improve symptoms and laboratory abnormalities.22–24 There is a correlation between the serum bile acid concentration and the incidence of fetal complications; women with a serum bile acid level greater than 40 mol/l have significantly higher rates of complications than women with lower levels of serum bile acids.25 The optimal treatment is delivery of the fetus, and in most women the cholestasis and pruritus resolve within 1–2 weeks postpartum. Unfortunately 60% of women with ICP will have a recurrence in future pregnancies. Acute Fatty Liver of Pregnancy (AFLP) AFLP is a diagnosis that gives any hepatologist palpitations. Although rare, it is a potentially fatal disease that occurs in the third trimester and carries a maternal and fetal mortality rate of 20%. It has been known to occur in the immediate postpartum period as well. In studies, it has been reported to occur in 1:6659 to 1:13 000 pregnancies in the United States.26,27 Although it can occur in any pregnancy, it is more common in primigravidas, in multiple gestation pregnancies, and in women with a male fetus.28 On the positive side, it is not likely to occur in future pregnancies. The pathogenesis of this disease is largely unknown. On liver biopsy there is microvesicular fatty infiltration of hepatocytes without significant inflammation or necrosis. There appears to be an association between AFLP and a

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fetal deficiency of the LCHAD (long-chain 3–hydroxyacyl CoA dehydrogenase) enzyme. This enzyme is involved in the mitochondrial beta-oxidation of fatty acids. A deficiency of this enzyme leads to increased levels of long-chain fatty acids. LCHAD-deficient fetuses spill unoxidized long chain fatty acids, which are hepatotoxic, into the maternal circulation.29–31 However, not all women pregnant with fetuses carrying the LCHAD deficiency will develop AFLP. In addition, other enzyme deficiencies of fatty acid oxidation can occur and may result in symptoms of liver failure similar to AFLP.32 Chorionic villous sampling or amniocentesis can assist in identification of fetuses with LCHAD deficiency. The early manifestations of AFLP are nonspecific and may be attributed to normal symptoms of pregnancy; these include fatigue, nausea, vomiting, and vague abdominal pain. Clinical evidence of significant hepatic dysfunction can occur within 1–2 weeks of onset of these vague symptoms. Liver failure then ensues with jaundice, encephalopathy, ascites and hypoglycemia. Up to 60% of patients will develop renal failure.33 Laboratory abnormalities include an elevated ALT and AST (1000 IU/l), prolongation of the prothrombin time, decreased fibrinogen, elevated creatinine, hypoglycemia, leukocytosis, thrombocytopenia, bilirubin levels of 1–10 mg/dl, and a reduction in antithrombin III levels (which is a particularly ominous sign).34 The diagnosis is confirmed by liver biopsy, although a biopsy is often not required to diagnose AFLP. Should a bio­ psy be performed, it is important to note that it often re­quires special stains such as oil red-O to detect microvesicular steatosis. Radiologic studies have limited sensitivity and specificity for the diagnosis of AFLP.35–39 Treatment requires prompt delivery of the fetus, which brings an end to the overload on the mother’s hepatic fattyacid oxidation system. Delivery, however, may be complicated by severe postpartum hemorrhage due to disseminated intravascular coagulopathy (DIC), which often complicates AFLP. Moreover, maternal DIC can lead to fibrin deposition in the placenta resulting in placental infarcts, placental insufficiency, and fetal asphyxiation.40 Delivery is often marked by prompt resolution of symptoms and return to a normal liver histology. The fetus does not carry a risk of developing liver disease or dysfunction. HELLP Syndrome HELLP syndrome, so called because of the specific lab abnormalities of Hemolysis, Elevated Liver enzymes and Low Platelets, probably represents a severe form of preeclampsia, although this remains somewhat controversial. The incidence of HELLP syndrome is approximately 1:1000 pregnancies with greater than 70% of cases occurring between 28 and 36 weeks’ gestation.41 Up to 30% of cases, however, may present after delivery, 20% of whom may have evidence of preeclampsia prior to delivery. Overall, 10% of patients with preeclampsia will develop HELLP syndrome.

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The pathogenesis is unclear, but, as mentioned above, many believe that it represents a severe form of preeclampsia. On the other hand, up to 20% of patients do not have any preceding hypertension or proteinuria. Fetuses have also been found to be lacking in LCHAD, the enzyme involved in the mitochondrial beta-oxidation of fatty acids that is more commonly associated with AFLP.31,42Other enzymes have also been implicated. The clinical features of patients with HELLP syndrome may not be much different from preeclampsia itself. Thus, affected patients may experience significant weight gain, edema, ascites, right upper quadrant pain, nausea, and vomiting. Hypertension and proteinuria are present in 80% of patients. The laboratory abnormalities are the sine qua non of the disorder: hemolysis with an elevated bilirubin and an elevated LDH (600 IU/l), moderately elevated AST and ALT (200–700 IU/l range), and thrombocytopenia (platelets less than 100 000/ml). Treatment is largely supportive, with close monitoring of the intravascular fluid balance and coagulopathy. Prompt delivery of the fetus is imperative. Antihypertensives (methyldopa or hydralazine) may be needed, as is prophylactic magnesium sulfate to prevent seizures. Maternal mortality ranges from 1 to 3% and is attributed to the disseminated intravascular coagulopathy and spontaneous postpartum hemorrhage. Fetal mortality can be as high as 30%, mostly because of placental compromise in the setting of the disseminated intravascular coagulopathy. There may continue to be a worsening of laboratory abnormalities up to 48 hours after delivery, but platelet count usually normalizes within the first week post partum.43 Hepatic Hemorrhage or Rupture Hepatic rupture is a rare complication of preeclampsia that occurs in the third trimester. Although it only affects 1:45 000 births,44 it has as high as a 30% maternal and fetal mortality.45 Patients can present with right upper quadrant pain, with rapid progression to hypovolemic shock, which can develop within a few hours of the hemorrhage/rupture. Older, multigravida mothers with preeclampsia are at the highest risk for developing hepatic rupture. Rarely, rupture and hemorrhage may complicate a growing adenoma or other hepatic mass during pregnancy. The pathophysiology is largely unknown. Liver biopsies have shown sinusoidal fibrin deposition, as well as neutrophilic infiltrates.46 Fibrin deposition may be responsible for liver distention, and ultimately rupture and/or liver necrosis. Severe hemorrhage may rupture the liver capsule, thus leading to hemoperitoneum.

Liver Diseases Coincidental to Pregnancy Certainly, any pregnant woman can acquire a viral hepatitis during the course of her pregnancy. Acute hepatitis A, B, and C have all been described, and are the most common

cause of jaundice in the pregnant woman. The course of most viral hepatitis infections is unaltered during pregnancy, with the exception of hepatitis E. Viral hepatitis is a major health concern in developing countries due to poor hygiene and sanitation. Fulminant hepatic failure from an acute viral hepatitis in all patients is much higher in developing nations when compared with developed nations. In Western nations, there does not appear to be a higher rate of hepatic failure from acute viral hepatitis in pregnant women vs. nonpregnant women.47,48 This is in contrast to developing nations where multiple studies have shown a significantly increased rate of fulminant liver failure from acute viral hepatitis in pregnant women compared to nonpregnant women: 61.8% vs. 10.1%, respectively.49–52 Hepatitis E Hepatitis E (HEV) is an enterically transmitted virus that has a good prognosis in males and non-pregnant females, but carries an increased mortality rate in pregnant women. In fact, the major cause of mortality in HEV epidemics is the high rate of fulminant hepatic failure in pregnant women: there is a 25% mortality rate in pregnant women compared with only a 1.9% mortality in all other patients. Vertical transmission commonly occurs with high fetal and neonatal morbidity and mortality.53 Khuroo et al. studied 76 pregnant women with sporadic viral hepatitis and found that 65 females developed acute hepatitis E, with a 69.2% rate of development of fulminant hepatic failure. This is in contrast to the 11 pregnant women who developed an acute non-HEV viral hepatitis, 18.2% of whom developed fulminant hepatic failure.51 Pregnant women have a shorter duration of disease, shorter pre-encephalopathy period, lower serum bilirubin levels and more frequent development of cerebral edema than nonpregnant women. There is also a 22.2% incidence of disseminated intravascular coagulopathy in pregnant women who develop acute hepatitis E. This bleeding disorder is one of the main causes of mortality in pregnant women with hepatitis E. The reason for this increased incidence and severity of hepatitis E infection in pregnant women is unknown, although many theories have been proposed. With pregnancy, there is a decrease in cell-mediated immunity, which is necessary to allow for fetal allograft retention. This marked reduction in CD4 cells also interferes with the maternal resistance to various infectious diseases.54,55 Moreover, hormonal secretion during pregnancy also influences cytokine production by activated T lymphocytes; in fact, estrogens are known to deplete CD4 and CD8 cells, and the development of T cells is blocked by progesterone.56–58 In animal models, cytokine, rather than antibody, production is favored in response to cytotoxic stimuli; if this occurs in humans as well, the compromised cytotoxic response may alter the ability to resist hepatitis E viral infection.59 In addition, an increased level of

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sex steroid hormones, particularly estrogens and progesterone, directly influence viral replication through their effects on the viral regulatory region.60,61 Most likely, it is the interplay of all these factors that influences the clinical course and prognosis of acute hepatitis E in pregnancy. Cholelithiasis Pregnancy is an independent risk factor for cholelithiasis, and this risk increases with each trimester, and with multiparity.62 There tend to be multiple, small stones. The reason for this increase in cholelithiasis is due to the hormonal changes in estrogen and progesterone during pregnancy. Estrogen progressively increases during the first two trimesters which affects biliary lipid secretion and cholesterol saturation. The increased progesterone decreases gallbladder motility and emptying, thus allowing for a more conducive environment for gallstone formation. During the postpartum period there is often spontaneous clearance of the gallstones. Cholelithiasis during pregnancy is often asymptomatic. If a patient presents with biliary colic or acute cholecystitis, conservative management with antibiotics, bowel rest, intravenous fluids, and pain medications is recommended. Should cholangitis or severe pancreatitis develop, an endoscopic retrograde cholangiopancreatogram (ERCP) with sphincterotomy can be performed; an extra lead shield should be applied to the patient’s abdomen in order to shield the fetus from the radiation. Surgery during the second trimester can be attempted if needed and does not appear to pose an increased risk to the mother or fetus. Chronic Liver Disease and Pregnancy Pregnancy is associated with normal changes in maternal physiology that should be considered when evaluating a patient for liver disease. Normally, spider angiomata and palmar erythema are noted in up to 60% of pregnant women. The high estrogen levels of pregnancy are thought to be responsible for these changes. Moreover, plasma and red cell volumes increase by about 50% and 25%, respectively. Hence, the degree of hemodilution, which correlates with the percentage decrease of the hematocrit, should be considered when interpreting laboratory values during pregnancy. Both plasma and red cell volumes return to normal range after delivery. Cardiac output increases 30–50%, beginning by week 6 of gestation and peaking at about 24 weeks, and then remains stable until delivery; however, it is important to note that the absolute hepatic blood flow remains unchanged. Moreover, in normal pregnancy most liver biochemical tests and prothrombin time remain within the normal range. Namely, an increase in serum aminotransferases, bilirubin, and/or fasting total bile acid concentrations during pregnancy should be considered pathologic. On the other hand, hypoalbuminemia and an elevated serum alkaline phosphatase may be expected during pregnancy,

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and per se does not indicate the presence of liver disease. The alkaline phosphatase levels increase progressively during the third trimester and may be two to three times the normal range at term; the increase is due to placental production of this enzyme.63–65 In a patient with underlying liver disease, these normal physiologic changes may adversely affect portal hypertension. The development of jaundice, ascites, encephalopathy, and/or postpartum hemorrhage have been reported in patients with cirrhosis.66 Perhaps the most feared complication of portal hypertension in pregnancy is esophageal variceal bleeding, which carries an almost 10% mortality rate; bleeding from esophageal varices occurs in 18–31% of pregnant cirrhotic women.67 Hence, cirrhotic patients should be screened for varices prior to conception, and preferably during the second trimester. Because of the potentially high risk of mortality with esophageal variceal bleeding, the prophylactic use of non-selective beta blockers is recommended in the cirrhotic pregnant woman with varices, despite the small potential for fetal bradycardia. It should be noted, however, that beta blockers are pregnancy class C drugs. Transjugular intrahepatic portosystemic shunts or portocaval shunts have been used successfully in pregnant women with variceal bleeding. Despite the lack of well-designed studies, an elective cesarean section, rather than a vaginal delivery, may be preferred in order to avoid straining during labor, and thus potentially decrease the risk of variceal bleeding. Prophylactic use of antibiotics at the time of delivery should be considered, as they may prevent infection in patients with cirrhosis. Pregnancy in cirrhosis is rare, however, because of reduced fertility, and the older age of the development of cirrhosis.68 Women with underlying severe liver disease can exhibit gonadal failure, amenorrhea, and infertility. In fact, infertility may be the initial presenting symptom for patients with chronic liver disease. In addition, spontaneous abortion rates in patients with cirrhosis are between 15 and 20%.68–70 If a cirrhotic woman does become pregnant, between 30 and 40% of them will have some degree of deterioration in liver function as measured by the serum bilirubin and alkaline phosphatase, with up to 66% of patients returning to their baseline after delivery.66 On the other hand, there is no evidence that pregnancy affects the natural history of chronic hepatitis B or C, unless underlying cirrhosis is present.

Pregnancy and Liver Transplant Childbearing after liver transplantation is uncommon and should be considered a high-risk pregnancy. The first documented pregnancy after orthotopic liver transplantation was hormonally assisted and reported in 1978, by Walcott et al. The recipient’s immunosuppressive regimen included prednisone and azathioprine. Pregnancy was uncomplicated, and a 2400 g, healthy male was delivered at term.71 However,

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questions still remain for both obstetricians and transplant hepatologists as to the safety of pregnancy after liver transplant. In 1990, Scantlebury et al. reported on 20 pregnancies in 17 liver transplant recipients, and found that allograft dysfunction was present in 37% of patients during pregnancy and 53% of women in the postpartum period.72 Later, in 1995, Radomski et al. reported on 37 pregnancies in liver transplant recipients and noted that 46% developed hypertension, 21% developed eclampsia/preeclampsia, 17% had allograft rejection, and 5.7% had graft loss; the newborns were also affected, and had a high rate of low birth weight and prematurity.73 On the other hand, data from the University of Pittsburgh suggest that when managed by experienced obstetricians and transplant hepatologists, pregnancy after liver transplantation has a good outcome.74 The use of tacrolimus appears to decrease the risk of preeclampsia, and most centers recommend prophylactic antibiotics at the time of delivery. Breastfeeding is generally not recommended. Of concern to any pregnant patient and the transplant hepatologist is the effect of immunosuppression on the fetus (Table 31.3). Calcineurin inhibitors have been safely used in pregnancy, but their levels need to be closely monitored; this is particularly important in the third trimester when fetal metabolism of cyclosporine and tacrolimus can lead to an overall increased clearance of the medication, thus resulting in lower (maternal) serum levels. Corticosteroids are generally safe during pregnancy. Cyclosporine has not been associated with congenital abnormalities, but it does increase the risk of low birthweight and maternal hypertension. It also increases the production of thromboxane and endothelin, which are implicated in the development of HELLP syndrome and preeclampsia. In general, by two years after liver transplantation, the risks of rejection and of infection are lower, and the level of immunosuppression is significantly decreased; hence, it is advisable that women of child-bearing age wait at least two years until they try to conceive. Moreover, those patients should be followed by both a high-risk obstetrician, and a transplant hepatologist.

Oral contraceptives and the liver Estrogens have been implicated in a variety of liver diseases and tumors. In contrast to this, however, estrogens have also been theorized to be protective against the progression of chronic liver disease.75,76 In this section we will only be discussing the hepatic pathology that estrogens may cause.

Cholestasis Conjugated hyperbilirubinemia and pruritus have been associated with the initiation of oral contraceptives, usually within the first two months. Mild hepatomegaly may be present, and there may be a slight increase in the serum

Table 31.3  Immunosuppression and pregnancy class rate and use during breastfeeding Drug

Pregnancy class rate Use during breastfeeding

Cyclosporine

C

Tacrolimus

C

Sirolimus Steroids

C Compatible

Mycophenolate mofetil

D

No adequate studies to determine risk to baby; not recommended by AAP Same concentration in breast milk as in serum; not recommended Not recommended Found to pass into breast milk and may cause growth problems in the baby but AAP considers it compatible with breastfeeding Not recommended during and for 6 weeks after discontinuation of medication

Source: AAP – American Academy of Pediatrics

aminotransferases and alkaline phosphatase. The hepatic synthetic function as measured by the prothrombin time and albumin is normal. Within two months of discontinuation of the medication, there is normalization of the bilirubin, aminotransferases, and alkaline phosphatase.

Cholelithiasis Exogenous estrogens are associated with the development of gallstones secondary to an increase in biliary cholesterol saturation. When oral contraceptives were first introduced, there appeared to be a two-to three-fold greater risk of development of cholelithiasis than compared to the general population.77 As the concentration of estrogens has decreased in oral contraceptives, so also has the risk for development of gallstones. Transdermal estrogens, on the other hand, do not increase biliary cholesterol saturation, and hence do not carry the same increased risk for gallstones as oral estrogens do.

Liver Tumors Hepatic adenomas and focal nodular hyperplasia are the two most common tumors associated with oral contraceptives. Hepatic Adenomas Adenomas are benign tumors that occur more frequently in women than in men, at a ratio of 9:1. Although adenomas have been known to occur in women with only a short history of oral contraceptive use, the majority are associated with long-term use. The estimated risk is 3–4:100 000.78

C h a p t e r 3 1     Liver Disease in Women l

HA may be asymptomatic and be incidentally discovered during imaging of the upper abdomen for other reasons. However, 25–43% of patients with adenoma(s) experience pain in the right upper quadrant or epigastrium. The pain usually is mild and ill-defined but may be severe as a result of hemorrhage, rupture or infarction of the tumor. If the liver is enlarged, the surface usually is smooth, and the liver may be slightly tender. The most alarming presentation is with an acute hemoperitoneum following rupture. Superficial, large adenomas (5 cm) have a higher risk of bleeding or rupture, with a mortality rate of 7%. In the case of hemoperitoneum, either angiography with embolization, resection, or packing are recommended. With discontinuation of the oral contraceptive, the lesions will often regress. Follow-up with serial imaging (CT scan and/or MRI) is recommended. In the literature, however, the most preferred management for symptomatic patients, is resection of the larger tumor(s).79 The major concern associated with hepatic adenomas is the risk of malignant transformation. The risk of transformation is not known exactly, but is reported to occur in less than 10% of cases. Adenomas should be followed serially, and should be promptly resected if they grow in size. Liver transplantation may be considered in patients who are determined to have a high risk for malignant transformation. However, there are no established guidelines for the management of those patients.80 Focal Nodular Hyperplasia The cause of focal nodular hyperplasia is unknown. Abnor­ malities in arteries in small and medium-sized portal tracts have been described. A role for oral contraceptive hormones in the development of the lesion was suggested, but the available evidence to support this association is less clear than with hepatic adenomas. In fact, FNH was first described in the early 1900s, long before the advent of oral contraceptives, and its incidence has not risen dramatically since the 1960s when oral contraceptives were introduced.81,82 Large and/or symptomatic lesions should be resected. Recurrence after resection is rare. Otherwise, FNH should be left alone, and, where indicated, discontinuation of contraceptive pills is recommended, which may result in regression of the lesion. The available evidence does not support a risk for malignant transformation in focal nodular hyperplasia.

Budd–Chiari Syndrome Budd–Chiari syndrome results from hepatic venous outflow obstruction because of thrombosis of the hepatic vein or suprahepatic inferior vena cava. This obstruction results in hepatic congestion and may potentially lead to hepatic necrosis and fibrosis. Up to 23% of cases are associated with a myeloproliferative disorder, such as hereditary thrombophilias, polycythemia vera, and myelodysplastic syndrome.83 Other causative factors include a hypercoagulable state (Factor V

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Leiden mutation, protein C and or S deficiency, prothrombin mutation G20210A, antithrombin III deficiency), pregnancy, hepatic venous or inferior venal caval webs, malignancy, abdominal trauma, and oral contraceptive use.84 The association between Budd–Chiari syndrome and oral contraceptive use has been documented since 1966.85 It is believed that excess estrogen in contraceptive pills leads to an increase in clotting factors and an increased tendency for venous thrombosis. The relative risk for development of Budd–Chiari syndrome while on oral contraceptives is estimated to be 2.37 over age-matched controls.84 The patient presentation is variable and depends on the degree of hepatic outflow obstruction. Ascites, hepatomegaly, and right upper quadrant pain constitute the classical symptom triad at presentation. Jaundice and other clinical stigmata of liver disease are absent typically. The gold standard for diagnosis has long been a hepatic venogram, but with improvements in radiology this is often not necessary for diagnosis alone. A hepatic Doppler ultrasound, three-dimensional CT scan or an MRI are currently used to support the diagnosis of Budd–Chiari syndrome. A liver biopsy is not necessary to make the diagnosis, but may help evaluate the extent of liver damage. The serum bilirubin and aminotransferases are rarely markedly abnormal. A significant elevation in the liver chemistries usually signifies severe hepatocyte damage and emergency decompression of the liver should be considered. Treatment goals revolve around decompression of the hepatic congestion. In the acute setting, thrombolytic therapy with streptokinase or urokinase has been employed.86–88 The mainstay of therapy is decompressive shunts–either a mesocaval shunt, portocaval shunt or a transjugular intrahepatic portosystemic shunt.89–91 Long-term anticoagulation also is required. Liver transplantation is indicated for patients with evidence of advanced synthetic dysfunction. In patients with protein C, protein S, or antithrombin III deficiency, liver transplantation also cures the underlying hypercoagulable state, although most patients will require lifelong anticoagulation. Underlying myeloproliferative disorders can be managed effectively with hydroxyurea and aspirin after liver transplantation. Recurrent Budd–Chiari syndrome after liver transplantation occurs in up to 10% of patients. Because of anticoagulation therapy, bleeding complications are more common. Despite these complications, the post-transplant 5–year survival rate for patients with Budd–Chiari syndrome remains greater than 85%.92–94

Autoimmune liver diseases Autoimmune diseases are more prevalent in females. Here, we will briefly discuss autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) as both of these diseases have an autoimmune pathogenesis.

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Autoimmune Hepatitis AIH is an unresolving liver inflammation of unknown cause. It is hypothesized that loss of self-tolerance ensues after repeated exposure to foreign antigens that resemble self-antigens. This repeated exposure in turn activates promiscuous T lymphocytes, which may in turn overcome self-tolerance. Liver cell destruction is accomplished by either cell-mediated cytotoxicity or antibody-dependent cell-mediated cytotoxicity, or a combination of both mechanisms.95 Over 80% of cases occur in women and there is a strong familial component. AIH typically affects young and middle aged women, but it also has been described in children and older women. Recent data suggest that blacks may have a more aggressive, treatment-resistant disease course.96 Patients may present with a wide-range of complaints: from fatigue and malaise to sub-fulminant liver failure. An acute onset of the disease can be seen in up to 25% of cases. Patients with AIH are usually more symptomatic on presentation than those with other liver diseases.97 There is also a strong association with other autoimmune diseases including autoimmune thyroid disease, CREST syndrome, Sjögren’s syndrome, diabetes mellitus, rheumatoid arthritis, polymyositis, mixed connective tissue disorder, hemolytic anemia, idiopathic thrombocytopenia, glomerulonephritis, and lichen planus. The hallmark of this disease is the presence of autoantibodies, particularly the antinuclear antibody, smooth muscle antibody, and liver-kidney microsomal antibody. Three types of AIH have been proposed on the basis of serologic markers. Classically, type 1 AIH is characterized by a positive antinuclear antibody and/or smooth muscle antibody. Type 2 is characterized by a positive liver-kidney microsomal type 1 (LKM-1) antibody, and is often found in adolescent or young women. Type 3 AIH was proposed because of the discovery of anti-SLA/LP (soluble liver antigen/liver pancreas) in some patients. Subsequent studies, however, indicated that type 3 classification is not justified since patients with anti-SLA/LP are indistinguishable from those with type 1 AIH. Hence, type 3 classification warrants continued investigation.98–101 In addition to these findings, laboratory examination also reveals elevated transaminases (rarely greater than 1000 IU/ml) and hypergammaglobulinemia. The liver biopsy is an important diagnostic tool in the confirmation of autoimmune hepatitis, and is characterized by the presence of interface hepatitis, whereby the limiting plate of the portal tract is disrupted by a lymphoplasmacytic infiltrate. This histologic pattern is the hallmark of autoimmune hepatitis, but it is not disease-specific. Diagnosis requires the exclusion of other chronic liver diseases that have similar features. The International Autoimmune Hepatitis Club has established a scoring system to aid in the diagnosis of autoimmune hepatitis: an aggregate score reflects the strength of the diagnosis.102 Regardless of the type of autoimmune

hepatitis, patients are treated the same: glucocorticoids with or without azathioprine usually are effective. Azathioprine with prednisone is preferred to prednisone alone because the combination produces fewer glucocorticoid-related side effects during comparable periods of treatment (10% vs. 44%). Histologic resolution lags behind clinical and laboratory resolution by 3–8 months. Hence, if drug withdrawal is being entertained, a liver biopsy examination may help ensure an optimal endpoint. Despite the high relapse rate with discontinuation of therapy, treatment discontinuation may be considered. Sustained remission after initial treatment is seen in only 21% of patients.103 But with continued treatment of the relapsers, up to 47% of patients achieve a sustained remission at 10 years.103 There is no reliable way to identify patients who will stay in remission other than to attempt to withdraw treatment and follow the transaminases closely. Czaja et al. found that death from hepatic failure and the need for liver transplantation occurred at similar rates in those who achieved sustained remission and those who did not.103 Hence, the main benefit of attempting to withdraw therapy is in the avoidance of drug toxicity. If a patient requires a liver transplant, recurrence of autoimmune hepatitis has been described in 17–25% of patients.104,105 De novo autoimmune hepatitis has also been described in up to 3.5% of patients after liver transplantation.106 It is unclear if gender plays a role in this phenomenon, but genetics are involved, as there is a higher prevalence rate of HLA DR-3 in patients with recurrent and de-novo autoimmune hepatitis after liver transplantation.107,108

Primary Biliary Cirrhosis Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic disease of presumed autoimmune etiology that affects up to 1 in 2500 middle-aged US women. The female to male ratio is 10:1. The incidence and prevalence of PBC have increased in recent years, most likely because of the diagnosis of asymptomatic patients with the widespread use of biochemical liver tests and antimitochondrial antibody (AMA) as part of routine screening. In recent studies the prevalence of asymptomatic disease is as high as 61%. The current consensus is that susceptibility to PBC in individual patients stems from a combination of environmental trigger(s) in a genetically susceptible individual.109,110 More than two-thirds of patients with PBC have an associated autoimmune disease, including keratoconjunctivitis sicca, polyarthritis, rheumatoid arthritis, scleroderma or autoimmune thyroid disease. Most patients will have an elevated IgM level as well as a positive AMA; AMA is present in close to 95% of patients. Neither the presence, nor the titer of antimitochondrial antibody, however, affects disease progression, survival or response to treatment. Original descriptions of PBC emphasized the association with severe progressive cholestasis, pruritus, portal hypertension, and

C h a p t e r 3 1     Liver Disease in Women l

liver synthetic dysfunction, and described a uniformly fatal condition. Increased awareness of this condition and implementation of diagnostic serology has led to earlier diagnosis. Currently the typical patient with PBC presents with fatigue, pruritus or with an asymptomatic elevation of alkaline phosphatase. This asymptomatic phase can last for up to 20 years but will eventually progress to a symptomatic phase for 5– 10 years and then to a short-term preterminal phase, characterized by severe jaundice. The diagnosis is based on history, biochemical and serolo­ gical tests, and liver histology examination. An elevated alka­ line phosphatase is often the only abnormal liver-associated enzyme. As previously mentioned, a positive AMA is seen in greater than 90% of patients. A liver biopsy will show the gradual damage to, and loss of, bile duct epithelial cells. Biliary epithelial loss is marked by a significant, mixed, inflammatory infiltrate, predominantly in the periductal areas. Granulomas may be seen. PBC is classified into four stages of severity based on histologic findings (Table 31.4).111 The use of ursodeoxycholic acid (UDCA) (13–15 mg/ kg/day) is recommended for patients with PBC. There is ongoing controversy, however, regarding the effect of UDCA on mortality. Taken together, the data suggest that UDCA improves the liver biochemical tests, slows disease progression and possibly improves transplant-free survival. However, data failed to confirm initial reports that suggested UDCA offered relief from fatigue and pruritus. Moreover, UDCA appears to be more effective in patients with early disease. Patients with advanced disease and complications of portal hypertension do not benefit from UDCA, and should be considered for liver transplantation.112–116 The mainstay of therapy, however, is aimed at maintaining nutrition and treating PBC-related complications. These include: pruritus, metabolic bone disease, hypercholesterolemia and xanthomata, malabsorption, fat-soluble vitamin deficiencies, hypothyroidism, and anemia. As the disease progresses, patients will develop malabsorption and fat-soluble vitamin deficiencies. Supplemental vitamin A, vitamin D, and calcium may be needed. Bone densitometry scans should be ordered every two years to screen for early osteopenia. Factors that worsen survival are jaundice, the irreversible loss of bile ducts, cirrhosis, and the coexistence of other autoimmune diseases. In patients with established cirrhosis, it takes an average of 5 years for Table 31.4  Histologic staging of PBC Stage

Histologic findings

I II

Inflammation in the portal space Inflammation extending into the hepatic parenchyma Septal or bridging fibrosis Cirrhosis with regenerative nodules

III IV

Adapted from Lindor, 2007:1525111

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serum bilirubin levels to reach 5 mg/dl. As patients progress and develop portal hypertension and synthetic dysfunction, liver transplantation will need to be considered.

Liver transplantation and surgery Multiple studies have been performed to evaluate donorrecipient factors that impact outcomes after liver transplantation. In addition to donor age, prior liver transplant, and MELD score at transplant, donor gender also appears to affect transplant outcomes. In 1993, Kahn et al. retrospectively analyzed 982 liver transplants and found that the donor-recipient gender combination of female-to-male had a 60% graft failure rate, as opposed to all other combinations, which had a 28–36% graft failure rate.117 In another study, by Marino et al. from the University of Pittsburgh, in which 462 transplants were examined, graft failure was significantly associated with donor age, donor gender, previous liver transplantation, and United Network Organ Sharing (UNOS) status of the recipient.118 Livers from female donors yielded a significantly poorer 2–year graft survival: 55% for female to male, 64% for female to female, 72% for male to male, and 78% for male to female.118 In an analysis of the UNOS database on 14 000 patients undergoing liver transplant from 1992 to 2000, gender mismatched recipients had a 6.9% increased likelihood of graft failure, with the female-to-male donor-recipient combination having the highest graft failure rate of 12.9%.119 These studies are in contrast to a study from Germany where 16 410 liver transplant recipients were analyzed with no difference found in outcomes depending on donor gender.120 Based on this latter study, it appears that donor gender did not affect graft survival in liver transplant recipients in Western Europe, but was relevant in the American population. The reasons for this discordance in results between Western Europe and the United States populations are not clear but may be related to differences in geographic disease prevalence, and/or the greater homogeneity in the European patient populations. It is our opinion that reported gender-related differences are indeed true; however, the mechanisms underlying this disparity remain unclear. Sensitization to biliary epithelium antigens after exposure to donor bile duct minor histocompatibility antigens, such as the male sex-related H-Y antigen, may provide one explanation. On the other hand, the human liver displays gender-related differences, such as increased hepatic content of microsomal oxidative enzymes in males.117 In a murine model of gender-mismatched transplantation, a reduction in the number of estrogen receptors in the livers of gender-mismatched recipients was noted as early as 10 days after transplantation.117 Hence, the decreased graft survival in male recipients of female grafts

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may be due to the reduced number of estrogen receptors in the male recipients. Hepatic surgery induces many stresses on the liver including the total occlusion of blood inflow and a major reduction in liver volume, but in animal models, the female liver is able to tolerate these stresses much better.121,122 Also, in the rat hepatectomy model, males or oophorectomized females were more susceptible to endotoxemia in the early phase after a hepatectomy than in females with ovaries.123 In prospectively collected data from 4218 patients in the intensive care unit, a significantly lower incidence of septic liver failure was observed in females compared to males with severe sepsis and/or septic shock.124 Estrogens are thus felt to play a key role in this gender dimorphic response. There are many mechanisms through which estrogens aid the liver during times of stress. Estrogens are believed to attenuate the activation of Kupffer cells, which are responsible for producing proinflammatory cytokines and hepatocellular dysfunction under conditions of hepatic stress.125,126 Nitric oxide, which protects against hepatic stress by attenuating the vascular sensitivity to vasoconstrictors, is increased in the presence of estrogens.127 In addition to the role nitric oxide plays in opposing vasoconstrictors, estrogens also inhibit endothelin release from endothelial cells in the umbilical vein, which may aid in preventing circulatory failure and vasoconstriction.128 Furthermore, estrogens maintain mesenteric blood flow after partial hepatectomy, which aids in liver regeneration.129 And finally, estrogens are known to inhibit oxygen radical production, thus leading to decreased cellular injury.130 Based on the above reported benefits of estrogens on the liver in the setting of hepatectomy, one may wonder whether estrogens could have a perioperative therapeutic role in enhancing liver regeneration. More studies will certainly need to be conducted before any such recommendation finds its way to medical management algorithms.

Alcoholic Liver Disease (ALD) Alcohol is one of the main causes of end-stage liver disease worldwide and alcoholic liver disease is the second most common reason for liver transplantation in the United States. Alcohol abuse and alcoholism are more common in men, but up to 33% of alcohol abusers in the United States are women.131 On average, women consume less alcohol than men, yet the drinking duration appears to be similar in both sexes.132 Although the majority of patients with ALD are male, females appear to be more susceptible to the toxic effects of alcohol, as they have a significantly higher risk of developing cirrhosis at any level of alcohol intake. In a 12–year study of 13 285 men and women in Denmark, women had

a higher risk of developing cirrhosis then men for any given level of alcohol intake.133 In subjects consuming 28–41 drinks/week (336–492 g of ethanol), men were found to have one-third the risk of developing cirrhosis when compared with women: a relative risk of 17 and 7, respectively. In fact, the threshold for developing alcoholic cirrhosis is lower in women than in men; men require greater than 40–80 g/ day of alcohol to increase the risk of developing cirrhosis, women require only 20–60 g/day of alcohol. Thus, women abusing alcohol tend to have a more rapid development of liver disease than men, as well as a more significant progression of liver disease once alcoholic hepatitis develops.134,135 There are many theories for the mechanisms underlying this more rapid progression of ALD in women. The first is the difference in ethanol pharmacokinetics between sexes. Following the intake of equal amounts of alcohol, women achieve a higher blood level than men. This may be attributed to the lower total body water, lower weight, and higher body fat mass. In addition, the increased risk of women developing ALD has been attributed to lower gastric alcohol dehydrogenase (ADH) activity. This latter has not been uniformly demonstrated among studies, however. Estrogens and androgens have been implicated in the gender differences of ALD: oophorectomized ethanol-fed rats had lower serum ALT levels, and fewer necrotic hepatocytes, than their counterparts on estrogen replacement, or those with ovaries.136 Estrogens could contribute to ethanol-induced liver injury by increasing gut permeability and portal endotoxin levels, and amplifying the Kupffer cell sensitivity and response to endotoxemia through increased expression of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-).136 Differences in alcohol elimination rates between women and men have also been implicated.137,138 Furthermore, the bioavailability of alcohol appears to be increased in women due to a decrease in gastric oxidation of alcohol.139 Taken together, the data indicate that the mechanisms that underlie the gender-related difference in alcohol-induced liver damage involve a variety of factors that include alcohol pharmacokinetics and metabolism, and the estrogen-dependent response to gut-derived endotoxin in the liver.

References 1. Ch’ng CL, et al. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 2002;51(6):876–80. 2. Levin ER, et al. Role of vascular endothelial cell growth factor in Ovarian Hyperstimulation Syndrome. J Clin Invest 1998;102(11):1978–85. 3. Schenker JG. Clinical aspects of ovarian hyperstimulation syndrome. Eur J Obstet Gynecol Reprod Biol 1999;85(1): 13–20. 4. Fabregues F, et al. Ascites and liver test abnormalities during severe ovarian hyperstimulation syndrome. Am J Gastroenterol 1999;94(4):994–99.

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5. Younis JS, et al. Transient liver function tests abnormalities in ovarian hyperstimulation syndrome. Fertil Steril 1988;50(1):176–78. 6. Sueldo CE, et al. Liver dysfunction in ovarian hyperstimulation syndrome. A case report. J Reprod Med 1988;33(4):387–90. 7. Ryley NG, et al. Liver abnormality in ovarian hyperstimulation syndrome. Hum Reprod 1990;5(8):938–43. 8. Balasch J, et al. Acute prerenal failure and liver dysfunction in a patient with severe ovarian hyperstimulation syndrome. Hum Reprod 1990;5(3):348–51. 9. Wakim AN, Fox SD. Elevated liver function tests in a case of moderate ovarian hyperstimulation syndrome. Hum Reprod 1996;11(3):588–89. 10. Simpson KJ, et al. Cytokines and the liver. J Hepatol 1997;27(6):1120–32. 11. Abell TL, Riely CA. Hyperemesis gravidarum. Gastroenterol Clin North Am 1992;21(4):835–49. 12. Larrey D, et al. Recurrent jaundice caused by recurrent hyperemesis gravidarum. Gut 1984;25(12):1414–15. 13. Zecca E, et al. Intrahepatic cholestasis of pregnancy and neonatal respiratory distress syndrome. Pediatrics 2006;117(5):1669–72. 14. Bacq Y, et al. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 1997;26(2):358–64. 15. Williamson C, et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004;111(7):676–81. 16. Germain AM, et al. Intrahepatic cholestasis of pregnancy: an intriguing pregnancy-specific disorder. J Soc Gynecol Invest 2002;9(1):10–14. 17. Reyes H, et al. HLA in Chileans with intrahepatic cholestasis of pregnancy. Hepatology 1982;2(4):463–66. 18. Schneider G, et al. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology 2007;45(1):150–58. 19. Reyes H, et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med 1978;88(4):487–93. 20. Haemmerli UP, Wyss HI. Recurrent intrahepatic cholestasis of pregnancy. Report of six cases, and review of the literature. Medicine (Baltimore) 1967;46(4):299–321. 21. Heikkinen J, et al. Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine. Eur J Obstet Gynecol Reprod Biol 1982;14(3):153–62. 22. Laatikainen T. Effect of cholestyramine and phenobarbital on pruritus and serum bile acid levels in cholestasis of pregnancy. Am J Obstet Gynecol 1978;132(5):501–6. 23. Reyes H, Ribalta J, Gonzalez-Ceron M. Idiopathic cholestasis of pregnancy in a large kindred. Gut 1976;17(9):709–13. 24. Palma J, et al. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992;15(6):1043–47. 25. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 2004;40(2):467–74. 26. Castro MA, et al. Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J Obstet Gynecol 1999;181(2):389–95.

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27. Pockros PJ, Peters RL, Reynolds TB. Idiopathic fatty liver of pregnancy: findings in ten cases. Medicine (Baltimore) 1984;63(1):1–11. 28. Reyes H, et al. Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients. Gut 1994;35(1):101–6. 29. Treem WR, et al. Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Gastroenterol 1996;91(11):2293–300. 30. Sims HF, et al. The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proc Natl Acad Sci U S A 1995;92(3):841–45. 31. Yang Z, et al. Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease. JAMA 2002;288(17):2163–66. 32. Innes AM, et al. Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy. Pediatr Res 2000;47(1):43–45. 33. Grunfeld JP, Pertuiset N. Acute renal failure in pregnancy. Am J Kidney Dis 1987;9(4):359–62. 34. Castro MA, et al. Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. Am J Obstet Gynecol 1996;174(1 Pt 1):211–16. 35. Bydder GM, et al. Accuracy of computed tomography in diagnosis of fatty liver. Br Med J 1980;281(6247):1042. 36. Campillo B, et al. Ultrasonography in acute fatty liver of pregnancy. Ann Intern Med 1986;105(3):383–84. 37. Farine D, et al. Magnetic resonance imaging and computed tomography scan for the diagnosis of acute fatty liver of pregnancy. Am J Perinatol 1990;7(4):316–18. 38. McKee CM, et al. Acute fatty liver of pregnancy and diagnosis by computed tomography. Br Med J (Clin Res Ed) 1986;292(6516):291–92. 39. Usta IM, et al. Acute fatty liver of pregnancy: an experience in the diagnosis and management of fourteen cases. Am J Obstet Gynecol 1994;171(5):1342–47. 40. Moise KJ Jr., Shah DM. Acute fatty liver of pregnancy: etiology of fetal distress and fetal wastage. Obstet Gynecol 1987;69(3 Pt 2):482–85. 41. Sibai BM, et al. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol 1993;169(4):1000–6. 42. Ibdah JA, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med 1999;340(22):1723–31. 43. Martin JN Jr., et al. Pregnancy complicated by preeclampsia-eclampsia with the syndrome of hemolysis, elevated liver enzymes and low platelet count: how rapid is postpartum recovery? Obstet Gynecol 1990;76(5 Pt 1):737–41. 44. Greenstein D, Henderson JM, Boyer TD. Liver hemorrhage: recurrent episodes during pregnancy complicated by pre­ eclampsia. Gastroenterology 1994;106(6):1668–71. 45. Manas KJ, et al. Hepatic hemorrhage without rupture in preeclampsia. N Engl J Med 1985;312(7):424–26. 46. Arias F, Mancilla-Jimenez R. Hepatic fibrinogen deposits in pre-eclampsia. Immunofluorescent evidence. N Engl J Med 1976;295(11):578–82.

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s e c t i o n 5     Gastroenterology l

47. Mishra L, Seeff LB. Viral hepatitis, A though E, complicating pregnancy. Gastroenterol Clin North Am 1992;21(4): 873–87. 48. Rustgi VK, Hoofnagle JH. Viral hepatitis during pregnancy. Semin Liver Dis 1987;7(1):40–46. 49. Khuroo MS, et al. Acute sporadic non-A, non-B hepatitis in India. Am J Epidemiol 1983;118(3):360–64. 50. Tsega E, et al. Acute sporadic viral hepatitis in Ethiopia: causes, risk factors, and effects on pregnancy. Clin Infect Dis 1992;14(4):961–65. 51. Khuroo MS, Kamili S. Aetiology and prognostic factors in acute liver failure in India. J Viral Hepat 2003;10(3):224–31. 52. Nouasria B, et al. Fulminant viral hepatitis and pregnancy in Algeria and France. Ann Trop Med Parasitol 1986;80(6):623–29. 53. Khuroo MS, Kamili S, Jameel S. Vertical transmission of hepatitis E virus. Lancet 1995;345(8956):1025–26. 54. Meeusen EN, Bischof RJ, Lee CS. Comparative T-cell responses during pregnancy in large animals and humans. Am J Reprod Immunol 2001;46(2):169–79. 55. Jilani N, et al. Hepatitis E virus infection and fulminant hepatic failure during pregnancy. J Gastroenterol Hepatol 2007;22(5):676–82. 56. Boll G, Reimann J. Oestrogen treatment depletes extrathymic T cells from intestinal lymphoid tissues. Scand J Immunol 1996;43(3):345–50. 57. Rijhsinghani AG, et al. Estrogen blocks early T cell development in the thymus. Am J Reprod Immunol 1996;36(5):269–77. 58. Tibbetts TA, et al. Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility. Proc Natl Acad Sci U S A 1999;96(21):12021–26. 59. Dudley DJ, et al. Adaptive immune responses during murine pregnancy: pregnancy-induced regulation of lymphokine production by activated T lymphocytes. Am J Obstet Gynecol 1993;168(4):1155–63. 60. Arankalle VA, et al. Role of immune serum globulins in pregnant women during an epidemic of hepatitis E. J Viral Hepat 1998;5(3):199–204. 61. Ponta H, et al. Hormonal regulation of cell surface expression of the major histocompatibility antigen H-2Ld in transfected cells. EMBO J 1985;4(13A):3447–53. 62. Basso L, et al. A study of cholelithiasis during pregnancy and its relationship with age, parity, menarche, breast-feeding, dysmenorrhea, oral contraception and a maternal history of cholelithiasis. Surg Gynecol Obstet 1992;175(1):41–46. 63. Maher JE, et al. Albumin levels in pregnancy: a hypothesis – decreased levels of albumin are related to increased levels of alpha-fetoprotein. Early Hum Dev 1993;34(3):209–15. 64. Bacq Y, et al. Liver function tests in normal pregnancy: a prospective study of 103 pregnant women and 103 matched controls. Hepatology 1996;23(5):1030–34. 65. Ueland K, Novy MJ, Metcalfe J. Cardiorespiratory responses to pregnancy and exercise in normal women and patients with heart disease. Am J Obstet Gynecol 1973;115(1):4–10. 66. Borhanmanesh F, Haghighi P. Pregnancy in patients with cirrhosis of the liver. Obstet Gynecol 1970;36(2):315–24. 67. Britton RC. Pregnancy and esophageal varices. Am J Surg 1982;143(4):421–25. 68. Green P, Rubin L. Amenorrhea as a manifestation of chronic liver disease. Am J Obstet Gynecol 1959;78(1):141–46.

69. Varma RR, et al. Pregnancy in cirrhotic and noncirrhotic portal hypertension. Obstet Gynecol 1977;50(2):217–22. 70. Whelton MJ, Sherlock S. Pregnancy in patients with hepatic cirrhosis. Management and outcome. Lancet 1968;2(7576): 995–99. 71. Walcott WO, et al. Successful pregnancy in a liver transplant patient. Am J Obstet Gynecol 1978;132(3):340–41. 72. Scantlebury V, et al. Childbearing after liver transplantation. Transplantation 1990;49(2):317–21. 73. Radomski JS, et al. National Transplantation Pregnancy Registry: analysis of pregnancy outcomes in female liver transplant recipients. Liver Transpl Surg 1995;1(5):281–84. 74. Jain A, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997;64(4):559–65. 75. Shimizu I, Ito S. Protection of estrogens against the progression of chronic liver disease. Hepatol Res 2007;37(4):239–47. 76. Shimizu I. Impact of oestrogens on the progression of liver disease. Liver Int 2003;23(1):63–69. 77. Everson GT, McKinley C, Kern F Jr.. Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism. J Clin Invest 1991;87(1):237–46. 78. Edmondson HA, Henderson B, Benton B. Liver-cell adenomas associated with use of oral contraceptives. N Engl J Med 1976;294(9):470–72. 79. Vetelainen R, et al. Liver adenomatosis: re-evaluation of aetiology and management. Liver Int 2008;28(4):499–508. 80. Foster JH, Berman MM. The malignant transformation of liver cell adenomas. Arch Surg 1994;129(7):712–17. 81. Scalori A, et al. Risk factors for focal nodular hyperplasia of the liver: an Italian case-control study. Am J Gastroenterol 2002;97(9):2371–73. 82. Mathieu D, et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 2000;118(3):560–64. 83. Murad SD, et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd–Chiari syndrome. Hepatology 2004;39(2):500–8. 84. Valla D, et al. Risk of hepatic vein thrombosis in relation to recent use of oral contraceptives. A case–control study. Gastroenterology 1986;90(4):807–11. 85. Ecker JA, McKittrick JE. Failing RM. Thrombosis of the hepatic veins. ‘The Budd–Chiari syndrome; – a possible link between oral contraceptives and thrombosis formation. Am J Gastroenterol 1966;45(6):429–43. 86. Sholar PW, Bell WE. Thrombolytic therapy for inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria. Ann Intern Med 1985;103(4):539–41. 87. Frank JW, Kamath PS, Stanson AW. Budd–Chiari syndrome: early intervention with angioplasty and thrombolytic therapy. Mayo Clin Proc 1994;69(9):877–81. 88. Raju GS, et al. Thrombolysis for acute Budd–Chiari syndrome: case report and literature review. Am J Gastroenterol 1996;91(6):1262–63. 89. Henderson JM, et al. Surgical options, hematologic evaluation, and pathologic changes in Budd–Chiari syndrome. Am J Surg 1996;159(1):41–48, discussion 48-50. 90. Ganguli SC, et al. Budd–Chiari syndrome in patients with hematological disease: a therapeutic challenge. Hepatology 1998;27(4):1157–61.

C h a p t e r 3 1     Liver Disease in Women l

91. Orloff MJ, et al. A 27-year experience with surgical treatment of Budd–Chiari syndrome. Ann Surg 2000;232(3):340–52. 92. Melear JM, et al. Hematologic aspects of liver transplantation for Budd–Chiari syndrome with special reference to myeloproliferative disorders. Transplantation 2002;74(8):1090–95. 93. Bahr MJ, et al. Recurrence of Budd–Chiari syndrome after liver transplantation in paroxysmal nocturnal hemoglobinuria. Transpl Int 2003;16(12):890–94. 94. Srinivasan P, et al. Liver transplantation for Budd–Chiari syndrome. Transplantation 2002;73(6):973–77. 95. Czaja AJ. Understanding the pathogenesis of autoimmune hepatitis. Am J Gastroenterol 2001;96(4):1224–31. 96. Verma S, Torbenson M, Thuluvath PJ. The impact of ethnicity on the natural history of autoimmune hepatitis. Hepatology 2007;46(6):1828–35. 97. Fried MW, et al. Clinical and serological differentiation of autoimmune and hepatitis C virus-related chronic hepatitis. Dig Dis Sci 1993;38(4):631–36. 98. Manns M, et al. Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1987;1(8528):292–94. 99. Stechemesser E, Klein R, Berg PA. Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis. Hepatology 1993;18(1):1–9. 100. Czaja AJ, Carpenter HA, Manns MP. Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis. Gastroenterology 1993;105(5):1522–28. 101. Kanzler S, et al. Clinical significance of autoantibodies to soluble liver antigen in autoimmune hepatitis. J Hepatol 1999;31(4):635–40. 102. Alvarez F, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31(5):929–38. 103. Czaja AJ, Menon KV, Carpenter HA. Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis. Hepatology 2002;35(4):890–97. 104. Reich DJ, et al. Liver transplantation for autoimmune hepatitis. Hepatology 2000;32(4 Pt 1):693–700. 105. Heffron TG, et al. Autoimmune hepatitis following liver transplantation: relationship to recurrent disease and steroid weaning. Transplant Proc 2002;34(8):3311–12. 106. Salcedo M, et al. Response to steroids in de novo autoimmune hepatitis after liver transplantation. Hepatology 2002;35(2):349–56. 107. Narumi S, et al. Liver transplantation for autoimmune hepatitis: rejection and recurrence. Transplant Proc 1999;31(5): 1955–56. 108. Gonzalez-Koch A, et al. Recurrent autoimmune hepatitis after orthotopic liver transplantation. Liver Transpl 2001; 7(4):302–10. 109. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med 2005;353(12):1261–73. 110. Prince M, et al. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 2002;123(4):1044–51. 111. Lindor K. Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. N Engl J Med 2007;357(15):1524–29.

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112. Lindor KD, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994;106(5): 1284–90. 113. Heathcote EJ, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994;19(5):1149–56. 114. Combes B, et al. Prolonged follow-up of patients in the U.S. multicenter trial of ursodeoxycholic acid for primary biliary cirrhosis. Am J Gastroenterol 2004;99(2):264–68. 115. Poupon RE, et al. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med 1991;324(22):1548–54. 116. Pares A, et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol 2000;32(4):561–66. 117. Kahn D, et al. Gender of donor influences outcome after orthotopic liver transplantation in adults. Dig Dis Sci 1993;38(8):1485–88. 118. Marino IR, et al. Effect of donor age and sex on the outcome of liver transplantation. Hepatology 1995;22(6):1754–62. 119. Rustgi VK, et al. Role of gender and race mismatch and graft failure in patients undergoing liver transplantation. Liver Transpl 2002;8(6):514–18. 120. Zeier M, et al. The effect of donor gender on graft survival. J Am Soc Nephrol 2002;13(10):2570–76. 121. Harada H, et al. Selected contribution: effects of gender on reduced-size liver ischemia and reperfusion injury. J Appl Physiol 2001;91(6):2816–22. 122. Jarrar D, et al. Insight into the mechanism by which estradiol improves organ functions after trauma-hemorrhage. Surgery 2000;128(2):246–2452. 123. Inaba K, et al. Sexual dimorphism in endotoxin susceptibility after partial hepatectomy in rats. J Hepatol 2005;42(5):719–27. 124. Wichmann MW, et al. Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Intensive Care Med 2000;26(2):167–72. 125. O’Neill PJ, et al. Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation. Shock 1994;1(1):43–47. 126. Koo DJ, Chaudry IH, Wang P. Kupffer cells are responsible for producing inflammatory cytokines and hepatocellular dysfunction during early sepsis. J Surg Res 1999;83(2):151–57. 127. Ashburn JH, et al. Remote trauma sensitizes hepatic microcirculation to endothelin via caveolin inhibition of eNOS activity. Shock 2004;22(2):120–30. 128. Bilsel AS, et al. Long-term effect of 17beta-estradiol and thrombin on tissue factor pathway inhibitor release from HUVEC. Thromb Res 2000;99(2):173–78. 129. Kawai T, et al. Does estrogen contribute to the hepatic regeneration following portal branch ligation in rats?. Am J Physiol Gastrointest Liver Physiol 2007;292(2): G582–89. 130. Arnal JF, et al. Ethinylestradiol does not enhance the expression of nitric oxide synthase in bovine endothelial cells but increases the release of bioactive nitric oxide by inhibiting

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superoxide anion production. Proc Natl Acad Sci U S A 1996;93(9):4108–13. 131. Cyr MG, McGarry KA. Alcohol use disorders in women. Screening methods and approaches to treatment. Postgrad Med 2002;112(6):31–32, 39–40, 43–7. 132. Bellentani S, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut 1997;41(6):845–50. 133. Becker U, et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology 1996;23(5):1025–29. 134. Pares A, et al. Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage. J Hepatol 1986;2(1):33–42.

135. Schenker S. Medical consequences of alcohol abuse: is gender a factor?. Alcohol Clin Exp Res 1997;21(1):179–81. 136. Yin M, et al. Estrogen is involved in early alcohol-induced liver injury in a rat enteral feeding model. Hepatology 2000;31(1):117–23. 137. Ammon E, et al. Disposition and first-pass metabolism of ethanol in humans: is it gastric or hepatic and does it depend on gender?. Clin Pharmacol Ther 1996;59(5):503–13. 138. Mishra L, et al. More rapid elimination of alcohol in women as compared to their male siblings. Alcohol Clin Exp Res 1989;13(6):752–54. 139. Frezza M, et al. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med 1990;322(2):95–99.

Section 6

Reproductive Biology

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Introduction

Lauri J. Romanzi Unlike other areas of adult human physiology, where the 70 kg man served until most recently as the gold-standard paradigm for all medical research, the functions and dysfunctions specific to the prostate, uterus, testicles, ovaries, and external genitalia share a historical apartheid regarding clinical care and grant-based clinical and basic science research, not to mention insurance reimbursement rates. No matter which of these body parts one considers, the clinical dichotomy stands in clear relief. Take as example chronic pelvic pain, where the non-bacterial prostatitis suffered by men is only recently demonstrated to be of arguably similar etiology to the vestibulitis and interstitial cystitis chronic pelvic pain conditions afflicting women. Or contraception, where the onus skews heavily toward the female, whose reproductive physiology renders itself more amenable, allegedly, to contraceptive control. On the international horizon, however, we find a growing body of male-based contraceptive data that warrants our attention and professional support.

Separate and not-so-equal economies of scale apply to sexual dysfunction no less, where that of men recently spawned a globally lucrative pharmacotherapeutic revolution in a North American setting where many women continue to pay out of pocket for contraception before menopause and for vaginal-dose estrogen after menopause, and where female-dose testosterone therapies can only be had ‘across the pond,’ further perpetuating cultural gender bias in which sexual gratification is the birthright of one gender and the holy grail of the other. Contributing colleagues, many of whom I have had the honor to work with in various circumstances, have labored diligently to illuminate the latest concepts, basic science, and translational data in their respective areas of focus. I trust the reader’s experience will reflect the collective wisdom and inspiration herein. The chapters of this section update a wide range of gender-specific pelvic conditions, separated out in each area except the bladder, that great equalizer of geriatric medicine, where one man’s prostate-related urgency is another woman’s overactive bladder, and the incontinence garment industry now markets gender-specific diapers.

Chapter

32

Gender Differences in Irritable Bowel Syndrome Octavia Pickett-Blakely, Linda A. Lee, and Gerald Mullin The Johns Hopkins University School of Medicine, Department of Gastroenterology and Hepatology, Baltimore, MD, USA

Introduction

Table 32.1  Rome III Criteria*: Irritable bowel syndrome  Recurrent abdominal pain or discomfort† at least 3 days per month in the last 3 months associated with two or more of the following:

l

Irritable bowel syndrome (IBS) is a common digestive dis­ order characterized by abdominal discomfort and altered bowel habits. Although the mechanisms are not entirely clear, IBS disproportionately affects women and men at a ratio of over 2:1. The complex interplay between IBS, sex, and gender has intrigued the medical community for dec­ ades, giving rise to many theories why IBS affects women and men differently.1 Some have proposed that the greater prevalence of IBS in women merely reflects an under­ estimation of prevalence in men due to symptom underreporting.2 Others have implicated psychosocial, anatomical, and biochemical factors such as a history of personal abuse, gastrointestinal tract anatomic or physiologic differences in disease expression, and symptom perception. This chapter explores the multiple possibilities why IBS is more com­ monly diagnosed in women. IBS is a clinical diagnosis based on fulfillment of the Rome III criteria (Table 32.1), which were originally established for investigational purposes. Depending on the predominant symptom, patients are categorized as constipation predomi­ nant (IBS-C), diarrhea predominant (IBS-D) or mixed.1 Each group is equally represented among patients with IBS, although differences exist between women and men in the clinical manifestations of IBS. Constipation is more com­ mon in women as are extracolonic symptoms. IBS symp­ toms are thought to occur as a result of dysregulation of the brain–gut axis, although a single underlying etiology of the disorder remains elusive. Treatment of IBS is individual­ ized and based on the predominant symptom(s). IBS can present as a single disorder, or coexist with gas­ trointestinal diseases such as inflammatory bowel disease or celiac disease.3–5 Patients with IBS are more likely to have extraintestinal co-morbid conditions like psychiatric illness, Principles of Gender-Specific Medicine

1. Improvement with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool Other symptoms that are not essential but support the diagnosis of IBS: l  Abnormal stool frequency (greater than 3 bowel movements/day or less than 3 bowel movements/week) l Abnormal stool form (lumpy/hard or loose/watery stool) l  Abnormal stool passage (straining, urgency, or feeling of incomplete bowel movement) l Passage of mucus l Bloating or feeling of abdominal distension l

* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. †’Discomfort’ means an uncomfortable sensation not described as pain.

chronic fatigue syndrome, fibromyalgia, migraines, cystitis and pelvic pain.6–8

Epidemiology IBS is the most frequently diagnosed gastrointestinal con­ dition with prevalence rates of 10–15%.9 Symptoms of IBS frequently lead to office visits with primary care physicians and specialists. In 2002, there were over 2 000 000 clinic vis­ its scheduled for IBS.10 Symptoms can be mild or severe, and can fluctuate in frequency and intensity. Quality of life and work productivity are adversely affected by IBS symptoms, 347

Copyright 2010 20 , Elsevier Inc. All rights reserved.

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more so in women who tend to report a significantly poorer health-related quality of life than men when survey tools such as the SF-36 and IBSQOL are used.11–13 Studies have repeatedly demonstrated that functional GI disorders perturb quality of life more significantly than organic GI disorders and other chronic diseases such as rheumatoid arthritis.14,15 IBS also has a significant economic impact. United States IBS-related costs were $1.35 billion in 2003, not including prescription and over-the-counter medications or supplements utilized by patients.16–18 IBS continues to be the second most common reason for work absenteeism.19 A survey of over 5000 persons from US households found that IBS patients missed an average of 13.4 days per year from work or school due to illness, compared to 4.9 days in sub­ jects without a gastrointestinal illness.20 Newcomer et al. reported that although the overall rate of unplanned work absence was low following routine colonoscopy, young, female patients were more likely to have an unplanned work absence due to bloating, fatigue, and sleepiness after the procedure.21

Pathophysiology The pathophysiology of IBS is complex and still poorly understood, but visceral hypersensitivity, disordered central pain processing, small bowel bacterial overgrowth, and increased intestinal permeability have each been implicated as a contributing factor to IBS. Of these possible mech­ anisms, gender differences have only been reported for vis­ ceral hypersensitivity and central pain processing. Whether anatomic or physiologic differences between the sexes account for the female predominance observed with IBS is unknown.

Visceral Hypersensitivity Visceral hypersensitivity is defined as having a low thresh­ old to painful stimuli arising from the gastrointestinal tract. In research settings, this has traditionally been assessed by measuring the pain response to inflation of a balloon within the digestive tract. IBS patients tend to experience more pain compared to controls for a given inflation volume. This was first documented in 1973 when inflation of a sigmoid balloon to 60 ml caused pain in 6% of controls but in 55% of patients with IBS.22 Luminal distention, triggered postprandially and exacerbated by gas-producing foods, may lead to the enhanced perception of bloating and abdominal pain in those with IBS. Why women are more often affected by IBS might be attributed to sex-related differences in visceral sensitivity, but here the data are conflicting. For example, although men and women with IBS share heightened rectal sensitivity as measured by barostat when compared to control subjects,

some studies have found no differences in the degree of hypersensitivity between men and women with IBS.23 Others have reported women with IBS have increased rectal hypersensitivity compared to men with IBS.24 Increased pain perception could be mediated at the level of extrinsic gut afferent nerves responsible for sensory percep­ tion as well as cortical processing that affects pain inhibition. Visceral hypersensitivity may be mediated by the neurotrans­ mitter, serotonin (also known as 5-hydroxytryptamine or 5HT), which is expressed in the gut and brain. Ninety-five percent of the serotonin in the human body is found in the gastrointestinal tract, mostly produced by the enterochro­ maffin cells of gastrointestinal epithelium.25 Enterochromaffin cells act as sensory transducers that release 5HT after meals. 5HT binds 5HT4 receptors present on visceral motor afferent nerves, which control gastrointestinal reflexes that govern intestinal motility and secretion. 5HT also regulates visceral sensation by binding 5HT3 receptors present on extrinsic gut afferent neurons, that are responsible for trans­ mitting sensory signals from gut to cortical regions.26 The amount of 5HT that is functionally active at any one time is determined by the rate of production by enterochromaf­ fin cells and the rate of re-uptake into mucosal enterocytes via serotonin reuptake transporters (SERT), where it is then catabolized. It has been postulated that defects in 5HT pro­ duction, SERT re-uptake, or metabolism can affect the pool of 5HT available and lead to alterations in visceral motility, secretion, and sensation. Increased 5HT bioavailability has been implicated in IBS-D, whereas reduced 5HT bioavail­ ability is associated with IBS-C.27,28 Data supporting a critical role of intestinal serotonin signaling in the pathogenesis of IBS have emerged from both animal and human studies. Post-prandial plasma 5HT levels are lower in individuals with IBS-C and higher in IBS-D patients compared to controls.27,28 A transgenic, SERT gene knockout mouse demonstrates increased rectal transit time resulting in wetter stools.29 However, a recent study of IBS-D and IBS-C patients revealed no differences in expression of SERT in colonic mucosa. Instead, expres­ sion of p11, a molecule that increases serotonergic receptor function (5HT1B), was increased in IBS.30 Identification of additional factors regulating 5HT signaling may lead to the development of novel therapeutic agents. Studies on post-infectious IBS (PI-IBS) also support the role of serotonin in IBS. Up to 17% of individuals with IBS report the first onset of IBS symptoms following a bout of infectious colitis.31 Predictors of developing PI-IBS include female gender, prolonged diarrhea (greater than 15 days), psychological factors, and severity of initial illness.32 Why women would be more prone to PI-IBS is unknown. PI-IBS has been reported following outbreaks of giardiasis,2 sal­ monellosis,32 shigellosis,23,33,34 and Campylobacter jejuni infection.35 In a rodent model of 2,4,6-trinitrobenzene sul­ fonic acid (TNBS) induced colitis, 5HT gut mucosal content, the number of 5HT-immunoreactive cells, and the proportion

C h a p t e r 3 2     Gender Differences in Irritable Bowel Syndrome l

of epithelial cells that were 5HT-immunoreactive was twofold higher than in control animals.36 Increased levels of enterochromaffin cells and 5HT levels have also been iden­ tified in the rectal mucosa of individuals suffering from PI-IBS.31,35

Central Pain Processing In addition to abnormalities in serotonin processing and function, alterations in central processing of pain signaling have now been demonstrated using positron emission tom­ ography (PET) and cortical functional magnetic resonance imaging (fMRI). Cortical fMRI indirectly measures cogni­ tive activity and neuronal activation by assessing changes in oxyhemoglobin that occur as a result of fluctuations in cerebral blood flow.37 fMRI has demonstrated that a pain­ ful rectal stimulus activates the anterior cingulate cortex (ACC), the central nervous system pain center, to a greater degree in IBS patients than controls.38 A small study of non-constipation IBS patients using positive emission tomography demonstrated that 5HT synthesis was great­ est in the female IBS patients in the right medial temporal gyrus (multimodal sensory association cortex) compared with female controls.39 Although these results are provoc­ ative, a concern raised about interpretation of IBS fMRI studies is that anticipation of pain and somatization may contribute to the patterns of neuronal activation seen, so that alterations in cognitive response rather than visceral hypersensitivity may contribute to the difference in fMRI results.40,41 Male and female patients with IBS differ in their cen­ tral responses to painful visceral stimuli.42 In response to a visceral stimulus, women showed greater activation in the ventromedial prefrontal cortex, right anterior cingulate cor­ tex, and left amygdala, whereas men showed greater activa­ tion of the right dorsolateral prefrontal cortex, insula, and dorsal pons/periaqueductal gray. Thus differences in brain activation patterns may partly explain gender differences in susceptibility and treatment of IBS.

Small Intestinal Bacterial Overgrowth Most studies have demonstrated 10% of IBS patients have small intestinal bacterial overgrowth (SIBO). Antibiotic therapy may improve IBS symptoms in a subset of IBS patients with SIBO.43,44 Impaired intestinal motility or diminished gastric acid secretion is a risk factor for the development of SIBO. Pimentel et al. demonstrated that patients with IBS and SIBO have reduced phase III of the migrating motor complex, the component of fasting gut motility responsible for clearing the small intestinal lumen of contents from the last meal.45 SIBO causes bloating, cramping, and diarrhea, which in the setting of visceral hyperalgesia, can lead to significant distress. These symptoms

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arise from malabsorption of ingested fat, protein, carbohy­ drates, and vitamins as a result of bacterial utilization of these macro- and micronutrients. Treatment of IBS symp­ toms in those with documented SIBO with antibiotics and/or probiotics in an effort to restore the equilibrium of enteric flora has yielded promising results.43,46,47

Increased Intestinal Permeability Post-infectious IBS (PI-IBS) may result from an increase in intestinal permeability as a result of inflammation triggered by infection. Intestinal permeability is detected non-invasively by measuring urinary excretion of orally consumed probe mol­ ecules, such as mannitol and lactulose.48,49 Increased intes­ tinal permeability is more frequently encoun­tered among patients with IBS-D and PI-IBS, particularly in those with a history of atopy.50 Although IBS has been classified as a functional disorder not typically associated with anatomic defects, an inflammatory component among those with PIIBS or IBS-D has been reported. An increased number of activated T lymphocytes and mast cells have been noted in the colonic51 and jejunal mucosa52 of patients with IBS-D, and the presence of these mast cells near enteric nerves may account for visceral pain or sensitivity. Increased intestinal permeability may also be related to elevated proinflamma­ tory cytokine production noted in peripheral blood mono­ cytes of IBS-D patients.53

Sex Differences in Intestinal Anatomy Anatomic differences of the colon of women and men54 may play a role in IBS symptom expression. The median colonic length is 155 cm in women and 145 cm in men with the transverse colon length accounting for most of this dif­ ference.55 In addition, the transverse colon reaches the true pelvis in 62% of women and only 26% of men. These ana­ tomic variations may partially explain why colonoscopy is perceived as more technically challenging in women.56,57 The transverse colon is not a fixed retroperitoneal structure, and thus, is more prone to redundancy. Whether a long, redundant colon, or ‘dolichocolon,’ is associated with IBS is unknown; however, case series have linked constipation and abdominal distress from bloating to dolichocolon.58,59 Intuitively, one might expect that a redundant colon might predispose patients to constipation and stasis, which may exacerbate abdominal pain and/or bloating. One might also speculate that a transverse colon that reaches the pelvis may relate to exacerbation of IBS symptoms during menses. The exacerbation of IBS symptoms with menses is a com­ mon clinical phenomenon.60 The mechanisms are likely multifactorial, including increased visceral hypersensitiv­ ity, anatomic proximity of the bowel and uterus, and the involvement of estrogen and progesterone. Increased rectal sensitivity in response to rectal balloon distention was dem­ onstrated during menses in a small study of 29 women.60

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Patients with dysmenorrhea and premenstrual syndrome also have increased IBS symptoms.61

Sex-related Differences in Gastrointestinal Motility Differences have been demonstrated in gastrointestinal motil­ ity, including impaired gallbladder contraction, delayed colonic transit and gastric emptying in women. A com­ parison of anorectal function in 15 healthy men (mean age, 41  3 years) and 20 women (mean age, 43  2 years, 5 nulliparous) found that healthy men had higher minimum and maximum basal anal sphincter pressures, higher anal pressures during maximum conscious sphincter contrac­ tion, lower rectal volumes required to cause an anal relaxa­ tion, and higher volumes to induce a desire to defecate.62 In addition, significantly fewer men experienced pain during a 1-minute 100 ml rectal distention (using syringe inflation) compared to women (13% vs. 55%). These results suggest that healthy men have stronger anal sphincter pressures and that women have either lower rectal compliance or increased rectal sensitivity. Symptoms of constipation may be associated with slow colonic transit in tertiary referral patients.63,64 Women, par­ ticularly premenopausal women, experience constipation more often than men.65 This could partly be explained by the prolonged mean colonic transit that has been shown in some studies.25,66 Rao et al. utilized ambulatory 24-hour colonic manometry to demonstrate significantly less pres­ sure activity in the transverse and descending colon during daytime hours in women compared to men.67 Unfortunately, there are no published studies comparing colonic motility in women and men with IBS to substantiate this theory. Some investigations have focused on female sex hor­ mones as a potential cause for constipation predominance in women. The rationale for examining the effect of female sex hormones is that symptoms of constipation often begin at menarche,68 and a large number of women experience a change in bowel habits (looser consistency) with onset of menses when progesterone and estradiol levels dramatically fall, thus leading to menstruation.69 Moreover, gastrointes­ tinal complaints during the menstrual cycle can be related to actual motor alterations in the gastrointestinal tract or a change in the perception of colonic motor events. As pre­ viously mentioned, approximately 35% of women without IBS and up to 50% with IBS report greater gastrointestinal symptoms at the time of their menstrual period.61 Women also develop lower gastrointestinal symptoms associated with hysterectomy.70 Pregnancy, a time when progesterone and estradiol levels are significantly elevated, is commonly complicated by con­ stipation.71 However, there are several other changes asso­ ciated with pregnancy such as the presence of an enlarging uterus. Female sex hormones also induce changes in the soft tissues of the pelvic floor in rats, apart from changes in

function that might occur in the colon.72 Progesterone and estradiol receptors have been found in normal colonic tis­ sue.73 At the tissue level, sex hormones inhibit muscle con­ tractility in a variety of sites, including uterus, gallbladder, lower esophageal sphincter, and colon.74,75

Risk factors and co-morbidities Psychosocial Predictors of IBS Many studies have linked IBS to a personal history of abuse.76–80 For the purpose of this discussion, abuse refers to physical, sexual and/or emotional acts perpetrated against the will of the victim. Physical abuse experienced in adult­ hood is often domestic violence, which, unfortunately, is more common than is realized. The Center for Disease Control reports an estimated 1.3 million women are victims of domestic violence annually, which comprises about 86% of all reported cases. In cases of family violence, approxi­ mately 73% of the victims are female.81,82 Given these sta­ tistics, and the known link of IBS and abuse history, it is no surprise that women have a higher prevalence of IBS. Likewise, of all patients with IBS that report a history of sexual abuse, more are women.76,83 Whether these data are influenced by reporting bias in women versus men is a ques­ tion that has yet to be answered. Not only is abuse history linked to IBS, but the severity of abuse also contributes to the health status of patients with functional disorders such as IBS.79 Childhood loss such as parental death, divorce, separation or abandonment has also been a proposed link to adult IBS.84 However, further study is needed in this area. Two studies seem to implicate affluent childhood socio­ economic status (SAS) as a risk factor for IBS.85–87 However, more data are needed in this area to substantiate these find­ ings and determine if there is a clear role of gender. Some have proposed that childhood modeling of learned illness behavior and parental reinforcement are also linked to IBS in adulthood.88,89 These data suggest that having a parent or sibling with IBS or other gastrointestinal disease, or a par­ ent who reinforces gastrointestinal complaints expressed by children may be linked to childhood IBS. Similarly, it is not know whether this process is influenced by gender.

Psychiatric Illness There is a well-established link between IBS and co-morbid psychiatric disease, with up to 54–94% of lBS patients who seek medical care meeting criteria for a primary psychiatric disorders.6 The lifetime prevalences of anxiety and mood disorders are 1.6 and 1.5 times greater in women than in men.90 Among the most common psychiatric diagnoses are major depression, anxiety, and somatoform disorders. In a study of patients with chronic abdominal pain, IBS patients were two to four times more likely to have suicidal

C h a p t e r 3 2     Gender Differences in Irritable Bowel Syndrome l

behavior.91–93 The authors concluded that chronic abdomi­ nal pain was an independent predictor of suicidal behavior after adjusting for co-morbid psychiatric conditions. It is unknown whether pre-existing psychiatric illness increases one’s risk of developing IBS, or if distress from IBS symp­ toms predisposes to psychiatric disease. Given that IBS and psychiatric disease often coexist, practitioners should screen patients for psychiatric disorders and consider the use of TCAs and SSRIs in symptom management. Poor baseline quality of life has also been implicated as a risk factor for new-onset IBS.94

Other associations Obesity Obesity, physical activity and diet also influence gastroin­ testinal symptoms.95 Levy et al. found a positive association of body mass index (BMI) with IBS, abdominal pain, and diarrhea. They also found an inverse relationship between some gastrointestinal symptoms and a diet rich in fiber, fruits, and vegetables. The obesity epidemic and higher prevalence of obesity in women, may further contribute to the female predominance in IBS.96

IBS and Atopy Tobin et al. reported that adults with atopic symptoms report a high incidence of IBS, suggesting a link between atopy and IBS.97 However, the relationship of gender and atopy has conflicting data. In childhood, boys have a greater risk of having atopy than girls.98 In adulthood, women more commonly have severe asthma and are more likely to develop asthma in adulthood.99 Elevated numbers of mast cells have been found to be a key feature of the lowgrade inflammatory infiltrate existing in the cecal mucosa of IBS patient in one small study.100 This study also found significant associations between the severity of fatigue and depression and mast cell infiltration of the lamina propria, in IBS patients. The mechanisms of the female predilec­ tion for PI-IBS and its relationship to atopy requires further study, however, knowing that young women are more likely to develop PI-IBS may prevent time-consuming and expen­ sive medical evaluations in these patients.

Diagnosis One study evaluated the sex-specific value of the Rome (I and II) and Manning criteria in sex-specific symptoms of IBS patients.101 All diagnostic criteria studied, showed comparable female predominance thus, substantiating a true female predominance in the prevalence of IBS.

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The higher prevalence of IBS in women may be the result of more women seeking medical care for symptoms and therefore, being diagnosed with IBS. Some speculate that patients with IBS are also more likely to seek a specialist consultation in reference to their symptoms.94,102 Ringstrom et al. conducted a study comparing patients with IBS who did not seek medical attention, sought consultation from one provider, and sought a second or third consultation regard­ ing symptoms.102 Patients who sought secondary and terti­ ary consultation were younger and, although not statistically insignificant, there was a trend toward female predominance compared to the group of patients who did not consult a phy­ sician for their symptoms. This study also found that patients in the secondary and tertiary consultation group had poorer health-related quality of life (HLQOL) and more severe psy­ chological symptoms. A natural history study of IBS patients also showed that among many other factors, female gender increased the likelihood of an IBS-related consultation.94 Gender role has also been raised as a reason why women present more frequently with IBS than men. Gender role is defined as, ‘generalizations about appropriate traits for males and females associated with masculinity and feminin­ ity.’103 When surveyed for gender traits, men with IBS were found to have more feminine traits than control subjects.104

Treatment Successful management of IBS requires an individualized approach, often incorporating dietary, pharmacologic, and mind–body therapies. Women are more likely than men to seek medical help for IBS symptoms. Many therapies used to manage IBS do not have a predi­ lection for being more effective in women. These therapies include increasing dietary fiber, or using antispasmod­ ics or antidiarrheal agents. However, there are some phar­ macologic agents that have shown to be more effective in women with IBS than men. For example, alosetron, a 5HT3 receptor antagonist, has been shown to improve symp­ toms of IBS-D by acting either on the enteric nervous sys­ tem to decrease afferent signaling to the brain, centrally to decrease pain sensation, or by altering intestinal motility and secretion.105,106 In the initial studies alosetron decreases stool frequency and abdominal discomfort in women to a greater extent than in men. Although men metabolize alo­ setron more quickly than women, this alone cannot explain sex differences in response to this therapy, as the differ­ ences in metabolism are only observed in women over the age of 65. The more dramatic response to alosetron by women may be related to differences in cerebral serotonin processing in response to alosetron observed among men and women measured by brain PET scanning.107 Animal studies offer another possible explanation for the different response in women and men. Studies in which

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alosetron was used to inhibit the frequency of the migrating motor complex in the small intestine of mice indicate that the threshold of inhibition is 100 times less in small intes­ tine isolated from females than from males.108 However, in a human study of gastrointestinal transit in IBS patients given alosetron, colonic transit was delayed more in females than males, but no delay in small intestinal transit was observed.109 A sex difference has also been observed in the clinical response to renzapride, a new agent under investigation for the treatment of IBS-C. Renzapride improves stool fre­ quency but did not achieve adequate relief of abdominal pain and/or discomfort. In a post-hoc analysis of women, however, relief from pain was greater than that seen in men, suggesting there could be a gender specific response. The basis for this difference is as yet unknown.110 Tegaserod is a selective 5-HT4 receptor partial agonist devoid of 5-HT3 receptor antagonist properties that was originally FDA approved for IBS-C before being voluntar­ ily withdrawn from the market by its manufacturer in 2007 because of safety issues. Tegaserod was approved for use in women because initial clinical trials included predomi­ nantly women,111–113 and no conclusions could be drawn about its efficacy in men until later studies were conducted exclusively in healthy men or those with IBS.114,115 Unlike alosetron, there is no sex-dependent difference in metabo­ lism of tegaserod. For the treatment of IBS-C in women, the FDA recently approved lubiprostone, a chloride channel activator that increases intestinal fluid secretion. Like tegaserod, FDA approval for this drug for women was based on clini­ cal trials that included predominantly women. Originally approved for treatment of functional constipation, lubi­ prostone was shown to reduce IBS-C symptoms at a dose of 8 g twice daily, as opposed to 24 g twice daily, the dose used for the treatment of functional constipation. Interestingly, FDA-approved use of lubiprostone for func­ tional constipation is not sex-specific. Use of antidepressants has increased recently in the management of the abdominal pain and discomfort associ­ ated with IBS, though their efficacy is somewhat contro­ versial. Because of their neuromodulatory and analgesic effects, tricyclic antidepressants (TCAs) and selective sero­ tonin reuptake inhibitors (SSRI) have been used to treat IBS patients, specifically those with pain as the predominant symptom.116–121 SSRIs may help modulate afferent pain sig­ naling from the enteric nervous system to higher pain centers in the brain. Tricyclic antidepressants may help to improve abdominal pain, but may not improve global IBS symp­ toms.122 A disadvantage is that some patients cannot tolerate side effects associated with some of these agents. In a small study of IBS patients without depression, the selective serot­ onin reuptake receptor inhibitor citalopram improved abdom­ inal pain, bloating, impact of symptoms on daily life, and overall wellbeing.123 However, another randomized-placebo

controlled trial in IBS-diarrhea patients showed no difference between citalopram and placebo. Women are more likely to use complementary thera­ pies in general124 and specifically for IBS symptoms, as a result of dissatisfaction with conventional therapies, desire to use a more ‘natural’ approach, or recommendation by a friend.125 Complementary therapies include food and herbal supplements, acupuncture, and mind–body therapies, such as cognitive behavioral therapy, gut-directed hypnotherapy, biofeedback or guided imagery. Cognitive behavior therapy (CBT), a form of psychotherapy used to modify maladap­ tive thinking, has been successfully used for the treatment of several psychiatric disorders, such as anxiety and depres­ sion. CBT has been studied in multiple clinical trials, and is now recommended as an IBS treatment option by the United Kingdom Department of Health.126 Hutton states in his review, ‘CBT is most appropriate for patients who are significantly distressed by their symptoms, are open to the idea that psychological factors play some role in their difficulties, are willing to take part in an intervention that requires their active participation and have already had reasonable medical investigations and interventions.’126 Gender does not seem to predict response to CBT.127 A Cochrane review to evaluate the efficacy of hypno­ therapy in the treatment of IBS identified few studies of sufficient quality or size for meta-analysis,128 but there are some studies demonstrating hypnotherapy which may help to improve abdominal pain and global IBS symptoms in those who have failed medical therapy.129–132 Relaxation therapies have also been studied in clinical trials as adjunc­ tive therapy to medical therapy with promising results.133 Although female physicians may be more likely to recom­ mend mind–body therapies to their patients,134 the use of psychological therapies in IBS management is still under­ utilized. Thus, psychological therapies could play a more significant role in the management of IBS as the under­ standing of brain–gut interaction evolves.

Conclusion Irritable bowel syndrome is a common disorder that not only disproportionately affects women in terms of preva­ lence, but also disproportionately affects the quality of life and treatment response of women compared to men. The clinical manifestations and impact of IBS in the women likely reflects certain anatomic, hormonal, and psycho­ social differences in comparison to men. Management of IBS should be individualized, using dietary, pharmacologic, and mind–body therapies. Some therapies show increased efficacy in women than in men, perhaps due to physiologic differences. This area is being extensively investigated and will undoubtedly provide a useful model for the study of personalized medicine in the future.

C h a p t e r 3 2     Gender Differences in Irritable Bowel Syndrome l

References 1. Payne S. Sex, gender, and irritable bowel syndrome: making the connections. Gend Med 2004;1:18–28. 2. Thompson WG. Gender differences in irritable bowel symp­ toms. Eur J Gastroenterol Hepatol 1997;9(3):299–302. 3. O’Leary C, Wieneke P, Buckley S, et al. Celiac disease and irritable bowel-type symptoms. Am J Gastroenterol 2002; 97(6):1463–67. 4. Sanders DS, Patel D, Stephenson TJ, et al. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003;4:407–13. 5. Isgar B, Harman M, Kaye MD, et al. Symptoms of irrita­ ble bowel syndrome in ulcerative colitis in remission. Gut 1983;24(3):190–92. 6. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disor­ ders: What are the causes and implications? Gastroenterology 2002;122(4):1140–56. 7. Garakani A, Win T, Virk S, et al. Comorbidity of irritable bowel syndrome in psychiatric patients: a review. Am J Ther 2003;10(1):61–67. 8. Whitehead WE, Palsson OS, Levy RR, et al. Comorbidity in irrita­ ble bowel syndrome. Am J Gastroenterol 2007;102(12):2767–76. 9. Thompson WG. Irritable bowel syndrome: prevalence, prog­ nosis and consequences. CMAJ 1986;134(2):111–13. 10. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases. Am J Gastroenterol 2006;101(9):2128–38. 11. Simren M, Abrahamsson H, Svedlund J, et al. Quality of life in patients with irritable bowel syndrome seen in referral cent­ ers versus primary care: the impact of gender and predominant bowel pattern. Scand J Gastroenterol 2001;36(5):545–52. 12. Amouretti M, Le Pen C, Gaudin AF, et al. Impact of irrita­ ble bowel syndrome (IBS) on health-related quality of life (HRQOL). Gastroenterol Clin Biol 2006;30(2):241–46. 13. Coffin B, Dapoigny M, Cloarec D, et al. Relationship between severity of symptoms and quality of life in 858 patients with irrita­ ble bowel syndrome. Gastroenterol Clin Biol 2004;28(1):11–15. 14. Simren M, Svedlund J, Posserud I, et al. Health-related qual­ ity of life in patients attending a gastroenterology outpatient clinic: functional disorders versus organic diseases. Clin Gastroenterol Hepatol 2006;4(2):187–95. 15. Frank L, Kleinman L, Rentz A, et al. Health-related quality of life associated with irritable bowel syndrome: comparison with other chronic diseases. Clin Ther 2002;24(4):675–89. 16. Leong SA, Barghout V, Birnbaum HG, et al. The economic consequences of irritable bowel syndrome: a US employer perspective. Arch Intern Med 2003;163(8):929–35. 17. Inadomi JM, Fennerty MB, Bjorkman D. Systematic review: the economic impact of irritable bowel syndrome. Aliment Pharmacol Ther 2003;18(7):671–82. 18. Hulisz D. The burden of illness of irritable bowel syndrome: current challenges and hope for the future. J Manag Care Pharm 2004;10(4):299–309. 19. Quigley EM. Changing face of irritable bowel syndrome. World J Gastroenterol 2006;12(1):1–5. 20. Drossman DA, Li Z, Andruzzi E, et al. U.S. householder survey of functional gastrointestinal disorders. prevalence, sociode­ mography, and health impact. Dig Dis Sci 1993;38(9):1569–80.

353

21. Newcomer MK, Shaw MJ, Williams DM, et al. Unplanned work absence following outpatient colonoscopy. J Clin Gastroenterol 1999;29(1):76–78. 22. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 1973;14(2):125–32. 23. Kim HS, Rhee PL, Park J, et al. Gender-related differences in visceral perception in health and irritable bowel syndrome. J Gastroenterol Hepatol 2006;21(2):468–73. 24. Chang L, Munakata J, Mayer EA, et al. Perceptual responses in patients with inflammatory and functional bowel disease. Gut 2000;47(4):497–505. 25. Rao SS, Sadeghi P, Batterson K, et al. Altered periodic rec­ tal motor activity: a mechanism for slow transit constipation. Neurogastroenterol Motil 2001;13(6):591–98. 26. Gershon MD. Review article: serotonin receptors and trans­ porters – roles in normal and abnormal gastrointestinal motil­ ity. Aliment Pharmacol Ther 2004;20(Suppl. 7):3–14. 27. Atkinson W, Lockhart S, Whorwell PJ, et al. Altered 5hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome. Gastroenterology 2006;130(1):34–43. 28. Dunlop SP, Coleman NS, Blackshaw E, et al. Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol 2005;3(4):349–57. 29. Chen JJ, Li Z, Pan H, et al. Maintenance of serotonin in the intes­ tinal mucosa and ganglia of mice that lack the high-affinity sero­ tonin transporter: abnormal intestinal motility and the expression of cation transporters. J Neurosci 2001;21(16):6348–61. 30. Camilleri M, Andrews CN, Bharucha AE, et al. Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome. Gastroenterology 2007;132(1):17–25. 31. Spiller RC. Role of infection in irritable bowel syndrome. J Gastroenterol 2007;42(Suppl. 17):41–47. 32. Mearin F, Perez-Oliveras M, Perello A, et al. Dyspepsia and irritable bowel syndrome after a salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 2005;129(1):98–104. 33. Ji S, Park H, Lee D, et al. Post-infectious irritable bowel syndrome in patients with shigella infection. J Gastroenterol Hepatol 2005;20(3):381–86. 34. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causa­ tive factor of irritable bowel syndrome and its pathogenesis. Gut 2004;53(8):1096–101. 35. Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depres­ sion in postinfectious IBS. Gastroenterology 2003;125(6): 1651–59. 36. Linden DR, Chen JX, Gershon MD, et al. Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol 2003;285(1):G207–16. 37. Amaro E Jr., Barker GJ. Study design in fMRI: basic princi­ ples. Brain Cogn 2006;60(3):220–32. 38. Mertz H, Morgan V, Tanner G, et al. Regional cerebral acti­ vation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 2000;118(5):842–48. 39. Nakai A, Kumakura Y, Boivin M, et al. Sex differences of brain serotonin synthesis in patients with irritable bowel syndrome using alpha-[11C]methyl-L-tryptophan, positron

354

40.

41.

42.

43.

44.

45.

46.

47.

48. 49. 50.

51.

52.

53.

54.

55.

56. 57.

s e c t i o n 6     Reproductive Biology l

emission tomography and statistical parametric mapping. Can J Gastroenterol 2003;17(3):191–96. Lawal A, Kern M, Sidhu H, et al. Novel evidence for hypersensitivity of visceral sensory neural circuitry in irritable bowel syndrome patients. Gastroenterology 2006;130(1):26–33. Naliboff BD, Mayer EA. Brain imaging in IBS: drawing the line between cognitive and non-cognitive processes. Gastroenterology 2006;130(1):267–70. Naliboff BD, Berman S, Chang L, et al. Sex-related differ­ ences in IBS patients: central processing of visceral stimuli. Gastroenterology 2003;124(7):1738–47. Pimentel M, Park S, Mirocha J, et al. The effect of a non­ absorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med 2006;145(8):557–63. Yang J, Lee HR, Low K, et al. Rifaximin versus other anti­ biotics in the primary treatment and retreatment of bacterial overgrowth in IBS. Dig Dis Sci 2008;53(1):169–74. Pimentel M, Soffer EE, Chow EJ, et al. Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test, suggesting bacterial overgrowth. Dig Dis Sci 2002;47(12):2639–43. Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol 2006;101(2):326–33. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 2006;101(7):1581–90. Camilleri M, Gorman H. Intestinal permeability and irritable bowel syndrome. Neurogastroenterol Motil 2007;19(7):545–52. Bjarnason I, MacPherson A, Hollander D. Intestinal perme­ ability: an overview. Gastroenterology 1995;108(5):1566–81. Dunlop SP, Hebden J, Campbell E, et al. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol 2006;101(6):1288–94. Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004;126(3):693–702. Guilarte M, Santos J, de Torres I, et al. Diarrhoea-predomi­ nant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007;56(2):203–9. Liebregts T, Adam B, Bredack C, et al. Immune activation in patients with irritable bowel syndrome. Gastroenterology 2007;132(3):913–20. Sadahiro S, Ohmura T, Yamada Y, et al. Analysis of length and surface area of each segment of the large intes­ tine according to age, sex and physique. Surg Radiol Anat 1992;14(3):251–57. Saunders BP, Fukumoto M, Halligan S, et al. Why is colon­ oscopy more difficult in women? Gastrointest Endosc 1996;43:124–26. Hull T, Church JM. Colonoscopy – how difficult, how pain­ ful? Surg Endosc 1994;8(7):784–87. Oh SY, Sohn CI, Sung IK, et al. Factors affecting the tech­ nical difficulty of colonoscopy. Hepatogastroenterology 2007;54(77):1403–6.

58. Brummer P, Seppala P, Wegelius U. Redundant colon as a cause of constipation. Gut 1962;3:140–41. 59. Kantor JL. Anomalies of the colon: their roentgen diagnosis and clinical significance. Radiology 1934;23:651–62. 60. Houghton LA, Lea R, Jackson N, et al. The menstrual cycle affects rectal sensitivity in patients with irritable bowel syn­ drome but not healthy volunteers. Gut 2002;50(4):471–74. 61. Altman G, Cain KC, Motzer S, et al. Increased symp­ toms in female IBS patients with dysmenorrhea and PMS. Gastroenterol Nurs 2006;29(1):4–11. 62. Sun WM, Read NW. Anorectal function in normal human sub­ jects: effect of gender. Int J Colorectal Dis 1989;4(3):188–96. 63. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999;45(Suppl. 2):II, 43–7. 64. Surrenti E, Rath DM, Pemberton JH, et al. Audit of consti­ pation in a tertiary referral gastroenterology practice. Am J Gastroenterol 1995;90(9):1471–75. 65. Heaton KW, Radvan J, Cripps H, et al. Defecation frequency and timing, and stool form in the general population: a pro­ spective study. Gut 1992;33(6):818–24. 66. Lampe JW, Fredstrom SB, Slavin JL, et al. Sex differences in colonic function: a randomised trial. Gut 1993;34(4):531–36. 67. Rao SS, Sadeghi P, Beaty J, et al. Ambulatory 24-h colonic man­ ometry in healthy humans. Am J Physiol 2001;280(4):G629–39. 68. Rees WD, Rhodes J. Altered bowel habit and menstruation. Lancet 1976;1(7982):475. 69. Wald A, Van Thiel DH, Hoechstetter L, et al. Gastrointestinal transit: the effect of the menstrual cycle. Gastroenterology 1981;80(6):1497–500. 70. DiPalma AM, DiPalma JA. Women’s colonic digestive health. Gastroenterol Nurs 2002;25(1):3–8. 71. Lawson M, Kern F Jr., Everson GT. Gastrointestinal tran­ sit time in human pregnancy: prolongation in the second and third trimesters followed by postpartum normalization. Gastroenterology 1985;89(5):996–99. 72. Clark AL, Slayden OD, Hettrich K, et al. Estrogen increases col­ lagen I and III mRNA expression in the pelvic support tissues of the rhesus macaque. Am J Obstet Gynecol 2005;192(5):1523–29. 73. Raigoso P, Sanz L, Vizoso F, et al. Estrogen and progesterone receptors in colorectal cancer and surrounding mucosa. Int J Biol Markers 2001;16(4):262–67. 74. Ryan JP, Pellecchia D. Effect of progesterone pretreatment on guinea pig gallbladder motility in vitro. Gastroenterology 1982;83(1 Pt 1):81–83. 75. Kamm MA, Farthing MJ, Lennard-Jones JE. Bowel function and transit rate during the menstrual cycle. Gut 1989;30(5):605–8. 76. Walker EA, Katon WJ, Roy-Byrne PP, et al. Histories of sexual victimization in patients with irritable bowel syndrome or inflam­ matory bowel disease. Am J Psychiatry 1993;150(10):1502–6. 77. Drossman DA, Talley NJ, Leserman J, et al. Sexual and phys­ ical abuse and gastrointestinal illness. Review and recommen­ dations. Ann Intern Med 1995;123(10):782–94. 78. Talley NJ, Fett SL, Zinsmeister AR. Self-reported abuse and gastrointestinal disease in outpatients: association with irritable bowel-type symptoms. Am J Gastroenterol 1995;90(3):366–71. 79. Drossman DA. Irritable bowel syndrome and sexual/physi­ cal abuse history. Eur J Gastroenterol Hepatol 1997;9(4): 327–30.

C h a p t e r 3 2     Gender Differences in Irritable Bowel Syndrome l

80. Ali A, Toner BB, Stuckless N, et al. Emotional abuse, selfblame, and self-silencing in women with irritable bowel syn­ drome. Psychosom Med 2000;62(1):76–82. 81. National Center for Injury Prevention and Control. Costs of Intimate Partner Violence Against Women in the United States. Atlanta, GA: Centers for Disease Control and Prevention; 2003. 82. Bureau of Justice Statistics. Family Violence Statistics: US Department of Justice; June 2005. 83. Delvaux M, Denis P, Allemand H. Sexual abuse is more fre­ quently reported by IBS patients than by patients with organic digestive diseases or controls. Results of a multicentre inquiry. French club of digestive motility. Eur J Gastroenterol Hepatol 1997;9(4):345–52. 84. Hislop IG. Childhood deprivation: an antecedent of the irrita­ ble bowel syndrome. Med J Aust 1979;1(9):372–74. 85. Kumar D, Pfeffer J, Wingate DL. Role of psychological factors in the irritable bowel syndrome. Digestion 1990;45(2):80–87. 86. Mendall MA, Kumar D. Antibiotic use, childhood affluence and irritable bowel syndrome (IBS). Eur J Gastroenterol Hepatol 1998;10(1):59–62. 87. Chitkara DK, van Tilburg MA, Blois-Martin N, et al. Early life risk factors that contribute to irritable bowel syn­ drome in adults: a systematic review. Am J Gastroenterol 2008;103(3):765–74. 88. Whitehead WE, Winget C, Fedoravicius AS, et al. Learned illness behavior in patients with irritable bowel syndrome and peptic ulcer. Dig Dis Sci 1982;27(3):202–8. 89. Levy RL, Whitehead WE, Walker LS, et al. Increased somatic complaints and health-care utilization in children: effects of parent IBS status and parent response to gastrointestinal symptoms. Am J Gastroenterol 2004;99(12):2442–51. 90. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry 2005;62(6):593–602. 91. Guthrie E, Creed F, Fernandes L, et al. Cluster analysis of symptoms and health seeking behaviour differentiates sub­ groups of patients with severe irritable bowel syndrome. Gut 2003;52(11):1616–22. 92. Miller V, Hopkins L, Whorwell PJ. Suicidal ideation in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2004;2(12):1064–68. 93. Spiegel B, Schoenfeld P, Naliboff B. Systematic review: the prevalence of suicidal behaviour in patients with chronic abdominal pain and irritable bowel syndrome. Aliment Pharmacol Ther 2007;26(2):183–93. 94. Ford AC, Forman D, Bailey AG, et al. Irritable bowel syn­ drome: a 10-yr natural history of symptoms and factors that influence consultation behavior. Am J Gastroenterol 2008;103(5):1229–39. 95. Levy RL, Linde JA, Feld KA, et al. The association of gas­ trointestinal symptoms with weight, diet, and exercise in weight-loss program participants. Clin Gastroenterol Hepatol 2005;3(10):992–96. 96. Ogden CL, Yanovski SZ, Carroll MD, et al. The epidemiol­ ogy of obesity. Gastroenterology 2007;132(6):2087–102. 97. Tobin MC, Moparty B, Farhadi A, et al. Atopic irritable bowel syndrome: a novel subgroup of irritable bowel syn­ drome with allergic manifestations. Ann Allergy Asthma Immunol 2008;100(1):49–53.

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  98. Govaere E, Van Gysel D, Massa G, et al. The influence of age and gender on sensitization to aero-allergens. Pediatr Allergy Immunol 2007;18(8):671–78.   99. Postma DS. Gender differences in asthma development and progression. Gend Med 2007;4(Suppl. B):S133–46. 100. Piche T, Saint-Paul MC, Dainese R, et al. Mast cells and cellular­ ity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome. Gut 2008;57(4):468–73. 101. Hammer J, Talley NJ. Value of different diagnostic criteria for the irritable bowel syndrome among men and women. J Clin Gastroenterol 2008;42(2):160–66. 102. Ringstrom G, Abrahamsson H, Strid H, et al. Why do sub­ jects with irritable bowel syndrome seek health care for their symptoms? Scand J Gastroenterol 2007;42(10):1194–203. 103. Toner BB, Akman D. Gender role and irritable bowel syn­ drome: literature review and hypothesis. Am J Gastroenterol 2000;95(1):11–16. 104. Miller V, Whitaker K, Morris JA, et al. Gender and irritable bowel syndrome: the male connection. J Clin Gastroenterol 2004;38(7):558–60. 105. Andresen V, Montori VM, Keller J, et al. Effects of 5hydroxytryptamine (serotonin) type 3 antagonists on symp­ tom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol 2008;6(5):545–55. 106. Krause R, Ameen V, Gordon SH, et al. A randomized, doubleblind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrheapredominant IBS. Am J Gastroenterol 2007;102(8):1709–19. 107. Nakai A, Diksic M, Kumakura Y, et al. The effects of the 5-HT3 antagonist, alosetron, on brain serotonin synthesis in patients with irritable bowel syndrome. Neurogastroenterol Motil 2005;17(2):212–21. 108. Bush TG, Spencer NJ, Watters N, et al. Effects of alosetron on spontaneous migrating motor complexes in murine small and large bowel in vitro. Am J Physiol Gastrointest Liver Physiol 2001;281(4):G974–83. 109. Viramontes BE, Camilleri M, McKinzie S, et al. Genderrelated differences in slowing colonic transit by a 5-HT3 antagonist in subjects with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 2001;96(9):2671–76. 110. George AM, Meyers NL, Hickling RI. Clinical trial: renz­ apride therapy for constipation-predominant irritable bowel syndrome – multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting. Aliment Pharmacol Ther 2008;27(9):830–37. 111. Muller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irri­ table bowel syndrome patients with abdominal pain, bloat­ ing and constipation. Aliment Pharmacol Ther 2001;15(10): 1655–66. 112. Kellow J, Lee OY, Chang FY, et al. An Asia–Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut 2003;52(5):671–76. 113. Novick J, Miner P, Krause R, et al. A randomized, doubleblind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2002;16(11):1877–88.

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114. Harish K, Hazeena K, Thomas V, et al. Effect of tegaserod on colonic transit time in male patients with constipationpredominant irritable bowel syndrome. J Gastroenterol Hepatol 2007;22(8):1183–89. 115. Degen L, Matzinger D, Merz M, et al. Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment Pharmacol Ther 2001;15(11):1745–51. 116. Heefner JD, Wilder RM, Wilson ID. Irritable colon and depression. Psychosomatics 1978;19(9):540–47. 117. Myren J, Groth H, Larssen SE, et al. The effect of trimi­ pramine in patients with the irritable bowel syndrome. A dou­ ble-blind study. Scand J Gastroenterol 1982;17(7):871–75. 118. Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain 1992;49(2):205–19. 119. Clouse RE, Lustman PJ, Geisman RA, et al. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Aliment Pharmacol Ther 1994;8(4):409–16. 120. Gorelick AB, Koshy SS, Hooper FG, et al. Differential effects of amitriptyline on perception of somatic and visceral stimu­ lation in healthy humans. Am J Physiol 1998;275(3 Pt 1): G460–66. 121. Camilleri M. Therapeutic approach to the patient with irrita­ ble bowel syndrome. Am J Med 1999;107(5A):27S–32S. 122. Schoenfeld P. Efficacy of current drug therapies in irri­ table bowel syndrome: what works and does not work. Gastroenterol Clin North Am 2005;34(2):319–35. 123. Tack J, Broekaert D, Fischler B, et al. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 2006;55(8):1095–103. 124. Barnes PM, Powell-Griner E, McFann K, et al. Complementary and alternative medicine use among adults: United States, 2002. Adv Data 2004;343:1–19.

125. Koloski NA, Talley NJ, Huskic SS, et al. Predictors of conven­ tional and alternative health care seeking for irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2003;17(6):841–51. 126. Hutton J. Cognitive behaviour therapy for irritable bowel syndrome. Eur J Gastroenterol Hepatol 2005;17(1):11–14. 127. Lackner JM, Jaccard J, Krasner SS, et al. How does cogni­ tive behavior therapy for irritable bowel syndrome work? A mediational analysis of a randomized clinical trial. Gastroenterology 2007;133(2):433–44. 128. Webb AN, Kukuruzovic RH, Catto-Smith AG, et al. Hypnotherapy for treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2007(4):CD005110. 129. Whorwell PJ, Prior A, Faragher EB. Controlled trial of hypnotherapy in the treatment of severe refractory irritablebowel syndrome. Lancet 1984;2:1232–34. 130. Galovski TE, Blanchard EB. The treatment of irritable bowel syndrome with hypnotherapy. Appl Psychophysiol Biofeedback 1998;23(4):219–32. 131. Palsson OS, Turner MJ, Johnson DA, et al. Hypnosis treatment for severe irritable bowel syndrome: investiga­ tion of mechanism and effects on symptoms. Dig Dis Sci 2002;47(11):2605–14. 132. Roberts L, Wilson S, Singh S, et al. Gut-directed hypno­ therapy for irritable bowel syndrome: piloting a primary care-based randomised controlled trial. Br J Gen Pract 2006;56(523):115–21. 133. van der Veek PP, van Rood YR, Masclee AA. Clinical trial: short- and long-term benefit of relaxation training for irritable bowel syndrome. Aliment Pharmacol Ther 2007;26(6):943–52. 134. Sierpina V, Levine R, Astin J, et al. Use of mind–body therapies in psychiatry and family medicine faculty and residents: attitudes, barriers, and gender differences. Explore (NY) 2007;3(2):129–35.

Chapter

33

Contraception Karen Feisullin1, and Carolyn Westhoff2 1 Community Health Services, Department of Women’s Health; Department of Obstetrics and Gynecology, Hartford Hospital, Hartford, CT, USA 2 Columbia University, Department of Obstetrics and Gynecology, Division of Family Planning and Preventive Services, New York, NY, USA

Introduction

avoid effective methods because they or their partners hold mistaken beliefs. Clinicians who correct these misconceptions and debunk contraceptive myths can improve continuation rates and compliance.3 Informational counseling is especially important for adolescents. About 1 million adolescent pregnancies occur each year in the United States, and about half of all adolescents use no contraception during the first episode of sexual intercourse. Clinicians should counsel adolescents in private, with assurance that all discussions will remain confidential. Early puberty is a good time to give a young patient notice that contraception is an acceptable topic for discussion. Assurance must be given that the discussion will remain private, and parents will not be notified without the patient’s consent. Although the advantages of abstinence merit discussion, clinicians must discuss contraception because many adolescents become sexually active sooner rather than later. All adolescents starting a method should receive explicit permission to make additional visits or telephone calls to discuss contraceptive concerns; this may prevent premature discontinuation. In adolescents and adults continuation rates may be improved by reviewing how contraceptives work and their expected side-effects, by giving oral and written instructions, and especially by providing samples at the initial visit and ample refills.4–6 A pelvic examination is useful to screen for sexually transmitted infection and to carry out a Pap test, but is unnecessary prior to initiating most contraceptives.

Every year in the United States, approximately one-half of the 6.3 million pregnancies are unplanned.1 Of these unplanned pregnancies, about half the women used a contraceptive method imperfectly and half used no method at all. Exceedingly few pregnancies are due to the failure of correctly used contraceptive methods. Women are sometimes reluctant to use contraceptives because of perceived health risks, but most women are unaware that pregnancy itself has far greater risks. Pregnancy can be complicated and dangerous for women with coexisting medical problems. Contraception also improves certain non-reproductive health outcomes; ovarian and endometrial cancer risk reduction in oral contraceptive users is the paramount example of such effects. In developing countries maternal deaths are common, with maternal mortality rates 20 to 100 times higher than those in the United States. The largest health impact of family planning in such settings is the reduction of maternal mortality through a decrease in unwanted and potentially dangerous pregnancies. Contraceptive use allows women to space pregnancies, which decreases infant mortality. Spacing pregnancies more than 2 years decreases infant mortality by 50%.2 In addition to these health benefits, allowing women to control their fertility can give them opportunities to pursue education and employment outside the home.

Contraceptive counseling

Contraceptive methods

The best contraceptive method is one a patient chooses and will use. Patients can make this decision only with timely access to the full spectrum of methods. Appropriate counseling requires presentation of a range of options with expected effectiveness rates and side-effects. Many women Principles of Gender-Specific Medicine

Highly Effective Reversible Methods: Injections, Intra-uterine Devices, and Implants Long-acting reversible methods have an efficacy rate of at least 99%. They provide continuous contraception and 357

Copyright 2010 20 , Elsevier Inc. All rights reserved.

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either cannot be passively discontinued (IUDs and implants) or are only slowly reversible (injections). None of these methods contains estrogen, and they are generally a first choice for women who cannot take estrogen and for those women in whom pregnancy is medically contraindicated. Injectable Contraceptives Depot medroxyprogesterone acetate (DMPA), or Depo Provera, is the most commonly used injectable contraceptive. It is available as a deep intramuscular injection of 150 mg every 12 weeks, or as a subcutaneous injection of 104 mg every 12 weeks. The failure rate under ideal conditions is 0.3% but the failure rate with typical use is 3%. Failure rates with typical use occur because of delays in scheduled injection every 12 weeks. Non-contraceptive benefits of DMPA include diminished menstrual bleeding and dysmenorrhea, decreased risk of pelvic inflammatory disease, endometrial and ovarian cancers, and fewer sickle cell crises.7 After their third injection, almost half of DMPA users become amenorrheic. Amenorrhea occurs in 70% of women after 2 years of use and 80% of women after 5 years. Data from prospective studies of Depo Provera do not support a causal relationship between its use and either depression or marked weight gain.8–12 Bone loss during use is comparable to that seen during breastfeeding, and studies indicate that bone is regained after discontinuing this method.13 DMPA is contraindicated in women who may be pregnant because it would offer no benefit, and its use may delay the diagnosis of pregnancy. The contraceptive effect of DMPA is very slowly reversible; the average time for return to ovulation is 6 months. Thus, DMPA is not a good method for women who are planning pregnancy soon. Intra-uterine Devices The ParaGard Copper T 380A intra-uterine device (IUD) is a highly effective low-maintenance method. It has greater than 99% efficacy, which is comparable to sterilization, and it may remain in place for up to 10 years. The mechanism of action of the Copper T is impairment of sperm function, rendering them unable to fertilize ova. It is recommended for women who desire long-term contraception, but due to the immediate return of fertility after removal, it is also suitable for women who are spacing pregnancies. The clinician can easily insert the IUD during an office visit at any time during the menstrual cycle.14 The copper IUD typically causes longer or heavier menstrual bleeding, especially in the first few months after insertion. The risk of involuntary expulsion is approximately 5% in the first year after insertion. In order to ensure that the device is still in place, women should be advised to feel the strings of the IUD after every menses. The initial cost of the IUD is higher than that of many other contraceptives, but IUDs become the most costeffective method when utilized for 2 years or longer.15 The

IUD can also be used for emergency contraception (see section on Emergency Contraception) as well as immediately post partum. Contraindications to IUD insertion are current pelvic infection and anomalies of the uterine cavity, as these might increase the risk of expulsion of the device. Insertion should not occur in the presence of active cervical or pelvic infection, but can occur after treatment of both partners. If, while an IUD is being used, an asymptomatic cervical infection is detected by screening, the woman can be treated with the device in situ. Contrary to recent practice and within the gui­ dance of new product labeling, the copper IUD can be used in nulliparous women, in adolescents, in women with a past ectopic pregnancy, in HIV-positive women, and in women with past pelvic infection.16,17 Fertility returns immediately after removal of the copper IUD. The Levonorgestrel Intra-uterine System (LNG-IUS), Mirena IUD also has greater than 99% efficacy and may remain in place for up to 5 years. The LNG-IUS releases 20 g of levonorgestrel into the endometrial cavity every day for 5 years. For the next 2 years, the LNG-IUS continues to release a therapeutic dose of levonorgestrel, 14 g per day. It may be effective for up to 7 years. The mechanisms of action are thickening of the cervical mucus, which impairs sperm motility, and suppression of the endometrium such that it becomes hostile to the ascent of sperm. In some women the systemic absorption of levonorgestrel may suppress ovulation. The LNG-IUS has major non-contraceptive benefits including improving dysmenorrhea, reducing menorrhagia with a 90% decrease in blood loss compared to a typical menstrual cycle, and the development of amenorrhea in approximately 20% of women. For women with menorrhagia, use of the LNG-IUS also provides an alternative to endometrial ablation and hysterectomy. Women using the LNG-IUS experience a gradual decrease in menstrual duration, blood loss, and spotting during the first 6 months after insertion. By the end of one year, spotting typically ceases and menses last about 1–2 days per month. The LNG-IUS is also acceptable for use to protect the endometrium in menopausal women using estrogen therapy.18 Subdermal Progestin Implants Implanon is a reversible single-rod implant that has been used outside of the United States and was approved by the FDA in 2006. The rod, a flexible device measuring 40 mm by 2 mm, is impregnated with 68 mg of etonogestrel, a progestin. The implant releases approximately 40 g of etonogestrel daily, providing continuous contraception for up to 3 years.19 With typical use, it has a failure rate of 0.1%.20 It is inserted subcutaneously in the upper arm during an office procedure performed by a trained clinician. Non-contraceptive benefits include improved dysmenorrhea. The main side-effect of this implant is irregular, unpredictable bleeding throughout use. Implanon does not adversely affect bone mineral density.21

C h a p t e r 3 3     Contraception l

Removal by a trained clinician entails a quick and simple office procedure. Fertility returns immediately after removal. The effectiveness of Implanon has not been evaluated in women with liver disease or those who take concomitant medications that might accelerate metabolism of the hormone. No longer in use in the United States, Norplant was a reversible six-rod implant system designed for 5 years of continuous use.

Effective Reversible Methods: Pills, Patch, and Vaginal Ring Combined ethinyl estradiol and progestin methods (pills, transdermal patch, and vaginal ring) and progestin-only pills have ‘perfect-use’ failure rates of 1–2%, and typical use failure rates of about 5%. Failure rates quoted with perfect use are achieved when the method is used exactly as directed. These hormonal methods all require active decision-making and a regular routine for successful use. These are generally cyclic methods designed to produce a regular withdrawal bleeding episode, but they have the potential for continuous rather than cyclic use. Oral Contraceptives Oral contraceptives (OCs) are the most popular reversible method of contraception in the United States. There are combined estrogen and progestin formulations (combined oral contraceptives, COCs) and progestin-only pills, POPs). The estrogen in combined oral contraceptives in the US has been ethinyl estradiol for decades, but new preparations may soon use estradiol. To decrease the risk of thromboembolic events, the COC estrogen dose has been steadily reduced since the first introduction of the pill in the 1960s. Currently, low-dose pills contain 20–35 g of ethinyl estradiol per tablet, compared to 100–150 g of ethinyl estradiol in the 1960s. The amount of progestin in the pill has been lowered even more than the amount of estrogen. There are at least six different progestins used in today’s pills. Many believe that the choice of progestin can influence the tolerability of the pill. Traditional cyclic use of combined oral contraceptives involves following the routine prescribed by the monthly pill pack for 28 days, taking 21 active pills followed by 7 placebo pills. The predictable withdrawal bleeding occurs during the week in which placebo pills are taken. A new pill pack is to be started the day after finishing the placebo pills regardless of the bleeding pattern. The most recently approved 28-day OC regimens typically contain more days of active pills and fewer days of placebo; the rationale is to minimize cyclic symptoms that may be related to fluctuations in hormone levels. These regimens may also yield fewer days of withdrawal bleeding. Continuous use of COCs is achieved, in two FDA-approved products, by daily use of active pills for 84 consecutive days followed by 7 days of placebo (or low estrogen-dose) tablets.

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The benefit of this approach is less frequent withdrawal bleeds. Another product contains active pills only, which is intended to avoid any scheduled withdrawal bleeding. Comparison of continuous and cyclic use of COCs demonstrates that continuous use is safe, effective and well tolerated. Breakthrough bleeding and spotting decrease with successive cycles.22 Conventional approaches to the initiation of oral contraception require waiting until the next menstrual period to take the first pill. Following this approach, up to 25% of women for whom an OC is prescribed never begin taking the pills; an alternative encourages patients to swallow the first tablet (preferably with direct observation) immediately upon prescription, regardless of menstrual cycle day. This approach, called Quick Start, has been shown to increase initiation of COC. The Quick Start approach is safe, acceptable, and useful for initiation of pills, DMPA and other hormonal contraceptives.23 Despite dose reductions, there remain some risks in the use of COCs. Some women should not take estrogencontaining contraception due to an increased risk of myocardial infarction or stroke; this contraindication applies to all women aged 35 or older who smoke or have diabetes, hypertension, or migraines.24 Family history does not raise the risk of adverse events. In younger women with these conditions, the underlying probability of cardiovascular events is so low that the possible risks of COC use are substantially smaller than the risks of pregnancy. Regardless of age, the use of an estrogen-containing COC is contraindicated in the presence of known ischemic heart disease, personal history of stroke, migraine with aura, diabetes with vascular changes, or uncontrolled hypertension. Such women need other forms of highly effective contraception due to the risks of major complications during pregnancy. The increased risk of venous thromboembolism (VTE) generally contraindicates the use of COCs (or patch or ring) in women with a personal history of VTE, those with a known high-risk thrombogenic mutation, those with morbid obesity (body mass index 40), and those women within 14 days of giving birth. An exception is that certain women currently receiving anticoagulant therapy will benefit from OC use. For example, ovulation may be catastrophic in an anticoagulated woman if a hemorrhagic cyst were to rupture. Also certain anticoagulants (e.g. warfarin) are teratogenic. The risk of VTE does vary among the estrogen-containing contraceptives. However, because the baseline risk of adverse effects is so low, even very large studies have not been able to precisely define VTE risk on a product-specific basis. Most studies agree that the greatest risk of VTE occurs in the first 1–2 years of OC use. The risk of VTE in young women is greatest during pregnancy, particularly during the puerperium; the risk during OC use is substantially lower than the risk during pregnancy. Use of COCs is indicated in breastfeeding women once milk flow is well established (approximately 4 weeks post partum), in women with benign breast disease or a family

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history of breast cancer, and in women with lupus who do not have antiphospholipid antibodies. Despite widely held beliefs that the use of COCs leads to weight gain, a systematic review of 44 randomized controlled trials found no evidence of a causal relationship between combination contraceptives and weight gain.25 Data indicating higher failure rates in obese women are inconsistent. Progestin-only pills (POPs), or ‘minipills,’ contain 0.35 mg of norethindrone, in Micronor, or 0.075 mg of norgesterel, in Ovrette. They are to be taken every day with no hormone-free interval. Although the failure rate with perfect use is 0.3% in the first year, with typical use the rate is 8%. This makes them slightly less effective in preventing pregnancy than are COCs. POPs may be most appropriate in women who should not take estrogen-containing contraceptives. Noncontraceptive benefits of POPs include reduced menstrual bleeding, anemia, dysmenorrhea, and premenstrual symptoms like bloating and breast tenderness. As with COCs there is decreased risk of endometrial and ovarian cancer. Like the COCs, the contraceptive effect of POPs is immediately reversible. Disadvantages of POPs include the need to take the pills on a very regular schedule. Back-up methods like condoms or other barrier methods (see Barrier Methods section) are generally recommended for 48 hours if a pill is taken more than 3 hours late. Drugs that increase hepatic enzyme levels probably decrease the efficacy of POPs. Menstrual irregularities are a reason that many women discontinue use of this particular type of OC; adequate counseling on this side effect may reduce discontinuation rates. Transdermal Contraceptive Patch Ortho Evra is a combined hormonal contraceptive patch. Each patch contains 0.75 mg ethinyl estradiol and 6.0 mg norelgestromin. As with COCs, the main mechanism of action is the prevention of ovulation. Each patch is worn for 7 days and replaced each week, for three weeks out of every four. A withdrawal bleed occurs during the fourth week, when the patch is not worn. Once-a-week dosing is convenient and may enhance the chances of correct use, compared to the OC. The benefits of the patch are similar to COCs, including usefulness in the management of both menorrhagia and dysmenorrhea. Disadvantages include lack of privacy when the patch is worn on a visible area, and possible skin irritation and pigment change at the application site. Like the OC, the patch does not protect against sexually transmitted infections. Women who have contraindications to using estrogen may not use the patch. In a clinical trial, Ortho Evra had a higher failure rate in women weighing more than 198 pounds (90 kg) compared to lighter women. In 2006, the manufacturer and the FDA notified healthcare professionals and patients about studies that found an approximate two-fold increase in the risk of medically verified VTE events in users of Ortho Evra compared to users of COCs containing 35 g of estrogen.

Vaginal Ring NuvaRing is a monthly vaginal contraceptive that is inserted by the patient and remains in place for 3 weeks. It is a soft flexible ring made of ethylene vinyl acetate. Its outer diameter is 5.4 cm and it is 4 mm thick. It contains ethinyl estradiol and etonogestrel which is dispersed evenly throughout the ring. In each 24 hour period, 15 g of ethinyl estradiol and 120 g of etonogestrel are released. The vaginal ring has the advantage of once-a-month dosing and its use is completely discreet.26 The vaginal ring may be used in a cyclic or continuous manner, both of which are acceptable to patients and well tolerated.27

Less Effective Reversible Methods: Barrier Methods, Periodic Abstinence, Lactational Anovulation Efficacy rates vary widely with less effective contraceptive methods. Annual failure rates with typical use range from 10% to 25%. Parous women experience higher failure rates. Barrier Methods: Condoms, Diaphragms, Sponges, and Spermicides Condoms Condoms are widely available and are the method most frequently used at first intercourse. The most recent National Survey of Family Growth (NSFG) showed an increase in condom use among adolescents and an increase in use at first intercourse.28 Male condoms are available in latex and, for latex-sensitive or allergic users, natural membrane from animal skin, and polyurethane and synthetic elastomers. The animal membrane material has a larger pore size that prevents transmission of sperm but may allow passage of infectious organisms. This type of condom is not recommended for prevention of sexually transmitted infections. A Cochrane Review of all randomized controlled trials evaluated male non-latex condom made of polyurethane film or synthetic elastomers as compared with latex condoms. Non-latex condoms have higher rates of breakage than latex condoms, but are still an acceptable alternative.29 Typical users of condoms report about 10 pregnancies per 100 couples in the first year of condom use. Actual per-use failure rates experienced by condom users vary greatly depending upon the correctness of and consistency in use. Reasons for condom failure include slippage and breakage, and non-use of the condom during the early minutes of intercourse, leading to insemination by the pre-ejaculatory fluid. Any of these occurrences can be remedied by use of emergency contraception. The key non-contraceptive benefit of synthetic condoms is that they are the only contraceptive method proven to reduce the risk of sexually transmitted infections, including HIV and HPV.14,30 ‘Dual method use’ refers to the simultaneous use of condoms and an additional effective or highly

C h a p t e r 3 3     Contraception l

effective pharmaceutical contraceptive to provide optimal protection against both infection and pregnancy. Women who rely on the effective pharmaceutical contraceptives, but who do not use condoms consistently have a higher risk of acquiring sexually transmitted infections. Consistent dual method use is uncommon. Female Condoms The first-generation FC female condom, formerly called Reality, is made of polyurethane. It is inserted in the vagina before sexual intercourse. FC2 is a second-generation female condom made of synthetic latex, which is less expensive than polyurethane. Female condoms are 17 cm long and contain two flexible polyurethane rings, one at each end. The ring at the closed end is inserted into the vagina, and the open ring remains outside the vagina after insertion. They provide protection against both pregnancy and sexually transmitted infections, and can be inserted up to 8 hours before intercourse. Female and male condoms should not be used together; they can adhere to each other, causing slippage or displacement of one or both devices. Female condom sixmonth failure rates are up to 9.5%.31 Diaphragm and Cervical Cap The diaphragm is a dome-shaped latex rubber cup that was much more popular decades ago before the introduction of more highly effective pharmaceutical methods. The diaphragm is now used by less than 1% of women in the United States. It has a flexible rim available with diameters from 60 to 100 mm. It is inserted into the vagina before intercourse, covering the cervix. The Prentif cavity rim cervical cap fits more tightly over the cervix than does the diaphragm, with diameters from 18 to 25 mm. Both the diaphragm and cap must be individually fitted. They are both designed for use with spermicide. After intercourse, the diaphragm must remain in place for 6 hours to maximize spermicidal action. Spermicide must be reapplied with an applicator with the diaphragm in place before subsequent intercourse. The cap can provide continuous contraception for 48 hours without the need to reapply spermicide. Prolonged use of either device for greater than 24 consecutive hours is associated with an increased risk of toxic shock syndrome,4 which is a systemic infection with Staphylococcus aureus. Both caps and diaphragms protect against upper genital tract infections that ordinarily gain entry via the cervical mucosa, including gonorrhea and chlamydia. Contraceptive failure rates are approximately 16% per year, with a wide range depending upon correct and consistent use. There is an increase in urinary tract infection risk among diaphragm users. If a woman has prolapse of the uterus or relaxation of the introitus or is immediately post partum, it may not be possible to fit a diaphragm or cap successfully. Users should be refitted after childbirth or substantial changes in weight.

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Spermicides Spermicides are reversible, temporary, non-prescription methods of contraception. They are available as foams, creams, jellies, film, and suppositories that melt after they are inserted. All spermicide preparations are short-acting with the intent of providing protection for a single act of intercourse that takes place within minutes to a few hours following the application of the spermicide. Suppositories and films need to melt and disperse in the vagina, and thus may not be active until 20 minutes after application. Efficacy in pregnancy prevention ranges from 70% to 85%. Spermicides may be used alone or as adjuncts to barrier contraceptive methods. Nonoxynol-9 is a spermicide that may irritate vaginal and rectal mucosa and thus may increase the risk of HIV and other sexually transmitted infections. Therefore, current recommendations are for nonoxynol-9 use only by couples at low risk of sexually transmitted infections.32 Hypersensitivity is a common adverse reaction, either from nonoxynol-9 itself or from the vehicle. Microbicides Microbicides are compounds that can be used vaginally or rectally to protect against sexually transmitted infections. Contraceptive microbicides are intended to prevent pregnancy as well as kill bacteria and viruses. Some microbicides provide a physical barrier to prevent exposure of cells in the vagina, cervix and rectum; some help maintain the natural vaginal acidic pH; and some kill or disable pathogens or prevent viral replication.33 Many phase III trials are ongoing to evaluate products in this group that simultaneously protect against infection, provide contraception, and not do disrupt the vaginal flora. There are no products on the market that achieve these objectives. Sponges The Today sponge is a polyurethane sperm barrier available over-the-counter. It contains 1 g of nonoxynol-9 spermicide. There is a dimple on one side that is designed to fit over the cervix, and a loop on the other side for removal. The sponge provides continuous contraception for 24 hours and must be left in place for 6 hours after intercourse. Wearing the sponge for greater than 30 hours may increase the risk of toxic shock syndrome. Periodic Abstinence Periodic abstinence methods (rhythm method) are designed to work by avoiding coitus during the fertile days of the menstrual cycle. All variations of this method rely on assumptions about the timing of ovulation. Examples of periodic abstinence methods include: the calendar method, which estimates fertile days based on cycle length; the temperature method, which relies on recording the basal body temperature to detect ovulation; and the sympto-thermal method which,

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uses temperature and cervical mucus changes. Advantages of periodic abstinence methods include no cost and no direct medical risks. Disadvantages include long training periods, unreliability in predicting fertility, poor compliance and continuation rates, and resulting high failure rates. This method is not suitable for women who are recently post-pregnancy, greater than age 35, or having irregular cycles. Anovulation During Lactational Amenorrhea Anovulation during lactational amenorrhea can be exploited as a contraceptive method. Natural postpartum infertility occurs when a woman is amenorrheic and fully breastfeeding. To rely on this method, women must be exclusively breastfeeding at least 6 times a day or 85% breastfeeding, have not had menses since delivery, and be less than 6 months post partum.2 Done correctly, this temporary method is highly effective (up to 98%). It does not, of course, protect against sexually transmitted infections.34

Emergency Contraception Emergency contraception (EC) is intended for use after unprotected intercourse or recognized contraceptive failure. It can reduce the risk of pregnancy by more than 75%. Research shows that EC prevents fertilization by delaying ovulation until viable sperm are no longer present in the upper female genital tract. Plan B is a progestin-only formulation with two tablets with 0.75 mg of levonorgestrel that may be taken in two divided doses 12 hours apart or once in a single dose.14 EC is more effective the sooner it is used, but it has been shown to decrease the incidence of pregnancy when taken up to 5 days later. EC will not end an established pregnancy. If EC is inadvertently used after a pregnancy is already established, teratogenic risk is unlikely because teratogenicity has not been seen with daily combined oral contraceptives.35 Women using EC after unprotected intercourse should start an effective form of contraception immediately. Apparent EC failure occurs due to additional unprotected acts of intercourse following treatment. Plan B is available over-the-counter for women over age 18, but a prescription is required for minors. Providing a prescription in advance increases the likelihood of use. Copper IUDs may also be used as an EC for up to 5 days after unprotected intercourse in women who desire long-term contraception.14,36 All methods of emergency contraception are cost-effective except for the IUD, which becomes more cost-effective only with extended use.15

high rate of sterilization in the United States as compared to other nations may be explained by several factors. First, sterilization rates rose precipitously during the mid-1970s through the 1980s,38 a period when the laparoscopic surgical approach became widespread. During this same period, the IUD fell out of favor in the United States to a much greater extent than in Europe, and oral contraceptive use also declined due to reports of cardiovascular complications. Female sterilization may be performed laparoscopically, hysteroscopically, through a minilaparotomy, or during another procedure, such as cesarean section. The fallopian tubes may be ligated, transected with unipolar cautery, coagulated with bipolar cautery, or occluded with Silastic rings, HulkaClemens spring clips, or Filshie clips. The hysteroscopic sterilization method relies on placement of intraluminal occlusive devices, which promote tubal scarring and permanent occlusion.39 Each method has unique advantages and disadvantages. Although sterilization should be considered final and irreversible, it is important to recognize that each method has a failure rate. The failure rate of sterilization overall is 1.85% over 10 years.40 The failure rate of sterilization appears to be dependent on the age of the patient at time of sterilization, the method chosen, and the skill of the operator. Younger patients are more likely to experience an unplanned pregnancy as long as 10 years after the procedure. At least onethird of late failures are ectopic pregnancies.40 Younger patients are also more likely to experience regret in the years following sterilization, with up to 25% of those sterilized at age younger than 30 requesting information about reversal.41

Male Methods Male Sterilization Male sterilization (vasectomy) is also a highly effective, permanent method of contraception. It is accomplished by making a small incision on either side of the scrotum and tying off the vas deferens, which transports sperm into the semen just prior to ejaculation. Compared to female sterilization, it is less expensive, more effective, easier to do with less surgical risk, and is easier to reverse.42 Vasectomy has no effect on male sexual function, including erectile function, ejaculation, volume of semen, or sexual pleasure. However, vasectomy rates consistently lag far behind those of female sterilization in all parts of the world, due mainly to cultural factors. Concerns regarding increases in prostate cancer, testicular cancer, and atherosclerotic disease in vasectomized men have proven unfounded.43 Other methods currently under investigation include the following.

Female Sterilization Female sterilization is the most common method of birth control for married couples in the United States. By 1995, 28% of reproductive age women relied on a female tubal occlusion method, representing 11 million women.37 The

Reversible Inhibition of Sperm Under Guidance (RISUG) The vas deferens is injected with styrene maleic anhydride in dimethyl sulfoxide solvent. This method partially

C h a p t e r 3 3     Contraception l

blocks sperm transport through the vas deferens, and strips membranes from the sperm that make it through, making it impossible for it to fuse with the oocyte. No pregnancies have been reported in men who were treated up to 15 years ago. Primate studies have shown this method is reversible.44 Adjudin Adjudin, also known as AF-2364, is an analogue of an old cancer drug called lonidamine that is conjugated to follicle stimulating hormone (FSH). Adjudin goes directly to Sertoli cells, which contain FSH receptors. The sperm made by these eggs is incapable of fertilizing an egg. This method is reversible in rats, and is in human trials.44 Intra-vas device (IVD) Two flexible silicon plugs are inserted in the vas deferens and physically block the passage of sperm. The plugs are sized to the width of the recipient’s vas deferens. They cannot be seen or palpated by the patient after insertion. This procedure can be performed by anyone who can perform a vasectomy, but it is easier and less expensive to reverse. Studies show 90 to 100% of men are azoospermic, and those with sperm present had very low counts. Human trials are currently under way in the United States. Another method, also called the intra-vas device, is a mesh-like vas deferens plug. Subfertile levels of sperm are allowed to pass to reduce buildup of pressure in the epididymis. It measures 1 mm in diameter and 17 mm in length, is inserted through a small incision into the vas. Trials are under way in China.44 Suppression of Spermatogenesis Hormonal Methods A Cochrane Review in 2007 examined all randomized controlled trials comparing a steroid hormone to another method. Results presented included studies of different formulations of testosterone and desogestrel, etonogestrel, or levonorgesterel. While some trials showed promising efficacy, no male hormonal contraceptive is ready for clinical use.45 Another method under investigation is trestolone. Trestolone is a synthetic androgen that inhibits release of FSH, and impairs spermatogenesis. Luteinizing hormone (LH) is also suppressed, which cuts production of testosterone. The azoospermia and oligozoospermia are reversible after discontinuation of trestolone. Trestolone has androgenic and anabolic properties, and loss of secondary sex characteristics is not seen.46 Nonhormonal Methods Nonhormonal methods include tripterygium extract, which is a plant used in Chinese traditional medicine. An observational study showed a significant decrease in mean sperm density compared to controls and no effect on libido.47

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Randomized, controlled trials of gossypol, which is derived from the cotton plant, demonstrated low efficacy and significant decrease in serum potassium. Additionally, there were men who did not recover normal sperm concentrations. For these reasons, the World Health Organization recommended there be no more trials with gossypol.44,47 Neem is a tree native to India, which animal studies have shown to be spermicidal. No studies are yet published on its effect in men.47 Heat-Based Contraception Raising the temperature of the scrotum above body temperature can affect fertility for months. This method involves heating the testicles so they do not produce sperm. Hot water, ultrasound-generated heat, and artificial cryptorchidism, which holds the testicles inside the abdomen using specialized briefs, are used to achieve contraceptive effect. Early studies suggest that it is effective and reversible.44 Formed-in-Place Silicone and Polyurethane Injectable Plugs These methods involve injecting liquid silicone or polyurethane plugs into the vas deferens, which act as barriers to sperm. This method is reversible, but problems with achieving azoospermia have made this method less attractive. It can take over one year for contraceptive effect, and sperm counts can be higher that with traditional vasectomy.44 Permanent Chemical Injection Injection into the vas deferens by a sclerosing agent can cause permanent sterilization. Up to 26 different combinations of chemicals have been tested, which may take several months to be effective contraception. This method has variable results, with one study showing azoospermia in only 83% of men treated. This method is no longer being actively studied.44

Patient education The following resources may be helpful: American College of Obstetricians and Gynecologists website: www.acog.org Association of Reproductive Health Professionals website: www.arhp.org ACOG Patient Information Pamphlets: Birth Control (brochure #AP005; Spanish SP005) The Intra-uterine Device (brochure #AP014; Spanish SP014) Birth Control Pills (brochure #AP021) Barrier Methods of Contraception(brochure #AP022; Spanish SP022)

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Natural Family Planning(brochure #AP024; Spanish SP024) Emergency Contraception(brochure #AP114) Hormonal Contraception – Injections, Rings, and Patches (brochure #AP159 Spanish SP159) Birth Control-Especially for Teens (brochure #AP114) Your First Gyn Visit – Especially for Teens (brochure #AP150 Spanish SP150) www.plannedparenthood.org/ www.not-2-late.com

References 1. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998;30:24–29, 46. 2. Population Reports – Saving children’s lives. Series J, Num­ ber 19. 3. De Cetina T, Canto P, Luna M. Effect of counseling to improve compliance in Mexican women receiving depotmedroxyprogesterone acetate. Contraception 2001;63:143–146. 4. Hatcher RA, Trussel J, et al. Contraceptive technology, 18. New York, NY: Ardent Media Inc; 2004. 5. Trussell J, Koenig J, Stewart F, et al. Medical care cost savings for adolescent contraceptive use. Fam Plann Perspect 1997;29:248–55, 295. 6. Moos M-K, Bartholomew NE, Lohr KN. Counseling in a clinical setting to prevent unintended pregnancy: an evidencebased research agenda. Contraception 2003;67:115–32. 7. deAbood M, de Castillo Z, et al. Effect of Depo-Provera or Microgynon on the painful crises of sickle cell anemia patients. Contraception 1997;56:313. 8. Westhoff C, Truman C, Kalmuss D, et al. Depressive symptoms and Depo-Provera. Contraception 1998;57:237–40. 9. Westhoff C, Wieland D, Tiezzi L. Depression in users of depo-medroxyprogesterone acetate. Contraception 1995;51: 351–54. 10. Westhoff C. Depot medroxyprogesterone acetate contraception: metabolic parameters and mood changes. J Reprod Med 1996;41(Suppl.):401–406. 11. Pelkman C. Hormones and weight change. J Reprod Med 2002;47:791–94. 12. Pelkman C, Chow M, Heinbach R, et al. Short-term effects of a progestational contraceptive drug on food intake, resting energy expenditure, and body weight in young women. Am J Clin Nutr 2001;73:19–26. 13. www.nih.gov/news/pr/sep2002/nichd-06.htm. 14. World Health Organization updates guidance on how to use contraceptives. INFO Reports. April 2005. 15. Trussell J, Koenig J, Ellertson C, et al. Preventing unintended pregnancy: the cost-effectiveness of three methods of emergency contraception. Am J Public Health 1997;87:932–37. 16. Hubacher D, Lara-Ricalde R, Taylor D, et al. Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women. N Engl J Med 2001;345:561–67. 17. www.paragard.com/paragard/index.php. 18. ACOG Committee opinion #337. Noncontraceptive uses of the levonorgesterel intrauterine system. June 2006.

19. Creinin M, Clark B. The latest contraceptive option: the single-rod implant. Contemp Ob/Gyn 2005:54–57. 20. Harrison-Woolrych M, Hill R. Unintended pregnancies with the etonorgestrel implant (Implanon): a case series from postmarketing experience in Australia. Contraception 2005;71:306–308. 21. Beerthuizen R, van Beek A, Massai R, et al. Bone mineral density during long-term use of the progestagen contraceptive implant Implanon compared to a non-hormonal method of contraception. Hum Reprod 2000;15:118–22. 22. Anderson F, Hait H. the Seasonale-301 Study Group. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception 2003;68:89–96. 23. Westhoff C, Kerns J, Morroni C, et al. Quick Start – a novel oral contraceptive initiation method. Contraception 2002;66:141–45. 24. ACOG. Use of hormonal contraception in women with coexisting medical conditions. Practice Bulletin I June 2006. 25. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives. Cochrane Database Sys Rev 2006(1), CD003987.. 26. www.organon.com/news/. 27. Miller L, Verhoeven CHJ. Results of a randomized, multicenter trial comparing extended contraceptive ring regimens. Obstet Gynecol 2005;105:6S. 28. www.cdc.gov/nchs/data/series/sr_23/sr23_024.pdf. 29. Gallo MF, Grimes DA, Lopez LM, et al. Non-latex versus latex condoms for contraception. Cochrane Database Syst Rev 2006(1), CD003987. 30. Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 2006;354:2645–54. 31. www.femalehealth.com/theproduct.html. 32. www.plannedparenthood.org/news-articles-press/politicspolicy-issues/birth-control-access-prevention/nonoxyonol-96546.htm. 33. www.who.int/hiv/topics/microbicides/microbicides/en/. 34. www.fhi.org/en/RH/FAQs/lam_faq.htm. 35. Bracken MB. Oral contraception and congenital malformations in offspring: a review and meta-analysis of the prospective studies. Obstet Gynecol 1990;76:552–58. 36. Westhoff C. Emergency contraception. N Engl J Med 2003; 349:1830–35. 37. Piccinino LJ, Mosher WD. Trends in contraceptive use in the United States: 1982–1995. Fam Plann Perspect 1998;30(1):4–11. 38. Westhoff C, Davis A. Tubal sterilization: focus on the U.S. experience. Fertil Steril 2000;73(5):913–22. 39. Population Reports – New contraceptive choices. April 2005; Series M, Number 19. www.infoforhealth.org/pr/m19/index. shtml. 40. Peterson HB, Xia Z, Hughes JM, et al. The risk of pregnancy after tubal sterilization: Findings from the U.S. Collaborative Review of Sterilization. Am J Obstet Gynecol 1996;174(4):1161–68. 41. Schmidt JE, Hillis SD, Marchbanks PA, et al. Requesting information about and obtaining reversal after tubal sterilization: Findings from the U.S. llaborative Review of Sterilization. Fertil Steril 2000;74(5):892–98. 42. Smith, G.L., Taylor, G.P., Smith, K.F., Comparative risks and costs of male and female sterilization. Am J Public Health 75(4):370–74.

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43. Bernal-Delgado E, Latour-Perez J, PradasArnal F, et al. The association between vasectomy and prostate cancer: a systematic review of the literature. Fertil Steril 1998;70(2):191–200. 44. www.newmalecontraception.org/index.htm. 45. Grimes DA, Lopez LM, Gallo MF, et al. Steroid hormones for contraception in men. Cochrane Database Syst Rev

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2007(2), Art No. CD004316.DOI:10.1002/14651858.CD004316.pub3. 46. www.popcouncil.org/projects/BIO_MENT.html. 47. Lopez L, Grimes DA, Schulz KF. Nonhormonal drugs for contraception in men: a systematic review. Obstet Gynecol Survey 2005;60(11):746–52.

C hap ter

34

Infertility: The Male Howard H. Kim1, Peter N. Schlegel2, and Marc Goldstein3 1 Fellow in Male Reproductive Medicine and Microsurgery, Department of Urology and Cornell Institute for Reproductive Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College; Research Fellow, The Population Council, Center for Biomedical Research, New York, NY, USA 2 Professor and Chairman, Department of Urology, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College, New York; Senior Scientist, The Population Council, Center for Biomedical Research, New York, NY, USA 3 Matthew P. Hardy Distinguished Professor of Reproductive Medicine and Urology, Surgeon-in-Chief, Male Reproductive Medicine and Surgery, Cornell Institute for Reproductive Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College; Senior Scientist, The Population Council, Center for Biomedical Research, New York, NY, USA

Approximately 16% of couples of reproductive age attempting conception fail to do so over a period of one year.1 An estimated 4–17% of couples seek medical treatment for infertility.2 Male factor is the sole cause in 20–42% of infertility cases, and contributes to an additional 19–39% of cases, depending on the measures of fertility and the geographic region surveyed (Figure 34.1).3–6 With the considerable progress in our understanding of male infertility, it is often possible to treat the specific disorder in the man without resorting to assisted reproductive techniques (ART) such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), which involve invasive treatment of the unaffected female partner. The majority of men who present with infertility have medically or surgically correctable diagnoses, and natural conception may be possible with appropriate therapy. Despite significant advances in the field, many couples undergo IVF with ICSI without evaluation by a male fertility specialist. A practice survey conducted by the National Regional Advisory Council of the American Society for Reproductive Medicine reported only 21.8–38.5% of couples with male factor infertility were referred to urologists for further evaluation and therapy.7 In one series, significant medical pathology requiring further treatment was diagnosed in 6% of men during an infertility evaluation.8 Diagnoses included cystic fibrosis mutations, karyotype abnormalities, testis cancer, prostate cancer, diabetes mellitus, and hypothyroidism.8 Furthermore, infertile men with abnormal semen analyses are over 20 times more likely to be diagnosed with testicular cancer compared to the general population.9 These data argue against bypassing the male evaluation in favor of ART. Principles of Gender-Specific Medicine

The potential etiologies of compromised fertility are diverse, including abnormalities of sperm production, sperm dysfunction, and obstruction of the excurrent ductal tract anywhere from the efferent ducts to the ejaculatory ducts (Figure 34.2). Evaluation of the male in an couple unable to conceive within one year of unprotected intercourse starts with a screening consisting of a reproductive history and two semen analyses obtained at least one month apart.10 If the initial screen reveals an abnormality, a full evaluation by the urologist or male fertility specialist ensues.10 According to the Male Infertility Best Practice Policy Committee of the American Urological Association, a full evaluation consists of a complete medical and reproductive history, physical examination, and at least two semen analyses, with additional laboratory and radiological testing as needed.10 More specific testing includes post-ejaculatory urine analysis, sperm function tests, endocrine evaluation, genetic testing, and ultrasonography. Infertility evaluation of both partners should be conducted simultaneously if pregnancy does not occur after one year of attempted conception. Evaluation should be considered sooner if known risk factors are present, such as female age greater than 35 years or male factors such as history of cryptorchidism.10

Basic evaluation Reproductive History The reproductive history is a critical component of the male evaluation. The first step is to distinguish between primary (no history of inducing a pregnancy) and secondary (history 366

Copyright 2010, Elsevier Inc. All rights reserved.

C h a p t e r 3 4     Infertility: The Male l

Abnormalities of sperm production Primary testicular failure (hypergonadotropic hypogonadism):

France Unknown 8%

• Genetic abnormality (Klinefelter syndrome, Y chromosome microdeletion, other)

Male 20%

Male and Female 39%

367

Secondary testicular failure:

Female 33%

• Hypogonadotropic hypogonadism • Cryptorchidism • Atrophy (orchitis) • Exogenous androgen use • Exposure to gonadotoxins/heat • Varicocele Abnormalities of sperm function

(a)

• • • •

Mongolia Unknown 10%

Male 25%

Male and Female 19%

Anti-sperm antibodies Infection Varicocele Sperm DNA fragmentation

• Sperm-cervical mucus interaction • Zona pellucida binding/sperm penetration • Acrosome reaction • Biochemical (reactive oxygen species) Obstruction of excurrent ductal system • • • •

Female 46%

(b)

Vasectomy Congenital absence of the vas deferens Epididymal obstruction (congenital or acquired) Ejaculatory duct obstruction (congenital or acquired)

Figure 34.2  Etiology of male infertility. Nigeria Unknown 11%

Male and Female 21%

Male 42%

Female 26%

(c)

Figure 34.1  Infertility etiology by sex in (a) France,3 (b) Mongolia,5 and (c) Nigeria6.

of pregnancy induction in the past, but unable to achieve at present) infertility. Prior history of pregnancies does not ensure lifelong fertility potential and patients with secondary or acquired infertility are evaluated in the same manner as those with primary infertility. Intercourse timing and frequency should be discussed in detail with the couple. Daily or every-other-day intercourse should begin two days before ovulation to ensure the presence of spermatozoa at ovulation. Many couples are not familiar with the timing of ovulation relative to the onset of the menstrual period and must be

counseled appropriately. The use of lubricants for intercourse should be questioned, as many commonly used products such as K-Y Jelly, Surgilube, Lubifax, Astroglide, Replens, Touch, olive oil, and saliva are known to impair sperm motility.11–13 Baby oil,11 canola oil,12 petroleum jelly,13 and glycerin13 had minimal detrimental effects on motility in these studies. Developmental abnormalities and history of childhood illnesses should be elicited during the interview. Although cryptorchidism is a risk factor for male infertility, the severity of its effects on individual reproductive potential is not always predictable.14 Whereas paternity rates are markedly reduced in men with bilateral cryptorchidism,15 at least one study found no difference in paternity rates in men with unilateral cryptorchidism compared to controls.16 Mumps infection contracted after the onset of puberty can involve the testis in 20–30% of cases, with bilateral involvement in one in six of those with testicular involvement.17 Long-term effects include testicular atrophy in 30–50% and oligospermia or asthenozoospermia in 7–13%, although sterility is rare.17 Endocrine function can be assessed from details about puberty and development of secondary sex characteristics such as body hair distribution. Sexually transmitted diseases such as gonorrhea and chlamydia are associated with excurrent ductal inflammation and can result in epididymal obstruction. Many environmental and occupational toxins are associated with abnormal sperm production and men should

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be questioned regarding exposure or use. Agents such as heat, radiation, heavy metals, organic solvents, pesticides, and estrogens have been shown to affect semen parameters. Medications such as sulfasalazine, colchicine, cimetidine, nitrofurantoin, and antidepressant medications and drugs such as caffeine, nicotine, alcohol, marijuana, and cocaine are also implicated in impaired fertility. Adverse effects of these substances on sperm are usually reversible with discontinuation of exposure or use. Whereas most agents act directly on sperm or sperm production, antidepressant medications may impair sperm transport, resulting in abnormal DNA fragmentation without an effect on semen parameters.18 The use of androgenic anabolic steroids by athletes depresses sperm production by interfering with the hypothalamic–pituitary–gonadal (HPG) axis, and these effects are not always reversible with drug cessation.

Medical History Medical illnesses such as diabetes mellitus can affect ferti­ lity. Diabetes mellitus is a systemic endocrinopathy that has multiple effects on reproductive potential, including erectile and ejaculatory dysfunction and impaired spermatogenesis.19 Upper respiratory tract disease may be associated with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A family history of male infertility may imply a genetic etiology. A surgical history, especially scrotal, inguinal, retroperitoneal, and lower urinary tract procedures may reveal iatrogenic injury to the vas deferens. Inguinal herniorrhaphy, renal transplantation, and scrotal surgery including orchiopexy and hydrocelectomy account for many of the cases of iatrogenic injury to the vas deferens or epididymis.20 Retroperitoneal procedures involving the sympathetic trunk can cause ejaculatory dysfunction.

Physical Examination A complete physical examination starts with an overall inspection of the patient’s body habitus with focus on secondary sex characteristics and signs of feminization. Although patients with sex-chromosome abnormalities such as Klinefelter syndrome (47,XXY) are classically described as tall and eunichoid with gynecomastia and small testes, the phenotype is variable and may not be apparent on physical exam. Scrotal examination is best performed in a relatively warm room. A heating pad provides additional relaxation of the dartos and cremaster muscles for easier palpation of scrotal contents. The testes are assessed for size and consistency. Normal testicular volume ranges from 15 to 25 ml21 with a firm consistency. Small, soft testes can result from primary (intrinsic defect in spermatogenesis) or secondary (endocrine or extrinsic factors such as exogenous androgens, heat and gonadotoxins) testicular failure. The presence and consistency of the epididymides and vasa deferentia are confirmed. Epididymal fullness correlates

with epididymal obstruction in men with azoospermia.22 Diagnosis of congenital absence of the vas deferens can by made by physical examination alone and does not require scrotal ultrasonography. Varicocele is an abnormal dilation of testicular veins that can be palpated within the spermatic cord through the scrotal skin. While 15% of fertile men are found to have varicocele, 35% of men with primary infertility and up to 80% of those with secondary infertility have varicocele.23 Varicocele is associated with decreased testicular volume, impaired sperm quality, and decline in Leydig cell function24 as well as diminished testosterone levels.25 The patient is examined for varicocele in both the upright and supine positions. Grade I varicocele is palpable only with the Valsalva maneuver, grade II is palpable in the standing position, and grade III is visible through the scrotal skin as a “bag of worms.” Digital rectal examination can detect the presence of midline cysts, significant prostatic asymmetry or dilated seminal vesicles. The vasa deferentia and seminal vesicles empty into the ejaculatory ducts, which in turn course through the central zone of the prostate to enter the prostatic urethra at the level of the utricle. Although ejaculatory obstruction may be secondary to a palpable utricular, Müllerian or Wolffian duct cyst with subsequent dilation of the seminal vesicles, these patients classically have normal physical examinations.26

Semen Analysis Semen analysis, the mainstay in the diagnosis of male infertility, should be performed according to the guidelines established by the World Health Organization (WHO)27 by a certified andrology laboratory. The semen specimen is collected by masturbation or by intercourse with a Silastic condom that does not contain substances toxic to spermatozoa. Collection should be performed following an abstinence period of 2 to 3 days. As the finding of decreased ejaculate volume most often results from incomplete specimen collection, the patient should be instructed to carefully collect the entire specimen or at least indicate if spillage occurs. Although andrology laboratories generally prefer samples collected in the office, many men elect to obtain the specimen at home and transport to the office for analysis within one hour of collection. If collected at home, the patient should transport the specimen in a sterile container; placing the container in a shirt or coat pocket during transportation will help to keep the specimen closer to body temperature. Complete semen analysis includes ejaculate volume, sperm count, concentration, motility, and morphology.27 Reference ranges determined by WHO are listed in Table 34.1.27 These values have been established based on clinical evidence and represent an estimate of the sperm parameters adequate to achieve pregnancy with intercourse. They do not reflect the average values of fertile men. If abnormal, another analysis should be performed in four weeks to confirm the initial findings.

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Table 34.1  Reference ranges for semen analysis27 Ejaculate volume Sperm concentration Total sperm count Motility

Normal morphology (strict criteria) pH

2.0 ml 20 million/ml 40 million/ejaculate 50% (grade a  b) or 25% (grade a) within 60 minutes of ejaculation 14% 7.2

Source: WHO Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction, 4th edn.27

Ejaculate Volume Decreased ejaculate volume may be seen in ejaculatory duct obstruction, primary testicular dysfunction, congenital bilateral absence of the vas deferens (CBAVD), and retrograde ejaculation. In ejaculatory duct obstruction and in most men with CBAVD, the alkaline seminal vesicle contribution is absent from the ejaculate. The acidic prostatic fluid component predominates resulting in an acidic shift (7.2) of the semen pH. Seminal vesicles contribute fructose to the ejaculate; diminished levels of fructose in the semen correlates with the degree of ejaculatory duct obstruction. In the classic case of complete, bilateral ejaculatory duct obstruction, semen analysis should demonstrate low volume azoospermia with acidic pH and absence of fructose. Seminal vesicle abnormalities (absence, cystic dilation) may accompany CBAVD. Bilateral testicular atrophy caused by primary or secondary testicular failure resulting in hypogonadism can also result in low ejaculate volume. Androgens control seminal vesicle and prostate secretions; as a result, ejaculate volume is reduced in the presence of low circulating testosterone. Retrograde ejaculation is detected by post-ejaculatory urine analysis and is described in a subsequent section. Sperm Concentration and Total Sperm Count Azoospermia, defined as the complete absence of sperm on standard microscopic semen analysis, is confirmed by centrifugation of the semen specimen at 2000  g for 10 minutes with meticulous high-powered (400) microscopic examination of the pellet. If no sperm are found, repeated tests with vigorous centrifugation at 3000  g for 15 minutes and microscopic examination should be performed before the diagnosis of azoospermia is recorded.28 Azoospermia should be further classified as obstructive (normal spermatogenesis) or nonobstructive (diminished or absent spermatogenesis). Obstructive azoospermia can occur anywhere in the excurrent ductal system from the efferent ducts to the ejaculatory ducts. Nonobstructive azoospermia may result from primary or secondary testicular failure. Low levels of spermatogenesis may be present in

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nonobstructive azoospermia, but not in sufficient quantity for epididymal transit and ejaculation.29 Evaluation of a centrifuged semen specimen can detect sperm in up to 35% of men who are diagnosed with nonobstructive azoospermia.30 The finding of sperm in this population can obviate the need for surgical sperm retrieval. Oligozoospermia is defined as sperm concentration less than 20 million/ml and severe oligozoospermia is sperm concentration less than 5 million/ml. Varicocele, the most common etiology for male infertility, often presents as oligozoospermia and abnormalities of sperm motility and forward progression. Microsurgical correction of clinically significant (palpable) varicocele improves sperm concentration, motility, and morphology with a corresponding increase in pregnancy rate. In a study by Madgar et al., 60% of men with abnormal semen analyses secondary only to varicocele who underwent varicocelectomy experienced pregnancy within one year compared to 10% of the control group whose varicocele went unrepaired.31 The control group subsequently underwent varicocelectomy and 44% initiated a pregnancy during the second year of the study.31 Varicocelectomy improves semen parameters sufficiently such that for many couples, ART are rendered unnecessary or the type of ART needed to achieve pregnancy is downstaged.32 Up to 50% of men with varicocele and azoospermia may have return of sperm to the ejaculate after varicocelectomy; however, most men will still require surgical testicular sperm extraction.33–35 Severe oligozoospermia is often idiopathic, but known etiologies include varicocele, endocrine deficiencies, and genetic disorders such as microdeletion of the Y chromosome (AZFc region). Hormone evaluation and genetic testing for Y chromosome microdeletions are indicated in this population and will be discussed later in this chapter. Total sperm count is a function of sperm concentration and semen volume. Low semen volume may result in low total count even with a normal concentration. Conversely, high semen volume may result in low concentration even with a normal count. Fluctuations between sperm concentration and volume are determined by complex factors including duration of abstinence and presence of physiol­ ogical and environmental stress. Fertility potential cannot be determined by specific values of semen parameters; total sperm count, sperm concentration, and semen volume are assessed together to predict adequacy. Motility And Forward Progression Motility is the percentage of sperm with any degree of tail motility. Forward progression is expressed as the percentage of motile sperm progressing in one general direction. Deficient sperm movement (asthenozoospermia) can result from various pathologic processes. The presence of antisperm antibodies (ASA) in the semen may induce sperm aggregation and impaired motility. ASA testing detects antibodies in both serum and semen. Genital tract infections

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are another cause of impaired sperm motility by increasing the number of leukocytes in the semen. White blood cells cannot be differentiated from immature germ cells on routine semen analysis and both types of cells are collectively called “round cells.” The sample should be analyzed for the presence of leukocytes if more than 5 million round cells/ml are found (see Leukocytospermia below). If no motile sperm are found on semen analysis, a viability stain helps to identify viable, nonmotile sperm. A large number of viable but immotile sperm may indicate a diagnosis of immotile cilia syndrome. In this rare disorder, sperm cannot move due to a lack of dynein arms within the axoneme of the flagellae. The cilia of the respiratory tract are also affected. When associated with situs inversus, immotile cilia syndrome is known as Kartagener’s syndrome. These patients present with chronic respiratory tract infections and infertility. The diagnosis is confirmed with electron microscopy of the spermatozoa. Asthenozoospermia and low semen volume are signs of partial ejaculatory duct obstruction. In men with a history of vasectomy reversal, asthenozoospermia with detectable levels of ASA portends partial obstruction of the vasal anastomosis. And the ubiquitous varicocele can diminish sperm motility and forward progression. Prolonged abstinence periods can also compromise motility. In most cases, impaired motility reflects defective testicular function and potential gonadotoxin exposures such as heat should be identified. Morphology Sperm morphology predicts not only the adequacy of spermatogenesis but the likelihood of achieving conception. Of all the semen parameters, morphology criteria have undergone the most significant revision among editions of the WHO laboratory manual. WHO normal morphology percentages have decreased sequentially from 50%36 to 30%37 to 14% in the most recent guidelines,27 which endorse the Kruger “strict” criteria. Strict criteria are based on the finding that IVF success rates were significantly higher in a population with greater than 14% normal morphology compared to a population with less than 14% normal morphology.38 Although this study established morphology standards for IVF, the relationship between the strict criteria and natural conception is not well established. In fact, Menkveld et al. proposed a reduction of strict criteria cut-off for normal spermatozoa to 3%.39 Five major published morphologic classification systems have been used over the past 50 years: ASCP, MacLeod, WHO 2nd edition, WHO 3rd edition, and WHO 4th edition/strict criteria.40 The lack of one designated classification protocol has led to some confusion among andrology laboratories as to which standard to follow for sperm morphology assessment.40 Indeed, detection of sperm morphologic abnormalities is a highly subjective evaluation and prone to significant variability.

Defects in sperm morphology (teratozoospermia) are categorized by location: head, neck (midpiece) or tail. All three segments must be normal for a sperm to be designated as such. Varicocele and testicular failure are two causes of teratozoospermia. Directed treatment of the specific disorder can improve morphology.

Advanced evaluation Hormone Assessment Derangements of the HPG axis (Figure 34.3) are associated with abnormalities of spermatogenesis and sexual function. Men with sperm concentration less than 10 million/ml, decreased libido or other clinical manifestations of endocrinopathy should undergo hormone evaluation.10 Initial testing includes serum testosterone and FSH, and a more extensive hormone panel is obtained if these values are abnormal. Results of the endocrine panel can be characteristic of a specific diagnosis (Table 34.2). Men with azoospermia secondary to testicular failure often present with small, soft testes measuring less than 10 ml in volume with small, flat epididymides. In primary testicular failure, decreased testosterone production diminishes negative feedback inhibition and gonadotropin production is stimulated (hypergonadotropic hypogonadism). These men often have excessive conversion of testosterone to estradiol by the aromatase enzyme and respond to aromatase inhibitor therapy with normalization of testosterone levels and improved spermatogenesis. Men with azoospermia secondary to obstruction have normal testosterone production and the hormone profile reflects the normal state. Although a significantly elevated FSH is consistent with spermatogenic failure, not all men with abnormal spermatogenesis have elevated FSH levels. In a study by Schoor et al., 96% of men with obstructive azoospermia had FSH levels less than or equal to 7.6 mIU/ml or testicular long axis greater than 4.6 cm, whereas 89% of men with nonobstructive azoospermia had FSH levels greater than 7.6 mIU/ml or testicular long axis less than or equal to 4.6 cm.41 The hormone evaluation must be interpreted in the context of the physical examination to differentiate whether azoospermia is caused by obstruction or by testicular failure. Men with primary testicular failure, small, soft testes, elevated FSH, and low ejaculate volume secondary to low androgen levels should be advised to undergo genetic evaluation to rule out chromosomal abnormalities such as Klinefelter syndrome and microdeletions of the Y chromosome. Low testosterone, low FSH, and low LH are typical findings in hypogonadotropic hypogonadism (HH) wherein the pituitary does not produce adequate levels of gonadotropins to maintain adequate testosterone production. HH may be congenital or acquired. Kallmann’s syndrome, a congenital disorder of the hypothalamus with failure of GnRH secretion, is HH associated with midline abnormalities such as

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Hypothalamus

(–)

GnRH

(–)

Prolactin

Pituitary

LH

FSH

(–)

(–) (+ )

Testes Sertoli cell

Leydig cell

Inhibin

Testosterone Dihydrotestosterone Estradiol

Activin

Figure 34.3  Hypothalamic–pituitary–gonadal axis. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone.

Table 34.2  Correlation between serum hormone levels and endocrine diagnosis T

FSH

LH

Prolactin

Diagnosis

Normal Low

Normal High

Normal Normal→High

Normal Normal

Low Low

Low Low→Normal

Low Low

Normal High

Normal Primary testicular failure (Hypergonadotropic hypogonadism) Hypogonadotropic hypogonadism Functional pituitary adenoma

FSH, follicle-stimulating hormone; LH, luteinizing hormone; T, testosterone.

anosmia42 and less commonly cleft palate and unilateral renal agenesis. Congenital HH may be associated with cryptorchidism and micropenis. Induction of spermatogenesis in men with HH is possible with administration of human chorionic gonadotropin (hCG) until normal serum testosterone levels are achieved followed by the combination of hCG and human menopausal gonadotropin (hMG) or FSH to complete spermatogenesis. Once the sperm concentration stabilizes, the hMG or FSH can be discontinued and spermatogenesis maintained with hCG monotherapy. Pituitary adenomas, isolated gonadotropin deficiency, panhypopituitarism or pituitary trauma are examples of acquired HH. Men with a hormone profile suggestive of HH should undergo cranial MRI to evaluate the sella turcica for

the presence of a pituitary adenoma. Functional adenomas of the pituitary may produce high levels of prolactin, which reduces gonadotropin release with feedback inhibition. Decreased libido often presages the hypogonadal state. Although medical treatment for both micro- and macroadenomas is usually the same, sizeable macroadenomas may cause significant morbidity from mass effect and should be followed by a neurosurgical consultant. Hyperprolactinemia is treated with daily administration of the dopaminergic agonist bromocriptine or the newer agent cabergoline which is associated with fewer side effects and is administered only twice per week. Empiric hormonal therapy has not been shown to improve sperm production or quality in men with nonobstructive

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azoospermia and normal hormone levels. In an investigation by Pavlovich et al., however, many men with nonobstructive azoospermia had low testosterone to estradiol (T:E2) ratios compared to the fertile population.43 Aromatase inhibitors decrease the conversion of testosterone and androstenedione to estradiol and estrone, respectively, increasing serum testosterone levels. Raman and Schlegel demonstrated increased T:E2 and improved semen parameters, including sperm concentration and motility, in infertile men with low T:E2 treated with an aromatase inhibitor.44 An E2 level may be obtained in infertile, oligozoospermic men to determine T:E2, although these data were not available for review and inclusion in the recommendations of the Male Infertility Best Practice Policy Committee.10

Post-ejaculatory Urinalysis Men with bladder neck dysfunction and retrograde flow of ejaculate into the bladder may present with low volume or absent ejaculate. Diabetes mellitus and surgical procedures of the urogenital tract such as bladder neck reconstruction and transurethral resection of the prostate are risk factors for retrograde ejaculation. Certain medications also can cause retrograde ejaculation. Men with ejaculate volume less than 1.0 ml who are not found to have HH or CBAVD should undergo post-ejaculatory urinalysis (PEU).10 Fluid production within the seminal vesicles and the prostate requires androgen stimulation which is deficient in HH. CBAVD is often associated with hypoplasia of the seminal vesicles or obstruction of the ejaculatory ducts, resulting in low volume ejaculate that is acidic and typically lacking in fructose. PEU determines the number of sperm that are present within the bladder following centrifugation of the specimen and careful examination of the pellet with light microscopy under 400 magnification. Retrograde ejaculation is diagnosed if any sperm are noted within the urine of a patient with azoospermia. The diagnosis is difficult in men with oligozoospermia, as sperm in the urine may reflect washout of the urethra with urination; more than 50% of sperm should be in the antegrade specimen rather than in the urine. Patients with retrograde ejaculation may benefit from shortterm administration of an adrenergic agonist such as pseudoephedrine HCl to induce closure of the bladder neck at the time of ejaculation and promote antegrade ejaculation. If medical therapy is unsuccessful, sperm may be retrieved from the urine for use in ART. The patient should be wellhydrated and the urine is alkalinized with administration of potassium citrate to avoid toxicity to sperm at retrieval.

Ultrasonography Transrectal ultrasonography (TRUS) should be obtained in men with palpable vasa deferentia and acidic, low-fructose and low-volume ejaculate to assess for ejaculatory duct obstruction. In partial or unilateral obstruction, the

semen may be only slightly acidic and contain fructose. Ultrasonography can detect seminal vesicle dilation (1.5 cm in anteroposterior diameter) and evidence of ejaculatory duct obstruction.45 In men with ejaculatory duct obstruction, the seminal vesicles may be aspirated under ultrasound guidance with intraoperative microscopic analysis of the aspirate.46 If present, motile sperm should be cryopreserved for ICSI. Jarow reported 50–75% return of sperm to the ejaculate and 25% pregnancy rate with transurethral resection of the ejaculatory ducts (TURED).47 Unfortunately, one study reported 20% of men treated with TURED experienced complications, including watery, high volume ejaculate, prolonged catheterization for gross hematuria, urinary tract infection, chronic epididymitis with recurrent pain, post-void dribbling, and premature ejaculation.48 ICSI is recommended for viable, but poor quality sperm in the ejaculate after TURED. Unilateral absence of a scrotal vas deferens may be associated with contralateral segmental atresia of the vas deferens or seminal vesicle.49 TRUS can evaluate the ampullary portion of the contralateral vas and seminal vesicle. In one study, 26% of men with congenital unilateral absence of the vas deferens and 11% of men with CBAVD had unilateral renal agenesis.50 Abdominal ultrasound is indicated to assess the kidneys in men with vasal agenesis. Scrotal ultrasonography is rarely necessary for the infertility evaluation, as the majority of scrotal pathology can be palpated on physical examination. Clinically significant varicoceles, CBAVD, and testis tumors are often diagnosed with palpation alone. Scrotal ultrasonography is not indicated unless findings on physical exam are equivocal or an adequate physical examination is not possible due to difficult anatomy or body habitus. Clinically palpable and significant varicoceles are usually at least 3 mm in size.

Genetic Analysis Chromosome abnormalities are associated with male infertility. The best characterized genetic anomalies affecting fertility are mutations in the CFTR gene, Klinefelter syndrome and microdeletions of the Y chromosome. Other karyotypic abnormalities in infertile men include autosomal translocations and inversions.51 Preimplantation genetic diagnosis (evaluation of fertilized embryos by biopsy during IVF) using fluorescence-in-situ hybridization for identification of chromosome composition may be considered when using sperm from men with known chromosomal abnormalities.52 Mutations In The Cftr Gene CBAVD, congenital unilateral absence of the vas deferens, congenital bilateral partial absence of the vas or epididymides, and congenital epididymal obstruction comprise the spectrum of vasal aplasia. CBAVD may occur in association with mesonephric (renal) anomalies or because of CFrelated defects. Oates and Amos found up to 80% of men

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with CBAVD to carry mutations in at least one allele of the CFTR gene,53 located on the long arm of chromosome 7. Chillon et al. reported a 72% mutation rate in at least one allele, 19% in both.54 The gene encodes an ion channel protein but also participates in the formation of the distal twothirds of the epididymis, vas deferens, seminal vesicle, and ejaculatory duct. As new mutations within the CFTR gene are discovered, the percentage of men with CBAVD who are found to harbor CFTR mutations increases. Perhaps all men with two orthotopic kidneys and CBAVD carry mutations in the CFTR gene; failure to detect these mutations reflects limitations of current testing methodologies. However, even if possible, testing for every mutation would not be practical, especially for rare mutations. Approximately 4% of whites are carriers of CFTR gene mutations.55 Since men with vasal agenesis are likely carriers of CFTR mutations, the female partner must be tested for CFTR gene mutations to determine the risk of cystic fibrosis or CBAVD in the offspring prior to attempting ICSI. The penetrance of the CFTR carrier state in transmitting CBAVD appears to be low.56 Men with CBAVD should be screened for renal anomalies with ultrasound or CT scan. As testicular sperm production in CBAVD is normal, epididymal sperm may be retrieved for ICSI. Klinefelter Syndrome Up to 10% of men with nonobstructive azoospermia have karyotypic abnormalities. The most common chromosome abnormality is Klinefelter syndrome (47,XXY or 46,XY; 47,XXY mosaicism). The clinical spectrum of spermatogenesis in Klinefelter syndrome varies. Testicular sperm may be recovered in most men with Klinefelter syndrome using microsurgical testicular sperm extraction (TESE) for use with ICSI. Microdeletions of The Y Chromosome Y chromosome microdeletions are identified in 3–13% of infertile men.57–59 Consequential microdeletions may be detected within three regions of the long arm of the Y chromosome, designated as AZF (AZoospermic Factor) a, b, and c.59 Too small to be identified by karyotype analysis alone, microdeletions are identified by a polymerase chain reaction-based technique using multiple sequence-tagged sites.60,61 Because microdeletion testing is not standardized, selection of an experienced laboratory that thoroughly tests for deletion of entire regions (not just partial deletion) is important, as clinically relevant prognostic information can only be applied to patients with complete deletion of one or more regions. Deletions of the different regions are associated with varying capacities for sperm production. Up to 75% of men with deletions of the AZFc region may have sufficient spermatogenesis to produce sperm in the ejaculate; for those with azoospermia, sperm may be retrieved by TESE in the

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majority of these men.62–64 However, men with deletions of the AZFa or AZFb regions invariably have azoospermia and a dismal prognosis for successful sperm retrieval.64–67 As the Y chromosome passes on to all male children, concern for transmission of impaired spermatogenesis to male offspring exists, and vertical transmission of deletions has been demonstrated.63,68–70 Because of the prognostic value and implications for offspring, all men with azoo- and oligozoospermia undergoing ICSI should be screened for both chromosomal abnormalities with karyotype analysis and Y chromosome microdeletions.10 Couples should be counseled not only about possible vertical transmission of infertility, but also about potential genetic abnormalities that are not detectable by current genetic testing methodologies.

Analysis of Sperm Function In certain circumstances, even a sufficient concentration of sperm with adequate motility and normal morphology may not be able to fertilize an oocyte or support embryo development and implantation. Additional analysis of sperm function can identify specific deficiencies of normal sperm action. Leukocytospermia Excess leukocytes in semen impair sperm function and motility. Infertile men have a greater number of white blood cells in their ejaculate compared to fertile men.71 On routine semen analysis, several cell types appear similar and cannot be differentiated from one another: epithelial cells, prostate cells, immature germ cells (round spermatids, spermatocytes, spermatogonia), and leukocytes. These cells are collectively referred to as round cells. If the number of round cells in a semen analysis exceeds 5 million/ml, the percentage of these cells represented by leukocytes is assessed for the likelihood of a genital tract infection. The histochemical peroxidase stain using ortho-toluidine or the immunocytochemical pan-leukocyte monoclonal antibody test, which has the advantage of detecting activated polymorphonuclear granulocytes as well as leukocytes that do not contain peroxidase, determines the concentration of white blood cells within the semen. White blood cell concentration greater than 1 million/ml may warrant semen culture for Mycoplasma hominis, Ureaplasma urealyticum, aerobic and anaerobic bacteria and testing for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis. However, Rodin et al. reported leukocytospermia did correlate with bacteriospermia or impaired semen quality.72 Streptococcus viridans and Enterococcus faecalis were two organisms associated with poor semen quality.72 Anti-Sperm Antibodies The blood–testis barrier created by tight junctions between Sertoli cells isolates sperm from immune recognition. When the barrier is disrupted and sperm are exposed to blood,

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an antigenic response is elicited. ASA may be found in serum, semen or bound to sperm. Those bound to sperm are the most clinically significant, as they impede transport through the cervical mucus73 and interfere with sperm and oocyte interaction such that fertilization cannot occur.74 Antibodies in semen are predominantly IgA and IgG and both types can diffuse into the genital tract. IgA antibodies are also secreted in the male reproductive tract. ASA are found in 80% of men who have undergone vasectomy75 and are also associated with infection,76 leukocytospermia,77 varicocele,78 cryptorchidism,79 and testicular torsion or trauma.75 ASA serves as a marker for obstruction of the excurrent ductal system. Lee et al. reported ASA to be highly predictive of obstruction in men with azoospermia, without the need for testicular biopsy to distinguish from non-obstructive azoospermia.80 Pregnancy rates are lower in men with ASA compared to men without, and among those with ASA, significantly higher pregnancy rates are achieved if fewer than 50% of the sperm are bound by antibodies.81 Men with clumping or agglutination of sperm or asthenozoospermia on analysis should undergo ASA assessment. Either the immunobead test or the mixed antiglobulin reaction test can be used. A fresh semen sample with at least 200 sperm must be available for evaluation.27 Although infertile men with ASA may be treated with corticosteroids with the intent to suppress antibody production, improvement in fertility potential has not been unequivocally proven in clinical trials.82 For many couples with infertility secondary to ASA, the best treatment option may be ICSI. Sperm Viability Sperm viability is critical for ICSI success. Assessement of viability is difficult for nonmotile sperm. Viability testing is used in the setting of sperm retrieved from the testis, asthenozoospermia and cryptozoospermia (sperm found only after centrifugation of the semen specimen within the pellet). Men with nonobstructive azoospermia who undergo TESE usually have low numbers of sperm with minimal motility. It is impossible to ascertain which sperm are viable for ICSI without conducting a sperm viability test. Viability testing is also useful for cryopreserved specimens after the thaw process. Cryopreservation decreases the number of viable sperm by 50%,83 and for specimens that contain few sperm prior to cryopreservation, very rare sperm may be available following thaw. Viability testing may be necessary to select nonmotile viable sperm for ICSI. If a large number of sperm are nonmotile, but viable, the diagnosis of immotile cilia syndrome must be considered. Viability testing is indicated if less than 50% of sperm are motile.27 Two types of tests are available: dye exclusion with Eosin Y and Nigrosin (Sigma-Aldrich, St Louis, MO) and hypo-osmotic swelling test (HOST).84 The dye exclusion test works on the principle that viable sperm with intact plasma membranes keep out the dye. Unfortunately, sperm

do not remain viable following the dye exclusion test and cannot be used for ICSI. In HOST, water follows the solute concentration gradient and diffuses into viable sperm, causing the plasma membrane to bulge and the tail to curl.85 The sperm are examined with phase-contrast microscopy. Nonviable cells cannot maintain the osmotic gradient and do not swell. Viable sperm found on HOST may be used in ICSI, but it has not been conclusively demonstrated that routine use of HOST improves ICSI outcomes. Another approach for detection of viable sperm is the use of pentoxifylline. Sperm are incubated with 3 mM pentoxifylline for one hour, after which the sperm are washed free of this medication. Motile sperm after treatment are viable and can be used effectively for ICSI. Sperm Dna Fragmentation The paternal contribution of undamaged sperm DNA is necessary for successful embryonic development. There are several assays of sperm DNA quality including single cell gel electrophoresis assay (Comet), terminal uridine nick end labeling assay (TUNEL), and sperm chromatin structure assay (SCSA). Many studies have evaluated whether sperm DNA integrity correlates with fertility potential, but results are conflicting. Researchers are studying the effects of sperm DNA fragmentation on fertilization, implantation, and embryo development to better predict the impact of DNA integrity on ART and natural pregnancy outcomes. One study reported that men with 30% or more sperm DNA damage (DNA fragmentation index 30%) detected with the SCSA were unable to initiate a pregnancy, whereas 84% of those who achieved pregnancy had a DNA fragmentation index less than 15%.86 In another study, sperm with greater than 12% DNA fragmentation on TUNEL did not result in pregnancy when used for intra-uterine insemination (IUI).87 No IVF or ICSI pregnancies were achieved with sperm with greater than 27% DNA denaturation detected by SCSA.88 Further investigation is needed before routine application of DNA fragmentation assays for male infertility. However, abnormal sperm DNA fragmentation is the only male factor identified with an impaired pregnancy rate using IVF or ICSI.89 The relationship between DNA integrity and embryo development and pregnancy loss with ICSI is more compelling.90 Sperm–Cervical Mucus Interaction (Post-Coital Test) Sperm must pass through cervical mucus to enter the uterus and fallopian tube. Just prior to ovulation, cervical mucus changes to become receptive to spermatozoa. The mucus serves as a barrier for abnormal sperm while providing a nutritive, protective reservoir to supply sperm to the uterus following intercourse. The post-coital test (PCT) is a microscopic evaluation of the cervical mucus following intercourse around the time of ovulation.91 The presence of

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motile sperm with adequate forward progression is a good indicator that the interaction between cervical mucus and sperm is not hostile.92 Routine use of PCT does not confer benefit to infertile couples.93 Computer-Assisted Semen Analysis Computer-assisted semen analysis (CASA) was introduced as a technology intended to provide a precise, automated, reproducible, objective assessment of sperm characteristics, specifically movement pattern and concentration. Computer analysis of digitized images procured with a video camera to identify specific characteristics of sperm motion potentially predicts fertility potential.94 For meaningful and reproducible results, CASA requires standardization of sample preparation, frame rate, and sperm concentration95 in addition to strict adherence to guidelines for instrument use. Widespread application of CASA is a complex endeavor. Whether this technology offers additional information of clinical benefit remains to be established.

Treatment Treatment of male infertility, as for all disease entities in medicine, is most successful when targeted to a specific etiology. Etiologies of male infertility can vary widely, from post-vasectomy vasal obstruction to varicocele, from endocrinopathies to idiopathic or unknown causes. Once the diagnosis of male infertility is made, the history, physical examination, semen analyses, and other tests can help to identify specific causes. In men with azoospermia, the first fork in the diagnostic pathway is obstructive versus nonobstructive etiologies.

Management of Obstructive Azoospermia Ejaculatory Duct Obstruction Up to 5% of men with azoospermia are diagnosed with ejaculatory duct obstruction.48 The obstruction may be congenital (atresia, stenosis or utricular cysts) or acquired (trauma, infection, inflammation or iatrogenic).96–98 The standard treatment of ejaculatory duct obstruction is transurethral resection of the ejaculatory ducts (TURED). In one study, 65% of 46 men who underwent TURED had improved semen quality and 20% initiated a pregnancy.48 The study also reported a 20% complication rate, including watery, high volume ejaculate, gross hematuria, urinary tract infection, chronic epididymitis with recurrent pain, post-void dribbling, and premature ejaculation.48 Furthermore, 4% of men with sperm in the preoperative ejaculation specimen developed azoospermia after treatment.48 Because of the potential for complications with TURED, proposed alternatives include antegrade balloon dilatation of the ejaculatory duct99 and transrectal ultrasonography-guided seminal vesicle aspiration of sperm for use with ART.100

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Vasal and Epididymal Obstruction Perhaps the best illustration of the management of vasal and epididymal obstruction is treatment for post-vasectomy obstructive azoospermia. Approximately 6% of men who undergo vasectomy eventually seek reversal.101 ICSI using surgically-retrieved sperm from the epididymis or testis of men who had undergone vasectomy is widely available and yield excellent success rates. However, almost all costeffectiveness analyses have demonstrated microsurgical reconstruction of the reproductive tract to be the most efficacious and economical management for post-vasectomy obstructive azoospermia,102–107 even for a second attempt at vasectomy reversal.108 In a recent study, the cost per live delivery in 2005 was calculated to be $25 903 for vasectomy reversal compared to $54 797–$56 861 for ART with surgical sperm retrieval.109 The Practice Committee of the American Society for Reproductive Medicine recommends microsurgical reconstruction if the obstructive interval after vasectomy is less than 15 years and no female risk factors are present.110 Reconstruction of epididymal obstruction should be performed by an expert microsurgeon.110 ICSI with sperm retrieval is recommended if female age is greater than 37 years, if fertility factors requiring IVF (such as tubal disease) are present, if the chance for success is greater with this technique or if the couple prefers this method for financial or other reasons.110 Advances in microsurgical techniques have resulted in excellent success rates for both vasovasostomy and vaso­epididymostomy, allowing for natural conception. Following vasovasostomy, sperm return to the ejaculate in up to 99.5% of men.111 Pregnancy occurred in 52% of couples.112 Delayed obstruction following initial patency has been observed in up to 12% of patients by 14 postoperative months.112 The greater the elapsed time between vasectomy and reconstruction, the higher the likelihood of epididymal obstruction from increased pressure within the testicular end of the vas deferens. This pressure is transmitted to the epididymis, causing rupture, scar and obstruction.113 Several factors impact the chance for anastomotic patency and eventual pregnancy, including prior fertility, age at vasectomy, obstruction interval, partner age and fertility status, presence of a sperm granuloma, intraoperative quality of the sperm and intravasal fluid, length of the testicular remnant vas deferens, and vasectomy site.114 For example, the quality of the sperm and intravasal fluid expressed from the testicular remnant of the vas deferens helps to determine whether a vasovasostomy or a vasoepididymostomy is needed. Thick, white, toothpaste-like intravasal fluid with no sperm on microscopic examination indicates likely epididymal obstruction, whereas copious, cloudy, thin watery intravasal fluid containing sperm with tails on microscopic examination heralds a good chance for a successful vasovasostomy.115 If intraoperative findings suggest epididymal obstruction, vasoepididymostomy not vasovasostomy should be performed. Accurate approximation

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of the vasal mucosa to the mucosa of a single epididymal tubule is possible with refined microsurgical techniques, resulting in patency rates exceeding 80%.116 As many as 21% of initially patent anastomoses may shut down by 14 months postoperatively.112 For this reason, sperm should be cryopreserved at the time of vasoepididymostomy and as soon as they appear in the ejaculate postoperatively to be used for ICSI if inadequate semen parameters preclude natural pregnancy following vasectomy reversal.

Management of Nonobstructive Azoospermia Almost two-thirds of patients with azoospermia have the nonobstructive type.117 The treatment for nonobstructive azoospermia secondary to testicular failure involves testicular sperm retrieval for use in IVF with ICSI. Sperm can be harvested from the testis with open surgical (microsurgical or conventional) and percutaneous techniques. Su et al. reported successful retrieval in 58% of 81 testicular sperm extraction attempts in men with nonobstructive azoospermia, with subsequent fertilization of 61% of 439 injected metaphase II oocytes with ICSI, clinical pregnancies in 55% of 47 cycles and ongoing pregnancies or live deliveries for 43% of 47.118 Ramasamy and Schlegel reported the correlation of the most advanced (not predominant) histologic pattern of spermatogenesis seen on diagnostic testis biopsy with sperm retrieval success: sperm was successfully harvested in 95% of 40 men with hypospermatogenesis, 68% of 38 men with maturation arrest, and 42% of 191 men with pure Sertoli-cell-only pattern.119

Endocrine Hormonal therapy represents another broad treatment category for male infertility. About 1.7% of infertile men have clinically significant endocrine diagnoses.120 Although this represents a small subset of infertile men, proper diagnosis of endocrinopathies is important because effective medical therapies are available. Problems along the HPG axis can be overcome with hormonal therapy. For example, men with hypogonadotropic hypogonadism who desire fertility can be treated with human chorionic gonadotropin (hCG) in combination with recombinant FSH. Hormonal therapy has also been applied empirically in men with idiopathic infertility for many years, in the hopes that optimizing the hormonal milieu will overcome the unknown factor inhibiting spermatogenesis. Unfortunately, the data for this application of endocrine therapy have been disappointing, and there are no conclusive studies to date that define the parameters for use of empiric hormonal treatment for male infertility.

Varicocele Although varicocele is one of the most common causes of male infertility, treatment is somewhat controversial,

perhaps because our understanding of varicocele pathophysiology is incomplete. There is no established medical therapy for varicocele; medications such as antioxidants are being evaluated. Treatment options include surgical varicocelectomy (conventional, laparoscopic or microsurgical), percutaneous embolization or ART. Each technique has its champions and detractors. To weigh in on the debate, Al-Said et al. reported their results from the largest prospective randomized trial to date comparing open, laparoscopic, and microsurgical approaches to varicocele surgery in 298 infertile men (446 clinically palpable varicoceles).121 Although early postoperative complications were comparable, the microsurgical group developed significantly fewer hydroceles and varicocele recurrences. Microsurgeons generally attribute these outcomes to superior visualization and preservation of the testicular artery and lymphatics. Studies of varicocelectomy efficacy have reported conflicting results, with some groups questioning the benefit of surgery or intervention.122 However, most male fertility specialists believe that varicocelectomy is an important treatment option for well-selected men with clinically significant varicoceles. In a recent meta-analysis, Marmar et al. reported the odds of spontaneous pregnancy after surgical varicocelectomy, compared with no or medical treatment for palpable varicocele to be 2.87 (95% CI, 1.33–6.20) with a random-effects model or 2.63 (95% CI, 1.60–4.33) with a fixed-effects model.123 Their analysis was limited to men with abnormal semen analyses and palpable varicoceles, excluding men being treated for subclinical lesions.123 Studies have reported induction of spermatogenesis and achievement of pregnancy in men with varicoceles and azoospermia or severe oligoasthenospermia.35 In general, surgery for bilateral and larger (higher grade) lesions result in significantly greater improvement in postoperative semen parameters.124,125

Conclusion Evaluation of infertile men involves a systematic process beginning with reproductive and medical histories, physical examination, and two semen analyses. This initial protocol determines the course of therapy or the need for further evaluation with additional studies. Although various laboratory and radiologic tests are available for the work up of male infertility, many have not been conclusively demonstrated to predict successful conception. Recent work has shed light on a few of the more promising assays, which eventually may become a definitive part of the male evaluation. Fortunately, the old-fashioned history, physical examination, and semen analysis impart significant prognostic information without the need for expensive testing, perhaps more so than for most other fields of medicine, which increasingly depend on technology for diagnosis. Also

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heartening is the availability of safe and effective therapies for male infertility with which even azoospermic men have the hope of fathering children. Not so long ago, men with CBAVD had few options for fatherhood beyond donor sperm or adoption. They now enjoy a high chance for successful conception with surgical sperm retrieval and ICSI.

Acknowledgment The authors acknowledge funding from the Ferdinand C. Valentine Fellowship of the New York Academy of Medicine & The Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust

References   1. Juul S, Karmaus W, Olsen J. Regional differences in waiting time to pregnancy: pregnancy-based surveys from Denmark, France, Germany, Italy and Sweden. The European Infertility and Subfecundity Study Group. Hum Reprod 1999;14:1250.   2. Nieschlag E. Scope and goals of andrology. In: E Nieschlag, HM Behre, eds. Andrology: Male Reproductive Health and Dysfunction, 2nd edn. Berlin: Springer-Verlag; 2001.   3. Thonneau P, Marchand S, Tallec A, et al. Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988–1989). Hum Reprod 1991;6:811.   4. Meacham RB, Joyce GF, Wise M, et al. Male infertility. J Urol 2007;177:2058.   5. Bayasgalan G, Naranbat D, Tsedmaa B, et al. Clinical patterns and major causes of infertility in Mongolia. J Obstet Gynaecol Res 2004;30:386.   6. Ikechebelu JI, Adinma JI, Orie EF, et al. High prevalence of male infertility in southeastern Nigeria. J Obstet Gynaecol 2003;23:657.   7. Corson SL, Maislin G. The National Regional Advisory Council practice survey for 2000. Fertil Steril 2002;77:448.   8. Kolettis PN, Sabanegh ES. Significant medical pathology discovered during a male infertility evaluation. J Urol 2001;166:178.   9. Raman JD, Nobert CF, Goldstein M. Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol 2005;174:1819. 10. Jarow JP, Sharlip ID, Belker AM, et al. Best practice policies for male infertility. J Urol 2002;167:2138. 11. Anderson L, Lewis SE, McClure N. The effects of coital lubricants on sperm motility in vitro. Hum Reprod 1998;13:3351. 12. Kutteh WH, Chao CH, Ritter JO, et al. Vaginal lubricants for the infertile couple: effect on sperm activity. Int J Fertil Menopausal Stud 1996:400. 13. Goldenberg RL, White R. The effect of vaginal lubricants on sperm motility in vitro. Fertil Steril 1975;26:872. 14. Trussell JC, Lee PA. The relationship of cryptorchidism to fertility. Curr Urol Rep 2004;5:142. 15. Lee PA, O’Leary LA, Songer NJ, et al. Paternity after bilateral cryptorchidism. A controlled study. Arch Pediatr Adolesc Med 1997;151:260.

377

16. Miller KD, Coughlin MT, Lee PA. Fertility after unilateral cryptorchidism. Paternity, time to conception, pretreatment testicular location and size, hormone and sperm parameters. Horm Res 2001;55:249. 17. Singh R, Mostafid H, Hindley RG. Measles, mumps and rubella – the urologist’s perspective. Int J Clin Pract 2006;60:335. 18. Tanrikut C, Schlegel PN. Antidepressant-associated changes in semen parameters. Urology 2007;69:185.e5. 19. Jarow JP. Endocrine causes of male infertility. Urol Clin North Am 2003;30:83. 20. Sheynkin YR, Hendin BN, Schlegel PN, et al. Microsurgical repair of iatrogenic injury to the vas deferens. J Urol 1998;159:139. 21. Prader A. Testicular size: assessment and clinical importance. Triangle 1966;7:240. 22. Kolettis PN. Is physical examination useful in predicting epididymal obstruction? Urology 2001;57:1138. 23. Gorelick JI, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril 1993;59:613. 24. World Health Organization. The Influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril 1992;57:1289. 25. Tanrikut C, Choi JM, Lee RK, et al. Varicocele is a risk factor for androgen deficiency. Fertil Steril 2007;88(Suppl. 1):S386. 26. Fisch H, Lambert SM, Goluboff ET. Management of ejaculatory duct obstruction: etiology, diagnosis, and treatment. World J Urol 2006;24:604. 27. WHO. Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction, 4th edn. Cambridge: Cambridge University Press; 1999. 28. McLachlan RI, Baker HW, Clarke GN, et al. Semen analysis: its place in modern reproductive medical practice. Pathology 2003;35:25. 29. Silber SJ, Nagy Z, Devroey P, et al. Distribution of spermatogenesis in the testicles of azoospermic men: the presence or absence of spermatids in the testes of men with germinal failure. Hum Reprod 1997;12:2422. 30. Ron-El R, Strassburger D, Friedler S, et al. Extended sperm preparation: an alternative to testicular sperm extraction in non-obstructive azoospermia. Hum Reprod 1997;12:1222. 31. Madgar I, Weissenberg R, Lunenfeld B, et al. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril 1995;63:120. 32. Cayan S, Erdemir F, Ozbey I, et al. Can varicocelectomy significantly change the way couples use assisted reproductive technologies? J Urol 2002;167:1749. 33. Pasqualotto FF, Sobreiro BP, Hallak J, et al. Induction of spermatogenesis in azoospermic men after varicocelectomy repair: an update. Fertil Steril 2006;85:635. 34. Kim ED, Leibman BB, Grinblat DM, et al. Varicocele repair improves semen parameters in azoospermic men with spermatogenic failure. J Urol 1999;162:737. 35. Matthews GJ, Matthews ED, Goldstein M. Induction of spermatogenesis and achievement of pregnancy after microsurgical varicocelectomy in men with azoospermia and severe oligoasthenospermia. Fertil Steril 1998;70:71. 36. WHO. Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction, 2nd edn. Cambridge: Cambridge University Press; 1987.

378

s e cti o n 6     Reproductive Biology l

37. WHO. Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction, 3rd edn. Cambridge: Cambridge University Press; 1993. 38. Kruger TF, Menkveld R, Stander FS, et al. Sperm morphologic features as a prognostic factor in in vitro fertilization. Fertil Steril 1986;46:1118. 39. Menkveld R, Wong WY, Lombard CJ, et al. Semen parameters, including WHO and strict criteria morphology, in a fertile and subfertile population: an effort towards standardization of in-vivo thresholds. Hum Reprod 2001;16:1165. 40. Rothmann SA. Sperm confirm: an atlas of semen cytology and sperm morphology. Fertil Solut Inc 1997. 41. Schoor RA, Elhanbly S, Niederberger CS, et al. The role of testicular biopsy in the modern management of male infertility. J Urol 2002;167:197. 42. Seminara SB, Hayes FJ, Crowley WF Jr. Gonadotropinreleasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations. Endocr Rev 1998;19:521. 43. Pavlovich CP, King P, Goldstein M, et al. Evidence of a treatable endocrinopathy in infertile men. J Urol 2001;165:837. 44. Raman JD, Schlegel PN. Aromatase inhibitors for male infertility. J Urol 2002;167:624. 45. Carter SS, Shinohara K, Lipshultz LI. Transrectal ultrasonography in disorders of the seminal vesicles and ejaculatory ducts. Urol Clin North Am 1989;16:773. 46. Jarow JP. Transrectal ultrasonography in the diagnosis and management of ejaculatory duct obstruction. J Androl 1996;17:467. 47. Jarow JP. Diagnosis and management of ejaculatory duct obstruction. Tech Urol 1996;2:79. 48. Turek PJ, Magana JO, Lipshultz LI. Semen parameters before and after transurethral surgery for ejaculatory duct obstruction. J Urol 1996;155:1291. 49. Hall S, Oates RD. Unilateral absence of the scrotal vas deferens associated with contralateral mesonephric duct anomalies resulting in infertility: laboratory, physical and radiographic findings, and therapeutic alternatives. J Urol 1993;150:1161. 50. Schlegel PN, Shin D, Goldstein M. Urogenital anomalies in men with congenital absence of the vas deferens. J Urol 1996;155:1644. 51. Rucker GB, Mielnik A, King P, et al. Preoperative screening for genetic abnormalities in men with nonobstructive azoospermia before testicular sperm extraction. J Urol 1998;160:2068. 52. Tournaye H, Staessen C, Liebaers I, et al. Testicular sperm recovery in nine 47,XXY Klinefelter patients. Hum Reprod 1996;11:1644. 53. Oates RD, Amos JA. The genetic basis of congenital bilateral absence of the vas deferens and cystic fibrosis. J Androl 1994;15:1. 54. Chillon M, Casals T, Mercier B, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995;332:1475. 55. Correlation between genotype and phenotype in patients with cystic fibrosis. The Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med 1993;329:1308. 56. Shin D, Gilbert F, Goldstein M, et al. Congenital absence of the vas deferens: incomplete penetrance of cystic fibrosis gene mutations. J Urol 1997;158:1794.

57. Reijo R, Lee TY, Salo P, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 1995;10:383. 58. Reijo R, Alagappan RK, Patrizio P, et al. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet 1996;347:1290. 59. Vogt PH, Edelmann A, Kirsch S, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet 1996;5:933. 60. Kuroda-Kawaguchi T, Skaletsky H, Brown LG, et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet 2001;29:279. 61. Repping S, Skaletsky H, Lange J, et al. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet 2002;71:906. 62. Mulhall JP, Reijo R, Alagappan R, et al. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod 1997;12:503. 63. Oates RD, Silber S, Brown LG, et al. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod 2002;17:2813. 64. Hopps CV, Mielnik A, Goldstein M, et al. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003;18:1660. 65. Kamp C, Huellen K, Fernandes S, et al. High deletion frequency of the complete AZFa sequence in men with Sertolicell-only syndrome. Mol Hum Reprod 2001;7:987. 66. Krausz C, Quintana-Murci L, McElreavey K. Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Reprod 2000;15:1431. 67. Brandell RA, Mielnik A, Liotta D, et al. AZFb deletions predict the absence of spermatozoa with testicular sperm extraction: preliminary report of a prognostic genetic test. Hum Reprod 1998;13:2812. 68. Silber SJ, Repping S. Transmission of male infertility to future generations: lessons from the Y chromosome. Hum Reprod Update 2002;8:217. 69. Cram DS, Ma K, Bhasin S, et al. Y chromosome analysis of infertile men and their sons conceived through intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions. Fertil Steril 2000;74:909. 70. Chang PL, Sauer MV, Brown S. Y chromosome microdeletion in a father and his four infertile sons. Hum Reprod 1999;14:2689. 71. Wolff H, Politch JA, Martinez A, et al. Leukocytospermia is associated with poor semen quality. Fertil Steril 1990;53:528. 72. Rodin DM, Larone D, Goldstein M. Relationship between semen cultures, leukospermia, and semen analysis in men undergoing fertility evaluation. Fertil Steril 2003;79 (Suppl. 3):1555. 73. Haas GG Jr. The inhibitory effect of sperm-associated immunoglobulins on cervical mucus penetration. Fertil Steril 1986;46:334.

C h a p t e r 3 4     Infertility: The Male l

74. Mahony MC, Blackmore PF, Bronson RA, et al. Inhibition of human sperm-zona pellucida tight binding in the presence of antisperm antibody positive polyclonal patient sera. J Reprod Immunol 1991;19:287. 75. Alexander NJ, Anderson DJ. Vasectomy: consequences of autoimmunity to sperm antigens. Fertil Steril 1979;32:253. 76. Munoz MG, Witkin SS. Autoimmunity to spermatozoa, asymptomatic Chlamydia trachomatis genital tract infection and gamma delta T lymphocytes in seminal fluid from the male partners of couples with unexplained infertility. Hum Reprod 1995;10:1070. 77. Kortebani G, Gonzales GF, Barrera C, et al. Leucocyte populations in semen and male accessory gland function: relationship with antisperm antibodies and seminal quality. Andrologia 1992;24:197. 78. Gilbert BR, Witkin SS, Goldstein M. Correlation of spermbound immunoglobulins with impaired semen analysis in infertile men with varicoceles. Fertil Steril 1989;52:469. 79. Sinisi AA, Pasquali D, Papparella A, et al. Antisperm antibodies in cryptorchidism before and after surgery. J Urol 1998;160:1834. 80. Lee R, Goldstein M, Ullery BW, et al. Value of serum antisperm antibodies in diagnosing obstructive azoospermia. J Urol 2009;181:264. 81. Ayvaliotis B, Bronson R, Rosenfeld D, et al. Conception rates in couples where autoimmunity to sperm is detected. Fertil Steril 1985;43:739. 82. Haas GG Jr, Manganiello P. A double-blind, placebocontrolled study of the use of methylprednisolone in infertile men with sperm-associated immunoglobulins. Fertil Steril 1987;47:295. 83. Prins GS, Dolgina R, Studney P, et al. Quality of cryopreserved testicular sperm in patients with obstructive and nonobstructive azoospermia. J Urol 1999;161:1504. 84. Agarwal A, Bragais FM, Sabanegh E. Assessing sperm function. Urol Clin North Am 2008;35:157. 85. Jeyendran RS, Van der Ven HH, Perez-Pelaez M, et al. Development of an assay to assess the functional integrity of the human sperm membrane and its relationship to other semen characteristics. J Reprod Fertil 1984;70:219. 86. Evenson DP, Jost LK, Marshall D, et al. Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. Hum Reprod 1999;14:1039. 87. Duran EH, Morshedi M, Taylor S, et al. Sperm DNA quality predicts intrauterine insemination outcome: a prospective cohort study. Hum Reprod 2002;17:3122. 88. Larson KL, DeJonge CJ, Barnes AM, et al. Sperm chromatin structure assay parameters as predictors of failed pregnancy following assisted reproductive techniques. Hum Reprod 2000;15:1717. 89. Collins JA, Barnhart KT, Schlegel PN. Do sperm DNA integrity tests predict pregnancy with in vitro fertilization? Fertil Steril 2008;89:823. 90. Borini A, Tarozzi N, Bizzaro D, et al. Sperm DNA fragmentation: paternal effect on early post-implantation embryo development in ART. Hum Reprod 2006;21:2876. 91. Moghissi KS. Postcoital test: physiologic basis, technique, and interpretation. Fertil Steril 1976;27:117. 92. Oei SG, Helmerhorst FM, Keirse MJ. When is the post-coital test normal? A critical appraisal. Hum Reprod 1995;10:1711.

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  93. Oei SG, Helmerhorst FM, Keirse MJ. Routine postcoital testing is unnecessary. Hum Reprod 2001;16:1051.   94. Katz DF, Davis RO. Automatic analysis of human sperm motion. J Androl 1987;8:170.   95. Davis RO, Katz DF. Standardization and comparability of CASA instruments. J Androl 1992;13:81.   96. Goldwasser BZ, Weinerth JL, Carson CC 3rd. Ejaculatory duct obstruction: the case for aggressive diagnosis and treatment. J Urol 1985;134:964.   97. Pryor JP, Hendry WF. Ejaculatory duct obstruction in subfertile males: analysis of 87 patients. Fertil Steril 1991;56:725.   98. Goluboff ET, Stifelman MD, Fisch H. Ejaculatory duct obstruction in the infertile male. Urology 1995;45:925.   99. Jarow JP, Zagoria RJ. Antegrade ejaculatory duct recanalization and dilation. Urology 1995;46:743. 100. Orhan I, Onur R, Cayan S, et al. Seminal vesicle sperm aspiration in the diagnosis of ejaculatory duct obstruction. BJU Int 1999;84:1050. 101. Goldstein M. Vasectomy reversal. Compr Ther 1993;19:37. 102. Pavlovich CP, Schlegel PN. Fertility options after vasectomy: a cost-effectiveness analysis. Fertil Steril 1997;67:133. 103. Kolettis PN, Thomas AJ Jr. Vasoepididymostomy for vasectomy reversal: a critical assessment in the era of intracytoplasmic sperm injection. J Urol 1997;158:467. 104. Heidenreich A, Altmann P, Engelmann UH. Microsurgical vasovasostomy versus microsurgical epididymal sperm aspiration/testicular extraction of sperm combined with intracytoplasmic sperm injection. A cost–benefit analysis. Eur Urol 2000;37:609. 105. Meng MV, Greene KL, Turek PJ. Surgery or assisted reproduction? A decision analysis of treatment costs in male infertility. J Urol 2005;174:1926. 106. Garceau L, Henderson J, Davis LJ, et al. Economic implications of assisted reproductive techniques: a systematic review. Hum Reprod 2002;17:3090. 107. Deck AJ, Berger RE. Should vasectomy reversal be performed in men with older female partners? J Urol 2000;163:105. 108. Donovan JF Jr, DiBaise M, Sparks AE, et al. Comparison of microscopic epididymal sperm aspiration and intracytoplasmic sperm injection/in-vitro fertilization with repeat microscopic reconstruction following vasectomy: is second attempt vas reversal worth the effort? Hum Reprod 1998;13:387. 109. Lee R, Li PS, Goldstein M, et al. A decision analysis of treatments for obstructive azoospermia. Hum Reprod 2008;23:2043. 110. Report on Management of Obstructive Azoospermia. Fertil Steril 2006;86:S259. 111. Goldstein M, Li PS, Matthews GJ. Microsurgical vasovasostomy: the microdot technique of precision suture placement. J Urol 1998;159:188. 112. Matthews GJ, Schlegel PN, Goldstein M. Patency following microsurgical vasoepididymostomy and vasovasostomy: temporal considerations. J Urol 1995;154:2070. 113. Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J Urol 1991;145:505. 114. Nagler HM, Rotman M. Predictive parameters for microsurgical reconstruction. Urol Clin North Am 2002;29:913.

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115. Anger JT, Goldstein M. Intravasal “toothpaste” in men with obstructive azoospermia is derived from vasal epithelium, not sperm. J Urol 2004;172:634. 116. Schiff J, Chan P, Li PS, et al. Outcome and late failures compared in 4 techniques of microsurgical vasoepididymostomy in 153 consecutive men. J Urol 2005;174:651. 117. Harris SE, Sandlow JI. Sperm acquisition in nonobstructive azoospermia: what are the options? Urol Clin North Am 2008;35:235. 118. Su LM, Palermo GD, Goldstein M, et al. Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia: testicular histology can predict success of sperm retrieval. J Urol 1999;161:112. 119. Ramasamy R, Schlegel PN. Microdissection testicular sperm extraction: effect of prior biopsy on success of sperm retrieval. J Urol 2007;177:1447. 120. Sigman M, Jarow JP. Endocrine evaluation of infertile men. Urology 1997;50:659.

121. Al-Said S, Al-Naimi A, Al-Ansari A, et al. Varicocelectomy for male infertility: a comparative study of open, laparoscopic and microsurgical approaches. J Urol 2008;180:266. 122. Evers JH, Collins J, Clarke J. Surgery or embolisation for varicoceles in subfertile men. Cochrane Database Syst Rev 2000, CD000479. 123. Marmar JL, Agarwal A, Prabakaran S, et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril 2007;88:639. 124. Scherr D, Goldstein M. Comparison of bilateral versus unilateral varicocelectomy in men with palpable bilateral varicoceles. J Urol 1999;162:85. 125. Steckel J, Dicker AP, Goldstein M. Relationship between varicocele size and response to varicocelectomy. J Urol 1993;149:769.

Chapter

35

Infertility and In Vitro Fertilization Elizabeth Barbieri1, Sonya Kashyap2, and Pak H. Chung3 1

Weill Cornell Medical College, Center for Reproductive Medicine and Infertility, New York, NY, USA Reproductive Endocrinologist, University of California at San Francisco, Center for Reproductive Health and Women’s Health Research Center, San Francisco, CA, USA 3 Reproductive Endocrinologist and Infertility Specialist, Weill Cornell Medical College, The Center for Reproductive Medicine and Infertility, New York, NY, USA 2

Infertility

Therefore, although the traditional definition of infertility has been failure to conceive after one year of unprotected intercourse, this definition should perhaps be amended for the current societal demographics. Older couples should perhaps be referred earlier for infertility work-up and therapy as there is a more urgent need to ‘beat the biological clock.’ Success rates, even with reproductive technology, are extremely limited in most centers for women beyond age 40. Infertility may be further classified into primary and secondary infertility. The former describes patients who have never conceived and the latter describes patients who have previously conceived but who have not been able to conceive the number of children wanted.

Infertility is defined as the inability to achieve conception after one year of regular, unprotected intercourse. Healthy young couples having unprotected intercourse of regular frequency may expect a 20–25% chance of pregnancy per month. Statistically, if cycle length is every 28 days, one would expect 98% of couples to achieve conception after one year. However, in actuality, only 85% of such couples achieve a pregnancy in one year. Variability in cycle length, coitus, and perceived pregnancy (i.e. biochemical pregnancy) may account for the discrepancy. Fecundability is the percent chance of achieving a pregnancy per cycle whereas fecundity is the percent chance of achieving a live birth from a pregnancy per cycle. Fertility clearly diminishes with age. This has been demonstrated repeatedly and scientifically. Each female fetus is endowed with a fixed number of oocytes (6–7 million) by 20 weeks’ gestational age. Through the process of follicular atresia, this number drops exponentially to 1–2 millions at birth. By menarche, it becomes 300 000 to 400 000, and 25 000 by age 37–38 till it reaches zero at menopause. Such changes are reflected in the average time to pregnancy. Assisted reproductive technology success rates also diminish drastically with age. Oocyte donation studies illustrate that IVF success depends on the age of the donor rather than the recipient and that oocyte age and health are stronger predictors of outcome than uterine senescence. Donor insemination programs also reflect the fact that female age predicts outcome. The percentage of couples presenting for infertility therapy has dramatically increased in the past 15 years, although the percentage of couples apparently suffering from infertility (10–15%) has not changed. The average age of marriage has increased and even married couples tend to delay childbearing. Also, awareness of subfertility and potential therapeutic options has increased. Principles of Gender-Specific Medicine

Etiologies and evaluations of infertility Fertility requires absence of pathology on both the male and female sides. Prerequisites to conception include: normal ovulation, sexual relations, sperm, normal sperm–cervical mucous interaction, an uninterrupted path for fertilization, normal fertilization, and a hospitable intra-uterine environment for implantation. Failure at any of these stages may result in infertility. Indeed, interruption at any, several or all of these stages provides the science for contraception. In approximately 50–60% of couple infertility is due to a female factor. Male factors account for another 40–50% of infertility. This chapter will mainly address female infertility. We refer readers to the chapter by Goldstein for male infertility (Chapter 34). Ten to 15% of patients will suffer from unexplained infertility. That is, after all investigations, specific cause for the infertility cannot be demonstrated. Taylor and Collins1 suggested that that the incidence of unexplained infertility may decrease with increased sophistication in 381

Copyright 2010 20 , Elsevier Inc. All rights reserved.

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diagnostic abilities with time. For example, the incidence of unexplained infertility dropped from 22% before 1940 to 14% after 1980. Evers reports that prior to 1900, virtually all infertility was ‘unexplained.’2 Among female factors for infertility, anatomic reasons (uterine and tuboperitoneal diseases) account for about 40%. Another 40% can be caused by ovulatory dysfunction. Other factors may include immunological factors, impenetrable cervical mucous, luteal phase defect or medical conditions (e.g. diabetes mellitus), which may interfere with implantation.

Uterine Factor A normal uterine cavity facilitates implantation. Intra-uterine filling defects including submucosal myoma, polyps, uterine synechiae (Asherman’s syndrome), and uterine septae are recognized as deterrents to pre-embryo implantation. Uterine defects can be identified by hysterosalpingogram (HSG, gold standard), saline infusion sonography or hysteroscopy. While hysteroscopy is generally considered a surgical procedure requiring anesthesia, some centers offer office hysteroscopy for diagnostic or therapeutic purposes.

Tuboperitoneal Defects Tuboperitoneal defects are common causes of infertility. Careful history may elicit a precipitating event. A history of sexually transmitted diseases, such as chlamydia or gonorrhea, suggests tubal disease. Westrom’s classic data delineates a dose–response effect. The incidence of infertility following one episode of laparoscopically documented pelvic inflammatory disease is 12%, two episodes are associated with a 23% infertility rate, and 54% of patients with three episodes of pelvic inflammatory disease will suffer from infertility.3 Pelvic inflammatory disease increases the risk of ectopic pregnancy (1% in the general population) in both natural and assisted reproductive technology conceptions (two- to six-fold).4 Half of all patients with tubal factor infertility may not report antecedent pelvic infection. Patients should be questioned for a history of unexplained abdominal pain and fever. Elevated serum chlamydial IgG titers are often found in patients with tubal factor infertility; however, the reported sensitivity and specificity varies.5 Tubal disease may result from alternative causes such as postpartum endometritis, diverticulitis, chronic or acute appendicitis, or pelvic adhesions from previous surgery. One recent epidemiologic study, however, disputed the traditional dictum that ruptured appendices may result in later tubal infertility due to adhesions and scarring. Interval sterilization, particularly with bipolar coagulation, if it fails is also likely to result in ectopic pregnancy.6 Conditions such as endometriosis may also cause tuboperitoneal defects. Endometriosis affects 5–10% of the general population but up to 25% of infertility patients have been diagnosed with endometriosis. Minimal to mild endometriosis

may be associated with actively secreting lesions which may impair tubal transport, oocyte quality or ovum pick-up. Moderate to severe endometriosis results in anatomical distortion, space occupying ovarian lesions, extensive adhesions, and scarring. At least one well-conducted randomized controlled trial demonstrated that ablative treatment of minimal to mild endometriosis is associated with a modest increase in fecundability when surgery is followed by expectant management.7 No randomized controlled trials are available regarding pregnancy outcomes following surgical correction of severe endometriosis versus in vitro fertilization. However, medical management does not appear to increase reproductive potential although it is associated with amelioration of symptoms. Hysterosalpingogram (HSG) has traditionally been the gold standard for tubal evaluation. Laparoscopy, however, has the advantage of more precise observation and documentation as well as the potential to correct or improve anatomic abnormalities and ablate endometriosis. Laparoscopy does carry the minimal but real risks of surgery including anesthesia, infection, bleeding, and injury to surrounding structures. HSG has the advantage of being an outpatient procedure and has been documented to be of therapeutic benefit as well. Patients who undergo HSG have increased pregnancy rates in the first 6 months following the procedure.8 If specific tubal information is not needed, as in preparation for in vitro fertilization, a saline sonogram can replace the HSG, as discussed above. A saline sonogram is a very sensitive test to detect intra-uterine filling defects, and is extremely specific for a normal cavity.

Ovulatory Disorders Ovulatory disorders are another cause of female infertility. Ninety-five percent of women who have regular menstrual cycles (24–32 days) are ovulatory. The most common anovulatory problem in young women is polycystic ovarian syndrome (PCOS). This is a syndrome characterized most frequently by the triad: oligo-/amenorrhea, obesity (although at least 10% of patients with PCOS are lean), and hirsutism. The diagnosis is clinical. However, characteristic biochemical abnormalities may exist which include hyperandrogenism (often with normal total testosterone but elevated free testosterone and/or DHEAS), increased estradiol levels, increased LH to FSH ratio 2:1, an altered lipid profile, and an elevated fasting insulin:glucose ratio due to insulin resistance. Patients with severe PCOS may present with HAIR-AN syndrome (Hyper-Androgenism, Insulin Resistance, Acanthosis Nigricans). This subset of PCOS is at increased risk for health sequelae other than infertility, such as cardiovascular disease, hyperlipidemia, diabetes mellitus type II, endometrial cancer (in the absence of regular withdrawal bleeds), and breast cancer. If they become pregnant, they may be at increased risk for pregnancy loss, gestational hypertension, and gestational diabetes. Fortunately, patients with PCOS in general have an excellent prognosis to achieve pregnancy with the use of ovulation induction techniques such as clomiphene citrate and

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controlled ovarian hyperstimulation utilizing gonadotropins. Insulin-­lowering agents such as metformin have been shown to resume regular ovulation and menstruation in as many as 95% of patients.9 Assisted reproduction, including IVF, can be used for extremely brittle PCOS patients who may tend to hyper-respond to controlled ovarian hyperstimulation. Hypothalamic anovulation and amenorrhea is common in anorexics, athletes, and at times of stress. Fortunately, hypothalamic amenorrhea also responds well to controlled ovarian hyperstimulation, although the underlying cause should be addressed. Thyroid disorders, particularly hypothyroidism, may be associated with anovulation. Thyroid stimulating hormone (TSH) should be screened and thyroid supplements administered where appropriate. Hyperprolactinemia alone or in response to elevated TSH should be corrected in a patient with infertility. Agents such as cabergoline or bromocriptine may be used. All patients with anovulation should be questioned and examined for the presence of unusual headache, temporal visual field loss, and galactorrhea. Unexplained, elevated fasting prolactin levels may require an MRI to rule out micro/macro pituitary adenomas, and more importantly any lesion outside the pituitary which may compress on the stalk. Microadenomas generally behave in a very benign fashion and rarely require intense follow-up. However, macroadenomas may require more sophisticated intervention with the appropriate endocrine and or neurological consults. Medical treatment using bromocriptine is usually first line management but transphenoidal resection may be used in certain cases. Euprolactinaemic patients who demonstrate galactorrhea and suffer infertility may also benefit from dopaminergic agents such as bromocriptine. The reason is that although serum levels appear ‘normal’, prolactin has at least two isoforms. Several other sources of elevated prolactin and galactorrhea should be excluded, which include: psychotropic medications, excessive nipple stimulation, pregnancy, thoracotomy scars or other stimuli of the neural arc, ectopic prolactin production by tumors, and hyperestrogenic states (such as pregnancy or oral contraceptive medication) which can inhibit prolactin inhibiting factor (dopamine).

Age and Diminished Ovarian Reserve Diminished ovarian reserve associated with age can obviously impede fertility. Although decreased ovarian reserve usually is not clinically imperceptible, it may be reflected in shorter cycles, or premature or early ovarian failure. Day 3 FSH and estradiol levels as well as clomiphene challenge tests (outlined later) may help identify this problem. An FSH level of 10 mIU/ml and estradiol level 60 pg/ml on cycle day 3 of the menstrual cycle suggest an optimal ovarian reserve. Patients with autoimmune processes (e.g. systemic lupus erythematosis, Hashimoto’s thyroiditis) have a higher incidence of early ovarian failure. Gonadal dysgenesis should be considered in women with premature ovarian failure (POF) before age 30. These women require a karyotype. Women with ovarian failure before 40 are considered to have

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premature ovarian failure. Fragile X premutation (55–200 CGG repeats) is a genetic cause premature ovarian failure and should be tested for in all patients with POF. Probability of conception decreases with age, although the fertile window (approximately 6 days before ovulation and 1 day after ovulation) does not change with age. Day-specific probability of pregnancy drops 50% for women in their late 20s to their late 30s.10 This statistic does not include the increased spontaneous abortion rate associated with sporadic genetic abnormalities associated with conceptuses of older patients.

Cervical Factors Appropriate sperm-cervical mucus interaction is necessary for spontaneous conception. The usefulness of the post-coital test is the subject of much controversy. A properly timed postcoital test reveals that sexual relations have occurred, that ejaculation has been achieved, and that sperm is present in sufficient quantities. It may also give a clue to immunological problems if the observed sperm are dead, nonmotile or simply ‘shaking in place’. Dead sperm may also result from the use of coital lubricants, of which many are spermicidal. Ideally, intercourse is achieved periovulation and the female patient presents for examination within 2–8 hours. The consistency of the cervical mucous is measured by the ‘spinnbarkeit’ and a sample of mucus is observed microscopically for sperm. Intra-uterine insemination (IUI) has been demonstrated to improve pregnancy results when there are fewer than 3 sperm per high power field (suboptimal post-coital test).

Luteal Phase Defect Adequacy of the luteal phase can be measured by the sum of three post-ovulatory progesterone levels (days 5, 7, and 9 post-ovulation) 30 ng/ml or a single level 10 ng/ml. An endometrial biopsy is the gold standard. It should be scheduled as close to the expected menstrual period as possible. The pathological dating of the biopsy will be compared to the actual date of the biopsy, which is calculated from the first day of the subsequent menses (assigned as day 28). If there is a lag of more than 2 days in two consecutive biopsies, luteal phase defect is diagnosed. History of the male partner and semen analysis should also be obtained. For more detail about male factor infertility see Chapter 34. Due to the age-related decline in fertility, patients who are older (35 years old) complaining of infertility should undergo expeditious work-up.

Treatment for infertility Infertility treatment should be targeted at the specific etiology.

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Ovulatory Dysfunction If there is an underlying cause for anovulation or oligo­ ovulation, such as thyroid dysfunction, treatment should be directed toward that specific etiology. Otherwise ovulation induction medications such as clomiphene citrate (CC) or injectable gonadotropins should be considered. CC can be used for ovulation induction in anovulatory or oligo-ovulatory patients, or for superovulation in those who regularly ovulate. Patients who best respond to CC tend to be relatively well estrogenized and have intact pituitary function/normal gonadotropin levels. Other patients who might benefit from CC are patients with luteal phase defects or unexplained infertility. CC has both estrogen antagonist and agonist effects. It ‘fools’ the pituitary gland to produce more gonadotropins to stimulate follicular growth. Due to its estrogen antagonistic effects, it can potentially thin out the endometrium lining and decrease cervical mucus production. The usual starting dose is 50–100 mg per day from day 3 to 7 or day 5 to 9. Once ovulation is attained with a certain dose, that dose should be maintained for several cycles before more aggressive treatment is attempted. Maximum daily dose used is 200–250 mg. The use of CC is not usually associated with intensive monitoring. If timed intercourse is anticipated, the patient can monitor urine LH from day 10 onward (given 28 days cycle). Intercourse is recommended on three consecutive nights starting the evening of the LH surge. If there is no surge detected by urine by day 14, vaginal ultrasound examination should be performed to determine follicular sizes. HCG triggering is then performed when the lead follicle is 18 mm or larger in diameter. If IUI is to be performed, patients can either monitor urine LH as described above, or be monitored starting day 10 by ultrasound examination. Once an LH surge is detected or lead follicle reaches 18 mm and HCG is given, patients are then scheduled for IUI for the following morning. The common side effects of CC include hot flushes, headaches/mood changes, and visual changes. Every patient who undergoes CC treatment should be counseled that there is a 12–15% multiple pregnancy rate, largely consisting of twins. If a patient does not respond to maximal doses of CC, prolonging the duration of CC treatment from 5 to 8 or 10 days can be considered. In PCOS patients, the use of glucophage may enhance the responsiveness of the ovaries to CC. Failure with the use of CC has to be defined as whether it is ovulation failure or conception failure. If a patient does not ovulate even with the highest dose of CC (200–250 mg per day), one has to resort to the use of gonadotropins. However, if it is conception failure, the patient and physician should be aware that each treatment cycle with CC/IUI is only associated with an 8–12% pregnancy rate. CC/IUI should be repeated up to 3–6 cycles (depending upon the age and the anxiety level of the patient) before treatment should be escalated. The next step in ovulation induction is the use of gonadotropins: FSH and LH. They are either urine-derived or manu­ factured using recombinant DNA technology. The starting

dosage of gonadotropins is based on the patient’s age, ovarian reserve, BMI, and past stimulation history (if any). Due to its increased risk of hyperstimulation, patients have to be monitored very closely by ultrasound examination and estradiol level examination. HCG trigger for ovulation should occur when follicles are 16–18 mm in size. About 36 hours after HCG administration, IUI can be performed. Luteal support with progesterone should be started 2 days after IUI. Gonadotropins are more potent stimulants to the ovaries than CC. Patients have to be counseled on the risk of multiple births and hyperstimulation. If more than 3–4 mature follicles are detected in any gonadotropin treatment cycle, consideration should be given to cancel the cycle or convert to IVF if it is an option. Tubal Factor Tubal obstruction as a cause for infertility can be managed by tuboplasty or bypassing the tubes with IVF. Tuboplasty is usually accomplished laparoscopically. However, in any subsequent pregnancy, there is an increased risk of ectopic pregnancy. Tubal surgery is considered only in the absence of male and ovarian reserve factor. Otherwise, IVF is the option for treatment. In vitro fertilization will be discussed in a subsequent section of this chapter.

Male Factor Refer to Chapter 34, which addresses male factor infertility. Cervical Factor If a hostile cervix is encountered, as in the case of antisperm antibodies, bypassing the cervix with IUI is recommended. Luteal Phase Defect The use of progesterone supplementation in the luteal phase can be considered. Some patients may benefit from CC to augment folliculogenesis.

History of IVF The first attempts at mammalian in vitro fertilization date back to the 1800s. In 1930, Pincus documented the first embryo transfer in a rabbit. The first recorded successful IVF was also by Pincus in 1934.11 For several reasons, this record was considered controversial. Before the advent of phase-microscopy, it would have been impossible by standard techniques to document fertilization. Also, parthogenic cleavage is possible in rabbit oocytes. The true test of successful IVF is the live birth of an observed in-vitro-fertilized pre-embryo. This did not unequivocally occur until 1954 under the direction of Thiabault.12 The first attempts at human IVF occurred in the 1960s and were initially limited by timing of ovulation, single oocyte retrieval, and low fertilization rates in vitro. The birth

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of Louise Brown in the UK in July 1978 marked the first live human birth from a human IVF conceptus. The second and third births occurred in Australia and the United States, respectively. The initial two births were the result of laparoscopic, single oocyte retrieval and IVF. Jones et al., however, used human menopausal gonadotropin to stimulate multiple follicular maturation in order to increase the chances of having a viable pre-embryo for transfer.13 The evolving progression of using vaginal ultrasoundguided retrieval, controlled ovarian hyperstimulation for multiple follicular recruitment, optimal laboratory condi­ tions, and micromanipulation techniques such as intra­ cytoplasmic sperm injection (ICSI) to overcome male factor infertility have greatly improved the efficiency of assisted reproductive technologies (ART). More recently, improved outcomes after embryo cryopreservation and blastocyst culture prevent embryo wastage and hold the promise of reducing the incidence of multiple births secondary to IVF. Preimplantation genetic diagnosis (PGD), as opposed to prenatal genetic diagnosis, allows pre-embryos to be biopsied and evaluated for a multitude of heritable diseases before they are transferred back to the uterus. Oocyte donation allows women with ovarian failure, poor oocyte health, or multiple failed IVF attempts to carry and deliver a pregnancy that carries the genetic contribution of the male partner. Gestational surrogacy offers the potential of women who have major uterine factor (e.g. congenital absence of the uterus) to have their genetic children.

Indications for IVF Tubal Disease IVF was originally intended to treat tubal infertility. Previously, such patients had very poor prognosis. Complete tubal obstruction prevents spontaneous conception. Partial obstruction is often associated with bilateral disease and macro or microscopic defects in tubal anatomy and ciliary function. In these patients, attempts at conception through both natural and controlled ovarian hyperstimulation/IUI methods have a significant risk (5–15%) of ectopic pregnancy (pregnancy outside the endometrial cavity) which may be life-threatening. The risk of ectopic pregnancy in the general population is approximately 1%. However, this figure increases with severity of tubal disease, number of episodes of pelvic inflammatory disease, and past history of ectopic pregnancy. In fact, the first efforts at assisted reproduction in mammals involved intra-uterine, cornual ovarian transplantation to the site of the removed obstructed tube.14 Patients with tubal infertility are generally considered very good prognosis IVF candidates, the reason being that they tend to be younger and have normal ovarian reserve and function. Tubal obstruction is a mechanical factor that is relatively easily overcome by IVF. Nevertheless, recently we have recognized that the degree of tubal disease may affect conception rates with IVF. Several

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randomized controlled trials and at least one systematic review (of three randomized-controlled trials) indicate that IVF outcome can be affected by the presence of hydrosalpinges.15–18 It is generally believed that the fluid of the dilated tubes may be inflammatory in nature and therefore detrimental to early embryonic growth if it is effluxed back to the uterine cavity after embryo transfer. Therefore, patients with hydrosalpinges can be optimized by either a salpingectomy or interruption of the tube (clip or cautery) via laparoscopy before IVF. Ectopic pregnancies in such patients are not completely avoided by IVF. Post embryo transfer, the embryo remains ‘floating’ in the endometrial cavity for approximately 2 days. During this time, the embryo may travel and implant in the fallopian tube, cervix, or in the peritoneum of the abdominal cavity. The incidence of ectopic pregnancy after IVF may be as high as 4%. We recently reviewed the results at our center and found the incidence of ectopic pregnancy after fresh embryo transfer to be 0.868%. However, this incidence appears to increase with a history of tubal disease. In our study, 46% of these ectopic pregnancies had a history of tubal disease. Of those patients with pre-existing tubal disease 67% had their ectopic pregnancy on the same side as the tubal disease.19 Endometriosis As discussed previously, endometriosis affects approximately 25% of infertile women as compared to 5–10% of women in the general population. Pathologic diagnosis of endometriosis requires biopsy of lesions and demonstration of glands, stroma, and hemosiderin by histology. There are several staging systems to describe the severity of endometriosis (minimal, mild, moderate, severe, and stage I–V). Recently, the American Society for Reproductive Medicine revised the classification system, based on observed findings at the time of surgery, to allow more consistent and accurate staging both for purposes of description and for following outcomes post treatment. Endometriotic lesions typically appear first on the ovarian surfaces, followed by the broad ligament and posterior cul de sac. In cases of severe endometriosis, lesions may be old and scarred. Therapeutic options for women with minimal to mild endometriosis include expectant management, surgery, and controlled ovarian hyperstimulation and intra-uterine insemination. Unfortunately, as in many areas of reproductive medicine there is, again, little information available in the form of randomized controlled trials to suggest optimal management. In cases of minimal to mild endometriosis, Marcoux et al., demonstrated, in a well-conducted randomized controlled trial, that surgical ablation of laparoscopically documented minimal to mild endometriotic lesions results in higher cumulative pregnancy rates (30% vs. 17%) over a period of 36 weeks, versus expectant management without ablation.7 Treatment of advanced stage endometriosis remains challenging. No randomized controlled data are available comparing surgery with IVF, and such types of studies would be difficult to undertake. Most of the available data are in

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the form of less robust retrospective case-controlled, cohort and case-series studies. Some authors have suggested conservative surgical therapy at the time of diagnosis to restore anatomy, followed either immediately, or after a period of observation, by IVF. We would recommend prompt ART in the case of severe endometriosis, because endometriosis has been documented to recur at a rate of 10–20% per year following conservative laparoscopy. There is clearly an absence of robust data to delineate the effects of endometriosis on assisted reproduction. Endometriosis may potentially affect assisted reproduction in several ways. Firstly, space-occupying lesions in the ovaries and anatomic distortion of the adnexae may interfere with both the number and quality of oocytes produced. There have been suggestions that the ability of pre-embryos to successfully implant in a hospitable endometrial environment can be affected in endometriosis. Immunological factors such as cytokines, interleukins, and natural killer cells also may interfere with host acceptance of the conceptus, and such factors, if directed toward pathologic, ectopically growing endometrium, may also attack normal uterine endometrium. In an effort to assess for a possible detrimental impact on the endometrium, Diaz undertook a study in which donor oocytes were split between recipient patients with and without endometriosis.20 Here, pregnancy rates were similar; however this study did not have sufficient power (57%) to exclude a difference. Other authors have suggested that oocyte quality may be affected in women with endometriosis and embryotoxic factors from endometriosis may affect implantation.21A large retrospective study from Cornell suggested that outcome was as good for patients with endometriosis as for patients with tubal infertility and did not vary appreciably by stage. Society of Assisted Reproductive Technology (SART) data support the latter concept.22,23 However, these studies may have lacked sufficient multivariate analysis to exclude the impact of confounding factors. In 2002, Barnhart et al. published a systematic review about the impact of endometriosis on IVF. They concluded that, after careful analysis of multiple confounding factors, endometriosis consistently adversely affected IVF outcome.24 Endometriosis patients were compared to patients with tubal factor infertility on all of the following parameters: peak estradiol levels, oocyte yield, fertilization rates, implantation rates, and absolute pregnancy rates. Overall, all factors were negatively affected. The overall pregnancy rates for endometriosis patients were consistently lower (OR 0.56; 95% CI 0.44–0.70). There was also a dose–response relationship to the severity of endometriosis and inverse pregnancy outcome. Pregnancy rates were better in patients with minimal to mild disease than in patients with moderate to severe disease (OR 0.46; 95% CI 0.28–0.74). The authors concluded that ‘patients with endometriosis should be referred for early, aggressive infertility treatment, including IVF, to increase the chances of conception.’ Whether the removal of large endometriomas before IVF improves the response to controlled ovarian stimulation

remains controversial. Nevertheless, these patients may benefit from gonadotropin-releasing hormone (GnRH) agonist suppression prior to stimulation.25–27 Because endometriomas also provide a good culture media for bacteria, we, therefore, routinely use antibiotic prophylaxis at oocyte retrieval in patients who have endometriomas demonstrated during their IVF cycles. Male Factor Male factor accounts for approximately 40–50% of infertility. In the past the only available therapy for significant male factor infertility was therapeutic donor insemination. In 1992, however, the development of a technique called intracytoplasmic sperm injection (ICSI) revolutionized the treatment of male infertility.28 It is now possible to achieve conception with a single viable spermatid by direct, facilitated injection through the zona pellucida of the oocyte. A recent study suggested that clinically significant semen analysis cut-offs for spontaneous conception are as follows: concentration less than 13.5 million sperm/ml, motility less than 32%, and less than 9% normal morphology according to strict WHO criteria.29 Even with conventional IVF, insemination rates are poor with motile sperm concentrations of less than 3 million per ejaculate.30 With ICSI and, more recently, advances in sperm retrieval directly from the testes or epididymis (TESE, MESA), even men with obstructive or nonobstructive azoospermia have the potential to father their own genetic offspring. The indications for ICSI are varied and differ slightly from center to center.31 In general they include the following: (1) previous failed IVF fertilization; (2) sperm concentrations less than 2–5  106 sperm per ml; (3) motility 5%; (4) normal morphology 4% by Kruger’s strict criteria; (5) use of surgically retrieved and therefore relatively limited number of immature spermatozoa; and (6) PGD because conventional insemination techniques may result in extra spermatozoa attached to the zona and therefore contaminate the sample for polymerase chain reaction (PCR) diagnosis. The factors that affect the success of ICSI have been shown to be relatively independent of the semen parameters and mostly dependent on factors such as techniques and experience of the embryologist performing ICSI, and also egg quality (age of the female). It is still too early to conclude on the absolute safety of the use of ICSI in IVF. Some studies have looked at sex chromosomes aberrations and ICSI.32 In our center, 15% of azoospermic males were found to have chromosomal abnormalities such as 47,XXY (Klinefelter syndrome). Also there was a higher incidence of aneuploidy in oligospermic men (3–6%). Y microdeletions studies of azoospermic or severely oligospermic men have also identified a higher incidence of nonkaryotypic genetic abnormalities (up to 13%). Therefore, genetic screening of azoospermic males should be recommended before IVF/ICSI. The partners of male patients with congenital unilateral or bilateral absence of the vas deferens should be

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screened for cystic fibrosis as should the partners of patients with idiopathic epididymal obstruction because a large proportion of these men are carriers of the cystic fibrosis mutation. The topic of ICSI is addressed in more detail in Chapter 34. Fertility Preservation More recently, IVF has also been used for the preservation of reproductive capacity for both men and women. Female cancer patients who face the prospect of decreased reproductive potential as a result of life-preserving chemotherapy may consider embryo cryopreservation. Not only does embryo cryopreservation allow preservation of reproductive potential but it also allows the couple to proceed with family planning at a time when the primary disease may be in remission or when pregnancy may not present a health risk to the mother. Recently, medications such as tamoxifen and letrozole have been investigated as protective agents for patients suffering from breast cancer who wish to undergo ovarian hyperstimulation (with the potential associated elevated estradiol levels) and embryo cryopreservation prior to antineoplastic therapy.33 Current research efforts are focusing on the preservation of ovarian tissue and oocytes (e.g. pre-reproductive aged patients and those without a male partner). Ovarian reserve is the most important limiting factor for IVF. Oocyte donation was initially developed for patients with ovarian failure. Through oocyte donation, a woman may gestate and deliver a pregnancy that carries the genetic contribution of her male partner. Women who have gonadal dysgenesis, premature ovarian failure, or early ovarian failure benefit from this procedure. Also, couples who have experienced repeated IVF failure, either due to implantation failure or fertilization failure secondary to oocyte health, are candidates for oocyte donation. Oocyte donation may also be indicated in cases where the mother carries a genetic risk/disorder for which PGD is not available, or as an alternative to PGD. In vitro fertilization for the treatment of irreparable uterine abnormalities is also possible. Patients with congenital absence of the uterus (Mayer–Rokitansky–Hauser syndrome) or patients who have undergone hysterectomy can undergo IVF with embryo transfer to a gestational surrogate resulting in birth of genetic offspring. Women who have medical disorders, which contraindicate pregnancy, can also conceive children through surrogacy. Ovulatory Disorders Women with ovulatory disorders (hypogonadotropic hypogonadism or polycystic ovarian syndrome) typically respond well to ovulation induction. For those women who have such an exaggerated response that the risk of higher order multiples or ovarian hyperstimulation is significant, conversion from a controlled ovarian hyperstimulation-intra-uterine insemination (COH-IUI) cycle to an IVF cycle is possible and can prevent cycle cancellation given the ability to restrict the number

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of embryos transferred. Success rates from these converted cycles appear comparable to cycles initially started as IVF. Additionally, patients who fail to conceive despite an ovulatory response to ovulation induction agents are reasonable candidates for IVF, if other treatable causes of infertility have been excluded. We have found that patients with unexplained infertility, some of whom have failed COH-IUI, may benefit from IVF. As discussed earlier, the category of unexplained infertility may be considered ‘as yet’ unexplained infertility before IVF. IVF may offer information on fertilization and early embryo development, which will not be available without IVF. Although a recent review of available literature by Evers suggested that the benefit of IVF over controlled ovarian hyperstimulation for patients with unexplained infertility may be marginal,2 other studies demonstrated a higher success rate in patients with a diagnosis of unexplained infertility with IVF than with more conservative treatments.34–36 However, they all agree that IVF may be beneficial by uncovering a cause such as fertilization failure or poor embryo development or quality. Genetic Disorders Preimplantation genetic diagnosis (PGD) allows the detection of significant genetic disease before embryo transfer and conception. PGD is most commonly used for autosomal recessive and sex-linked disorders. Other indications for PGD include the diagnosis of aneuploidy (associated with age); assessment of patients with a history of recurrent abortions, especially if a balanced translocation has been identified in one of the parents; and the evaluation of embryos of women with repeated, unexplained IVF failure despite good embryo morphology. Age Age is the strongest predictor of ovarian reserve. Reproductive success diminishes exponentially with advancing maternal age. The classic studies of the Hutterite population evaluate a society where the average age of marriage is 22 and the only fertility barriers include lactational amenorrhea and a natural age- and parity-related decrease in coitus.37 Donor insemination programs also demonstrate a female-dependent decrease in fecundity. A recent epidemiological study of almost 800 couples practicing natural family planning revealed that female fecundability begins to decline in the late 20s and male fertility demonstrated a less, although significant, decline in the late 30s. Biochemical measures of ovarian reserve are available which may predict a patient’s prognosis and response to stimu­lation. Day 3 FSH and estradiol have been correlated with IVF success in terms of pregnancy rates, number of oocytes retrieved, and peak estradiol levels.38–40 For younger patients, FSH and estradiol levels may more accurately reflect a patient’s ovarian reserve than her age alone. However, it must be emphasized that normal FSH and estradiol levels in the

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older patient do not override the impact of chronological age on outcome. The clomid challenge test (CCCT) can also be used to prognosticate ovarian reserve. The FSH is measured on day 3 and then again on day 10 following oral administration of clomid 100 mg on days 5–9. Poor ovarian reserve is defined as a day 10 FSH level greater than 2 standard deviations above the mean. Navot et al. reported that of patients with an exaggerated response, only 5.5% subsequently conceived versus 42% of patients with a normal response.40 Some authors have suggested that the CCCT might be more sensitive than basal FSH levels alone but it is not clear whether basal estradiol levels were taken into account in these studies, or whether basal FSH levels were assessed in more than one cycle.

Basic Evaluations Before IVF The initial evaluation for IVF should include a basic infertility work-up, as previously outlined, and a thorough history including a review of previous pregnancies, pregnancy outcomes, and fertility treatments including COH-IUI and IVF. Physical examination should assess abnormalities of the thyroid, galactorrhea, previous surgical scars, and the pelvic examination. The pelvic examination generally includes cultures for chlamydia, gonorrhea, and other organisms as indicated. Cervical cytology should be up-to-date. A sounding (trial transfer) of the endometrial cavity for depth, position, and accessibility should also be performed, once negative cervical cultures have been obtained. An ultrasound assessment of the uterus, endometrial cavity, and adnexae may also be performed to rule out any abnormalities such as ovarian cysts. If previous hysterosalpingogram films are available, these should be reviewed for the presence of intracavitary defects and hydrosalpinges. Depending on the history, surgical correction of hydrosalpinges may be indicated. The male partner should also be evaluated. The evaluation of the male is addressed in further detail in Chapter 34. Male medical history should include any previously fathered pregnancies; history of mechanical or infectious testicular injury; prior surgery including varicoceles, vasectomy, and vasovasostomy; previous semen analyses and/or tests for anti-sperm antibodies; social habits including the use of tobacco, alcohol, prescription medications, and nonprescription substances; exposure to chemicals, toxins, radiation or extremes of temperature (e.g. saunas, hot tubs); and sexual function. A semen analysis should be obtained prior to IVF. Semen cultures may be performed as indicated.

Protocols for Ovarian Stimulation for IVF The first IVF baby (Louise Brown, England) resulted from harvest of a single oocyte in a spontaneous, nonstimulated menstrual cycle.13 The second IVF baby was born after a similar cycle in Australia. The third baby, the first North

American baby, was born in the United States. Human menopausal gonadotropin was used to achieve multiple follicular development and therefore improved the number of oocytes retrieved and the number of embryos formed. Ovarian hyperstimulation protocols have since been used to maximize the efficiency of the IVF process. Natural cycle IVF has been limited by relatively poor success rates. Natural cycle IVF involves the retrieval of a single oocyte, which effectively eliminates the ability to select and/ or cryopreserve embryos and limits the pregnancy rates to the implantation rate of a single conceptus. Additionally, ancillary reproductive technology procedures such as preimplant­ ation genetic diagnosis and intracytoplasmic sperm injection optimally require the harvest of multiple mature oocytes. Moreover, patients undergoing natural cycle IVF may ovulate spontaneously before oocyte retrieval. As described later, the introduction of GnRH antagonists may avoid cancellations due to premature LH surges and improve success rates following natural cycle IVF. Nevertheless, natural cycle IVF remains an option for patients who respond poorly to ovarian stimulation (i.e. produce only one or two follicles) or who have medical reasons to avoid supraphysiologic estradiol levels. The use of ovulation-inducing medications such as clomiphene citrate (CC) and, more significantly, gonadotropins (human menopausal gonadotropin [hMG] and both urinary and recombinant follicular stimulating hormone [FSH]) have allowed the recruitment of multiple oocytes per IVF cycle, improving the odds of fertilization, increasing the number of embryos available for selection and transfer, and improved pregnancy rates. Clomiphene citrate is seldom used alone for IVF but can be used in combination with gonadotropins. GnRH agonists/antagonists The development of the GnRH agonists has enhanced the efficiency of IVF. Prior to the routine use of GnRH agonists, premature luteinization accounted for cancellation of up to 20% of IVF cycles.41 Currently fewer than 2% of cycles are cancelled due to premature LH surges.42 For over a decade, GnRH agonists have been used in the majority of ART stimulation protocols. Native GnRH, first characterized in 1967, is a decapeptide produced in the arcuate nucleus of the hypothalamus. However, GnRH agonists (e.g. leuprolide acetate) and more recently GnRH antagonists did not become available until much later. The GnRH agonists are produced by substitution of the amino acids at positions 6 and 10. Native GNRH has a half-life of 2–4 minutes. The substituted agonists have half-lives of up to 3 hours. Agonists result in pituitary desensitization through prolonged receptor occupancy. However, the initial effect of GnRH agonists is a flare through the increased release of stored gonadotropins. This effect is especially noticeable if given during the early follicular phase. After the initial flare, the suppressive effect of the GnRH

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agonist, which is desired for IVF to prevent early luteinization, is observed as early as after 1 week of administration. GnRH agonists do not block pituitary gonadotropin production completely, and small LH pulses may still be observed. GnRH agonists can be used in long, short or ultra-short protocols, as described later, to maximize the benefit of their differential effects dependant on dose and duration of use. Development of well-tolerated, effective GnRH antagonists occurred more recently. The second generation compounds exhibit side effects of histamine release, and potentially, anaphylaxis. Third-generation compounds have now become available for clinical use in the United States. Side effects appear to be mainly limited to those of estrogen withdrawal and localized, short duration erythema at the injection site. GnRH antagonists have altered amino acids at positions 6, 10, 1, 2, 3, and 8. They inhibit pituitary gonadotropin output through competitive inhibition of the pituitary GnRH receptors but, unlike the agonists, are not accompanied by the ‘flare’ effect (i.e. suppression is immediate). The half-life is 6–30 hours for the non-Depot form. The half-lives of the available antagonists suggest that minimal GnRH antagonist activity should be available in the peri-implantation window.43 The debate regarding the importance of LH for ovarian stimulation is ongoing. The GnRH agonist does not completely abolish endogenous LH production, whereas the antagonist does. At many centers, antagonist cycles are supplemented with exogenous LH (e.g. hMG) at the time of initiation of the antagonist, if recombinant FSH is being used as the sole initial agent. Without adjuvant LH, estradiol levels may drop, although clinical significance of this phenomenon is not clear.44 No adverse effects on children born from GnRH antagonist cycles have been reported. 45 IVF medication protocols are optimally selected according to a patient’s age, ovarian reserve, body mass index, and history of prior response to stimulation. For patients who are likely to have a good response, one of the objectives is to avoid overstimulation, including full-blown ovarian hyperstimulation syndrome (OHSS), which is potentially lifethreatening. One commonly utilized protocol is the long GnRH agonist protocol. Here, the agonist is initiated one week following ovulation (e.g. documentation of the LH surge). Once adequate suppression has been documented by withdrawal bleeding and appropriately suppressed estradiol levels, exogenous gonadotropins are initiated at a dose and in a combination tailored to the individual patient. A typical starting dose is 3–4 ampules (225–300 IU) of FSH and/or hMG per day. Either a fixed, step-up or a step-down protocol may be used, i.e. the gonadotropins can be started at a low dose and increased according to estradiol levels or a protocol with a higher starting dose can be employed with the dosage decreased according to the response. Once the lead follicles attain a mean diameter of approximately 16–18 mm, hCG is administered usually at a dose of 5000–10 000 IU. This allows maturation of the oocytes (resumption of meiosis) for retrieval 34–36 hours later.

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Patients are advised not to try to conceive in the periovulatory window of the cycle, when they are to start the agonist. The agonist may rescue the corpus luteum and therefore rescue a very early pregnancy. While it is prudent to avoid administering GnRH-agonist during a known pregnancy, GnRH agonists taken inadvertently have not demonstrated any adverse impact on the very early pregnancy. High Responders Several stimulation approaches have been used in an effort to improve outcomes in the anticipated high responder (young, PCOS, history of high response) who is at increased risk for OHSS. The objective is to suppress ovarian response to allow only 5–15 oocytes to develop and to maintain an estradiol level less than 3000 pg/ml. Dual suppression with both an oral contraceptive pill overlapping with a GnRH agonist has been shown to attenuate the response to stimulation and reduce the risk of excess numbers of oocytes and excessive estradiol concentrations. Lower doses of gonadotropins are administered in these patients as well (e.g. 150 IU/day). Poor Responders The poor responder poses a far greater challenge. The true test of ovarian reserve is the response to ovarian hyperstimulation. The approaches to stimulation of the poor responder are generally three-fold: (1) to maximize exogenous gonadotropin stimulation by increasing the number of ampules of gonadotropins prescribed; (2) to prevent ovarian suppression by avoiding the use of luteal lupron; and (3) to maximize the simultaneous endogenous pituitary gonadotropin complement by employing protocols that produce an early follicular, pituitary flare effect in addition to maximal exogenous injectable gonadotropins.

The IVF Procedure Oocyte Retrieval Oocyte retrieval is generally performed 34–36 hours post hCG administration. Either urinary hCG or recombinant hCG may be used. The interval between hCG and retrieval allows resumption of meiosis I. The first human successful IVF attempt occurred in 1944.46 The eggs were retrieved during laparotomy, between cycle days 10 and 12, and then incubated in human serum for 27 hours. Hopkins et al. first introduced gynecologic laparoscopy in 1954.13 In 1968, Steptoe published an article about ovulation and laparoscopy.47 Steptoe and Edwards then collaborated to develop a laparoscopic method for timed oocyte retrieval following superovulation and human chorionic gonadotropin administration.48 Transvaginal ultrasound has since become the standard route of oocyte harvest and requires minimal anesthesia and recovery time. Another advantage of ultrasound-guided retrieval is that inadequate ovarian access is an extremely rare phenomenon, even in

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patients with extensive previous surgical history. The patient is prepped and draped in the dorsal lithotomy position under intravenous sedation. Antiseptics may be toxic to oocytes and are therefore prohibited in some centers. A transvaginal ultrasound probe with a high frequency transducer (5–7 MHz) and needle guide is used to identify the follicles and align the follicles in their largest diameter. The follicles are then aspirated under negative pressure (100–120 mmHg) with flushing of the tubing following each withdrawal of the needle, to maximize oocyte recovery. ‘Empty follicle syndrome’ is a clinical scenario in which, despite the presence of ovarian follicles, no oocytes are retrieved at harvest; although this could rarely be due to technical difficulties, most often it occurs when the patient fails to appropriately administer the hCG. We therefore measure serum LH and/or hCG levels the day before retrieval to ensure adequate hCG exposure. The debate regarding the need for prophylactic antibiotics is ongoing. We typically advocate a four-day course of oral tetracycline started immediately following retrieval. We routinely use pre-retrieval intravenous antibiotic prophylaxis (e.g. cefoxitin) for high-risk patients (i.e. with a history of pelvic inflammatory disease and/or endometriomas) because it has been shown that endometriomas are a risk for abscess formation post retrieval. Postoperative complications are reported to occur in 0.3–3% of cases. The most common complication post-retrieval is pelvic infection. Bleeding is also a risk and may result from injury to uterine, vaginal, infundibulopelvic, or iliac vessels as well as from the ovary itself whose vascularity is increased during stimulation. Injury to abdominal viscera is extremely rare but possible. In addition, anesthesia carries some inherent risk. In Vitro Insemination and Fertilization As described previously, harvested oocytes exhibit various stages of maturity, and therefore require varying intervals of preincubation up to 36 hours before insemination. For mature oocytes (metaphase II), the oocytes are incubated briefly and insemination is performed at approximately 4 hours (range 2–8) following retrieval. A semen sample should be obtained by masturbation just before or after retrieval. It is usually collected in a sterile plastic jar or a Silastic condom. The sample is allowed to liquefy at room temperature before preparation. Two methods are commonly used for sperm preparation: the swim-up method or the gradient centrifugation method. The objective is to isolate a highly motile fraction of sperm for insemination. The highly motile fraction is then incubated in a highprotein supplemented media for 30 minutes to 4 hours to initiate capacitation. Generally each oocyte is incubated with between 50 000 to 200 000 motile sperm for a period of 12–18 hours at 37°C, 5% CO2 in air, and 98% relative humidity. The acrosome reaction, which is necessary for the spermatozoa to penetrate the zona pellucida, is initiated by contact between the zona

pellucida and the sperm. Exocytosis of cortical granules from the ooplasm (cortical reaction) causes the zona pellucida to become relatively refractory to polyspermy. Occasionally incubation with greater than 200 000 sperm per oocyte is undertaken in male factor cases to improve fertilization rates. This practice can result in a higher incidence of polyspermy. Sperm penetration of the oocyte induces oocyte activation and initiates the second meiotic division, which then separates the chromatids between the oocyte and 2nd polar body. Oocytes are evaluated for fertilization at 18 hours post insemination. The presence of two pronuclei, one each from the oocyte and spermatozoa, and two polar bodies in the perivitelline space indicates normal fertilization. Polyploidy occurs in 5–10% of IVF embryos with 1–2% in mature oocytes and up to 30% in immature oocytes. In addition to polyspermy, polyploidy may result from digyny, with origin of the extra chromosomal complement from the oocyte, which may occur due to meiotic spindle errors or failure to extrude a polar body. These events are more common in aging oocytes or immature or post-mature oocytes. ICSI may result in a polyploid embryo due to digyny (retention of the second polar body). The process of fertilization takes approximately 24 hours and is completed with the initiation of the first mitotic cleavage. Embryo Transfer Embryo transfer is most commonly performed after 72 hours (day 3 post retrieval). ‘Blastocyst transfer’ is generally performed at 120 hours (day 5 post retrieval). Blastocyst transfer will be detailed below; the principal advantage of blastocyst transfer is the replacement of fewer embryos (generally 1–2), given their apparent higher implantation potential. Transfer of fewer day 3 embryos reduces the incidence of higher order and twin multiple gestations. Pre-embryos transferred on day 3 have generally cleaved to 6–8 cells. Techniques for grading of the quality of embryos vary from center to center. The objective of embryo transfer is to maximize the chance for pregnancy while limiting the number of multiple gestations. Both of these outcomes are directly correlated with the number of pre-embryos transferred.49 The optimal number of embryos to transfer is individualized, based on the individual’s expected implantation rate per embryo. Maternal age and embryo quality are important factors determining the implantation potential for each embryo.50 Some centers calculate the number of embryos for transfer on the basis of a cumulative embryo score. The cumulative embryo score is derived from morphological analysis of the embryo as well as the number of blastomeres. Maternal age is also an important predictor for implantation potential. Fewer embryos are generally transferred to younger patients and some authors advocate the replacement of only a single embryo, in these cases; this cannot be universally applied to all patients given different anticipated implantation and pregnancy rates.51

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Schoolcraft et al. have recently published a summary of the literature regarding variables that can affect the success of embryo transfer.52 Although much of the literature is based on retrospective observational data, this paper attempts to address such issues as bedrest post-transfer, physician factor, catheter type, loading of the catheter, placement of the catheter tip, trial transfer, uterine contractions, effect of blood or mucus on or in the catheter, and perceived difficulty of transfer. Frank blood on the catheter may be an indicator of endometrial trauma. Ultrasonography at the time of transfer has been suggested to improve implantation rates, but randomized controlled trials are lacking.53 It is likely that ultrasound guidance is most useful for difficult transfers (e.g., as with a tortuous cervical canal). The embryo transfer is generally performed with the patient in the dorsal lithotomy position. The cervix is cleansed with transfer medium and a mock transfer may be performed to ensure accessibility of the cavity and the correct bend, if necessary, of the catheter. Soft catheters have been shown to be associated with less local trauma. After the embryo transfer, the patient is transferred to a holding area where she remains supine for 30 minutes or more. The interval of rest following transfer does not appear to be clinically important. Zygote intrafallopian tube transfer (ZIFT) and gamete intrafallopian tube transfer (GIFT) entail the laparoscopic transfer of the zygotes or oocytes/sperm, respectively. At one time these techniques were advocated as being more successful than IVF for patients with normal fallopian tubes but advances in the IVF laboratory have all but relegated these procedures to the archives. Blastocyst Transfer The first human IVF pregnancy was achieved after blasto­ cyst transfer.1 Since then most transfers have been performed with day 2 or 3 pre-embryos due to difficulties in successfully maintaining pre-embryos in culture to the blastocyst stage. Recently, newer sequential media have led to renewed interest in blastocyst transfer. Compaction of the pre-embryo usually occurs at the 8–16cell stage. Before the 8-cell stage, assessment of the preembryo is preliminary since the embryonic genotype has not yet been activated. Therefore, it is difficult to specifically predict pregnancy success rates from a day 3 preembryo assessment. Advantages to blastocyst transfer include excellent implantation rates in good prognosis patients, an extended window of opportunity for ancillary procedures such as preimplantation genetic diagnosis, and a decrease in the number of embryos transferred due to better implantation rates. Patients who have a good response to stimulation and at least four good quality pre-embryos on day 3 may be good candidates for blastocyst culture; it should be noted that generally fewer than 50% of in vitro fertilized oocytes will

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attain the blastocyst stage even in sequential media. The debate is still ongoing as to whether patients with poor prognosis might benefit from blastocyst culture. For pre-embryos with a poorer prognosis, earlier placement in the uterus may be advised. Single blastocyst transfer should be advocated in women who have contraindications to carrying twins or more, as in the case of some congenital uterine anomaly. Donor egg recipients are excellent candidates for blastocyst transfer as well in light of the young age of the embryos. Luteal Phase Support Centers vary in their approach to management of the luteal phase. The prevalent practice is to provide luteal phase support in the form of either supplemental hCG or progesterone until sonographic documentation of pregnancy and placental progesterone production (approximately 7–8 weeks’ gestation).54 Ovarian hyperstimulation results in supraphysiologic estradiol levels. Although we assume that multiple corpora lutea are developed post-hCG, aspiration of follicles may debulk some of the granulosa-theca cells destined to produce progesterone. Therefore, to ensure counterbalance of supraphysiologic estradiol levels with adequate progesterone, we supplement progesterone. Luteal phase support may be accomplished with additional hCG injections or daily progesterone supplementation. However, the risk of ovarian hyperstimulation syndrome is increased as exogenous hCG re-stimulates the ovaries. Progesterone supplementation may be administered once daily in an intramuscular dose of 25–50 mg or it can also be given as oral, or more commonly vaginal, micronized progesterone, e.g. 100–200 mg tid. At our center, we recommend intramuscular progesterone. The initial dose is given the day after retrieval. Studies to date have suggested superior efficacy of intramuscular progesterone.55 The concern with vaginal progesterone is that it is more rapidly absorbed locally to the uterus and that it increases uterine contractions. However, it is possible that vaginal progesterone could be as effective as intramuscular progesterone if the timing of the first dose is adjusted. Patients who experience local reactions to intramuscular progesterone in oil may be switched to vaginal progesterone after the initial doses. Progesterone supplementation is maintained until the placental progesterone production is established and adequate. This usually occurs between 6 and 7 weeks’ gestatational age and is clinically documented by the presence of a fetal heart. Care must be taken that progesterone supplements are in fact progesterone (often micronized) and not progestin. Progestin is a synthetic, androgenic compound which may potentially be teratogenic. Progesterone supplements should not be continued beyond 9 weeks’ gestational age because of theoretical androgenic effects on external female genital differentiation. The exception to this rule is in patients who are recipients of donor embryo in a programmed cycle who may not produce adequate progesterone. We measure

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serum progesterone levels during the first trimester and we are reassured by levels greater than 20 ng/ml.

Ancillary Techniques and Micromanipulation Embryo Co-Culture Systems Standard culture media for human pre-embryos are typically formulated to mimic human tubal fluid. In a natural cycle the oocyte is usually fertilized in the distal third of the fallopian tube. Ham’s F-10 or HTF are media commonly used in US IVF programs. Maternal serum or protein substitutes are often used to supplement the media. Optimal conditions for pre-embryonic culture remain elusive. Embryo co-culture is an attempt to decrease fragmentation and improve cleavage and implantation rates by co-incubation of pre-embryos with another in vitro cell system which more closely mimics the in vivo system. Indications for embryonic co-culture include situations of implantation history of poor quality embryo or implantation failure despite good embryo quality. The original attempts at co-culture involved incubation of embryos with culture media that included tubal cells, usually harvested from bovine or primate monkey species. For obvious reasons, access to human tubal cells would be extremely limited. Due to the theoretical concerns about infection, we developed a system at our center whereby autologous endometrial cells collected at biopsy before IVF are used in the culture media. A good mix of glands and stroma is preferred. Recent clinical trials suggest that co-culture may be of particular benefit to patients with poor IVF prognosis, particularly those who have failed multiple previous cycles.56–58 Current FDA regulations have significantly limited the application of nonautologous co-culture system given the concern for transmission of potential infectious agents. Assisted Hatching Observations of improved implantation rates in pre-embryos that had undergone partial zona drilling led to the concept of assisted hatching. Assisted hatching (AHA) involves the thinning or partial disruption of the zona pellucida just prior to embryo transfer. The objective of this procedure may be two-fold. It may improve implantation rates for patients with a thick zona pellucida, and allows for removal of fragments from the perivitelline space. Such fragments have been correlated with embryo implantation failure (although they may be increased with chromosomal abnormalities, this correlation is not perfect). AHA may be performed early or late (2 cell embryo to a blastocyst) but it is generally performed on day 3 embryos. The size of the zona gap should not be too small so as to interfere with escape of the embryo from the zona pellucida. Complications of AHA include embryo loss at the time of transfer if the hole is too large. Also, if the hole is too small the blastocyst may be trapped. The incidence of monozygotic twinning appears to be increased by AHA.59 In the early to mid 1990s AHA gained popularity

especially for the following indications: advanced maternal age, poor reproductive history with IVF, poor ovarian reserve, poor embryo morphology, increased cytoplasmic fragmentation, and thick/abnormal zona pellucida. However, some more recent small randomized controlled trials have challenged this concept and assisted hatching at our institution is not performed routinely but only on indicated patients. Assisted Fertilization (Intracytoplasmic Sperm Injection, ICSI) During the last decade and a half rapid advances have been seen in micromanipulation technology. Assisted fertilization (ICSI) and preimplantation genetic diagnosis are two commonly applied micromanipulation procedures. ICSI is addressed in more detail in Chapter 34. Prior to the advent of assisted fertilization, couples who suffered from severe male factor infertility experienced very limited success with IVF. The first human births from intracytoplasmic sperm injection (ICSI) were reported in 1992.28 ICSI involves the injection of a single, viable sperm into a single oocyte. The development of ICSI has revolutionized the treatment of male factor infertility. Previously, semen concentrations of less than 5   106 sperm/ml were associated with poor IVF outcome. With ICSI and, more recently, advances in sperm retrieval directly from the testes or epididymis (TESE, MESA), even men with obstructive or nonobstructive azoospermia have the potential to fertilize oocytes and father their own genetic offspring. Much attention has recently been focused on the outcome of ICSI pregnancies. Several initial reports did not observe untoward neonatal effects from ICSI, and a recent update of a study done at Cornell again confirmed these findings.60 This study also suggested a lower incidence (0.17%) of sex chromosomal abnormalities than the previous Lancet article.32 Palermo et al. did not observe a higher incidence of other chromosomal abnormalities, spontaneous abortions or congenital anomalies when compared to IVF or general population statistics for women of similar ages. Bowen et al. evaluated medical and developmental outcome of children born from ICSI at 21 years of age.61 They compared children born from ICSI, IVF, and natural conception. Although there were no significant health problem and the mean Bayley MDI for development was within the normal range for most children, the ICSI subset did have a significantly lower score than the IVF and natural conception group. However, fathers of ICSI children were found to be significantly different from the other groups in that the former were more likely to hold ‘unskilled’ occupation. Nevertheless, when the subgroup analysis was done a significant difference remained. Another recent study suggested that the incidence of major birth defect is increased after ICSI.62 Nevertheless, this study did not differentiate major from minor birth defects and was suspect to multiple biases characteristic of observational data, such as surveillance bias and confounding, as well as lack of an appropriate

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control group. Obviously, more controlled studies are needed to evaluate the offspring of ICSI treatment. Cryopreservation Successful cryopreservation of embryos has been a revolution in ART. The first pregnancy from a cryopreserved conceptus was reported in 1983. Before embryo cryopreservation, patients and their physicians often faced a dilemma regarding the optimal number of oocytes to inseminate in order to maximize the likelihood of pregnancy but minimize potential embryo wastage. Advances in the success of cryopreservation have drastically improved the efficiency and safety of IVF. Approximately 60–70% of frozen pre-embryos survive the thaw process. Once the conceptus has survived the thaw process, the success rate of a frozen cycle transfer approaches two-thirds that of a fresh cycle. Cryopreserved embryos from IVF cycles where the fresh embryos resulted in pregnancy are also more likely to result in pregnancy. Success of frozen cycle transfers increases the overall pregnancy rate per retrieval.58 In some instances, patients may complete their family through a single IVF cycle that results in frozen embryos that are subsequently transferred. Patients who are identified as having significant risk for ovarian hyperstimulation may benefit from cryopreservation of all pre-embryos immediately and subsequent transfer in a later frozen cycle.64 Conceptuses may be frozen safely for at least 7 years. Those frozen for more than 12 months appear to have better success than those frozen for less. This fact may reflect that patients who have a successful pregnancy from the fresh transfer return later for the frozen transfers.65 Fertility preservation for patients with cancer or other significant medical illnesses often depends on the success of embryo cryopreservation. Such patients may undergo ovarian hyperstimulation and IVF with cryopreservation of resultant embryos for a later date when their active disease is in remission or their prognosis is known. Frozen pre-embryos may be transferred into the endometrial cavity in a natural cycle for patients with regular ovulation and menses. For patients without regular cycles, ovulation may be suppressed and the cycle programmed with the use of exogenous estrogen and progesterone. The transfer is timed so that the endometrium is synchronous with the embryo development stage as per the number of days post insemination. No differences in success between natural or programmed cycles are apparent.66 Preimplantation Genetic Diagnosis Preimplantation genetic diagnosis (PGD) has become a relatively recent indication for IVF. PGD allows diagnosis at three levels: sex chromosome abnormalities/aneuploidy, structural chromosomal abnormalities, and single gene diagnosis. The first reported cases of PGD were undertaken for

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sex-determination of embryos to prevent transmission of X-linked genetic disorders. These initial cases were reported in 1989. Subsequently, PGD was used to prevent single gene disorders such as cystic fibrosis. The two most common single gene disorders diagnosed by PGD are cystic fibrosis and sickle cell disease.67 Recently the indications for PGD have been expanded to include the diagnosis of embryo aneuploidy in women of advanced maternal age, previous IVF failures, and history of previously affected embryos or offspring. Diagnosis of structural chromosomal abnormalities in couples having balanced translocations is also possible with PGD, particularly in the treatment of recurrent miscarriage. Recently whole genome amplification with comparative genomic hybridization has been used to derive the entire karyotype for PGD, but the results are still very preliminary and the procedure is lengthy.68 There are many potential advantages to PGD. PGD can limit the occurrence of known lethal or severely disabling inherited genetic diseases and potentially even remove these diseases from a familial lineage completely. PGD can be used to identify the specific causes of recurrent implantation or pregnancy failure. This ability may serve two purposes: (1) it may help resolve issues for such couples who have been unable to succeed with reproductive technology and allow them closure so that they may decide to proceed with alternatives such as oocyte donation or adoption, and (2) once we are able to identify a particular disorder, we may be able to improve the implantation rates and ongoing pregnancy rates by transferring only those embryos that are genetically normal. This would help reduce the emotional burden of recurrent miscarriages for affected couples. Another advantage of PGD is the ability to avoid later pregnancy termination in patients who have a high risk of genetically abnormal conceptuses by preventing transfer of an identified genetically abnormal embryo. Many couples may consider PGD a preferable alternative to prenatal diagnosis and pregnancy termination. PGD to avoid a particular disease, e.g. Fanconi’s anemia, while at the same time producing an offspring who is HLA-compatible with an affected sibling is also possible and has been previously achieved.69 There are several potential limitations for PGD. PGD opens many ethical controversies with regards to selection for traits that do not specifically make a difference in the viability of offspring. Also, with the availability of HLA typing, the risk exists of couples reproducing for the express purpose of providing a marrow donor or rescue sibling for an affected child. There are several technical limitations to PGD. The technology has been mostly limited to centers that are expert in both molecular genetic and reproductive technology although collaboration between centers has recently been reported. The relatively small number of PGD cycles completed and the pregnancy success rate (which rarely exceeds 30%) has limited the availability of outcomes studies. This has several implications. Prenatal diagnosis is still recommended to confirm the accuracy of PGD. PGD

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may be likened to CVS in that error is possible through several mechanisms. For single gene defects, PCR is used to amplify the genetic signal. Contamination from several sources is possible, including the maternal cumulus cells, copies of paternal DNA available from extra sperm attached to the zona pellucida (ICSI is therefore utilized), and the operator or any contacts with the PCR procedure may contribute exogenous DNA. Also, the DNA may be obtained at different stages: from the polar body, from the cleavage stage (6–8 cell) embryo or from the blastocyst trophoectoderm. The sources may not accurately reflect the DNA constitution of the remainder of the embryonic cells, e.g. mosaicism may exist, similar to that seen with CVS. For single gene diagnosis, allelic dropout poses a serious threat of misdiagnosis. A limited number of liveborn infants have been available to ensure that there are no long-term consequences of these procedures and not all outcomes have been reported.70–72 The diagnoses are also limited by incomplete identification of all possible mutations. For example, for a single gene defect such as cystic fibrosis, the most common allelic mutation is the delta 508, however several other mutations may lead to compound heterozygotes that also may be affected. The ability to identify these compound heterozygotes depends on the availability of the appropriate probes and the fact that certain mutations have not yet been identified. Also, when one is searching for structural abnormalities, the error rate for aneuploidy may be as high as 15%. Generally 1–2 blastomeres are removed from a cleavage stage embryo and multiple probes for different chromosomes are used in the same recycled blastomere, e.g. 13, 16, 18, 21, X,Y. Generally the number of probes that can be used on a single cell is limited to approximately seven. Therefore, only those numerical chromosomal abnormalities related to the tested chromosomes can be identified. Errors due to background signals, weak signals, etc., can interfere with the diagnosis. Often polar body biopsy is used for preimplantation genetic screening (preimplantation genetic diagnosis of aneuploid embryos in couples with no specific family history but who may have, for example, advanced maternal age) since the abnormal chromosomal complement usually comes from the mother. Nevertheless, errors in diagnosis can occur because of recombination events or because the paternal complement has not been examined. The number of embryos obtained also limits PGD. For example, a couple with advanced maternal age who have few embryos (e.g. 5) risk reduced viability of even a normal embryo from the procedure. The two most common approaches to PGD are first polar body biopsy and, more commonly, blastomere biopsy. First polar body biopsy is often used for structural chromosomal analysis for anomalies of maternal origin, since fertilization has not yet occurred. First polar body biopsy is often therefore referred to as preconception genetic diagnosis. Blastomere biopsy may be performed at the 6–8 cell stage and is necessary for assessment of disorders of paternal origin but is also more accurate for both numerical, structural

and single gene diagnosis. Theoretically, biopsy of one blastomere should represent all other embryonic cells at this stage, although embryonic chromosomal mosaicism can interfere with the diagnosis. Structural chromosomal analysis is generally achieved with florescent in situ hybridization (FISH) as the results are available in 12 hours. Polymerase chain reaction is required for single gene diagnosis. Oocyte Donation Oocyte donation has proven to be a successful option for women who cannot conceive with their own oocytes, due to advanced age, diminished ovarian reserve, or genetic disease. Oocyte donation allows the female partner to carry and deliver a pregnancy with her husband’s genetic contribution. The success of oocyte donation is mainly limited by the age of the donor, who should optimally be younger than 35 years old. Although endometrial receptivity may diminish somewhat with age, the contribution of this uterine factor appears minimal in comparison to oocyte quality. For this reason, the optimal number of embryos to be transferred to the recipient is also principally determined by the age of the donor, rather than that of the recipient.73,74 Oocyte donors may be either known or unknown to the recipient. Known donors are often biologically related donors (e.g. sister or cousin donors). Since most donors, and particularly anonymous donors, are young, their oocytes and resultant embryos have a good prognosis. The risks of the ART procedure for the donor are confined to the risks associated with stimulation and retrieval since the donor does not carry the pregnancy. The primary risk of donation for the recipient is the transmission of infection. Despite the fact that the donors are screened at multiple intervals for infectious diseases, the fact that fresh embryos are used, due to lower implantation rates with frozen embryos, gives rise to a small, theoretical risk of transmission of diseases such as human immunodeficiency virus (HIV), although such transmission has not been documented with oocyte donation. After oocyte retrieval, the surrounding cells are removed completely from the oocyte prior to insemination and the oocytes are washed of any blood cells. In contrast to semen, isolated oocytes do not represent a leukocyte-rich source. Although this risk appears to be mainly theoretical, the alternative of cryopreserving and quarantining embryos resulting from donor oocytes should be discussed with recipients, including a discussion of relative implantation and survival rates with freezing and thawing conceptuses. A key component of successful oocyte donation is synchronization of the recipient’s menstrual cycle with the donor’s cycle. In a recipient with intact ovarian function, this can be achieved through GnRH downregulation followed by hormonal support with exogenous estrogen and progesterone. The day that the progesterone is started is designated as day 15. The greatest success rates appear to occur with transfer on day 17, 18, or 19. A mock (prep) cycle may be undertaken to ensure

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that the recipient responds appropriately to hormonal support and that her endometrial lining develops adequately. Estrogen and progesterone support are continued throughout the first trimester, until approximately 10 weeks, and are discontinued once adequate placental steroidogenesis is documented.

IVF Outcome In vitro fertilization outcomes have improved throughout the years. In 2005, 97 442 fresh non-donor cycles were started in the United States with an overall delivery rate of 28%. Although advancing maternal age has a negative effect on prognosis, analysis of outcomes over the past three years shows a steady improvement in outcomes for each of the maternal age groups: younger than 35 years, 35–37 years, 38–40 years, and older than 40 years. Factors that have been shown to affect outcome include: maternal age, clinic size, the use of fresh versus cryopreserved embryos and oocyte donation.75 The direct risks of IVF to the mother include the risks associated with the procedure (bleeding, infection, and injury to surrounding structures) as outlined above and the risk of ovarian hyperstimulation syndrome (OHSS). OHSS can be mild, moderate or severe. The trigger for OHSS is hCG. In the absence of pregnancy or if hCG administration is withheld in light of risk for OHSS, the syndrome, if it occurs, usually adopts a very mild and self-limiting course. The incidence of moderate to severe hyperstimulation has been reported to be 2–4%. Rarely, severe OHSS can occur. It is a condition in which enlarged ovaries, encumbered by multiple follicles, exude fluid in the third space, and ascites, pleural effusions, pericardial effusions, electrolyte imbalances, hypovolemia, oliguria, and venous thromboembolism can be observed. Therefore, it potentially may be life-threatening. Although OHSS may potentially occur in any patient, younger patients, patients with PCOS, patients with very high estradiol levels or excessive number of follicles may be at greater risk. OHSS virtually does not occur in the absence of hCG. Therefore, in the very high risk patient, a decision to withhold hCG may be prudent if estradiol levels are high during stimulation. It is also extremely important in such an individual to avoid a natural LH surge and or conception by maintaining leuprolide or GnRH antagonist injections. Patients who appear to be at high risk after oocyte retrieval may delay embryo transfer from day 3 to day 5. If sufficient resolution of symptoms has not occurred by then, consideration may be given to embryo cryopreservation and embryo transfer at a later date. Management of mild to moderate OHSS requires careful monitoring of symptoms like abdominal pain, and shortness of breath, weight, abdominal girth, fluid intake and urine output, ovarian size, and ascites. Serum for hematocrit, platelets, electrolytes, and coagulation profiles should be monitored. Due to the enlarged ovarian size, ovarian torsion is a risk and patients must be advised of warning signs.

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Severe OHSS can be life-threatening. Such patients should be admitted on bedrest with frequent vital signs and closely monitored for the following: daily weights, fluid intake and output, blood tests, and electrocardiogram (EKG). Abdominal and pelvic examination should be strictly avoided as enlarged ovaries may be very fragile and prone to rupture and hemorrhage. Attention should be paid particularly to renal function, pulmonary edema, and thromboembolic risk. Thromboprophylaxis should be considered, particularly if the patient is hemoconcentrated. Diuretics should generally be avoided as these patients are intravascularly volume-depleted. However, some authors have recommended the use of plasma expanders (such as albumin, pentaspan) to draw the fluid out of the third space, followed by a touch of diuretic chasers. Therapeutic, ultrasound-guided paracentesis may be required to relieve abdominal distension, discomfort, and intrabdominal pressure in some situations. In general, however, primary therapy is conservative and mainly supportive. A major concern regarding reproductive technology has been an increased incidence of multiple births.76–78 Both pregnancy rates and multiple birth rates are directly correlated to number of embryos transferred. In 2005, live births from IVF had the following constitution: 68% singletons, 29.7% twins, 2.4% triplets or higher order multiples deliveries. Morbidity and mortality are significantly increased in pregnancies complicated by multiple gestations. Approaches to decrease the number of multiple births may also decrease the number of successes per fresh IVF cycle, e.g. by decreasing the number of embryos transferred. However, with laboratory conditions being more optimized, the trend to replace fewer day 3 embryos in any category is an appropriate one. Transfer of one or more blastocysts should prevent higher order multiples. As discussed earlier, the incidence of ectopic pregnancies according to some studies is increased after IVF compared with the general population (1%). The most recent report from SART cited an incidence of 2.1%. We recently reviewed the incidence of laparoscopically/ultrasonographically confirmed ectopic pregnancy and found the incidence after fresh embryo transfer at our center to be only 0.898%. However, the incidence is higher in the specific population with tubal infertility. Little practical information is available regarding the overall incidence of heterotopic pregnancies (simultaneously occurring intra-uterine and ectopic pregnancies) from IVF. Most of the available data is in the form of case reports. We have recently reviewed our statistics and found an incidence of 0.18% heterotopic pregnancies.19,79 Interestingly, tubal disease was a risk factor in all of the heterotopic pregnancies, and the intra-uterine pregnancies were all delivered successfully at term following surgical intervention for the ectopic pregnancy. Early monitoring ultrasound surveillance is important to diagnose heterotopic pregnancies. Recent data evaluating the outcomes of children born from IVF has become available. One study specifically assessed growth, physical, and developmental health of children born

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from cryopreserved embryos compared to fresh IVF cycles and also compared these to spontaneous conceptions. There were no significant differences with respect to chronic illness, congenital anomalies, chromosomal anomalies, and neurological or developmental health between the three groups. However, there were statistically significant differences found for growth in the cryopreserved embryo group. The authors concluded that these small differences, however, were not clinically significant.80 Three other recent cohort studies have recently suggested that outcomes of IVF children, in some cases specifically ICSI children, may be different from spontaneous conception with regards to neurological development, congenital anomalies, and low birthweight.62,81,82 As with most observational data, however, these studies suffer from multiple biases, including surveillance bias, confounding, reporter bias, and misclassification and lack of an adequate control group. One consistent finding that is concerning, however, is that singleton births from IVF do appear to have lower gestational ages and birthweights compared to spontaneous conceptions.82 This might be related to the differences in obstetrical practice patterns on IVF versus naturally conceived patients. Available data concerning the link between ovarian cancer and ovulation induction has recently proven to be reassuring. Several meta-analyses have shown that the risk appears to be more related to infertility rather than the use of fertility drugs.83 In fact, a recent meta-analysis by one of the authors suggests that women who suffer from infertility may be protected form ovarian cancer if they conceive with therapy.84 Preliminary data from a large, prospective cohort study conducted with the National Institutes of Health are also reassuring.

Acupuncture A practice used for centuries, acupuncture is a vital healing modality in Traditional Chinese Medicine. The utilization of acupuncture by patients undergoing infertility treatment has been increasing in recent years. The general belief of acupuncture is based on the notion that there is a pattern of energy flow (qi) through meridians in the body, which is paramount for health. And, according to acupuncture theory, the disruption of such flow results in disease. Acupuncture is thought to modulate physiologic processes through stimulation of specific points along pathways (meridans) in which qi flows. The potential mechanisms underlying acupuncture’s impact on fertility include (1) modulating neuroendocrine factors, (2) increasing uterine blood flow, and (3) reducing stress associated with the infertility process. Because acupuncture treatment impacts on -endorphin levels, which in turn affect GnRH secretion and the menstrual cycle, it is logical to hypothesize that acupuncture may influence ovulation and infertility.85 The hypothalamic–pituitary–ovarian axis is affected by a multitude of and fluctuations of neurotransmitters. Acupunc­ ture stimulates the release of opioids and neurotransmitters, which can modulate hypothalamic influence on reproduction.

Acupuncture has been shown to induce an increase in endorphin levels that last up to 24 hours. Acupuncture also stimulates release of opioids, which have been associated with the initiation of the mid-cycle LH surge. These can influence the GnRH secretion, which can impact ovulatory function as well as affect the menstrual cycle. Acupuncture has been demonstrated to modulate circulation to many parts of the body. Through its actions on the sympathic nervous system, acupuncture may reduce uterine artery impedance, resulting in increased blood flow to the uterus. As endometrial thickness has been considered an important factor for embryo implantation, and increased blood flow to the uterus would enhance endometrial lining development, acupuncture may influence endometrial lining thickness and embryo implantation. A recent meta-analysis including seven randomized controlled trials with a total of 1366 women undergoing acupuncture at time of embryo transfer during their IVF cycle demonstrated an association between acupuncture and improved pregnancy rates (OR 1.65).86 Additionally, acupuncture appears to improve depression, anxiety, and stress of women undergoing infertility. It has been demonstrated that depression and anxiety are correlated with poorer IVF outcome while stress reduction appears to improve fertility. Through improvement in mood, acupuncture may serve enhance IVF outcomes. As the body of literature on acupuncture use in infertility is growing, the addition of more randomized controlled trials would strengthen the association of acupuncture and fertility treatment outcomes.

Conclusions The desire to procreate and have one’s own genetically descended offspring is an extremely visceral desire. Under­ standing of reproductive physiology is essential to the treatment of such patients. Assisted reproduction has evolved immensely during the past decade. The development of GnRH antagonists, sequential media for blastocyst culture, assisted fertilization (especially ICSI), and advances in cryopreservation have contributed to the increased success rates of IVF. Additionally, ancillary techniques such as preimplantation genetic diagnosis allow us not only to ‘cure’ infertility, but also to prevent potentially devastating and tragic diseases. Oocyte donation allows couples who cannot conceive with their own oocytes to gestate and deliver a pregnancy. Multiple births from IVF are a significant issue. One problem is that in a capitalistic society where medicine is a private and competitive industry, success rates are reported by pregnancy rate per transfer procedure or retrieval. A second problem is that patients, often anxious for success and perhaps because of misinformation or lack of patient education, feel that multiple birth is a more palatable option than a negative pregnancy test. With advances in the successes of blastocyst transfer, embryo cryopreservation, physician and patient education about the complications of multiple births, and hopefully

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a more responsible reporting system that accounts for all pregnancies achieved from a single IVF cycle (either by fresh or frozen embryo transfer), we can prevent high-order multiple pregnancies. In fact, in some countries, the governments limit the number of pre-embryos to be transferred to one or two with the remainder of concepti frozen for later cycles. Assisted reproduction combines both art and science. Both meticulous clinical and laboratory management are required to maximize the potential of the existing technology. Future directions such as cytoplasmic transfer, nuclear cloning, and oocyte/ ovarian tissue freezing are on the horizon. We expect that future developments in this field will be as exciting as its history.

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References   1. Taylor P, Collins J. Unexplained Infertility. New York NY: Oxford University Press; 1992, 153-169.   2. Evers JL. Female subfertility. Lancet 2002;360:151–59.   3. Westrom I. Incidence, prevalence, and trends of acute pelvic inflammatory disease and its consequences in industrialized countries. Am J Obstet Gynecol 1980;138:880.   4. Pisarka M, Carson S, Buster J. Ectopic pregnancy. Lancet 1998;351:1115.   5. Mol B, Dijkman B, Wertheim P, Lijmer J, Van Der Veen F, Bossuyt PM. The accuracy of serum chlamydial antibodies in the diagnosis of tubal pathology: a meta-analysis. Fertility Sterility 1997;67:1031–37.   6. Petersen H, Xia Z, Hughes J, et al. The risk of ectopic pregnancy after tubal sterilization. N Engl J Med 1997;336:762.   7. Marcoux S, Maheux R, Berube S, et al. Laparoscopic surgery in infertile women with minimal to mild endometriosis. N Engl J Med 1997;337:217–22.   8. Soules M, Spadoni L. Oil versus aqueous media for hysterosalpingography: a continuing debate based on many opinions and few facts. Fertil Steril 1982;38:1–11.   9. Flemming R, Hopkinson ZE, Wallace M, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metabol 2002;87:569–74. 10. Dunson DB, Colombo B, Baird DD. Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 2002;17:1399–403. 11. Pincus G, Enzmann E. Can mammalian eggs undergo normal development in vitro? Proc Natl Acad Sci U S A 1934;20:121. 12. Thibault C, Dauzier L, Wintenberger S. Etude cytologique de la fecondation in vitro de l’oeuf de la lapine. C R Soc Biol Paris 1954;148:789. 13. Perone N. In vitro fertilization and embryo transfer: a historical perspective. J Reprod Med 1994;39:695–700. 14. Estes WJ. Ovarian implantation for sterility. Surg Gynecol Obstet 1924;38:394. 15. Strandell A, Lindhard A. Why does hydrosalpinx reduce fertility? The importance of hydrosalpinx fluid. Hum Reprod 2002;17:1141–45. 16. Johnson N, Mak W, Sowter M. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. The Cochrane Library 2002;2. 17. Strandell A, Lindhard A, Waldenstrom U, Thorburn J, Janson P, Hamberger L. Hydrosalpinx and IVF outcome: a prospective,

22.

23.

24. 25.

26.

27.

28.

29.

30.

31. 32.

33.

34.

35.

397

randomized multi-centre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod 1999;14:2762–69. Strandell A, Lindhard A, Waldenstrom U, Thorburn J. Hyd­ rosalpinx and IVF outcome: cumulative results after salpingectomy in a randomized controlled trial. Hum Reprod 2001; 16:2403–10. Kashyap S, Chung P, Kligman I, Rosenwaks Z. 7 year descriptive summary of ectopic pregnancies occurring after fresh and frozen IVF cycles. Fertility Sterility 2002;78:S137. Diaz I, Navarro J, Blasco L, et al. Impact of stage III-IV endometriosis on recipients of sibling oocytes: matched casecontrol study. Fertil Steril 2000;74:31–34. Toya M, Saito H, Saito T, et al. Moderate and severe endometriosis is associated with alterations in the cell cycle of granulose cells in patients undergoing in vitro fertilization and embryo transfer. Fertil Steril 2000;73:344–50. Oliviennes F, Feldberg D, Liu H, et al. Endometriosis: a stage-by-stage analysis: the role of in vitro fertilization. Fertil Steril 1995;64:392–98. Medicine. SARTatASRM. Assisted reproductive technology in the United States: 1998 results generated from the American Society for Reproductive Medicine/Society for Assisted Repro­ ductive Technology Registry. Fertil Steril 2002;77:18–31. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002;77:1148–55. Marcus S, Edwards R. High rates of pregnancy after longterm down-regulation of women with severe endometriosis. Am J Obstet Gynecol 1994;171:812–17. Nakamura K, Oosawa M, Kondou I, et al. Menotropin stimulation after prolonged gonadotropin releasing hormone agonist pretreatment for in vitro fertilization in patients with endometriosis. J Assist Reprod Genet 1992;9:113–17. Dicker D, Goldman J, Levy T, et al. The impact of long-term gonadotropin-releasing hormone analogue treatment in preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization-embryo transfer. Fertil Steril 1996;65:791–95. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992;340:17–18. Guzick D, Overstreet J, Factor-Litvak P, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001;345:1388–93. Van Uem J, Acosta A, Swanson R, et al. Male factor evaluation in in vitro fertilization: Norfolk experience. Fertil Steril 1985;44:375. Schlegel P, Girardi S. In vitro fertilization for male factor infertility. J Clin Endocrinol Metabol 1997;82:709–16. In’t Veld P, Brandenberg H, Verhoff A, Dhont A, Los F. Sex chromosomal abnormalities and intracytoplasmic sperm injection. Lancet 1995;336:776. Oktay K, Buyuk E, Davis O, Yermakova I, Veeck L, Rosenwaks Z. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 2003;18:90–95. Aboulghar M, Mansour R, Serour G, Abdrazek A, Amin Y, Rhodes C. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials. Fertil Steril 2001;75: 88–91. Ruiz A, Remohi J, Minguez Y, Guanes P, Simon C, Pellicer A. The role of in vitro fertilization and intracytoplasmic sperm

398

36.

37. 38.

39.

40. 41.

42.

43.

44.

45.

46. 47. 48.

49.

50.

51. 52. 53.

54.

55.

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injection in couples with unexplained infertility after failed intrauterine insemination. Fertil Steril 1997;68:171–73. Crosignani P, Walters D, Soliani AHR. The ESHRE multicentre trial on the treatment of unexplained infertility: a preliminary report. European Society of Human Reproduction and Embryology. Hum Reprod 1991;6:953–58. Tietze C. Reproductive span and rate of reproduction among Hutterite women. Fertil Steril 1957;8:89. Damario MA, Davis O, Rosenwaks Z. The role of maternal age in the assisted reproductive technologies. Reprod Med Rev 1999;7:141–60. Liccardi F, Liu H, Rosenwaks Z. Day 3 estradiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization. Fertil Steril 1995;64:991–94. Navot D, Rosenwaks Z, Margalioth E. Prognositic assessment of female fecundity. Lancet 1987:1. Edwards R, Lobo R, Bouchard P, et al. Dose-finding study of triptolrelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo­controlled study. Human Reprod 2000;15:2333–40. Diedrich K, Ludwig M, Felberbaum R. The role of gonadotropin-releasing hormone antagonists in in vitro fertilization. Semin Reprod Med 2001:213–20. Ludwig M, Felberbaum R, Albano C, et al. Cetrorelix levels in plasma and follicular fluid. Gynecol Endocrinol 2000;13 (Suppl 1):030. Levy D, Navarro J, Schattman G, Davis O, Rosenwaks Z. The role of LH in ovarian stimulation. Hum Reprod 2000;15: 2258–65. Ludwig M, Reithmuller-Winzen H, Felberbaum R, et al. Health of 227 children born after controlled ovarian stimulation for invitro fertilization using the luteinizing hormone-releasing hormone antagonist cetrorelix. Fertil Steril 2001;75(1):18–22. Rock J, Menkin M. In vitro fertilization and cleavage of human ovarian eggs. Science 1944;100:105–7. Steptoe P. Laparoscopy and ovulation. Lancet 1968;ii:913. Steptoe P, Edwards R. Laparoscopic recovery of preovulatory human oocytes after priming of ovaries with gonadotropins. Lancet 1970;i:683–89. Muasher S, Wilkes C, Carcia J, Rosenwaks Z, Jones HJ. Benefits and risks of multiple transfer with in vitro fertilization. Lancet 1984;i:570. Schulman A, Ben-Nun I, Ghetler Y, et al. Relationship between embryo morphology and implantation rate after in vitro fertilization treatment in conception cycles. Fertil Steril 1993; 60:123. Dhont M. Single embryo transfer. Semin Reprod Med 2001;19: 251–58. Schoolcraft W, Surrey E, Gardner D. Embryo transfer: techniques and variables affecting success. Fertil Steril 2001;67:863–70. Coroleu B, Carreras O, Veiga A, et al. Embryo transfer under ultrasound guidance improves pregnancy rate after in vitro fertilization. Hum Reprod 2000;15:616–20. Soliman S, Daya S, Collins J, Hughes E. The role of luteal phase support in infertility treatment: a meta-analysis of randomized controlled trials. Fertil Steril 1994;61:1068. Damario M, Goudas V, Session D, Hammitt D, Dumesic D. Crinone 8% vaginal progesterone gel results in lower embryonic implantation efficiency after in vitro fertilization-embryo transfer. Fertil Steril 1999;72:830–36.

56. Simon C, Mercader A, Garcia-Velasco J, et al. Coculture of human embryos with autologous human endometrial epithelial cells in patients with implantation failure. J Clin Endocrinol Metabol 1999;84:2638–46. 57. Wiemer K, Cohen J, Tucker M, Godke R. The application of co-culture in assisted reproduction: 10 years of experience with human embryos. Hum Reprod 1998;13:226–38. 58. Barmat L, Liu H, Spandorfer S. Human preembryo development on autologous endometrial coculture versus conventional medium. Fertil Steril 1998;70:1109–13. 59. Schieve L, Meikle S, Peterson H, Jeng G, Burnett N, Wilcox L. Does assisted hatching pose a risk for monozygotic twinning in pregnancies conceived through in vitro fertilization? Fertil Steril 2000;74:288–94. 60. Palermo G, Neri Q, Rafaelli R, Davis O, Rosenwaks Z. Evolution of pregnancies and follow-up of newborns delivered after intracytoplasmic sperm injection. In: T Rabe, K Diedrich, T Strowitzki, eds. Manual on Assisted Reproduction, 2nd edn. Berlin: Springer; 2000. 61. Bowen J, Gibson F, Leslie G, Saunders D. Medical and developmental outcome at 1 year for children conceived by intracy­toplasmic sperm injection. Lancet 1998;351:1529–34. 62. Hansen M, Kurinczuk J, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;346:725–30. 63. Damario M, Hammitt D, Session D, Dumesic D. Embryo cryo­ preservation at the pronuclear stage and efficient embryo use optimizes the chance for a liveborn infant from a single oocyte retrieval. Fertil Steril 2000;73:757–73. 64. Ferraretti A, Gianoroli L, Magli C, Fortini D, Selman H, Feliciani E. Elective cryopreservation of all pronucleate embryos in women at risk of ovarian hyperstimulation syndrome: efficiency and safety. Hum Reprod 1999;14:1457–60. 65. Lin Y, Cassidenti D, Chacon R, et al. Successful implantation of frozen sibling embryos is influenced by the outcome of the cycle from which they were derived. Fertil Steril 1995;63:262–67. 66. Oehninger S, Mayer J, Muasher S. Impact of different clinical variables on pregnancy outcome following embryo cryopreservation. Mol Cell Endocrinol 2000;169:73–77. 67. Xu K, Shi Z, Veeck L, Hughes M, Rosenwaks Z. First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. JAMA 1999;281:1701–6. 68. Elias S. Preimplantation genetic diagnosis by comparative genomic hybridization. N Engl J Med 2001;345:1569–71. 69. Verlinsky Y, Rechitsky S, Schoolcraft W, Strom C, Kuliev A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA 2001;285:3143–44. 70. Committee. EPCS. ESHRE Preimplantation Genetic Diagnosis (PGD) Consortium: data collection II. Hum Reprod 2000;15:2673–83. 71. Strom C, Levin R, Strom S, Masciangelo C, Kuliev A, Verlinsky Y. Neonatal outcome of preimplantation genetic diagnosis by polar body removal: the first 109 infants. Pediatrics 2000;106:650–53. 72. Bonduelle M, Van Asche E, Sermon K, et al. Neonatal outcome following preimplantation genetic diagnosis (PGD) as an alternative to prenatal diagnosis. Eur J Hum Genet 1999;7:38. 73. Shulman A, Frenkel Y, Dor J, Levran D, Shiff E, Maschiach S. The best donor. Hum Reprod 1999;14(10):2493–96. 74. Faber B, Mercan R, Hamacher P, Muasher S, Toner J. The impact of an egg donor’s age and her prior fertility on recipient pregnancy outcome. Fertil Steril 1997;68:370–72.

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75. Templeton A, Morris J, Parslow W. Factors that affect outcome of in-vitro fertilization treatment. Lancet 1996;348:1402–6. 76. Callahan T, Hill J, Ettner S, et al. The economic impact of multiple gestation pregnancies and the contribution of assisted reproduction techniques to their incidence. N Engl J Med 1994; 331:244–49. 77. Cohen J, Jones H. How to avoid multiple pregnancies in assisted reproductive technologies. Semin Reprod Med 2001;19:269–79. 78. Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 1998;339:573–77. 79. Kashyap S, Kligman I, Chung P, Rosenwaks Z. Heterotopic pregnancies after IVF: a case-control study. Fertil Steril 2002; 78:S248–49. 80. Wennerholm U, Albertsson-Wilkand K, Bergh C, et al. Postnatal growth and health of children born after cryopreservation as embryos. Lancet 1998;351:1085–90.

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81. Stromberg B, Dahlquist G, Ericson A, et al. Neurological sequelae in children born after in-vitro fertilization: a population based study. Lancet 2002;359:461–65. 82. Schieve L, Meikle S, Ferre C, et al. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731–37. 83. Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002;155:217–24. 84. Kashyap S, Moher D, Fung MFK. Induction of ovulation and ovarian cancer: a meta-analysis. Fertil Steril 2002;78:S154. 85. Chang R, Chung P, Rosenwaks Z. Role of acupuncture in the treatment of female infertility. Fertil Steril 2002;78:1149–53. 86. Manheimer E, Zhang G, Udoff L, et al. Effects of acupuncture on rates of pregnancy and live birth among women undergoing in vitro fertilization: systemic review and meta-analysis. Br Med J 2008;336(7643):545–49.

C HAPTER

36

Female Sexual Health Barbara D. Bartlik1, Julie A. Kolzet2, Nazia ahmad3, tahmina parveen3, and sarah alvi4 1 Assistant Professor of Psychiatry and Psychiatry in Obstetrics and Gynecology, Weill Cornell Medical College, Department of Psychiatry, New York, NY, USA 2 Weill Cornell Medical College, Department of Psychiatry, New York, NY, USA 3 CUNY Hunter College, New York, NY, USA 4 University of Massachusetts, Amherst, MA, USA

Prevalence

dysfunction in women with psychiatric disturbances, chronic illness, or circulatory or neurologic problems, to be higher than that in a healthy population. One limitation of the NHSLS survey is that it included only those individuals who reported sexual activity with a partner in the 12-month period prior to the interview. The responses of 139 men and 238 women (approximately 10% and 14%, respectively) were excluded from the analysis based on the individual’s failure to meet these selection criteria. It is probable that a percentage of these individuals had a diagnosable sexual problem. Therefore, the survey may have underreported the degree to which sexual dysfunction actually is present. Moreover, the study excluded individuals over 60 years of age. Since the prevalence of sexual dysfunction increases with age, this, too, may have reduced the reported prevalence of sexual dysfunction in the study population. Nonetheless, the data gleaned from the NHSLS survey offer insight into both the magnitude and make-up of sexual dysfunction within the population, and makes a strong case for additional epidemiological studies.

Female sexual dysfunction (FSD) is a complex, highly prevalent medical problem with biological, psychological, and interpersonal influences. The effects of FSD can be extensive, potentially disrupting physical, emotional, and social aspects of the lives of women of all ages. FSD can be considered a public health issue in that it affects the quality for life of a large portion of the female population. FSD is divided into four categories including problems of desire, arousal, orgasm, and pain, which approximate the phases of the sexual response cycle1. As the first population-based assessment of sexual dysfunction in the half-century since Kinsey, the National Health and Social Life Survey (NHSLS) often is considered the best estimate of sexual problems in the United States for both genders.2,3 The NHSLS is a 1992 national probability sample of 1410 men and 1749 women between the ages of 18 and 59 years living in US households. Approximately 43% of women and 31% of men reported some form of sexual dysfunction during the 12 months prior to the survey. Response items covered the major problem areas addressed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) classification for sexual dysfunction. Among female respondents who reported sexual dysfunction, roughly 22% suffered from desire problems, 14% from arousal problems (including inability to achieve climax), and 7% from pain-related problems.3 Moreover, several predictors of sexual dysfunction are mentioned in the NHSLS survey. These include health status and emotional or stress-related problems. The data are consistent with the belief that the prevalence of sexual

Principles of Gender-Specific Medicine

Anatomy and physiology The sexual response is mediated by the central, autonomic, and somatic nervous systems, the spinal cord, peripheral nerves of the lower abdomen, the endocrine system, and the peripheral circulatory system at the level of the genitalia. These systems interact and work in concert with one another in a complex manner.4 Damage to or disregulation in any one of these systems can result in FSD.

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Suspensory ligament Pubic symphysis Pubic bone

Shaft of clitoris Hood of clitoris Glans of clitoris Outer labia

Crura

Urethral sponge

Urethral opening

Bulbs

Inner labia Vagina

Fourchette Perineal sponge

Anus External Structure

Internal Structure

Figure 36.1  The female genitals in the aroused state showing the internal (italic labels) and external structures. Original drawing by Beatrix Carroll and Barbara Bartlik.

The Clitoris The clitoris is more than just a pencil-erased protuberance anterior to the urethral opening. It also includes deeper structures that become engorged during sexual arousal, which provide both protection from injury during intercourse, as well as pleasure.5 As in the male, the clitoris contains two corpora cavernosa and one corpus spongiosum. In the female, the corpus spongiosum is split in two, forming two bodies of erectile tissue in each of the labia majora. These are called the bulbs of the vestibule. Valves in the arteries and veins of the bulbs close shut and blood becomes trapped within.6 The corpora cavernosa form the legs of the clitoris, or the crura, which anchor the clitoris to the underlying bone5 and become quite firm during arousal. The glans of the clitoris is the area most responsive to sexual stimulation. It is the most densely innervated part of the human body,7,8 with neural pathways that both receive and respond to sexual stimulation. As arousal proceeds, the clitoral hood enlarges and its supporting ligament shortens, effectively pulling on the clitoral shaft and causing the glans to recede beneath the hood.6 It may appear as though the glans is smaller during high arousal, but actually it is only less visible.6

The Vulva In addition to the deeper clitoral structures, the tissues of the labia minora also become engorged during arousal. They protrude rendering the woman more receptive to penetration. Penile thrusting has the effect of pulling on the labia minora, which indirectly stimulates the body and glans of the clitoris.5

The Vagina The vagina possesses a rich arterial blood supply and a plexus of veins particularly in the lower portion.5 With arousal, a modified plasma transudate is extruded through the vaginal wall, which reduces friction and heightens pleasure. The introitus narrows and becomes tighter with high arousal. The lower portion of the vagina is surrounded by the muscles of the pelvic floor. Spasm in these muscles can lead to vaginismus, which can make penetration difficult if not impossible. On the other hand, lax muscle tone in the area may lead to arousal or orgasm problems.5

The Uterus During arousal the uterus also becomes engorged and increases in size. It rises in the pelvis as the broad ligament

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tightens, which serves the purpose of moving the cervix out of the way, reducing the risk of injury or pain during intercourse.5,6 The upper portion of the vaginal canal enlarges as the uterus lifts. As delineated above, if a woman is not sufficiently aroused prior to intercourse, there are many potential causes for discomfort.

less activity in the pelvic floor muscles and more activity in the uterus and cervix.10 Both the G-spot and the clitorally-stimulated orgasm typically last less than ten seconds. Continued stimulation can produce additional orgasms in some females, referred to as multiple orgasms. Orgasm is followed by a pleasurable period of relaxation.10

Peripheral Neurophysiology Little is known about the exact nature of the afferent innervation of the female genital. The hypogastric and pelvic nerves relay sensory information from the internal pelvic organs, and they may be important in vaginal orgasm. The pudendal nerve relays sensory information from the vulva and the perineal musculature and is responsible for clitoral orgasm. An afferent vagal pathway may also be involved, since women with complete spinal cord resections have had orgasms from vaginal and cervical stimulation alone.9

General Responses During Sexual Arousal During high arousal, arteries dilate, blood pressure and pulse increase, and blood flow to the muscles involved in sexual activity increases. Respiration becomes shallow and rapid, aiding in oxygenation of the blood. Increased perspiration and flushing also occur as the body attempts to dissipate heat.5 After an adequate period of sexual stimulation, which varies a great deal from woman to woman, orgasm may occur.

Orgasm During orgasm, the pelvic floor muscles contract rhythmically in unison, at a frequency of 0.8 per second for 5–8 contractions.5 The contractions often are associated with the peak of sexual pleasure, during which there may be a slight closing of the introitus, as well as contraction of striated muscle. Orgasms are felt not only in the clitoris but in the pelvis and entire genital region.10 The contractions compress the engorged clitoral tissues. In a small proportion of women, orgasm results in the emission of fluid, referred to as female ejaculation. The ejaculate is extruded from the peri-urethral glands through the tiny peri-urethral ducts. As in the male, the female ejaculate contains prostate-specific antigen (PSA) and is different, chemically, from urine.11

The G-Spot, Vaginal, Clitoral, and Multiple Orgasm The G-spot is an area of heightened sensitivity on the anterior wall of the vagina, about 4 cm from the introitus. Some women particularly enjoy having this area stimulated, during intercourse or through other means. Stimulation of the G-spot is associated with ‘vaginal’ orgasm in some women, which occurs without direct stimulation of the clitoral glands or shaft. The G-spot-stimulated orgasm is associated with

Clinical practice Health-Related Factors Associated with FSD As with male sexual dysfunction, the health-related problems associated with FSD include hypertension, smoking, hyperlipidemia, and endothelial dysfunction.12 Sexual dysfunction in both men and women has been associated with epilepsy, stroke, and Parkinson’s disease.4 Moreover, 24–34% of women with Type I diabetes have decreased lubrication or impaired desire.13 In women with Type II diabetes, 29% had inadequate lubrication and 32% had orgasm disorder.14 Other medical problems associated with FSD include hypogonadism (low estrogen and low testosterone), elevated prolactin, hypothyroidism or hyperthyroidism, pelvic floor dysfunction, the postpartum state, lower urinary tract conditions, persistent vaginal infections, vulvar cysts, gastrointestinal problems, arthritic pain, clitoral phimosis, pudendal or other neuropathy, lower back injury, and scar tissue from episiotomy or other surgery.4,15,16 Women who have undergone chemotherapy for breast cancer are at increased risk of developing FSD, as are women who have undergone hysterectomy. In most cases, these problems may be attributed to hormonal factors. Even ovarysparing hysterectomies are associated with sexual dysfunction due to damage to the ovarian blood supply. Hormonal birth control is associated with decreased sexual desire, orgasm and pain disorders, as well as increased vulnerability to psychiatric illness. Medications and substances that can contribute to FSD include: antihypertensives, alcohol, nicotine, cannabis, selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, benzodiazepines, psycho-stimulants, antipsychotics, allergy and cold medications, lipid-lowering medications, and hormone replacement therapy.17 Additional medications may be associated with sexual dysfunction in both men and women; however, most of the evidence is anecdotal, since sexual side effects of pharmacologic agents, typically, are not well studied.

Psychological Factors Associated with FSD Psychological variables that interfere with sexual functioning include a history of sexual abuse or trauma, the early loss of a parent, a difficult relationship with a parent(s), strict prohibitions against sexual behavior in childhood, and psychiatric disorders, such as depression, anxiety, posttraumatic

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stress disorder (PTSD), and obsessive–compulsive disorder (OCD).18,19 Health-related problems, such as those mentioned earlier, also have psychological consequences such as depression and anxiety, which themselves adversely affect sexual functioning. Psychological variables may enable a sexual problem to persist even after the medical problem no longer exists.

The Sexual Evaluation Medical practitioners across specialties are strongly encouraged to inquire about the sexual functioning of their patients. This issue may be of increased importance to female patients because medical practitioners are more inclined to ask male patients about their sexual functioning. Kaplan18 provides an excellent framework for evaluating sexual problems. In the sexual status examination, the patient’s thoughts, feelings, and behavior during each phase of the sexual response cycle (desire, excitement, orgasm, and resolution) are evaluated. The sexual status examination is designed to assess an individual’s current level of sexual functioning. In addition, Kaplan’s sexual evaluation also includes valuable information on the factors that contribute to the sexual problem, including previous experience with mental health treatment and psychiatric medication, the state of the patient’s physical health (present and past), their family of origin, their relationship history, and their current relationship. The evaluation enables the clinician to skillfully and efficiently assess his or her patient’s sexual functioning. It also helps the clinician to formulate a diagnosis and arrive at a plan for managing the sexual problem. While treatment plans are patient-specific, most include educating the patient about the sexual problem and giving the patient permission to discuss and enjoy their sexual experience. In more severe cases of FSD the treatment plan is likely to include a referral to a clinician with advanced training in sex therapy.

Medical Examinations, Laboratories, and Specialized Tests If it appears that a physical problem is responsible for the sexual dysfunction, it is appropriate to address it medically. This may entail a physical examination and, possibly, a referral to a specialist in urology, gynecology, internal medicine, endocrinology, or other specialty. Most women seeking treatment for a sexual problem should have a general gynecological examination for gynecologic health reasons and to ensure that a treatable physical problem is not the cause. In addition, patients should undergo a sexual evaluation that addresses the physical, psychological, behavioral, and relational causes of sexual problems. In order to understand the patient’s sexual problem, the clinician should inquire about the specifics of the sexual problem that brought the patient to treatment, when the problem first began, whether the problem came on suddenly or gradually, and what makes the problem better or worse.

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Laboratory tests that may be helpful in evaluating female patients with sexual dysfunction include estradiol, follicle-stimulating hormone (FSH), progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), total testosterone, free testosterone, sex hormone-binding globulin (SHBG), albumin, prolactin, thyroid function tests, B6, B3, zinc, complete blood count with differential, fasting glucose or glycosylated hemoglobin, creatinine, lipid profile, B12, folate, RBC magnesium level 25 hydroxy Vitamin D, and comprehensive metabolic panel. Under certain circumstances, specialized diagnostic procedures may be performed; however, in women, physiologic measures of sexual functioning are not the norm outside of specialized sexual dysfunction treatment centers and research settings. Physiologic measures of sexual functioning include vaginal pH, vaginal pressure volume changes, genital vibratory perception threshold, genital blood flow via duplex Doppler ultrasound, selective pudendal arteriogram, and testing for perception of vaginal and clitoral temperature.20 These modalities may shed light on the pathophysiology underlying the sexual problem.

Common sexual problems Hypoactive Sexual Desire Disorder (HSDD) The desire phase refers to the mental components of sexual appetite. Hypoactive sexual desire is one of the most common sexual problems among women. It is characterized by recurrent and persistent absence of sexual desire or interest in sexual activity. As with all of the sexual disorders, in order to meet the DSM-IV criteria for hypoactive sexual desire disorder the woman must experience ‘marked distress or interpersonal difficulty’ related to sexual desire; the sexual dysfunction is not better accounted for by another Axis I disorder (except another sexual dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.1 When making the diagnosis one should specify if it is life-long or acquired, of the generalized or situational type, and whether it is due to psychological factors or combined factors.1 The diagnosis of HSDD is complicated by the fact that desire is subjective and there is controversy as to what constitutes it. Moreover, the ideal sexual frequency also is variable among individuals. Age, sociocultural factors, educational factors and affect levels of desire.21 The diagnosis of HSDD further is complicated by the fact that low desire often coexists with other sexual dysfunctions.22 Desire levels often are evaluated by the frequency of sexual thoughts and fantasies, sexual urges, masturbation, and receptability to sexual stimuli. Frequency of sexual intercourse is not the best indicator of desire because women often engage in

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intercourse without experiencing desire. Want to please one’s partner and maintain domestic harmony may cause a woman to have intercourse despite her own lack of libido. Hormone deficiencies and inadequate androgen levels often are associated with low sexual desire.23 Chronic illness, pain, and medication also affect sexual desire levels. Emotional trauma or sexual or physical abuse, negative attitudes about sex and masturbation, and marital or relationship conflict are among the psychological variables associated with HSDD.24

Female Sexual Arousal Disorder Arousal refers to the phase of the sexual response cycle during which the genital structures become engorged and a subjective feeling of sexual pleasure develops. During the arousal phase, lubrication occurs in the female and penile erection in the male. In order to meet the DSM-IV criteria for female sexual arousal disorder, there must be a recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement.1 Often, it is difficult to tease apart problems of arousal from problems of desire and orgasm. Women with low interest in sexual activity often experience diminished sexual response and struggle with orgasm difficulties. Normal agerelated changes that occur with menopause such as decreased lubrication also may mimic FSAD. As with other sexual dysfunctions, physical and/or psychological factors, as mentioned previously with respect to HSDD affect arousability.

Female Orgasmic Disorder The DSM-IV defines female orgasmic disorder (FOD) as the persistent or recurrent delay in, or absence of, orgasm following a normal sexual excitement phase. Female orgasm disorder can be primary, meaning that the woman has never reached an orgasm, or secondary, in that a woman can no longer achieve orgasm.1 The absence of orgasm during intercourse, in and of itself, does not represent female sexual dysfunction. In addition, in order to meet DSM-IV criteria for FOD, sexual desire and a sufficient degree of arousal must to be obtained. However, it should be noted that there is a correlation between low levels of sexual arousal and greater difficulty obtaining orgasm.25 Due to the inter-relational nature of problems of sexual desire, arousal, and orgasm, it can be difficult, at times, to formulate a diagnosis. Physical problems often associated with FOD include the loosening of the muscles that support internal pelvic organs (pelvic floor prolapse), and severed pelvic nerves as a result of surgery. Moreover, many women are unable to achieve orgasm due to inadequate physical or mental stimulation, such as fantasy, and the inability to be open with their partner about their sexual needs.

Dyspareunia Dyspareunia is painful sexual intercourse, most commonly experienced in women, that may be related both to medical and psychological causes. The diagnosis of dyspareunia is made when the patient complains of recurrent or persistent genital pain before, during, or after sexual intercourse that is not caused exclusively by lack of lubrication or by vaginismus.1 A thorough medical or gynecological examination can help to establish the origin of the pain. Physical examinations often can reproduce the pain associated with dyspareunia. Frequently, dyspareunia can be traced to physical causes. The physical problems associated with this sexual pain disorder are extensive and include infections (candidiasis, chlamydia, trichomoniasis, urinary tract infections, yeast infections), endometriosis, xerosis (dryness, especially after the menopause), and lichen sclerosus et atrophicus (LSA).26 Moreover, psychological factors, such as a history of sexual trauma, depression, anxiety, and negative attitudes toward sexuality, as discussed elsewhere in this chapter may be at the root of the pain and/or serve to maintain it.27

Vaginismus Vaginismus is characterized in the DSM-IV as ‘recurrent or persistent involuntary spasms of the musculature of the outer third of the vagina’.1 These spasms are observable and in some cases cause pain. However, the experience of pain is not necessary in order to meet the diagnostic criteria for vaginismus. Pain often is experienced as a result of a conditioned reflex or spasm of the pubococcygeus (PC) muscle, which is referred to as the ‘PC muscle.’ The spasm of vaginismus is not conscious or controllable. Vaginismus can impair a woman’s ability to engage in any form of vaginal penetration, including penile penetration, insertion of tampons, and the penetration involved in gynecological examinations. Often, the gynecologist confirms the presence of vaginal spasms, and makes the diagnosis as a result of the patient’s inability to tolerate the exam. The causes of vaginismus may be due to physical factors, such as a yeast infection or trauma during childbirth, or, it may be due to the psychological causes mentioned throughout this chapter. In addition, experiences with medical interventions during childhood have been linked to vaginismus.28 At times, it is difficult to differentiate dyspareunia from vaginismus. Vaginismus may occur secondary to a history of dyspareunia, and even mild vaginismus often is accompanied by dyspareunia.

Treatment Behavioral Treatment Approaches Masturbation Training Many women who experience difficulty during partner sex do not know how to have an orgasm on their own. They may

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never have learned to masturbate or they may not be comfortable incorporating their masturbatory technique into their love-making with their partner. These patients benefit greatly from being given permission by a healthcare provider or a coach to pleasure themselves in whatever way is necessary to achieve satisfaction. Vaginal Dilators Women with sexual pain problems (dyspareunia or vaginismus) can benefit from the use of vaginal dilators. Dilators come in a set of usually four or five of varying sizes ranging from the size of a finger to the size of an erect penis. The patient is advised to insert the dilator into her vagina while lying on her back and move it around while stretching the vaginal walls for at least 10 minutes per day. With time and practice, the woman becomes comfortable using dilators of larger sizes and, in some cases, a more realistic appearing dildo. Gradually, she is able to attempt intercourse with her partner, usually starting with the female superior position. Kegel Exercises Kegel exercises help to strengthen the pubococcygeus (PC) muscle, which supports the pelvic floor. The potential benefits of doing Kegel exercises on a regular basis include: greater ease in achieving orgasm, increased intensity of orgasm, increased lubrication, heightened control over sensation during penetration, and protection against urinary incontinence and bladder prolapse. PC muscles are activated when one stops the flow of urine. Clinicians are encouraged to use this example when teaching patients about Kegel exercises. Often, a total of 200 repetitions are recommended per day, not necessarily all at one time. Sensate Focus Sensate focus is commonly recommended to couples receiving treatment for a sexual problem. It is a series of exercises that help couples connect and be sensual despite the presence of a sexual problem. The exercises place emphasis on communication, pleasure, and broadening the sensual experience. Sensate focus begins with each partner concentrating on what feels good, as his or her non-erotic zones are caressed. Non-erotic areas include general areas of the body such as the neck, back, and toes, but not the breasts, genitalia, or anal area. With time and practice, the couple progresses to caressing one another’s erotic areas as well. This may be continued until orgasm is achieved. Eventually, the couple adds sexual intercourse to the experience.

FDA-Approved Prescription Treatment Options While sexual problems are highly prevalent in both genders there are large differences in the availability of treatment options. A multitude of Federal Drug Administration

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(FDA)-approved prescription treatment options are available for men with sexual problems. Conversely, there is only one FDA-approved prescription treatment option for women with sexual dysfunction, a suction device called the EROS-CTD (Clitoral Therapy Device). While a plethora of over-the-counter nutritional supplements and topical vulvar creams are widely available, they have not been proven to be either effective or safe.

Emerging Therapies for FSD Phosphodiesterase 5 (PDE5) Inhibitors Some studies suggest that PDE5 inhibitors may be indicated for the treatment of antidepressant-induced FSD.29 Theo­ retically, women should respond similarly to these medications. According to Brown et al.,30 the clitoris and the penis are derived from the same embryonic stem cells and both possess corpus cavernosal tissue. Women also have genital erectile tissue that becomes engorged with sexual arousal, resulting in lubrication and clitoral erection. Moreover, PDE5 is known to exist in vaginal and clitoral tissue.30 Topical Pge 1 Agonists Prostaglandin E1 relaxes smooth muscle and leads to vasodilatation in the vagina, penis, and uterus. The synthetic PGE1 alprostadil, which has long been used in an injectable form to threat erectile disorder in men, may be effective as a topical treatment for FSD. In several studies, when PGE 1 is applied to the vulva and the clitoris as a gel/cream or liquid it leads to heightened lubrication and arousal. Side effects include local edema, soreness and burning.30,31 Neutral Endopeptidase (NEP) Inhibitors Vasoactive intestine peptide (VIP) is a neuropeptide vasodilator that plays a role in regulating vaginal blood flow. NEP, which is present in clitoral and vaginal tissues, is an enzyme that degrades VIP. Several NEP-inhibiting compounds are being investigated for their ability to increase female genital blood flow and, possibly, to treat FSD.30,32 Other Peripherally Acting Agents L-Arginine is a precursor to nitric oxide (NO), a potent vasodilator. It is an ingredient in a number of over-the-counter sexual enhancement products, both oral and topical. In one study premenopausal and perimenopausal women experienced significant improvement in sexual functioning while postmenopausal women did not.33 The authors surmised that the hormonal status of the subjects may play a role. Other peripherally acting agents under investigation for women include the NO Donor (NM-870), the 2-adrenoceptor antagonist yohimbine, the non-selective -adrenoceptor antagonist phentolamine, and the 1-adrenoceptor antagonist REC2615.30

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Melanocortin Agonists A synthetic alpha-melanocyte stimulating hormone (alphaMSH) is currently being studied as a treatment for FSAD. When administered intranasally, it has been shown to increase sexual desire and arousal, and to enhance vaginal blood flow in response to sexual stimulation. The main side effects are nausea and headache.30,34 Dopamine Agonists Dopamine is an important mediator of sexual functioning. Bupropion and apomorphine have sex-positive effects by virtue of their dopaminergic properties. Bupropion, an antidepressant, is commonly used to alleviate sexual dysfunction secondary to psychiatric medication. The dopamine agonist apomorphine may enhance sexual arousal in women.35,36 Apomorphine, however, is not FDA approved for either gender in the United States. It may promote vaginal and clitoral engorgement in females by virtue of its dopaminergic action at the level of the para-ventricular nuclei and the preoptic hypothalamus in the brain. These actions result in stimulation of the pelvic nerve and increased vascular flow in the clitoral arteries. 5-HT1A Agonists Flibanserin, the 5-HT1A agonist and 5-HT2A antagonist, has demonstrated potential for treating FSD. The 5-HT1A receptor antagonist OPC-14523 improved sexual function in both men and women.30 Testosterone A testosterone patch for women is available currently in Europe. It has been approved for postmenopausal women receiving estrogen supplementation, with or without progesterone. It has been shown to significantly improve libido and the frequency of satisfying sexual experiences in preand postmenopausal women with HSDD. It also is effective in women who have undergone hysterectomy.37 Currently, many American women are receiving off-label prescriptions for specially compounded testosterone creams and gels, since testosterone is not FDA approved for FSD. Tibolone Estrogen, testosterone, and progesterone play a major role in modulating sexual function both in the brain and the peripheral tissues. Tibolone, a synthetic steroid with properties of all three, is well known for treating hot flashes and vaginal dryness of menopause. It also may be effective in improving sexual desire and arousal in postmenopausal women. Its major adverse effect is weight gain.30 Oxytocin Oxytocin plays a major role in human sexual response both in neuroendocrine function and postcoital behavior. Oxytocin,

available via compounding pharmacies as sublingual drops and in a nasal spray form, may improve female sexual arousal.38

Conclusion FSD is a widespread public health problem affecting women of all ages, particularly those with medical and psychiatric problems. The major categories of female sexual dysfunction are disorders of desire, arousal, orgasm, and pain. The physiology of the female sexual response is very similar to that of the male; however, many questions still remain unanswered with regard to the female. In addition, although there are a multitude of prescription products available to treat male sexual problems, there is only one FDA-approved prescription treatment for women with FSD. Numerous compounds are under development, which may prove beneficial in the future for women who suffer from sexual disorders.

References 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. 2. Laumann EO, Gagnon JH, Michael RT, et al. The Social Organization of Sexuality: Sexual Practices in the United States. Chicago, IL: University of Chicago Press; 1994. 3. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281(6): 537–44. 4. Lechtenberg R, Ohl DA. Sexual Dysfunction: Neurologic, Urologic, and Gynecologic Aspects. Malvern, PA: Lea & Febiger; 1994. 5. Bancroft J. Human Sexuality and Its Problems, 2nd edn. London: Churchill Livingstone; 1989. 6. Federation of Feminist Women’s Health Centers. A New View of a Woman’s Body. Los Angeles, CA: Feminist Health Press; 1991. 7. Baskin LS, Erol A, Li YW, et al. Anatomical studies of the human clitoris. J Urol 1999;162:1015–20. 8. Crouch NS, Minto CL, Laio LM, et al. Genital sensation after feminizing genitoplasty for congenital adrenal hyperplasia: a pilot study. BJU Int 2003;93(1):135–38. 9. Giuliano F. Neurophysiology of female genital sexual response. In: I Goldstein, ed. Women’s Sexual Function and Dysfunction: Study, Diagnosis and Treatment (pp.168–172). New York, NY: Informa HealthCare; 2005:168–72. 10. Foley S, Sally A, Kope SA, et al. Sex Matters for Women: A Complete Guide to Taking Care of Your Sexual Self. New York, NY: Guilford Press; 2001. 11. Wimpissinger F, Stifter K, Grin W, et al. The female prostate revisited: perineal ultrasound and biochemical studies of female ejaculate. J Sex Med 2007;4:1388–93. 12. Oksuz E, Malhan S. Prevalence and risk factors for female sexual dysfunction in turkish women. J Urol 2006;175(2): 654–58.

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13. Basson R, Schultz W. Sexual sequelae of general medical disorders. Lancet 2007;369:409. 14. Schreiner-Engel P. Diabetes mellitus and female sexuality. Sexuality Disability 1983;6:83–92. 15. Basson R. Female sexual response: a different model. J Sex Marital Ther 2003;26:51–65. 16. Basson R, Althof S, Davis S, et al. Summary of the recommendations on sexual dysfunctions in women. J Sexual Med 2004;1(1):24–34. 17. Rosen RC, Kostis JB, Jekelis A, et al. Sexual sequelae of antihypertensive drugs: treatment effects on self-report and physiological measures in middle-aged male hypertensives. Arch Sexual Behav 1994;23:135–52. 18. Kaplan HS. The Evaluation of Sexual Disorders: Psychological and Medical Aspects. New York, NY: Brunner/Mazel. 19. Bartlik B, Rosenfield S, Beaton C. Assessment of sexual functioning: sexual history taking for health care practitioners. Epilepsy Behav 2005;7:S15–21. 20. Berman JR, Berman LA, Lin H, et al. Effect of Sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J Sex Marital Ther 2001;27(5):411–20. 21. Beck JG. Hypoactive sexual desire disorder: an overview. J Consulting Clin Psychol 1995;63:919–27. 22. Segraves KB, Segraves RT. Diagnosis of female arousal disorders. J Sex Marital Ther 1991;6:9–13. 23. Regan PC. Hormonal correlates and causes of sexual desire: a review. Canad J Hum Sexuality 1999;8:1–16. 24. Becker JV, Skinner LJ, Abel GG, et al. Sexual problems of sexual assault survivors. Women Health 1984;9:5–20. 25. Anderson BL. A comparison of systematic desensitization and directed masturbation in the treatment of primary orgasmic dysfunction in females. J Consult Clin Psychol 1981;49:568–70. 26. Steege JF, Ling FW. Dyspareunia: a special type of chronic pelvic pain. Obstet Gynecol Clin North Am 1993;20:779. 27. Lazarus AA. Dyspareunia: a multimodal psychotherapeutic perspective. In: SR Leiblum, RC Rosen, eds. Principles and Practice of Sex Therapy: Update for the 1990s, 2nd edn. New York, NY: Guilford Press; 1989:89–112.

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28. Reissing E, Binik YM, Khalife S. Does vaginismus exist? A critical review of the literature. J Nerv Ment Dis 1999;187(5): 261–74. 29. Nurnberg G, Hensley PL, Heiman JR, et al. Sildenafil treatment of women with antidepressant-associated sexual dysfunction: a randomized controlled trial. JAMA 2008;300:395–404. 30. Brown AD, Blagg J, Reynolds DS. Designing drugs for the treatment of female sexual dysfunction. Drug Discovery Today 2007;12(17–18):757–66. 31. Ückert S, Mayer ME, Jonas U, et al. Potential future options in the pharmacotherapy of female sexual dysfunction. World J Urol 2006;24:630–38. 32. Ottesen B, Pedersen B, Nielsen J, et al. Vasoactive intestinal polypeptide (VIP) provokes vaginal lubrication in normal women. Peptides 1987;8:797–800. 33. Ito TY, Polan M, Whipple B, et al. The enhancement of female sexual function with ArginMax, a nutritional supplement, among women differing in menopausal status. J Sex Marital Ther 2006;32:369–78. 34. Pfaus JG, Shadiack A, Van Soest T, et al. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc Natl Acad Sci U S A 2004;101:10201–4. 35. Bechara A, Bertolino M, Casabe A, et al. A double-blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine. J Sex Med 2008;1(2):209–14. 36. Beharry RKS, Hale TM, Heaton JPW, et al. Restoration of female genital vasocongestive arousal responses in young and aged rats. J Sex Med 2008;5:804–12. 37. Braunstein GD, Sundwall DA, Katz M, et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women. Arch Intern Med 2005;165:1582–89. 38. Blaicher W, Gruber D, Bieglmayer C, et al. The role of oxytocin in relation to female sexual arousal. Gynecol Obstet Invest 1999;47(2):125–26.

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Male Sexual Dysfunction Serkan Deveci1 and John P. Mulhall2 1

Memorial Sloan Kettering Cancer Center, Department of Urology, New York, NY, USA Director Male Sexual and Reproductive Medicine Program Memorial Sloan Kettering Cancer Center, Department of Surgery/ Urology Service, New York, NY, USA 2

Physiology

NO/cGMP pathway, which results in increased blood flow through the penile arteries. This blood flow expands the sinusoids. The compression of subtunical venules between the tunica albuginea and the peripheral sinusoids reduces the venous outflow. The increase in intracavernous pressure changes the position of the penis to the full erect state. The contraction of ischiocavernosus muscles results in a rigid erection at the time of orgasm.6–8

Erection is the final common pathway of an integrative physiological complex of psychological, neuronal, hormonal, vascular, and cavernous smooth muscle systems. This process begins in the brain and involves neural and vascular systems. The autonomic spinal erection centers are located at levels S2–S4 (parasympathetic) and T12–L2 (sympathetic) of the spinal cord. These segments form the hypogastric and pelvic plexi to send nerve branches to the pelvic organs. The fibers innervating the penis (the cavernous nerve) travel along the posterolateral aspect of the prostate and then accompany the membranous urethra through the genitourinary diaphragm. The terminal branches of the cavernous nerves innervate the helicine arteries and trabecular smooth muscle, which are responsible for the vascular events during erection. The penis is a composition of three structures, the paired corpora cavernosa and the corpus spongiosum, which hosts the urethra. The tunica albuginea surrounds these layers. The inner layer of tunica albuginea contains and supports the cavernous tissue which provides the flexibility, rigidity, and strength of the penis. The arteries of penis stem from the internal pudental artery, which inside the penis subdivides into three branches (dorsal, cavernosal, and bulbourethral arteries). The cavernosal arteries end at the helicine arteries which open into the lacunar spaces. The venous system is comprised of deep (deep dorsal, circumflex, emissary, cavernous, and crural veins) and superficial veins. The lacunar spaces drain into subtunical venules which emerge as emissary veins.1–4 The cavernous smooth muscle plays a key role in erectile function. The smooth muscle is contracted in the flaccid state of the penis. The erectile process begins with sexual stimulation. Sexual stimulation increases the parasympathetic activity that stimulates the release of neurotransmitters from cavernous nerve terminals or from the endothelium resulting in relaxation of the penile smooth muscle.4,5 This event is mediated by activation of the Principles of Gender-Specific Medicine

Definition and pathophysiology of erectile dysfunction Erectile dysfunction (ED) is defined as the consistent inability to obtain and maintain an erection for satisfactory sexual relations.9 ED is clinically classified in three groups; psychogenic, organic, and mixed.10 Previously psychogenic ED was believed to be the most common cause of ED.11 Recently, mixed organic and psychogenic are accepted as the most common. Psychogenic ED is the persistent inability to obtain and/or maintain adequate erection for sufficient sexual intercourse due primarily to psychological or relationship factors. A lot of psychological conditions such as performance anxiety, lack of sexual arousal, major life stress, or depression, can cause or aggravate ED. The term psychogenic should not be used when the etiology is uncertain or unknown. The diagnosis of psychogenic ED is based on history and psychical examination and is a diagnosis of exclusion. The patient should not be referred to receive psychotherapy until the organic causes of ED are excluded. The acceptance of psychotherapy is much more easy when associated with organic conditions.12 Organic ED can be classified according to the underlying etiology as neurogenic, hormonal, arterial, cavernosal (veno-occlusive), and drug-induced. Diseases involving the brain, spinal cord, and cavernous or pudendal nerves are associated with ED. Hormonal disorders such as hypogonadism may suppress sexual interest and nocturnal erections. Hyperprolactinemia 408

Copyright 2010, Elsevier Inc. All rights reserved.

C h a p t e r 3 7     Male Sexual Dysfunction l

and thyroid disorders also affect the quality of erections.13 Although arteriogenic ED can occur as a result of a trauma or congenital anomalies, in most of the cases arteriogenic ED is a part of generalized arteriosclerotic process. Cavernosal (veno-occlusive) ED occurs as a result of impaired smooth muscle relaxation arising from the change in the smooth muscle–collagen ratio and dysfunctional endothelium.14–16 There are many drugs that can cause ED (Table 37.1). Longterm usage of alcohol, smoking, and consumption of cocaine have also been cited as causes of ED.17–18

Epidemiology

Table 37.1  Drugs that can cause erectile dysfunction Psychiatric medications

Fluoxetine Tranylcypromine Sertraline Isocarboxazid Amitriptyline Amoxipine Clomipramine Desipramine Nortriptyline Phenytoin

Phenelzine Buspirone Chlordiazepoxide Clorazepate Diazepam Doxepin Imipramine Lorazepam Oxazepam

Anti-hypertensive drugs

Atenolol Bethanidine Bumetanide Captopril Chlorothiazide Chlorthalidone Clonidine Enalapril Furosemide Guanabenz Guanethidine Guanfacine Haloperidol Hydralazine Hydrochlorothiazide Labetalol

Methyldopa Metoprolol Minoxidil Nifedipine Phenoxybenzamine Phentolamine Prazosin Propranolol Reserpine Spironolactone Triamterene Verapamil

Hormonal drugs and chemotherapy

Antiandrogens (bicalutamide, flutamide, nilutamide) Busulfan Cyclophosphamide Ketoconazole LHRH agonists (leuprolide, goserelin)

Recreational drugs

Alcohol Amphetamines Barbiturates Cocaine Marijuana Heroin Nicotine

Antihistamines

Dimehydrinate Diphenhydramine Hydroxyzine Meclizine Promethazine

Others

Atropine, digoksin, pseudoephedrine, estrogen, finasteride, cyproteron, indomethacin, clofibrate, NSAIDs (naproxen etc.), antihistamines (cimetidine, ranitidine etc.)

The Massachusetts Male Aging Study was a communitybased survey of 1290 men aged between 40 and 70 years in areas around Boston. The combined prevalence of ED was found to be 52%. Seventeen percent of men reported mild, 25% moderate and 10% severe ED in this study. Erectile dysfunction is more common among elderly men.19–20

Risk factors The major risk factors of ED are diabetes mellitus, heart disease, hypertension, dyslipidemia, lower urinary tract symptoms (LUTS), and cigarette smoking. In patients with diabetes the prevalence of ED is approximately 50% which depends on patient age, duration and the severity of diabetes. Diabetic are four times as likely to have ED compared to the general population. Patients with LUTS are 2.5–11 times more likely to have ED depending on the severity of the LUTS. Many medications, including anti-hypertensive drugs, anti-depressants, anti-androgens, are associated with erectile dysfunction. There is a higher prevalence of ED in men who have undergone radiotherapy or surgery for prostate cancer.21–26

Evaluation Medical and Sexual History The first step is a medical history searching for risk factors for erectile function, including hypertension, atherosclerotic coronary and peripheral vascular disease, diabetes mellitus, smoking, and medications. A detailed history may help to differentiate the etiology but history is notoriously inaccurate at assigning an etiology to the ED.27

Questionnaires The patients are asked to complete a validated questionnaire to measure their sexual interest, satisfaction, performance, and the severity of ED. These self-administered

409

questionnaires also allow the efficacy of pharmacotherapy to be assessed. They are, however, not able to differentiate between organic, psychogenic or mixed causes of ED. There are many questionnaires used by clinicians. The most commonly used is the International Index of Erectile

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Function (IIEF), which has been statistically validated in many languages and used worldwide. It contains 15 questions that addresses five domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. An abridged five-item version of IIEF (IIEF-5) has been developed. Four of the five items of IIEF5 were taken from the erectile function domain of IIEF-15. The final item addresses sexual intercourse satisfaction. Based on IIEF, ED severity is classified into five categories: no ED (score 22–25), mild (17–21), mild to moderate (12–16), moderate (8–11), and severe (5–7).28–31

Physical Examination The secondary sex characters and external genital organs should be examined, the penis should be palpated for Peyronie’s disease plaques, and testicles should be palpated for size and consistency.

Laboratory Tests The laboratory tests should be done to identify treatable conditions that may affect erectile function. The optional laboratory tests are fasting glucose or glycosylated hemoglobin, complete blood count, urinalysis, creatinine, lipid profile, testosterone, and prolactin values. PSA should be obtained from patients older than 50 years.32

Vascular Testing It is difficult to differentiate between psychogenic and organic ED without vascular evaluation. Historically, penile brachial index and plethysmography were the tests used to evaluate vascular function of the penis but both have been replaced with more modern methodologies. Duplex ultrasonography is the main method of vascular testing. It consists of intracavernous injection of a vasodilator following the measurement of penile blood flow by duplex Doppler ultrasound. The most commonly used vasodilators are PGE1, papaverine, and phentolamine. A peak systolic flow rate more than 25–30 cm/s and absence of end diastolic flow is accepted as normal. Dynamic infusion cavernosometry is a sophisticated vascular assessment reserved for complex or pre-surgical cases.33–35

Special tests Nocturnal Penile Tumescence Test (NPT) Nocturnal erections occur in every healthy man of all ages. Eighty percent of these erections occur in REM sleep. NPT measures the number of erectile episodes, tumescence (circumference), maximal penile rigidity, and duration of the nocturnal erections. It was firstly designed to differentiate between organic and psychogenic ED; recently its use is limited to medicolegal conditions.36,37

First line therapy PDE5 inhibitors

Vacuum devices

Second line therapy Intracavernous injections

Intraurethral alprostadil

Third line therapy Penile prosthesis implantation

Vascular surgery

Figure 37.1  Treatment options for ED.

Goal-Directed Approach Erectile dysfunction can be primarily psychogenic in origin but most of the patients have an organic disorder with psychogenic overlay. A goal-directed approach is used successfully in the evaluation of ED. The first step consists of a careful and detailed medical and sexual history, physical examination, and hormonal and basic laboratory testing, followed by a discussion of treatment options without further diagnostic tests. The patient is given a therapeutic option such as PDE5 inhibitor (PDE5i), a vacuum constriction device, or intracavernous injection as first-line therapies. Second phase management includes diagnostic tests such as nocturnal penile tumescence (NPT) testing, penile Doppler USG or DICC to identify the cause of ED. Smoking, medication, alcohol consumption and risk factors for ED should be noted. The presence of nocturnal and early morning erections means that the origin of ED is not based on organic factors.38 Figure 37.1 illustrates the treatment strategy for ED.39

Non-surgical therapy: PDE5i, urethral suppositories, ICI, VED Phosphodiesterase Type Inhibitors (PDE5i) PDE is the enzyme that breaks down the intracellular second messenger of erection cGMP. Type 5 is the predominant form of PDE in the penis, thus inhibiting this enzyme enhances penile erection. There are three PDE5i licensed in the treatment of ED; sildenafil, vardenafil, and tadalafil. Sildenafil is the first oral PDE5i approved by FDA and has the most experience and data confirming its activity and safety. The peak blood flow is achieved after 30–60 minutes with oral administration. Sildenafil and vardenafil have similar half-lives of about approximately 4 hours whereas the half-life of tadalafil is about 17.5 hours. All three agents are effective in patients with organic, psychogenic, and mixed etiology ED. A high fat meal or alcohol

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411

Table 37.2  PDE5 inhibitors Dosage (mg)

Tmax(h)

T½ (h)

Common adverse effects

Sildenafil

25, 50, 100

1

2.6–3.7

Vardenafil

2.5, 5, 10, 20

0.9

3.9

Tadalafil

5, 10, 20

2*

17.5

Headache, flushing, dyspepsia, nasal congestion, dizziness, visual disturbance Headache, flushing, dyspepsia, nasal congestion, dizziness, visual disturbances Headache, flushing, dyspepsia, myalgia, nasal congestion

Tmax, time to maximum plasma concentration; T½, plasma elimination half-life * median (as opposed to mean).

slow the rate of absorption and delay the peak plasma concentrations of sildenafil and vardenafil but not that of with tadalafil. All three drugs have similar efficacy and toxicity profiles. They are absolutely contraindicated for men using nitrates because of potentiating the hypotensive effects of all nitrates.40–43 Table 37.2 highlights the characteristics of the three PDE5 inhibitors.39

Intracavernous Injection (ICI) Papaverine, phentolamine, and alprostadil (PGE1) are the drugs that have been used for intracavernous injection therapy. Papaverine is an inhibitor of PDE enzyme leading to increase cGMP in penile tissue. The major disadvantage of papaverine is corporal fibrozis thought to be a result of low acidity. Phentolamine is an -receptor antagonist that increases blood flow. Systemic hypotension and tachycardia are its major adverse effects. Alprostadil causes smooth muscle relaxation and vasodilation in corporal tissue by elevating intracellular cAMP. Pain at the site of injection during erection, hematoma/ecchymosis are the most common side effect of alprostadil. These three agents can be used together: the most common combinations are bimix (papaverine/phentolamine) and trimix (papaverine/phentolamine/alprostadil).44–46

Urethral Suppositories Alprostadil (PGE1) is the only agent approved by FDA for treatment of ED by the transurethral route. Alprostadil is transferred from the corpus spongiosum to the corpus cavernosum through venous channels. The medicated urethral system for erection (MUSE: VIVUS, Inc, Menlo Park, CA) consists of a very small semisolid pellet (3  1 mm) administered into the distal urethra (3 cm) by a proprietary applicator (MUSE). Clinical trials showed that 66% of men responded to an in-office trial; of these, 65% had successful intercourse at least once at home with MUSE, giving a success rate of 43%.47,48

Vacuum Erection Device (VED) A VED consists of a plastic cylinder connected directly or by tubing to a vacuum-generating source. The penis is

engorged by the negative pressure and a constriction ring is applied to the base of the penis to maintain erection. Penile pain, difficulty in ejaculation, ecchymosis, and petechiae are the main complications of VED. The satisfaction rate has been reported to be 68–83%.49

Surgical therapy Vascular Surgery ED in young men with isolated stenosis or occlusion of penile arteries as a result of pelvic/perineal trauma is amenable to surgical repair. The most commonly used surgical technique for penile revascularization is a bypass from the inferior epigastric artery to the dorsal artery or deep dorsal vein of the penis.50 Venous leak is the result of structural changes within erectile tissue. Penile venous surgery is used only in selected patients, such as young men with congenital or traumatic venous leakage. Venous ligation surgery has a low success rate, cited as 30–50%. The ligation of the most posterior portions of the erectile bodies from the crura seems superior to other methods.51,52,53

Penile Prosthesis Penile implant surgery is a gold standard therapy for men with erectile dysfunction refractory to pharmacotherapy. There are three different types of penile prosthesis: malleable, mechanical, and inflatable devices. The malleable device is made of silicone rubber. The mechanical device is also made of silicone rubber but contains polytetrafluoroethylene-coated rings. The inflatable devices are divided into two- and three-piece devices. The two-piece device contains a pair of cylinders attached to a scrotal pump reservoir. The three-piece device contains a suprapubic fluid reservoir additionally. The selection of the appropriate device is based on the patient’s preference, the cost, and the surgeon’s choice.54–56

References 1. Paick JS, Donatucci CF, Lue TF. Anatomy of cavernous nerves distal to prostate: microdissection study in adult male cadavers. Urology 1993;42:145.

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  2. Paick JS, Goldsmith PC, Batra AK, et al. Relationship between venous incompetence and cavernous nerve injury: ultrastructural alteration of cavernous smooth muscle in the neurotomized dog. Int J Impotence Res 1991;3:185–95.   3. Lue TF, Takamura T, Schmidt RA, et al. Hemodynamics of erection in the monkey. J Urol 1983;130:1237–41.   4. Ignarro LJ, Bush PA, Buga GM, et al. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Comm 1990;170:843–50.   5. Levin RM, Hypolite J, Broderick GA. Comparative studies on intracellular calcium and NADH fluorescence of the rabbit corpus cavernosum. Neurourol Urodyn 1994;13: 609–18.   6. Gupta S, Moreland RB, Munarriz R, et al. Possible role of Na()-K()-ATPase in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide. Br J Pharmacol 1995;116(4):2201–6.   7. Burnett AL, Lowenstein CJ, Bredt DS, et al. Nitric oxide: a physiologic mediator of penile erection. Science 1992; 257:401–3.   8. Kim N, Azadzoi KM, Goldstein I, et al. A nitric oxide-like factor mediates nonadrenergic-noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J Clin Invest 1991;88:112–18.   9. NIH Consensus Panel on Impotence. JAMA 1993;270:83. 10. Lizza EF, Rosen RC. Definition and classification of erectile dysfunction: Report of the Nomenclature Committee of the International Society of Impotence Research. Int J Impot Res 1999;11:141–43. 11. Masters WH, Johnson VE. Human Sexual Response. Boston, MA: Little, Brown; 1970. 12. Bancroft J. Psychogenic erectile dysfunction – a theoretical approach. Int J Impot Res 2000;12:S46–8. 13. Leonard MP, Nickel CJ, Morales A. Hyperprolactinemia and impotence: why, when and how to investigate. J Urol 1989; 142:992–94. 14. Rajfer J, Rosciszewski A, Mehringer M. Prevalence of corporal venous leakage in impotent men. J Urol 1988;140:69–71. 15. Christ GJ, Maayani S, Valcic M, et al. Pharmacologic studies of human erectile tissue: characteristics of spontaneous contractions and alterations in alpha-adrenoceptor responsiveness with age and disease in isolated tissues. Br J Pharmacol 1990; 101:375–81. 16. Lue TF. Erectile dysfunction. N Engl J Med 2000;342:1802–13. 17. McVary KT. Clinical practice. Erectile dysfunction. N Engl J Med 2007;357(24):2472–81. 18. Junemann KP, Lue TF, Luo JA, et al. The effect of cigarette smoking on penile erection. J Urol 1987;138:438–41. 19. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massa­chusetts Male Aging Study. J Urol 1994;151:54–61. 20. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537–44. 21. Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men aged 40–69: longitudinal results from the Massachusetts male aging study. J Urol 2000;163:460. 22. Cellek S, Rodrigo J, Lobos E, et al. Selective nitrergic neurodegeneration in diabetes mellitus – a nitric oxide-dependent phenomenon. Br J Pharmacol 1999;128:1804–12.

23. Billups KL, Bank AJ, Padma-Nathan H, et al. Erectile dysfunction as a harbinger for increased cardiometabolic risk. Int J Impot Res 2008;Jan 17, [Epub ahead of print]. 24. Azadzoi KM, Saenz de Tejada I. Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1991;146:238–40. 25. Mulhall JP, Slovick R, Hotaling J, et al. Erectile dysfunction after radical prostatectomy: hemodynamic profiles and their correlation with the recovery of erectile function. J Urol 2002;167(3):1371–75. 26. Montague DK, Barada JH, Belker AM, et al. Clinical guidelines panel on erectile dysfunction: summary report on the treatment of organic erectile dysfunction. J Urol 1996;156:2007–11. 27. Brian DJ, Tiefer L, Melman A, et al. Accuracy of the initial history and physical examination to establish the etiology of erectile dysfunction. Urology 1995;45(3):498–502. 28. Rosen RC, Wiley A, Wagner G, et al. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822–30. 29. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319–326. 30. Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 1999; 54:346–51. 31. Rosen RC, Cappelleri JC, Gendrano N. The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impot Res 2002;14:226–44. 32. Carroll JL, Ellis D, Bagley DH. Impotence in the elderly: evaluation of erectile failure in men older than seventy years of age. Jefferson Sexual Function Center. Urology 1992;39:226–30. 33. Goldstein I, Udelson D. Axial penile rigidity: determinants and relation to hemodynamic parameters. Int J Impot Res 1998;10 (Suppl 2):S28. 34. Donatucci CF, Lue TF. The combined intracavernous injection and stimulation test: diagnostic accuracy. J Urol 1992;148:61–62. 35. Landwehr P. Penile vessels: erectile dysfunction. In: K-J Wolf, F Fobbe, eds. Color Duplex Sonography: Principles and Clinical Application. Stuttgart: Thieme Medical; 1995:204–15. 36. Djamilian M, Stief CG, Hartmann U, et al. Predictive value of real-time RigiScan monitoring for the etiology of organogenic impotence. J Urol 1993;149:1269–71. 37. Karacan I. NPT/Rigidometry. In: RS Kirby, CC Carson, GD Webster, eds. Impotence: Diagnosis and Management of Male Erectile Dysfunction. Oxford: Butterworth–Heinemann; 1991: 62–71. 38. Lue TF. Impotence: a patient goal directed approach to treatment. World J Urol 1990;8:67–74. 39. Wespes E, Amar A, Hatzichristou K, et al. EAU guidelines on erectile dysfunction: an update. Eur Urol 2006;49(5):806–15. 40. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998;338:1397–404. 41. Carson CC. PDE5 inhibitors: are there differences? Can J Urol 2006;13 (Suppl 1):34–39. 42. Hatzimouratidis K, Hatzichristou DG. Looking to the future for erectile dysfunction therapies. Drugs 2008;68(2):231–50. 43. Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract 2006;60(8):967–75.

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44. Zorgniotti AW, Lefleur RS. Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J Urol 1985;133:39–41. 45. Virag R, Shoukry K, Floresco J, et al. Intracavernous selfinjection of vasoactive drugs in the treatment of impotence: 8-year experience with 615 cases. J Urol 1991;145:287–92, discussion 292–293. 46. Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N Engl J Med 1996;334:873–77. 47. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997;336:1–7. 48. Hellstrom WJ, Bennett AH, Gesundheit N, et al. A doubleblind, placebo-controlled evaluation of the erectile response to transurethral alprostadil. Urology 1996;48:851–56. 49. Cookson MS, Nadig PW. Long-term results with vacuum constriction device. J Urol 1993;149:290–94. 50. Hatzichristou D, Goldstein I. Penile microvascular and arterial bypass surgery. Urol Clin North Am 1993;1:39–60.

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51. Melman A, Riccardi R. The success of microsurgical penile revascularization in treating arteriogenic impotence. Int J Impot Res 1993;5:47–52. 52. Lue TF. Treatment of venogenic impotence. In: EA Tanagho, TF Lue, RD McClure, eds. Contemporary Management of Impotence and Infertility. Baltimore, MD: Williams & Wilkins; 1988:175–77. 53. Mulhall JP, Martin D, Ergin E, et al. Crural ligation surgery for the young male with venogenic erectile dysfunction: technique. Tech Urol 2001;7(4):290–93. 54. Montorsi F, Guazzoni G, Bergamaschi F, et al. Patient-partner satisfaction with semirigid penile prosthesis for Peyronie’s disease: a 5-year follow-up study. J Urol 1993;150:1819–21. 55. Mulcahy JJ. Implantation of hydraulic penile prostheses. Urol Clin North Am 1993;1:71–92. 56. Akın-Olugbade O, Parker M, Guhring P, et al. Determinants of patient satisfaction following penile prosthesis surgery. J Sex Med 2006;3(4):743–48.

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Pelvic Pain: Urogenital Female Disorders Andrew T. Goldstein1, and Lara J. Burrows2 1

Johns Hopkins Medicine, Division of Gynecologic Specialties, Department of Gynecology and Obstetrics, Baltimore, MD, USA The Center for Vulvovaginal Disorders, Washington, DC, USA

2

There are several disease processes that are specific to the female pelvis. The vulva specifically may be affected by uncommon dermatologic disorders and pain syndromes. Additionally, injury to the levator ani muscles (termed ‘levator ani spasm’ or ‘pelvic floor dysfunction’) can cause referred vulvar pain. The word ‘vulvodynia’ is a term that may cause confusion and is frequently used incorrectly. In 2003, the International Society for the Study of Vulvovaginal Disease (ISSVD) issued a new terminology for vulvar pain disorders and defined vulvodynia as ‘vulvar discomfort, most often described as burning pain, occurring in the absence of relevant visible findings or a specific, clinically identifiable, neurologic disorder’.1 This classification acknowledges that vulvar pain may be attributable to other diagnosable and treatable disorders. However, the salient point is: definable causes of vulvar pain are not defined as vulvodynia.

blood flow which causes a build-up of lactic acid and this may cause considerable discomfort for the patient both in the pelvic floor and in the vulva. Physical therapy is highly effective in decreasing levator ani hypertonus, in normalizing muscle tone, increasing pelvic floor strength, desensitizing local tissues, and improving vulvovaginal elasticity. The range of treatments administered by a physical therapist includes internal (vaginal and rectal) and external soft tissue mobilization and myofascial release; trigger-point pressure; visceral, urogenital, and joint manipulation; electrical stimulation; therapeutic exercises; active pelvic floor retraining; biofeedback; therapeutic ultrasound; and home vaginal dilation. With the aid of a biofeedback machine, women can view a display of numbers on a meter, or colored lights, to assess the tension in their muscles. In this way, it is possible to develop voluntary control over those biological systems involved in pain, discomfort, and disease. The time required for biofeedback and the frequencies of visits will vary with each person. Success rates in the 60–80% range have been reported.2 Physical therapists with experience in vulvodynia are extremely helpful. They frequently do a thorough evaluation and assessment of pelvic muscle tone, posture, mobility, and muscle strength.3 Then, specific exercises can be prescribed, often with good results. Given that pain can be referred to other parts of the body, such as the back and hips, a thorough musculoskeletal evaluation should be performed. Hartmann and Nelson reported an improvement in sexual functioning and in quality of life issues, after pelvic floor physical therapy.4 Bergeron and colleagues found that 71% of women treated by physical therapy for LAS experienced complete, great, or moderate improvement.5 They also showed an increase in intercourse frequency as well as a decrease in pain with intercourse and with the gynecologic examination.

Specific causes of vulvar pain Levator Ani Spasm Levator ani spasm (LAS), or hypertonus of the levator ani muscles, is a common finding in women with vulvar pain. In fact, patients with vestibular pain in general have increased resting tone and decreased contraction tone of the pelvic floor muscles. LAS may be diagnosed by digital examination using one finger. The finger is gently inserted through the hymen and the levator ani muscles are systematically palpated for evidence of pain, hypertonus, or trigger points, indicating pelvic floor dysfunction. It is not clear exactly what causes LAS. However, it is known that contraction of the muscles leads to decreased Principles of Gender-Specific Medicine

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In the author’s experience, botulinum toxin A may be beneficial in augmenting pelvic floor physical therapy in women with refractory levator ani muscle hypertonicity. However, its use may be limited due to the high cost.

Vulvodynia Vulvodynia is often described as discomfort or burning pain in the vulvar area, occurring in the absence of visible pathology or a specific, clinically identifiable disorder. Per the ISSVD classification, vulvodynia may be either generalized or localized pain. These two categories are further subdivided into provoked and unprovoked pain. Lastly, there is a category for pain that is both provoked and unprovoked (mixed).1 Vestibulodynia, which is a type of vulvodynia, is pain that is localized only to the vulvar vestibule, and it is also classified as primary or secondary. In the primary subset, the pain has been present since the first tampon use or intercourse, and with secondary vestibulodynia women have had painless tampon insertion or intercourse, with the subsequent development of vestibular pain. Vestobulodynia was formerly called ‘vulvar vestibulitis.’ The suffix ‘-itis’ was excluded from the recent ISSVD terminology because it may be misleading, as some studies have found a lack of association between excised tissue and inflammation.6 The estimated prevalence of vulvodynia may be as high as 15% of all women, based on a report from a general gynecologic practice population.7 A study from 1998 reported that 1.3% of women in a genitourinary medicine clinic population had vulvodynia.8 In 2002, a sample of women was invited to participate in a Web-based survey found that a history of pain at the vulvar vestibule was reported by 28%, with 7.8% reporting pain within the past 6 months, 3% reporting pain that lasted 3 or more months, and 1.7% reporting vestibular pain lasting 3 or more months that occurred within the past 6 months.9 Women with vestibulodynia have classically been characterized as white, young (mean age 32 years), and nulliparous. In 2003 the prevalence of chronic unexplained vulvar pain in an ethnically diverse population-based sample found that approximately 16% reported chronic burning, knife-like pain, or pain on vulvar contact that lasted for at least 3 months or longer. Contrary to earlier assessments, white and black women were reported to have a similar lifetime prevalence. Interestingly, Hispanic women were 80% more likely to experience chronic vulvar pain than their white and black counterparts. The authors concluded that as many as 14 million women in the United States may experience chronic vulvar pain during their lifetime. Thus, even if only a small percentage of these women have true vulvodynia, the number of women with the problem is enormous. Unfortunately, at least 30% will suffer without seeking medical care.10 The etiology of vulvodynia is unknown. It most likely occurs from a variety of sources and represents many different disease processes. Possible causes include abnormalities

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of embryologic development, as recent research indicates that primary vestibulodynia is due to a defect in the primitive urogenital sinus and may therefore be thought of as a congenital disorder.8 Other data have implicated genetic and/or immunologic factors; Witkin and colleagues have demonstrated polymorphisms in genes coding for various proteins in women with vestibulodynia.11–13 Additionally, there is an increasing interest in hormonal factors with strong evidence that oral contraceptive pill use strongly increases the risk of developing vestibulodynia.14 It is also likely that there is both a peripheral and central neuropathic process in some women with vestibulodynia. Several researchers have found an increased number of C-afferent nociceptors in the vestibular mucosa of women with vestibulodynia.15–17 Bornstein and colleagues have also shown a marked increase in mast cells in the vestibular mucosa of these women.16 These findings have led to a theory that activated mast cells release nerve growth factor, which leads to the proliferation of nociceptors. It is likely that the increased density of nociceptors is at least partially responsible for the extreme pain experienced by women who suffer from vestibulodynia. Nevertheless, the increase in nociceptive pain does not completely account for all of the symptoms of vulvodynia; Pukall et al. found that patients with vestibulodynia have a systemic (i.e., nonlocalized) hypersensitivity to tactile and pain stimuli.18 This suggests that some of the symptoms of vulvodynia are due to a central neuropathic pain process. Lastly, other data have implicated allergic reactions,16,19 myofascial hypertonicity, 18 and nerve entrapment or injury as potential causes of vulvar pain.20 In summary, it is likely that there are many different diseases that yield similar symptoms and cause vulvodynia. Earlier theories regarding the etiology of vulvodynia have recently been questioned. The role of human papilloma virus, increased urinary oxalate, and a prior history of candidiasis, as causative agents of vulvodynia is uncertain. A few clinicians believe that vulvodynia occurs directly as a result of psychological or sexual dysfunction. This viewpoint, however, is rejected by most patients and by the majority of the clinicians who treat these patients. Almost all experts agree that the presence of chronic pain, such as with vulvodynia, can have profound psychosocial consequences. In 2003, thought leaders at a National Institute of Health-sponsored conference on vulvodynia concluded that generalized, non-provoked vulvodynia is described most accurately when it is thought of as a complex regional pain syndrome (CRPS), similar to other CRPS such as fibromyalgia and interstitial cystitis.21 Like women with other CRPS, women with vulvodynia exhibit enhanced systemic pain perception, a process known as central nervous system sensitization.22 Secondly, women with vulvodynia are more likely to have other CRPS, such as interstitial cystitis.23 All women with vulvar pain should have a thorough phy­ sical examination. The goal of this exam is to find evidence of an identifiable disease, which can cause vulvovaginal

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pain. The vulva should be examined for evidence of infection, trauma, or dermatitis. Specifically, the observer should note any inflammation, induration, excoriation, fissures, ulceration, lichenification, hypopigmentation, hyperpigmentation, scarring, or architectural changes of the vulva. Using a colposcope can greatly enhance the visual inspection of the vulva (dermatologic diseases are discussed below) as any abnormalities found on visual examination of the vulva should be biopsied, and the tissue sent to a dermatopathologist. However, biopsies of the vulvar vestibule should be performed with caution; when the only physical finding is erythema, as the results of these biopsies are almost always nondiagnostic. After the visual exam, a sensory exam should be completed. A moistened cotton swab should be used to palpate the labia majora, interlabial sulcus, perineum, prepuce, labia minora, clitoris, and vulvar vestibule. Particular attention should be paid to the tissue immediately lateral and medial to Hart’s line on the labia minora. Frequently, there will be normal sensation lateral to Hart’s line and extreme pain medial to this important anatomic boundary. Pain medial to Hart’s line and distal to the introitus establishes the diagnosis of vestibulodynia. The vestibule should then be gently palpated in seven locations: anterior and inferior to the urethra, laterally to the urethra on both sides, and in the posterior vestibule at the 4, 6, and 8 o’clock positions. The vagina should then be examined by inserting a ­pediatric-sized speculum through the hymen without touching the vestibule to avoiding causing the patient pain. The vaginal mucosa should be examined for loss of rugae and erythema, which is suggestive of atrophy. Additionally, erosions, ulcerations, or synechiae could indicate erosive lichen planus. Discharge should be obtained for a wet mount and culture to rule on infectious or inflammatory vaginitis. A digital exam is then performed using only one finger as described above for LAS. The urethra and bladder are then palpated; tenderness can be evidence of interstitial cystitis. The uterus, adnexa, and rectovaginal septum are then palpated to look for evidence of masses, scarring, or endometriosis. Lastly, the pudendal nerves are palpated at the ischial spines as tenderness can be a sign of pudendal neuropathy or pudendal nerve entrapment.

Treatment Everyday Vulvar Hygiene Common recommendations for minimizing vulvar irritation include the use of 100% cotton underwear and not wearing underwear while sleeping. Patients should avoid vulvar irritants and douching, and be advised to use mild soap for bathing without applying soaps to the vulva. After washing, the area should then be gently patted dry. After bathing in a tub or shower, we advise patients to pat dry the genital area.

If the skin is dry, emollients (plain petrolatum) may be used topically to hold moisture and improve the barrier function. We recommend against using face cloths for washing. The daily use of pantyliners can be especially irritating and we recommend unscented, undyed, cotton menstrual pads during menstruation. Inadequate lubrication during intercourse can greatly exacerbate vulvar discomfort; the authors recommend water-based lubricants or natural oils (olive, tea tree, sweet almond, sesame, rosehip, grape seed, and wheat germ). Ice packs, cool gel packs, or other forms of cold application are helpful in some patients, but they may produce irritation when overused.

Topical Treatments Some patients find relief from vulvodynia with topical anesthetics. All topical anesthetics may cause initial burning and stinging upon application; the discomfort lasts for a few minutes until the area is numb. The longer the ointment is on the area, the deeper the anesthesia. The most commonly prescribed topical medication is lidocaine (Xylocaine; AstraZeneca Pharmaceuticals, Wilmington, DE) jelly 2% or ointment 5%. The long-term use of overnight topical lidocaine has been shown to provide a significant decrease in pain with sexual activity. Topical medications that have been used include estradiol, capsaicin,24 atropine, testosterone, nitroglycerine,25 doxepin, amitriptyline, baclofen, and gabapentin.26 Unfortunately there are few adequate trials assessing the efficacy in vulvodynia. Although not supported by controlled trials, the authors have found that for women who have developed vestibulodynia while on oral contraceptives, topical estradiol and testosterone can be very effective. Topical therapies that patients describe as not having significant benefit for vulvodynia are important to note in order to avoid side effects and symptom exacerbation. Although topical corticosteroids logically should improve the pain of vestibulodynia, they generally do not. In addition, topical antifungals are often used empirically by many clinicians. However, topical antifungal therapy generally does not improve vulvodynia. All topical preparations may provide some relief, but this is most likely due to the soothing properties in the vehicle itself. Furthermore, these topical preparations may cause a superimposed irritant or allergic vulvovaginitis.

Oral Treatment Antidepressants are commonly used in the treatment of many chronic pain conditions that are thought to have a neuropathic etiology. A common treatment for vulvodynia is the use of oral tricyclic antidepressants such as amitriptyline (Elavil; Astra-Zeneca Pharmaceuticals), nortriptyline (Pamelor; Novartis Pharmaceuticals, East Hanover, NJ), and desipramine (Norpramin; Aventis Pharmaceuticals,

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Bridgewater, NJ). The mechanism of action is believed to be associated with blocking reuptake of norepinephrine and serotonin transmitters, although the mechanism may actually be attributable to the anticholinergic effects.26 Should a patient choose tricyclic antidepressants as a treatment for vulvodynia, it is important for the clinician to emphasize that their effect is for pain rather than depression. The dosages of tricyclic antidepressants used for vulvodynia are significantly less than those used for depression. Facilitating the patient’s understanding of her treatment ideally will enhance patient compliance. Patients on tricyclic antidepressants should not be pregnant, intend to become pregnant, or breastfeed while using these medications. Appropriate contraception should be initiated (or continued) for patients of reproductive age if they are sexually active. It is important to remember that these medicines will exacerbate the effects of alcohol and other central nervous system depressants. Other antidepressants have been used for pain control, including selective serotonin reuptake inhibitors (SSRIs), but the serotonin and norepinephrine reuptake inhibitors (SNRIs) have been more effective in treating vulvodynia. These include venlafaxine (Effexor XR; Wyeth and duloxetine (Cymbalta; Eli Lilly and Company, Indianapolis, IN). Side effects include nausea, dizziness, somnolence, and fatigue. When discontinuing this medication, tapering is recommended. Gabapentin (Neurontin; Pfizer Inc., New York, NY) and carbamazepine (Tegretol; Novartis Pharmaceuticals, East Hanover, NJ) have been used to treat chronic pain conditions, including vulvodynia.27

Intralesional Injections While topical steroids generally do not improve patients with vulvodynia, occasionally a triggerpoint injection may be of benefit. Trigger-point steroid and bupivacaine injections have been successful for some patients with localized vulvodynia. Patients typically do not tolerate more than three or four injections. Other regimens include submucosal methylprednisolone and lidocaine.28 Interferon-alpha, a naturally occurring protein produced by leukocytes, improves the immunologic function, decreases inflammation, and inhibits mast cells. Recently, the use of botulinum toxin A (Botox; Allergan Inc., Irvine, CA) has been successfully used for the treatment of vulvodynia (see above).

Surgical Treatment For patients who have exhausted the other treatment options and have still not achieved adequate relief of their pain, surgical management should be considered. It should be emphasized to the patient that her recovery will take several weeks, and that she should not expect an ‘immediate’ cure. In our experience, under the best of circumstances, patients are ready to begin therapy with vaginal dilators at

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6 weeks postoperatively, and may attempt sexual activity by approximately 4 months. Prior to surgery, it is important to evaluate the patient for levator ani spasm (pelvic floor).6 Additionally, counseling may enhance postoperative improvement by reducing pelvic floor hypertonicity and poor sexual arousal, which can develop after long-standing dyspareunia.

Vulvar dermatoses There are many ways in which the skin of the vulva differs from skin on the rest of the body. It is the only area of the human body where epithelium from all three embryologic layers comes together. In addition, because the vulvovaginal tract contains foreign proteins and antigens necessary for reproduction, this area of the body has a unique immunologic response.29 Lastly, the subcutaneous tissue of the labia majora is looser, allowing for considerable edema to form. Vulvar dermatoses may present in a variety of ways and are a common cause of vulvar pain. Potential dermatological vulvar disorders include: lichen sclerosus, lichen planus, intraepithelial neoplasia, a vulvar malignancy, vulvar Crohn’s disease, vulvar ulcerations due to a sexually transmitted disease, plasma cell vulvitis (a very rare disorder), and other dermatoses that may be found elsewhere on the body, such as psoriasis.

Initial Evaluation All patients with complaints of vulvar pain should undergo a comprehensive history and physical examination as discussed above. Vulvoscopy can be extremely useful in the evaluation of vulvar dermatoses as magnification allows the clinician to see the disease process in greater detail, aiding an accurate diagnosis and ruling out a malignant or premalignant condition. Lastly, photographs at the initial visit are especially useful in both documenting baseline physical examination findings as well as progress with treatment.

Specific Dermatoses Irritant and Allergic Contact Dermatitis Contact dermatitis is an inflammation of the skin because of an external agent acting as an irritant or allergen. An irritant is any substance that causes inflammation, erythema, and induration upon exposure to the dermis, whereas an allergen is any substance that stimulates a type IV delayed hypersensitivity reaction in sensitized individuals.30 The incidence of vulvar contact dermatitis in the general population is unknown; however, the reported incidence in a vulvar clinic in the United Kingdom was 20–30%, and in an Australian vulvar clinic the incidence was 15%.31,32 However, it is generally accepted among specialists in vulvar

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disease that as women increasingly apply products to the vulva, the incidence of contact dermatitis increases. Common products containing chemicals that may cause contact dermatitis include soaps, menstrual pads, panty liners, toilet paper, diapers, fabric detergents, fabric softeners, feminine sprays, cosmetics, spermicides, pessaries, and condoms. Additionally, medications that frequently cause contact ­dermatitis include benzocaine, hormonal creams, corticosteroids, topical antifungals, and antibiotics.30 Women with contact dermatitis present with burning, itching, dyspareunia, and fissuring around the introitus.31 Physical examination findings may range from mild erythema to weeping, lesions. Histologically, findings are non-specific. Continued exposure to the irritant and chronic rubbing or scratching may eventually lead to lichen simplex chronicus (LSC). The diagnosis of contact dermatitis of the vulva is made by taking a detailed history and careful physical examination. As for any vulvar finding, one should have a low threshold to perform a biopsy to both diagnose the lesion in question and rule out coexisting conditions. The cornerstone of treatment of contact dermatitis is identification and removal of the causative irritant or allergen. Fluconazole can be used to treat a superimposed fungal infection and oral antibiotics can be used to treat a superimposed bacterial infection. Lichen Simplex Chronicus Lichen simplex chronicus (LSC) of the vulva is an eczematous disorder characterized by itching, scratching, and lichenification.33 The condition is the end-stage of an itch–scratch–itch cycle. The etiology of the initiating pruritus that leads to LSC includes numerous irritative and ­infectious disorders including candidiasis, atopic dermatitis, contact dermatitis, and eczema.29 The intense, chronic itching caused by these conditions leads the patient to repetitively rub and scratch the affected area. The skin responds by thickening. As numerous vulvar disorders may present with pruritis, a biopsy should be performed to distinguish LSC from lichen sclerosus (LS), lichen planus (LP) or neoplasia. As with irritant and allergic dermatitis, specifics of the patient’s daily routine for hygiene should be determined and proper vulvar care should be reviewed. Treatment includes agents to decrease inflammation (triamcinolone 0.1% ointment twice a day for moderate cases and clobetasol 0.05% ointment once a day may be prescribed for severe cases). Ice packs (or bags of frozen peas) and antihistamines such as hydroxyzine can be used to help alleviate pruritus. Lowdose tricyclic antidepressants such as amitriptyline can be used to help women stop scratching in their sleep. The duration of treatment and any changes to a treatment regimen should be guided by the patient’s symptoms. Patients should be seen 1 month after initiating treatment.

Lichen Sclerosus Lichen sclerosus (LS) is a chronic, lymphocyte-mediated cutaneous disorder affecting approximately one in seventy women.34 There is a bimodal peaked incidence in premenarchal girls and in menopausal women with the average age of diagnosis being 51 years.35 Extragenital lesions may occur in 11% of female patients.36 While the etiology of LS has not been completely elucidated, it is most likely that LS is an autoimmune disorder as it is highly associated with other autoimmune disorders. Women with LS have a 4–6% risk of developing vulvar carcinoma.35,36 Clinically, while some patients are asymptomatic, most give a history of pruritis or pain.35 On physical examination, one may see white atrophic plaques (‘cigarette paper’), depigmentation, submucosal hemorrhage, and, because of the chronic inflammation associated with this condition, scarring with narrowing of the introitus and distortion of the vulvar architecture. With time, scarring and decreased elasticity of the skin may predispose to fissuring of the posterior fourchette. LS may involve the labia minora and inner portion of the labia majora, interlabial sulcus, clitoris, and the perianal region, but almost never involves the vagina. A biopsy specimen should be obtained to confirm the diagnosis as the histopathologic changes of LS are distinctive and make biopsy a very useful diagnostic tool. It is essential to obtain the biopsy prior to starting corticosteroids as the pathognomonic changes seen histologically can resolve with the application of corticosteroids.37 After histologic confirmation of the diagnosis and the biopsy site has healed, the mainstay of treatment is ultrapotent topical corticosteroid ointment, such as clobetasol propionate ointment, applied daily until all active disease has resolved.38 To facilitate the absorption, patients may be instructed to soak in warm water for 15 minutes and pat the skin dry before applying the medication. Patients should be seen 2–3 month after initiating therapy to confirm improvement. Areas of ulceration that do not resolve after appropriate treatment with corticosteroids must be biopsied to rule out vulvar intraepithelial neoplasia or carcinoma. Lichen Planus Lichen planus is an inflammatory, autoimmune, mucocutaneous disorder, with multiple clinical variants that may involve both keratinized skin and mucosal surfaces. There are three clinical variants of vulvar LP. The most common form, erosive LP, affects the vulva and vagina. Papulosquamous LP affects the vulva and hypertrophic LP involves the perineum and perianal area. Lichen planus affects approximately 1% of all women, and the most common site of involvement is the oral mucosa.39 Approximately 25% of women with oral LP also have vulvovaginal involvement.40 Erosive lichen planus (LP) is characterized by glassy, brightly erythematous erosions associated with white striae (Wickham’s striae).41 The disease may involve the labia

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minora and vestibule while sparing the vulva, or may be associated with loss of the labia minora, narrowing of the introitus, and obliteration of the vagina. Vaginal involvement has been reported in up to 70% of patients with erosive LP.42,43 Patients frequently have copious yellow discharge composed of lymphocytes and parabasal cells (immature epithelial cells of the vagina).41 In severe cases, intravaginal synechiae may form, causing partial or complete obliteration the vagina. It is important to note that there are no pathognomonic histologic features of LP, unlike LS. To distinguish erosive LP from immunobullous diseases (mucous membrane pemphigoid, pemphigus vulgaris, and linear IgA bullous disease), a biopsy taken from normal tissue at the edge of an erosion should be sent for direct immunofluorescence. A positive result excludes the diagnosis of LP. Women with LP of the vulvovaginal region may present with itching, burning, vulvovaginal discomfort, dyspareunia, postcoital bleeding, vaginal discharge, and destruction of the vulvovaginal architecture. On physical examination, the vulvar skin and vaginal mucosa are friable, and bleed easily upon insertion of a speculum. In severe cases, there is narrowing or obliteration of the vaginal canal. LP is commonly misdiagnosed as LS. However, the lesions of LP do not exhibit the classic ‘cigarette paper’ appearance of LS. Furthermore, vaginal involvement in LS is very rare; however, LS and LP may be found in the same patient. Unfortunately, LP is not readily treated as the lesions frequently are impervious to current therapies. Some authors have recommended the initial use of topical medications, reserving systemic treatments for patients who fail topical treatments or those with extensive disease affecting multiple areas of the body.44 First-line treatment of vulvar LP are daily topical potent or ultrapotent corticosteroid ointments such as fluocinonide 0.05% or clobetasol propionate 0.05%.41 Vaginal LP is treated with intravaginal hydrocortisone suppositories. Commonly used formulations are those used to treat hemorrhoids.30 Other treatment options include potent corticosteroid ointment applied to a vaginal dilator and inserted into the vagina. This treatment also helps in preventing obliteration of the vagina. Tacrolimus, a topical macrolide immunosuppressant has recently been described for the treatment of a vulvovaginal LP.45,46 Topical cyclosporine has also been described for the treatment of oral and vulvovaginal LP. However, it is of limited utility because of its irritative properties and high cost. For women whose disease is refractory to topical treatments, oral corticosteroids such as prednisone will usually control the disease. In general, patients with LP should be seen within 1 month of initiating treatment. The frequency of office visits thereafter will be dictated by the patient’s symptoms and severity of disease. Topical corticosteroids should be used until all active lesions have resolved. The frequency of application is then tapered.

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It is extremely important to counsel patients that this is a chronic disease and that treatment only when symptomatic is not sufficient as there can be active disease without symptoms. Thus, patients require lifetime therapy for this disorder. Frequently, they can be managed with a onceweekly application of clobetasol and should have an annual physical examination.

Conclusion Vulvar pain is common in women and the etiology may be multifactorial. A detailed history, careful physical examination, appropriate laboratory testing, and histologic evaluation will aid in establishing the diagnosis. These patients require a compassionate and empathetic approach, frequently from an experienced team of providers.

References   1. Lynch, PJ, Moyal-Barrocco, M, Bogliatto, F, Micheletti, L, Scurry, J. 2006 ISSVD classification of vulvar dermatoses: pathologic subsets and their clinical correlates. J Reprod Med 2007;52(1):3–9.   2. Glazer HI, Rodke G, Swencionis C, Hertz R, Young AW. Treatment of vulvar vestibulitis syndrome with electromyographic biofeedback of pelvic floor musculature. J Reprod Med 1995;40(4):283–290.   3. Rosenbaum TY. Physiotherapy treatment of sexual pain disorders. J Sex Marital Ther 2005;31(4):329–340.   4. Hartmann D, Nelson C. The perceived effectiveness of physical therapy treatment on women complaining of chronic vulvar pain and diagnosed with either vulvar vestibulitis syndrome or dysestheic vulvodynia. J Sect Women’s Health APTA 2001;25:13–18.   5. Bergeron S, Brown C, Lord MJ et al. Physical therapy for vulvar vestibulitis syndrome: a retrospective study. J Sex Marital Ther 2002;28(3):183–192.   6. Goldstein AT, Marinoff SC, Haefner HK. Vulvodynia: strategies for treatment. Clin Obstet Gynecol 2005;48(4):769–785.   7. Jones KD, Lehr ST. Vulvodynia: diagnostic techniques and treatment modalities. Nurse Pract 1994;19(4):34, 37–46.   8. Denbow ML, Byrne MA. Prevalence, causes and outcome of vulval pain in a genitourinary medicine clinic population. Int J STD AIDS 1998;9(2):88–91.   9. Reed BD, Crawford S, Couper M, Cave C, Haefner HK. Pain at the vulvar vestibule: a web-based survey. J Low Genit Tract Dis 2004;8(1):48–57. 10. Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc 2003;58(2):82–88. 11. Witkin SS, Gerber S, Ledger WJ. Differential characterization of women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 2002;187(3):589–594. 12. Witkin SS, Gerber S, Ledger WJ. Influence of interleukin1 receptor antagonist gene polymorphism on disease. Clin Infect Dis 2002;34(2):204–209.

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13. Babula O, Danielsson I, Sjoberg I, Ledger WJ, Witkin SS. Altered distribution of mannose-binding lectin alleles at exon I codon 54 in women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 2004;191(3):762–766. 14. Bohm-Starke N, Johannesson U, Hilliges M, Rylander E, Torebjork E. Decreased mechanical pain threshold in the vestibular mucosa of women using oral contraceptives: a contributing factor in vulvar vestibulitis? J Reprod Med 2004;49(11):888–892. 15. Bohm-Starke N, Hilliges M, Falconer C, Rylander E. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1998;46(4):256–260. 16. Bornstein J, Goldschmid N, Sabo E. Hyperinnervation and mast cell activation may be used as histopathologic diagnostic criteria for vulvar vestibulitis. Gynecol Obstet Invest 2004;58(3):171–178. 17. Westrom LV, Willen R. Vestibular nerve fiber proliferation in vulvar vestibulitis syndrome. Obstet Gynecol 1998;91(4):572–576. 18. Pukall CF, Binik YM, Khalife S et al. Vestibular tactile and pain thresholds in women with vulvar vestibulitis syndrome. Pain 2002;96(1-2):163–175. 19. Babula O, Lazdane G, Kroica J, Ledger WJ, Witkin SS. Immunoglobulin E antibodies to seminal fluid in women with vulvar vestibulitis syndrome: relation to onset and timing of symptoms. Am J Obstet Gynecol 2004;190(3):663–667. 20. Shafik A. Pudendal canal syndrome and proctalgia fugax. Dis Colon Rectum 1997;40(4):504. 21. Edwards L. New concepts in vulvodynia. Am J Obstet Gynecol 2003;189(Suppl. 3):S24–30. 22. Pukall CF, Strigo IA, Binik YM, Amsel R, Khalife S, Bushnell MC. Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome. Pain 2005;115(1-2):118–127. 23. Gordon AS, Panahian-Jand M, Mccomb F, Melegari C, Sharp S. Characteristics of women with vulvar pain disorders: responses to a Web-based survey. J Sex Marital Ther 2003;29(Suppl. 1):45–58. 24. Steinberg AC, Oyama IA, Rejba AE, Kellogg-Spadt S, Whitmore KE. Capsaicin for the treatment of vulvar vestibulitis. Am J Obstet Gynecol 2005;192(5):1549–1553. 25. Walsh KE, Berman JR, Berman LA, Vierregger K. Safety and efficacy of topical nitroglycerin for treatment of vulvar pain in women with vulvodynia: a pilot study. J Gend Specif Med 2002;5(4):21–27. 26. Munday PE. Response to treatment in dysaesthetic vulvodynia. J Obstet Gynaecol 2001;21(6):610–613. 27. Haefner HK, Collins ME, Davis GD, et al. The vulvodynia guideline. J Low Genit Tract Dis 2005;9(1):40–51. 28. Murina F, Tassan P, Roberti P, Bianco V, Roberti P, Bianco V. Treatment of vulvar vestibulitis with submucous infiltrations of methylprednisolone and lidocaine. An alternative approach. J Reprod Med 2001;46(8):713–716.

29. Foster DC. Vulvar disease. Obstet Gynecol 2002;100(1):145–63. 30. Margesson LJ. Contact dermatitis of the vulva. Dermatol Ther 2004;17(1):20–27. 31. Crone AM, Stewart EJ, Wojnarowska F, Powell SM. Aetiological factors in vulvar dermatitis. J Eur Acad Dermatol Venereol 2000;14(3):181–186. 32. Brenan JA, Dennerstein GJ, Sfameni SF, et al. Evaluation of patch testing in patients with chronic vulvar symptoms. Australas J Dermatol 1996;37(1):40–43. 33. Ball SB, Wojnarowska F. Vulvar dermatoses: lichen sclerosus, lichen planus, and vulval dermatitis/lichen simplex chronicus. Semin Cutan Med Surg 1998;17(3):182–188. 34. Wallace HJ. Lichen sclerosus et atrophicus. Trans St Johns Hosp Dermatol Soc 1971;57(1):9–30. 35. Goldstein AT, Christopher K, Burrows LJ. Prevalence of vulvar lichen sclerosus in a general gynecology practice. J Reprod Med 2005;50(7):477–480. 36. Rouzier R, Haddad B, Deyrolle C, Pelisse M, Moyal-Barracco M, Paniel BJ. Perineoplasty for the treatment of introital stenosis related to vulvar lichen sclerosus. Am J Obstet Gynecol 2002;186(1):49–52. 37. Lorenz B, Kaufman RH, Kutzner SK. Lichen sclerosus: therapy with clobetasol propionate. J Reprod Med 1998;43(9): 790–94. 38. Bornstein J, Heifetz S, Kellner Y, Stolar Z, Abramovici H. Clobetasol dipropionate 0.05% versus testosterone propionate 2% topical application for severe vulvar lichen sclerosus. Am J Obstet Gynecol 1998;178(1 Pt 1):80–84. 39. Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol 2002;46(2):207–214. 40. Eisen D. The evaluation of cutaneous, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88(4):431–436. 41. Moyal-Barracco M, Edwards L. Diagnosis and therapy of anogenital lichen planus. Dermatol Ther 2004;17(1):38–46. 42. Lewis FM, Shah M, Harrington CI. Vulval involvement in lichen planus: a study of 37 women. Br J Dermatol 1996; 135(1):89–91. 43. Ridley CM. Chronic erosive vulval disease. Clin Exp Dermatol 1990;15(4):245–252. 44. Goldstein AT, Metz A. Vulvar lichen planus. Clin Obstet Gynecol 2005;48(4):818–823. 45. Kirtschig G, Van Der Meulen AJ, Ion Lipan JW, et al. Successful treatment of erosive vulvovaginal lichen planus with topical tacrolimus. Br J Dermatol 2002;147(3):625–626. 46. Byrd JA, Davis MD, Rogers RS 3rd. Recalcitrant symptomatic vulvar lichen planus: response to topical tacrolimus. Arch Dermatol 2004;140(6):715–720.

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39

Lower Urogenital Tract Dysfunction in Men and Women Doreen E. Chung1, Alexis E. Te2, and Renuka Tyagi3 1

Weill Cornell Medical College, Department of Urology, New York, NY, USA Associate Professor of Urology, Weill Cornell Medical College, Department of Urology, New York, NY, USA 3 Assistant Professor of Urology in Obstetrics and Gynecology, Weill Cornell Medical College, Department of Urology, New York, NY, USA 2

Lower urinary tract dysfunction: definitions, symptoms, and classification

can be classified as failure of the storage or voiding phase and may be secondary to reasons related to the bladder, the urethra, or both.2,4 There are many classification systems for lower urinary tract dysfunction. One that is widely accepted is the International Continence Society (ICS) system (Figure 39.3). It is based on the distinction between the storage and voiding phases as well as between bladder and urethral function.5–8 For example, incontinence is a symptom that occurs in the storage phase. It can occur in both men and women, but for divergent reasons.

Relevant Anatomy(Figures 39.1, 39.2)  The components of the lower urinary tract in both men and women are the bladder and the urethra. Gender-specific differences in anatomy predispose men and women to different conditions. Women have a shorter urethra (3–4 cm), making them more prone to urinary tract infections and incontinence. The male urethra is much longer and has four parts: the penile urethra, bulbous urethra (which passes through the scrotum), membranous urethra (located at the external urethral sphincter), and the prostatic urethra. Due to its length the male urethra is more prone than the female urethra to traumatic injury and stricture formation. Conditions of the prostate comprise a significant part of lower urogenital dysfunction in men. Previously, lower urinary tract symptoms in aging men, such as weak stream and urinary frequency, were thought to be exclusively as a consequence of an enlarged prostate and were referred to as ‘prostatism.’ It is clear now that these symptoms are not only a consequence of an enlarging prostate and obstruction, but also the effects of aging on the lower urinary tract. Furthermore, as men and women age, the prevalence of LUTS increases. Paul Abrams has coined the phrase lower urinary tract symptoms (LUTS) to replace the misleading and genderspecific term ‘prostatism.’1

Classification and Definitions of Symptoms Definitions of the most common LUTS (ICS definitions) The following are the definitions of the most common LUTS adapted from the guidelines of the ICS standardization sub-committee.7 Symptoms are the subjective indicator of a disease or change in condition as perceived by the patient, carer or partner and may lead him/her to seek help from health care professionals. Storage symptoms: Storage symptoms are experienced during the storage phase of the bladder and include daytime frequency and nocturia. Increased daytime frequency is the complaint by the patient who considers that he/she voids too often by day. Nocturia is the complaint that the individual has to wake at night one or more times to void. Urgency is the complaint of a sudden compelling desire to pass urine which is difficult to defer. Urinary incontinence is the complaint of any involuntary leakage of urine.

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Classification of Lower Urinary Tract Dysfunction The micturition cycle has two distinct functional phases: the storage (bladder filling) phase, and the voiding (bladder emptying) phase.2,3 Dysfunction of the lower urinary tract Principles of Gender-Specific Medicine

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Body detrusor

Detrusor

Superficial trigone

Uretero trigone Periureteric sheath

Deep trigone

Base detrusor

Bladder neck

Lissosphincter

Urethral muscularis

Urethral smooth muscle Periurethral striated muscle

Rhabdosphincter

Rhabdosphincter or intramural striated muscle

Figure 39.1  Female lower urinary tract: Anatomy of the bladder and its outlet as defined by Gosling and Dixon (left) versus Elbadawi and co-workers (right). Reproduced from Torrens M, Morrison JFB. The Physiology of the Urinary Bladder. Berlin: Springer-Verlag; 1987:1

Urge urinary incontinence is the complaint of involuntary leakage accompanied by or immediately preceded by urgency. Mixed urinary incontinence is the complaint of involuntary leakage associated with urgency and also with exertion, effort, sneezing or coughing. Nocturnal enuresis is the complaint of loss of urine occurring during sleep. Continuous urinary incontinence is the complaint of continuous leakage. Bladder sensation can be defined, during history-taking, by five categories: normal, increased, reduced, absent, or non-specific Voiding symptoms: voiding symptoms are experienced during the voiding phase. Slow stream is reported by the individual as his or her perception of reduced urine flow, usually compared to previous performance or in comparison to others. Intermittent stream (Intermittency) is the term used when the individual describes urine flow which stops and starts, on one or more occasions, during micturition. Hesitancy is the term used when an individual describes difficulty in initiating micturition resulting in a delay in the onset of voiding after the individual is ready to pass urine. Straining to void describes the muscular effort used to initiate, maintain or improve the urinary stream. l

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Figure 39.2  Male lower urinary tract: View from in front the trigone (T) is represented as a surface feature on the luminal aspect of the trigonal detrusor thickening. D, detrusor muscle; IS, internal sphincter; PS, periurethral striated muscle; ES, distal or external striated urethral sphincter. Reproduced from Kirby RS, McConnell JD, Fitzpatrick JM, Roehrborn CG, Boyle P, eds. Textbook of Benign Prostatic Hyperplasia. London: Taylor & Francis; 2004

Stress urinary incontinence is the complaint of involuntary leakage on effort or exertion, or on sneezing or coughing.

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STORAGE PHASE • Bladder function • Bladder sensation • Absent • Reduced • Increased • Normal • Bladder capacity • Low • High • Normal • Bladder compliance • Normal • Decreased • Detrusor activity • Normal or stable • Overactive • Neurogenic • Idiopathic • Urethral function • Normal closure mechanism

•

Genital and urinary tract pain. Pain, discomfort and pressure are part of a spectrum of abnormal sensations felt by the individual. Pain may be related to bladder filling or voiding, may be felt after micturition, or be continuous. Pain should also be characterized by type, frequency, duration, precipitating and relieving factors, and by location: bladder, urethral, vulvar, vaginal, scrotal, perineal, and pelvic. Symptom syndromes Symptom syndromes that suggest lower urinary tract dysfunction include: Urgency, with or without urge incontinence, usually with frequency and nocturia, can be described as the overactive bladder syndrome, urge syndrome or urgency–frequency syndrome. Lower urinary tract symptoms suggestive of bladder outlet obstruction is a term used when a man complains predominately of voiding symptoms in the absence of infection or obvious pathology other than possible causes of outlet obstruction. l

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Incompetent closure mechanism

VOIDING PHASE • Bladder Function • Detrusor activity • Normal detrusor function • Abnormal detrusor activity • Detrusor underactivity • Acontractile detrusor • Urethral Function • Normal

•

Abnormal • Bladder outlet obstruction • Dysfunctional voiding • Detrusor sphincter dyssynergia • Non-relaxing urethral sphincter obstruction

Conditions causing lower urinary tract symptoms in men, women, and both sexes according to symptoms Conditions Affecting Men and Women Transient Conditions Transient incontinence: Transient incontinence is common in elderly patients and causes can be remembered by the mnemonic ‘DIAPERS’.9 Delirium/confusional state Infection – urinary with symptoms Atrophic urethritis/vaginitis Pharmaceuticals – ACE inhibitors, diuretics, alcohol Excess urine output Restricted mobility Stool impaction Transient storage symptoms Infection Urinary tract infection – bacterial, viral, candidal, parasitic Urethritis – chlamydia, gonorrhea Volume-related – diuretics, caffeine, diabetes, peripheral edema leading to nocturia, chronic renal failure Foreign body – in bladder or urethra Inflammatory – urethritis (Reiter’s syndrome), chemical cystitis (cyclophosphamide, ketamine) Trauma Transient voiding symptoms Medications – sympathomimetics, anticholinergic agents Stool impaction Post anesthesia

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Figure 39.3  The International Continence Society Classification Adapted from Abrams et al.7,8

Terminal dribble is the term used when an individual describes a prolonged final part of micturition, when the flow has slowed to a trickle/dribble. Post-micturition symptoms: Post-micturition symptoms are experienced immediately after micturition. Feeling of incomplete emptying is a self-explanatory term for a feeling experienced by the individual after passing urine. Post-micturition dribble is the term used when an individual describes the involuntary loss of urine immediately after he or she has finished passing urine, usually after leaving the toilet in men, or after rising from the toilet in women. Other symptoms Symptoms associated with pelvic organ prolapse. The feeling of a lump (‘something coming down’), low backache, heaviness, dragging sensation, or the need to digitally replace the prolapse in order to defecate or micturate, are amongst the symptoms women may describe who have a prolapse. l

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Foreign body Acute stroke Acute spinal cord injury – spinal shock Idiopathic

Chronic Conditions Chronic storage symptoms Neurologic disease – stroke, Parkinson’s disease, spinal cord injury Inflammatory – radiation cystitis, chemical cystitis, zeosinophilic cystitis, painful bladder syndrome, interstitial cystitis, overactive bladder syndrome Malignancy – transitional cell carcinoma of the bladder, adenocarcinoma of the bladder Hinman’s syndrome – non-neurogenic neurogenic bladder Incontinence – stress and urge Chronic voiding symptoms Urethral stricture Neurologic disease – sacral spinal cord injury, diabetic neuropathy Idiopathic voiding dysfunction Malignancy – urethral cancer

Transient voiding symptoms Fowler’s syndrome – unexplained urinary retention in young women Genital herpes

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Chronic Conditions Chronic storage symptoms Stress urinary incontinence Urge urinary incontinence Fistula – incontinence – vesicovaginal fistula, ureterovaginal fistula, urethrovaginal fistula Atrophic vaginitis/urethritis Congenital – ectopic ureter Chronic voiding symptoms Pelvic organ prolapse Urethral diverticulum Malignancy – vaginal or cervical cancer Congenital – obstructing ureterocele Non-neurogenic neurogenic bladder (Hinman syndrome, ‘learned’ voiding dysfunction)

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Conditions Affecting Only Men Transient Conditions Transient storage symptoms Acute bacterial prostatitis Transient voiding symptoms Acute bacterial prostatitis Phimosis Paraphimosis

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Chronic Conditions Chronic storage symptoms BPH Chronic prostatitis Incontinence – iatrogenic after surgery or radiation for prostate cancer Chronic voiding symptoms BPH Malignancy – prostate cancer Foreign body – bladder stones Meatal stenosis Congenital – posterior urethral valves Non-neurogenic neurogenic bladder (Hinman syndrome, ‘learned’ voiding dysfunction)

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Urinary Incontinence The principal reason for incontinence in men is iatrogenic injury, most commonly from pelvic surgery such as radical prostatectomy for prostate cancer. Neurologic disease in men can also lead to incontinence. In contrast, because women have a much shorter urethra, the predominate reason for incontinence in women is urethral hypermobility. With a rise in intra-abdominal pressure, force is transmitted to the urethra. The superior wall of the urethra is then pressed towards the inferior wall and its connective tissue supports, which act as a backboard, causing urethral closure. This is called the ‘hammock hypothesis.’10 In urethral hypermobility, there is inadequate support of the inferior urethra resulting in urine leakage. Intrinsic sphincter deficiency is another mechanism of stress incontinence in women. Urge incontinence secondary to overactive bladder syndrome is also very common. Many women have mixed incontinence, with both stress and urge components. Women patients with neurologic disease also are at risk for neurogenic detrusor overactivity leading to incontinence. This will be discussed in the following section.

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Conditions Affecting Only Women Transient Conditions Transient storage symptoms UTI – very common in young and perimenopausal women, very uncommon in young men

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Overactive bladder (OAB) syndrome is very common in both men and women. The International Continence Society (ICS) defines OAB syndrome as a syndrome characterized by urgency with or without urge incontinence, usually with frequency and nocturia. The term detrusor overactivity is an urodynamic observation characterized by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked. The incidence of detrusor overactivity in the

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general population is approximately 16% in individuals older than age 40 and becomes more prevalent with increasing age.11 Idiopathic detrusor overactivity is detrusor overactivity with no defined cause. Neurogenic detrusor overactivity results from neurologic injury to inhibitory nerve supply to the bladder.

Benign Prostate Hypertrophy (BPH) in Men BPH is a benign histologic process of hyperplasia that contributes to, but it not solely responsible, for lower urinary tract symptoms (LUTS) in the aging male. Previously, LUTS in older men were considered to be completely a result of increased prostate mass and elevated urethral resistance. These symptoms were known as ‘prostatism.’ However, we now understand that LUTS in the aging male are only partially due to BPH and are also caused by age-related detrusor dysfunction as well as bladder outlet obstruction-related detrusor dysfunction, and detrusor overactivity.12 A significant proportion of men with symptoms of BPH also have symptoms of OAB (see Figure 39.4). The linkage between BPH and OAB symptoms is not well understood.13

Bladder Outlet Obstruction in Women In women, bladder outlet obstruction (BOO) is relatively rare. These patients may present with storage, voiding, or mixed urinary symptoms. Obstruction may be functional, neurologic, or anatomic. The most common anatomic cause of BOO in women is urethral surgery, such as an incontinence procedure or urethral diverticulectomy. Other causes include pelvic organ prolapse (POP), urethral diverticulum, trauma, and neoplasm.

Functional and Neurogenic Causes of Bladder Outlet Obstruction in Men and Women Functional causes of BOO in men and women include ‘learned’ voiding dysfunction, which is otherwise known as Hinman syndrome, and non-neurogenic neurogenic bladder. Patients with this condition subconsciously or consciously contract the urethral sphincter during micturition.14 In patients with neurologic disease, detrusor-external sphincter dyssynergia (DESD) can occur. More specifically, there can be uncoordinated activity of the detrusor muscle and the urinary sphincter causing obstruction during voiding. DESD also occurs in male patients. LUTS BPH

OAB

Figure 39.4  Relationship between LUTS, BPH, and OAB

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Assessment of lower urinary tract dysfunction in men and women Assessment of lower urinary tract dysfunction in men and women involves many different modalities. Some tests are more useful in one sex than the other. For example, uroflowmetry is very useful in men to help quantify obstruction whereas in women obstruction is less common. A careful history and physical examination should always be performed. Additional testing may be very helpful but only needs to be done in selected patients. In the office a urinalysis and culture may provide useful information. Noninvasive testing includes voiding diary, pad test, uroflowmetry, and post-void residual test. More invasive investigations are cystourethroscopy and urodynamic testing.

History A careful history is very important in the assessment of lower urinary tract dysfunction. It is important to ask about storage symptoms (frequency, urgency, nocturia, incontinence) as well as voiding symptoms (hesitancy, straining, intermittency, post-void dribble, incomplete emptying, dysuria). Important associated symptoms include hematuria and pain. Bowel function can impact lower urinary tract function. Asking about the onset of symptoms helps determine whether the condition is transient or chronic. When assessing incontinence, it is important to determine whether it is stress, urge, or mixed. In men with incontinence, the etiology is almost always iatrogenic or neurogenic. Hence in men with incontinence one must ask about prior surgery or radiation therapy. In women, stress incontinence due to urethral hypermobility is highly prevalent. It is very important in both men and women to ask about degree of bother. Validated questionnaires, in conjunction with careful history-taking, allow the physician to compare the patient’s recorded responses with the patient’s reported symptoms to help clarify areas where the symptoms are unclear. In addition, they allow one to follow patient’s severity of symptoms over time. When assessing lower urinary tract symptoms it is important to ask both men and women about sexual activity and practices. This is helpful in generating a differential diagnosis and also impacts making treatment decisions, particularly those of a surgical nature. Other lifestyle components to a urologic history include smoking, alcohol, and caffeine use. Smoking predisposes to urologic malignancies. Alcohol acts as a diuretic and can exacerbate urinary symptoms. Caffeine has multiple effects on the lower urinary tract.15 Another important aspect of the history is the presence or absence of neurologic symptoms. Perineal or genital anesthesia can be a consequence of damage to the sacral nerves (S2 to S4) or their roots, which innervate the bladder. Lower urinary tract symptoms may be the first sign

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of multiple sclerosis or multiple system atrophy. Many neurologic conditions affect the lower urinary tract. Some examples are stroke, Parkinson’s disease, dementia, acute transverse myelitis, spinal cord injury, spinal stenosis, multiple sclerosis, and degenerative disk disease. Other components of a detailed history include systemic illness, malignancy, and previous surgery. Over time, diabetes can lead to impaired bladder sensation and poor detrusor contractility. Radiation can affect all components of the lower urinary tract and chemotherapeutic agents, such as cyclophosphamide can cause cystitis. Pelvic surgery often leads to lower urinary tract trauma and during radical pelvic surgery there can be damage to the nerves that innervate the bladder. Many different classes of medications can affect the lower urinary tract. Decongestants, due to sympathomimetic activity, can cause men with BPH to have acute urinary retention. Other drugs that impair bladder emptying include anticholinergic medications, tricyclic antidepressants, calcium-channel blockers, drugs for Parkinson’s disease, opiates, and antihistamines. Medications that can contribute to incontinence, as mentioned previously, include ACE inhibitors, diuretics, and alpha-adrenergic medications.

Physical Examination A proper physical examination begins with blood pressure measurement. An elevated blood pressure may signal severe lower urinary tract dysfunction that has led to renal impairment. In both men and women, the back should be inspected to identify any spinal abnormalities. The abdomen should be examined for surgical scars and palpated for a full bladder, or suprapubic fullness. One should also palpate for costovertebral angle (CVA) tenderness. Examination of the deep tendon reflexes, anal tone, and bulbocavernosus reflexes may be helpful in determining neurologic injury that may affect the urinary tract. In women, a pelvic examination should be performed. Special attention to pelvic organ prolapse (POP) and menopause-induced urogenital atrophy is essential. Women can develop a cystocele, rectocele, enterocele, and/or uterine prolapse. In addition to examining the anterior, posterior, and central compartments, the pelvic floor musculature should also be examined. Because of the close proximity between the bladder, urethra, uterus, and vagina, incontinence and POP are interrelated. It is common for POP and stress incontinence to occur concomitantly and furthermore surgical correction of POP can unmask stress incontinence. Women should be examined both supine and standing for a more accurate assessment of incontinence and POP. In men, a digital rectal examination is recommended to assess the size and characteristics of the prostate gland. One should examine the urethral meatus to rule out meatal stenosis. The penis, in particular the corpus spongiosum

where the urethra is located, should be palpated to feel for strictures, masses, and skin lesions that can lead to stricture formation, such as balanitix xerotica obliterans (BXO).

Urinalysis Between 25 and 30% of women between the ages of 20 and 40 years have had a urinary tract infection, whereas very few men with normal urinary tracts in this age group will develop infection.16 Urinary tract infections account for 1.2% of office visits by women and 0.6% of visits by men.17 When a patient has symptoms of frequency, urgency, and/or dysuria it may be due to urinary tract infection. In such a case, the urinalysis will show pyuria. A urinalysis will also determine if microscopic hematuria is present. Microscopic hematuria in men and woman can be due to different reasons. In young women, the most common causes are infection, stones, and renal disease. In young men, the most common causes are stones, renal disease, and trauma. However in men older than 65 the most common origins of microscopic hematuria are BPH, infection, and malignancy and for elderly women they are infection, malignancy, and stones. The workup for microscopic hematuria includes upper tract imaging, urine culture, urine microscopy, examination of urine for proteinuria, and cystoscopy, and cytology in select patients. These patients are those who are over age 40 or have a history of smoking, chemical exposure, gross hematuria, irritative voiding symptoms, analgesic abuse, pelvic irradiation, or a history of a urologic disorder or disease.18

Voiding Diary In a voiding diary, patients should record the time and volume of each micturition event as well as symptoms such as pain, urgency, or incontinence for a variable period of time, usually 24–72 hours. This helps the physician to gain a more detailed understanding of the patient’s symptoms as well as to assess functional bladder capacity, nocturnal urine volume, and number of daily voids.

Uroflowmetry Uroflowmetry is a non-invasive inexpensive screening tool. It is a more useful test in men, where urethral obstruction, usually from BPH, is very common. The principal determinants of urine flow rate are the strength of bladder contraction and the resistance of the bladder outlet. A normal non-obstructed flow curve approximates a bell curve. Obstructed voiding flow curves have a plateau configuration. In general, in men peak flow rates (Qmax) greater than 15–20 ml/second are considered normal in young men and rates less than 10 ml/second are considered abnormal. These numbers decline approximately 1–2 ml/second every 5 years and maximum flow rate at age 80 is 5.5 ml/second.19

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In women maximum flow rate can be faster than 30 ml/second and is also shaped like a bell curve. In contrast to in men, flow rate in women is not dependent on age. Flow rate is not accurate when voided volume is less than 150 ml. Furthermore, this test cannot distinguish between weak detrusor contraction and physical obstruction. For a more detailed evaluation, uroflow may be measured simultaneously with detrusor pressure, as part of a urodynamic study.

Pad Test A pad test helps identify and quantify leakage of urine. It generally adds more clinical information in women than in men. According to the third International Consultation on Incontinence, a pad weight gain of more than 1.3 g over 24 hours is a ‘positive’ test.20 Other groups, however, have shown that a weight gain up to 8 g is normal.21,22 No standardization of the quantity exists. An adjunct to the pad test in women is a tampon test, which is helpful in determining whether leakage of urine is from the vagina (as in a vesicovaginal fistula) or urethral meatus.

the bladder, the outlet, or both. Finally urodynamic testing helps to identify patients who are at risk of upper urinary tract damage. The parameters measured during the filling phase include abdominal pressure, vesical pressure, detrusor pressure (the pressure exerted by the detrusor muscle which is abdominal pressure minus vesical pressure), capacity, compliance, sensation, and presence of involuntary or unstable contractions. In incontinent patients, abdominal leak point pressure and detrusor leak point pressure are determined. During the voiding phase the parameters measured are urine flow, abdominal pressure, vesical pressure, detrusor pressure, sphincter electromyography (EMG), bladder contractility, and bladder outlet obstruction. Sphincter EMG identifies uncoordinated contractions of the sphincter that can be caused by neurologic lesions or acquired subconscious voluntary activity. Video urodynamics includes fluoroscopic images taken during both the filling and voiding phases. This component helps to identify the anatomic level of obstruction, if vesicoureteric reflux is present, bladder pathology (such as stones, diverticulae, and fistulae), and urethral pathology (such as diverticulae and fistulae).

Post void Residual Urine Post-void residual (PVR) urine is defined as the amount of urine left in the bladder at the end of micturition. It can be measured by catheterization or non-invasively by ultrasonography. PVR varies in a given individual, hence multiple measurements are often necessary. There is no evidence-based maximum volume that is considered normal.23 The Agency for Health Care Policy and Research (AHCPR) guidelines state that, in general, a PVR less than 50 ml is adequate bladder empting and a PVR more than 200 ml is inadequate emptying.24

Cystourethroscopy In patients with risk factors for bladder pathology, such as hematuria, urgency, and urge incontinence, cystourethroscopy should be done to rule out intravesical tumors and bladder calculi. In men cystourethroscopy is helpful in evaluating degree and anatomy of prostatic obstruction or urethral strictures. In women, cystoscopy is also helpful in evaluating for vesicovaginal fistulae and urethral diverticulae.

Imaging In men a voiding cystourethrogram (VCUG) is useful in the evaluation of urethral strictures. In women it can be helpful in evaluating for vesicovaginal fistulae, urethrovaginal fistulae, and urethral diverticulae. Magnetic resonance imaging (MRI) is another helpful adjunct in the evaluation of a urethral diverticulum. In both sexes, VCUG detects the presence of vesicoureteral reflux.

Upper Tract Imaging In a subset of high-risk patients who have high-grade POP, detrusor-sphincter dyssynergia, urethral obstruction, and low bladder compliance, imaging of the upper urinary tract, usually by sonogram, computed tomography (CT), or MRI is important because of the incidence of associated vesicoureteral reflux and the potential for kidney damage. Another reason to assess the upper urinary tract, by intravenous pyelogram or CT urogram is in a patient with incontinence, where ureterovaginal fistula is suspected.

Therapy

Urodynamic Testing Urodynamic testing allows the physician to determine whether symptoms are secondary to storage problems or voiding problems. In both men and women this is important during the evaluation for incontinence. Furthermore, by measuring abdominal and intravesical pressures, one can determine whether symptoms are due to a problem with

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Treatment of Storage Problems (with or without Incontinence) Detrusor overactivity Treat the underlying condition (i.e. UTI, bladder stone, bladder outlet obstruction)

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Lifestyle/behavioral changes Scheduled voiding (bladder retraining) Limitation of excess fluid intake Pelvic floor muscle therapy (Kegels) Oral medications Anticholinergic agents (oxybutynin, tolterodine, trospium, darefenacin, solefenacin, fesoterodine) Tricyclic antidepressants Intravesical agents Oxybutynin Transdermal agents Oxybutynin transdermal system, oxybutynin gel 10% Botulinum toxin Surgery Augmentation cytoplasty Neuromodulation Urinary diversion Low bladder compliance Oral medications Anticholinergic agents (oxybutynin, tolterodine, trospium, darifenacin, solefenacin) Tricyclic antidepressants Intravesical agents Oxybutynin Botulinum toxin Surgery Augmentation cytoplasty Neuromodulation Urinary diversion Urethral hypermobility/sphincteric incompetence/ fistula Behavioral modification/lifestyle changes Pelvic floor muscle therapy Oral medications Serotonin-norepinephrine reuptake inhibitors Tricyclic antidepressants alpha-agonists Surgery Midurethral sling Pubovaginal sling Male sling Urethral suspension Urethral bulking agents Artificial urinary sphincter Fistula repair l

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Behavioral Modification and Lifestyle Changes Behavioral treatment is based on the concept that the incontinent patient can be educated about his or her condition and develop strategies to minimize or eliminate incontinence.25 It is applicable to both male and female patients. Scheduled voiding or bladder retraining is recommended as first-line treatment for incontinence and is effective in treating both stress and urge types. One should instruct the patient to void at a fixed time interval before the patient

usually experiences urge or incontinence. The interval is then increased with clinical improvement. Other lifestyle changes proven to improve incontinence include decreasing caffeine consumption, avoiding alcohol intake, and weight loss for obese patients. The simplest form of pelvic floor muscle exercises are Kegels, which can be done at home. A suggested training schedule for Kegels is a routine of 10–12 contractions, each held for 6–8 seconds, performed 5–6 times per day. These exercises may be helpful in both men and women but are likely more effective in women with incontinence. Biofeedback is a method that uses monitoring equipment to help a patient develop conscious control of body functions. In the patient with storage or voiding problems, this means working with a therapist to gain better control of the pelvic floor muscles. Medical Treatment Oral medications are very useful in treating both men and women with detrusor overactivity. Most agents for treating overactive bladder inhibit bladder contractility. These same agents are also useful in treating patients with poor bladder compliance, which can lead to upper urinary tract damage. Medications for the treatment of stress incontinence, such as tricyclic antidepressants, also increase sphincter tone through alpha-adrenergic activity. Furthermore, tricyclic antidepressants have a local anesthetic effect. Anticholinergic medications are competitive inhibitors of acetylcholine and block muscarinic receptors. The anticholinergics that are most common to urologic practice include oxybutynin, tolterodine, trospium, darifenacin, and solifenacin. They are equally effective. Oxybutynin comes in a dermal patch formulation in addition to the oral preparation. Common side effects of anticholinergic medications include dry mouth, dry eyes, constipation, headache, and mental status changes. It is very important to monitor elderly patients for decreased mentation or confusion after prescribing them anticholinergics. The only agent that does not cross the blood–brain barrier is trospium. Side effects of tricyclic antidepressants include the anticholinergic effects mentioned as well as alpha-adrenergic effects such as tachycardia, hypertension, and arrhythmias. Surgical Treatment The treatment of incontinence in men and women differs. The treatment of incontinence in men is exclusively surgical in nature. In women, medical therapy for detrusor overactivity can be quite effective. For female patients the most frequently used and efficacious surgical treatment is the midurethral or pubovaginal sling. For male patients, the artificial urinary sphincter is more successful than the male sling. Augmentation cystoplasty and urinary diversion are more invasive surgical solutions for incontinence in both men and women.

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Treatment of Voiding Problems Bladder outlet obstruction Medical therapy Men alpha-adrenergic blockers (doxazosin, terazosin, tamsulosin, alfuzosin) 5-reductase inhibitors (finasteride, dutasteride) Phytotherapy – saw palmetto Surgery Men BPH Transurethral resection of prostate (TURP) Transurethral microwave therapy (TUMT) Transurethral needle ablation of the prostate (TUNA) Open simple prostatectomy Laser procedures: –  Transurethral ultrasound-guided laser-induced prostatectomy (TULIP) –  Visual laser ablation of the prostate (VLAP) –  Holmium laser enucleation of the prostate (HoLEP) –  Photoselective vaporization of the prostate (PVP) Prostatic stents – i.e. Urolume stent Injection of botulinum toxin into the prostate Urethral stricture Visual internal urethrotomy (VIU) Urethroplasty Urolume stent Bladder neck contracture Transurethral resection of bladder neck Urolume stent Surgery Women Urethrolysis Urethral diverticulectomy Pelvic reconstruction procedure for pelvic organ prolapse Circumventing the problem Foley catheter Suprapubic tube Weak detrusor Clean intermittent catheterization Non-neurogenic neurogenic bladder/detrusorsphincter-dyssynergia (in men and women) Non-neurogenic neurogenic bladder (functional bladder neck or sphincteric obstruction) Behavioral therapy – biofeedback, pelvic floor muscle therapy alpha-adrenergic blockers transurethral resection of the bladder neck Detrusor-external sphincter-dyssynergia (DESD) Clean intermittent catheterization Continuous catheterization Sphincterotomy Stent placement across sphincter

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Injection of botulinum toxin into the urethral sphincter Augmentation cystoplasty  catheterizable stoma Urinary diversion

Medical Treatment of BPH Advances in pharmacologic agents for BPH have radically altered the nature of treatment, which used to be primarily surgical. Over the past two decades, medical therapy has become the most common modality of treatment for BPH. Therapy may be targeted at either the treatment of symptoms and/or preventing progression of disease. The main categories of pharmacologic agents include alpha-adrenergic blockers, androgen suppression agents, anticholinergic agents, phytotherapeutic agents, and botulinum toxin. These agents can be used alone or in combination. Alpha-Adrenergic Blockers It has been hypothesized that BPH causes bladder outlet obstruction and symptoms partially through increased smooth muscle tone. Alpha-adrenergic stimulation leads to increased urethral smooth muscle tone and intraurethral pressure. It follows that alpha-adrenergic blockers are useful in the treatment of BPH symptoms. The two most commonly used alpha-adrenergic blockers are tamsulosin and alfuzosin SR, which are both selective for the 1-adrenoreceptor. Tamsulosin is subtype selective for the 1a-adrenoreceptor, and the drug is in theory more specific for the prostate. Terazosin and doxazosin are older 1-adrenoreceptor blockers and may be useful in treating BPH and hypertension simultaneously. All of the mentioned agents are safe and effective for the treatment of symptoms associated with BPH. Side effects of alpha-adrenergic blockers include dizziness, postural hypotension, asthenia, rhinitis, and sexual dysfunction.

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5α-Reductase Inhibitors The use of 5-reductase inhibitors in the treatment of BPH is based on the finding that castration and pharmacologic agents that suppress testosterone and/or DHT secretion reduce the prostate size in men with BPH.26 There are two 5-reductase inhibitors approved by the FDA. Dutasteride inhibits both type 1 and type 2 isoenzymes whereas finasteride inhibits only the type 2 isoenzyme. Dutasteride inhibits 5-reductase type 1 and type 2. After beginning therapy with 5-reductase inhibitors it is important to remember that within 3 months PSA decreases to approximately half the value prior to starting therapy. This is important for PSA monitoring. Clinical effects of 5-reductase inhibitors include decrease in serum DHT, decrease in serum PSA, decreased risk of symptomatic progression of BPH,27 reduction in risk of acute urinary retention, reduction in need for surgery for BPH, decreased risk of prostate cancer,28

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and prevention of gross hematuria secondary to BPH.29 The side effects of 5-reductase inhibitors are decreased libido, impotence, decreased ejaculation volume, ejaculation disorders, breast enlargement, breast tenderness, and generalized rash. Combination Therapy Combination therapy with an alpha-adrenergic blocker as well as a 5-reductase inhibitors has been proven to be more effective than monotherapy in progression of LUTS from BPH.27 Surgical Treatment of BPH There are many techniques for surgery for BPH. Minimallyinvasive endoscopic techniques are the most common. With laser techniques, even patients who require anticoagulation can have the procedure done. For larger prostates, an open procedure may be necessary. Injection of botulinum toxin into the prostate is currently being evaluated in clinical studies. So far, results are promising.30 Even after surgical relief of bladder outlet obstruction from BPH, storage symptoms may persist and can often be treated by an urologist with anticholinergic medication.

Conclusions Anatomic differences in the lower urinary tract in men and women account for differences in rates of infection, obstruction, and incontinence. Physicians who treat urinary problems in men and women should be aware of the impact of gender on lower urinary tract symptoms and pathology.

References   1. Abrams P. New words for old: lower urinary tract symptoms for ‘prostatism’. Br Med J 1994;308:929–930.   2. Wein AJ, Barrett DM. Voiding Function and Dysfunction. Chicago, IL: Year Book Medical; 1988.   3. Wein AJ, Rovner ES. Voiding Function and Dysfunction. New York: McGraw–Hill; 2001.   4. Wein AJ. Classification of neurogenic voiding dysfunction. J Urol 1981;125:605–609.   5. Abrams P, Blaivas JG, Stanton S et al. ICS standardization of terminology of lower urinary tract function. Scand J Urol Nephrol 1988;114:5–19.   6. Abrams P, Blaivas J, Stanton S et al. ICS 6th report on the standardization of terminology of lower urinary tract function. Neurourol Urodyn 1992;11:593–603.   7. Abrams P, Cardozo L, Fall M et al. The standardization of terminology in lower urinary tract function: Report from the standardization subcommittee of the International Continence Society. Neurourol Urodyn 2002;21:167–178.   8. Abrams P, Cardozo L, Fall M et al. The standardization of terminology in lower urinary tract function: Report from the standardization subcommittee of the International Continence Society. Urology 2003;61:37–49.

  9. Resnick NM. Voiding Dysfunction in the Elderly. New York: Macmillan; 1988. 10. DeLancey JO. The pathophysiology of stress urinary incontinence in women and its implications for surgical treatment. World J Urol 1997;15:267–274. 11. Milsom I, Abrams P, Cardozo L et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU International 2001;87:760–766. 12. Jaffe WI, Te AE. Overactive bladder in the male patient: epidemiology, etiology, evaluation, and treatment. Curr Urol Rep 2005;6:410–418. 13. Blake-James BT, Rashidian A, Ikeda Y, Emberton M. The role of anticholinergics in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis. BJU International 2007;99:85–96. 14. Groutz A, Blaivas JG, Pies C, Sassone AM. Learned voiding dysfunction (non-neurogenic bladder) among adults. Neurourol Urodyn 2001;20:259–268. 15. Bird ET, Parker BD, Hyun SK, Coffield KS. Caffeine ingestion and lower urinary tract symptoms in healthy volunteers. Neurourol Urodyn 2005;24:611–615. 16. Schaeffer AJ, Schaeffer EM et al. Infections of the urinary tract. In: Wein AJ et al. editors Campbell-Walsh Urology, nineth ed.. Philadelphia, PA: Saunders; 2007. 17. Schappert SM. Ambulatory care visits of physician offices, hospital outpatient departments, and emergency departments: United States. Vital Health Stat 1997;13:1–38. 18. Grossfield JD, Wolf JS, Litwin MS et al. Asymptomatic microscopic hematuria in adults: summary of the AUA best practice recommendations. Am Family Phys 2001;63:1145. 19. Jorgensen JB, Jensen K, Bille-Brahe NE, Morgensen P. Uroflowmetry in asymptomatic elderly males. Br J Urol 1986;58:390–395. 20. Tubaro A et al. Imaging and other investigations. Incon­tinence: 3rd International Consultation on Incontinence, (Edition 2005). Health Publications Ltd, Plymouth, UK, 2005, 707–797. 21. Lose G, Jorgensen L, Thunedborg P. 24-hour home pad weighing test versus 10 hour ward test in the assessment of mild stress incontinence. Acta Obstet Gynecol Scand 1989; 68:211–215. 22. Versi E, Orrego G, Hardy E et al. Evaluation of the home pad test in the investigation of female urinary incontinence. Br J Obstet Gynaecol 1996;103:162–197. 23. Staskin D, Hilton P, Emmanuel A et al. Initial assessment of incontinence. In: Incontinence: 3rd International Consultation on Incontinence, (Edition 2005). Health Publications Ltd, Plymouth, UK, 2005, 485–517. 24. Fantl JA, Newman DK, Colling J et al. Urinary Incontinence in Adults: Acute and Chronic Management, Clinical Practice Guideline No. 2, 1996 Update (AHCPR Publication No. 960682). Rockville, MD: P. H. S. U.S. Department of Health and Human Services; 1996, Agency for Health Care Policy and Research. 25. Payne CK et al. Conservative management of urinary incontinence: behavioral and pelvic floor therapy, urethral and pelvic devices. In: Wein AJ et al. editors Campbell-Walsh Urology, nineth ed.. Philadelphia, PA: Saunders; 2007. 26. McConnell JD. Medical management of benign prostatic hyperplasia with androgen suppression. Prostate 1990;3 (Suppl.):49–59.

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27. McConnell JD, Roehrborn CG, Bautista OM et al. The Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. NEJM 2003;349:2387–2398. 28. Thompson IM, Lucia PM, Goodman MS et al. The influence of finasteride on the development of prostate cancer. NEJM 2003;349:215–224.

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29. Foley SJ, Solomon L, Wedderburn AW et al. A prospective study of the natural history of hematuria associated with benign prostatic hyperplasia and the effect of finasteride. J Urol 2000;163:496–498. 30. Maria G, Brisinda G, Civello IM, Bentivoglio AR, Sganga G, Albanese A. Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study. Urology 2003;62:259–264.

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Aging and the Lower Urogenital System Catherine E. DuBeau Professor of Medicine, University of Massachusetts Medical Center, Departments of Internal Medicine, Family and Community Health, and Obstetrics & Gynecology, Worcester, MA, USA

directly related to aging per se, and therefore are best considered ‘age-associated’: that is, they are more commonly found in older persons but their etiology may be more related to co-morbidity and other factors than aging. Clinically, the prevalence of LUT symptoms in older persons may be underestimated because of patient underreporting due to embarrassment, reticence, or assumption that such symptoms are ‘normal.’ Assessment of symptom severity can be compromised by a person’s acceptance of ‘old age’ (e.g., ‘that’s what happened to my mother and grandmother’). The fact that only half of older persons with LUT symptoms report them as impacting daily life may have more to do with circumstances and psychological factors than symptom severity. Furthermore, it is crucial to differentiate age-related changes and age-associated pathophysiology from both symptoms and function. Observed changes may not impair function or cause symptoms, but can predispose to dysfunction especially when an additional ‘insult’ occurs. Older individuals have decreased physiological reserve, a phenomenon called ‘homeostenosis.’7 Therefore, even a small additional effect can have a major impact on function: e.g., a continent man with an elevated post-voiding residual volume from prostatic obstruction does not become incontinent until an anticholinergic drug impairs his bladder contractility and precipitates urinary retention.

Age cannot wither her, nor custom stale Her infinite variety. William Shakespeare, Antony and Cleopatra

Introduction Persons aged 65 years constitute the fastest growing group in the American population, and the proportion 85 years and older is the fastest growing of all. By 2030, fully 25% of the population will be aged 65,1 with women comprising the majority at a ratio of almost 4:3 among all older adults. By 2004, average life expectancy at age 65 was nearly 19 years.2 Thus, at least one-third to one-half of women’s lives now extend beyond menopause. With age, chronic disease and disability become more prevalent: 37% of older persons have three or more chronic conditions, and over 40% have some limitation in activity.3 Prostate hyperplasia becomes nearly universal in men by the eighth decade,4 and prostate cancer is the most common solid tumor malignancy in older men.5 Therefore, lower urinary tract (LUT) function in older persons reflects not only aging per se, but also co-morbid disease and changes in sex hormones. Women’s focus on the LUT shifts from reproduction to other functions, especially continence and sexual health,6 whereas that of men increasingly turns to prostate disease. The prevalence of LUT symptoms, such as nocturia, vaginal dryness, and urinary incontinence, increase with age, yet this association is not absolute. Age brings with it increased inter-individual variability, making chronological age a poor marker for health status: an 80-year-old may be a nursing home resident with end-stage dementia, or a vibrant, sexually active working woman. Nearly all of the ‘aging’ changes described in this chapter have yet to be proven to be

Principles of Gender-Specific Medicine

Age-related changes in the lower urinary tract The literature on ‘normal’ LUT aging has many confounding problems: many cellular and neurochemical data come from animal studies; morphologic studies use cadavers with unknown parity, co-morbidity, and LUT symptoms; ageeffects are derived from studies of symptomatic persons;

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‘normal’ controls are surgical patients at tertiary centers; and cross-sectional results may be due entirely to timedependent cohort effects, such as change in delivery practices. Even the definition of ‘normal’ can be difficult: is it a person with intact function, without symptoms, without co-morbid disease, or with normal physiologic testing?8 The following sections focus on findings from the more robust (and where possible, confirmatory) studies, with caveats noted where this is not possible.

Vagina and Vulva The prevalence of age-related changes in the vagina varies with hormonal status, coexistent vascular disease, and the continuation or lack of sexual activity.9 The postmenopausal decrease in estrogen plays a part in many age-associated vaginal changes. Estrogen is trophic for much of the LUT track in women, with estrogen receptors found in the vagina, vestibule, distal urethra, bladder trigone, pelvic muscles, and ligamentum rotundum.10 Yet, as the Women’s Health Initiative trial has shown,11 one cannot assume that the association between low estrogen levels and physiological changes implies that hormone replacement will reverse these changes, restore function, or reduce symptoms. Moreover, the data are equivocal on whether and how LUT estrogen receptors change in number, density, or function in older women.12 Following menopause, the superficial and intermediate layers of the vaginal epithelium thin and may disappear. Mucosal thinning may be associated with inflammation, evident as erythema, telangiectasia, petechiae, friability, and erosions, and may be responsible for urgency and frequency in some elderly women. In addition, there is loss

of epithelial glycogen and lubrication, and mucosal pH increases from 4.5–5.5 to 7.0–7.4.12 These changes can lead to loss of normal adherent lactobacillus flora, colonization with pathogenic organisms such as Escherichia coli and enterococci, and increase in bacteriuria and recurrent symptomatic urinary tract infections (UTIs).13 Mucosal integrity and submucosal fullness also depend on vaginal blood flow, which decreases with age.14 Whether this is estrogen-related and/or due to concomitant vascular disease is unknown. Collagen and lipofuscin deposition in the stroma increases, and may be accompanied by invasion by lymphocytes and plasma cells.12 The combined epithelial and stromal changes are associated with vaginal wall thinning and flattening of rugae.10 The vaginal vault may shorten and narrow, but this may not be clinically relevant: in one case series of more than 3000 women attending a general clinic, total vaginal length decreased by only 0.08 cm over 10-year periods.15 The introital opening may decrease (and in severe cases become stenotic), making intercourse and vaginal examination difficult. Vaginal shape also may be altered by pelvic organ prolapse. Sexually active women may develop the same sexually transmitted infections as younger women. Older women also are prone to a number of chronic vulvar diseases (Table 40.1).16 The question whether vulvovaginal symptoms are truly age-related is complicated by under-reporting, an increased acceptance of symptoms, and lack of sex partners.9 Furthermore, one should not assume a causal relationship between the presence of urogenital atrophy and existence of urogenital symptoms, or between symptoms and quality of life. Not all older women have atrophic vaginal mucosa, and symptoms such as dyspareunia have a wide differential diagnosis beyond urogenital atrophy that should be evaluated

Table 40.1  Vulvar conditions in older women Condition

Description

General treatment*

Dermatitis

Erythema

Eczema Infectious vulvitis Lichen simplex chronicus

Erythema, often with scaling Typical candidal rash Pruritic, symmetric, leathery or coarse areas with variable pigmentation Depigmentation with submucosal hemorrhage, reduced tissue elasticity involving vulva, introitus and perianal areas. Small but definite association with vulvar carcinoma Oral and genital lesions. Erosive type: erosive lesions extending into vagina. Classic type: cutaneous violaceous demarcated plaques Typical pink psoriatic plaques Variable appearance Variable appearance Pruritic, scaly deep red demarcated plaques

Determine irritant or allergen; topical low- to mid-potency steroids Topical mid- to high-potency steroids Antifungal agents Topical mid- to high-potency steroids

Lichen sclerosus

Lichen planus

Psoriasis Squamous cell carcinoma Intraepithelial neoplasia Paget’s disease

Data adapted from Foster, 200216 * see this reference also for additional treatment approaches.

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Topical mid- to high-potency steroid (clobetasol) Topical mid- to high-potency steroid

Topical mid- to high-potency steroid Wide excision Wide excision Excision

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before instituting treatment. Moreover, very few randomized trials of estrogen for urogenital symptoms include women over age 75, use patient-defined outcomes in addition to physiological measures, or evaluate quality of life outcomes.17 There is insufficient data to provide an evidence-based approach to symptomatic urogenital atrophy in older women. Expert opinion does suggest that if estrogen treatment is tried, it should be limited to topical formulations (which now include cream, intravaginal tablets, and an estrogen-impregnated, pessary-like ring).

Bladder Studies of age-related changes in the bladder function often lack longitudinal data, use variable definitions of ‘normal,’ and employ potentially biased (and symptomatic) referral populations. It is difficult to differentiate between the effects of poor voiding habits, co-morbidity and vascular disease, alterations in central and peripheral nervous system function, and reflex patterns on bladder function in older persons.18 The majority of the research focuses on detrusor smooth muscle, including its innervation, urodynamic function (physiologic measurement of bladder and urethral function during filling and voiding), neurohumoral responsiveness, and ultrastructure. Despite the increasing evidence of the key role of the urothelium and afferent systems in normal voiding and incontinence, very little is known about urothelial changes with age. There are two major physiologic changes in bladder function with age found on urodynamic testing: an increased prevalence of detrusor overactivity (DO) (uninhibited bladder contractions)19 and decreased detrusor (bladder smooth muscle) contraction strength.20 DO may be idiopathic, agerelated, secondary to lesions in cerebral and spinal inhibitory pathways, or due to bladder outlet obstruction. Recent evidence suggests that increased afferent signaling from the detrusor may also contribute to urgency, DO, and urge urinary incontinence (UI). Factors that may underlie decreased contractility include: increased fibrosis around detrusor smooth muscle fascicles,21 separation of submuscosal collagen fibrils that encroach on neurovascular bundles and accumulation of extracellular matrix particles,22 and vascular disease with concomitant ischemic-reperfusion injury resulting in patchy denervation.23 Possible causes include detrusor smooth muscle damage (e.g., from ische­ mia, scarring, fibrosis), peripheral neuropathy (diabetes mellitus, vitamin B12 deficiency, alcoholism), or damage to the sacral cord and spinal bladder efferents by disc herniation, spinal stenosis, tumor, or degenerative neurologic disease. Neurological diseases affecting the sacral spinal cord can cause detrusor underactivity and/or neurally mediated obstruction, depending on the exact level and extent of damage. DO and decreased contractility partially explain the age-associated decrease in maximum urine flow rate, voided volume, and bladder capacity, and increase in

postvoiding residual volume (PVR) (up to 50 ml is considered normal in older persons); other factors may be at least as important.24 In one case series of older, continent, community-dwelling women, DO was present in 42%, and one-third of patients with DO were totally free of voiding symptoms.8 Notably, completely normal urodynamic studies were found in only 18%. Even in older men with prostatic hypertrophy, increases in PVR more likely reflect decreased bladder contractility than obstructed voiding.25 Frail older persons may have a combination of DO and significant decrease in contractility, a condition termed detrusor hyperactivity with impaired contractility (DHIC).20,26 In these patients, the bladder contraction does not empty the bladder fully, leaving a large PVR otherwise not explained by any bladder outlet obstruction. DHIC symptoms include leakage with urgency and increased abdominal pressure, dribbling, frequency, and nocturia – similar to other LUT conditions such as stress incontinence and obstruction, for both of which DHIC may be mistaken. Ultrastructural studies of bladder biopsies from symptomatic and asymptomatic older persons demonstrate specific patterns that correlate with functional urodynamic observations: Healthy older persons without LUT symptoms and no urodynamic evidence of DO have ‘dense band’ pattern in the sarcolemma of the detrusor smooth muscle, with depleted caveolae and slight widening of intracellular spaces, and overall little collagen content.22 Older persons with DO have an additional ‘dysjunction pattern’ with moderately widened intercellular spaces, scarce intermediate muscle cell junctions, and ‘protrusion’ junctions with ultra-close cell abutments that may facilitate propagation of nerve signals.21 Urodynamically defined decreased contractility is associated with widespread degeneration of smooth muscle and axons.22 Persons with DHIC have both degeneration and the dysjunction pattern seen with DO. Bladder outlet obstruction is associated with smooth muscle cell hypertrophy, with wide separation of individual muscle cells by collagen and depleted intermediate cell junctions.27 Reduction in intrinsic innervation also has been observed in men with obstruction,28 including evidence of re-innervation after relief of obstruction by prostatectomy.29

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The concordance between urodynamic function and ultrastructural changes appears to remain constant over time, even as urodynamic function changes.30

Urethra Due to their common embryological origin, the urethra has similar mucosal and stromal age-related changes as the vagina, and urethral changes in women can be partially

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inferred from examination of vaginal tissue. Because of the difficulty of obtaining non-cadaveric urethral tissue, the data on urethral smooth and striated muscle changes with age may be confounded by parity, co-morbidity, and definitions of controls. The major age-associated change in urethral function is a decrease in closure pressure (pressure in the urethra when it closes at the end of voiding).19,31,32 Several anatomical and physiologic changes likely account for this decline. Mucosal thinning and lack of proteoglycans reduce urethral wall apposition, and may contribute to retrograde movement of perineal bacteria into the bladder causing urinary tract infections. These mucosal changes may extend up to the bladder trigone, causing irritation of sensory afferent nerves, and possibly triggering DO. Other alterations in the urethral stroma are increased volume of connective tissue, decreased ratio of proteoglycans to collagen, and decrease in nerve density.33,34 The volume, consistency, and vascularity of the submucosa add to resting urethral compression. With age, the submuscosal venous plexus in the proximal urethra loses its corkscrew shape, the number and volume of arterial vessels decrease, and vascular pulsations lessen. Several studies, using different measurement techniques, have shown that urethral vascular density and blood flow, but not vascular flow velocity, decrease with age.14,35,36 However, in one study age explained only 9% of the variability in vascular density,14 and no study controlled for vascular risk factors, e.g., hypertension and diabetes. The relative importance of decreased vascular volume versus hypoxia on urethral functional integrity is unclear. Urethral sensation, measured as current perception thresholds, increases with age in women with37 and without urge UI.38 Whether an age-related LUT sensory neuropathy actually contributes to a higher prevalence of urgency and urge UI is uncertain, as sensation thresholds were higher in women with urge UI regardless of age and parity.37 Cadaver studies have shown that the number and density of urethral striated muscle fibers decreases with age by approximately 1% per year, especially in the ventral wall of the proximal urethra.39,40 However, there is large inter-individual variation only partially explained by differences in age and parity, suggesting that yet-defined factors play an important role. Circular smooth muscle fiber counts and muscle width are lower in older compared with younger women.41 Crosssectional striated muscle fiber area decreases as well, with fiber diameter is preserved.39,40 Loss of striated muscle in the anterior urethra in older women correlates with circular smooth muscle loss.41 Although it is logical to assume age, parity, and hormonal status affect urethral smooth muscle contractility, this has not been well investigated.23 With age, the urethral meatus generally moves toward the vaginal introitus, and may be difficult to see if there is considerable introital stenosis. Caruncles – benign violaceous soft nodules – often appear at the meatus, and are not problematic unless they cause discomfort or obstruction.

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Urethral diverticula can be a diagnostic challenge, especially in older women, because the symptoms (pain, UI, frequency, urgency, dyspareunia) may be attributed to postmenopausal changes, age, urgency, or urge UI.42 Diverticula should be considered in women with LUT symptoms who have repeatedly failed usual treatment. Diagnosis requires voiding cystourethrography or imaging by ultrasound or magnetic resonance scan. Urethral obstruction is relatively uncommon in older women, and is nearly always secondary to other LUT dysfunction (e.g., pelvic organ prolapse) or is iatrogenic (from LUT/pelvic surgery or radiation). In men, age-related decrease in striated sphincter muscle cell density occurs as well,43,44 and has been associated with increased muscle cell apoptosis.43 While some investigations describe an increase in resting prostatic urethral pressure with age,45 others note the increase occurs only to the sixth decade then subsequently decreases, along with a shortening of sphincteric urethral length.46 These discrepancies may reflect differences in prostate volume and morphology. The major urethral change in older men is obstruction from prostatic enlargement (either benign or malignant).

Pelvic Floor Pelvic floor changes in normal older men have not been well studied. In women, the effect of age on pelvic floor structure and function is difficult to differentiate from the effects of hormonal status and parity. A number of studies are cross-sectional rather than longitudinal, and focus on symptomatic women. For example, a questionnaire study of over 4000 community women aged 25–84 found no association between age and stress UI (SUI), OAB, or anal UI, after adjustment for obesity, birth history, menopause, and hormone use.47 Similarly, in a random sample of 343 Austrian women aged 18–79 years, impaired pelvic muscle contraction (graded by the Modified Oxford Scale) was weakly associated with parity and body mass index but not age.48 Evidence of denervation and changes in pelvic striated muscle fiber number, type, and diameter have been found in asymptomatic and nulliparous women. For example, in a sample of 82 nulliparous women, neither levator function (measured by resting vaginal closure force and augmentation of vaginal closure force) nor pelvic organ support (on pelvic exam) showed an association with age.49 A histomorphometric study, using levator ani muscle from 94 female cadavers (ages 15–58), 10 male cadavers (aged 23–35), and 24 women undergoing pelvic surgery, found that myogenic cell damage was associated with both parity and age (/ age 35), but there was no difference between nulliparous women, men, and women with POP and/or UI.50 Total collagen content in pelvic muscle and fascia declines with age, with increased cross-linking and decreased elasticity,51 but this association does not imply a direct causative effect of ‘ageing.’ Constipation

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may independently contribute to pelvic floor dysfunction in older women.52

Prostate Benign prostate hyperplasia (BPH) and associated hypertrophy and enlargement are strongly age-related, with concomitant impact on LUT function and symptoms. Although a complete discussion of prostate disease is beyond the scope of this chapter, several points are germane. While many LUT changes in women are associated with lower estrogen levels, BPH results from the development of an estrogen-predominant hormonal milieu in the prostate. The trophic androgen in the prostate is dihydrotesterone (DHT), formed by the 5- reduction of testosterone. Testosterone and DHT levels decrease with age, while estradiol (E2) concentrations increase in the prostate stroma and remain constant in epithelial tissues. The resultant increase in the E2/DHT ratio53,54 promotes stromal proliferation. Epithelial hyperplasia in turn is mediated by an array of stromal factors. Histological BPH occurs in nearly 80% of men by age 80. Mean prostate volume increases with age but is very variable; its strongest predictor is prostate-specific antigen (PSA) levels 1.4–2 ng/ml.55 LUTS in men increase linearly over time, with the fastest rate during the seventh decade, such that by age 80 approximately one-third of men have received treatment for moderate to severe LUTS.56 Natural history studies and randomized intervention trials, however, consistently demonstrate that symptomatic progression of benign prostate disease is not inevitable. LUTS remits in about one-third of symptomatic men without treatment.56 Prostate enlargement is associated not only with bladder outlet obstruction (BOO), but approximately one-third of affected men develop DO.57 Thus, even in the presence of demonstrable prostate enlargement, the etiology of LUTS is multifactorial, making BPH- and BOO-related LUTS a diagnosis of exclusion. It is not certain whether prostatic inflammation, either acute or chronic, contributes to urinary retention and LUTS in older men. In a single institution case series of 374 men undergoing prostatectomy for acute urinary retention (AUR) or LUTS, pathological evidence of acute inflammation was significantly more common in men presenting with AUR than with LUTS (70% vs. 45%).58 However, in a much smaller case series of 70 men presenting with AUR, there was no association between inflammation from prostate infarction and AUR.59

Urinary tract infections Urinary tract infections (UTIs) are extremely common in older persons, especially women. In younger persons, UTI

prevalence is greater in women than men by a factor of 40, yet the ratio progressively equalizes with age, starting in the seventh decade.60,61 UTIs are especially common in institutionalized frail elderly persons. Factors predisposing to UTIs in older women are urethral mucosal atrophy, high vaginal pH, altered immune function, cystocele, fecal incontinence, and diabetes mellitus;13 women with UI or previous UTI are more likely to have recurrent UTIs.62 Also, the prevalence of bacteriuria in women increases with age, from 10–15% in middle-aged women to 15–20% in those aged 80.13 Additional risk factors in both men and women are indwelling catheter, PVR 100 ml, renal insufficiency, and structural LUT abnormalities (e.g., vesicourethral reflux).13 In frail older persons, additional risk factors are poor perineal hygiene, cognitive impairment, and lack of caretakers. The diagnosis of UTI in older persons, especially the frail, is not straightforward. First, in older women there is the high prevalence of asymptomatic bacteriuria, which is not associated with either active infection or increased morbidity and mortality. Treatment of asymptomatic bacteriuria does not affect UI.63,64 Second, current consensus criteria for UTI are poorly sensitive and only fairly specific in frail elderly persons. In a prospective cohort of 340 nursing home residents, in which UTI was defined as pyuria (10 white cells) with 100 000 colony forming units on culture, the McGeer, Loeb, and also the revised Loeb UTI criteria had sensitivity of only 19–30% and specificity of 79–89%.65 Dipstick analysis of leukocyte esterase and nitrite can be sensitive but not specific; if both are negative, a UTI can be safely excluded.13 And third, UTI diagnosis should be individualized and clinical, and not based solely on urinalysis and culture. UTI symptoms may be subtle and nonspecific in frailer older persons, and include new or worsening of UI, altered mental status in persons with dementia, decreased oral intake, and a decline in functional ability.13 Some authors emphasize that UTI diagnosis requires additional symptoms such as dysuria, pain, new/worsening UI, hematuria, suprapubic discomfort, and costovertebral angle tenderness, with or without fever.13 Given the nonspecific presentation of illness in frail (and especially cognitively impaired) older persons, there has been a tendency to initiate antibiotics when bacteriuria is found in patients with delirium, anorexia, and malaise. However, such assumptions easily lead to over-diagnosis and over-treatment,13 and to antibiotic resistance (already present in10–40% of community-dwelling and institutionalized older persons52). Antibiotic treatment of UTI should be guided by local resistance patterns, and empiric therapy should be followed by a change to a less broad-spectrum agent, if possible, as soon as culture and sensitivity results become available. Treatment of catheter-related UTIs require replacement of the existing catheter; for full discussion, see the 2008 updated guidelines.66

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The association between UTIs and postmenopausal changes in vaginal and urethral mucosa suggests that estrogen could be used to treat recurrent UTIs. Trial results, however, have been equivocal. A meta-analysis of five randomized trials17 found an overall benefit to estrogen, yet: the total number of patients included was small (334, with 169 on estrogen); the types, doses, and route of administration of the estrogen preparations varied widely; and one of the two positive studies had an extremely wide confidence interval. Another treatment for recurrent UTIs in institutionalized women is cranberry juice (300 ml/day), which in one randomized trial decreased bacteriuria by 42% (95% CI, 0.23–0.76), with effects noticeable by two months.67

Urinary incontinence in older persons Epidemiology The prevalence of UI increases with age. Moderate to severe UI (at least weekly leakage or monthly leakage of more than just drops) affects 7% of women aged 20–39, 17% aged 40–59, 23% aged 60–79, and 32% aged 80 years.68 The prevalence in men is approximately one-third that of women, until it equalizes in the ninth decade.69 UI affects 17–21% of men aged 60, of whom 42% report daily UI.70 Nursing home residents have very high rates of UI, ranging from 60–78% in women and 45–72% in men.71 Several studies have found lower rates of total and stress UI in black compared with non-Hispanic white women,69 but not all.72 Prevalence and type of UI does not appear to vary by race or ethnicity in men. The primary impact of UI is on quality of life, including work, relationships, sexuality, and self-esteem. The economic cost of UI continues to rise; from 1992 to 1998, costs among older women alone increased from $128 million to $234 million, primarily due to the larger number of women treated.70 UI significantly adds to the care-giving costs for the frail elderly, amounting to an estimated $6 billion annually.73

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Risk factors for UI in older persons include impaired mobility, falls, medications, depression, transient ischemic attacks and stroke, dementia, congestive heart failure, fecal incontinence and constipation, and obesity.74 Not all persons with a co-morbid condition or taking a medication that is associated with UI will develop UI, and the presence of such factors in an individual person with UI does not imply that they are causative. Although an important UI risk factor in younger women, childbirth is not associated with UI in older women.

Types of Incontinence UI nomenclature can be confusing, especially when the same terms are used to describe symptoms, signs, and pathophysiological (urodynamic) abnormalities which in fact do not have a consistent one-to-one correspondence.75 Some general associations between symptoms and pathophysiology are possible: Urge UI is the symptom of leakage associated with compelling, often sudden, urgency to void. Urge UI is usually associated with DO. As noted above, up to 40% of continent healthy older adults have DO on urodynamic testing, suggesting that urge UI requires not just DO but impaired compensatory mechanisms (e.g., central nervous system control) as well. Overactive bladder, with symptoms of urgency, frequency, and nocturia, may or may not have associated UI. Stress UI is the symptom of leakage associated with an increase in intra-abdominal pressure. It is caused by either impaired urethral support or urethral damage, as may occur with surgical scarring, radical prostatectomy, and some spinal cord injuries. DO may cause apparent ‘stress’ UI, when a cough triggers an uninhibited contraction: in such cases leakage usually occurs after and not coincident with the cough, is large volume, and difficult to stop. Mixed UI is the symptom of leakage with features of both urge and stress UI, and is most common in middle-aged women. Either urge or stress UI symptoms may predominate. UI with impaired bladder emptying is leakage associated with an elevated PVR, either due to bladder outlet obstruction, decreased detrusor contractility, or both. The most common cause of obstruction in men is prostate disease, and in women the causes include urethral scarring or marked pelvic floor prolapse with a large cystocele that kinks the urethra.

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Etiology Whereas UI in younger persons is overwhelmingly due to alteration in the LUT and its innervation, in older persons UI represents a geriatric syndrome with broadly based, patient-level risk factors that include age-related changes in physiology, co-morbidity, medications, and especially functional impairments. In younger persons UI primarily impacts quality of life, whereas in older persons UI can cause significant morbidity (such as falls and fractures) and functional impairment, and lead to caregiver stress and institutionalization. Therefore, the assessment UI in older persons requires a broader medical and functional scope, and management usually must be multicomponent.

Persons with UI usually have several other lower urinary tract symptoms (LUTS), including: frequency (patient perception of frequent voiding and/or documentation of 6–7 daytime voids); nocturia (need to wake 2 times during the night to void); slow stream (complaint of reduced urine flow); intermittent stream (urine flow which stops and starts during voiding); hesitancy (difficulty in initiating voiding);

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straining (effort to either initiate, maintain or improve urine flow); and sense of incomplete bladder emptying. These LUTS lack specificity, especially frequency (which can reflect increased fluid intake and/or increased diuresis from many causes) and nocturia (which may be due to a primary sleep disturbance [e.g., sleep apnea] or nocturnal polyuria [from pedal edema and its many causes, congestive heart failure, evening fluids]). Estimates of the prevalence of the different types of UI in older women vary widely, predominantly due to different epidemiological questionnaires. Prevalence of urge UI ranges from 10–33%, stress 29–38%, and mixed 29–61%.76 In general, over age 65 urge UI increases, stress UI decreases, mixed UI remains stable, and UI due to impaired emptying (so-called ‘overflow UI’) is rare, even among frailer older persons.77 Urge UI is the most common type in older men, but the prevalence of stress UI is increasing, largely due to radical prostatectomy for prostate cancer.

Evaluation For older persons, the evaluation of UI should be multifactorial, focusing on co-morbidity, function, and medications as potential etiologic or contributing factors (see Tables 40.2 and 40.3). Overall, a systematic assessment including history, physical examination, and bedside tests has moderate value in diagnosing stress UI (positive likelihood ratio 3.7 [95% CI, 2.6–5.2], negative likelihood ratio 0.20 [95% CI, 0.08]) but is less helpful in the diagnosis of urge UI (positive likelihood ratio 2.2 [95% CI, 0.55–8.7], negative likelihood ratio 0.63 [95% CI, 0.34–1.17]).78 The important first step is active screening for UI, because 50% of affected persons do not volunteer their symptoms to a provider. A typical question is, ‘Have you had any problems with bladder or urine control?’ If the patient answers no, this should be followed with, ‘Do you ever leak urine when you don’t want to?’ Next questions should determine the type of UI by asking, ‘Do you lose urine during coughing, sneezing, or lifting (stress UI)?’ and ‘Do you experience such a strong and sudden urge to urinate that you leak before reaching the toilet (urge UI)?’79 In women, such simple questions are most helpful to diagnose urge UI and, slightly less so, stress UI.78 However, if a woman denies stress leakage, it is highly unlikely that she has physiological stress UI. The history should include UI onset, frequency, volume, timing, and associated factors or events (e.g., timing and type fluid intake, recent changes in medications or co-morbid conditions). UI may be the herald symptom of serious underlying disease. ‘Red flag’ symptoms of possible neurological or malignant disease are abrupt onset of UI, pelvic pain, and hematuria. Review of systems should include fecal incontinence, which is common in older persons with UI. Patients (and, where appropriate, caregivers) should be asked about UI-associated bother and quality of life impact,

starting with simple questions (e.g., ‘What bothers you most about your leakage?’, ‘How does leakage affect your life?’), followed by more specific probes, as appropriate, regarding activities of daily living, social role, emotional and interpersonal relations, sexual function and relations, self-concept, general health perception, and financial burden. In older persons with UI, the physical examination should focus on co-morbidity associated with UI, and include cognition and functional status (if not recently assessed). Abdominal palpation is neither sensitive nor specific for bladder distention. The rectal exam assesses masses, tone (rest and volitional, tightening around examiner’s finger), and prostate nodules or firmness in men (prostate sizing by digital examination is inaccurate). The neurologic evaluation should include evaluation of sacral cord integrity with perineal sensation, anal ‘wink’ (anal sphincter contraction when the perirectal skin is lightly scratched), and bulbocavernosus reflex (anal sphincter contraction when either the clitoris or glans is lightly touched). Vaginal mucosa should be evaluated for atrophy. The pelvic exam should include evaluation for pelvic organ prolapse (cystocele, rectocele, uterine prolapse) with straining and standing. Uncircumcised men should be checked for phimosis, paraphimosis, and balanitis.

Additional Testing Urinalysis is recommended for all patients to look for hematuria (and glycosuria in diabetics). Pyuria and/or bacteriuria likely represents asymptomatic bacteriuria – not cystitis – in women without dysuria, fever, or other signs of UTI, especially if UI is not acute (see Urinary Tract Infections above). Although previous guidelines recommended PVR testing in all older persons with UI, the supporting evidence was only expert opinion. More recent guidelines make PVR optional even for older men with LUTS and known/suspected prostate disease.80 Although frail elderly persons may have a higher prevalence of elevated PVR, especially in association with DHIC,81 it is not clear that knowing the PVR would always alter management. Therefore, a more prudent approach is to limit PVR testing to targeted patients with either diabetes, previous urinary retention or elevated PVR, recurrent UTIs, severe constipation, complex neurological disease (e.g., Parkinson’s), marked pelvic organ prolapse, prior anti-incontinence surgery (women), medications known to decrease detrusor contractility, or prior urodynamic evaluation demonstrating decreased contractility or outlet obstruction.82 A clinical stress test should be done in patients with stress UI symptoms. To do a stress test, the patient should have a full bladder, stand upright with a relaxed perineum and buttocks, and give a single vigorous cough, with the examiner positioned to observe any leakage that occurs. This test is specific for stress UI if leakage is instantaneous,

Table 40.2  Common medical conditions associated with incontinence Condition

Effect on continence

Neurological disease Cerebrovascular disease; stroke

Parkinson’s disease

Dementia

Delirium Normal pressure hydrocephalus Spinal stenosis Multisystem atrophy Spinal cord injury

Detrusor overactivity from damage to detrusor upper motor neurons Impaired coordination of micturition from interruption of subcortical pathways Impaired functional status and cognition Detrusor instability from loss of substantia nigra inhibitory inputs to pontine micturition center Striated sphincter bradykinesia (controversial) Impaired functional status and cognition Urinary retention and overflow incontinence from constipation Detrusor overactivity from damage to detrusor upper motor neurons Impaired functional status, especially transfers Impaired cognition Impaired functional status and cognition Detrusor overactivity from periventricular compression of frontal inhibitory centers Impaired functional status (gait) and cognition Detrusor overactivity from damage to detrusor upper motor neurons (cervical stenosis), or detrusor overactivity or areflexia (lumbar stenosis) Detrusor and sphincter areflexia from damage to spinal intermediolateral tracts Detrusor overactivity or areflexia, sphincter dyssynergia or areflexia (dependent on level of injury)

Metabolic disease Diabetes mellitus

Hypercalcemia Vitamin B 12 deficiency

Detrusor overactivity Detrusor underactivity due to diabetic neuropathy Osmotic diuresis from hyperglycemia Altered mental status from hyper- or hypoglycemia Urinary retention and overflow incontinence from constipation Osmotic diuresis Altered mental status Impaired bladder sensation and detrusor underactivity from peripheral neuropathy

Infectious disease Tuberculosis Herpes zoster

Neurosyphilis Human immunodeficiency virus

Inanition and functional impairments (note: sterile pyuria found in 50% of genitourinary TB cases) Urinary retention if sacral dermatomes involved Outlet obstruction from viral prostatitis in men Urinary retention and overflow incontinence from constipation Detrusor overactivity or areflexia, sphincter dyssynergia or areflexia (dependent on site of neurological damage). Detrusor overactivity or areflexia, sphincter dyssynergia or areflexia (dependent on site of neurological damage).

Psychiatric disease Alcoholism Psychosis Affective and anxiety disorders

Functional and cognitive impairment Rapid diuresis and urinary retention in acute intoxication Functional and cognitive impairment Decreased motivation Decreased motivation

Cardiovascular disease Congestive heart failure Arteriovascular disease Musculoskeletal disease Pulmonary disease Gastrointestinal disease Adapted from DuBeau, 20073

Nocturnal diuresis. Detrusor underactivity/areflexia from ischemic detrusor ischemia and/or neuropathy In general, mobility impairment Detrusor overactivity from cervical myelopathy in rheumatoid arthritis Exacerbation of stress incontinence by chronic cough Urinary retention and overflow incontinence from constipation

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Table 40.3  Medications that may cause or worsen incontinence Class and examples

Mechanism(s)

Anticholinergics (antipsychotics; tricyclic antidepressants; diphenhydramine) Loop diuretics (furosemide) Antipsychotics (haloperidol, risperidol)

Impaired detrusor contractility, retention, delirium, constipation/fecal impaction

Sedative/hypnotics (lorzepam, alprazolam) Narcotic analgesics Alpha-adrenergic blockers Alpha-adrenergic agonists Calcium-channel blockers ACE inhibitors Alcohol Gabapentin and pregabalin Thiazolidinediones Nonsteroidal anti-inflammatory agents Cholinesterase inhibitors

Rapid diuresis, polyuria, frequency, urgency Anticholinergic actions, sedation, impaired mobility, rigidity, constipation/fecal impaction Sedation, disorientation, delirium, impaired mobility, sleep alteration Impaired detrusor contractility, retention, delirium, constipation/fecal impaction Stress incontinence (women) Urinary retention (men) All: impaired detrusor contractility, retention Nifedipine, amlodipine: nocturnal polyuria from pedal edema Stress incontinence from cough Rapid diuresis, frequency, urgency, sedation, delirium, immobility Nocturnal polyuria from pedal edema Nocturnal polyuria from pedal edema Nocturnal polyuria from pedal edema; may impair detrusor contractility Interference with antimuscarinic agents

Adapted from DuBeau CE. Functional and overflow incontinence. In: Chapple C, Zimmern PE, Brubaker L, Smith ARB, Norton C, Bo K, eds. Multidisciplinary Management of Female Pelvic Floor Disorders. London: Elsevier;2006:65–74

and most sensitive when the patient is upright. It is insensitive if the patient cannot cooperate, is inhibited, or the bladder volume is low.78 Bladder diaries can be helpful to determine whether urine output contributes to frequency, nocturia, and/or timing of UI.83 The diary entails recording the time and volume of all continent voids and UI episodes, typically over three days (see Figure 40.1). Routine urodynamic testing is not necessary, and may be misleading because of the high prevalence of DO in healthy, continent older persons.74 Urodynamics should be done in patients considering invasive treatment, when the etiology of UI is unclear and knowing it would change management (e.g., men with severe urge UI who may have benign prostatic obstruction), or when empiric treatment has failed.74 Renal ultrasound is not required in men, because significant hydronephrosis occurs in only 3 to 10% of men with LUTS, and the association between elevated PVR and hydronephrosis in individual patients is unclear.84 Ultrasound or computerized tomographic scanning should be considered when there is hematuria, recurrent urinary tract infections, previous LUT surgery, or a history of bladder stones. Cystoscopy is neither sensitive nor specific for BOO.80

Treatment Most older persons will have several etiologic factors causing UI, including LUT pathophysiology and co-morbid conditions. Treatment should proceed stepwise, starting with correction of contributory factors and lifestyle modification, then moving on to behavioral interventions, medications,

and then, if necessary and appropriate, minimally invasive procedures and surgery. Not all steps will be needed or appropriate for all patients, and some patients may want to proceed directly to surgery (e.g., women with severe stress UI). Some treatments are effective for several types of UI (see below). Management should focus on relieving the aspect of UI that is most bothersome for the patient; e.g., treatment that only decreases daytime UI episodes may not be sufficient for persons most bothered by nocturia. Lifestyle Modification Weight loss significantly reduces stress UI in obese middle-aged women.85,86 Other lifestyle interventions, which lack confirmatory evidence but may be helpful in individual patients, include: avoiding extremes of fluid intake, caffeinated beverages, and alcohol; minimizing evening intake for nocturia; and smoking cessation (and/or other interventions to reduce coughing) for patients with stress UI. Behavioral Therapy Bladder training and pelvic muscle exercise (PME) are effective for urge, mixed, and stress UI, and are often used in combination.87,88 Bladder training employs two principles: frequent voluntary voiding to keep bladder volume low, and urgency suppression using central nervous system and pelvic mechanisms The initial toileting frequency can be every 2 hours or based on the smallest voiding interval on a bladder diary. When urgency occurs, patients should stand still or sit down, perform several pelvic muscle contractions, and

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Date

Time

10/1

3:50 pm 6:05 8:15 10:20 12:00 2:15 am 3:40 am 5:00 am 6:05 am

90 ml 90 ml 120 ml 150 ml 30 ml 150 ml 120 ml 120 ml 240 ml

Are you Wet or Dry? Dry Dry Dry Dry Dry Dry Dry Dry Dry

8:40 am 12:50 pm 6:00 pm 9:20 pm 11:40 pm 2:00 am 4:50 am 6:20 am

120 ml 120 ml 120 ml 210 ml 120 ml 150 ml 180 ml 180 ml

Dry Dry Dry Dry Dry Dry Dry Dry

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Urine volume

Approximate amount of leakage

441

Comments Daytime output (incomplete) Nocturnal output Almost had accident Coffee

Daytime output

Dribbled on way Nocturnal output

Bladder diary of an older woman with nocturia 4–5 times a night, occasional urge incontinence (less than daily), and frequency (‘every 2 or 3 hours’). The diary shows that she does not in fact have the reported daytime frequency, and that her functional bladder capacity (usual voided volume) is about 240 ml. Her nocturnal urine output (shaded areas, including all voids from bedtime up to and including first morning void) is 630–660 ml, or just over 50% of her total 24 hr output on 10/2 (630 ml nighttime ÷ [630 ml nighttime + 570 ml daytime]). This amount of nocturnal polyuria must result in at least two episodes of nocturia (630 ml ÷ 240 ml). Thus, despite the presence of daytime urgency and rare urge incontinence, the cause of her nocturia is likely nocturnal polyuria. Evaluation and treatment should focus on potentially reversible causes of nocturnal polyuria, such as peripheral edema and sleep apnea.

Figure 40.1  Using a bladder diary.

concentrate on making the urgency decrease (e.g., by taking a deep breath and letting it out slowly, or visualizing the urgency as a wave that peaks and then falls). Once patients feel more in control, they should walk to a bathroom and void. After 2 days without leakage, the time between scheduled voids can be increased by 30–60 minutes, until the person is dry when voiding every 4 hours. Successful bladder training usually takes several weeks, and patients need reassurance to proceed despite any initial failure. PME are effective for urge, mixed, and stress UI.87 PME are also effective for prevention and treatment of postprostatectomy UI.89 PME require patient instruction and motivation, although simple instruction booklets alone have moderate benefit (PME handouts are available through the advocacy organizations listed at chapter end). Cure rates are significantly higher than no treatment (RR 7.25, 95% CI 1.99–26.49);90 the marginal benefit of adding biofeedback is uncertain, yet many experts feel that it is useful for teaching.91 Medicare covers biofeedback for patients who do not improve after 4 weeks of conventional instruction. To do PME, the patient performs an isolated pelvic muscle contraction, without contracting buttocks, abdomen, or thighs (this can be checked during a bimanual exam in women), holds it for 6 to 8 seconds (only shorter durations may be initially possible), and then relaxes. The contractions are repeated 8 to 12 times (one set), and the patient should begin with three sets of contractions done 3 to 4 times

a week, continuing for at least 15–20 weeks.91 Over time, patients should try to increase the intensity and duration of the contraction, perform PME in various positions (sitting, standing, walking), and alternate fast and slower contractions. The only behavioral treatment with proven efficacy in cognitively impaired patients is prompted voiding.92 A caretaker monitors the patient and encourages them to report any need to void; prompts the patient to toilet on a regular schedule during the day (usually every 2–3 hours) and leads them to the bathroom; and praises them with positive feedback when they toilet. Persons most likely to improve leak 4 times during the day (12 hours) and toilet correctly at least 75% of the time with an initial trial 3-day trial.93 Toileting routines without prompting, such as habit training (based on a patient’s usual voiding schedule) and scheduled voiding (using a set schedule) are not effective.94 Watchful waiting is appropriate for men with BPOrelated LUTS who have mild to moderate symptoms, are comfortable with this approach, and can be followed reliably.80 They should be followed at least yearly to monitor symptoms and (if appropriate) PVR and PSA level. They should be counseled to avoid medications that may precipitate urinary retention (e.g., over-the-counter ‘cold’ tablets containing alpha-agonists and antihistamines), and monitored carefully if prescribed anticholinergic or calciumchannel blocking drugs.

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Pharmacological Therapy Drug therapy of UI is largely limited to antimuscarinic agents for urge UI, urgency, and mixed UI. Oral estrogen, with or without progestins, is ineffective for either stress or urge UI.95 The norepinephrine- and serotonin-reuptake inhibitor duloxetine significantly reduces stress UI,87 but its use can be limited by initial nausea and it is not FDAapproved for this indication. Alpha-agonists (e.g., phenylpropanolamine), which facilitate sphincter contraction via urethral smooth muscle alpha receptors, are no longer available, and tricyclic antidepressants such as amitriptyline lack robust evidence and are limited by marked anticholinergic effects. Other agents (e.g., propantheline, dicyclomine, imipramine, etc.) have scant or poor evidence of efficacy, and there is good evidence that flavoxate is ineffective.74 Desmopressin (DDAVP) should not be used for nocturia in older persons because of the risk of hyponatremia.96 Alphablockers and 5-reductase inhibitors used to treat men with LUTS from prostatic obstruction are less effective in reducing UI or urgency (see below). Antimuscarinics used for UI target detrusor muscarinic M2 and M3 receptors, acting primarily by increasing bladder capacity. Although their site of action was thought to be detrusor smooth muscle (and possibly presynaptic efferent neurons) during contraction, there is growing evidence that their primary action occurs at M2 and M3 receptors in the urothelium and interstitial cells during bladder filling.97 This may explain why, despite the age-related decrease in detrusor contractility, antimuscarinics do not appear to be less effective or more likely to cause urinary retention in older persons. Antimuscarinics with robust evidence-based efficacy98 are: oxybutynin (immediate-release, 2.5–5 mg two to four times daily; extended-release 5–20 mg once daily; topical patch 3.9 mg applied to abdomen, thighs, or buttocks twice weekly); tolterodine (immediate-release 1–2 mg twice daily, extended-release 2–4 mg once daily); trospium 20 mg once or twice daily, or extended-release 60 mg once daily; darifenacin 7.5–15 mg once daily; and solifenacin 5–10 mg once daily. Fesoterodine (4–8 mg once daily), a prodrug that is metabolized to tolterodine by non-specific esterases, received FDA approval in late 2008. They all have similar efficacy in reducing UI, but differ in adverse events, metabolism, drug interactions, and dosing requirements.74,98 In general, they result in continence rates of approximately 30% (pooled risk difference, 0.18 [95% CI, 0.13–0.22]),87 and reduce UI by an average of half an episode or more per day over placebo.87,98 Common adverse effects include dry mouth, constipation, and blurry vision. Dry mouth is the most common adverse effect (RR 2.56, 95% CI 2.24–2.92),99 and is not just bothersome but it increases the risk of caries and tooth loss; patients on chronic antimuscarinics should have regular dental care. Constipation appears to be more prevalent with solifenacin and especially darifenacin, compared to the other agents.

Combining antimuscarinics with behavioral therapy is more effective than either approach alone,100 especially for quality of life outcomes.101 Antimuscarinics are safe in men with urgency and urge UI associated with prostatic obstruction, especially when combined with alpha-blockers.102 Cognitive impairment is a potential adverse effect of antimuscarinics especially in frailer older persons, but its risk, incidence, type, and magnitude with specific UI antimuscarinics is unknown. Evidence for cognitive effects came largely from case reports and prescription-event monitoring.103 Several prospective trials have not shown large effects. A 3-week study in 49 cognitively intact older persons compared titrated doses of darifenacin, extended-release oxybutynin, and placebo, using an extensive computerbased cognitive battery.104 Oxybutynin but not darifenacin or placebo adversely affected the primary endpoint, delayed recall on the Name–Face Association test. However, oxybutynin was titrated one week earlier than darifenacin, and to a final dose (20 mg daily) much higher than is commonly used in clinical practice. Also, there were no differences between the two drugs and placebo for many other domains of the cognitive battery. A randomized trial of extended-release oxybutynin 5 mg daily found no evidence of increased delirium among incontinent nursing home residents with dementia.105 Concomitant use of antimuscarinics with cholinesterase inhibitors (used to treat dementia) is another concern. In a case series of 216 patients with probable Alzheimer’s disease attending a memory treatment center, cholinesterase inhibitors were associated with a 7% risk of new UI.106 Nursing home residents with dementia newly treated with cholinesterase inhibitors were subsequently more likely to be prescribed an antimuscarinic for UI.107 Concomitant use of these agents in nursing home residents was associated with a decline in ADL function but not worsening cognition, possibly because the cognitive measure was inadequately sensitive.108 Choice of a specific antimuscarinic for a particular patient should depend on potential adverse effects to be avoided, possible drug–drug and drug–disease interactions, dosing frequency, titration range, and cost (see Figure 40.2). A lack of response to one agent does not preclude response to another. Minimally Invasive Procedures Pessaries may benefit women with stress and urge UI exacerbated or caused by pelvic organ prolapse.109 There is increasing evidence that intravesical injection of botulinum toxin is effective for urge UI refractory to drug treatment. Botulinum toxin, however, is not FDA approved for UI, and patients must be willing to do self-catheterization because of the risk of urinary retention.110 Another alternative for patients with refractory urge UI is sacral nerve neuromodulation.111 The procedure involves percutaneous implantation

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• • • • • •

Cost Dose size and escalation Dosing frequency Timing with other meds Drug-drug interactions Drug-disease interactions

443

Dry mouth (oral oxybutynin worst) Constipation (darifenacin, solifenacin, oxybutynin worse than tolterodine) Cognition (no agent clearly superior/worse than others)

No Differences

Efficacy

Tolerability Adverse effects

Figure 40.2  Individualizing antimuscarinic therapy Reproduced from DuBeau CE. Therapeutic/pharmacologic approaches to urinary incontinence in older adults. Clin Pharm Ther, 85(1):101; advance publication on line, www.nature.com/doifinder/10.1038/clpt.2008.230.

of a trial electrode at the S3 sacral root, which is connected to an external stimulator. Permanent lead implantation is done in patients who respond to an initial trial, at which time a pacemaker-like energy source is implanted under the skin. The mechanism of action is unknown, especially as this treatment also can be effective for idiopathic and neurogenic urinary retention. Surgery Surgery provides the highest cure rates for stress UI in women. The most commonly used procedures are colposuspension (Burch operation) and suburethral slings (synthetic tape or mesh, or autologous or cadaveric fascia). A recent randomized controlled trial found that fascial slings had better subjective outcomes but more morbidity than the Burch procedure.112 Complication rates for slings can be as high as 10%.105 There are few data to assist in procedure and patient selection for older women, especially if they have mixed UI, detrusor underactivity, significant comorbidity, or have failed prior anti-incontinence surgery. Periurethral injection of collagen is a short-term (1 year) alternative, and usually requires a series of injections.87 Surgery for urge UI (for example, augmentation cystoplasty) is reserved for intractable severe cases, usually in younger patients with neurological disease. Early short-term, small single-center reports suggest a possible role for suburethral slings in men with persistent post-prostatectomy UI,113 although others argue that artificial sphincters are preferable.114 Artificial sphincters involve an inflatable cuff placed internally around the urethra; its inflation is controlled by the patient squeezing a reservoir device placed in either the scrotum or labia. They can be effective but require manual dexterity and intact cognition; an alert bracelet should be considered, because

catheter insertion through a closed artificial sphincter can cause significant damage. Revision rates can be high (up to 40%).115 Urodynamics should assist patient selection, as outcomes are worse with severe DO and poor detrusor compliance. Supportive Care Pads and protective garments should be chosen based on patient gender and the type and volume of UI. For example, an absorbent sheath may be sufficient for a man with mild post-prostatectomy UI. In some states Medicaid may cover pads; Medicare and private insurance does not. Medical supply companies and patient advocacy groups (see listing at end of chapter) publish illustrated catalogs to guide product selection. Because these products are often expensive, some patients may not change pads frequently enough.

Treatment of BPO-Associated LUTS in Men Alpha-1-selective adrenergic blockers decrease BPO-related LUTS by 30–40% over placebo in 50–70% of moderately symptomatic men, and result in better disease-specific functional outcomes than placebo.116 They do not have a large impact on quality of life nor do they prevent urinary retention. Time to onset of action is 2–4 weeks, and efficacy is durable.117 Agents include prazosin (1–2 mg twice a day), terazosin (2–10 mg daily), doxazosin (4–8 mg daily), and the alpha-1A-selective tamsulosin (0.4 mg daily) and silodosin (8 mg daily). All result in similar symptom reduction. Side effects include asthenia, headache, dizziness, lightheadedness, and orthostatic hypotension. Significant decrease in blood pressure and orthostatic hypotension are more likely with the non-specific agents (prazosin, doxazosin, terazosin), existing hypertension (whether treated or not), and

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other drugs with alpha-blocking effects (e.g., verapamil).92,93 The alpha 01A-selective agents are uniquely associated with retrograde or delayed ejaculation (0–14%)117 and a complication during cataract surgery, ‘floppy iris syndrome.’118 Doxazosin increases the risk for congestive heart failure in men with cardiac risk factors.119 5-reductase inhibitors (finasteride 5 mg daily and dutasteride 0.5 mg daily) result in significant yet modest symptom improvement. Time to symptom improvement greater than placebo may take 6 or more months. Efficacy is best in men with larger prostates, as indicated by either transrectal ultrasound or higher prostate-specific antigen levels.120 Side effects include decreased libido (6%), decreased ejaculate volume (4%), and impotence (8%). 5-reductase inhibitors are less effective than alpha-blockers for short-term symptom reduction, but more effective long term (4 years in the pivotal trial).116 Finasteride reduces the risk of urinary retention (1.1% vs. 2.7% with placebo, number needed to treat (NNT) 62) and TURP (4.2% vs. 6.5% with placebo, NNT 44).121 PSA levels fall by 40–60% at one year; if PSA does not decline in a compliant patient, he should be evaluated further with prostate biopsy. Antimuscarinics used for UI are also effective and safe in men with BPO-associated LUTS. In a systematic review, antimuscarinics improved urgency, frequency, and nocturia but did not increase flow rate.122 There was no significant increase in PVR (mean increase 11.6 ml [95% CI 4.5–18.6] and there was no difference between antimuscarinics and placebo for urinary retention (both 0.3% at 12 weeks). In a trial examining combination treatment with alpha-blocker and an antimuscarinic together, the combination was effective although neither the alpha-blocker nor antimuscarinic alone was more effective than placebo, possibly due to a very high placebo response rate (62%).123 Several other agents have been used or are under investigation for treatment of BPO-associated LUTS. Initial trials with phosphodiesterase-5 inhibitors (used to treat erectile dysfunction) indicate greater decrease in symptom scores compared with placebo.124 There are preliminary reports using intraprostatic injection of botulinum toxin.125 It is unclear whether plant-derived compounds are effective for BPO-related LUTS. Although a systematic review concluded that saw palmetto increased flow rate and decreased nocturia compared with placebo,126 a subsequent randomized controlled trial, using saw palmetto extract (160 mg twice a day) or placebo for one year in 225 men with moderate-to-severe LUTS, found no treatment benefit.127 Case series suggest a role for antiandrogens and LHRH agonists to facilitate indwelling catheter removal in frail older men with obstruction, if no other treatment is possible.128 Surgical transurethral resection of the prostate remains the standard treatment for obstruction from BPH, with symptom improvement rates of 80–88%.106 The absolute indications for TURP are urodynamic evidence of high grade BOO, urinary retention (medical causes excluded), recurrent urinary

infections, hydronephrosis, recurrent hematuria, and renal impairment;107 most surgical decisions, however, are based on symptom severity. Men with urodynamically proven BOO have better symptomatic outcomes,108 and quality of life improves only in men with severe LUTS.109 It is not known whether ‘earlier’ surgery could prevent detrusor compensation. Re-operation rate across trials is 1% per year, and efficacy may decline over time: percent of men with improved LUTS falls from 87% to 75% at seven years.110 Success rates tend to be lower in older men.111 TURP-associated erectile dysfunction rate increases with age. Laser prostatectomy is increasingly used as an alternative to TURP; results with TURP are superior in the first 7 months postoperatively, but outcomes become equivalent at one year.112 Men with glands 30 g can be treated with transurethral incision of the prostate, a technically easier procedure with shorter operation time that may be done under local anesthesia.113 This may be a reasonable alternative for older men with higher operative risk in whom medical management has failed. Transurethral microwave thermotherapy appears to have only modest efficacy, and its future is uncertain.

Future directions Many unanswered questions remain in our understanding of urogenital aging in women and men. Continued work is necessary to address: differential effects of aging per se and pregnancy/delivery on pelvic floor function whether there are age-related changes in detrusor afferent signaling, and their role in incontinence and urgency the effect of aging and disease on central mechanisms mediating LUT function alternatives to antimuscarinics for pharmacological treatment of urge UI, and novel agents for treatment of stress UI optimal patient selection for all types of UI treatment.

l

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Conclusions Older persons should not be discouraged by what their mothers, brothers, peers, and medical science have long told them were degenerative, unfortunate, and inevitable effects of urogenital aging. Much of what has been taken for ‘aging’ likely reflects other factors, such as co-morbid disease, sexual activity, labor and delivery practices, diet, and exercise. The recent findings about hormone replacement therapy for heart disease are but one indication that assumptions about postmenopausal health need to be revisited, and rigorously investigated. Large cultural and health trends are likely to reshape present assumptions and change

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the future experience of aging. Furthermore, we know very little about prevention of the age-associated problems and LUT symptoms. The most important thing that medical providers can do is to enquire after and pursue discussion of LUT symptoms in all older persons, and to work with them to thoroughly investigate them. Hopefully then, we can leave behind us these days in which the response to the older persons with LUT symptoms is, ‘What do you expect at your age?’

Resources Patient Care Resources The Simon Foundation for Continence, www.simonfoundation.org National Association for Continence, www.nafc.org

Useful Websites International Continence Society: www.continet.org (includes links to other continence organizations and resources) American Urological Association: www.aua.org American Urological Association Foundation: www. urologyhealth.org/auafhome.asp American Urogynecologic Society: www.augs.org American Medical Directors Association: www.amda. com (UI treatment in long-term care)

References 1. U.S. Population Projections for Selected Age Groups by State: 2005–2030. www.aoa.dhhs.gov/prof/Statistics/future_growth/ State-5-yr-age-projections-2005-2030.pdf. 2. Life expectancy at birth, 65 and 85 years of age, United States, Selected Years 1900–2004. http://205.207.175.93/aging/Table Viewer/tableView.aspx?ReportId  438. 3. DuBeau CE. Beyond the bladder. management of urinary incontinence in older women. Clin Obstet Gynecol 2007;50(3): 720–34. 4. Berry S, Coffey D, Walsh P, Ewing L. The development of human benign prostatic hyperplasia with age. J Urol 1984;132:474–79. 5. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun M. Cancer statistics 2007. CA Cancer J Clin 2007;57:43–66. 6. Wright HJ. The female perspective. Women’s attitudes toward urogenital aging. Am J Obstet Gynecol 1998;178(5): S250–53. 7. Besdine R. Functional assessment in the elderly. In: J Rowe, R Besdine, eds. Geriatric Medicine, second ed. Boston, MA: Little, Brown; 1988:37–51. 8. Resnick NM, Yalla SV. Age and the lower urinary tract. What is normal? Neurourol Urodyn 1995;14:577–79. 9. Bachmann G. Urogenital ageing. An old problem newly recognized. Maturitas 1995;22(Suppl.):S1–S5.

445

10. Stenberg A, Heimer G, Ulmsten U. The prevalence of urogenital symptoms in postmenopausal women. Maturitas 1995;22(Suppl.):S17–S20. 11. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy. JAMA 2002;288(1):49–57. 12. Forsberg JG. A morphologist’s approach to the vagina--agerelated changes and estrogen sensitivity. Maturitas 1995;22(Suppl.):S7–S15. 13. Nicolle LE. Urinary tract infection in geriatric and institutionalized patients. Curr Opin Urol 2002;12(1):51–55. 14. Yang J, Yang S, Huang W. Functional correlates of Doppler flow study of the female urethral vasculature. Ultrasound Obstet Gynecol 2006;28:96–102. 15. Tan J, Lukacz E, Menefee S, et al. Determinants of vaginal length. Am J Obstet Gynecol 2006;195:1846–1850. 16. Foster DC. Vulvar disease. Obstet Gynecol 2002;100(1): 145–163. 17. Cardozo L, Lose G, McClish D, Versi E, de Koning Gans H. A systematic review of estrogens for recurrent urinary tract infections. Third report of the hormones and urogenital therapy (HUT) committee. Int Urogynecol J 2001;12(1):15–20. 18. Nordling J. The aging bladder – a significant but underestimated role in the development of lower urinary tract symptoms. Exp Gerontol 2002;37(8-9):991–999. 19. Pfisterer MH, Griffiths DJ, Schaefer W, Resnick NM. The effect of age on lower urinary tract function. A study in women. J Am Geriatr Soc 2006;54(3):405–412. 20. Taylor JA III., Kuchel GA. Detrusor underactivity. Clinical features and pathogenesis of an underdiagnosed geriatric condition. J Am Geriatr Soc 2006;54(12):1920–1932. 21. Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. III: Detrusor overactivity. J Urol 1993;150(5 Pt 2):1668–1680. 22. Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. II: Aging detrusor. Normal versus impaired contractility. J Urol 1993;150(5 Pt 2):1657–1667. 23. DeLancey J. Gross anatomy and cell biology of the lower urinary tract. In: P Abrams, L Cardozo, S Khoury, A Wein, eds. Incontinence: Third International Consultation on Incontinence, second ed. Plymouth, UK: Health Publications Ltd.; 2002:19–82. 24. Madersbacher S, Pycha A, Schatzl G, Mian C, Klingler CH, Marberger M. The aging lower urinary tract. A comparative urodynamic study of men and women. Urology 1998;51(2): 206–212. 25. Abrams P, Griffiths D. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979;51:129–133. 26. Resnick NM, Yalla SV. Detrusor hyperactivity with impaired contractile function: an unrecognized but common cause of incontinence in elderly patients. JAMA 1987;257(22): 3076–3081. 27. Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. IV. Bladder outlet obstruction. J Urol 1993;150(5 Pt 2):1681–1695. 28. Gosling J, Gilpin S, Dixon J, Gilpin C. Decrease in the autonomic innervation of human detrusor muscle in outflow obstruction. J Urol 1986;136:501–504. 29. Cumming J, Chisholm G. Changes in detrusor innervation with relief of outflow tract obstruction. Br J Urol 1992;69:7–11.

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30. Elbadawi A, Hailemariam S, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. VII: Prospective ultrastructural/urodynamic evaluation of its natural evolution. J Urol 1997;157(5):1814–1822. 31. Rud T. Urethral pressure profile in continent women from childhood to old age. Acta Obstet Gynecol Scand 1980;59: 331–335. 32. Hilton P, Stanton S. Urethral pressure measurement by microtransducer. The results in symptom-free women and in those with genuine stress incontinence. BJOG 1983;90: 919–933. 33. Carlile A, Davies I, Rigby A, Brocklehurst JC. Age changes in the human female urethra. A morphometric study. J Urol 1988;139(3):532–535. 34. Verelst M, Maltau JM, Orbo A. Computerised morphometric study of the paraurethral tissue in young and elderly women. Neurourol Urodyn 2002;21(6):529–533. 35. Siracusano S, Bertolotto M, Cucchi A, et al. Application of ultrasound contrast agents for the characterization of female urethral vascularization in healthy pre- and postmenopausal volunteers. Eur Urol 2006;50:1316–1322. 36. Liang C, Chang S, Chang Y, Wei T, Wu H, Chao A. Threedimensional power Doppler measurement of perfusion of the periurethral tissue in incontinent women: a preliminary report. Acta Obstet Gynecol Scand 2006;85:608–613. 37. Kenton K, Lowenstein L, Simmons J, Brubaker L. Aging and overactive bladder may be associated with loss of urethral sensation in women. Neurourol Urodyn 2007;26:981–984. 38. Kenton K, Simmons J, FitzGerald M, Lowenstein L, Brubaker L. Urethral and bladder current perception thresholds. Normative data in women. J Urol 2007;178:189–192. 39. Perucchini D, DeLancey JO, Ashton-Miller JA, Peschers U, Kataria T. Age effects on urethral striated muscle. I: Changes in number and diameter of striated muscle fibers in the ventral urethra. Am J Obstet Gynecol 2002;186(3):351–355. 40. Perucchini D, DeLancey JO, Ashton-Miller JA, Galecki A, Schaer GN. Age effects on urethral striated muscle. II: anatomic location of muscle loss. Am J Obstet Gynecol 2002;186(3):356–360. 41. Clobes A, DeLancey J, Morgan D. Urethral circular smooth muscle in young and old women. J Obstet Gynecol 2008;198, 587e581-587e585. 42. Romanzi LJ, Groutz A, Blaivas JG. Urethral diverticulum in women: diverse presentations resulting in diagnostic delay and mismanagement. J Urol 2000;164(2):428–433. 43. Strasser H, Tiefenthaler M, Steinlechner M, Bartsch G, Konwalinka G. Urinary incontinence in the elderly and age-dependent apoptosis of rhabdosphincter cells. Lancet 1999;354(9182):918–919. 44. Rother P, Loffler S, Dorschner W, Reibiger I, Bengs T. Anatomic basis of micturition and urinary continence: muscle systems in urinary bladder neck during ageing. Surg Radiol Anat 1996;18(3):173–177. 45. Bagi P, Vejborg I, Colstrup H, Kristensen JK. Pressure/crosssectional area relations in the proximal urethra of healthy males. Part 1: elastance and estimated pressure in the uninstrumented urethra. Eur Urol 1995;28(1):51–57. 46. Hammerer P, Michl U, Meyer-Moldenhauer WH, Huland H. Urethral closure pressure changes with age in men. J Urol 1996;156(5):1741–1743.

47. Lawrence J, Lukacz E, Nager C, Hsu J, Luber K. Prevalence and co-occurrence of pelvic floor disorders in communitydwelling women. Obstet Gynecol 2008;111:678–685. 48. Talasz H, Himmer-Perschak G, Marth E, Fischer-Colbrie J, Hoefner E, Lechleitner M. Evaluation of pelvic floor muscle function in a random group of adult women in Austria. Int Urogynecol J 2008;19:131–135. 49. Trowbridge E, Wei J, Fenner D, Ashton-Miller J, Delancey J. Effects of aging on lower urinary tract and pelvic floor function in nulliparous women. Obstet Gynecol 2007;109: 715–720. 50. Jundt K, Kiening M, Fischer P, et al. Is the histomorphological concept of female pelvic floor and its changes due to age and vaginal delivery correct? Neurourol Urodyn 2005;24: 44–50. 51. Norton PA. Pelvic floor disorders: the role of fascia and ligaments. Clin Obstet Gynecol 1993;36(4):926–938. 52. Spence-Jones C, Kamm MA, Henry MM, Hudson CN. Bowel dysfunction: a pathogenic factor in uterovaginal prolapse and urinary stress incontinence. Br J Obstet Gynaecol 1994;101(2):147–152. 53. Shibata Y, Ito K, Suzuki K, et al. Changes in the endocrine environment of the human prostate transition zone with aging. Simultaneous quantitative analysis of prostatic sex steroids and comparison with human prostatic histological composition. Prostate 2000;42(1):45–55. 54. Griffiths K. Estrogens and prostatic disease. International Prostate Health Council Study Group. Prostate 2000;45(2): 87–100. 55. Roehrborn CG, Boyle P, Bergner D, et al. Serum prostatespecific antigen and prostate volume predict long-term changes in symptoms and flow rate. results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 1999;54(4):662–669. 56. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Treatment for benign prostatic hyperplasia among community dwelling men. the Olmsted County study of urinary symptoms and health status. J Urol 1999;162(4):1301–1306. 57. Coolsaet B, van Venrooij G, Block C. Prostatism: rationalization of urodynamic testing. World J Urol 1984;2:216–221. 58. Mishra V, Allen D, Nicolaou C, et al. Does intraprostatic inflammation have a role in the pathogenesis and progression of benign prostatic hyperplasia? BJU Int 2007;100: 327–331. 59. Anjum I, Ahmed M, Azzopardi A, Mufti G. Prostatic infarction/infection in acute urinary retention secondary to benign prostatic hyperplasia. J Urol 1998;160:792–793. 60. Anger J, Saigal C, Stothers L, Thom D, Rodríguez L, Litwin Mand the Urologic Diseases of America Project. The prevalence of urinary incontinence among community dwelling men: results from the National Health and Nutrition Examination Survey. J Urol 2006;176:2103–2108. 61. Anger J, Saigal C, Litwin MS. The Urologic Diseases of America Project. The prevalence of urinary incontinence among community dwelling adult women: results from the National Health and Nutrition Examination Survey. J Urol 2006;175:601–604. 62. Raz R, Gennersin Y, Wasser J, et al. Recurrent urinary tract infections in postmenopausal women. Clin Infect Dis 2000;30:152–156.

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63. Ouslander JG, Schapira M, Schnelle JF, et al. Does eradicating bacteriuria affect the severity of chronic urinary incontinence in nursing home residents? Ann Intern Med 1995;122(10):749–754. 64. Ouslander JG, Schapira M, Schnelle JF, Fingold S. Pyuria among chronically incontinent but otherwise asymptomatic nursing home residents. J Am Geriatr Soc 1996;44(4):420–423. 65. Juthani-Mehta M, Tinetti M, Perrelli E, Towle V, Van Ness P, Quagliarello V. Diagnostic accuracy of criteria for urinary tract infection in a cohort of nursing home residents. J Am Geriatr Soc 2007;55:1072–1077. 66. Lo E, Nicolle L, Classen D, et al. Strategies to prevent catheter-associated urinary tract infections in acute care hospitals. Infect Control Hosp Epidemiol 2008;29(s1):S41–S50. 67. Avorn J, Monane M, Gurwitz J, et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994;71:751–754. 68. Nygaard I, Barber M, Burgio K. Prevalence of symptomatic pelvic floor disorders in US women. JAMA 2008;300:1311. 69. Tennstedt S, Link C, Steers W, McKinlay J. Prevalence of and risk factors for urine leakage in a racially and ethnically diverse population of adults. The Boston Area Community Health (BACH) Survey. Am J Epidemiol 2008;167 (4):390–399. 70. Anger J, Saigal C, Madison R, Joyce G, Litwin M. Urological Diseases of America Project. Increasing costs of urinary incontinence among female Medicare beneficiaries. J Urol 2006;176:247–251. 71. Sahyoun NR, Pratt LA, Lentzner H, Dey A, Robinson KN. The changing profile of nursing home residents. 1985-1997. Aging Trends 2001;4:1–8. 72. Goode P, Burgio K, Redden D, et al. Population based study of incidence and predictors of urinary incontinence in black and white older adults. J Urol 2008;179:1449. 73. Langa KM, Fultz NH, Saint S, Kabeto MU, Herzog AR. Informal caregiving time and costs for urinary incontinence in older individuals in the United States. J Am Geriatr Soc 2002;50(4):733–777. 74. Fonda D, DuBeau C, Harari D, Palmer M, Ouslander J, Roe B. Incontinence in the frail elderly. In: P Abrams, L Cardozo, S Khoury, A Wein, eds. Incontinence: Third International Consultation on Incontinence, 2005 Edition. Plymouth, UK: Health Publications Ltd.; 2005:1163–1239. 75. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function. Neurourol Urodyn 2002;21:167–178. 76. Hunskaar S, Burgio K, Clark A, et al. Epidemiology of urinary and faecal incontinence and pelvic organ prolapse. In: P Abrams, L Cardozo, S Khoury, A Wein, eds. Incontinence: Third International Consultation on Incontinence, 2005 Edition. Plymouth, UK: Health Publication Ltd.; 2005:255–311. 77. Resnick NM, Yalla SV, Laurino E. The pathophysiology of urinary incontinence among institutionalized elderly persons. N Engl J Med 1989;320(1):1–7. 78. Holroyd-Leduc J, Tannenbaum C, Thorpe K, Straus S. What type of urinary incontinence does this woman have? JAMA 2008;299:1446–1456. 79. Sandvik H, Hunskaar S, Vanvik A, Bratt H, Seim A, Hermstad R. Diagnostic classification of female urinary

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

447

incontinence. An epidemiological survey corrected for validity. J Clin Epidemiol 1995;48:339–343. Roehrborn C, O’Connell J, Barry M, et al. American Urological Association Guideline on the Management of Benign Prostatic Hyperplasia (BPH). Update 2006 http:// www.auanet.org/content/guidelines-and-quality-care/clinicalguidelines.cfm?subbph. Grosshans C, Passadori Y, Peter B. Urinary retention in the elderly. A study of 100 hospitalized patients. J Am Geriatr Soc 1993;41:633–638. C. DuBeau, T. Johnson, II, G. Kuchel, M. Palmer, A. Wagg, Incontinence in the frail elderly. in: P. Abrams, L. Cardozo, S. Khoury, A. Wein (Eds.), Incontinence: 4th International Consultation on Incontinence, 2009, in press. DuBeau C.E., Urinary incontinence. in: Geriatric Review Syllabus, 7th edn. American Geriatrics Society, New York, NY, 2010, in press. Courtney S, Wightman J. The value of ultrasound scanning of the upper urinary tract in patients with bladder outlet obstruction. Br J Urol 1991;68:169–171. Subak L, Whitcomb E, Shen H, et al. Weight loss. A novel and effective treatment for urinary incontinence. J Urol 2005;174:190. Brown J, Wing R, Barrett-Connor E, et al. Lifestyle intervention is associated with lower prevalence of urinary incontinence. The diabetes prevention program. Diabetes Care 2006;29:385. Shamliyan TA, Kane RL, Wyman J, Wilt TJ. Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women. Ann Intern Med 2008;148:459–473. Roe B, Ostaszkiewicz J, Milne J, Wallace S. Systematic reviews of bladder training and voiding programmes in adults. A synopsis of findings from data analysis and outcomes using metastudy techniques. J Adv Nurs 2007;57(1):15–31. MacDonald R, Fink H, Huckabay C, Monga M, Wilt T. Pelvic floor muscle training to improve urinary incontinence after radical prostatectomy. A systematic review of effectiveness. BJU Int 2007;100:76–81. Hay-Smith J, Mørkved S, Fairbrother K, Herbison G. Pelvic floor muscle training for prevention and treatment of urinary and faecal incontinence in antenatal and postnatal women. Cochrane Database of Systematic Reviews 2008(3):CD005429. Wilson P, Bø K, Hay-Smith J, et al. Conservative treatment in women. In: P Abrams, L Cardozo, S Khoury, A Wein, eds. Incontinence: 2nd International Consultation on Incontinence, 2nd edn. Plymouth, UK: Health Publication Ltd.; 2002:3573–3578. Eustice S, Roe B, Paterson J. Prompted voiding for the management of urinary incontinence in adults. Cochrane Database Syst Rev 2000(2):CD002113. Ouslander JG, Schnelle JF, Uman G, et al. Predictors of successful prompted voiding among incontinent nursing home residents. JAMA 1995;273(17):1366–1370. Ostaszkiewicz J, Chestney T, Roe B. Habit retraining for the management of urinary incontinence in adults. Cochrane Database Syst Rev 2004(2):CD002801. Hendrix S, Cochrane B, Nygaard I et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005;293:935–948.

448

s e c t i o n 6     Reproductive Biology l

96. Rembratt A, Riis A, Norgaard J. Desmopressin treatment in nocturia; an analysis of risk factors for hyponatremia. Neurourol Urodyn 2006;25:105–109. 97. Finney S, Andersson K, Gillespie J, Stewart L. Anti­ muscarinic drugs in detrusor overactivity and the overactive bladder syndrome. Motor or sensory actions? BJU Int 2006; 98:503–507. 98. Chapple C, Khullar V, Gabrielc Z, Dooley J. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 2005;48:5–26. 99. Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder. Systematic review. BMJ 2003;326:841–844. 100. Burgio K, Locher J, Goode P. Combined behavioral and drug therapy for urge incontinence in older women. J Am Geriatr Soc 2000;48:370–374. 101. Burgio K, Kraus S, Menefee S et al. Behavioral therapy to enable women with urge incontinence to discontinue drug treatment: a randomized trial. Ann Intern Med 2008;149:161–169. 102. Kaplan SA, D’Alisera PM. Tolerability of alpha-blockade with doxazosin as a therapeutic option for symptomatic benign prostatic hyperplasia in the elderly patient. A pooled analysis of seven double-blind, placebo-controlled studies. J Gerontol Ser A Biol Sci Med Sci 1998;53(3):M201–M206. 103. Layton D, Pearce GL, Shakir SA. Safety profile of tolterodine as used in general practice in England. Results of prescription-event monitoring. Drug Safety 2001;24(9): 703–713. 104. Kay G et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 2006;50:317–326. 105. Lackner T, Wyman J, McCarthy T, Monigold M, Davey C. Randomized, placebo-controlled trial of the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents with urge urinary incontinence. J Am Geriatr Soc 2008;56:862–870. 106. Starr J. Cholinesterase inhibitor treatment and urinary incontinence in Alzheimer’s disease. J Am Geriatr Soc 2007;55:800–801. 107. Gill SS, Mamdani M, Naglie G et al. A prescribing cascade involving cholinesterase inhibitors and anticholinergic drugs. Arch Intern Med 2005;165(7):808–813. 108. Sink K, Thomas J 3rd., Xu H, Craig B, Kritchevsky S, Sands L. Dual use of bladder anticholinergics and cholinesterase inhibitors. Long-term functional and cognitive outcomes. J Am Geriatr Soc 2008;56:847–853. 109. Trowbridge E, Fenner D. Practicalities and pitfalls of pessaries in older women. Clin Obstet Gynecol 2007;50: 709–719. 110. Sahai A, Khan M, Gregson N, Smith K, Dasgupta P. Botulinum toxin for detrusor overactivity and symptoms of overactive bladder. Where we are now and where we are going. Nature Clin Pract Urol 2007;4:379–386. 111. van Kerrebroeck P, van Voskuilen A, Heesakkers J et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction. Outcomes of a prospective, worldwide clinical study. J Urol 2007;178:2029–2034.

112. Albo M, Richter H, Brubaker L et al. Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med 2007;356:2143–2155. 113. Gallagher BL, Dwyer NT, Gaynor-Krupnick DM, Latini JM, Kreder KJ. Objective and Quality-of-Life outcomes with bone-anchored male bulbourethral sling. Urology 2007;69(6):1090–1094. 114. Montague D, Angermeier K. Treatment, of postprostatectomy urinary incontinence. The case against the male sling. Nat Clin Pract Urol 2006;3:290–291. 115. Hussain M, Greenwell T, Venn S, Mundy A. The current role of the artificial urinary sphincter for the treatment of urinary incontinence. J Urol 2005;174:418–424. 116. McConnell J, Roehrborn C, Bautista O, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progressin of benign prostatic hyperplasia. N Engl J Med 2003;349:2387–2398. 117. Lepor H, Lones K, Williford W. The mechansim of adverse events associated with terazosin. An analysis of the Veterans Affairs Cooperative Study. J Urol 2000;163: 1134–1137. 118. Lawrentschuk N, Bylsma G. Intraoperative ‘floppy iris’ syndrome and its relationship to tamsulosin. A urologist’s guide. BJU Int 2006;97:2–4. 119. ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. The antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000;283:1967–1975. 120. Marberger M. Drug insight. 5-reductase inhibitors for the treatment of benign prostatic hyperplasia. Nat Clin Pract Urol 2006;3:495–503. 121. McConnell J, Bruskewitz R, Walsh P,et al. The effect of finasteride on the risk of acute urinary retention in the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557–563. 122. Blake-James R, Ikeda U, Emberton M. The role of anticholinergics in men with lower urinary symptoms suggestive of benign prostatic hyperplasia. A systematic review and meta-analysis. BJU Int 2006;99:85–96. 123. Kaplan S, Roehrborn C, Rovner E et al. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 2006;296:2319–2328. 124. McVary K, Roehrborn C, Kaminetsky J et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 2007;177:1401–1407. 125. Chuang U-C, Chancellor M. The application of botulinum toxin in the prostate. J Urol 2006;176:2375–2382. 126. Wilt T, Ishani A, Stark G, MacDonald R, Lau J, Mulrow C. Saw palmetto extracts for treatment of benign prostatic hyperplasia. A systematic review. JAMA 1998;280: 1604–1609. 127. Bent S, Kane C, Shinohara K et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med 2006;354: 557–566. 128. McConnell J. Medical management of benign prostatic hyperplasia with androgen suppression. Prostate 1990;3 (Suppl.):49–59.

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Menopause Gloria Bachmann1, and Nora J. Doty2 1 Associate Dean for Women’s Health, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ, USA 2 Research Assistant, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Introduction

to menopause. In an attempt to address this clinical question, the Stages of Reproductive Aging Workshop (STRAW) developed a staging system based on menstrual cycle features to better characterize the typical woman’s late reproductive function as she transitions to natural menopause. A woman traverses from the reproductive stage of her life cycle to the menopausal transition at a point when her regular menstrual cycles remain regular but they vary more than seven days in length from previous cycle lengths; this is the early menopausal transition. Usually the variation is shorter cycles than the previous menstrual cycle lengths that the woman recorded in her earlier reproductive years. The late menopausal transition occurs when there are two or more skipped cycles with at least one intermenstrual interval of 60 days or greater. The menopausal transition ends with the final menstrual period, which marks the onset of menopause. Early postmenopause is the first 5 years after the final menstrual period. The life cycle years after this point denote the late postmenopause years, which categorize that reproductive period of a woman’s life cycle until that woman’s death.3 Many studies have investigated the age of menopause and factors associated with late or early menopause. A large multi-ethnic, cross-sectional study found that the median age of natural menopause is 51.4 years of age in the United States. In this study, current smoking, being single, and lower educational attainment were all independently associated with earlier age at menopause. This study also found that a history of oral contraceptive use, increasing parity, and Japanese-American ethnicity were associated with later age at menopause. In these data, the average age of menopause in Japanese women was 51.8 years, while there was no significant difference in the age of menopause in White, Hispanic, black, or Chinese women in the US.4 Data are also being reported that the US population is an aging one. By the year 2020 45% of the female population in the US will be over the age of 45.5 Healthy women live

Menopause is a natural part of the reproductive life cycle that portends significant meaning in many women’s lives. The menopausal experience is greatly influenced by varied cultural and psychosocial backgrounds which affect each individual woman’s understanding of these hormonal changes and her choice of acceptable management strategies. Women experiencing the menopausal transition will typically seek treatment for symptoms associated with the transition and/ or preventative health care. Adverse changes in function and number of germ cells as well as hormone milieu underlie this pivotal event in reproductive aging. Menopause is a uniquely female experience; although men undergo gonadal and hormonal changes in reproductive functioning as they age, there is no male equivalent to menopause. Menopause, clinically interpreted as the permanent cessation of menstruation in age-appropriate women, is caused by a decline in ovarian follicular activity. It is useful to categorize types of menopause based on the cause and the timing of the final menstrual period. Natural menopause is a retrospective diagnosis made after 12 months of amenorrhea with no apparent pathologic cause. Induced menopause is the permanent cessation of menstruation after surgery, chemotherapy, or radiation treatment caused by the iatrogenic destruction of germ cells. Early menopause can be either a natural or induced final menstrual period that occurs before age 45. Premature menopause is diagnosed when a woman has a final menstrual period before age 40 and can be natural or induced. This is in contrast to premature ovarian failure, which is ovarian insufficiency that occurs before age 40 that results in permanent or transient amenorrhea.1,2 In retrospect, the final menstrual period is an easily identifiable sign of menopause, but this is of limited use to women and clinicians who are often concerned with wanting to determine where the patient is in her natural transition

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over one-third of their life as post-menopausal, so the study of this time frame in women’s lives is taking on greater significance for clinicians. Current and future physicians who care for older women will require the skill-set to deal with the issues unique not only to aging, but also to the adverse changes that occur in women with significantly diminished gonadal function.

Physiology The occurrence of menopause is not a discrete event but rather is one point on a continuum of reproductive changes that occur throughout a woman’s life cycle. The underlying factor in the onset of the menopausal transition is the decrease in the number and quality of primordial follicles, which results in a decrease in the number of recruited antral follicles. Ultimately, the decreased number of follicles alters hormone concentrations and affects the hypothalamic–pituitary–ovarian axis.6 The absolute decrease in the number of functional ovarian follicles is the major factor in signaling the onset of menopause. The number of primordial follicles is decreasing throughout the life cycle of the female, with the commencement of this decrease occurring while the female is in utero. Of interest, for all human females the time that their ovaries have the maximum number of oocytes is at the 20th week of gestation in utero. The absolute number of follicles and their rate of loss appear to determine the onset of menopause. One study counted the number of follicles in 10 m sections of surgically removed ovaries in 17 women ages 45–55 and found that women with regular menses had a 10–fold increase in the number of follicles (1392  355) compared to perimenopausal women (142  72). However, the rate of decline in follicular number is not constant throughout the woman’s life cycle. There is an increased rate of follicular depletion in the 10 years prior to menopause compared to the rate of decline at other adult ages.7 Current data are suggesting that anti-Müllerian hormone is the best marker for this decreasing follicular reserve.8 The ovary is a major estrogen-producing organ for the duration of a woman’s reproductive life. In addition to 17-estradiol and estrone, the ovary produces the steroid hormones progesterone, testosterone, androstendion, and DHEA as well as peptide hormones like inhibin. After menopause, the ovary continues to produce gonadal hormones, but in decreased absolute and relative amounts compared to premenopausal levels. The decrease in estrogen, progesterone, and inhibin B production appears to be a direct result of decreased number of follicles. For example, when there are fewer primordial follicles, there are fewer numbers of antral follicles recruited each cycle and thus fewer granulosa cells to secrete inhibin B. Inhibin B is normally secreted during the follicular phase of the menstrual cycle to downregulate

follicular-stimulating hormone (FSH) secretion from the pituitary.9 The decreased level of inhibin B that occurs during the menopausal transition results in decreased negativefeedback and subsequent increased FSH. Elevated FSH levels have been associated with a decreased follicular phase length of the ovarian cycle and a decreased menstrual cycle length of the endometrial cycle, which translates into shorter intervals between menses reported by women in their early menopausal transition.10 The elevated FSH levels most likely cause earlier follicle development and dominant follicle selection, resulting in a shorter follicular phase and overall menstrual cycle length.11 However, FSH levels, which are noted to widely fluctuate in midlife women, are not a reliable indicator of ovarian function; some women with regular menstrual cycles at age 40 have elevated FSH and some women in the menopausal transition may have normal FSH levels in some cycles.9 As well, during the menopausal transition, there are often points during the menstrual cycle in which there are increased serum estradiol concentrations, in response to these fluctuating levels of FSH.12 Ultimately, menopause is associated with decreased serum estradiol. An overall decrease in gonadal hormone production by the postmenopausal ovary is caused by both the absolute decrease in the number of follicles and the increased resistance of the remaining follicles to FSH and LH.13 Therefore, even when stimulated by high levels of LH and FSH, aging granulosa cells produce less estradiol.8 Some studies have found that progesterone levels may also decrease during the menopausal transition, with the greatest decrease during anovulatory cycles and prolonged ovulatory cycles, indicating no corpus luteum has been generated by the ovary during that menstrual cycle or by corpus luteum dysfunction.9 Other studies find that progesterone levels do not significantly decrease during the menopause transition when measured during ovulatory cycles.13 Androgen levels also decrease during the menopausal transition and this decrease is not as closely linked to follicular quantity and quality as is estrogen and progesterone diminution.8 Ovarian testosterone secretion from theca cells is under the control of LH from the pituitary and estrogen from granulosa cells, so androgen levels do not significantly decrease until after the marked decline in estradiol and follicle number.3,14 In fact, free testosterone may be increased during the menopausal transition since the level of sexbinding hormone globulin (SBHG) is decreased.9 The change in gonadal hormones and follicular function that occurs during the menopausal transition ultimately results in changes in the menstrual cycle and finally menstrual cycle absence. Women will have occasional ovulatory menstrual cycles amidst increasing numbers of anovulatory cycles as they progress through the menopausal transition.13 One study reported that in women experiencing a natural menopause, 38% of the last ten cycles prior to the final menstrual period were ovulatory.13 Anovulatory cycles during

C hapter 4 1     Menopause l

the menopause transition are caused by an estrogen withdrawal bleed secondary to an inadequate luteal phase and to a diminished or absent progesterone production if there is no dominant follicle. However, an infrequent ovulatory cycle may occur in an environment of mainly anovulatory cycles; as follicles are exposed to increasing levels of FSH, a follicle can become responsive to this stimulation and produce ovulatory quantities of estradiol and progesterone. This situation will clinically manifest as a long cycle with late ovulation.10 There are no accurate serum markers for the menopausal transition, even though menopause is associated with increased FSH and decreased estradiol levels. FSH and estradiol levels vary between women and the same stage of transition and levels fluctuate within a woman from cycle to cycle.15 Anti-Müllerian hormone (AMH) levels appear to have the most predictive value in predicting the timing of menopause. Data suggest that AMH levels are a good indicator of the size of the remaining follicular pool.16 This value may prove a better indicator than either FSH levels or inhibin B levels. The ovaries of postmenopausal women remain active in hormone production, but in different amounts and at different rates when compared to their premenopausal functioning. Ovarian granulosa cells are the main source of estradiol, and plasma levels of estradiol fall from 40 to 400 pg/ml during menstrual cycles to postmenopausal levels of 5–20 pg/ ml. However, the postmenopausal woman still produces significant quantities of estrone by peripheral conversion of ovarian and adrenal androsetendione to estrone. Estrone is the main source of estrogen in postmenopausal women.17 Ovaries continue to secrete androgens in postmenopausal women; each ovary secretes about 25 g of testosterone and 11.5 g of androstenedione a day. The postmenopausal ovary also appears to produce estrone and estradiol.18

Evaluation of women Women seeking treatment for preventative care and symptoms related to the menopausal transition and menopause should have an assessment that includes what the woman’s expectations of menopause management are. Some women may only want non-hormonal options whereas others with clear contraindications to hormonal therapy may desire this therapy and need to fully understand the reasons why menopausal hormonal therapy is not a treatment option. Indications and contraindications to hormonal therapy should be assessed after the woman’s medical history, her physical and pelvic examination, and baseline studies including mammography and bone density testing are completed.

Quality of Life Concerns While many symptoms are popularly attributed to menopause, the only symptoms consistently associated with the

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menopausal transition and menopause are vasomotor instability, urogenital atrophy, and irregular menstrual bleeding. Frequently, women also express concern about changes in memory or mood instability during the menopausal transition, although studies have not shown these concerns to be significantly associated with menopause and may be more related to aging or psychological issues. Vasomotor Instability Vasomotor instability, also referred to as hot flashing or hot flushing, is a subjective sensation of heat associated with cutaneous vasodilation and a compensatory decrease in core body temperature that lasts about 4 minutes. Associated symptoms often include cardiac palpitations, obvious perspiration, and heightened anxiety.19 Hot flashes are the most commonly reported symptom of menopause, experienced by more than 75% of women in the menopausal transition. Symptoms of vasomotor instability are most frequent in the year of the final menstrual period and then subside in most women, although symptoms persist for several years in 17% of postmenopausal women.20 For most women, especially those experiencing a natural menopause, vasomotor symptoms cause marked distress in the woman for less than 1 year.21 The mechanism of hot flashes involves a change in the thermoregulatory set point in the hypothalamus. The role of estrogen is not clear in this process, although it appears to be due to abrupt drops in estrogen levels rather than absolute circulating levels of this hormone. Although exogenously administered estrogen has been empirically shown to alleviate symptoms, there is no correlation between serum levels of estradiol and symptom severity.20 Serotonin may play a role in increasing the hypothalamic set point by overloading serotonin receptor sites or indirectly modulating noradrenergic or dopaminergic receptor sites.21 Symptoms from vasomotor instability vary in severity and duration. There is likely a connection between hot flushes and sleep disturbances commonly reported by women in the menopausal transition.22 Women can be advised behavioral and lifestyle modifications to attempt to diminish the symptoms, but medical treatment is indicated if women find the symptoms of vasomotor instability distressing despite nonhormonal interventions. As already noted, most women with symptoms will report resolution regardless of whether therapy is used or not used.23 Urogenital Atrophy Symptoms of urogenital atrophy include vaginal dryness, pruritus, and burning, and insertional or superficial dyspareunia. Unlike vasomotor symptoms which typically abate with time, symptoms of urogenital atrophy are usually progressive. Ten to forty percent of women experience symptoms of urogenital atrophy;23 of these women, studies have suggested that 75% describe vaginal dryness, 38% dyspareunia, and 15% vaginal discharge, pruritus, and pain.24 The most distressing outcome of urogenital atrophy is sexual

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dysfunction, which is a perceived decrease in sexual functioning that the woman finds distressing.19 Decreased circulating estrogen levels adversely affect the urogenital epithelium in numerous ways, resulting in the signs and symptoms of urogenital atrophy. Decreased blood flow in the epithelium leads to diminished oxygenation and nourishment, which results in a decline in the number of healthy collagen and elastin fibers. This can lead to decreased elasticity of postmenopausal vaginal tissue and the sign of vaginal vault stenosis and the complaint of insertional dyspareunia. Concurrently, an increase in fibrin and connective tissue causes vaginal epithelial thinning and loss of rugae. Dryness and an increased pH are caused by decreased hyaluronic acid and mucopolysaccharides production. A decrease in the amount of intracellular glycogen, which is the energy source for the acid-producing vaginal flora lactobacilli, also causes an increase in pH of vaginal secretions. With decreased estrogen levels in the postmenopausal woman, delayed lubrication with arousal as well as a decrease in the quantity of vaginal secretions from sebaceous glands with sexual stimulation, there are frequent complaints of painful coital activity by aging women. Although these sebaceous glands remain prominent throughout the life cycle, the quantity of secretions produced diminishes, which not only leads to sexual dysfunction, but combined with the adverse anatomic changes and the elevated pH, the woman is also at increased risk of urogenital trauma, infection, and non-sexually related pain, itching, and burning.19,24 Before low dose vaginal estrogen is prescribed, other sources of symptoms such as malignancy, foreign body, or inflammatory conditions of the vulva should be ruled out.25 As well, first-line therapy for urogenital atrophy before estrogen is recommended includes non-hormonal lubricants and counseling for the woman to continue to engage in sexual activity.23 Some data suggest that vaginal tissue remains healthier in postmenopausal women who engage in regular activity as compared to sexually abstinent postmenopausal women.19 If non-hormonal management strategies do not achieve the desired effects, estrogen therapy should be recommended for women who do not have a contraindication to this intervention. Abnormal Uterine Bleeding Menstrual irregularity is the most common characteristic described by women entering into the menopausal transition as well as a frequent reason that many women seek advice from clinicians during this time. Anovulatory cycles associated with variable cycle lengths and lighter menstrual bleeding of unpredictable duration are increasingly common as women near the final menstrual period. In contrast, irregular uterine bleeding from other etiologies, such as uterine fibroids or endometrial hyperplasia, is often associated with heavy bleeding often accompanied by clots. The only definitive way of ruling out endometrial hyperplasia or endometrial cancer in women with irregular bleeding is

with an endometrial biopsy, which yields a histologic evaluation of the tissue.26 Clinicians should also consider pregnancy as a cause of menstrual irregularity, especially in women who have skipped periods and complain of breast tenderness or other symptoms of pregnancy. Although fertility does decline with age, there are an estimated 10.7 conceptions per 1000 women over age 4027 and the frequency of terminations of pregnancy in this same age group is exceeded only by that seen in the teenager population.28 If all other causes of menstrual irregularity are ruled out, women can be reassured that changes in menstrual cycle timing and menstrual flow are normal components of the menopausal transition. Mood and Cognition Lifetime prevalence of major depressive disorder in women is 13%, with the highest prevalence between the times of puberty and mid-life. While transitions in reproductive functioning are associated with increased risk of mood disorders, most women in the menopausal transition do not have depressive symptoms. Estimates of the prevalence of depressive symptoms in women in the menopausal transition vary from 15–50%. Experiencing vasomotor symptoms or sleep disturbances are associated with an increased risk of depressive symptoms during this transition.29 The brain contains estrogen receptors and functional brain studies show that estrogen modulates neuron activity during cognitive tasks. Despite evidence for estrogen’s involvement in brain functioning, studies have demonstrated that natural menopause has no effect on cognition, although women may self-report an increased frequency of memory problems around this time.30 Clinicians should obtain a detailed account of a woman’s concerns regarding memory loss if she reports symptoms and refer her for additional testing if warranted.

Other Health Concerns Women have an increased risk of developing chronic medical conditions around the same age that they experience menopause.31 Health concerns for women in this age group include cardiovascular disease, osteoporosis, and cancer. Postmenopausal women have an increased risk of cardiovascular disease (CVD); the lifetime risk of heart disease after menopause approaches 1 in 2 women.32 There is an increased relative risk of CVD after induced menopause, specifically menopause induced by bilateral salpingoophorectomy, compared to the risk of heart disease in premenopausal women or women after natural menopause.33 The increased risk of heart disease in postmenopausal women is due to increased LDL and total cholesterol as well as adverse vascular changes and other risk factors.34 Other risk factors for heart disease, that are elevated in postmenopausal women, are serum levels of homocysteine

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and asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor.35 Clinicians can help reduce a patient’s risk of cardiovascular disease by increasing awareness, controlling modifiable risk factors, and aggressively treating at-risk patients. The American Heart Association recommends that physicians counsel women on smoking cessation; increasing physical activity to 30 minutes daily; consuming a diet of fruits and vegetables, whole grains, fiber and fish; limiting saturated fat and cholesterol in diets; and maintaining a BMI of less than 25 and waist circumference less than 35 inches. Physicians should maintain patients’ blood pressures at less than 120/80 and maintain optimal lipid profiles based on each patient’s risk category.32 Osteoporosis Osteoporosis and osteopenia are major causes of morbidity and mortality in the postmenopausal population. A woman’s lifetime risk of osteoporotic fracture after age 50 is 40%.36 Osteoporotic fractures occur secondary to decreased bone mineral density and decreased bone quality, which are affected by genetic makeup, life style, and gonadal hormones. Genetic factors are likely the most important contributors to bone density, accounting for about 75% of the variation in bone density in postmenopausal patients.12 There are ethnic differences in the rates of osteoporosis and fracture. White and Hispanic women have the highest risk of fracture, whereas Native American, black and AsianAmerican women have lower fracture risks.37 Estrogen acts to suppress bone resorption by suppressing production of pro-resorptive cytokines by megakaryocytes. The decreased levels of estrogen in postmenopausal women therefore causes increased bone resorption, especially in the early postmenopause stage. This phenomenon along with the decreased responsiveness of bone to mechanical forces leads to decreased bone density.38 Lifestyle factors that affect bone density include weightbearing exercise and calcium and vitamin D intake. Since these are modifiable risk factors, clinicians should encourage postmenopausal patients to consume 1000–1500 mg/ day of calcium with 400–800 IU of vitamin D in addition to engaging in weight-bearing exercise to improve bone density.12 Dual electron x-ray absorptimetry (DXA) scans are used to screen for osteoporosis. It is recommended that women over age 65 and women with identified risk factors receive screening so that treatment can be initiated if appropriate.12 DXA results are reported in T-scores and Z-scores. A Tscore is the number of standard deviation units a woman is from the mean peak bone mineral density of a white woman aged 20–29. Osteoporosis is diagnosed with a T-score of less than 2.5 or clinically with the presence of a fragility fracture. Osteopenia is diagnosed by a T-score between 1.0 and 2.5.37

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The goal of treatment of osteoporosis and osteopenia is to reduce the risk of bone fracture. Lifestyle modifications that should be recommended include smoking cessation, increasing vitamin D and calcium intake, and weight-bearing exercise. Pharmacologic interventions include selective estrogen-receptor modifiers (SERMs), bisphosphonates, and hormone therapy. Bisphosphonates are first-line treatment, which act by inhibiting osteoclast activity.12 SERMs act as estrogen agonists in bone and estrogen antagonists in breast and uterine tissue. Hormone therapy is recommended for women who cannot tolerate these other pharmacologic interventions or for women who have additional indications for hormone therapy, such as vasomotor symptoms. Breast Cancer Cancer rates increase with age; breast cancer is the most common cancer diagnosed in women and the cancer with the second highest mortality, after lung cancer. There are no current screening recommendations for lung cancer in asymptomatic women.39 Risk factors for breast cancer include age, family history, early age of menarche, nulliparity, and obesity. It is recommended that all women over the age of 40 have an annual mammogram and clinical breast examination.12

Role of hormone therapy Hormone therapy (HT) has been the principal treatment of menopause-related symptoms for over 50 years. The goal of HT is to adequately treat distressing symptoms of menopause with the lowest effective dose and the shortest duration of treatment. Hormone therapies differ by route of administration and formulation. HT can be administrated orally, transdermally, or locally. Hormone therapy is available as estrogen-only (ET) or estrogen–progesterone treatment (EPT). The primary indication for the addition of progesterone is to reduce the risk of endometrial cancer that occurs with unopposed estrogen. In addition, some studies have shown that the use of progesterone with low-dose estrogen may be more effective in treating vasomotor symptoms than estrogen-only formulations.2 Before commencing HT, a woman’s benefit  risk ratio for HT should be considered, which will differ based on a patient’s age, age at menopause, prior use of HT, and baseline risk of disease.2 Once a woman, in conjunction with her clinician, decides to use HT, she should be reevaluated annually to ensure that the treatment is still necessary and appropriate. The FDA recognizes three approved uses for HT: treatment of moderate to severe vasomotor symptoms, treatment of moderate to severe symptoms of vulvar and vaginal atrophy, and the prevention of postmenopausal osteoporosis

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when other treatments have failed and the risks outweigh the benefits.40 Furthermore, HT may reduce total mortality when initiated in women under the age of 60 years.2 HT is the most effective treatment for vasomotor symptoms. ET is also the most effective treatment for moderate to severe symptoms of urogenital atrophy. Many ETs and EPTs as well as all local estrogen therapies are shown to be effective in treating urogenital atrophy. If symptoms of urogenital atrophy are the only indications for treatment, the use of local, vaginal estrogen is recommended since this delivery method and low dose evokes minimal systemic absorption.2 HT reduces the number of osteoporotic fractures even in women without osteoporosis and can be used to prevent bone loss and reduce fracture risk in women. The effect of HT on the risk of cardiovascular disease depends on the individual patient profile. Analysis of data from the Women’s Health Initiative (WHI) has shown that HT may reduce the risk of heart disease when it is initiated in younger women, within 10 years of menopause, whereas the risk of heart disease is increased in women who initiate HT more than 10 years after menopause. Even though HT decreases heart disease risk in certain patient populations, it is not recommended for the prevention of cardiovascular disease as a primary use. There is inconsistent evidence as to whether HT increases the risk of stroke; both the ET and EPT arms of the WHI demonstrate an increased risk of ischemic stroke and no change in risk of hemorrhagic stroke, although overall, stroke events were rare events. HT has been found to increase the risk of venous thromboembolism, with a greater risk in patients over age 60.2,41 In the Women’s Health Initiative, the use of estrogen with progestin has been associated with the diagnosis of an additional 4–6 cases of invasive breast cancer per 10 000 women per year when women were treated for greater than 5 years. No such increase was found after 5 years of treatment in postmenopausal women using estrogen-only therapy. HT use in women with a history of breast cancer continues to be controversial.2 Estrogen therapy increases the risk of endometrial cancer that is related to the dose and duration of treatment; the risk of endometrial cancer is increased by five times when women are treated at a standard dose of estrogen (0.625 mg of conjugated equine estrogens) for more than 3 years. The risk of endometrial cancer is reduced by adding concurrent progesterone to treatment in at risk women.2 There has been an increased interest in bioidentical hormones, which might be attributable to societal concerns about safety of HT after publication of the WHI results. A recent study reported that women believed ‘natural hormones’ to be safer and more effective than conventional HT.42 Bioidentical hormones are hormones that are chemically identical to hormones produced in women. However, the term bioidentical hormone has more recently come to describe hormone therapies that are custom-compounded by pharmacists, said to be based on identified hormone deficiencies from each woman’s salivary assay. Because there are no clear data on the efficacy

of bioidentical hormones and the benefits and risks of conventional HT are better identified, conventional HT is considered more appropriate for treatment of postmenopausal patients. Conventional HT is also more cost-effective.2,17

Treatment alternatives to HT Recently, there has been increased interest in non-hormonal treatments for menopause symptoms. These treatments include prescribed medications like SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin-norepinephrine reuptake inhibitors), gabapentin, and clonidine, as well as non-prescribed treatments like red-clover and soy isoflavones. There are also practitioners who believe behavioral modification also has a role in management strategies. Randomized controlled trials have found SSRIs and SNRIs are effective in reducing the number and severity of hot flashes. Gabapentin has also been shown to reduce hot flash severity and frequency at a dose of 900 mg per day. Studies are inconsistent with regard to the efficacy of clonidine in reducing hot flash severity and frequency.43 Because these medications have moderate symptom relief with associated side effects, it is important that women be given realistic expectations with the use of these interventions. Red-clover isoflavones and soy isoflavones are two of the main sources of phytoestrogens. Most studies have shown that red-clover and soy isoflavones have no effect on the severity or frequency of hot flashes. However, red-clover isoflavones appear to be no different than placebo in adverse effects.44

Conclusion The menopausal transition and menopause are significant events in women’s lives. They serve as identifiable markers of a woman’s aging, and they often herald other health, psychosocial, and cultural changes, often with negative consequences. After a full medical evaluation, management should include assessing the woman’s views on menopause, addressing individual concerns, advising women about treatment options, and setting realistic goals from a prescribed management plan. HT is an option for the distressing vasomotor and urogenital symptoms experienced by some women during the menopausal transition and the menopause as well as an option for some women at risk for fracture.

References   1. Nelson HD. Menopause. Lancet 2008;371:760–70.   2. The North American Menopause Society. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of the North American Menopause Society. Menopause 2008;15(4):584–602.   3. Executive summary: stages of reproductive aging workshop (STRAW) Park City, Utah, July 2001. Menopause 8 (6) 402–407.

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  4. Gold EB, Bromberger J, Crawford S, et al. Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am J Epidemiol 2001;153(9):865–74.   5. Population Division, US Census Bureau. Percent distribution of the projected population by selected age groups and sex for the United States: 2010 to 2050. www.census.gov/population/www/projections/files/nation/summary/np2008-t3.csv. (Accessed 12/1/2008.)   6. Hale GE, Burger HG. Perimenopausal reproductive endocrinology. Endocrinol Metab Clin North Am 2005;34:907–22.   7. Richardson SJ, Nelson JF. Follicular depletion during the menopausal transition. Ann NY Acad Sci 1990;592:13–20.   8. Burger HG, Hale GE, Dennerstein L, Robertson DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause 2008;15(4):603–12.   9. Burger HG, Hale GE, Robertson DM, Dennerstein L. A review of hormonal changes during the menopausal transition: focus on findings from the Melbourne Women’s Midlife Project. Hum Reprod Update 2007;13(6):559–65. 10. Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest 1975;55(4):699–706. 11. Klein NA, Harper AJ, Houmard BS, Sluss PM, Soules MR. Is the short follicular phase in older women secondary to advanced or accelerated dominant follicle development?. J Clin Endocrinol Metab 2002;87(12):5746–50. 12. Lund KJ. Menopause and the menopausal transition. Med Clin North Am 2008;95:1253–71. 13. Landgren BM, Collins A, Csemiczky G, Burger HG, Baksheev L, Robertson DM. Menopause transition: annual changes in serum hormonal patterns over the menstrual cycle in women during a nine-year period prior to menopause. J Clin Endocrinol Metab 2004;89(6):2763–69. 14. Santoro N. The menopausal transition. Am J Med 2005; S12B:8–13. 15. The Practice Committee of the American Society of Repro­ ductive Medicine Committee Opinion. The menopausal transition. Fertil Steril 2006;86(4):S253–56. 16. Lee JG. Hormonal markers predicts menopause onset. Endocrine News 2008;33:24–25. 17. Cirigliano M. Bioidentical hormone therapy: a review of the evidence. J Womens Health 2007;16(5):600–31. 18. Fogle RH, Stanczyk FZ, Zhang X, Paulson RJ. Ovarian androgen production in postmenopausal women. J Clin Endocrinol Metabol 2007;92(8):3040–43. 19. Blake J. Menopause: evidence-based practice. Best Pract Res Clin Obstet Gynaecol 2006;20(6):799–839. 20. Santoro N. Symptoms of menopause: hot flushes. Clin Obstet Gynecol 2008;51(3):539–48. 21. Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes DF. Hot flushes. Lancet 2002;360:1851–61. 22. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96(3):351–58. 23. North American Menopause Society Position Statement. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women, position statement of the North American Menopause Society. Menopause 2007;14(3):357–69. 24. Wines N, Wilsteed E. Menopause and the skin. Australas J Dermatol 2001;42(3):149–60.

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25. Mehta A, Bachmann G. Vulvovaginal complaints. Clin Obstet Gynecol 2008;51(3):549–55. 26. Van Voorhis BJ, Santoro N, Harlow S, Crawford SL, Randolph J. The relationship of bleeding patterns to daily reproductive hormones in women approaching menopause. Obstet Gynecol 2008;112(1):101–8. 27. Bhathena RK, Guillebaud J. Contraception for the older woman: an update. Climacteric 2006;9:264–76. 28. La ValluerJ, Wysocki S. Selection of oral contraceptives or hormone replacement therapy: patient communication and counseling issues. Am J Obstet Gynecol 2001;185(Suppl. 2):S57–64. 29. Clayton A, Guico-Pabia C. Recognition of depression among women presenting with menopausal symptoms. Menopause 2008;15(4):758–67. 30. Henderson VW. Cognitive changes after menopause: influences of estrogen. Clin Obstet Gynecol 2008;51(3):618–26. 31. Owens GM. Gender differences in health care expenditures, resource utilization, and quality of care. J Manag Care Pharm 2008;14(Suppl. 3):2–6. 32. Mosca L, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115(11):1481–501. 33. Stampfer MJ, Colditz GA, Willett WC. Menopause and heart disease: a review. Ann N Y Acad Sci 1990;592:193–203. 34. Fukami K, Koike K, Hirota K, Yoshikawa H, Miyake A. Perimenopausal changes in serum lipids and lipoproteins: a 7year longitudinal study. Maturitas 1995;22:193–97. 35. Verhoeven MO, van der Mooren MJ, Teerlink T, Verheijen RHM, Scheffer PG, Kenemans P. The influence of physiological and surgical menopause on coronary heart disease risk markers. Menopause 2009;16(1), [Epub ahead of print]. 36. Owens GM. Gender differences in health care expenditures, resource utilization, and quality of care. J Manag Care Pharm 2008;14(Suppl. 3):2–6. 37. The North American Menopause Society. Management of osteoporosis in postmenopausal women, position statement of the North American Menopause Society. Menopause 2006;13(3):340–67. 38. Zofkova I. Hormonal aspects of the muscle-bone unit. Physiol Res 2008;57(S1):159–69. 39. US Preventive Services Task Force. Lung cancer screening recommendation statement. Available at www.ahrq.gov/clinic/ uspstf/uspslung.htm. Accessed 8 December 2008. 40. FDA approves new labels for estrogen and estrogen with progestin therapies for postmenopausal women following review of women’s health initiative data. www.fda.gov/bbs/topics/ NEWS/2003/NEW00863.html. Accessed 3 December 2008. 41. Anderson GL, Limacher M, Assaf AR, et al. For the Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701–12. 42. Adams C, Cannell S. Women’s beliefs about ‘natural’ hormones and natural hormone replacement therapy. Menopause 2001;8(6):433–40. 43. Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for hot flashes. JAMA 2006;295(17):2057–71. 44. Rees M. Alternative treatments for menopause 2008. Best Pract Res Clin Obstet Gynaecol 2009;23(1):151–61.

Section 7

Oncology

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INTRODUCTION

Nancy E. Davidson Although cancer is a pervasive illness, its burden is not felt equally by men and women. In the United States it is estimated that 1 in 2 men and 1 in 3 women will develop cancer during their lifetimes. Thus gender differences are apparent at the highest level. Of course some types of cancer are gender-specific, e.g. prostate cancer in men and endometrial cancer in women. But most cancers are diagnosed in both men and women, and variation in incidence may reflect differences in specific risk factors like smoking or other unknown variables. In addition to gender-related differences in incidence, variations in biology, treatment, and outcomes may also be observed between the sexes. For example, data about gender differences in outcome for lung cancer treatment between men and woman are emerging. Nowhere is the field of gender-specific differences in malignancy better understood than in two reproductive cancers: breast cancer and germ cell tumors. Breast cancer is the most common non-skin cancer in women and among the least common cancers in men. It is hormone-responsive in the vast majority of men and a smaller fraction of women. Thus it has been suggested that male breast cancer be approached in an analogous fashion to postmenopausal hormone-responsive breast cancer. In the chapters that

f­ ollow, this hypothesis is elegantly addressed by Omene and Tiersten. In contrast, germ cell tumors are among the least common tumors in both men and women. As outlined by LaNatra and Tiersten, there is a greater knowledge gap in our understanding of the molecular mechanisms underlying germ cell transformation in women than in men. Despite differences in anatomy, however, the principles of surgery, radiation, and chemotherapy are similar. Finally, the genomic era has brought us closer to a time of personalized medicine. A key part of this will be the ability to carry out individualized genetic assessment to counsel individuals about their innate genetic predisposition to malignancy and risk reduction strategies. Such genetic counseling is already possible for several of the hereditary cancer syndromes, including breast, ovarian, endometrial, colorectal, and endocrine cancer syndromes. The nuances and practical applications of gender differences in these syndromes are eloquently summarized by Chung. Cancer incidence and mortality have begun to fall in the United States. Nonetheless it is predicted that cancer will surpass heart disease as the top killer in the United States in 2010. These statistics provide the imperative to understand all aspects of cancer so that we can exploit these findings to facilitate prevention, early detection, treatment, and survivorship. We should not forget, however, that there are likely to be gender-specific features that must be used to guide research and application.

Chapter

42

The Differences between Male and Female Breast Cancer Coral Omene1, and Amy Tiersten2 1

New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA Associate Professor of Medicine (Oncology), New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA 2

Introduction

Male and female breasts are similar at birth, consisting of a small number of rudimentary branching ducts beneath the nipple–areola complex. They diverge at the time of puberty. In males, development ceases. In females there is continued growth and branching of the lactiferous ducts and increased adipose and stromal tissue. As a result, progressive enlargement of the breasts occurs. Eventually, the terminal ducts give rise to saccular buds from which secretory glands develop during pregnancy. After lactation ceases, there is glandular atrophy and once again the stromal elements are the predominant component of the breast.

Breast cancer is a disease that develops in both men and women. While there are similarities in this disease between the two genders, there are also differences. It is the most commonly diagnosed malignancy in women, second only to skin cancer, with associated immense socioeconomic ramifications. However, in men, breast cancer is rare. Is this disease biologically different in men and women? Or is it similar between the sexes with the same etiologic, prognostic, and clinical features? The data to date suggest that breast cancer in men is fundamentally identical to breast cancer in women with few exceptions. This chapter explores the classic features of breast cancer in both sexes, highlighting the differences and the similarities between them and what is as yet unknown.

Epidemiology Breast cancer has a significant impact on the health of women. It is the most common cancer among women other than skin cancer and the second leading cause of death in women after lung cancer. It represents 31% of all cancers diagnosed and 15% of all cancer deaths in women.1 Approximately 184 450 women in the United States were diagnosed with invasive breast cancer in 2008 and 40 930 women died from the disease.2 Through age 85, the lifetime risk of being diagnosed with breast cancer for an American woman is or 1 in 8 and the chance of dying from the disease is 1 in 33.1 This is in contrast to men in whom breast cancer is a rare disease. Male breast cancer accounts for less than 1% (0.7%) of all breast cancer diagnoses,3 and 0.2% of all male cancer deaths.3 Similarly to breast cancer in women, breast cancer in men has been increasing; the incidence has climbed 26% over the past 25 years. However, the overall incidence in the United States remains low: approximately

Anatomy and development Both men and women have breasts; however, the rate of breast cancer is much higher in women. This is due, in part, to the anatomic differences between them. Breast tissue is well developed only in women. The female breast consists of some 15–20 lobules of glandular tissue that form the functional units of the breast. Each lobule is drained by a lactiferous duct, which opens on the nipple. Deep to the areola, each duct enlarges to form a lactiferous sinus in which milk can accumulate. The lobules are connected and supported by various amounts of fibrous connective tissue and adipose tissue. It is these stromal elements that comprise the majority of the breast volume in the nonlactational state.

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one case per 100 000 population per year.4 It is dissimilar to female breast cancer, in that the incidence rates are higher among black men than white men and continue rising in men aged 55 years or older, resulting in a late average age at onset.5,6 The mean age at diagnosis for men with breast cancer is 67 years, which is 5 years older than the average age at diagnosis for women.7 According to the SEER database of the National Cancer Institute, the estimated numbers of male breast cancer cases expected in the United States are rising. Since 1987 the annual number of breast cancer cases in males has increased 1.6 times.8,9 In a retrospective review of 217 cases of male breast cancer obtained from tumor registries at 18 institutions between 1953 to 1995, the number of cases registered annually increased progressively.8 Fifty of the cases were diagnosed after 1986 (Figure 42.1). This increase is likely multifactorial, influenced by the proliferation of tumor registries, increased use of urban healthcare facilities, and perhaps by a true rise in the incidence of the disease. In addition, the increased awareness and public education regarding breast cancer and screening directed toward women may play a role in the recognition of this disease by men and their doctors. Female breast cancer incidence and mortality rates vary between countries and to a lesser extent within different areas of the United States.10 The incidence is highest in the United States and Northern Europe and is lowest in Asia. Muir et al.11 report that the highest incidence for male breast cancer occurs in Brazil, at a rate of 3.4 cases per 100 000 versus Columbia, Singapore, Hungary, and Japan, where the incidence is much lower at 0.1 cases per 100 000. In the United States, the overall age-adjusted breast cancer incidence rate is higher among white than black women, although black women age 35 have a higher incidence rate than white women.10 However, with regards to male breast cancer, black men seem to have a higher incidence of breast cancer than white and Asian-Pacific men in the United States.5,6

Number of cases

30

20

10

1953 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1966 1968 1969 1970 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996

0

Year of diagnosis

Figure 42.1  Male breast carcinoma cases by year of diagnosis. The majority were diagnosed after 1981. Reproduced from Donegan et al., 1998.8 Copyright 1998, American Cancer Society. This material is reproduced with permission of WileyLiss, Inc., a subsidiary of John Wiley & Sons, Inc.

Risk factors Breast cancer in females has been extensively studied and this has resulted in a wealth of information of the known factors that may increase a woman’s risk for this disease. However, little is known about the etiology of male breast cancer. This difference is mostly due to the rarity of the disease in men, which greatly limits the application of epidemiologic methodology to studies in male breast cancer, thus, far fewer data have accumulated. Therefore, risk factors in general remain uncertain. There are some epidemiologic studies that have afforded some insight into this disease. Various hormonal, lifestyle, and genetic factors reported to play a role in the development of breast cancer are described in the following sections. However, most individuals of either gender who develop breast cancer have no apparent risk factor for the disease, and most male patients have no detectable hormonal imbalances.12

Reproductive and Hormonal In epidemiologic studies, a woman’s reproductive history has been consistently shown to contribute to the risk of developing breast cancer, underscoring the role of endogenous related risk factors in normal and abnormal breast development. Early menarche, shorter cycle length, nulliparity or low parity, and late menopause are several reproductive variables that increase a woman’s risk for developing breast cancer. After menopause, adipose tissue becomes the major source of estrogen and obese, postmenopausal women have higher levels of endogenous estrogen and a higher risk of developing cancer.13 Exogenous estrogen use in the form of oral contraceptives use and the risk of subsequent breast cancer is an important concern of women. The Nurses’ Health Study examined more than 3000 cases of breast cancer diagnosed prospectively between 1976 to 1992. At the start of the study, 46% of women reported past or current use of oral contraceptive pills. In sum, they found no increased risk of breast cancer associated with the use or duration of use of oral contraceptives. No conclusions could be drawn, however, for women younger than 40 because there were too few cases of breast cancer in that age group.14 Other studies have suggested a risk for developing breast cancer in women who use oral contraceptives when they are younger than 35 years. In a case-control study of women between the ages of 20 through 44 years, which examined 1648 cases of breast cancer and 1505 controls, the relative risk (RR) for breast cancer development was 1.3 in oral contraceptive users younger than age 45. The RR increased to 1.7 in users younger than 35 years and up to 2.2 in women using the pill for more than 10 years.15 This slight increase in RR is unlikely to translate into large differences in attributable risk, because the incidence of breast cancer is so low in this population. The data regarding postmenopausal hormone replacement therapy have also been examined in many epidemiologic studies.

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One study of note is the estrogen plus progestin component of the Women’s Health Initiative (WHI), a randomized controlled primary prevention trial, in which 16 608 postmenopausal women aged 50–79 years were recruited by 40 US clinical centers in 1993–8. The study was stopped early due to the estimated hazard ratios for breast cancer of 1.26 (1.00–1.59) with 290 cases. The overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women.16 However, data from the estrogen-alone component of the WHI study showed that invasive breast cancer was diagnosed at a 23% lower rate in the estrogen-alone group compared to placebo and this comparison narrowly missed statistical significance.17 The hormonal influence on breast cancer risk in men has also been described. Conditions that result in relative estrogen excess or lack of androgens have been linked to cases of male breast cancer in epidemiologic studies. The strongest risk factor for developing male breast cancer is Klinefelter syndrome, a condition that results from the inheritance of an additional X chromosome. Affected males have atrophic testes resulting in low plasma levels of testosterone. Their circulating levels of gonadotropins (follicle-stimulating hormone and luteinizing hormone) remain high, thus exposing them to a high estrogen/testosterone ratio. These men have a 50 times higher rate of developing breast cancer than those with no genetic abnormality and may account for up to 3–7% of male breast cancers.18,19 Other conditions affecting the testes have also been reported to increase risk, including mumps orchitis, undescended testes, or testicular injury.20 This too may suggest a hormonal association; however, it remains unclear if testosterone levels are actually abnormal at the time of breast cancer diagnosis in these men.20 Chronic liver disease leading to cirrhosis may predispose males to the development of breast cancer. There have been reports of a four-fold and a nonsignificant three-fold increase in risk associated with liver cirrhosis and male breast cancer.21,22 It is believed that the diseased liver and its altered metabolism lead to a hyperestrogenic state promoting the growth of breast tissue and subsequent risk of malignant transformation. Gynecomastia has been reported in association with breast cancer in men. However, the role of gynecomastia as a risk factor in male breast cancer is unclear as it is found in up to 50% of male breast cancer patients at autopsy and is relatively common in healthy men. It may impart an increased risk for the development of breast cancer or simply serves as a marker for an underlying hyperestrogenic state.23 Exogenous estrogens have also been implicated in this disease. There have been reports of transsexuals developing breast cancer. Treatment required to induce maleto-female sexual change include surgical and chemical castration and prolonged administration of large doses of female hormones, especially estrogens. Castration may lower androgen levels creating a high estrogen-to-androgen

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ratio, thus potentially increasing the risk for breast cancer.24 There have been several documented cases of breast cancer among transsexuals, which are characterized by short latent periods (5–10 years) after exposure to female hormones before the appearance of tumor and at earlier diagnosis.25 Additionally, there have been reports of breast cancer in men receiving treatment for prostate cancer.24–26

Dietary and Environmental The causal relationship between dietary fat consumption and breast cancer remains controversial. There have been several prospective cohort studies examining this issue and in those with over 200 incident cases of breast cancer there was no association seen with dietary fat intake.27–32 Hunter et al.33 published a pooled analysis of 4980 cases of breast cancer in 337 819 women and again no association was observed between intake of total, saturated, monounsaturated, or polyunsaturated fat and risk of breast cancer. What does appear to play an important but complex role in the causation of breast cancer is energy balance. High-energy intake in relation to expenditure accelerates growth and the onset of menstruation. If this positive balance continues it can lead to weight gain later in life and overall increases a woman’s risk of subsequent breast cancer. Other dietary factors, including vitamins, fiber, alcohol consumption, and caffeine, and the role they play in the development of breast cancer, have also been thoroughly explored in women. It appears that alcohol intake is the best-established specific dietary risk factor for breast cancer in women.34 The studies performed to examine this relationship, all of which were controlled for other major breast cancer risk factors, consistently support the existence of a positive association between alcohol consumption and risk of breast cancer in women. In addition, it has been shown that moderate alcohol consumption of approximately two drinks per day has been shown to increase estrogen levels providing a mechanism by which breast cancer risk might be increased.35 In men, two studies of chronic alcoholics noted a two-fold increase in risk in male breast cancer36 and a population-based case-control study observed an approximately six-fold increase in risk in the highest alcohol exposure category compared with light drinkers and non-drinkers.37 While these similarities have been reported, other studies have shown no association.38 Clearly, there are numerous studies examining female breast cancer and potential risk factors for this disease. Through these efforts, an abundance of knowledge has been gained. It remains less clear which of these established or potential risk factors plays a role in the development of male breast cancer. There have been some reported casecontrol studies in the literature that attempt to further define this issue. For example, Rosenblatt et al. investigated the relationship between food and beverage consumption and the development of breast cancer in men in a report of 220 cases of male breast cancer and 291 controls.38 No trends in

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risk were observed with increasing intakes of specific food, with the exception of citrus fruits. The authors conclude that dietary factors are unlikely to be strong determinants of breast cancer in men.38 Obesity has been implicated in the etiology of male breast cancer due to higher circulating estrogen levels and has fairly consistently been associated with an increased risk of breast cancer in men. For example, Hsing et al. in a case-control study obtained demographic and dietary information from next-of-kin interviews of 178 men who had died of breast cancer and 512 male controls.39 This study reported that obesity was a significant risk factor for male breast cancer whether evaluated by usual adult weight, body mass index or perceived overweight.39

Genetics Several genes that are associated with a high lifetime risk of breast cancer in females have been identified. These genes appear responsible for 5–10% of all breast cancer cases.40 Two such susceptibility genes are BRCA1 located on chromosome 17 and BRCA2 on chromosome 13. Mutations in both genes predispose to earlier onset and increase risk of female breast cancer, but the risk profile and risk of cancers at other sites differs between the two genes.40 Studies by the Breast Cancer Linkage Consortium (BCLC) have shown that both genes increase the risk of female breast cancer to 80–85% by the age of 80.41,42 For ovarian cancer, BRCA1 confers a 60% lifetime risk and BRCA2 a 27% risk.42 Both genes are also now thought to increase the risk of prostate cancer, and BRCA2 has been associated with a variety of other malignant disorders as well, including male breast cancer.43 In one study that included 237 hereditary breast carcinoma families, 26 families had at least one male member who had been diagnosed with breast cancer and in 77% the disease was linked to mutations in BRCA2.42 Similar to female breast cancer, BRCA2 mutations are thought to be associated with a 6% lifetime risk of male breast cancer representing a 100-fold increased RR over the general population.43 One report by Couch et al.44 analyzed 50 cases of male breast cancer for BRCA2 mutations. The mutation was found in 14% of the cases, but these were men who had a significant family history of breast cancer. The prevalence of BRCA2 mutations in male breast cancer cases unselected for family history has been reported by Friedman et al.45 This study demonstrated a 4% prevalence of BRCA2 mutations. The data remain inconclusive mainly because male breast cancer is an infrequent occurrence and even more difficult to study in the context of an inheritable familial disease. In a recent report examining 94 cases of male breast cancer, there were 9.37 excess cases of breast cancer in female first-degree relatives of which only one was accounted for by BRCA2.46 The authors concluded that BRCA2 accounts for approximately 15% of the excess risk. The association between male breast cancer and a deleterious germline mutation in BRCA1 is less clear. Initial data

suggested that inherited male breast cancer was not linked to germline mutations in BRCA1.47 However, a more recent study in a series of 10 000 individuals reported that 21 of 76 men with breast cancer had mutations in either BRCA1 or BRCA2 and that more than one-third of those mutations were in BRCA1.48 In a most recent study, Tai et al.49 reports the estimated cumulative risk of breast cancer for male BRAC1 muta­tion carriers at age 70 years to be 1.2% and for BRCA2 mutation carriers to be 6.8%. The relative risks of developing male breast cancer were highest for men in their 30s and 40s and decreased with increasing age. This trend was most pronounced in BRCA2 mutation carriers, where the relative risk at age 30 years was 22.3 times that at age 70 years. The possibility of additional male breast cancer susceptibility genes is suggested and remains an area of active investigation. Families have been identified with mutations of the androgen receptor gene, PTEN (Cowden’s syndrome)50,51 and mismatch repair gene genes (hMLH1) in male patients with breast cancer.52 However, none of these genes has been demonstrated to have a causal association with male breast cancer. Further studies are needed to elucidate their role.

Clinical factors and diagnosis Breast cancer in males generally occurs a decade later than breast cancer in females with a mean age of presentation ranging from 60 to 65.12 The presenting symptom in most patients is a nontender, palpable mass that is centrally located 70–90% of the time.12 Nipple involvement is a fairly early event, with retraction seen in 9%, discharge in 6%, and ulceration in 6% of male breast cancer patients. Paget’s disease is rare, being the presenting feature in only 1%, with a mean age of 60 years, similar to that of other men with breast cancer.53,54 Serosanguineous or bloody discharge from the male breast is associated with malignancy in 75% of the cases and should always be investigated by biopsy.12,55 When bloody discharge occurs from the female breast it is most commonly due to a benign papillary adenoma. Axillary adenopathy suspicious for metastatic disease is clinically detected in 40–55% of male patients at diagnosis. Bilateral breast cancer occurs much less freque­ ntly in males than in females and is reported to be in the range of 1.4–1.9%.55 This is likely due to the lack of lobular differentiation in men because it is frequently the lobular forms of cancer that present with multicentric and bilateral disease. As in women, there is a slight preponderance of left-sided versus right-sided disease.56 Both male and female breast cancers are staged according to the American Joint Committee Clinical Staging System (AJCC), which is based on tumor size, axillary lymph node involvement, and evidence of distant metastases. In general, breast cancer in men presents at a later

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stage than the disease in women.23,57,58 This has been attributed to a delay in diagnosis. The rarity of male breast cancer and therefore the low index of suspicion of both patients and doctors have been largely responsible for the delay in diagnosis. The older series reported a mean duration of symptoms anywhere between 14 and 21 months, suggesting a lack of recognition of this uncommon entity by men and their physicians.12 One of the largest retrospective series included 215 cases of male breast cancer from 1953 to 1995.8 In this study the average duration of symptoms was 10.2 months. Over time, this appeared to improve as reflected by a decrease in the mean tumor size from 2.87 cm to 2.42 cm during two time periods analyzed (1953–1985 and 1986–1995).8 AJCC TMN staging was available for 155 of these cases (72%). Stage I represented 19%, stage II was 46%, and stages III and IV accounted for 13% and 14% of the cases, respectively.8 Another series of 104 men with breast cancer reported by Borgen et al. compared the stage at presentation of the male patients to a female cohort treated at the same time.23 They found a preponderance of stage III tumors in the male group. Between 1975 to 1990, there were 95 male breast cancer cases: 17% of these were stage 0, 27% stage I, 33% stage II, and 22% stage III. In a female cohort of 932 patients who presented to a single institution in 1989 there were 18% with stage 0 disease, 32% with stage I disease, 39% with stage II disease, and only 6% with stage III disease.23 In the evaluation of suspected female breast disease, mammography plays a pivotal and well-accepted role. Most women are diagnosed in an asymptomatic state due largely to mammography. In addition, when used as a screening tool in asymptomatic, older women it has been shown to reduce mortality from breast cancer by 30%.59 Results from seven population-based community screening programs in the United States on 463 372 screening mammograms in women revealed an overall sensitivity of 75% and specificity of 92.3%.60 The role of mammography in male breast disease is much less defined. Ideally it would serve to distinguish benign from malignant processes; however, there is no consensus to date on its utility in this capacity. Evans et al.61 attempted to define the diagnostic accuracy of mammography in evaluation of male breast disease. Using 104 mammograms categorized into malignant, benign, gynecomastia, or normal and comparing them to definitive tissue diagnoses they determined a sensitivity of 92%, specificity of 90%, positive predictive value of 55%, and a negative predictive value of 99% for mammography in diagnosis of malignant disease. In this series, 11 of 12 breast cancers in men were detected by mammography; 6 of the cases had concurrent gynecomastia. Clinical, radiographic, and pathologic records of 165 symptomatic men presenting to breast imaging over a 4 year period were restrospectively reviewed. Twelve with benign mammographic findings had benign biopsies. All men with benign mammography not undergoing biopsy were cancer free. Sensitivity for cancer detection

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(mammography) was 100% and specificity was 90%. Positive predictive value (mammography) was 32% (6 of 19) and the negative predictive value was 100%. Thus, it was concluded that mammography had excellent sensitivity and specificity for breast cancer detection and should be included as the initial imaging examination of men with clinical breast symptoms. The negative predictive value of 100% for mammography suggests that mammograms read as normal or negative need no further examination if the clinical findings are not suspicious.62 Although this study addresses the accuracy of mammography, other factors such as history and physical examination (PE) clearly play a role in making the diagnosis and cannot be replaced by a single test. Many investigators argue that the algorithm in diagnosing male breast disease should involve PE followed by biopsy when needed with mammography reserved for excluding contralateral malignant disease.23,63 In addition, because of the rare nature of male breast cancer, screening mammography is not advocated for the general male population. Vetto et al.63 studied the combination of PE and fine needle aspiration (FNA) with or without mammography as an alternative approach to surgical biopsy in the diagnosis of breast masses in men. They looked at 51 consecutive men with unilateral breast masses and using these tools scored them as benign or malignant. All tests were benign in 38 cases and no cancers subsequently developed. In six cases, the tests were suspicious and open biopsy confirmed malignancy. There were seven cases in which PE and FNA were not in agreement, so open biopsy was performed leading to a diagnosis of benign disease. Mammography, which was performed in 13 of the cases, added no further information. They concluded that the combination of an adequate FNA and PE is diagnostically accurate and when used appropriately can avoid unnecessary biopsies for benign disease.63 Breast magnetic resonance imaging (MRI) plays an increasing role in the management of selected breast cancer patients. MRI is recognized as the most sensitive modality for the detection of invasive breast cancer and several valuable clinical applications of MRI have emerged for breast cancer detection and diagnosis from clinical investigations. Annual MRI plus mammography is now the standard of care for screening women aged 30 years or older who are known or likely to have inherited a strong predisposition to breast cancer such as breast cancer gene carriers and patients treated with chest radiation. Breast MRI is helpful for women diagnosed with breast cancer who contemplate breast-conserving surgery; it provides valuable information on the extent of the disease and it can also help assess for residual invasive cancer in patients who have undergone lumpectomy with positive margins at pathology.64 Furthermore, MRI is also reliable in finding breast cancer in women with axillary nodal metastases and unknown primary tumour and can help to monitor the response to chemotherapy.64 However, in general, MRI should not be used in

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place of a well-formed mammogram or ultrasound.64 While MRI is used in women, it has not been studied regarding sensitivity in diagnosis in men, but since lesions are always palpable and can be biopsied easily under palpation, there is no clear role for MRI in male breast cancer.

Pathologic features Since male breast tissue is rudimentary, it usually does not differentiate and undergo lobule formation unless exposed to increased concentrations of endogenous or exogenous estrogen. Thus, similarly to its female counterpart, the most common histology of male breast cancer is invasive ductal carcinoma, which accounts for more than 90% of all male breast tumors. Because of the lack of lobules in the male breast, lobular carcinoma is very uncommon (1%) but has been reported in the literature.65 In situ ductal carcinoma is seen in 20–25% of female breast cancer cases. In men, the percentage is much less, ranging from 0% to 17% .66 There are many pathologic subtypes used to describe female breast cancer-medullary, mucinous, squamous, papillary, and adenocystic-and in general all of these different subtypes have also been reported in men. Estrogen receptor (ER) and progesterone receptor (PR) status is routine in the pathologic evaluation of female breast cancer. One, or both, is positive in 60–70% of the cases.67 From the literature there seems to be a consensus that cancers of the male breast are significantly more likely than cancers of the female breast to express hormone receptors, even after adjustment for tumor stage, grade and patient age.67 There have now been several published series that reported an ER and/or PR positivity rate in male breast tumors of greater than 90%.68 In other published reports the rate is slightly lower ranging between 70% and 90%.53As in female breast cancer, the rates of hormone-receptor positivity increase with increasing patient age.7 The study of molecular markers including protooncogenes, cell cycle regulatory proteins, and markers of apoptosis have led to new insights into the biology of female breast cancer. The HER2-neu protein is a transmembrane receptor protein with tyrosine kinase activity involved in normal cell growth and division. HER2 overexpression, usually secondary to gene amplification, is seen in 20–30% of invasive female breast cancers and is associated with a poorer outcome and shortened survival.69 The two methods used to assess HER2-neu status include immunohistochemistry and fluorescence in situ hybridization (FISH); these are routinely used in the evaluation of female breast tumors. Much less is known about the presence and prognostic significance of these molecular markers in males with breast cancer although data are emerging.67,70 Table 42.1 highlights rates of HER2-neu overexpression in various series of male breast cancer reported in the literature. These early

Table 42.1  Rates of HER2-neu positivity in male breast cancer reported in the literature Study

No. of cases

HER2- neu

Wick et al.67 Rayson et al.68 Joshe et al.58 Andre et al.71 Shpitz et al.72 Pich et al.73

10 76 17 82 26 50

30% 29% 41% 12% 39% 56%

reports have suggested equivalent rates of HER2-neu overexpression between male and female breast cancers, however it is thought that these results were an overestimation likely attributable to periods before improved standardization of methodology. In support of this, there have been studies that show that HER2-neu proto-oncogene is less likely to be overexpressed in male breast cancer. In one study of a series of 75 patients, only 5% of male breast cancers overexpressed HER2-neu.74 Similarly, Bloom et al. found that only one of 58 male breast cancers overexpressed HER2-neu and that zero of 58 had gene amplification, compared with 26% of female breast cancer tumors showing overexpression and 27% manifesting amplification.75 In a series of 111 male breast cancer patients from the Mayo Clinic, tumor samples were analyzed for the presence of various markers. Androgen receptor was almost uniformly present, positive in 95% of the cases. HER2 was positive in 29% and p53 in 21% of the cases. The cell cycle regulatory protein cyclin Dl, which is expressed in approximately 50% of female breast tumors, was also present in 58% of male cases. Shpitz et al.72 in a report of 26 male breast cancer patients found that p53 and HER2-neu were expressed in 46% and 39%, respectively. They found no correlation between the presence of these biomarkers and adverse clinical features or survival. This is in contrary to a report by Pich et al.74 They retrospectively reviewed 50 male patients with breast cancer and found that HER2-2 and p53 protein overexpression significantly correlated with a worse prognosis. The rate of HER2 positivity was 56% in their series.

Prognostic factors Prognostic factors are those measurements available at the time of diagnosis that are associated with disease-free or overall survival and can often be used to predict the natural history of the tumor. Optimizing treatment based on prognostic factors plays an important role in the management of female breast cancer. The standard prognostic factors currently applied in new cases of breast cancer include axillary lymph node status, histologic subtype, tumor size, nuclear

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Table 42.2  Survival rates based on axillary lymph node status in males with breast cancer Study

No.

Nodal

5-year survival

5-year DSS

10-year survival

10-year DSS

Cutuli et al.

308

Guinee et al.79

224

Borgen et al.23

104

Herman et al.76

45

McLachlan et al.77

66

Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative

63% 82% NR NR 60% 100% 59.6% 87.4% 55% 81%

67% 93% 65–73% 90% NR NR NR NR NR NR

28% 58% NR NR NR NR 58.3% 28.6% NR NR

39% 77% 14–44%* 84% NR NR NR NR NR NR

78

NR, not reported. * Ranges depending on number of involved nodes (1–3 or 4).

Table 42.3  Five-year survival in men based on stage reported in the literature Study

No. of cases

Stage I

Stage II

Stage III

Stage IV

Borgen et al.23 Donegan et al.8 Joshe et al.58

104 155 46

83% 85% 100%

70% 60% 83%

74% 30% 60%

NR 10% 25%

NR, not reported.

grade, hormone receptor status, measures of proliferation, and molecular markers such as HER2 overexpression. Of these, the presence or absence of metastatic carcinoma in the axillary lymph nodes is the most powerful prognostic factor for patients with primary breast cancer. In male breast cancer, tumor size, and lymph node involvement are two clear prognostic factors for male patients with breast cancer.7 Men with tumors measuring 2–5 cm have a 40% higher risk of death than men with tumors 2 cm in maximum diameter.7 Similarly, men with lymph node involvement have a 50% higher risk of death than those without lymph node involvement.7 There are a number of reports in male breast cancer that also correlate outcome with nodal involvement (Table 42.2).76,77 Guinee et al.,79 after reviewing 335 cases of male breast cancer over a 20-year period, found 10-year survival to be 84% for patients with histologically negative nodes, 44% if one to three nodes were positive, and 14% in those patients with more than four positive nodes. Five-year survival in male breast cancer declines with increasing stage of disease (Table 42.3). This is similar to what is seen in females (Table 42.4). Of the other prognostic factors frequently considered in female breast cancer, controversy exists over their usefulness in male breast cancer cases. There are numerous series in the literature addressing these issues, but, because of the rarity of male breast cancer, none of them is large enough or designed appropriately to evaluate potential molecular or pathologic markers as prognostic indicators.

Table 42.4  Ten-year relative survival rates in women undergoing local and adjuvant treatment Stage of disease

10-year survival

0 I II III IV

95% 88% 66% 36% 7% Source: Fremgen, AM, Bland KI, McGinnis LS Jr et al. Clinical highlights from the National Cancer Data Base, 1999. CA Cancer J Clin 1999;49:145-58

Treatment Surgical Management The mainstay of managing early stage breast cancer is surgical removal of the tumor. In women, both modified radical mastectomy and lumpectomy with radiation are equivalent approaches.80 This differs in men. Compared with mastectomy, lumpectomy was associated with significantly worse control rate in a Canadian series of 229 patients treated over 40 years where 8.7% of whom where treated with lumpectomy.81 Because of the lack of breast tissue and central location of most tumors, breast conservation is not a viable option. Historically, radical mastectomy was often performed, but retrospective studies indicate that the outcome for men is equally good when treated with less invasive surgery.82 The transition to the modified radical mastectomy in men was also based on the equivalent outcomes to radical mastectomy seen with this approach in women.11 Whether or not the lymph nodes are involved is one of the major prognostic factors in breast cancer, and knowing the status of the axillary lymph nodes is critical in guiding further management of the patient. Sentinel lymph node biopsy (SLNB) is a widely implemented technique for evaluating the axillary status in clinically node-negative cases in

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women. Several case series have established the feasibility of sentinel node biopsy in male breast cancer. Among a total of 56 male patients combined from these reports, the sentinel node was successfully identified in all but one patient.83–86 A combined total of 11 patients with a negative sentinel node biopsy underwent confirmatory axillary dissection and none had any additional nodes.83–86 This procedure is now being increasingly used in male patients who are clinically node-negative. So, similarly to women, most men are treated with modified radical mastectomy with axillary lymph node dissection or sentinel lymph node biopsy.56

Adjuvant Systemic Therapy Unfortunately, despite adequate removal of the tumor and regional lymphatics, recent surgical series still produce a 10-year disease-free survival rate of 50%. Thirty percent of node-negative and 75% of node-positive patients eventually have recurrences and die of their disease when surgery is the only therapeutic modality.87 Adjuvant systemic therapy, which is given after the primary surgery to kill or inhibit clinically occult micrometastases, has been extensively studied in women. Physicians can draw on data consisting of many randomized clinical trials with extensive followup to assist in counseling and treating their female patients with breast cancer. It has been well established that the use of cytotoxic chemotherapy and/or endocrine therapy in the adjuvant setting improves long-term survival of women with breast cancer.87 Endocrine Therapy In men, the low incidence of breast cancer precludes the development and completion of clinical trials to assess the efficacy of adjuvant therapy. Therefore, the standard treatment of male breast cancer has generally been extrapolated from the treatment used in women. As male breast cancers are predominately ER- and/or PR-positive tumors; the use of adjuvant endocrine therapy is recommended. The most commonly used endocrine agent in male breast cancer is tamoxifen. In a report by Ribeiro et al.88 39 male patients who received tamoxifen were compared with a historical control group. Overall survival and disease-free survival at 5 years were higher in the group that received tamoxifen (61% vs. 44% and 56% vs. 28%). The most common sideeffects of tamoxifen include decreased libido, weight gain, hot flashes, and mood alterations. More men have been shown to discontinue the drug as compared with females because of side-effects.89 Giordano et al.90 reported data on 38 men who received adjuvant hormonal therapy (including 35 who received tamoxifen) which showed that the recurrence rate (HR of 0.49) and overall survival (HR 0.45) was significantly better for men who received adjuvant hormonal therapy compared with no adjuvant therapy. As adjuvant hormonal therapy for 5 years, the aromatase inhibitor,

anastrozole has recently been shown to impart significantly prolonged disease-free survival and time to recurrence compared to tamoxifen in a large multicenter trial in 9366 postmenopausal women with localized breast cancer.90 However use of aromatase inhibitors alone in the absence of orchiectomy is biologically doubtful in men given the 20% of circulating estrogens produced by the testes and independent of the aromase enzyme. No data exist currently regarding the use of gonadal ablation by gonadotropin-releasing hormone (GnRH) analogue with aromatase inhibitors. Chemotherapy Similarly to women with breast cancer, adjuvant chemotherapy is used to treat male patients who have a substantial risk of recurrence and death from breast cancer. Whereas the data supporting adjuvant chemotherapy in women is strong, there is little information on the effectiveness of adjuvant chemotherapy in men. The limited data that have been published, however, support a similar benefit in male and female patients. One prospective study with a series of 24 male patients with stage II breast cancer treated with adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy projected a 5 year overall survival rate of 80%, which was significantly higher than a similar cohort of untreated historical controls.91 In another study of 11 patients with stage II or III disease treated with 5-fluoro-adriamycin-cyclosphosphamide (FAC), 63% disease-free survival rate and a 91% survival rate at 52 months was reported.92 A recent 20-year follow-up study of adjuvant CMF in males reports an overall survival probability at 10 years of 64.5%, 15 years of 51.6%, and at 20 years of 42.4%.93 Given the established benefit of chemotherapy in women and suggestive evidence in men, most clinicians use similar guidelines for adjuvant chemotherapy in male and female patients. For instance, at the University of Texas M.D. Anderson Cancer Center chemotherapy is offered to those male patients with breast tumors 1 cm or with lymph node involvement; anthracycline-based chemotherapy is offered to patients without lymph node involvement, while both anthracyclines and taxanes are used for patients with lymph node involvement.

Targeted Therapy Finally, although there are no proven clinical trials, male breast cancer patients with HER2 overexpression may benefit from humanized anti-HER2 monoclonal antibody, trastuzumab, especially in light of its proven efficacy in women.68 Future promising agents include PARP-1 inhibitors; PARP-1 is a 113 kDa nuclear enzyme that plays a critical role in the repair of DNA single-stranded breaks via the base excision pathway.94 The first clinical evidence that BRCA-mutated cancers may be sensitive to PARP inhibition was presented at the 2007 American Society of Clinical

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Oncology (ASCO), where in a phase I trial of oral PARP inhibitor, AZD2281 in a population of BRCA mutation carriers, there were partial responses either radiologically or by reduction in tumor markers in 4 out of 10 ovarian cancer patients. Data for breast cancer-associated BRCA mutations were immature and so not presented.95

Radiation Therapy Radiation therapy was initially used in the treatment of chest wall recurrences or advanced disease, but, currently, it plays an integral role in managing women after lumpectomy and in postmastectomy patients who are at high risk for local recurrence. There are no clinical trials available in male breast cancer patients to evaluate the role of postoperative radiotherapy. However, in several series radiation appeared to reduce postmastectomy recurrence in men but had no obvious impact on survival.96 In a recent review of 42 male breast cancers, superior 10-year disease-free and overall survival rates were seen when both tamoxifen and radiation were used as adjuvant therapy in male breast cancer.97 Given that the data in women do show a survival advantage, it seems prudent to extrapolate this to the male patient with breast cancer,98,99 and in general, similar guidelines are recommended in men as in women.

Treatment of Metastatic Disease Despite continued advances in the surgical and adjuvant management of breast cancer, 20–30% of patients will relapse. In addition, 5–10% will present initially with metastatic disease.100 Stage IV breast cancer treatment varies little between the sexes. Both women and men can be treated with hormonal manipulation, cytotoxic chemotherapy, or both with similar responses. Endocrine Therapy Because the goal of treatment in metastatic disease is palliation of symptoms while maintaining quality of life, most clinicians tailor therapy to obtain responses with the least toxicity. For hormone receptor-positive patients, endocrine therapy plays an important role. Traditionally, tamoxifen is usually the agent of first choice. Second-line and even third-line endocrine therapies include estrogen-deprivation therapy in premenopausal women, either by oophorectomy or a luteinizing hormone-releasing hormone agonist, aromatase inhibitors (AIs), and progestational agents such as megestrol acetate. Published studies have now shown that AIs are superior to tamoxifen in hormone receptor-positive postmenopausal women as first-line therapy.101,102 Given that the vast majority of men have estrogen-receptor-positive tumors, hormonal the­ rapy is often the first approach and response rates as high as 81% have been reported to tamoxifen103 and this is conside­ red the preferred first-line approach. There are individual case reports of the efficacy of aromatase inhibitors, anastrozole

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and letrozole, in metastatic male breast cancer.103,104 In fema­ les with advanced breast cancer, fulvestrant (Faslodex), a pure antiestrogen, has been shown to be at least as efficacious as tamoxifen105 and anastrozole.106 A recent report on two males with metastatic breast cancer showed an objective response, stable disease in one patient and a partial response in the other, to fulvestrant when given as a first-line primary endocrine therapy.107 Chemotherapy Breast cancer is considered one of the most chemosensitive solid tumors. Previously untreated patients receiving chemotherapy for metastatic disease have a significant chance of responding and therefore benefiting. This benefit comes at the expense of greater toxicity that must be considered with each patient before embarking on a new therapy. The most commonly used agents include: the anthracyclines, particularly doxorubicin; cyclophosphamide; methotrexate; 5-fluorouracil and its oral derivatives; taxanes; and the vinca alkaloids among others. The use of these chemotherapeutic agents in metastatic disease has been well studied in women, but less so for men. However, systemic chemotherapy is another option for men with metastatic breast cancer, but is usually reserved for second-line or third-line therapy since most men will respond favorably to hormonal manipulation. There have been reports of response in hormone refractory breast cancer in males of 13% for single agent 5-fluorouracil to as high as 67% for 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC).108

Targeted Therapy Targeted therapy has become one of the fastest-growing approaches to managing breast cancer. Trastuzumab is a recombinant monoclonal antibody against HER2, which, as previously discussed, is overexpressed in 20–30% of breast cancer and portends a worse prognosis. Trastuzumab when used alone in HER2-overexpressing metastatic breast cancer is well tolerated and produces durable objective responses.109 A randomized controlled study was conducted in women with metastatic HER2-overexpressing breast cancer comparing trastuzumab plus chemotherapy with chemotherapy alone. The addition of trastuzumab to chemotherapy was associated with an improved disease-free and overall survival.69 It has become an important addition to the management of female metastatic breast carcinoma. HER-2 status has also been evaluated in male breast cancer.110 The rates of overexpression are variable in the published series, and trastuzumab as a treatment modality has not been investigated. Lapatinib is an oral dual tyrosine kinase inhibitor against members of the human epidermal growth factor receptor HER family, and is used in female patients whose breast cancer has become resistant to therapy including anthracycline, taxanes, and trastuzumab.111 Phase II clinical trials

s e c t i o n 7     Oncology l

Prognosis and survival Male breast cancer is classically described as having a poorer prognosis than female breast cancer, suggesting that, in males, it is a more aggressive disease. However, evidence is accumulating that suggests the disease is biologically similar in both sexes. Despite this, a poorer survival in men is a consistent finding.8 This has been attributed to a delay in diagnosis, later stage at presentation, anatomic factors, and an older age at diagnosis with an increase in non-breast cancer related deaths that is seen in most series of male breast cancer.8,58,114 Because of the older age at diagnosis, many of these patients have co-morbidities and deaths unrelated to breast cancer. Guinee et al.77 reported on 335 male patients: 83 (47%) of the 178 deaths were due to causes other than breast cancer. In another paper, comprising 397 cases of male breast cancer, 39.5% of the deaths were unrelated to breast cancer.78 The prognosis for male breast cancer has been described as worse or similar to that of age- and stage-matched women.56,57,58,78,79,115,116 In a comparative study using data from the National Cancer Data Base of 4755 men and 624 174 women, 3627 pairs of men and women with breast cancer were matched for age, stage, and demographics. Age-corrected relative survival was equivalent for men and women with stage 0, I, and II disease. The survival curves diverge for stage III and IV disease; men showed worse 5-year survival rates than women, although this did not reach statistical significance.56 In a study by Borgen et al. the

1 0.9 Percent surviving

have reported an overall response rate of 22% and 14% for lapatinib.111 Ixabepilone, a new agent recently approved for metastatic breast cancer, is an antimicrotubule agent and is used in female patients whose breast cancer has become resistant to therapy including anthracycline, taxanes, and trastuzumab. Phase III clinical data have shown an objective response rate increase from 14% to 35% for ixabepilone compared to another agent, capecitabine.112 Bevacizumab (Avastin), a monoclonal antibody that targets vascular endothelial growth factor (VEGF), providing direct inhibition of angiogenesis was also recently approved by the FDA for use in the first line treatment of patients with locally recurrent or metastatic breast cancer.113 This was based on a Phase III clinical trial data that showed bevacizumab plus paclitaxel resulted in a progression-free survival (PFS) of 11.8 months vs. 5.9 months when compared with paclitaxel alone.113 No data yet exist for these drugs in male breast cancer, but based on prior therapeutic agents, these may be promising agents in the future for male breast cancer. The rarity of male breast cancer poses a significant impediment to the prospective study of treatment options in this disease. In general, recommendations have primarily been based on successes seen in clinical trials of females with breast cancer.

0.8 0.7 0.6 58 Male cases 0.5 0.4

174 Female cases 0

12

24

36

48 60 Months

72

84

96

108 120

Figure 42.2  Breast cancer survival of 58 male and 174 female breast cancer patients. Reproduced with kind permission from Springer Science  Business Media: Borgen et al., 1997 (Fig. 1).116 Copyright 1997 1 0.9

Percent surviving

468

0.8 0.7 33 Male neg

0.6

96 Female neg 25 Male neg

0.5 0.4

78 Female neg

0

12

24

36

48

60

72

84

96

108

120

Months

Figure 42.3  Breast cancer survival of 58 male and 174 female breast cancer patients according to nodal status at diagnosis. Reproduced with kind permission from Springer Science  Business Media: Borgen et al., 1997 (Fig. 2).116 Copyright 1997

survival of 58 men with breast cancer was compared to that of 174 women who were matched for stage and age at diagnosis.116 All patients had stage I or II disease and were treated with mastectomy and axillary dissection. He found breast cancer survival at 10 years to be similar between the sexes (Figure 42.2). After stratification by nodal status, survival differences between men and women were more pronounced in the positive-node patients (Figure 42.3) but did not reach statistical significance.116 Another matched study was performed in the United Kingdom by Willsher et al.117 Fortyone male patients and 123 female patients with invasive cancer were matched for age, pathologic size and grade of the primary tumor, and pathologic lymph node status. The authors also found no statistical difference in disease-free or overall survival between the groups. When these patients were compared with more than 3000 unmatched women with breast cancer treated at the same time, both the male and female matched groups had a worse outcome (Figure 42.4).

C h a p t e r 4 2    The Differences between Male and Female Breast Cancer

469

l

1

Table 42.5  Treatment and recurrence rates, overall for male breast cancer patients: Cohort A (1972–1991) and Cohort B (1992–2005)

Surviving fraction

0.9 0.8 0.7 0.6

Male Matched female Unmatched female

0.5 0.4

0

12

24

36

48

60

72

Treatment modality

Cohort A

Cohort B

Surgery Chemotherapy Radiation therapy Hormonal therapy Recurrence 5-year survival

93% 36% 46% 18% 50% 43%

96% 53% 43% 39% 50% 51%

Survival (months)

Reproduced from Willsher et al. 1997.117 Copyright (1997) with permission from Elsevier

The authors suggested that this difference, and the worse outcome in general with male breast cancer patients, is due to a difference in the distribution of prognostic factors. In this case, there was a preponderance of grade 3 tumors, which were seen in 73% of the cases.117 While multi-modality treatment with chemotherapy, radiation, and hormonal therapy have resulted in an increase in survival for women, this may not be true for men with breast cancer currently (Table 42.5). In a retrospective study by Shaub et al.118 of male breast cancer patients at a single institution from 1972 to 1991 (Cohort A) and 1992 to 2005 (Cohort B), more patients received multimodality treatment in Cohort B, although not statistically significant, but the recurrence rates were similar at 50% for Cohort A and B and the 5-year survival was similar at 43% and 51% respectively, which was not statistically significant (Figure 42.5). The failure to improve 5-year survival was attributed to an overall decrease in the use of multi-modality therapy compared with female patients. Interestingly, male breast cancer survivors have an increased risk of developing second primary cancers. Published reports from the SEER cancer registry have shown that men with a history of breast cancer have a relative risk 30-fold greater of developing contralateral breast cancer compared with a two- to four-fold risk among women with breast cancer.119

1.00 Cohort A Cohort B Surviving fraction

Figure 42.4  Survival curves for male and matched female patients with breast cancer showing no significant difference (p  0.27). Compared with an unmatched female series, both the male patients (p  0.0003) and matched female patients (p  0.0006) have a worse outcome.

Source: Schaub et al. 2008118

0.75

0.50

0.25

0.00 0

31

62

93

123

Survival (months)

Figure 42.5  Overall survival curves for male breast cancer patients: Cohort A (1972–1991) and Cohort B (1992–2005). Reproduced from Shaub et al. 2008.118 Copyright 2008. Reproduced with permission from the copyright owner

are not that different. Given that breast cancer in women is a prevalent disease and the second leading cause of cancerrelated death, there is a great socioeconomic burden. This has led to extensive research into this disease. The risk factors, prognostic factors, and treatment algorithm have all been thoroughly explored, and clinicians have resources to draw on when treating their female patients. This is the major difference between the sexes. Breast cancer is a rarity in males; therefore, it is much less studied. Although there have been some emerging data in male breast cancer, most knowledge and treatment approaches for this disease in males come from the extrapolation of information about female patients with breast cancer.

References Conclusion In summary, it appears that breast cancer is a similar disease in men and women. Despite the clear disparity in the incide­ nce of breast cancer between the sexes, once it occurs in either a man or a woman its clinical presentation, pathologic appearance, response to treatment, and overall prognosis

1. Greenlee RH, Hill-Harmon M, Murray T, Thun M. Cancer statistics. CA Cancer J Clin. 2001;51:15–36. 2. National Comprehensive Cancer Network. NCCN practice guidelines for breast cancer, v.1. 2009. Available from www. nccn.org/professionals/physician_gls/PDF/breast.pdf. Accessed January 2009. 3. Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2005;55(1):10–30.

470

s e c t i o n 7     Oncology l

4. Surveillance, Epidemiology, and End Results Program. Avail­ able at www.seer.cancer.gov. Accessed August 16, 2004. 5. Anderson WF, Althuis MD, Brinton LA, Devesa SS. Is male breast cancer similar or different than female breast cancer? Breast Cancer Res Treat 2004;83(1):77–86. 6. Goodman MT, Tung KH, Wilkens LR. Comparative epidemiology of breast cancer among men and women in the US, 1996 to 2000. Cancer Causes Control 2006;17(2):127–36. 7. Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breast carcinoma in men: a population-based study. Cancer 2004;101:51–77. 8. Donegan WL, Redlich P, Lang P, Gall M. Carcinoma of the breast in males, a multiinstitutional study. Cancer 1998;83: 408–509. 9. Statistics. SEER Cancer Statistics Review, 1973–1995. Bethesda, MD: US National Cancer Institute; 1998. 10. Smigal C, Jemal A, Ward E, et al. Trends in breast cancer by race and ethnicity: update 2006. CA Cancer J Clin 2006;56(3):168–83. 11. Muir C, Waterhouse J, Mack T. Cancer incidence in five continents. In: Lyons, ed. Cancervol. 5. France: International Agency for Research on Cancer Scientific Publications; 1987. 12. Ravandi-Kashani F, Hayes TG. Male breast cancer: a review of the literature. Eur J Cancer 1998;34:1341–47. 13. Jardines L, Haffty BG, Fisher P, et al. Breast cancer overview. In: R Pazdur., ed. Cancer Management: A Multidisciplinary Approach, eleventh ed.. Kansas: CMP Medica Publishers; 2008:169–200. 14. Hankinson SE, Colditz GA, Manson IE, et al. A prospective study of oral contraceptive use and risk of breast cancer (Nurses’ Health Study, United States). Cancer Causes Control 1997;8(1):65–72. 15. Brinton LA, Daling JR, Liff JM, et al. Oral contraceptives and breast cancer risk among younger women. J Natl Cancer Inst 1995;87:827–35. 16. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321–33. 17. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291(14):1701–12. 18. Scheike O, Visfeldt J, Peterson B. Breast carcinoma in association with Klinefelter’s syndrome. Acta Pathol Microbiol Scand 1973;81:352. 19. Hultborn R, Hanson C, Kopf I, et al. Prevalence of Klinefelter’s syndrome in male breast cancer patients. Anticancer Res 1997; 17:4293. 20. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet 2006;367:595–604. 21. Lenfant-Pejovic MH, Milka-Cabanne N, Bonchardy C, Auquier A. Risk factors for male breast cancer: a FrancoSwiss case-control study. Int J Cancer 1990;45:660. 22. Sorensen HT, Friis S, Olsen JH, et al. Risk of breast cancer in men with liver cirrhosis. Am J Gastroenterol 1998;93:231. 23. Borgen PI, Wong GY, Vlamis V, et al. Current management of male breast cancer: a review of 104 cases. Ann Surg 1992;215:451–57, discussion 457-9.

24. Kanhai RC, Hage JJ, van Diest PJ, Bloemena E, Mulder JW. Short-term, and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men. Am J Surg Pathol 2000;24:74–80. 25. Ganly I, Taylor EW. Breast cancer in a trans-sexual man receiving hormone replacement therapy. Br J Surg 1995;82:341. 26. Pritchard TJ, Pankowsky DA, Crowe JP, Abdul-Karim FW. Breast cancer in a male-to-female transsexual. A case report. JAMA 1988;259:2278–80. 27. Kushi LH, Sellers TA, Potter JD, et al. Dietary fat and postmenopausal breast cancer. J Natl Cancer Inst 1992;84: 1092–99. 28. Graham S, Hellman R, Marshall J, et al. Nutritional epidemiology of postmenopausal breast cancer in western New York. Am J Epidemiol 1991;134:552–666. 29. Howe GR, Friedenreich CM, Jain M, Miller AB. A cohort study of fat intake and risk of breast cancer. J Natl Cancer Inst 1991;83:336–440. 30. Mills PK, Deeson WL, Phillips RL, Fraser GE. Dietary habits and breast cancer incidence among Seventh-day Adventists. Cancer 1989;64:582–90. 31. van den Brandt PA, Vantveer P, Goldbohm RA, et al. A prospective cohort study on dietary fat and the risk of postmenopausal breast cancer. Cancer Res 1993;53:75–82. 32. Walk A, Bergstrom R, Hunter D, et al. A prospective study of association of monounsaturated fat and other types of fat with risk of breast cancer. Arch Intern Med 1998;158:41–51. 33. Hunter DJ, Spiegalman D, Adami HO, et al. Cohort studies of fat intake and the risk of breast cancer. N Engl J Med 1996;334:356–61. 34. Smith-Warner SA, Spiegelman D, Yaun SS, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998;279:535–40. 35. Reichman ME, Judd JT, Longscope C, et al. Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women. J Natl Cancer Inst 1993;85:722–77. 36. Keller AZ. Demographic, clinical and survivorship characteristics of males with primary cancer of the breast. Am J Epidemiol 1967;85:183–99. 37. Guenel P, Cyr D, Sabroe S, et al. Alcohol drinking may increase risk of breast cancer in men: a European population-based casecontrol study. Cancer Causes Control 2004;15:571–80. 38. Rosenblatt KA, Thomas DB, Jimenez LM, et al. The relationship between diet and breast cancer in men (United States). Cancer Causes Control 1999;10:107–13. 39. Hsing AW, McLanghlan JK, Cocco P, et al. Risk factors for male breast cancer (United States). Cancer Causes Control 1998;9:269–75. 40. Eeles R, Powles T. Chemoprevention options for BRCAI and BRCA2 mutation carriers. J Clin Oncol 2000;18(2Is):93s–99s. 41. Ford D, Easton D, Peto J. Estimates of the gene frequency and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 1995;57:1457–62. 42. Ford D, Easton D, Stratton MR. Genetic heterogeneity and penetrance analysis of the BRCAI and BRCA2 genes in breast cancer families. Am J Hum Genet 1998;62:676–89. 43. Breast Cancer Linkage Consortium. Carrier risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999;91:1310–16.

C h a p t e r 4 2    The Differences between Male and Female Breast Cancer l

44. Couch FJ, Fario LM, Deshano ML, et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet 1996;13:123–25. 45. Friedman LS, Gayther SA, Kurosaki T, et al. Mutation analysis of BRCA I and BRCA2 in a male breast cancer population. Nat Genet 1997;60(2):313–19. 46. Basham VM, Lipscombe JM, Ward JM, et al. BRCAI and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 2002;4:R2. 47. Stratton MR, Ford D, Neuhasen S, et al. Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nat Genet 1994;7:103–7. 48. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 2002;20:1480–90. 49. Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2007;99:1811–14. 50. Wooster R, Mangion J, Eeles R, et al. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat Genet 1992;2:132. 51. Fackenthal JD, Marsh DJ, Richardson AL, et al. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet 2001;38:159–64. 52. Boyd J, Rhei E, Federici MG, et al. Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 1999;53:87–91. 53. van Geel AN, van Slooten EA, Mavrunac M, et al. A retrospective study of male breast cancer in Holland. Br J Surg 1985;72:724–77. 54. Heller KS, Rosen PP, Schottenfeld D, et al. Male breast cancer: a clinicopathologic study of 97 cases. Ann Surg 1978;188:60–65. 55. Carmalt H, Mann L, Kennedy C, et al. Carcinoma of the male breast: a review and recommendations for management. Aust N Z J Surg 1998;68:712–15. 56. Scott-Conner CE, Jochimsen PR, Menck AR, et al. An analysis of male and female breast cancer treatment and survival among demographically identical pairs of patients. Surgery 1999;126:775–80, discussion 780-1. 57. Salvadori B, Saccozzi R, Manzari A, et al. Prognosis of breast cancer III males: an analysis of 170 cases. Eur J Cancer 1994;30A:930–35. 58. Joshe M, Lee A, Loda M, et al. Male breast carcinoma: an evaluation of prognostic factors contributing to a poorer outcome. Cancer 1996;77:490–98. 59. Shapiro S. Evidence on screening for breast cancer from a randomized trial. Cancer 1977;39(Suppl. 6):2772–82. 60. Carney PA, Miglioretti DL, Yankaskas BC, et al. Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med 2003;138:168–75. 61. Evans G, Anthony T, Appelbaum A, et al. The diagnostic accuracy of mammography in the evaluation of male breast disease. Am J Surg 2001;181:96–100. 62. Patterson SK, Helvie MA, Aziz K, Nees AV. Outcome of men presenting with clinical breast problems: the role of mammography and ultrasound. Breast J 2006;12(5):418–23.

471

63. Vetto J, Schmidt W, Pommier R, et al. Accurate and costeffective evaluation of breast masses in males. Am J Surg 1998;175:383–87. 64. Lalonde L, David J, Trop I. Magnetic resonance imaging of the breast: current indications. Can Assoc Radiol J 2005;56(5):301–8. 65. Michaels BM, Nunn CR, Roses DF. Lobular carcinoma of the male breast. Surgery 1994;115:402. 66. Camus MG, Joshi MG, Mackarem G, et al. Ductal carcinoma in situ of the male breast. Cancer 1994;83:154. 67. Wick M, Sayadi H, Ritter J, et al. Low stage carcinoma of the male breast. Am J Clin Pathol 1999;111:59–69. 68. Rayson D, Erlichman C, Suman VJ, et al. Molecular markers in male breast carcinoma. Cancer 1998;83:1947. 69. Siamon DJ, Leylano-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92. 70. Clark J, Nguyen P, Jaszcz W, et al. Prognostic variables in male breast cancer. Am Surg 2000;66:502–10. 71. Andre S, Fonseca I. Male breast cancer: a reappraisal of clinical and biologic indicators of prognosis. Acta Oncol 2001;40:472–78. 72. Shpitz B, Bornstein Y, Sternberg A, et al. Angiogenesis, p53, and c erbB-2 immunoreactivity and clinicopathological features in male breast cancer. J Surg Oncol 2000;75:252–57. 73. Pich A, Margaria E, Chiusa L. Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival. J Clin. Oncol 2000;18:2948–56. 74. Muir D, Kanthan R, Kanthan SC. Male versus female breast cancers. A population-based comparative immunohistochemical analysis. Arch Pathol Lab Med 2003;127:36–41. 75. Bloom KJ, Govil H, Gattuso P, et al. Status of HER-2 in male and female breast carcinoma. Am J Surg 2001;182:389–92. 76. Herman K, Lobaziewicz W, Skotnicki P, et al. Male breast cancer. Does the prognosis differ compared to female?. Neoplasma 2000;47(3):191–95. 77. McLachlan SA, Etuchman C, Liu FF, et al. Male breast cancer: an 11-year review of 66 patients. Breast Cancer Res Treat 1996;40(3):225–30. 78. Cutuli B, Lacroze M, Dilhuydy JM, et al. Male breast cancer: results of the treatments and prognostic factors in 397 cases. Eur J Cancer 1995;3IA:1960–64. 79. Guinee VF, Olsson H, Moller T, et al. The prognosis of breast cancer in males. A report of 335 cases. Cancer 1993;71:154–60. 80. Fisher B, Redmond C, Poissen R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822–28. 81. Goss PE, Reid C, Pintilie M, Lim R, Miller N. Male breast carcinoma: a review of 229 patients who presented to the Princess Margaret Hospital during 40 years: 1955–1996. Cancer 1999;85(3):629–39. 82. Gough DB, Donohue JH, Evans MM, et al. A 50-year experience of male breast cancer: is outcome changing?. Surg Oncol 1993;2(6):325–33. 83. Albo D, Ames FC, Hunt KK, et al. Evaluation of lymph node status in male breast cancer patients: a role for sentinel lymph node biopsy. Breast Cancer Res Treat 2003;77:9–14.

472

s e c t i o n 7     Oncology l

84. Cimmino VM, Degnim AC, Sabel MS, et al. Efficacy of sentinel lymph node biopsy in male breast cancer. J Surg Oncol 2004;86:74–77. 85. Goyal A, Horgan K, Kissin M, et al. Sentinel lymph node biopsy in male breast cancer patients. Eur J Surg Oncol 2004;30:480–83. 86. De Cicco C, Baio SM, Veronesi P, et al. Sentinel node biopsy in male breast cancer. Nucl Med Commun 2004;25:139–43. 87. Jardines L, Haffty BG, Royce M. Stage, II breast cancer. In: R Pazdur, ed. Cancer Management: A Multidisciplinary Approach, eleventh ed.. Kansas: CMP Medica Publishers; 2008:219–41. 88. Ribeiro G, Swindell R. Adjuvant tamoxifen for male breast cancer (MBC). Br J Cancer 1992;65:252–54. 89. Anelli TF, Anelli A, Tran KN, et al. Tamoxifen is associated with a high rate of treatment-limiting symptoms in male breast cancer patients. Cancer 1994;74:74–77. 90. Giordano SH. A review of the diagnosis and management of male breast cancer. The Oncologist 2005;10:471–79. 91. Bagley CS, Wesley MN, Young RC, Lippman ME. Adju­ vant chemotherapy in males with cancer of the breast. Am J Clin Oncol 1987;10:55. 92. Patel HZ 2nd., Buzdar AU, Hortobagyi GN. Role of adju­ vant chemotherapy in male breast cancer. Cancer 1989;64: 1583–85. 93. Walshe JM, Berman AW, Vatas U, et al. A prospective study of adjuvant CMF in males with node positive breast cancer: 20 year follow-up. Breast Cancer Res Treat 2007;103:177–83. 94. Schreiber VF, Dantzer JC, et al. Poly(ADP-ribnose): novel functions for an old molecule. Nat Rev Mol Cell Biol 2006;7:517–28. 95. Yap TA, Boss DS, Fong PC, et al. First in human phase 1 pharmacokinetic and pharmacodynamic study of KU-0059436 (Ku), a small molecule inhibitor of Poly(ADP-ribose) polymerase (PARP) in cancer patients including BRCA1/2 mutation carriers. Proc Am Soc Clin Oncol 2007, Abstract: 3529.51. 96. Schuchardt U, Sergenschmiedt MH, Kirschner MJ, et al. Adjuvant radiotherapy for breast carcinoma in men: a 20 year clinical experience. Am J Clin Oncol 1996;19:330. 97. Howell A, Cuzick J, Baum M, et al. ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365(9453):60–62. 98. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer cooperative Group 82 b trial. N Engl J Med 1997;337:949. 99. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive women with breast cancer. N Engl J Med 1997;337:956. 100. Jardines L, Haffty BG, Royce M, Jaiyesimi I, et al. Stage III and IV breast cancer. In: R Pazdur, ed. Cancer Management: A Multidisciplinary Approach, eleventh ed.. Kansas: CMP Medica Publishers; 2008:243–68. 101. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000;18:3758–67.

102. Mouridsen H, Bershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as frrst-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596–606. 103. Giordano SH, Valero V, Buzdar AU, Hortobagyi GN. Effi­ cacy of anastrozole in male breast cancer. Am J Clin Oncol 2002;25(3):235–37. 104. Italiano A, Largillier R, Marcy PY, et al. Complete remission obtained with letrozole in a man treated with metastatic breast cancer. Rev Med Int 2004;25:323–24. 105. Howell A, Robertson JF, Abram P, et al. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, doubleblind, randomized trial. J Clin Oncol 2004;22(9):1605–13. 106. Howell A, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma. Cancer 2005;104(2):236–39. 107. Agrawal A, Cheung K, Robertson J. Fulvestrant in adva­ nced male breast cancer. Breast Cancer Res Treat 2007; 101:123. 108. Jaiyesimi LA, Buzdar AU, Sabin AA, Ross MA. Carcinoma of the male breast. Ann lntem Med 1992;117:771–77. 109. Cobleigh M, Vogel C, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639–48. 110. Bloom K, Govil H, Gattuso P, Reddy V, Francescatti D. Status of HER2 in male and female breast carcinoma. Am J Surg 2001;182:389–92. 111. Bilancia D, Rosati G, Dinota A, Germano D, Romano R, Manzione L. Lapatinib in breast cancer. Ann Oncol 2007;18(Suppl. 6):vi26–30. 112. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine f or metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007;25:5210–17. 113. Sachdev JC, Jahanzeb M. Evolution of bevacizumab-based therapy in the management of breast cancer. Clin Breast Cancer 2000;8(5):402–10. 114. Meijer-van Gelder ME, Look MF, Bolt-De-Vries J, et al. Clinical relevance of biologic factors in male breast cancer. Breast Cancer Res Treat 2001;68:249–60. 115. Winchester DJ. Male breast cancer. Semin Surg Oncol 1996;12:364–69. 116. Borgen P, Senie R, McKinnon W, Rosen P. Carcinoma of the male breast: analysis of prognosis compared with matched female patients. Ann Surg Oncol 1997;4:385–88. 117. Willsher P, Leach I, Ellis I, et al. A comparison outcome of male breast cancer with female breast cancer. Am J Surg 1997;173:185–88. 118. Schaub NP, Maloney N, Schneider H, et al. Changes in male breast cancer over a 30 year period. Am Surg 2008;74:707–12. 119. Auvinen A, Curtis RE, Ron E. Risk of subsequent cancer following breast cancer in men. J Natl Cancer Inst 2002;94:1330–32.

CHAPTER

43

Difference in Germ Cell Tumors of the Reproductive Tract in Men and Women Nicole LaNatra1, and Amy Tiersten2 1

New York University School of Medicine, Division of Oncology, New York, NY, USA Associate Professor of Medicine (Oncology), New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA 2

Introduction

Origin of germ cells

Germ cells (primordial cells) are cells stored in the male and female reproductive tracts (testis and ovary) that carry the reproductive machinery in both sexes. A unique characteristic of these cells is that they divide by meiosis retaining only half of the cell chromosomes (haploid); thus, when the male sperm cell and female ovum join, the resulting human embryo has normal diploid somatic cell number of chromosomes. Although they have the same function and originate from the same cells, their development, number, maturation, and pathology vary between men and women. Germ cell tumors (GCTs) constitute a remarkably heterogeneous group of neoplasms that can arise from the germ cells in the gonads (testis and ovary) or in extragonadal sites (mainly in the sacrococcygeal region, retroperitoneum, mediastinum, and central nervous system). An estimate for 2008 put the number of new cases diagnosed at 8090, with 380 deaths resulting from cancer of the testis.1 Despite their common cells of origin, GCTs differ greatly between men and women. In women, ovarian GCTs comprise 15–20% of all ovarian neoplasms, and only 3–5% of these are malignant. Therefore, while GCTs occur more frequently in women than in men, most of these tumors in women are of a benign nature.2 The pathogenesis, clinical presentation, treatment, and outcome of ovarian germ cell and epithelial cancer are very different. In this chapter we concentrate on the GCTs. On the other hand, 98% of testicular neoplasms are comprised of testicular GCTs, making it the most common malignancy in American men between the ages of 15 and 34.3 To understand this significant difference in GCTs between sexes it is necessary to describe the difference in germ cell development. The main differences between male and female germ cells are presented in Table 43.1. Principles of Gender-Specific Medicine

Primordial germ cells arise in the endoderm of the embryonic yolk sac, allantois, and hindgut of the male and female embryo. The germ cells migrate and multiply through the wall of the midgut to the genital ridge at 4–5 weeks of gestation. The migration proceeds along the paravertebral gonadal ridge in a caudal to cranial direction. Germ cells arrested in this migration are thought to be the source of the extragonadal GCTs in both sexes, including the sacrococcygeal region, retroperitoneum, mediastinum, pineal, and suprasellar area.4 The midline location of the paravertebral gonadal ridge explains the near midline location of most extragonadal GCTs. The reasons for migration arrest of germ cells are unknown. Before the eighth week of gestation, the sex of the embryo cannot be determined.5 Appropriately, this period is termed the indifferent phase of sexual development. After 8 weeks of gestation the embryo acquires two duct systems within the primitive kidney. The Müllerian duct forms the female internal reproductive organs, and the Wolffian duct gives rise to the male reproductive organs.

Embryologic Development and Maturation of Germ Cells in Men The germ cells are incorporated in the developing gonad around the eighth week of gestation, when they are called the gonocytes.5 They differentiate into spermatogonia during the second and third trimester of pregnancy. In the postnatal testis, the spermatogonial cells undergo a series of mitotic divisions leading to the development of type A, intermediate type, and type B spermatogonia. The type B spermatogonium undergoes meiosis followed by mitosis, 473

Copyright 2010 2010, Elsevier Inc. All rights reserved.

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Table 43.1  Characteristics of Germ Cells in Men and Women During the Human Lifetime Time

Chactereristic

Men

Women

Endoderm Migration to genital ridge Duct formation Müllerian Wolffian Number of germ cells Cell division Mitosis Meiosis Number of germ cells

 

 





 Millions

 1 Millions

In contrast to the situation in the male, female germ cells stop dividing by mitosis during prenatal life. As mentioned previously, this may be the reason for the low rate of development of ovarian GCTs.

Prental Origin 5 weeks 8 weeks

24 weeks Birth

  Millions

  400 000

Present Present

 

  Millions

  400

Postnatal Until puberty

Lifetime

Cell division Mitosis Meiosis Cell division Mitosis Meiosis Number of germ cells

resulting in four haploid cells that develop into spermatids and spermatozoa. Apoptotic or programmed cell death plays an important role during the development of the sperm cells by regulating the number of surviving cells in relation to the availability of growth factors. It is apparent that male germ cells divide and undergo apoptosis at a high rate during the entire male life. The high rate of turnover (mitosis and apoptosis) is thought to be the main reason for mistakes in the DNA control and thus development of testicular tumors. Ovarian GCTs develop rarely because the germ cells stop dividing early in the female embryonic development.

Embryologic Development and Maturation of Germ Cells in Women The germ cells incorporated in the developing ovary multiply at a high rate, and, by 24 weeks of gestation, there are 7 million oogonia in the primitive ovaries. Even though they continue to multiply, most die by apoptosis, leaving only about 1 million primary oocytes at birth.5 By puberty, this number decreases to about 400 000. The surviving oogonia are arrested at prophase of meiosis. Completion of the first division of meiosis does not occur until the time of ovulation. Only about 400 of these oocytes actually mature and are released by ovulation in a woman’s lifetime; the others undergo apoptosis and die at various stages of development.

Gender differences in the epidemiology of germ cell tumors Childhood Germ Cell Tumors In contrast to the rarity of GCTs in adult females, ovarian tumors account for approximately 25% of all (male and female) pediatric GCTs. Also, both benign and malignant extragonadal GCTs are more frequent in girls. The reason for this difference is unclear. One possibility is that female germ cells undergo most of their divisions and apoptosis early in human life, so the chances of malignant transformation of their genome is highest during this period. In contrast to female cells, male germ cells divide and mature during the male’s entire life. The peak incidence of ovarian GCTs is 10 years of age.6 Most of these tumors are benign mature cystic teratomas, although nearly one-third contain malignant elements. In contrast to adult ovarian tumors, malignancies of epithelial or stromal cell origin are uncommon in girls. The most common pediatric ovarian neoplasms are dysgerminomas and yolk sac tumors. Immature teratomas account for approximately 10% of ovarian masses.7 Testicular tumors comprise approximately 10% of all pediatric GCTs. In contrast to ovarian tumors, most male GCTs are malignant (80%), characteristically containing yolk sac elements.6 Pediatric testicular GCTs follow a bimodal age distribution, occurring in very young children and in adolescent boys. Boys with yolk sac tumors of the testis have been diagnosed with additional anomalies including inguinal hernia, double ureter, ectopic kidney, and renal agenesis.8 GCTs in children most commonly present as extragonadal disease, 40% of which occur in the sacrococcygeal region.9 Most of these are teratomas and are usually diagnosed at birth or during the first month of life.10

Adult Germ Cell Tumors As mentioned previously GCTs are rare in adult females. In contrast to pediatric ovarian tumors, GCTs of the ovary are much less common than epithelial ovarian neoplasms in the adult female. They represent 3–5% of all ovarian cancers in Western countries. They almost always occur in younger women, and their peak incidence is in the early 20s. An increased incidence of GCTs is found in Asians and Africans, and these tumors represent as many as 15% of all ovarian cancers in these populations.11 The reasons

C hapter 4 3     Difference in Germ Cell Tumors of the Reproductive Tract in Men and Women l

for this racial difference in GCT development in females are unclear. GCTs are the most common solid tumors in men between the ages of 15 and 34 years. In contrast to GCTs in adult females, male GCTs have two modal peaks: ages 25–40 and approximately age 60.12 In contrast to ovarian tumors, GCTs of the testis are more common in young whites with ratios between whites and blacks in the US military of 40:1 (annual incidence).13 In blacks, GCTs behave similarly to those of the general population. The main differences between gonadal male and female GCTs are presented in Table 43.2. Extragonadal GCTs are very rare in adults, representing only 5–10% of all GCTs.9 The mediastinum is the most common site for their development. GCTs discovered in the anterior mediastinum are usually the primary site of origin, while GCTs arising in the posterior mediastinum are usually found to arise from either a testicular or retroperitoneal primary. In adults, benign GCTs have no gender predilection. Malignant extragonadal GCTs in contrast occur almost exclusively in men.14 They are more commonly diagnosed in the third decade of life, but have been reported in patients as old as 60 years. The incidence of these neoplasms is equal in all races.15

Biology and risk factors for germ cell tumors: are they gender-specific? Biology and Risk Factors of Male Germ Cell Tumors Cytogenetic and molecular genetic analysis of male GCTs has yielded important data relevant to the understanding of the mechanism of germ cell malignant transformation. Virtually 100% of male GCTs show the same abnormal increased number of copies of the 12p chromosome.16 This chromosome marker is present in the first recognizable stage of GCT development, carcinoma in situ, suggesting that this abnormality may be the earliest genetic change in the development of GCTs.17 The most likely driver gene candidate for GCT development in the 12p region is the cyclin D2 gene. Its function is to regulate phosphorylation of pRE protein, which in turn controls the G l-S cell cycle checkpoint. Disruption of this checkpoint through overexpression of cyclin D2 is known to be one of the important pathways in human tumor development.18 Immunohistochemical analysis of normal testis germ cells and GCTs also suggests that cyclin D2 plays a major role in the development of GCTs as it is only occasionally expressed in the normal testis, whereas most aberrant germ cells in carcinoma in situ and GCTs overexpress cyclin D2.19 Two models of origin of GCTs have been proposed. Skakkebaek et al.20,21 suggested that germ cell kit receptor/

475

Table 43.2  Characteristics of Adult Gonadal Male and Female Germ Cell Tumors Characteristic of germ cell tumors Cell origin Incidence in young adults 12p chromosome copies Cyclin D2 overexpression Main clinical symptom Response to chemotherapy

Male

Female

Germ cells High

Germ cells Low

Increased

Unknown

Present

Unknown

Testicular mass

Nonspecific

High

High

stem cell factor paracrine loop dysregulation leads to uncontrolled proliferation of gonocytes on gonadotropin stimulation during postnatal life and puberty. A second model proposed by Chaganti and Houldsworth22 suggested that aberrant chromatid exchange events during meiotic crossing over may lead to increased 12p copy number and overexpression of cyclin D2.22 Germ cells containing unrepaired DNA breaks that would normally undergo apoptosis, in the presence of increased concentration of cyclin D2, may block a p 53-dependent apoptotic response and lead to reinitiation of cell-cycle, genomic instability, and neoplastic transformation of the germ cells.23 Because testicular germ cells undergo many more meiotic divisions than ovarian germ cells the likelihood of the previously described errors is much higher in men. Again, this may explain the higher incidence of GCTs in men. The strongest risk factor for male GCTs is previous history of testicular cancer. It represents a 500-fold increase in incidence compared with the normal male population.24 Cryptorchidism increases the risk 20- to 40-fold compared with their normal counterparts. Genetic abnormalities such as Klinefelter and Down syndromes have been reported to increase the risk for GCTs. Weak association with GCTs was suggested for diethylstilbestrol in utero exposure and Agent Orange exposure. Prior trauma, elevated scrotal temperature (secondary to use of thermal underwear), and recurrent exercises that impact the scrotum such as horseback and motorcycle riding do not appear to be related to the development of testicular cancer.

Biology of Female Germ Cell Tumors Female GCTs have been studied less in the past, likely because of their rare occurrence. Very little is known about their biology and risk factors. It is not currently known if female GCTs overexpress cyclin D2, if they have an abnormal increase in copy number of the 12p chromosome as

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seen in male GCTs, or if they originate in carcinoma in-situ lesions. It is not known with certainty why adult female GCTs are much less common than male GCTs. Several theories mentioned previously, based on knowledge about male GCTs, are currently being investigated.16 Due to the differing rates of maturation between male and female germ cells and the fact that new growth ceases in a female’s postnatal life, studying the female adult GCTs may give answers about the behavior and the mechanisms of malignant transformation of all germ cells. Very little is known about the risk factors for female GCTs. As there are few reports in the literature about familial ovarian germ cell cancers, the genes and the pathogenesis of these tumors are largely unknown. Several families have been reported where both males and females have been diagnosed with malignant GCTs.25 Given the similar histology of testicular and ovarian GCTs, and the presence of both tumor types in several reported families, it is possible that these tumors may arise from a common genetic etiology.

Origin of Extragonadal Germ Cell Tumors Most of the extragonadal GCTs in men and women occur in the mediastinum, retroperitoneum, and the pineal gland. Most adult patients with malignant extragonadal GCTs are male.26 Retroperitoneal tumors are generally considered to be metastases of primary gonadal lesions, whereas the origin of primary mediastinal and pineal lesions has been a matter of speculation. The view suggesting that tumors in these locations are the result of local transformation of germ cells misplaced during embryogenesis is questioned by the failure of multiple researchers to identify evidence of the presence of any misplaced germ cells in human and murine embryos.27 Cytogenetic studies showed that extragonadal GCTs are not different from gonadal GCTs in the pattern of differentiation and have no specific chromosomal aberrations or incidence of recurring breakpoints.28,29 On the basis of these observations, an alternative suggestion was made that extragonadal GCTs represent reverse migration of occult germ cell carcinoma in-situ of the gonads and may be gonadal in origin. These tumors are very rare and, thus far, there are no studies about possible gender differences in their biology.

Histology of germ cell tumors Although they differ in their incidences, male and female GCTs have similar histologic features. Female GCTs are divided into dysgerminomas and nondysgerminomas (­endodermal sinus tumor, embryonal carcinoma, teratoma, and choriocarcinoma). Male GCTs are divided into seminomas and nonseminomas (endodermal sinus tumor, embryonal carcinoma, teratoma, and choriocarcinoma). Seminoma and dysgerminoma cells are large with abundant cytoplasm and areas arranged in sheets with

trophoblastic giant cells producing human chorionic gonadotropin. The prognosis of both is favorable compared with nonseminomas and nondysgerminomas. Nonseminomas (testicular) and nondysgerminomas (ovary) have a worse prognosis than seminomas and dysgerminomas in both sexes. They have very different histology and produce different tumor markers than seminomas and dysgerminomas. For example, choriocarcinomas produce high levels of betahuman chorionic gonadotropin (hCG), while endodermal sinus tumors produce alpha fetoprotein (AFP). It is important to emphasize that, in the presence of even a minimal amount of the more malignant tumor type in either a man or a woman, the whole neoplasm should be classified as the more malignant tumor type and treated as such (nonseminoma in a man and nondysgerminoma in a woman).

Gender differences in clinical presentation of germ cell tumors Because gonadal germ cells have different anatomic locations in men and women, their clinical presentation also differs. The location of extragonadal GCTs is the same in both sexes, and therefore their clinical presentation is also similar.

Clinical Features of Male Germ Cell Tumors Male GCTs commonly present as a painless, swollen testicle, sometimes with distinct palpable masses. Very often men experience a sensation of heaviness, whereas pain is a less common presenting symptom. Men presenting with metastatic disease may complain of back pain from retroperitoneal lymphadenopathy. Symptoms from other metastatic sites such as hemoptysis from lung metastasis are rare. Gynecomastia can sometimes be seen in patients with a very high beta-hCG. Low sperm counts are associated with GCTs, and sometimes a diagnosis can result from a workup for infertility.

Clinical Features of Female Germ Cell Tumors Women with GCTs of the ovary commonly present with complaints of abdominal pain, pelvic fullness, or urinary symptoms. In a minority of patients (approximately 10%), abdominal pain can be severe, resulting from hemorrhage, rupture, or torsion of the tumor. Abdominal distension can also be a presenting symptom and often is associated with ascites.

Clinical Features of Extragonadal Germ Cell Tumors In both men and women, primary mediastinal GCTs often present with symptoms of local compression including superior vena cava syndrome, dysphagia, cough, or dyspnea.

C hapter 4 3     Difference in Germ Cell Tumors of the Reproductive Tract in Men and Women l

Pineal GCTs are very rare, representing 0.5% of all intracranial tumors.30 Neurologic signs and symptoms are caused by obstructive hydrocephalus and involvement of ocular pathways regardless of gender. Common symptoms include headache, nausea, vomiting, lethargy, and diplopia. The major ocular manifestation is paralysis of conjugate gaze (Parinaud’s syndrome).

Table 43.3  FIGO Staging Systems for Ovarian Cancer Stage

Characteristics

I II

Growth limited to the ovaries Growth involving one or both ovaries with pelvic extension Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal lymph nodes; superficial liver metastasis; tumor is limited to the pelvis but with histologically verified malignant extension to the small bowel or omentum

III

Diagnosis of male and female germ cell tumors As male and female gonadal GCTs are anatomically situated differently, thus having different clinical presentations, the approach for diagnosis is specific to gender. The metastatic workup is similar, as the biology of these tumors in men and women is similar. Any man with a testicular mass or who experiences the sensation of heaviness should have an immediate testicular ultrasound. Occasionally when clinically indicated, a short course of antibiotics for possible epididymitis or orchitis can be given before pursuing the ultrasound. Testicular biopsy and scrotal orchiectomy are rarely indicated because of the risk of tumor seeding of the scrotum and possible inguinal and pelvic metastasis from retroperitoneal lymphatic and vascular drainage.31 Radical inguinal orchiectomy in which the spermatic cord is ligated at the internal ring is the procedure of choice. Any woman with a palpable adnexal mass should be evaluated with a pelvic ultrasound. All adnexal masses that are equal to or larger than 8 cm require surgical exploration.11 Extragonadal mediastinal GCTs in both men and women are most often detected on chest x-ray examination as an anterior (95%) or posterior (5%) mediastinal mass.26 Staging workup in men and women for gonadal and extragonadal GCTs should include a complete blood count, serum lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), betasubunit human chorionic gonadotropin (beta-hCG), computed tomography (CT) scans of the abdomen and pelvis, and chest x-ray examination. If the chest x-ray film is abnormal or there is evidence of abdominal or pelvic lymphadenopathy, CT of the chest should be performed. If neurologic findings are present, a CT or magnetic resonance imaging (MRl) scan of the brain should be done.31

Treatment of male and female germ cell tumors Because of the different anatomic locations of GCTs in men and women, the initial surgical approach also differs. Because of the similar biology, male and female GCTs have similar sensitivities to chemotherapy and radiation. Thus, multiple chemotherapy regimens tested on the more prevalent testicular GCTs were adopted for treatment of ovarian GCTs.

477

IV

Growth involving one or both ovaries with distant metastasis FIGO, International Federation of Gynecology and Obstetrics

Table 43.4  TNM Staging System for Testicular Cancer TNM stage

Description

I

N0 Disease confined to the testis and peritesticular tissue N1, N2a Fewer than six positive lymph nodes without extension into retroperitoneal fat, no node 2 cm N2b Six or more positive lymph nodes, well encapsulated and/or retroperitoneal fat extension; any node 2 cm N3 Any node 5 cm

II

III

Disseminated disease (lung, liver, bone, or supradiaphragmatic spread) TNM, tumor, lymph nodes, metastasis.

Different staging systems are used to classify male and female GCTs. The female GCTs are staged in the same way as the more prevalent epithelial ovarian neoplasms, according to the Federation of Gynecology and Obstetrics (FIGO) (Table 43.3). Male GCTs are staged using the tumor, nodal, metastasis (TNM) system (Table 43.4).

Male Seminomas and Female Dysgerminomas Seminomas and dysgerminomas share many biologic similarities that make them very responsive to both radiation and chemotherapy. Treatment of Stage I Seminomas and Dysgerminomas Localized or stage I disease is defined as no lymph node involvement and growth limited to one gonad (ovary or testis).11,31 For these patients, surgery is the initial therapeutic approach, regardless of gender. There is a surgical staging standard performed for all women with ovarian

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cancers which includes transverse incision, inspection of the peritoneal cavity, histologic examination of the peritoneal washings, random biopsies, and oophorectomy. Although dysgerminomas frequently spread to the contralateral ovary, bilateral oophorectomy is not routinely performed as postoperative chemotherapy is curative, therefore potentially preserving fertility.11 Initial intervention for testicular cancers is radical inguinal nerve-sparing orchiectomy.31 As 80% of men with stage I seminomas and women with stage I dysgerminomas are cured with surgery alone, it would seem that surveillance may be a reasonable approach postoperatively.31–33 However, because surveillance requires frequent abdominal CT scans in addition to the fact that progression or recurrence is usually not associated with symptoms until the tumor burden is large, most groups have discontinued surveillance protocols in lieu of prophylactic radiotherapy to the draining lymphatics or a course of adjuvant chemotherapy.31

and 16; VP16 100 mg/m2 on days 1 to 5; and cisplatin 20 mg/m2 on days 1 to 5 given every 21 days (BEP). This regimen has been shown to be very effective in both seminomas and dysgerminomas with a complete response rate of greater than 90% in most studies.35 The management of patients with bulky disease after chemotherapy (residual mass 3 cm) is somewhat controversial. Some investigators suggest radiotherapy or surgical resection, but in one study a relapse rate of 10–15% in patients with residual masses was found with or without postchemotherapy surgery or radiotherapy.31

Male Nonseminomas and Female Nondysgerminomas

Treatment of Stage II Seminomas and Dysgerminoma Stage II disease for dysgerminomas in women is defined as growth involving one or both ovaries with pelvic extension (uterus, fallopian tubes, positive peritoneal washings, tumor on the surface of the ovaries, ruptured capsule, malignant cells in the ascites) with no lymph node involvement. Stage II disease for seminomas in men is defined as disease involving the testis and abdominal lymph nodes without distant metastasis. Dysgerminoma is currently staged the same as all other epithelial tumors of the ovary, meaning that spread of the tumor to the lymph nodes represents stage III disease. This difference in the staging of tumors with identical biology creates confusion in the possible transfer of knowledge established for the management of the more frequent seminomas to the management of dysgerminomas. Men who present with a seminoma and infradiaphragmatic adenopathy of less than 5 cm are treated with postsurgical radiotherapy alone, whereas those with larger lymph nodes are treated with platinum-based ­ chemotherapy.34 For women with dysgerminomas, strict guidelines have not been established, and thus the current approach is ­postsurgical cisplatin-based chemotherapy for both stage II and III disease.11

Male Nonseminomas Because female nondysgerminomas are very rare and their staging differs from nonseminomas, they are described separately. In order to find answers to our therapeutic questions in the future, we may need to define a common staging system and conduct clinical trials that include both men and women, as the biology of these tumors is similar. Stage I nonseminomas are treated with surgery alone and close follow-up.31 In patients with stage II disease with tumors measuring 3–cm or less, primary radical lymph node dissection is considered standard of care. For patients with stage II disease with masses larger than 3 cm, primary platinum-based chemotherapy is preferred. For low-risk patients with stage III disease (low AFP, nonmediastinal primary, or absence of nonpulmonary visceral metastasis), BEP combination chemotherapy is used with a greater than 90% cure rate. If the mass persists 4–6 weeks post chemotherapy treatment with normalization serum markers, surgical resection is recommended.36 If the tumor still contains malignant cells, two additional cycles of cisplatin are given. For high-risk patients (high AFP, mediastinal primary site, or presence of nonpulmonary visceral metastasis) platinumbased chemotherapy, radiation, and resection are used, with a cure rate of less than 50%. New experimental therapies for these patients include ifosfamide, high-dose chemotherapy followed by bone marrow transplant, paclitaxel, and gemcitabine.

Treatment of Advanced Seminoma and Dysgerminoma Patients with stage III seminomas have disseminated disease (lung, liver, bone, or supradiaphragmatic spread). Advanced dysgerminoma is considered stage IV disease and includes growth in distant metastatic sites (lungs, liver, brain). Chemotherapy is the preferred treatment for patients with advanced seminoma and dysgerminoma. The regimen used for both sexes is bleomycin, 30 IU/week on days 2, 9,

Female Nondysgerminoma Most female nondysgerminomas irrespective of stage are treated with comprehensive surgical staging followed by chemotherapy. Stage I dysgerminomas and grade I, stage I immature teratomas are treated with complete surgical staging alone. All other dysgerminomas undergo complete surgical staging followed by BEP combination chemotherapy. As mentioned before, the BEP regimen has been studied and is well established in patients with testicular cancer.33,35

C hapter 4 3     Difference in Germ Cell Tumors of the Reproductive Tract in Men and Women l

Endodermal sinus tumors are treated with surgical resection and chemotherapy regardless of the extent of the tumor seen in the initial surgical staging procedure.37 Survival rates have increased dramatically with the introduction of platinum-based chemotherapy regimens, in which a response rate of approximately 60% is observed. Embryonal carcinoma and nongestational choriocarcinoma are extremely rare. Currently, the recommended treatment is complete surgical staging followed by platinumbased chemotherapy.37

Suggestions for further investigations Germ cells are one of the rare cell types in humans in that they have the same embryonal origin and function in both sexes but undergo different stages of development. In addition, they are exposed to different environments and hormonal stimulation during an individual’s lifetime. Despite the varying proliferation rates of these cells in men and women (very high in men, none after birth in women), the tumors arising from these cells have very similar biologic characteristics. Could it be that the high frequency of testicular GCTs as compared to ovarian GCTs is because of the very high proliferative rate and therefore a much higher likelihood of a ‘genetic mistake’ in men? Because adult testicular cancer is more common than ovarian GCTs in women, it has been studied in the past in much more detail. However, studying rare ovarian GCTs in women may help answer many questions about their etiology, behavior, and ultimately the management of these tumors. Some of the questions that require further investigation in the future are as follows: Is the abnormal genetic finding in virtually all male GCTs also present in female GCTs? Is cyclin D2 overexpressed in the normal and neoplastic female germ cells? Should investigators develop a universal staging system for male and female GCTs in order to conduct ­ clinical ­trials that would include both men and women, thus allowing for information relevant to the treatment of both male and female GCTs?

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References 1. Ries LAG, Melbert D, Krapcho M eds, et al. SEER Cancer Statistics Review. Bethesda, MD: National Cancer Institute; 1975–2005. 2. Smith HO, Berwick M, Verschraegen CF et al. Incidence and survival rates for female malignant germ cell tumors. Obstet Gynecol 2006;107:1075–85. 3. McGlynn KA, Devesa SS, Sigurdson AJ, Brown LM, Tsao L, Tarone RE. Trends in the incidence of testicular germ cell tumors in the United States. Cancer 2003;97:63–70.

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4. Pinkerton CR. Malignant germ cell tumors in childhood. Eur J Cancer 1997;33:895. 5. Lingappa VR. Disorders of the female reproductive tract. In: S McPhee, ed. Pathophysiology of Disease. Columbus, OH: McGraw–Hill; 2003:612–42. 6. Ebb DH, Green MD, Shamberger CR, Tarbell NJ. Solid tumors of childhood. In: VT DeVita, ed. Jr. Cancer: Principles and Practice of Oncology, sixth ed.. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2169–202. 7. Gobel V, Calaminus G, Engert J et al. Teratomas of infancy and childhood. Med Ped Oncol 1998;31:8. 8. Birch JM, Marsden HB, Swindell R. Pre-natal factors in the origin of germ cell tumors of childhood. Carcinogenesis 1982;3:75. 9. Ebb DH, Green MD, Shamberger CR, Tarbell NJ. Solid tumors of childhood. In: VT DeVita Jr., S Hellman, S Rosenberg, eds. Cancer: Principles and Practice of Oncology, seventh ed.. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1926. 10. Alttnan RP, Randolph JG, Lilly JR. Sacrococcygeal teratoma: American academy of pediatrics surgical section survey – 1973. J Pediatr Surg 1974;9:389. 11. Ozols FO, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: VT De Vita, ed. Jr. Cancer: Principles and Practice of Oncology, sixth ed.. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:1597–628. 12. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin 2000;50:7. 13. Daniels JL, Stutzman R, McLeod D. A comparison of testicular tumors in black and white patients. J Urol 1981;125:341. 14. Luna M, Valenzuela-Tamaritz J. Germ cell tumors of the mediastinum: postmortem findings. Am J Clin Pathol 1976;65:450. 15. Cameron RB, Sr. Loehrer PJ, Thomas CR Jr.. Neoplasms of the mediastinum. In: VT Devita. Jr., S Hellman, S Rosenberg, eds. Cancer: Principles and Practice of Oncology, seventh ed.. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:853. 16. Chaganti RSK, Houldsworth J. Genetics and biology of adult human germ cell tumors. Cancer Res 2000;60:1475. 17. Vos A, Oosterhuis JW, de Jong B et al. Cytogenetics of carcinoma in situ of the testis. Cancer Genet Cytogenet 1990;46:75. 18. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995;81:323. 19. Houldsworth J, Reuter V, Bosl OJ et al. Aberrant expression of cyclin D2 is an early event in human male germ cell tumorigenesis. Cell Growth Differ 1997;8:293. 20. Skakkebaek NE, Rajpert-de Meyts E, Jorgensen N et al. Germ cell cancer and disorders of spermatogenesis: an environmental connection? Acta Pathol Microbiolimmunol Scand 1998;106:3. 21. Skakkebaek NE, Berthelsen JG, Giwercman A et al. Carcinoma in situ of the testis: possible origin from gonocytes and precursors of all types of germ cell tumors except spermatocytoma. Int J Androl 1987;10:19. 22. Chaganti RSK, Houldsworth J. The cytogenetic theory of the pathogenesis of human adult male germ cell tumors. Acta Pathol Microbiolimmunol Scand 1998;106:80.

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23. Schwartz D, Goldfinger N, Kam Z et al. p53 control low DNA damage-dependent premeiotic checkpoint and facilitates DNA repair during spermatogenesis. Cell Growth Differ 1999;10:665. 24. van der Maase H, Specht L, Jacobsen GK et al. Surveillance following orchiectomy for stage I seminoma of the testis. Eur J Cancer 1993;29A:1931. 25. Stettner A, Hartenbach EM, Schink JC et al. Familial ovarian germ cell cancer: report and review. Am J Med Genet 1999;84:43. 26. Kuhn M, Weissbach L. Localization, incidence, diagnosis and treatment of extratesticular germ cell tumors. Urol Int 1985;40:166. 27. Witschi E. Migration of the germ cells of human embryos from the yolk sac to the primitive gonadal folds. Contr Embryol Carnegie Inst 1948;32:67. 28. Wylie C. Germ cells. Cell 1999;96:165. 29. Chaganti RSK, Rodriguez E, Mathew S. Origin of adult male mediastinal germ cell tumors. Lancet 1994;343:1130. 30. Hoffman HJ. Pineal region tumors. Prog Exp Tumor Res 1987;30:281.

31. Loehrer PJ, Ahlering TE, Pollack A. Testicular cancer. In: R Pazdur, LR Coia, W Hoskins, L Wagman, eds. Cancer Management: A Multidisciplinary Approach, third edn.. New York, NY: The Oncology Group; 2001:383–403. 32. Williams SD. Current management of ovarian germ cell tumors. Semin Oncol 1994;8:53. 33. Williams SD. Ovarian germ cell tumors: an update. Semin Oncol 1998;25:407. 34. Dosmann MA, Zagars GK. Postorchiectomy radiotherapy for stages I and II testicular sentinoma. Int J Radiat Oncol Biol Phys 1993;26:381. 35. Williams SD, Blessing JA, Hatch KD et al. Chemotherapy for advanced dysgerminoma: trials of the gynecolgic oncology group. J Clin Oncol 1991;9:1950. 36. Einhorn LH. Salvage therapy for germ cell tumors. Semin Oncol 1994;21:47. 37. Williams S, Blessing JA, Liao SY et al. Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the gynecologic oncology group. J Clin Oncol 1994;12:701.

Chapter

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Gender Differences in Hereditary Cancer Syndromes: Risks, Management, and Testing for Inherited Predisposition to Cancer Wendy K. Chung Herbert Irving Assistant Professor of Pediatrics and Medicine, Director of Clinical Genetics, Columbia University, New York, NY, USA

Cancer genetics: Overview

environmental interactions will likely be identified to enable better strategies for cancer prevention. Most individuals who develop cancer do not carry mutations in the inherited cancer genes that are discussed in this chapter. Individuals with mutations in highly penetrant genes can be clinically distinguished on the basis of their strong family history with multiple individuals in multiple generations affected with cancer, early age of onset of cancer, multiple primary cancers in a single individual, and clustering of particular types of cancer within either the individual or the family. In some cases, ethnicity also may be a predisposing factor. Although all ethnic groups have been found to carry mutations in these genes, certain ethnic groups may carry particular founder mutations at higher frequency. In addition to rare but highly penetrant monogenic (single gene) cancer susceptibility syndromes, another 5–30% of cancer is familial and likely represents the interaction of a small number of cancer susceptibility genes that in combination with each other and the environment increase the susceptibility to cancer. In families with familial rather than monogenic cancer susceptibility, the age of onset is often older and the number of affected family members is often fewer. Most highly penetrant inherited cancer susceptibility genes are autosomal dominantly inherited. Autosomal dominant conditions are characterized by a 50% chance for both males and females to inherit a mutated gene from a carrier parent; they may pass it on to their children if and only if they are carriers. Although both males and females may carry a genetic mutation, this mutation may have different disease manifestations or expression in the two genders largely because of anatomic or hormonal differences between the sexes. This may give the appearance of ‘skipping

The specific cause of cancer in most individuals is largely unknown but likely involves a combination of environmental and inherited genetic factors. For a minority of individuals there is an inherited predisposition to cancer resulting from a monogenic cancer predisposing mutation with high penetrance or likelihood that an individual will develop disease if he or she has inherited the genetic susceptibility. With advances in the field of human genetics, several of these genes that underlie cancer susceptibility have been identified, and clinical diagnostic tests to identify mutations in these genes have been developed. These tests are available to physicians to be used in overall assessment of the risk of an individual’s susceptibility to cancer so that an appropriately individualized management plan can be developed for each patient for prevention or early detection of cancer based on individual genetic predisposition. However, predictions for any one individual mutation carrier are limited because of the uncertainty of if, when, or in what organ a cancer may develop because predictions are based on population studies that cannot yet account for all individual variation in other interacting genes or environmental exposures. Furthermore, many of the hereditary cancer syndromes discussed in this chapter have different manifestations in men and women because they predispose to cancers of organs that are sex-specific. Recently, several less highly penetrant, common polymorphisms have been identified to predispose to cancers through genome-wide association studies,1 but how these genetic variants with relatively modest relative risk of 1.2–1.4 will be used clinically is yet to be determined. In the future, additional genes and important gene

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a generation,’ if the gene is passed through an individual less likely to express disease (i.e., a male for a breast cancer gene). As discussed in further detail, the cancer spectrum differs by gender in cancer syndromes involving breast, prostate, ovarian, endometrial, and testicular cancer. Regardless of whether an individual manifests disease, individuals can still pass on this mutation to the next generation. This has important implications when taking a family history to assess risk of cancer because susceptibility is equally likely to be inherited through the paternal as the maternal side. For instance, when taking a family history for breast cancer, one should always ask about cases of breast cancer in paternal aunts, cousins, and grandmothers. Although not commonly pursued, because of the autosomal dominant manner in which these mutations are inherited, an individual carrying one of these cancer susceptibility genes may seek either prenatal diagnosis or preimplantation genetic diagnosis (PGD) to avoid transmission of the mutation to future generations.2 Prenatal testing can be performed as early as 10–11 weeks of gestation via chorionic villus sampling with results generally available within 2 weeks. PGD requires in vitro fertilization, molecular genetic test development in each family, is not frequently covered by insurance, is associated with diagnostic errors in 2–3% of cases, and has only a 20–25% take-home baby rate/cycle.3 However, the main advantage of PGD is avoidance of the ethical difficulty for some couples of pregnancy termination. Although most cancer susceptibility genes are inherited in an autosomal dominant manner, they act recessively at a cellular level. Most cancer susceptibility genes are tumor suppressor genes that protect the cell from progression to uncontrolled growth. Although an individual has inherited a defect in one of these tumor suppressor genes, as long as the second copy of that gene functions normally, unregulated cell growth will still be suppressed. However, over time, the normal copy of the tumor suppressor gene may become somatically mutated. Such somatic mutations are not in the germline and are not passed down to the next generation, but these somatic mutations allow those somatic cells carrying two mutated genes to begin the process of tumor progression. The two-hit hypothesis was originally described by Knudson for retinoblastoma,4 but it is equally relevant to most of the other cancer syndromes that are discussed in this chapter. In the two-hit hypothesis, the first hit or mutation is inherited and the second hit is acquired somatically. Because a second somatic mutation must be acquired, an inherited mutation in a tumor suppressor gene greatly increases the likelihood of cancer but does not make cancer inevitable.

Breast cancer Hereditary Breast Cancer Syndromes The hereditary breast cancer syndromes account for approximately 5–10% of all breast cancer and include a broad

group of hereditary predisposition syndromes in which breast cancer is a component tumor. Among the hereditary breast cancers are hereditary breast–ovarian cancer (HBOC) syndrome, Cowden syndrome (CS), Li–Fraumeni syndrome (LFS), Peutz–Jeghers syndrome (PJS), and ataxia telangiectasia (ATM). The National Comprehensive Cancer Network (NCCN) Genetics Familial High Risk Panel5 has developed criteria for consideration of a hereditary breast cancer syndrome including (1) multiple cases of breast and/ or ovarian cancer in the same individual or in close relatives; (2) clustering of breast cancer with male breast cancer, thyroid cancer, sarcoma, adrenocortical carcinoma, brain tumors, and/or leukemia and lymphoma in the same family; and (3) a member of a family with a known mutation in a breast cancer susceptibility gene. Although hereditary breast cancer syndromes primarily cause breast and ovarian cancer in women, men can be carriers of a cancer susceptibility gene and have increased risks for associated cancers. Hereditary Breast–Ovarian Cancer Syndrome Hereditary breast–ovarian cancer syndrome has variable expression and can present in families with breast cancer only, ovarian cancer only, or with both breast and ovarian cancers. One should consider HBOC when two or more first-degree relatives have breast and/or ovarian cancer, especially if the cancer onset is in young patients, if there is multifocal or bilateral disease, if breast and ovarian cancer occur in a single individual, and if a case of male breast cancer is present in the family. In addition, Ashkenazi Jewish ancestry is associated with a higher prevalence of breast and ovarian cancers resulting from HBOC. There are two major HBOC cancer susceptibility genes, BRCA1 and BRCA2, both of which are tumor suppressor genes. Mutations in BRCA1 and BRCA2 are characterized by high lifetime risks for development of breast cancer (55–85%) and ovarian cancer (20–44%), as well as much lower risks of prostate cancer, colon cancer, pancreatic cancer, melanoma, male breast cancer, and other cancers.6,7 More than 2000 distinct pathogenic mutations have been identified in these two genes. There are founder mutations in certain populations, such as the Ashkenazim,8,9 Dutch,10,11 Icelandics,12 and French Canadians.12 Importantly, one of the three founder mutations in Ashkenazi Jewish individuals, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2, account for 20–35% of early onset breast cancer and ovarian cancer at any age in Ashkenazi individuals7 as compared with other populations in which germline BRCA1 and BRCA2 mutations are detected in only 5–10% of young patients with breast cancer or ovarian cancer.13,14 DNA-based testing for BRCA1 and BRCA2 cancerpredisposing mutations is available on a clinical basis for individuals identified by personal or family history to be at increased risk for having a germline BRCA1/BRCA2 mutation and for at-risk relatives of an individual with an identified BRCA1/BRCA2 mutation. At present, the available

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clinical testing includes direct sequence analysis of all coding exons and splice sites and analysis of common deletions. BART testing which includes more extensive testing for deletions, duplications, and complex re-arrangements in BRCA1/BRCA2 became available in 2007, but is only performed by request or reflexively for patients with normal BRCA1/BRCA2 sequence and a high pretest probability of carrying a mutation. Current clinical testing is estimated to be at least 90% sensitive but could theoretically fail to detect intronic or regulatory variants that would alter splicing or gene expression. Furthermore, variants of uncertain significance (VUS) may be identified, especially in minority populations with whom there is less experience to know which variants are benign polymorphisms segregating in the population without functional effects on BRCA1/ BRCA2. With additional experience in testing larger numbers of patients, segregation analysis within families, and functional studies in some cases, some VUS have been reclassified as either benign polymorphisms or pathogenic mutations,15 and revised reports are issued as this information becomes available. Given the substantially increased risk of breast, ovarian, and other cancers in HBOC, the management of individuals with BRCA1/BRCA2 cancer-predisposing mutations includes discussion of enhanced cancer screening protocols, chemoprevention strategies, and options for prophylactic mastectomy and/or salpingo-oophorectomy. None of these strategies has been assessed by randomized clinical trials or case control studies in high-risk women, and current recommendations are made on the basis of retrospective studies and expert clinical opinion. Recommendations of the National Comprehensive Cancer Network16 for cancer screening of individuals with a BRCA1/ BRCA2 mutation include the following: Breast cancer screening Monthly breast self-examination starting in early adulthood Semiannual clinical breast examination beginning at age 25–35 years Annual mammography beginning at age 25–35 years Annual MRI. n

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● ●

Men with BRCA2 cancer-predisposing mutations may also be at increased risk for breast cancer, and evaluation of any breast mass or change is advisable; however, there are insufficient data to recommend a formal program of surveillance. Ovarian cancer screening

n

Annual or semiannual pelvic examination beginning at ●

age 25–35 years Annual or semiannual transvaginal ultrasound examination with color Doppler beginning at age 25–35 years. Annual serum CA-125 concentration beginning at age 25–35 years



●



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Colon cancer screening Annual stool occult blood testing beginning at age 50 years Colonoscopy every 3–5 years beginning at age 50 years. Prostate cancer screening Prostate-specific antigen (PSA) serum screening starting at age 50 Clinical digital rectal examination starting at age 50. n



●

●

n

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●

Chemoprevention strategies should be discussed with BRCA1/BRCA2 mutation carriers. The efficacy of tamoxifen for breast cancer risk reduction in women with BRCA1 and BRCA2 mutations is controversial. Although a randomized clinical trial of treatment with tamoxifen in women identified by the Gail model to have an increased breast cancer risk reported a 49% reduction in breast cancer in the treated group,17 tamoxifen reduced the incidence of breast cancers that were estrogen receptor positive but not estrogen receptor negative. Because breast cancers occurring in women with BRCA1 mutations are more likely to be estrogen receptor negative, it is difficult to estimate the benefit of tamoxifen prophylaxis in BRCA1 carriers although there does appear to be some benefit. It is possible that premalignant lesions in BRCA1 carrier are estrogen responsive and amenable to tamoxifen prophylaxis at least at some point during the premalignant phase. The efficacy of oral contraceptives for ovarian cancer risk reduction in women with BRCA1 or BRCA2 mutations is unclear. One case control study found a decreased risk of ovarian cancer in women with BRCA1 or BRCA2 carriers who took oral contraceptives for more than 3 years.18 However, a more recent study did not confirm these findings and raised the concern that oral contraceptive use may increase the risk of breast cancer in women with BRCA1 or BRCA2 cancer-predisposing mutations.19 Because early detection does not prevent cancer, it is necessary to discuss the options of risk-reducing surgery including prophylactic mastectomy and prophylactic ­salpingo-oophorectomy. Tissue removed prophylactically should be carefully examined for malignancy, a finding that could alter medical management. At the time of prophylactic oophorectomy, ovarian or Fallopian tube cancer is detected in 2–5% of cases. Theoretical modelling and epidemiologic studies suggest that prophylactic surgeries do significantly decrease the risk of developing these cancers by greater than 90% but do not completely eliminate all cancer risk. Prophylactic mastectomy can be effectively performed with skin-sparing procedures with reconstruction. Prophylactic mastectomy can also be performed with nipple preservation, but this procedure has a higher residual risk of breast cancer. Prophylactic oophorectomy can decrease the risk of breast cancer by up to 50% if performed at the age of 40 and not followed by hormone replacement. However, hormone replacement is acceptable

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and does not significantly increase the risk of breast cancer above the baseline in BRCA1 and BRCA2 mutation carriers. Consideration is also made for total abdominal hysterectomy to either decrease the risk of endometrial cancer if tamoxifen is considered or to use unopposed estrogens for hormone replacement which many be associated with less breast cancer risk than estrogen/progesterone replacement. Even after prophylactic oophorectomy, there is still a small residual risk of primary peritoneal cancer. Cancer-predisposing mutations in BRCA1 and BRCA2 are inherited in an autosomal dominant manner; both men and women are equally likely to be mutation carriers. The most informative genetic result in a family is obtained by identifying the specific cancer-predisposing mutation in an affected family member before offering molecular genetic testing to asymptomatic at-risk family members. Without knowing if there is a BRCA1 or BRCA2 mutation segregating in the family, a negative genetic test result in an unaffected family member is ambiguous and cannot be easily interpreted. Therefore, genetic testing within a family should ideally begin with an individual with a history of breast and/or ovarian cancer. If there are multiple members in the family who are affected, the highest yield from the genetic testing is obtained by initially testing the youngest affected family member, an affected family member with breast and ovarian cancer, or an affected family member with bilateral breast cancer. First-degree relatives (parents, children, siblings) of individuals with a BRCA1 or BRCA2 mutation each have an independent 50% chance of inheriting the gene mutation. Cowden Syndrome Cowden syndrome is a rare cause of hereditary breast cancer characterized by multiple benign hamartomas including the pathognomonic trichilemmoma (a benign tumor of the infundibulum of the hair follicle), breast cancer, and thyroid cancer resulting from autosomal dominantly inherited mutations in the tumor suppressor gene Phosphatase and Tensin Homolog deleted on chromosome ten (PTEN). Other clinical manifestations of CS include acral keratoses, verrucoid or papillomatous papules, goiter or thyroid adenoma, fibrocystic breasts, hamartomatous intestinal polyps, macrocephaly, autism, and uterine leiomyomas. An increase in endometrial cancer has been reported. By age 40, most affected individuals develop the mucocutaneous features of CS. For carriers of PTEN mutations there is a 3–10% lifetime risk of nonmedullary thyroid carcinoma, usually follicular.20,21 Females with CS have a 67% risk of developing fibrocystic breast disease and a 25–50% lifetime risk of developing breast cancer.20,21 The age of diagnosis of breast cancer is approximately 10 years earlier than average21,22 but rarely before age 30. The estimated gene frequency for CS is 1 in a million,23 but it has been argued that this may be a gross underestimate resulting from underdiagnosis because of the variable and subtle clinical manifestations.24

With increased recognition of PTEN mutations as a cause of developmental delay and autism associated with macrocephaly in children, PTEN carriers are increasingly identified through autistic probands rather than due to their cancer family histories. Clinical genetic testing of PTEN is available and can be useful in assessing risk to family members. The most specific clinical feature is trichilemmomas. Families with only thyroid and breast cancers without mucocutaneous lesions have only a 2% probability of having PTEN mutations.25 PTEN mutations carriers should have annual physical examinations of the thyroid beginning in their late teens and annual breast examinations beginning in their mid 20s. Screening for endometrial cancer should begin at age 35. Annual mammograms and breast ultrasounds should be started at age 30 or 10 years before the earliest breast cancer in the family, whichever is younger. Li–Fraumeni Syndrome Li-Fraumeni syndrome is another rare cancer syndrome associated with a wide variety of pediatric and adult onset cancers. The clinical criteria for the diagnosis in an individual are bone or soft tissue sarcoma before the age of 45 with a family history significant for a first-degree relative with cancer before the age of 45 and a first- or seconddegree relative with cancer before age 45 or sarcoma at any age. The most frequently associated cancers are soft tissue sarcomas and early onset breast cancer, often before the age of 30. Other less frequently occurring tumors include acute leukemias, brain, lung, pancreatic, skin, and adrenocortical tumors. Adrenocortical carcinoma is relatively specific to LFS, and as many as 50% of children with adrenocortical carcinoma even without a family history supportive of LFS have germline mutations in TP53.26,27 Three percent of children with osteosarcomas28 and 9% of children with rhabdosarcomas29 regardless of family history have inherited TP53 mutations with as many as 50% of those families not yet fulfilling clinical criteria for diagnosis. Cancer often develops in the parent of an affected child after the child has been diagnosed and emphasizes the need to constantly re-evaluate the dynamic family history over time. Affected individuals often have multiple primary cancers.30 The relative risk of developing a second primary for TP53 carriers is 5.3 with a 57% chance of having a second primary in the 30-year period following diagnosis of the first cancer.30 This cancer syndrome is autosomal dominantly inherited and is caused by missense mutations in the tumor suppressor gene TP53 that acts as a transcription factor to regulate expression of genes controlling cell growth. The mutation frequency is approximately 1 in 50 000 with a penetrance of 50% by age 30 and 90% by age 60.31 Age-specific penetrance is higher for females because of the association with breast cancer. The relative risk of mutation carriers in developing childhood cancer is 100 times the background. Somatic rather

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than inherited germline mutations of TP53 also commonly occur in a variety of cancers but are not associated with LFS. Genetic testing for germline mutations in TP53 is available. However, it is currently unclear what effective therapeutic intervention options are available to mutations carriers. Patients with LFS should avoid excessive radiation, either for therapeutic or diagnostic purposes. Therefore, the most common reason to pursue genetic testing is to determine safety of radiation treatment. The cancers associated with LFS are difficult to cure with the exception of early stage breast cancer, childhood acute lymphoblastic leukemia, and germ cell tumors of the testis. Some had advocated PET MRI for cancer surveillance, but there are not data sufficient to support its efficacy. The only effective intervention is increased and earlier surveillance for breast cancer in at-risk women.32 For that reason, diagnostic genetic testing should be done only after careful genetic counseling to explore the impact of a genetic diagnosis on a given individual. Presymptomatic carrier testing of minors is appropriate since pediatric cancers are associated with LFS. Peutz–Jeghers Syndrome Peutz–Jeghers syndrome, a rare breast cancer syndrome, is characterized by mucocutaneous melanin pigmentation and intestinal hamartomatous polyposis33 resulting from autosomal dominantly inherited inactivating mutations in the serine/threonine kinase LKB1. The melanotic pigmentation is seen in and around the mouth, on the hands and feet, and in the axilla. The pigmentation may be mild or even absent in some individuals. More specific are the hamartomatous polyps that have a core of smooth muscle cells with an arborizing pattern that extends to the lamina propria and that have overlying folded epithelium without evidence of neoplasia. Neoplastic changes can arise within these polyps. The numbers of polyps is usually small but can be as many as several dozen. The polyps are usually located in the small intestine and may present as a bowel obstruction. Unlike some of the other oncogenetic associations, the variety of neoplasms associated with PJS is large. Patients with this syndrome are predisposed to a variety of cancers, including breast, cervical, ovarian, and gastrointestinal. Benign ovarian and testicular lesions such as granulosa cell tumors and Sertoli cell tumors, respectively, are also more common in patients with PJS.33 The frequency of the syndrome itself is low (1 in 8300 to 1 in 29 000),34 making accurate delineation of the clinical features difficult. The rate of de novo mutations is also relatively high, so that not all affected individuals have a significant family history.35 The lifetime risk of all cancer in carriers is 18fold higher in women and 6.2-fold higher in men.36 Genetic testing for germline mutations in LKB1 can be useful in some families because the pigmentation findings are variable and not specific to PJS. There are no highly prevalent founder mutations, and most mutations are specific to the individual family. Once a mutation is identified within the

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family, other family members can then be genetically tested to stratify risk. At-risk individuals should then be monitored for gastrointestinal, breast, and gynecologic tumors. Ataxia Telangiectasia Ataxia telangiectasia is an autosomal recessive condition for which carriers may have a slightly higher risk of breast cancer. Ataxia telangiectasia is associated with progressive cerebellar ataxia, ocular apraxia, telangiectasias, and cardiomyopathy in affected individuals. The gene ATM encodes a large protein kinase and is thought to interact with proteins upstream of p53 in sensing DNA damage associated with double-stranded breaks. The incidence of ATM mutations is 1 in 40 000 live births and, therefore, the heterozygous ATM mutation carrier frequency is 1%. All ethnic groups are affected. Female ATM mutation carriers were initially reported to have a five-fold increase in breast cancer.37,38 However, subsequent studies have not replicated these initial findings.39–42 The exact type of mutation, missense or nonsense, may be associated with different cellular phenotypes. It is possible that only missense mutations are associated with increased breast cancer susceptibility through a dominant negative effect.43 It appears that ATM mutations account for a small proportion of inherited or familial breast cancer but may play a role in the more common apparently sporadic breast cancer that is due to the interaction of environmental factors with many low-penetrance genes. Low Penetrance Genes Genome-wide association studies using thousands of cases of breast cancer and thousands of controls, largely in white populations, have identified single nucleotide polymorphisms in five genes that confer a modest relative risk of 1.2–1.4 of breast cancer.1 The most consistently associated gene across multiple independent studies is FGFR2. Individuals with the at-risk genotype for any one gene are at such modestly increased risk of breast cancer, it is not yet clear how to use this information effectively. However, there are a small percentage of women who will carry at-risk genotypes for the majority of these genes, for whom there may be additive or multiplicative interactions between genes that will place them at significantly increased risk that would approach the risk conferred by some of the monogenic disorders discussed above. Although genetic testing is currently offered by DECODE, 23 and me, and Navigenics, the clinical utility of these tests has not yet been validated and should not be used for routine clinical practice until more data are available.

Endometrial and gastrointestinal cancer Most individuals with colorectal cancer have sporadic disease without a family history. However, in approximately 20%

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of individuals with colon cancer there is a definable genetic component.44,45 Germline mutations conferring high lifetime risk of colorectal cancer account for 5–6% of all colorectal cancer cases. The two best-defined colorectal cancer genetic syndromes are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC).

Familial Adenomatous Polyposis Familial adenomatous polyposis is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop, beginning at a mean age of 16 years (range 7–36 years).46 Seven percent of untreated patients with FAP develop colon cancer by age 21 years, 87% by 45 years, and 93% by 50 years with a mean age of colon cancer diagnosis of 39 years.47 Associated extracolonic neoplasms include duodenal carcinomas, especially around the ampulla of Vater; follicular or papillary thyroid cancer; childhood hepatoblastoma; gastric carcinoma; and central nervous system tumors, predominantly medulloblastomas. Other benign manifestations include gastric and duodenal polyps, osteomas, dental anomalies, congenital hypertrophy of the retina pigment epithelium (CHRPE), and desmoid tumors.48 The desmoid tumors can be particularly difficult to manage since they often wrap around vital abdominal structures and are difficult to completely resect. Both sexes are equally affected. Familial adenomatous polyposis is diagnosed clinically in individuals with greater than 100 colorectal adenomatous polyps or with fewer than 100 adenomatous polyps if there is a family history of FAP. Attenuated FAP is associated with fewer colonic adenomas than seen in classic FAP, and polyps are located predominantly in the proximal colon.49 Colon cancer risk in attenuated FAP is usually delayed by approximately 12 years relative to classic FAP. Genetic testing is considered standard of care in families with FAP and should be performed in children by the age of 10 to determine if an individual is at risk and should begin screening. Familial adenomatous polyposis is caused by inherited mutations in the APC gene,50 a tumor suppressor gene with more than 300 different disease-associated mutations.51 Genetic testing of APC detects up to 95% of disease-causing mutations and is clinically available. Genetic testing is most often used to confirm the clinical diagnosis of FAP and to identify presymptomatic carriers in affected families. Protein truncating mutations in the extreme 5’ or 3’ end of the gene are associated with attenuated FAP.52,53 Polymorphisms in APC have been identified and one specific missense mutation (Ile1307Lys), found exclusively in Ashkenazi Jewish individuals, results in a two-fold relative risk of colonic adenomas and adenocarcinomas.54 In contrast to classic FAP, this polymorphism does not predispose to the polyposis phenotype. Familial adenomatous polyposis is autosomal dominantly inherited. Approximately 75–80% of individuals

with FAP have an affected parent, and the mutation can be passed either from the maternal or paternal line. About 25% of cases present represent de novo mutations. Each child of an affected individual has a 50% chance of inheriting the familial mutation. Early recognition of FAP and attenuated FAP allow for increased surveillance and surgical prophylaxis that improve survival. For this reason, FAP is one of the few cancer syndromes for which genetic testing is appropriate in children. Genetic testing for FAP should be offered to children at age 8–10 years before the commencement of colon cancer screening. For attenuated FAP, genetic testing is offered at age 18. The American Gastroenterological Association55 recommends surveillance of individuals with a known APC mutation or who are at 50% risk of FAP based on a family history. This surveillance includes the following: Annual screening for hepatoblastoma from birth to 5 years of age Sigmoidoscopy every 1–2 years beginning at age 10–12 years Colonoscopy once polyps are detected Upper endoscopy when colonic polyposis is detected or by age 25 and repeated every 1–3 years, the frequency of which is dependent on the severity of duodenal adenomas Small bowel x-ray when duodenal adenomas are detected or prior to colectomy, repeated every 1–3 years depending on findings and presence of symptoms Attention to extraintestinal manifestations Annual physical examination including palpation of the thyroid.

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The recommended surveillance of persons at risk for attenuated FAP includes the following: Colonoscopy every 2–3 years beginning at 18–20 years of age, depending on the number of polyps Colectomy should be considered when polyps emerge with timing depending on the size and number of adenomatous polyps. For individuals with attenuated FAP, colectomy may ultimately be necessary but may be deferred until polyps become difficult to individually remove.

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Hereditary Nonpolyposis Colon Cancer Hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome is an autosomal dominantly inherited predisposition to colon carcinoma that is not associated with polyposis, unlike FAP. Several other types of cancer can also be associated with HNPCC including endometrial, small intestinal, ovarian, stomach, urinary tract, and brain cancer.56–58 HNPCC is genetically heterogeneous and involves inactivating mutations in one of several mismatch repair genes including MHS2, MLH1, MSH6, PMSl, and PMS2.

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Table 44.1  Amsterdam criteria for hereditary nonpolyposis colorectal cancer • • • • •

At least three affected relatives with colorectal cancer At least one is a first-degree relative of the other two Familial adenomatous polyposis has been excluded At least two successive generations are affected One colon cancer occurs before the age of 50

Mutations in MSH2 and MLH1 account for 31% and 33% of families with HNPCC, whereas 32% of families have mutations in yet undefined genes.59 Identification of the underlying genetic basis for HNPCC revealed a new mechanism of cancer progression with hypermutability leading to accumulation of changes in the DNA that ultimately lead to uncontrolled cell growth and division. This hypermutability can be detected in colonic polyps as acquired microsatellite instability (MSI), resulting from mutations of simple repetitive elements (usually dinucleotide repeats) called microsatellites. This hypermutability leaves cells susceptible to the accumulation of pathogenic mutations that ultimately lead to neoplasia. Clinical criteria to make the diagnosis of Lynch syndrome were developed in 1991 and are called the Amsterdam criteria60 (Table 44.1). The diagnosis relies on an accurate and complete family history. However, these criteria were found to be too restrictive, and they decreased the sensitivity of identifying affected families. The criteria were, therefore, liberalized and these more inclusive criteria are called the Bethesda criteria (Table 44.2). A subset of HNPCC families have HNPCC-associated cancers and sebaceous gland tumors (adenomas, epitheliomas, and carcinomas) and keratoacanthomas and are called the Muir–Torre variant due to mutations in MSH2.61,62 Once a clinical diagnosis has been made, genetic testing can be used for risk assessment of unaffected members of the family. Screening for HNPCC can also be directly performed on the tumor for testing for MSI or lack of immunohistochemistry (IHC) for MHS2, MLH1, and MSH6. The most sensitive and efficient method to identify symptomatic HNPCC mutation carriers would be to screen all colon cancers by immunohistochemistry63 followed by DNA mutation analysis on patients with tumors that fail to stain. Some IHC tumors will be negative due to epigenetic changes rather than germline mutations, so IHC should be considered only a screening test. Expressivity of HNPCC is sex-dependent. Men with HNPCC mutations are most likely to develop colon cancer, whereas women with HNPCC mutations are most likely to develop endometrial cancer. The lifetime risk of endometrial cancer has been estimated at 61% and 42% for MSH2 and MLH1 mutations, respectively64 compared with the population risk of 3%. The median age of endometrial cancer diagnosis is 46 years.57 The relative risk for other extracolonic HNPCC-associated cancers is 4.1–4.4 for stomach, 6.4–8.0 for ovarian, 103–292 for small intestinal, and 75.3 for renal and ureteral.64 The relative risk varies somewhat

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Table 44.2  Betheseda criteria for hereditary nonpolyposis colorectal cancer (HNPCC) • Families that meet Amsterdam criteria • Individuals with two HNPCC-related cancers including synchronous or metachronous colorectal cancer or extracolonic cancers including endometrial, ovarian, gastric, hepatobiliary, small bowel, or transitional cell carcinoma of the renal pelvis or ureter • Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed at age younger than 45, the adenoma at age younger than 40 • Individuals with colorectal cancer or endometrial cancer diagnosed at age younger than 45 • Individuals with right-sided colorectal cancer with an undifferentiated pattern on histopathology diagnosed at age younger than 45 • Individuals with signet ring cell type colorectal cancer diagnosed at age younger than 45 • Individuals with adenomas diagnosed at age younger than 40

depending on the specific gene implicated. Identification of patients with HNPCC is important because of the high probability of a metachronous cancer after successful treatment of the first neoplasm. Prognosis of colon cancer is, however, no worse and may be somewhat better with HNPCCassociated colon cancer. Surgical treatment of colon cancer should be total colon resection. Presymptomatic mutation carriers should follow a cancer surveillance protocol consisting of colorectal cancer surveillance and endometrial carcinoma screening starting at the age of 25–35. There is no consensus about the optimal method of endometrial carcinoma screening, but ultrasound and endometrial biopsy are usually done on an annual basis. Ovarian cancer screening consists of annual CA-125 and transvaginal ultrasound but is not associated with decreased mortality. Therefore, mutation carriers may consider prophylactic total hysterectomy to maximally reduce their cancer risk once childbearing is complete. Screening methods and frequency for other HNPCC-associated cancers has not yet been standardized.

Testicular cancer Testicular cancer composes only 2% of all malignancies, but it is the most common type of cancer in men between the ages of 20 to 40.65 Several risk factors for testicular cancer have been identified including cryptorchidism, testicular dysgenesis, Klinefelter syndrome, prior history of a germ cell tumor, and a family history of an affected firstdegree relative. There is a 6- to 10-fold relative risk of testicular cancer with an affected first-degree relative,66,67 and approximately 2% of all men with germ cell tumors have

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an affected family member.68 The familial aggregation of testicular cancer is stronger with a history of an affected sibling rather than an affected father, which suggests that shared environmental contributions in addition to shared genetic factors are important. The International Testicular Cancer Linkage Consortium is working to identify genomic regions of linkage with testicular cancer, but the data to date have demonstrated only suggestive linkages with several chromosomal regions including Xq27-28, 18q22-qter, and 16p13 without clear identification of a major testicular cancer susceptibility locus.68 Because no genes have been identified that confer high risk of testicular cancer, no clinical genetic testing is currently available for risk assessment.

Multiple endocrine neoplasia type 2 (MEN2) Multiple endocrine neoplasia type 2 is a rare cancer syndrome associated with medullary thyroid cancer, pheochromocytomas, and parathyroid hyperplasia or adenomas affecting 1 in 30 000 individuals resulting from autosomal dominant inheritance of activating mutations in the oncogene rearranged in transfection (RET), a receptor tyrosine kinase. MEN2 families are characterized by one or more of these MEN2 endocrine tumors either in the same individual or in close relatives. Several subtypes of MEN2 have been identified, including MEN2A with the clinical features described previously, which accounts for at least 65% of MEN2 families.69 MEN2B is characterized by an earlier age of onset and more aggressive medullary thyroid cancer; pheochromocytomas; hyperplasia of the intestinal autonomic nerve plexuses; and disorganized growth of peripheral nerve axons in the lips, oral mucosa, and conjunctiva. MEN2B is also autosomal dominantly inherited resulting from mutations in RET. Familial medullary thyroid cancer is associated in some cases with mutations in the same RET gene. The location of mutations in RET tend to be specific to the phenotypes of MEN2A, MEN2B, or familial medullary thyroid cancer. The penetrance of MEN2A is approximately 70%, with an initial presentation usually of medullary thyroid cancer.70 Approximately 50% of patients with MEN2A develop pheochromocytoma and 5–10% develop hyperparathyroidism. MEN2B is characterized by an earlier mean age of onset of medullary thyroid cancer (18 years) and pheochromocytoma (24 years).71 Genetic testing of at-risk individuals is clinically available and considered the standard of care. It is imperative that at-risk individuals receive genetic testing before the age of 5 in MEN2A and before the age of 1 in MEN2B to prevent medullary thyroid cancer. Prophylactic total thyroidectomy is performed after the genetic diagnosis is made.72 Pre­ symptomatic mutation carriers are also followed by annual monitoring of blood pressure, urinary catecholamines, and

serum metanephrine for pheochromocytomas and monitoring of serum calcium for evidence of hyperparathyroidism. In addition to testing those families with classic features of MEN2, some have advocated that all patients with medullary thyroid cancer regardless of family history be tested for inherited RET mutations because 10% of these patients have RET mutations that would predispose them to pheochromocytomas or hyperparathyroidism.

Prostate cancer Prostate cancer is the most common noncutaneous cancer and is the second leading cause of cancer death among men.73 Evidence of an underlying genetic contribution to prostate cancer includes familial clustering and differing prevalence by ethnicity and country of origin.74 Twenty-five percent of men with prostate cancer report a positive family history. The concordance rate of prostate cancer in monozygotic twins is 0.11–0.21 compared with dizygotic twins of only 0.03–0.06,75–77 indicating that prostate cancer is likely a result of interactions of genetic and environmental factors. Prostate cancer is more common in black men, and among black men there is a higher proportion who present with metastases at diagnosis and a higher cancer-specific mortality.78 Men with a single first-degree relative (father, brother, or son) with prostate cancer are twice as likely to develop prostate cancer as those without affected close relatives. As the number of affected relatives increases to two and three first-degree relatives, the risk of prostate cancer increases 5- and 11-fold, respectively.79 Epidemiologic studies suggest that 5–10% of all prostate cancers are attributable to highly penetrant susceptibility genes.80 Although there is clear evidence of a genetic contribution to prostate cancer, identifying those genes conferring increased susceptibility to prostate cancer has been difficult because of the multifactorial nature of the disease. Genetic models assuming a dominant mode of inheritance suggest that 9% of all prostate cancer and 43% of prostate cancer diagnosed before the age of 55 years could be attributable to a single gene with a mutant allele frequency of 0.36–1.67%.80,81 There is evidence of locus heterogeneity for inherited factors with linkage of prostate cancer with several different chromosomal regions. Despite multiple studies, no prostate cancer genes have been definitively identified by linkage analysis.82 Genome-wide association studies have begun to identify several loci associated with increased prostate cancer risk, and some of them such as the 8q24 locus have susceptibility allele frequencies that are particularly high, specifically in the black population.83–86 However, none of these susceptibility alleles is associated with high risk. Prostate cancer is seen at low frequency with some inherited cancer syndromes. Although BRCA1 and BRCA2 confer the majority of their cancer risk for breast and ovarian

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cancer, there is an increased frequency of prostate cancer in men who carry mutations in either of these tumor suppressor genes,7,87,88 with an approximately three-fold higher lifetime relative risk of developing prostate cancer in mutationpositive males6 who have an earlier age of onset of prostate cancer. However, on a population-wide basis, the number of cases of prostate cancer attributable to mutations in either BRCA1 or BRCA2 is low. Currently, the only clinical genetic testing that is available for inherited prostate cancer is BRCA1 and BRCA2 testing, although this should change as additional genes are identified.

Cancer risk assessment, counseling, and testing With the recent identification of genes for a variety of hereditary cancer syndromes, risk assessment based on individual genetic test results is now feasible. When used appropriately, genetic testing for hereditary cancer facilitates the development of individualized surveillance and prevention strategies for at-risk individuals. However, care must be taken not to misinterpret negative test results to falsely reassure patients regarding risks for cancer in cases in which a familial mutation has not been identified. Currently, most research on the impact of testing for cancer predisposition has focused on hereditary breast/ovarian cancer (HBOC) families and hereditary nonpolyposis colon cancer (HNPCC) families. The following section focuses on these two well-described cancer syndromes in relation to the process of genetic counseling. They serve as important models for understanding the medical, sociodemographic, psychological, and family variables that arise in counseling individuals about increased cancer risks. Although limited research has been done on gender differences in genetic counseling for cancer-predisposing mutations, some preliminary information is available.

Genetic Counseling Genetic counseling translates basic scientific advances into clinically practical and understandable information for patients. Accurate cancer risk assessment requires collection of accurate medical and family history and recognition of patterns of inheritance and clinical characteristics of cancer syndromes. The National Society of Genetic Counselors has developed practice principles for genetic counseling including respect for autonomy and privacy of the individual, the need for confidentiality and informed consent, and the provision of information to the patient in a nondirective manner.89–91 In oncogenetics, cancer prevention education is the central goal. Oncogenetic testing should include both pre-test and post-test genetic counseling, informed consent, and careful interpretation and explanation of the results.

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Specialized programs have been developed to provide comprehensive services in cancer genetics (www.cancer.gov).

Importance of the Family History The patient’s personal history of cancer and a carefully ascertained three-generation family history of cancer remain the key components for identification of hereditary cancer syndromes. Based on this information, one can determine who in the family should be tested, which genes should be tested, and what is the best surveillance and management strategy is. For all relatives it is important to document whether they have had any cancer, the primary cancer site(s), the age at diagnosis, the presence of bilaterality or multiple primary tumors, the tumor histology/stage, current age, history of chronic diseases that predispose to cancer (particularly Crohn’s disease and ulcerative colitis for colon cancer risk), potential occupational and environmental exposures, age at and cause of death, and ethnic background. To accurately assess the family history often requires contacting multiple family members and obtaining medical records on deceased individuals. It is also important to note pieces of the family history that are unknown and to appreciate the limitations of self-reported family history. It is important to consider factors that may confound the pedigree interpretation, such as small family size, premature death because of trauma or war, prophylactic surgery that may mask the presence of a genetic susceptibility, and nonpaternity. Finally, family history is dynamic and changes over time and should be kept current. The main features of a pedigree that suggest a hereditary cancer syndrome are the following: Autosomal dominant pattern of inheritance of cancer A pattern of cancer types associated with a known cancer syndrome Early onset cancer Multiple relatives with the same or associated cancers Bilateral, synchronous, or metachronous cancers or multiple primary cancers in the same individual Rare cancers, such as male breast cancer.

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In addition to assessing the family risk, the pedigree can also be important in identifying unaffected members who would benefit from enhanced cancer surveillance. Before the advent of genetic testing, the diagnosis of a hereditary cancer syndrome was made on the basis of established clinical criteria and all at-risk relatives would be advised to have screening for the development of the cancers associated with the cancer syndrome. Now when a mutation is identified within a family, genetic testing allows accurate, relatively inexpensive risk stratification by differentiating presymptomatic genetic carriers from noncarriers who have no increased risk of cancer. It is important to note, however, that some families that meet the clinical criteria of a cancer syndrome may not have a detectable mutation

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because their cancer syndrome is caused by a mutation in an undiscovered gene or because the current testing method is not able to detect all mutations.

Genetic Testing Several medical organizations have offered guidelines that support genetic testing for cancer risk. Some of these include the American Society of Clinical Oncology,92 the American College of Medical Genetics,93 the American Society of Human Genetics.93 and the American Gastroenterological Association.55 Genetic testing offers many benefits, but, because of the inherent challenges, the following critical recommendations should be followed: Pretest genetic counseling and written informed consent should proceed genetic testing An affected individual should be the first in the family to be tested, whenever possible Genetic testing should be offered to families with a substantial pretest probability of carrying a mutation and used only when the results will influence the clinical management of the patient or family member The test must be interpretable.

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Informed Consent The American Society of Clinical Oncology has identified essential elements to be discussed in conjunction with written informed consent for genetic testing.92 First, information should be provided about the specific test being performed and the implications of a positive, a negative, and an uninformative result. Second, education about the medical aspects of the disorder, the mode of inheritance, cancer risks associated with a positive genetic test result, and the options and limitations of medical surveillance and screening should be provided. Third, the risks of genetic testing should be discussed, including short- and long-term psychological effects of having a positive genetic test, the risk of discrimination, and patient confidentiality. With the passage of the Genetic Information Non-discrimination Act (GINA), there is now federal legislation protecting again discrimination in health insurance regardless of provider and employment discrimination. GINA does not however protect against differential rates for life insurance or long-term disability based upon genetic test results. Fourth, the technical accuracy of the test and the cost of genetic counseling and genetic testing should be explained. In addition, the Cancer Genetics Studies Consortium stresses that genetic professionals should assist patients in exploring their beliefs, values, and experiences with the disorder in the family.

Hereditary Breast–Ovarian Cancer Syndrome Although it is clear that genetic testing for cancer risk has potential benefits for carefully selected and counseled

patients and family members, it also has the potential to increase anxiety or depression and negatively affect family relationships.94 Much of initial understanding of interest and use of predictive genetic testing comes from research studies that have offered BRCA1 and BRCA2 testing to members of HBOC families. Studying HBOC families, Biesceker et al.52 reported that 55% of eligible relatives contacted by letter and telephone chose to participate in the education and counseling and to have BRCA1 and BRCA2 testing. Most studies suggest that individuals seeking predictive genetic testing for BRCA1 and BRCA2 are female and in their early to mid 40s.95,96 In general, studies have shown that both unaffected women with a family history of breast or ovarian cancer and women affected with these cancers greatly overestimate their risk for breast cancer.97–99 Young unaffected women experience more psychological burden. Perception of personal breast cancer risk was nearly twice as high for unaffected women as compared with perceived risk before the diagnosis for the affected women (59% vs. 31%), even with similar family histories.100 Not surprisingly, a higher perception of risk is related to the expectation of being a gene carrier, which is overestimated before counseling. However, following genetic counseling the perception of cancer risk is markedly reduced.101 Men usually seek genetic testing for HBOC for the sake of their children and are often referred by a family member, whereas females more often seek testing to manage their own clinical care and to reduce anxiety. Most men believe that they were at increased risk of development of cancer (prostate, breast, colorectal, and skin cancer), and, similar to their female counterparts, more than half (55%) had intrusive thoughts about their cancer risk.102

Hereditary Nonpolyposis Colon Cancer Analogous to benefits in families with BRCA1 and BRCA2, the absence or presence of a HNPCC mutation is of considerable medical and psychological significance. Importantly, patients with a predisposing mutation can benefit from a medical surveillance program that has been shown to reduce the risk of developing colorectal cancer and decrease the overall mortality by 65%.103,104 In contrast to cancer risks in BRCA1 and BRCA2 that predominately affect female mutation carriers, HNPCC-associated cancer risks affect both male and female mutation carriers. A recent study of 18 clinically ascertained HNPCC families (523 subjects) with identified mutations showed that slightly more women than men (62% vs. 51%) sought genetic testing, which may reflect the additional risk for endometrial cancer in female mutation carriers.105

Psychological Issues The potential adverse psychological impact of genetic testing for hereditary cancer susceptibility is of great concern;

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however, there are scarce data to address this issue. Members of families with hereditary cancer syndromes often have been faced with close relatives who have died of cancer, sometimes at a young age. Knowledge of being at high risk of cancer has been associated with anxiety or depression106 and the possibility of predisposition testing may add further psychological burden. To date, studies performed worldwide on ethnically diverse populations show that genetic counseling and testing for BRCA1 and BRCA2 can be performed without a significant increase in anxiety and distress.99,107–11 There were some initial concerns that genetic test results might negatively affect insurability, but there is now federal and state legislation in place to protect Americans from having individually assessed health insurance rates or coverage determined on the basis of genetic predisposition.

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Conclusion During the past decade there have been major advances in clinical oncogenetics, and genetic testing for several hereditary cancer syndromes is now the standard of care. Recognizing the clues of hereditary cancer susceptibility can have lifesaving potential for the patient and at-risk relatives by developing an enhanced surveillance and/or preventive or therapeutic interventions based on the underlying genetic cancer predisposition. Additional cancer susceptibility genes including those that account for the less penetrant but more common familial cancer susceptibility are likely to be identified allowing for more accurate risk assessment and cancer prevention in the years to come.

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References   1. Easton DF, Pooley KA, Dunning AM, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007;447(7148):1087–93.   2. Offit K, Kohut K, Clagett B, et al. Cancer genetic testing and assisted reproduction. J Clin Oncol 2006;24(29):4775–82.   3. Grace J, El Toukhy T, Braude P. Pre-implantation genetic testing. BJOG 2004;111(11):1165–73.   4. Hethcote HW, Knudson AG Jr. Model for the incidence of embryonal cancers: application to retinoblastoma. Proc Natl Acad Sci U S A 1978;75(5):2453–57.   5. National Comprehensive Cancer Network. NCCN practice guidelines: genetics. Familial high risk cancer. Oncology 1999;13:161–86.   6. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast cancer linkage consortium. Lancet 1994;343(8899):692–95.   7. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among ashkenazi jews. N Engl J Med 1997;336(20):1401–8.   8. Oddoux C, Struewing JP, Clayton CM, et al. The carrier frequency of the BRCA2 6174delT mutation among

20. 21.

22. 23.

24.

25.

26.

491

ashkenazi jewish individuals is approximately 1%. Nat Genet 1996;14(2):188–1890. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 1996;14(2):185–87. Petrij-Bosch A, Peelen T, van Vliet M, et al. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 1997;17(3):341–45. Verhoog LC, Berns EM, Brekelmans CT, et al. Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients. J Clin Oncol 2000;18(Suppl. 21):119S–124S. Thorlacius S, Olafsdottir G, Tryggvadottir L, et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 1996;13(1):117–19. Couch FJ, DeShano ML, Blackwood MA, et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 1997;336(20):1409–15. FitzGerald MG, MacDonald DJ, Krainer M, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 1996;334(3):143–49. Easton DF, Deffenbaugh AM, Pruss D, et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancerpredisposition genes. Am J Hum Genet 2007;81(5):873–83. Clinical practice guidelines in oncology: genetic/familial highrisk assessment: breast and ovarian.Version 1.2008. www. nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf. National Comprehensive Cancer Network; 2008. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 1998;90(18):1371–88. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary ovarian cancer clinical study group. N Engl J Med 1998;339(7):424–28. Modan B, Hartge P, Hirsh-Yechezkel G,  et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345(4):235–40. Hanssen AM, Fryns JP. Cowden syndrome. J Med Genet 1995;32(2):117–19. Starink TM, van der Veen JP, Arwert F, et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 1986;29(3):222–33. Longy M, Lacombe D. Cowden disease. Report of a family and review. Ann Genet 1996;39(1):35–42. Nelen MR, Padberg GW, Peeters EA, Lin AY, et al. Localization of the gene for cowden disease to chromosome 10q22-23. Nat Genet 1996;13(1):114–16. Haibach H, Burns TW, Carlson HE, Burman KD, Deftos LJ. Multiple hamartoma syndrome (Cowden’s disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Am J Clin Pathol 1992;97(5):705–12. Marsh DJ, Dahia PL, Caron S, et al. Germline PTEN mutations in Cowden syndrome-like families. J Med Genet 1998;35(11):881–85. Sameshima Y, Tsunematsu Y, Watanabe S, et al. Detection of novel germ-line p53 mutations in diverse-cancer-prone families

492

27.

28.

29.

30.

31.

32. 33.

34. 35.

36.

37.

38.

39.

40.

41.

42.

43.

44. 45.

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identified by selecting patients with childhood adrenocortical carcinoma. J Natl Cancer Inst 1992;84(9):703–7. Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D. High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 1994;86(22): 1707–10. McIntyre JF, Smith-Sorensen B, Friend SH, et al. Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol 1994;12(5):925–30. Diller L, Sexsmith E, Gottlieb A, Li FP, Malkin D. Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest 1995;95(4):1606–11. Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986; 53(5):661–71. Williams WR, Strong LC. Genetic epidemiology of soft tissue sarcomas in children. In: H Muller, W Weber, eds. Familial Cancer: First International Research Conference on Familial Cancer. Basle: AG Karger; 1985. Shapiro S. Determining the efficacy of breast cancer screening. Cancer 1989;63(10):1873–80. Phillips RKS, Spigelman AD, Thomson JPS. Familial Adenomatous Polyposis and Other Polyposis Syndromes. London: Edward Arnold; 1994. Finan MC, Ray MK. Gastrointestinal polyposis syndromes. Dermatol Clin 1989;7(3):419–34. Westerman AM, Entius MM, Boor PP, et al. Novel mutations in the LKB1/STK11 gene in dutch peutz-jeghers families. Hum Mutat 1999;13(6):476–81. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with the Peutz–Jeghers syndrome. Ann Intern Med 1998;128(11):896–99. Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 1991;325(26):1831–36. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 1987;316(21):1289–94. Bay JO, Grancho M, Pernin D, et al. No evidence for constitutional ATM mutation in breast/gastric cancer families. Int J Oncol 1998;12(6):1385–90. Chen J, Birkholtz GG, Lindblom P, Rubio C, Lindblom A. The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 1998;58(7):1376–79. FitzGerald MG, Bean JM, Hegde SR, et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 1997;15(3):307–10. Vorechovsky I, Rasio D, Luo L, et al. The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation. Cancer Res 1996;56(12): 2726–32. Gatti RA, Tward A, Concannon P. Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab 1999;68(4):419–23. Cancer Facts and Figures. American Cancer Society, Atlanta, GA, 2002. Burt RW, Petersen GM. Familial colorectal cancer: diagnosis and management. In: GP Young, P Rozen, B Levine, eds. Prevention and Early Detection of Colorectal Cancer. London: WB Saunders; 1996:171–94.

46. Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology 1991;100(6):1658–64. 47. Bussey HJR. Familial Polyposis Coli. Family Studies, Histo­ pathology, Differential Diagnosis, and Results of Treatment. Baltimore, MD and London: Johns Hopkins University Press; 1975. 48. Burt RW. Colon cancer screening. Gastroenterology 2000; 119(3):837–53. 49. Lynch HT, Smyrk TC, Watson P, et al. Hereditary flat adenoma syndrome: a variant of familial adenomatous polyposis? Dis Colon Rectum 1992;35(5):411–21. 50. Kinzler KW, Nilbert MC, Su LK, et al. Identification of FAP locus genes from chromosome 5q21. Science 1991;253(5020):661–65. 51. Laurent-Puig P, Beroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucl Acids Res 1998;26(1):269–70. 52. Biesecker BB, Ishibe N, Hadley DW, et al. Psychosocial factors predicting BRCA1/BRCA2 testing decisions in members of hereditary breast and ovarian cancer families. Am J Med Genet 2000;93(4):257–63. 53. Giardiello FM, Brensinger JD, Luce MC, et al. Phenotypic expression of disease in families that have mutations in the 5’ region of the adenomatous polyposis coli gene. Ann Intern Med 1997;126(7):514–19. 54. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 1997;17(1):79–83. 55. American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterol. 121 (1) (2001) 195-197. 56. Lynch HT, Ens J, Lynch JF, Watson P. Tumor variation in three extended lynch syndrome II kindreds. Am J Gastroenterol 1988;83(7):741–47. 57. Lynch HT, Lanspa S, Smyrk T, Boman B, Watson P, Lynch J. Hereditary nonpolyposis colorectal cancer (Lynch syndromes I & II). Genetics, pathology, natural history, and cancer control, part I. Cancer Genet Cytogenet 1991;53(2):143–60. 58. Vasen HF, Offerhaus GJ, den Hartog Jager FC, et al. The tumour spectrum in hereditary non-polyposis colorectal cancer: a study of 24 kindreds in the Netherlands. Int J Cancer 1990;46(1):31–34. 59. Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993;75(6):1215–25. 60. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 1991;34(5):424–25. 61. Honchel R, Halling KC, Schaid DJ, Pittelkow M, Thibodeau SN. Microsatellite instability in Muir–Torre syndrome. Cancer Res 1994;54(5):1159–63. 62. Kolodner RD, Hall NR, Lipford J, et al. Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics 1994;24(3):516–26. 63. Hampel H, Frankel WL, Martin E, et al. Screening for the lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352(18):1851–60. 64. Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110(4):1020–27.

C h a p t e r 4 4     Gender Differences in Hereditary Cancer Syndromes l

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65. Schottenfeld D. Testis. In: D Schalenfeld, JF Fraumeni, eds. Cancer Epidemiology and Prevention. London: WB Saunders; 1982:947–57. 66. Forman D, Oliver RT, Brett AR, et al. Familial testicular cancer: a report of the UK family register, estimation of risk and an HLA class 1 sib-pair analysis. Br J Cancer 1992;65(2):255–62. 67. Heimdal K, Lothe RA, Lystad S, Holm R, Fossa SD, Borresen AL. No germline TP53 mutations detected in familial and bilateral testicular cancer. Gene Chromosome Can 1993;6(2):92–97. 68. Candidate regions for testicular cancer susceptibility genes. The International Testicular Cancer Linkage Consortium. APMIS, 106 (1) 64–70, discussion 1-2 69. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996;276(19):1575–15179. 70. Easton DF, Ponder MA, Cummings T, et al. The clinical and screening age-at-onset distribution for the MEN-2 syndrome. Am J Hum Genet 1989;44(2):208–15. 71. Vasen HF, Nieuwenhuijzen Kruseman AC, Berkel H, et al. Multiple endocrine neoplasia syndrome type 2: the value of screening and central registration. A study of 15 kindreds in the Netherlands. Am J Med 1987;83(5):847–52. 72. Gagel RF, Tashjian AH Jr., Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988;318(8):478–84. 73. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin 1999;49(1):8–31, 1. 74. Pienta KJ, Esper PS. Risk factors for prostate cancer. Ann Intern Med 1993;118(10):793–803. 75. Ahlbom A, Lichtenstein P, Malmstrom H, Feychting M, Hemminki K, Pedersen NL. Cancer in twins: genetic and nongenetic familial risk factors. J Natl Cancer Inst 1997;89(4):287–93. 76. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000;343(2):78–85. 77. Verkasalo PK, Kaprio J, Koskenvuo M, Pukkala E. Genetic predisposition, environment and cancer incidence: a nationwide twin study in Finland, 1976–1995. Int J Cancer 1999;83(6):743–49. 78. Wingo PA, Bolden S, Tong T, Parker SL, Martin LM, Heath CW Jr. Cancer statistics for African Americans. CA Cancer J Clin 1996;46(2):113–25. 79. Walsh PC, Partin AW. Family history facilitates the early diagnosis of prostate carcinoma. Cancer 1997;80(9):1871–74. 80. Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 1992;89(8):3367–71. 81. Gronberg H, Damber L, Damber JE, Iselius L. Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 1997;146(7):552–57. 82. Schaid DJ. The complex genetic epidemiology of prostate cancer. Hum Mol Genet 2004;13, Spec No 1:R103-21. 83. Cheng I, Plummer SJ, Jorgenson E, et al. 8q24 and prostate cancer: association with advanced disease and meta-analysis. Eur J Hum Genet 2008;16(4):496–505.

  84. Eeles RA, Kote-Jarai Z, Giles GG, et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 2008;40(3):316–21.   85. Gudmundsson J, Sulem P, Manolescu A, et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 2007;39(5):631–37.   86. Thomas G, Jacobs KB, Yeager M, et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 2008;40(3):310–15.   87. Easton DF, Steele L, Fields P, et al. Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. Am J Hum Genet 1997;61(1):120–28.   88. Sigurdsson S, Thorlacius S, Tomasson J, et al. BRCA2 mutation in Icelandic prostate cancer patients. J Mol Med 1997;75(10):758–61.   89. Fine B, Baker D, Fiddler MB. Practice-based competencies for accreditation of training in graduate programs in genetic counseling. J Genet Counsel 1996;5(3):113–21.   90. Kessler S. The Psychological Foundations of Genetic Counseling. Genetic Counseling: Psychological Dimensions. Baltimore, MD: Academic Press; 1979.   91. McKinnon WC, Baty BJ, Bennett RL, et al. Predisposition genetic testing for late-onset disorders in adults. A position paper of the national society of genetic counselors. JAMA 1997;278(15):1217–20.   92. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J. Clin. Oncol. 14 (5) (1996) 1730-1736, discussion 7-40.   93. Genetic testing for colon cancer: joint statement of the American College of Medical Genetics and American Society of Human Genetics. Joint Test and Technology Transfer Committee Working Group. Genet. Med. 2 (6) (2000) 362-366.   94. Lerman C, Croyle R. Psychological issues in genetic testing for breast cancer susceptibility. Arch Intern Med 1994;154(6):609–16.   95. Lerman C, Schwartz MD, Lin TH, Hughes C, Narod S, Lynch HT. The influence of psychological distress on use of genetic testing for cancer risk. J Consult Clin Psychol 1997;65(3):414–20.   96. Reichelt JG, Dahl AA, Heimdal K, Moller P. Uptake of genetic testing and pre-test levels of mental distress in norwegian families with known BRCA1 mutations. Dis Markers 1999;15(1-3):139–43.   97. Bluman LG, Rimer BK, Berry DA, et al. Attitudes, knowledge, and risk perceptions of women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2. J Clin Oncol 1999;17(3):1040–46.   98. Smith BL, Gadd MA, Lawler C, et al. Perception of breast cancer risk among women in breast center and primary care settings: correlation with age and family history of breast cancer. Surgery 1996;120(2):297–303.   99. Watson M, Lloyd S, Davidson J, et al. The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer. Br J Cancer 1999;79(5-6):868–74. 100. MacDonald DJ, Choi J, Ferrell B, et al. Concerns of women presenting to a comprehensive cancer centre for genetic cancer risk assessment. J Med Genet 2002;39(7):526–30. 101. Bish A, Sutton S, Jacobs C, Levene S, Ramirez A, Hodgson S. Changes in psychological distress after cancer genetic

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102.

103.

104.

105.

106.

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counselling: a comparison of affected and unaffected women. Br J Cancer 2002;86(1):43–50. Liede A, Metcalfe K, Hanna D, et al. Evaluation of the needs of male carriers of mutations in BRCA1 or BRCA2 who have undergone genetic counseling. Am J Hum Genet 2000;67(6):1494–504. Jarvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118(5):829–34. Renkonen-Sinisalo L, Aarnio M, Mecklin JP, Jarvinen HJ. Surveillance improves survival of colorectal cancer in patients with hereditary nonpolyposis colorectal cancer. Cancer Detect Prev 2000;24(2):137–42. Wagner A, Tops C, Wijnen JT, et al. Genetic testing in hereditary non-polyposis colorectal cancer families with a MSH2, MLH1, or MSH6 mutation. J Med Genet 2002;39(11):833–37. Lerman C, Daly M, Masny A, Balshem A. Attitudes about genetic testing for breast-ovarian cancer susceptibility. J Clin Oncol 1994;12(4):843–50.

107. Broadstock M, Michie S, Marteau T. Psychological consequences of predictive genetic testing: a systematic review. Eur J Hum Genet 2000;8(10):731–38. 108. Croyle RT, Smith KR, Botkin JR, Baty B, Nash J. Psychological responses to BRCA1 mutation testing: preliminary findings. Health Psychol 1997;16(1):63–72. 109. DudokdeWit AC, Tibben A, Frets PG, et al. BRCA1 in the family: a case description of the psychological implications. Am J Med Genet 1997;71(1):63–71. 110. Lerman C, Narod S, Schulman K, et al. BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. JAMA 1996;275(24):1885–92. 111. Wood ME, Mullineaux L, Rahm AK, Fairclough D, Wenzel L. Impact of BRCA1 testing on women with cancer: a pilot study. Genet Test 2000;4(3):265–72.

Section 8 Infectious Disease

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INTRODUCTION Michael Rendel

Since the last edition of The Principles of Gender-Specific Medicine, the world has become an even more complicated place. Society is far more interdependent economically, politically, and medically than ever before. Infectious disease issues such as tuberculosis, malaria, and HIV have received widespread attention and will require a global response. Bioterrorist threats such as anthrax or smallpox are not an abstract possibility but a realistic threat. Pandemic influenza has mandated global response planning, as the world learns lessons after the 2009 outbreak of Influenza A H1N1 (‘swine flu’) and the previous outbreak of SARS. The contents of this chapter have been reformulated to reflect these themes of global relevance. Rather than categorize chapters by specific infectious diseases and their etiologic agents, the authors have chosen important current medical issues and subjected them to the gender-related scrutiny that is the focus of this text. Dr Sharon Lewin addresses gender differences in emerging infectious diseases. She includes such far-flung diseases as Nipah virus and monkeypox as well as everyday infections here at home such as MRSA and West Nile virus. In each case, clinical and epidemiologic elements are reviewed as they relate to gender differences in outcome and treatment. Dr Anne Rampalo discusses more familiar terrain: sexually transmitted infections. She and her co-author, Dr Khalil Ghanem, report on the impact of immunologic and hormonal effects on the genital tract and its subsequent

susceptibility to disease. They also discuss commonly seen STIs and their manifestations in primary, secondary, and recurrent forms. Drs Bruce Polsky and Mia Sordillo have written a comprehensive chapter on infections in pregnancy. Not only do they discuss the impact of hormonal and immunologic changes on infections as was discussed in the chapter on STIs, but they examine the effect of the physiologic changes in pregnancy on disease as well. They go on to analyze a variety of infections and their relationship to disease in mother and/or child. Finally, they address emerging infections in pregnancy, bioterrorist agents, and the management of antibiotics. Drs Sally Hodder, Debra Chew, and Shobha Swaminathan review adult immunizations in men and women. They address issues concerning the newer vaccines (such as HPV and zoster vaccines), long-standing vaccines (including influenza, pneumococcus, and the hepatitis vaccines), as well as new versions of standard immunizations (as seen in Tdap and conjugate meningitis vaccines). Further, they address issues regarding immunization in pregnancy. These topics reflect the interest in infectious disease issues that impact our everyday lives as well as those that may be significant in years to come. As we have seen in recent times, we must remain vigilant about both commonly seen infections as well as those that are in evolution. While the impending threat of a mutated virus or a bioterrorist event is real and must be addressed, we cannot ignore the commonly seen infections that are the cause of widespread suffering and disease worldwide.

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Gender Differences in Emerging Infectious Diseases Sharon Lewin Fellow, Royal College of Physicians, Canada; Attending Physician, St. Luke’s–Roosevelt Hospital Center, Division of Infectious Disease, New York, NY; Attending Physician, New York Presbyterian Hospital Center, Division of Internal Medicine, New York, NY; Assistant Clinical Professor of Medicine, Columbia University School of Medicine, New York, NY, USA

Introduction

Climate change increases the risk of infectious diseases by many mechanisms. Mosquito populations will increase where they already exist. Mosquitoes and other arthropod vectors will migrate to new habitats where warmer climate is conducive to their survival. For vector-borne diseases to occur, only a host reservoir and a specific vector are necessary. If humans are the reservoir and the vector has been able to adapt to new locales, a previous zoonosis or confined disease has the potential to become a global disease. The emergence of West Nile virus infection in North America is the best example of vectors and/or amplifying hosts migrating to a new location. Insect vectors can also overcome geographic barriers via global shipping of goods and human air travel. Introduction of foreign plants, animals, and invertebrates is being increasingly noted in temperate climates.4 Hantavirus infection in the Four Corners region of the United States was traced to imported prairie dogs from Africa. Increased precipitation, a result of climate change, leads to more agricultural run-off, allowing pathogens to enter drinking water systems. In developing countries where poverty and inadequate infrastructure are the norm, public health monitoring systems must be supported and improved so that new or more severe risks to health can be identified and curtailed. As new infectious diseases are recognized, critical issues arise regarding pregnant women and their unborn children. Physiologic changes during pregnancy and gestational age both alter decision-making regarding vaccinations and medications. Because the infectious diseases discussed in this chapter are emerging pathogens or known pathogens with new epidemiology, much is unknown and unstudied regarding gender differences in disease severity, risk to the pregnant woman or impact on the fetus.

An urgent worldwide threat is posed by the introduction and spread of novel infectious diseases. The reasons for emerging infectious diseases are numerous and complex. An emerging infectious disease is defined as any of the following:1 a newly recognized illness a known pathogen now affecting new populations a known pathogen previously responsible for limited, sporadic disease now infecting large numbers of animals or people a known pathogen now causing disease in new geographic areas a known pathogen now resistant to previously effective treatment.

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Among the most significant explanations for these emerging diseases are changes in environment and ecology caused by natural phenomena such as droughts, hurricanes, and floods; and human-made phenomena such as agricultural development, urbanization, and denuding of forests. Nipah virus infection in Bangladesh, discussed in this chapter, is largely attributable to migration of flying foxes whose natural habitat has been deforested. World-wide conflict, including wars, ethnic cleansing, and genocide, have led to displacement of large populations into overcrowded settlements where safe water is not available and sanitation is poor. For example, unsanitary conditions led to a huge increase in the rat population in post-war Kosovo, resulting in a tularemia outbreak with 327 confirmed cases in 8 months.2 Regional conflict leads to breakdown in infection control, inadequate surveillance, impeded access to populations, and spread of infectious diseases through movement of refugees and aid workers.3

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Questions regarding pregnancy’s effect on the clinical course of these new diseases, implications for prophylaxis, and treatment of exposed pregnant women, and transmission of disease during pregnancy, labor, delivery, and breastfeeding are, as yet, unanswered in many emerging infectious diseases.5 Wherever there is information, it will be discussed. Health disparities exist for women around the globe. Poverty, malnutrition, and educational inequities fuel the spread of disease. Poor women are much more vulnerable to disease than their male counterparts. Disparate factors ranging from immune alterations in pregnancy, economic factors, and complex cultural expectations are partial explanations. The majority of the 1.2 billion people living in extreme poverty are women (70%). Unemployment is higher among women in most developing countries, and even when employed, women’s salaries are lower. The World Health Organization (WHO) reports that less is spent on healthcare for women and girls worldwide than for men and boys. Access to doctors, clinics, and hospitals is hampered by the fact that women remain in rural areas while men travel to work in urban areas more accessible to medical care. Lack of employment and high illiteracy rates among women in developing nations create huge obstacles to healthcare. More than one-third of 15- to 19-year-old girls in parts of Africa and Asia are married. Once married, the husband’s family is unlikely to support continued education of their daughter-in-law.6 Education must be provided to improve women’s socioeconomic status. Black women have higher infant death rates than mixedrace and white women. Although greater than eight years of education lowers infant death rates significantly, the three groups still stratify similarly based on race.7 Unfortunately, violence against women, despite awareness in developed nations, has not been stanched at home or abroad. Unprotected sex and rape occur with much greater regularity and aggression in areas where there is armed conflict and civil unrest. Measurable increases of HIV and other sexually transmitted diseases occur but so do the intangibles of fear, humiliation, and social stigma. Pregnant women may fare poorly even in developed countries because they are often denied medications and vaccines because of unknown effects on the fetus. Healthcare workers and public health officials must be knowledgeable about benefits and risks of drugs and immunizations in pregnancy, so they assist their patients in making informed decisions.8 Pregnant patients and their physicians overestimate the risk to the fetus of medication.9 Misconceptions abound even about vaccines and medications proven to be safe and beneficial in pregnancy, often resulting in healthcare workers either not offering their pregnant patients appropriate prophylaxis or treatment, or pregnant patients declining interventions that are likely to protect or benefit themselves and their fetuses.

Data from pregnant women are often not collected in surveillance of a recognized infectious disease outbreak. When a second outbreak occurs, there will be little information about the natural history of that particular infection in pregnant women. Obstetrician-gynecologists are often the only physicians a woman may see and, therefore, are in a unique position to detect unusual patterns of illness or novel diseases.10 Pregnant women may have more severe illness in some emerging infectious diseases such as SARS (severe acute respiratory syndrome) and the hemorrhagic fevers. An attempt to avoid radiographs and scans in pregnant patients may lead to diagnostic delays. Ciprofloxaxin is normally contraindicated in pregnancy because of studies suggesting joint and cartilage toxicity in juvenile animals from fluoro­ quinolones. Despite this data, during the anthrax attacks in 2001, the CDC recommended a 60 day course of ciprofloxacin prophylaxis for pregnant women who had a highrisk exposure.11 The Second International Conference on Women and Infectious Disease was held in Atlanta in 2006. The conference underlined the need for accumulating gender-based information on infectious diseases. Monitoring pregnant women during outbreaks must become an integral part of public health investigations. If general guidelines exist for an emerging infectious disease outbreak, pre-event recom­ mendations for prophylaxis and treatment of pregnant women must also be specifically provided, rather than cobbling together guidelines for these vulnerable women and their fetuses during an emergency. Dozens of new diseases, new syndromes, well-known infectious agents which have become resistant to treatment, and known diseases with a recently identified organism contribute to a vast number of emerging infectious diseases at home and abroad. Space and time do not permit a discussion of all of them. Five emerging viral infections, three bacterial infections, and one prion disease will be discussed in this chapter.

Emerging viral infections Nipah Virus Nipah virus (NiV), along with Hendra virus (HeV), belongs to the family Paramyxoviridae. Over the past decade, both have recently emerged in humans and livestock in Australia and South-East Asia as contagious, virulent viruses capable of causing illness and death. Due to little immunological cross-reactivity with other paramyxoviruses, HeV and NiV have been classified into a new genus within the family Paramyxoviridae named Henipavirus.12 HeV and NiV are designated as biosafety level (BSL) 4 agents and are potential bioterrorist agents because there is no licensed vaccine or antiviral therapy. The emergence of

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henipaviruses has been linked to increased contact between bats and humans, paralleling the emergence of other zoonotic viruses such as SARS, coronavirus, Australian bat lyssavirus, Manangle virus, and probably Ebola and Marburg. Loss of habitat and food availability has driven bats toward human-populated areas, and encroachment by human agriculture into bat habitats create exposure to these emerging pathogens. Hendra virus was discovered in Australia in 1994 when a pregnant mare named Drama Series fell ill and died. A prominent horse trainer who nursed the mare became ill within one week and died from respiratory and renal failure. The source of the virus was thought to be the mare’s frothy nasal discharge. Altogether, 19 of 23 horses housed with the index case were stricken and 12 of those died. This outbreak suggested both high attack and high mortality rates. Nipah virus, named after the village Sungai Nipah in Malaysia, was first identified in 1999 when 265 people became ill and 105 of them died. Ninety percent of the human cases were pig farmers or had contact with pigs. Pigs tested positive for the virus which was highly contagious among them, spread by coughing. Over a million pigs were destroyed on the Malay peninsula to try to contain the outbreak. Eleven cases in Singapore (with one death) occurred in abattoir workers exposed to pigs from those Malaysian farms.13 The primary reservoir for NiV is the Pteropid fruit bat, also called the flying fox.14 At the index farm, fruit orchards were close to confined swine herds, allowing bat urine, feces, and fruit partially eaten by the bats to contaminate pig feed. Since the original reports, there have been at least eight more outbreaks of Nipah virus in India and Bangladesh. Case fatality rates have ranged from 33% to 92%. In Siliguri, India in January 2001 75% of the infected patients were either hospital staff or visitors of a sick patient, suggesting person-to-person transmission. In an outbreak in April 2004 in Bangladesh, epidemiologic evidence once again strongly suggested that personto-person transmission occurred. There was no apparent intermediate animal host. Most of the cases were relatives of a local religious leader. Twenty-seven of 36 persons died. Sharing eating utensils with the sick, sleeping in their beds, close contact at the time of death, and a ritual of special cleansing of the orifices of the dead bodies for burial may have all contributed to person-to-person spread.15 In January 2005, also in Bangladesh, an outbreak of Nipah virus infection in 12 people, 11 of whom died, was traced to drinking raw date-palm juice. Fruit bats, a nuisance to datepalm juice collectors, drink date-palm juice directly from the cut in the tree or the clay pot used to collect the sweet sap overnight. The juice is gathered in the morning and sold fresh as it ferments quickly and loses its sweet taste. Because palm juice is consumed within a few hours of harvest, Nipah virus, introduced into the juice by the fruit bats, might be able to survive in sufficient numbers for transmission.16

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Clinical Illness The illness begins with fever, myalgia, and headache after an incubation period ranging from 7 to 40 days. Cough and dyspnea are common. In 60% of patients the disease progresses rapidly, with drowsiness, disorientation, and confusion with ensuing coma in 5–7 days. Neurologic findings include seizures, myoclonus, cerebellar dysfunction, and areflexia. Survivors of NiV may have persistent fatigue and neurologic impairment, such as convulsions and personality changes.17 Laboratory Findings Laboratory abnormalities are non-specific. Moderate thrombocytopenia and elevated liver enzymes can occur. In patients with neurologic involvement, cerebrospinal fluid (CSF) findings are lymphocytic pleocytosis and elevated protein with normal glucose, in keeping with other viral central nervous system infections. Chest radiographs may show scattered infiltrates. Magnetic resonance imaging (MRI) of brain imaging may show multiple, small asymmetric focal lesions in subcortical and deep white matter, presumably areas of microinfarction; but similar findings are noted in other viral encephalitides.18 EEG shows diffuse slow waves, and in some cases periodic bitemporal sharp waves. Viral isolation is not done as Nipah virus is classified as a biohazard. ELISA can establish the diagnosis of Nipah virus infection. Both an IgM capture ELISA and an indirect IgG ELISA and highly specific PCR assays can detect viral sequences in tissue or CSF specimens. Pathology Post-mortem CNS findings in patients who died from Nipah encephalitis show widespread ischemia, thrombosis, and infarction with areas of necrotizing vasculitis and syncytia. Viral inclusions are seen adjacent to vasculitic vessels.19 Treatment Ribavirin has shown in vitro activity against HeV and NiV. Clinical trials have been inconclusive. Treatment is supportive. Airway protection should be initiated with the onset of neurologic decline. Antithrombotic agents have been used based on pathologic findings of ischemia and infarction in autopsy specimens, but have not been studied. Prevention Human disease has been associated with infection in intermediate species such as horses with HeV and swine with NiV. The most crucial way of limiting future human disease is early recognition of illness in intermediate animal hosts. Gender In the first Nipah outbreak among pig farmers, the male to female ratio was 4.5 to 1, reflecting that males are more

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likely to have direct exposure to the pigs. Otherwise there has been no significant difference in gender susceptibility. Early abortion and stillbirths have been reported in sows. No data are available in human women.

Chikungunya Fever Chikungunya fever, seen in Africa and Asia, is caused by an alphavirus, a large group of viruses that cause fever, rash, and polyarthritis. Alphaviruses, previously known as ‘group A arboviruses’ (arthropod-borne viruses) comprise a genus within the family Togaviridae. New World alphaviruses are EEE, WEE, and VEE. Old world alphaviruses of major importance, in addition to chikungunya, include O’nyongnyong virus in Africa, Mayaro virus in South America, and Ross River virus in Australia and Oceania. Alphaviruses occur in distinct geographic regions based on the range of their respective arthropod vectors. Epidemics of chikungunya prior to 2005 have occurred periodically based on serologic surveys, but disease has usually been sporadic. The virus was first isolated during an epidemic in Tanzania in 1952 and 1953.20 Chikungunya is endemic in parts of Africa, SouthEast Asia and on the Indian sub-continent. In 2005–2006 a major outbreak occurred in the Indian Ocean, starting in Kenya and moving to the Comoro Islands, Mauritius, the Seychelles, Madagascar, Mayotte, and Reunion and finally reaching India, where 1.4 million cases were reported. In some areas the attack rates reached 45%. Asymptomatic chikungunya infection was rare; almost everyone infected became ill. In Reunion, of 265 000 cases of chikungunya there were 237 deaths. Deaths were more common in the elderly and people with other underlying diseases.21 More than 1000 European and American travelers to India during the epidemic returned home with chikungunya fever. Despite the relatively low fatality rate, widespread epidemics are responsible for considerable morbidity and substantial economic loss. Chikungunya, from the Makonde language of Mozam­ bique, means ‘that which bends up,’ which describes the crippling symptoms of the infection. Aedes mosquitoes are known to be the principal vectors of chikungunya: Aedes aegypti in Africa, Aedes albopictus (the Asian tiger mosquito) in Reunion, and other species in sylvatic cycles. Nonhuman primates appear to be the reservoir, but dense areas of infected humans may also provide a reservoir. High levels of viremia (109 virus particles per milliliter of serum) make transmission from person to person possible.21 Epidemics usually occur during the tropical rainy season and abate during the dry season.22 The vast size of the epidemic that spread to India was attributed to a new variant of chikungunya virus.23 Between July and September 2007, 247 cases of chikungunya infection were reported in Italy, the first reports of infection in Europe.

Clinical Manifestations After an incubation pesriod of 1 to 12 days, chikungunya presents as a very acute illness with severe polyarticular arthralgias, shaking chills, and fever as high as 40 °C. The illness is biphasic, with the fever abating and then returning, described as a ‘saddle-back’ fever curve.24 Other symptoms may include myalgias, headache, photophobia, retro-orbital pain, pharyngitis, nausea, and vomiting. The arthralgias in chikungunya infection favor the wrists and ankles or previously injured joints, and are worse after a period of rest. Pressure on the wrist produces intense pain, often considered to be a diagnostic sign.21 There may be joint swelling but usually effusions are absent. Patients remain as immobile as possible.25 In HLA-B27 positive patients, joint involvement may be permanent.26 In the early phase of illness there may be a flush over the face and neck which evolves to a more widespread maculopapular and sometimes pruritic rash, including the palms and soles. The illness may last from a week to as long as several months. Although rarely fatal, convalescence from chikungunya fever may be prolonged, up to a year. Patients presenting with chikungunya infection may be indistinguishable from patients with other alphavirus infections known also to cause fever, rash, and polyarthritis, such as Mayaro, O’nyong-nyong, and Ross River viruses. Other illnesses in the differential diagnosis are dengue, parvovirus, hepatitis B prodrome, juvenile rheumatoid arthritis, and rubella. Laboratory Findings Laboratory results include lymphopenia and thrombocytopenia, the latter sometimes severe enough to cause bleeding gums and epistaxis. Hepatic enzymes are commonly elevated, and the erythrocyte sedimentation rate is usually markedly elevated. Chikungunya virus may be rapidly detected via a reverse transcription loop-mediated isothermal amplification assay (RT-LAMP). Diagnosis may also be aided by antibody capture IgM ELISA which can be arranged through public health authorities.27 Treatment No specific treatment is available for any alphavirus infections. Supportive care, analgesics, and antipyretics may mitigate symptoms. Aspirin should be avoided. No vaccine is commercially available.28 Gender Differences Infection rates appear to be equal in males and females. Much of the information on pregnancy, fetal, and neonatal exposure to chikungunya comes from the Reunion Island outbreak in 2005. No increase in birth defects were associated with chikungunya during pregnancy. In a study of 160 pregnant mothers infected with chikungunya, 3 of

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9 miscarriages before 22 weeks gestation were attributable to the virus. The greatest risk of vertical transmission of chikungunya appears to be at delivery. Of the remaining 151 infected women who carried to term, 33 were viremic at delivery. Almost half the newborns (48.5%) born to those viremic mothers had neonatal chikungunya infection. Cesarean section did not protect against transmission. Infected neonates were asymptomatic at birth and became ill within 3–7 days.29 Although preliminary reports suggested that 90% of affected newborns recovered quickly without sequelae, a retrospective analysis of 38 neonates showed a high rate of morbidity. Complications included seizures with abnormal brain MRI findings in 14 of 25 infants, hemorrhagic symptoms, hemodynamic disorders with abnormal echocardiographic findings, and one death from necrotizing enterocolitis.30 Of the remaining 118 women who had been infected during their pregnancies but were non-viremic at delivery, all gave birth to healthy newborns.29,31 There is no evidence the virus is transmitted through breastfeeding.

Hantavirus Hantavirus infection was first identified during the Korean War when several thousand US and UN forces became ill with fever, hypotension, renal failure, and DIC. The name given to the syndrome was hemorrhagic fever with renal syndrome (HFRS). Symptoms and signs of clinical illness were fever, hypotension, thrombocytopenia, DIC, and renal failure. The etiologic agent was named Hantaan, after the Hantaan River in Korea. Hantavirus is an RNA virus belonging to the bunyavirus family. In 1993 in New Mexico, 3 persons died in the Four Corners region of the southwestern US. Four Corners is the intersection of four states: Utah, New Mexico, Arizona, and Colorado. Another cluster of 5 deaths, also in the Four Corners region, led to a public health investigation by state, local health organizations and the Centers for Disease Control and Prevention (CDC). All of the cases had a similar clinical illness of fever, chills, and myalgias, then cough, shortness of breath, and progression to cardiovascular collapse and respiratory failure. The mortality rate was approximately 80%. After only a month, the investigators identified the etiologic virus as well as the deer mouse as both reservoir and vector. The new virus was originally called Sin Nombre (Spanish for ‘the virus with no name’), later it was identified as a hantavirus. The syndrome in the Four Corners outbreak was named hantavirus cardiopulmonary syndrome (HCPS). The Four Corners 1993 outbreak was thought to be caused by a preceding wet, mild winter (El Nino) which led to a steep increase in the food supply for mice and a tenfold increase in their numbers in the Four Corners region.32 Increased rodent density in turn led a higher percentage of infected mice who readily entered homes and farm buildings. Deer mice shed virus in their urine, droppings and

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saliva. Transmission to humans occurs when they breathe in contaminated air. Although the greatest risk factor appeared to be living in a rodent infested dwelling, in one study, simply entering a long-closed-up building was an important means of exposure. Hantavirus can cause two distinct clinical entities, HCPS and HFRS. Old World viruses cause HFRS and occur worldwide, especially in Asia. China has approximately 100 000 cases of HFRS each year. These hantaviruses have been called Seoul virus, Dobrava virus, and Puumala virus. In the New World, 13 different hantaviruses have been identified. Some cause HCPS and some cause HCPS with renal failure. Dozens of HCPS cases have been reported in Alberta, Canada. In South America, at least four strains of hantavirus have been reported to cause HCPS. One of them, the Andes virus, causes person-to-person transmission and high pediatric mortality. Infection occurs by inhalation of aerosolized virus from feces, urine or saliva of infected rodents. Immune reactivity rather than direct viral injury is likely responsible for plasma leakage in HFRS and HCPS. In HCPS, fulminant pulmonary edema ensues from damage to pulmonary endothelium. Cardiogenic shock in HCPS appears to result from an as yet unidentified myocardial depressant. Mortality rate in the 1993 outbreak in the southwestern US was 80%. Most of the deaths occurred within 24 hours of admission to hospital. Because of recognition of the disease and earlier diagnosis, more aggressive intervention has dropped the death rate considerably. By the end of 2000, 227 HCPS cases were reported in 31 states west of the Mississippi. The mean age of cases was 38 years, indicating a predilection in young adults. Most of the cases were rural and occurred in the spring and fall, when residents were exposed to rodents during seasonal planting and harvesting. Clinical Presentation After exposure, there is an incubation period of 2–3 weeks, when the prodrome of fever chills and myalgias begins, lasting 3–10 days. HCPS is heralded by hypoxemia and tachycardia leading to precipitous clinical deterioration. Patients who recover may have no residual deficits apart from several months of fatigue and decreased exercise tolerance. Because the differential diagnosis is so broad and early HCPS can mimic (among other diseases) influenza, congestive heart failure, bacterial pneumonia, pneumonic plague and tularemia, obtaining a history of rodent exposure or exposure to rodent excreta is essential. Laboratory Findings Laboratory findings may show elevated AST and LDH during the prodrome. WBC is usually elevated with a left shift. A falling platelet count reliably precedes the cardiopulmonary collapse of HCPS patients. Hemoconcentration may

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occur because of capillary leak. Progressive lactic acidosis and severe hypoxemia are ominous signs. Serologic assays can be done using ELISA for circulating IgM and IgG. Western blot uses a nucleocapsid antigen for the detection of hantavirus antibodies. A very sensitive test is a rapid immunoblot strip assay (RIBA) that detects hantavirus antibodies during the acute clinical phase of the illness. One third of patients on initial chest x-ray have pulmonary edema. Gender Differences Males account for 60% of HCPS cases, probably reflecting a greater occupational exposure to deer mice. Hantavirus appears to be rare in pregnancy. A pregnant woman with HFRS was reported in 1992. Another report of a pregnant woman who presented after 6 days of high fever and 2 days of no fetal movement gave birth to a stillborn 3200 g infant. She was diagnosed with HFRS based on a high IgM titer to hantavirus. The mother recovered with aggressive care and hemodialysis.33 A small review of five pregnant women with HCPS included one death. There were two fetal losses which, at autopsy, showed no evidence of hantavirus infection either microscopically or with immunhistochemical studies. The three surviving children similarly had no evidence of infection, suggesting that transplacental transmission of hantavirus does not occur.34 Like any life-threatening illness accompanied by hypoxemia, hantavirus infected mothers may give birth to infants who have suffered hypoxemic damage in utero.

Monkeypox Along with vaccinia (cowpox) and variola (smallpox) virus, monkeypox virus is in the family of DNA viruses Poxviridae, genus Orthopoxvirus. Monkeypox, enzootic among squirrels and monkeys in rainforests of western and central Africa, creates a vesicular illness similar to variola. The disease was first found in 1958 in laboratory monkeys. A smallpox-like illness in humans in Africa in 1970 led to the first report of monkeypox.35 Transmission from person to person and mortality from monkeypox is much lower than from smallpox. Fifty-nine cases of monkeypox in humans were reported from western and central African rainforests in the decade from 1970 to 1980. The mortality rate was 17%. All the human monkeypox cases had been in contact with small forest animals. Transmission occurs from bites or contact with blood, body fluid, vesicles or respiratory droplets of the infected animals. Between 1981 and 1986, WHO surveillance revealed more than 400 additional monkeypox virus infections in humans. Most were children under 10, and the attack rate correlated with time spent outdoors. The secondary cases

numbered eight times higher in people who had not received smallpox vaccine versus than those who had.36 Between 1996 and 1998 a very large outbreak of monkeypox occurred in the Democratic Republic of Congo. The large number of cases was attributed to military unrest in the region which drove people deeper into the rainforests, and a population of predominately non-smallpox vaccinated people. From 1998 to 2002, 1625 more cases of monkeypox were reported in the Democratic Republic of Congo.37 In 1997, wild animals caught in the DRC were tested for the monkeypox virus. Several animals were found to have neutralizing antibodies against the monkeypox virus: domestic pig, Gambian rat, elephant shrew, and several species of squirrel. Prior to 2003, monkeypox virus infection had never been reported in the Western hemisphere.38 Early in June 2003, the Centers for Disease Control and Prevention (CDC) announced the first evidence of community-acquired monkeypox in the United States. By July 30, 2003, a total of 72 cases had been reported to CDC from six states. The index case was a 3-year-old Wisconsin girl who developed fever and cellulitis after a prairie dog bite, initially, thought to be an isolated event. However, 2 weeks later the girl’s mother became ill and a sample from one of the mother’s skin lesions demonstrated a poxvirus on electron microscopy. Another report of a sick meat inspector who distributed exotic animals led to an investigation. Most of the 72 cases became ill after contact with sick pet prairie dogs with monkeypox. The introduction of monkeypox into Wisconsin was traced to a distributor in Illinois, who had received a shipment of exotic animals imported into the United States through Texas from Ghana, West Africa. On arrival to the United States, imported prairie dogs were housed at the same distribution facility as Gambian giant rats, along with other exotic animals. The prairie dogs likely acquired the virus from the Gambian rats. Clinical Illness From seroepidemiologic data, most monkeypox infections are asymptomatic. Symptomatic monkeypox in humans resembles smallpox, but patients are less ill and more likely to have lymphadenopathy. The incubation period is approximately 12 days. Despite early reports, secondary cases are unusual, as opposed to smallpox, which is extremely contagious. Symptoms of monkeypox virus infection are fever, headache, myalgias, and fatigue, followed in 1–3 days by a rash which starts on the trunk and then spreads peripherally. Palms and soles are usually involved, as is the face. Patients may also have mucous membrane lesions as large as 1 cm. Initially the rash is maculopapular and then evolves over a 2–4 week period to vesicles. As the vesicles heal, they umbilicate, become pustular, and then form eschars which desquamate. Patients are ill for as long as 4 weeks, but may still have healing vesicular lesions once they feel well.

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Mortality in African cases has ranged from 1% to 10% but risk is lower in the United States, where nutrition and access to medical care are better.39 Smallpox vaccination with vaccinia virus confers significant protection against infection with monkeypox virus, 85% or higher. Both smallpox and monkey-pox are orthopoxviruses, and the vaccinia immunization induces cross-immunity to monkeypox virus. Two other infections may mimic monkeypox: varicella and smallpox. Smallpox has been eradicated worldwide, and is therefore unlikely in the absence of a laboratory accident or bioterrorism. Monkeypox vesicles look alike at each stage of the illness, whereas in varicella the lesions are all at different stages of development. Diagnosis If the diagnosis of monkeypox is being considered, local health authorities and the CDC should be notified. Diagnostic methods include virus isolation, real-time PCR, ELISA, immunofluorescent antibody assay, and electron microscopy. Gender Differences Information about gender differences and pregnancy in monkeypox illness is extremely limited. One case from Zaire (Democratic Republic of Congo) reported a woman at 24 weeks gestation with fever and a rash. Monkeypox virus was isolated. At 30 weeks, she gave birth to a 1500 g infant with a generalized skin rash consistent with monkeypox.35 In the 2003 outbreak in the United States, there were pregnant mothers in several of the affected households. The CDC recommended that anyone exposed either to a sick prairie dog or an infected person receive the smallpox (vaccinia) vaccine, whether they were pregnant or not. Treatment Treatment is largely supportive. No information is available on post-exposure smallpox vaccination. Cidofovir has both in vitro activity against monkeypox virus and in vivo activity in some animal studies.40 No data are available regarding vaccinia immune globulin.

West Nile Virus West Nile virus is perhaps the best example of the introduction, establishment, and distribution of a new zoonosis in densely inhabited urban areas. Its emergence in 1999 in the United States and its rapid spread across the country demonstrates that arboviruses can pose a threat in temperate climates. West Nile virus (WNV), transmitted to humans by mosquitoes, is a single-stranded RNA virus in the genus Flavivirus, a group of zoonotic or arthropod-borne viruses.41 WNV is related antigenically to the Japanese encephalitis virus (JEV) complex, which includes several neurotropic viruses

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associated with human encephalitis. These include JEV, St Louis encephalitis, Murray Valley encephalitis, and Kunjin, an Australian subtype of WNV. The virus was first identified in 1937 in the West Nile area of Uganda. Until 1999, the virus was found only in Africa, Asia, the Middle East, and Europe. Human outbreaks were rare and associated with mild illness, usually in soldiers, children, and healthy adults. However, in 1957 in Israel an outbreak in nursing homes associated with severe neurologic disease with fatalities led to recognition of WNV as a cause of severe human meningoencephalitis. Leading up to the identification of WNV infection in the United States, outbreaks in Romania (1996) and Russia (1999) involved hundreds of cases with severe neurologic symptoms, suggesting that WNV disease was increasing not only in frequency but severity. The first human outbreak of WNV in the United States began in 1999 with 62 reported cases and 7 deaths in New York, New Jersey, and Connecticut.42 To date, the number of WNV cases appears to have peaked in 2001 at 9862 cases, 2866 with neuroinvasive disease.43 Peak incidence of human disease in North America occurs in late August to mid-September. Sporadic cases occur year-round in the south. The seasonality is due to mosquitoes’ emergence in the spring in temperate climates.44 WNV is spread by infected Culex mosquitoes who feed on infected birds who act as amplifying hosts. The mosquitoes carry virus in their salivary glands and in turn infect susceptible bird species, thus maintaining the bird-mosquito-bird transmission cycle. Humans, horses, and other vertebrates are incidental hosts and unlikely to be sources of transmission, since viremia is low grade and brief. In a very small number of cases, WNV has been spread through blood transfusions and organ transplants. Wild birds develop sustained high levels of viremia but generally are not ill. In the United States and Israel, WNV causes high mortality in avian populations. The presence of dead birds may herald an outbreak of human disease. Migration of birds and/or the Culex mosquito are the likely explanation for dissemination of WNV to the United States. Clinical Illness Eighty percent of WNV infections are asymptomatic. The clinical illness with WNV can be divided into two categories: West Nile fever and West Nile neuroinvasive disease. Most of the remaining 20% of infected individuals will develop West Nile fever, with symptoms of headache, myalgias, and nausea in addition to fever. The incubation is 3–14 days. Signs of illness are occasional adenopathy and a rash that lasts a few days to several weeks. This is usually a self-limited illness lasting 3–6 days, indistinguishable from other viral infections. One out of 150 infected persons, usually elderly, will become seriously ill with neuroinvasive West Nile disease. Patients present with any combination of high fever,

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headache, neck stiffness, stupor, coma, convulsions, and blindness. Patients presenting with encephalitis associated with muscle weakness and flaccid paralysis should be strongly suspected to have WNV infection.45 The illness lasts for several weeks and may leave patients with permanent neurologic sequelae such as muscle weakness, concentration problems, confusion and depression. In addition to encephalitis, cranial nerve palsies, myelitis, and aseptic meningitis have been described. West Nile poliomyelitis, an acute flaccid paralysis without fever, occurs rarely. Most patients with the polio presentation of WNV recover incompletely and are left with profound residual deficits. Although central nervous system disease is most serious, other organs may become involved including muscles, liver, pancreas, and heart. Fatal hemorrhagic fever has been reported, but is rare. West Nile infection in the elderly may simply reflect waning immunity with advancing age, however, proclivity to neuroinvasion may be based on functional or structural CNS changes.44 In addition to age, alcohol abuse and diabetes have been associated with West Nile encephalitis;46 as had solid organ transplantation.47 Laboratory Findings General laboratory findings are non-specific. Hyponatremia may be present in encephalitis patients. Cerebrospinal fluid shows a lymphocytic pleocytosis, elevated protein and normal glucose. CT and MRI brain imaging are useful only to rule out other processes, as imaging findings in WNV neurologic disease are non-specific. The best diagnostic method is a four-fold or greater change in serum IgM antibody to WNV or IgM antibody-capture ELISA in CSF. Diagnosis relies on a high index of suspicion. WNV should always be considered in patients with otherwise unexplained febrile illness, encephalitis, and/or meningitis, or flaccid paralysis during mosquito season. Closely related arboviruses cross-react in serologic tests. To pinpoint the etiologic agent it may be necessary to conduct tests using a battery of closely related viruses. Treatment Treatment is supportive. In milder cases, patients will recover on their own. For severe disease, hospitalization with intravenous fluids and ventilatory support may be necessary. Prevention Prevention is simply avoiding mosquito bites, which occur most commonly at dusk and dawn when mosquitoes are most active. Use of insect repellents (DEET), pants that tuck into socks, long sleeves with cuffs, and insect screens on doors and windows are all effective deterrents. Clothing should be sprayed with permethrin- or DEET-containing products. Standing water in flower pots, buckets, rain barrels,

pet dishes, and bird baths are invitations for mosquito infestation. Tire swings should have holes so rain water drains out and children’s wading pools should be empty and stored sideways when not in use. No human vaccine against WNV is currently available. Gender Differences In surveillance reports, the number of cases of WNV in men has been slightly greater than women, but not statistically significant. This may be explained by greater numbers of men than women working outdoors. Severity of illness correlates with age rather than gender. Limited information about WNV in pregnancy is available, with few case reports. Flavivirus infections during pregnancy have been rarely associated with spontaneous abortion and neonatal illness, but no known birth defects.48 It is not clear whether pregnant women are more susceptible to infection with WNV or whether they become more ill than non-pregnant women. In 2002 a woman developed WNV encephalitis during her 27th week of pregnancy. At 38 weeks she delivered an infant with chorioretinitis, cystic destruction of cerebral tissue, and laboratory evidence of congenitally acquired WNV infection. This appears to be the only case of documented vertical transmission of WNV.49 In another case of WNV meningoencephalitis during pregnancy, the mother was induced at 32 weeks for pre-eclampsia and fetal growth restriction. Her infant did not have serologic evaluation for WNV, making it unclear whether maternal hypertension or WNV or both led to the growth restriction.50 In four other cases of reported WNV infections in pregnancy, all delivered full-term infants with grossly normal appearance and negative laboratory findings of WNV. In 2003 the CDC developed a registry to track pregnant women with WNV infection. During 2003 and 2004, 77 pregnant women with WNV had 72 live infants, 4 miscarriages and 2 elective abortions. None of the 72 infants followed to date have had conclusive laboratory evidence of WNV infection. However, the sensitivity of IgM testing for WNV in newborns is unknown. Three infants born to mothers ill with WNV within 3 weeks of delivery had symptomatic WN disease at birth.51 If WNV is diagnosed during pregnancy, a detailed ultrasound examination should be done in the first few weeks after the mother becomes ill. If an infant is born to a mother who had documented WNV, a thorough evaluation of the infant is recommended with careful physical exam, serologic testing for WNV, hearing evaluation, and pathological examination of the placenta. If the infant appears to be ill, the infant should undergo brain CT scan, neurologic and ophthalmologic specialist consultations, complete blood work including WNV serology, and close follow-up through the first six months with repeat evaluations as indicated.52 One probable case of WNV transmitted from mother to infant via breast milk has been reported.53

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Emerging bacterial infections Bartonellosis In 1909 A.L. Barton described organisms that adhered to red blood cells. The organism was named Bartonella bacilliformis and was the only species identified in this genus until 1993, when Dolan and colleagues isolated Bartonella henselae (previously named Rochalimae henselae), a curved, pleomorphic Gram-negative intracellular bacillus, from lymph nodes of patients with cat scratch disease.54 The clinical syndrome of cat scratch disease had been recognized for nearly a century but prior to Dolan’s work had been a disease without a known etiology. Bartonella organisms were originally thought to be rickettsiae but differ in that the former can grow on artificial media. At least a dozen species have now been identified within the genus Bartonella. In a tragic story in infectious disease lore, in 1885 a Peruvian medical student, Daniel Alcides Carrion, injected himself with the pus of a lesion from a patient who had verruga peruana, a strange purplish eruption. Three weeks later Carrion developed Oroya fever, showing that verruga peruana (the eruptive phase) and Oroya fever (the hematic phase) were two stages of the same disease. Carrion died several weeks after becoming ill. The causative organism of this two-stage disease, now also called Carrion’s disease, is Bartonella bacilliformis. This is a rare disease found only in the Andes in Peru, Ecuador, and Columbia and is transmitted by sandflies.55 Bartonella species first came to clinical attention in the United States in 1990 when they were identified as the cause of unusual opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS).56 Clinical Illness Bartonellosis encompasses a spectrum of infectious diseases ranging from mild lymphadenopathy seen in cat scratch disease to life-threatening disease in the immunocompromised host. One pathogenic process unique to this genus is endothelial cell proliferation and neovascularization, a syndrome called peliosis hepatis. The commonest manifestation of disease caused by Bartonella species, usually Bartonella henselae, is cat scratch disease (CSD). The host for this organism is the cat, and cat fleas are the vector which spread the organism to other cats. There is no evidence of transmission of Bartonella from cat fleas to humans. Patients with cat scratch disease (CSD) present 1 week to 2 months after a bite or scratch from a domestic or feral cat, usually a kitten, with regional tender adenopathy proximal to the injury. A primary cutaneous inoculation site may be seen at the site of the bite or scratch, developing into a papule or pustule a week after exposure. Constitutional symptoms are mild and non-specific and include low-grade

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fever and malaise. The disease is seasonal, the majority of cases occurring in the fall and early winter, presumably due to a midsummer rise in kitten births and increased flea infestation. CSD is usually self-limited and is one of the common causes of prolonged fever in children and fever of unknown etiology in adults. In 1993 the Centers for Disease Control and Prevention reported approximately 22 000 cases of CSD annually, although many more cases may be unrecognized.57 Atypical presentations of CSD occur in 10% of cases and may include encephalopathy with seizures, neuroretinitis with sudden blindness, joint pain, and atypical pneumonia. Abdominal pain may signal CSD granulomatous hepatitis and splenitis, a self-limited condition in healthy hosts. Parinaud oculoglandular syndrome, an uncommon presentation (5% of cases), consists of a granulomatous conjunctivitis (caused usually by the patient’s own hand spreading the organism to the eye) associated with ipsilateral preauricular lymphadenopathy. Bartonella quintana is found worldwide and was first described during World War I as responsible for causing trench fever in soldiers in Europe, Mesopotamia, and Egypt. Trench fever was the most prevalent disease among Allied troops. After World War I, trench fever seemed to disappear, but reemerged in the German army in Russia during World War II, with attack rates up to 30%. The organism is spread by the body louse, Pediculus humanus corporis. After a two-week incubation period, the illness begins with a sudden high fever, headache, and myalgias. The fever typically lasts five days and remits, but may relapse several times for five days, hence the name quintana. An unusual symptom of hyperesthesia of the shins may aid in diagnosis. Over the past decade, a contemporary B. quintana infection emerged in various US cities and abroad and was dubbed urban trench fever. This disease primarily affects inner-city dwellers, chronic alcohol abusers, and political refugees. Trench fever is almost always self-limited and affected patients recover without treatment.58 Bartonella is an increasingly important cause of culturenegative endocarditis. Six different species have been identified, but the majority of endocarditis cases are caused by B. quintana and B. henselae.59 Body louse infestation, contact with cats, and underlying valvular heart disease are the major risk factors for Bartonella endocarditis. A predilection exists for the aortic valve. A high rate (60%) of valve replacement appears to be necessary. Most cases occur on native valves, but aggressive prosthetic valve endocarditis with rapid valve destruction has been reported.60 Bacillary angiomatosis, first described in 1983 in HIVinfected patients and organ transplant recipients, is a vascular proliferative disease usually involving the skin, but also reported in liver, spleen, bone, brain, and other organs. Cutaneous lesions are papular, purple to red-black in color, and highly vascular. Both B. henselae and B. quintana have

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been identified as causative agents.61 Bacillary angiomatosis occurs in advanced AIDS patients with a median CD4 lymphocyte count of 50 cells/microliter.62 Disseminated, severe, progressive disease may also occur in patients with other forms of immunosuppressive disease or alcoholism. Close observation and treatment with antibiotics are indicated in these populations. Also seen in HIV-infected individuals and transplant recipients, peliosis hepatis caused by Bartonella henselae is a vascular proliferation of hepatic capillaries that create blood-filled spaces in the liver.63 Laboratory Findings As the spectrum of disease attributed to Bartonella is further defined, reliable laboratory methods to identify these unique organisms will become increasingly important. Diagnosis of CSD can be confirmed with a four-fold rise in antibody levels, first IgM, followed by IgG. Bartonella species are rod-shaped and slightly curved fastidious bacteria which are difficult to isolate from tissue and therefore require a high clinical suspicion and communication with the microbiology laboratory. Growth requires at least 3 weeks in 5% carbon dioxide. Histopathology, when available, may demonstrate the organisms using a Warthin–Starry silver stain. Gram and acid-fast stains are almost always negative. Indirect immunofluorescence assay (IFA) and ELISA are the two most common serologic tests for Bartonella. Western immunoblot appears to be sensitive and specific for Bartonella endocarditis. PCR methods appear promising as well. In bacillary angiomatosis, diagnosis is confirmed by biopsy and histopathology, which shows vascular proliferation along with numerous bacilli that take up the modified silver stain. Treatment Incision and drainage of cat scratch lymph nodes should be avoided. Thin-needle aspiration is much less likely to lead to fistulas. Bartonella infections respond to doxycycline, erythromycin, and the newer macrolides, azithromycin, and clarithromycin. In a healthy host, CSD is self-limited and may not require treatment. However, once a patient presents to a physician with CSD, therapy is typically given because the patient is uncomfortable and early treatment may reduce the risk of more complicated or disseminated disease. For severe infections, rifampin or gentamicin can be added to doxycycline. Duration of therapy may be 2 months or longer for patients with peliosis hepatis or disseminated disease. Pregnant women with bartonellosis should be treated with erythromycin. For endocarditis with Bartonella sp. the recommended regimen is ceftriaxone 2 g daily for 6 weeks plus gentamicin

1 mg/kg every 8 hours for 2 weeks with dosage adjustment to achieve peak serum concentration of 3–4 g/ml and trough of 1 g/ml. Doxycycline 100 mg twice daily either intravenously or orally may be added. Penicillins and first and second generation cephalosporins are not active against these organisms and should not be used.66 Fluoroquinolone activity against Bartonella spp. is inconsistent and therefore not recommended for treatment. Gender Differences The male-to-female ratio is 3:2. Eighty percent of patients with CSD are under 21 years old. Bartonellosis during pregnancy has been associated with a more severe course and high rates of maternal and perinatal mortality in immunocompetent women. In one report a pregnant patient developed life-threatening anasarca and cardiac tamponade.64 Overall, more than 70% of Bartonella endocarditis cases have occurred in men. This male predominance may be related to infestation with body lice associated in homeless and alcoholic men leading to infection with B. quintana.65

Enterohemorrhagic E. coli 0157 Escherichia coli are lactose fermenting Gram-negative rods, and exist as part of the normal flora of the human colon. E. coli strains are the most frequent bacterial causes of diarrhea, causing several distinct clinical diarrheal syndromes. In the clinical microbiology laboratory, different strains of E. coli are not distinguishable from one another except for enterohemorrhagic E. coli (EHEC 0157). Enterotoxigenic E. coli (ETEC) are the most common cause of diarrhea in children under 2 in the developing world. They are also responsible for most cases of travelers’ diarrhea.67 In June 1998 a large foodborne outbreak of diarrheal disease caused by ETEC occurred in Cook County, Illinois. A delicatessen was identified as the common source. As many as 3300 persons developed gastroenteritis.68 The illness caused by ETEC requires a large inoculum. Incubation is short, and onset of nausea and watery diarrhea is rapid. Usually the illness lasts 24 hours but may last a few days. It is almost always self-limited. Therapy consists mainly of oral rehydration. Antibiotics are not indicated. Enteropathic E. coli (EPEC) have caused sporadic outbreaks of diarrhea, usually in neonates. The illness can be severe and persistent, particularly in developing countries. Enteroinvasive E. coli (EIEC) are closely related to Shigella, and are uncommon causes of disease. Enteroaggregative E. coli (EAEC) were identified in the late 1980s and cause persistent diarrhea in children in developing and industrialized regions, HIV-infected adults, and international travelers. This section will focus on enterohemorrhagic E. coli (EHEC). In 1982, two outbreaks of bloody diarrhea occurred in Oregon and Michigan related to ingestion of hamburgers

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at a fast-food chain. A previously unidentified serotype of E. coli, 0157:H7, was isolated from the patients with diarrhea and the hamburger meat, but not from stool cultures of healthy controls.69 This new class of E. coli was termed enterohemorrhagic E. coli (EHEC). Subsequently, EHEC have been responsible for large outbreaks and sporadic cases of diarrhea in the United States and around the world. EHEC differ from other groups of diarrhea-associated E. coli because they produce Shiga toxin. Therefore, they are sometimes called STEC (Shiga-toxin producing E. coli). In the United States, most of the EHEC strains have continued to be 0157:H7, as in the 1982 outbreak. The majority of Shiga-toxin producing EHEC in other countries are non 0157:H7, and non 0157:H7 serotypes are increasing in prevalence in the United States as well.70 An outbreak in Montana in 1994 was an E. coli 0104 serotype. The inoculum required for EHEC with serotype 0157:H7 is very small, only 10–100 organisms, compared to clinical infection with Salmonella which requires more than 105 organisms. Therefore only a few EHEC 0157:H7 need to survive for transmission from food to humans. More than half the cases of EHEC due to E. coli 0157: H7 have been traced to ground beef. Patients have also been infected from produce such as apples and radish sprouts.71 Human-to-human transmission occurs in 14% of cases, 9% are waterborne, and in 21% of cases, the source can not be identified. Cattle are the most important reservoir for E. coli 0157: H7. Ten percent of healthy cattle excrete the organism in their stool. Beef becomes contaminated during slaughter or processing when it comes in contact with intestinal contents from an infected animal. Despite efforts to reduce E. coli 0157:H7 by screening beef at meatpacking plants, spread of infected beef continues to occur. In June 2002 a recall was issued by one meat-packing plant of 350 000 pounds of culture-positive ground beef. Enough of this contaminated beef had been distributed, however, to cause 28 cases of EHEC in seven states. In mid-July 2002, one of the largest recalls in US history, 18.6 million pounds of fresh and frozen beef was recalled. In 2003 E. coli 0157:H7 accounted for 3% of all acute foodborne illness in the United States.72 In one study, if the stool sample was visibly bloody, 39% of isolates were E. coli 0157:H7.73 In Washington state in 2005 an outbreak occurred in persons consuming raw milk from a particular farm. Fresh spinach was the cause of an outbreak in 100 people in late summer 2006. Half were hospitalized and three died. Cases of EHEC have been traced to petting zoos as well as a contaminated building. In 2008, several grocery chains were forced to recall beef after illness due to E. coli 0157 occurred in several states. The contamination was linked to a meat-processing plant in Nebraska which had been shut down three times in 2002 and 2003 by the US Department of Agriculture, and

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cited again in 2004, 2005, and 2006. Five million pounds of beef were recalled. As of July 15, 2008, 44 confirmed cases of E. coli were reported, with 21 hospitalizations. Patients ranged in age from 2 to 78 with a median age of 20.74 Between June 2 and August 6, 2008 seven people in Massachusetts were sickened with E. coli. Their beef had been purchased from an upscale retailer known for its high prices and presumed high quality. The beef from the Massachusetts outbreak was traced to the same supplier in Nebraska. An additional 1.2 million pounds of beef were recalled. Clinical Manifestations The incubation period for infection with enterohemorrhagic E. coli can range from 1 to 9 days but is usually 3–4 days. Hemorrhagic colitis is the most common and typical syndrome. Fever is usually absent but patients complain of abdominal pain. Abdominal tenderness is present on examination. Hospitalization is required in 23–47% of patients with acute diarrhea. Mortality rates are 1–2% in uncomplicated cases, but may be higher in elderly patients.75 Laboratory Findings The peripheral WBC is usually elevated. There is blood in the stool. Up to 9% of all EHEC infections have been seriously complicated by hemolytic uremic syndrome (HUS), a triad of microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia. HUS begins within 5–13 days after the diarrhea. In children under age 10 HUS complicates approximately 15% of cases of EHEC.76 Thrombotic thrombocytopenic purpura (TTP) is a disorder related to HUS in which patients have, in addition to the HUS triad, fever and neurologic symptoms. Fifty percent of HUS patients require dialysis. Mortality is 3–5%. Up to 10% will have residual renal or neurologic disease. At least 70% of postdiarrheal HUS in the United States has been linked to EHEC infection, and 80% of these are caused by E. coli 0157:H7. In Australia, patients with postdiarrheal HUS usually have non-0157 E. coli.77 Treatment Current treatment is supportive with monitoring for complications, especially in patients with HUS. Antiperistaltic agents are contraindicated as they increase risk of systemic complications. Antibiotic therapy is of no established bene­ fit. One study in 71 children under 10 years old showed a steep rise in risk of HUS following antibiotic therapy.78 No vaccine is currently available. Precautions Safeguards to minimize E. coli infection include refrigerating meat as soon as possible after purchase, cooking

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ground beef to an internal temperature of 160 degrees, and re-refrigerating meat within two hours of cooking. Ground meat that is pink should not be eaten. If an undercooked hamburger is served in a restaurant, the diner should request that the meat be cooked through and served with a new bun on a clean plate. Assiduous universal and contact precautions should be in place to prevent transmission to hospital staff and other patients. Household spread to siblings may be mitigated by admitting infected children to hospital. The importance of handwashing by children and staff in daycare and school settings cannot be overemphasized. Higher standards in meat processing plants and close government monitoring are essential to reduce future cases of EHEC. Gender Differences Although male:female attack rates differ in various outbreaks, no consistent pattern is noted, nor is there a difference in incidence of HUS based on gender. No specific information on EHEC in pregnancy or in the peripartum period is available. Exclusive breastfeeding of young infants appears to confer protection against severe ETEC diarrhea79 and Shigella.80

Methicillin-resistant Staphylococcus aureus Methicillin-resistant Staphylococcus aureus (MRSA) bacteria are defined as organisms having an minimum inhibitory concentration (MIC) to oxacillin of 4 mg/l or greater or an MIC to methicillin of 16 mg/l or greater. MRSA was first isolated in England in 196181 shortly after the antibiotic methicillin was introduced. The isolates recovered during that decade were likely a single clone, but by 2002 five MRSA clones worldwide had been reported. Emergence of MRSA was probably due to antibiotic selection pressure. Epidemiologically, MRSA infections have been divided into HA-MRSA (healthcare-associated MRSA) and CAMRSA (community-acquired MRSA). HA-MRSA has been a growing problem worldwide in hospitalized patients since the 1960s and often causes severe, invasive disease. Between 1995 and 2001 in the United States the proportion of MRSA isolates increased from 22% to 57% in over 24 000 cases of nosocomial S. aureus bacteremia. Nosocomial MRSA infections are responsible for longer hospital stays, higher mortality, and higher costs than patients with methicillin-sensitive S. aureus (MSSA). Risk factors for HA-MRSA infections include antibiotic use, surgery, intravenous devices, prosthetic devices such as artificial joints and heart valves, intensive care unit stays, hemodialysis, and exposure to other patients with MRSA. The most common mode of transmission of HA-MRSA is contaminated hands of healthcare workers. However, fomites such as stethoscope

ear tips and surfaces proximate to infected patients can also serve as reservoirs. In one study, environmental surfaces had an MRSA contamination rate of 59% in the hospital rooms of patients with heavy gastrointestinal MRSA colon­ ization and diarrhea.82,83 CA-MRSA infection is defined as MRSA infection in an individual without recent hospitalization, surgery, stay in a long-term care facility, dialysis, or indwelling medical devices. The first reports of CA-MRSA were reported in intravenous drug users in the early 1980s.84 Based on molecular evidence, CA-MRSA strains evolved spontaneously rather than migrating from hospitals to communities. CA-MRSA differs from HA-MRSA in genetic makeup, increased pathogenicity, and antibiotic susceptibility. Most CA-MRSA strains in the United States encoded with the novel mecA gene sequence, which until recently, had not been present in HAMRSA strains. MecA produces PBP2a, a penicillin-binding peptide that decreases beta-lactam affinity for MRSA. MecA is a subset of a larger mobile genetic element called staphylococcal chromosome cassette (SCCmec) which governs other differences between HA-MRSA and CA-MRSA.85 While CA-MRSA usually retain their susceptibility to many non-beta-lactam agents, HA-MRSA strains do not. CA strains produce virulence factors and destructive toxins not commonly found in HA strains, particularly Panton–Valentine leukocidin. USA 300 and USA 400 are the predominant clones of CA-MRSA infections, with USA 300 most common.86 In a population review in three communities, the annual incidence of CA-MRSA during 2001–2 was 18–25 per 100 000. Twenty-three percent of patients required hospitalization. CA-MRSA infections most often present with skin and soft tissue infections in young, healthy people who neither work nor have been in hospitals or other healthcare settings.87 These organisms are usually sensitive to non-betalactam antibiotics. CA-MRSA has now become the most frequent cause of skin and soft tissue infections in emergency rooms in the United States.88,89 In men who have sex with men, multidrug-resistant isolates containing a plasmid pUSA03 have been described. These MRSA isolates may be resistant, in addition to betalactams, to fluoroquinolones, tetracycline, macrolides, clindamycin, and mupirocin.90 Clusters of CA-MRSA skin and soft tissue infections have been reported in aboriginal communities; athletic teams including football, wrestling, fencing, and canoeing; daycare centers; military personnel; men having sex with men; prison inmates; and prison guards. Suboptimal hygiene, lacerations, abrasions, shaving, shared gym equipment, tattoos, incarceration, close physical contact with other MRSA carriers, and HIV infection91 have all been identified as risk factors, but are poorly predictive. Farm animals (notably pigs) and even family pets have all been indentified as sources. Many patients presenting with CAMRSA lack any obvious risk factors or exposure.92

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Four children died of fulminant CA-MRSA in Minnesota and North Dakota from 1997 to 1999.93 Countless other outbreaks of CA-MRSA have been reported. Some of them will be described here. In Ohio, Kentucky, and Vermont in 2004 and 2005 44 tattoo recipients from 13 unlicensed tattoo parlors developed CA-MRSA infections. Thirty-four cases were primary. Ten cases were secondary through direct contact with a primary case. Only one patient had hepatitis C; all the others had no underlying disease. Symptoms occurred 4–22 days after receiving the tattoo. Adherence to hygiene among the tattooists was poor. Three of the tattooists in Ohio had recently been in correctional facilities. Some tattooists used homemade equipment including guitar-string tattoo needles and computer ink-jet cartridges for dye.94 The Los Angeles County Jail is the largest jail in the United States, with 165 000 incarcerated individuals each year. In 2002, 928 inmates were diagnosed with MRSA wound infections. Sixty-six required hospitalization. At least 10 of them developed invasive disease, including bacteremia, endocarditis or osteomyelitis.95 Several publicized reports of CA-MRSA have been in college or professional football teams. Eleven cases of CAMRSA (type USA300) skin and soft tissue infections, boils being the most common, occurred in 2003 in a Los Angeles team of 107 players. Linemen, who have frequent and aggressive close physical contact during play, were identified as a high-risk subgroup.96 The distinctions between CA-MRSA and HA-MRSA are no longer well-defined, because individuals may be colon­ ized in one setting and develop infection in the other. For example, in one study of over 200 patients discharged home from hospital, 49% of them developed new MRSA infections outside the hospital within 18 months after discharge.97 Conversely, patients who acquire CA-MRSA in the community may be hospitalized and transmit their strains to other in-patients. Colonized individuals serve as a reservoir for MRSA. They also have a higher risk for MRSA infection. The commonest site of colonization is the anterior nares. Colonized individuals may also have MRSA on their hands, axillae, anovaginal areas, and (in infants) umbilici. Clinical Presentation The clinical presentation of CA-MRSA is usually a boil or abscess, often mistakenly diagnosed both by patients and physicians as a spider-bite.98 The area is red, swollen, and tender. Drainage may be yellow pus or pus mixed with blood. There may be a surrounding area of cellulitis. Patients with skin and soft tissue infections do not usually appear ill. If fever, chills or malaise are present or the patient has localizing signs apart from the skin or soft tissue, appropriate investigations should be performed. Blood cultures, radiographs, echocardiography, and vigorous debridement should all be employed when clinically appropriate.99

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More severe invasive disease with CA-MRSA does occur. Pneumonia, endocarditis, osteomyelitis, necrotizing fasciitis, and death due to overwhelming sepsis have all been reported. Treatment First-line treatment in uncomplicated cases may simply be incision and drainage. All abscess or debrided material should be sent for culture and susceptibility testing, without exception. Numerous cases have become unnecessarily complicated because no culture is sent, the presence of MRSA is not suspected, and patients are treated with ineffective antibiotics. If cellulitis is present, or the affected area is phlegmonous and not ready to be drained, antibiotics should be given. Beta-lactam agents are no longer appropriate empiric therapy for skin and soft tissue infections because of the increasing prevalence of MRSA. Because local antibiotic patterns differ, and certain populations may have resistance to multiple non-beta-lactam antibiotics, the clinician must tailor treatment accordingly. Several antibiotic options are available for suspected or known CA-MRSA. Double strength trimethoprimsulfamethoxazole twice daily with or without rifampin 600 mg daily in non-sulfa-allergic patients is first-line therapy. Patients must be warned about sulfonamide toxicity, including fever and rash, which, if it occurs can be severe. Doxycycline 100 mg twice daily may be used, with tetracycline or minocycline as alternatives. Rifampin may be used in combination with sulfonamides or tetracycline, but never alone because of rapid development of resistance. Ninety-six percent of CA-MRSA strains are sensitive to clindamycin. Clindamycin has the advantage of inhibiting bacterial toxin production including Panton–Valentine leukocidin and other virulence factors. However, if in vitro testing shows an MRSA isolate to be susceptible to clindamycin but resistant to erythromycin, the isolate when exposed to clindamycin may acquire resistance via an inducible macrolide-lincosamide-streptogramin B (iMLSb) phenotype.100 Also, some theoretical concern exists regarding clindamycin as a bacteriostatic rather than bacteriocidal agent. At least a third of CA-MRSA strains are resistant to fluoroquinones. Even if in vitro testing indicates susceptibility, resistance to ciprofloxacin can readily develop during treatment.101 Beta-lactams should not be used, and oral vancomycin is not absorbed and is therefore not appropriate therapy. Linezolid, a relatively new synthetic antibiotic in the oxazolidinone class, is available for oral as well as intravenous use.102 It is highly effective but its use is limited by cost, drug interactions, toxicity and development of resistance, and should be limited to patients who either are allergic to or fail older agents.103 Nasal mupirocin ointment may help to eradicate nasal colonization, but resistance to this topical agent is increasingly reported.

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For hospitalized patients, intravenous vancomycin is usually effective but reports of CA-MRSA with intermediate or high MICs to vancomycin are increasing.104,105 Daptomycin, a cyclic lipopeptide bactericidal antibiotic, can be used for complicated skin and soft tissue infections, bacteremia, and endocarditis due to MRSA. Daptomycin cannot be used for pulmonary infection because it is inactivated by pulmonary surfactant.106 Tigecycline, a broad-spectrum glycylcycline antibiotic derived from minocycline, is approved for skin and skin-structure infections due to MRSA.107 Quinupristin–dalfopristin, a streptogramin antibiotic approved for vancomycin-resistant enterococcal infections, has activity against MRSA and vancomycinintermediate Staphylococcus aureus (VISA) isolates.108 Group A streptococci are capable of causing skin and soft tissue infections similar to S. aureus. If, in addition to MRSA infection, group A streptococcal infection is suspected, a beta-lactam agent should be added to trimethoprimsulfa, tetracyclines, and fluoroquinolones until culture data are available. Clindamycin, linezolid, daptomycin, quinupristin–dalfopristin, and intravenous vancomycin are all appropriate anti-streptococcal agents. Prevention of spread of CA-MRSA is based on proper hygiene, hand washing, covering open wounds, not sharing personal razors or towels, and routine cleaning of equipment. A number of new agents are under development for the treatment of MRSA infections. Dalbavancin is one of several glycopeptide agents being studied. It has a long halflife, permitting weekly dosing.109 Two new cephalosporins, ceftaroline and ceftobiprole, appear to be effective against MRSA, as does a new carbapenem.110 A new topical cationic peptide, omiganan pentahydrochloride, is also being studied for MRSA catheter-associated infections.111 Tefibazumab, a monoclonal antibody, targets a surface protein of S. aureus, preventing the organism from binding to human fibrinogen.112 Gender Differences Because of the risk groups of men having sex with men and a male predominance in many other risk groups such as prisoners, military recruits, and football players, more CAMRSA cases are reported in men than women. While there is no evidence that susceptibility is greater, opportunity for exposure is greater. MRSA infection outbreaks have been documented in pregnant and postpartum women and in infants in neonatal intensive care units. In one 6 month study of 2963 rectal and vaginal specimens from pregnant women between 35 and 37 weeks gestation, 17% were positive for S. aureus. Only 2.8% of the S. aureus isolated were MRSA cases (14), an overall MRSA prevalence of 0.05%. Thirteen of the 14 were found to be CA-MRSA based on their susceptibility to several common non-beta-lactam antibiotics.113 Another study of 288 expectant mothers also found MRSA to be

uncommon (2.1%) and no transmission to vaginally delivered newborns occurred.114 One study over a 3-year period of more than 5700 mothers showed an overall MRSA colonization rate of 3.5%. No invasive neonatal MRSA infection occurred among study infants. Colonization by MSSA and MRSA were significantly more common among women colonized with group B streptococcus (GBS) than among GBS-negative women.115 CA-MRSA has been reported as the etiologic agent in mastitis in postpartum women.116 One case report demonstrated passage of MRSA to 2 of 3 pre-term triplets from contaminated breast milk delivered by nasogastric tube. One of the infants developed sepsis on day 14 of life, the other was less ill with conjunctivitis. The mother had no clinical evidence of infection.117 A retrospective cohort study of 57 pregnant women with CA-MRSA infection at Parkland Memorial Hospital in Dallas, Texas, showed no evidence of increased risk for chorioamnionitis or neonatal sepsis. One-fifth of patients had a history of drug abuse. Co-morbid conditions were HIV infection, asthma, and diabetes. The CA-MRSA infected women were significantly more likely to be multi­ parous and have had a previous cesarean delivery when compared to the general obstetric population.118

Emerging prion infection Variant Creutzfeldt–Jakob Disease In 1982 Prusiner coined the term prion for agents causing transmissible neurodegenerative diseases. A prion is defined as a small misfolded proteinaceous infectious pathogen resistant to normal decontaminating procedures.119 Diseases caused by prions are unique in that they are sporadic, genetic, and transmissible. Prions do not elicit any specific immunologic response in the host. They are not eradicable by conventional inactivation or sterilization procedures. They have long incubation periods and cause inexorable progression to dementia and usually death. Classic Creutzfeldt–Jakob disease (CJD) is the most common human prion disease, but remains a rare disease with approximately 1 case per million people worldwide. Ninety percent of cases of CJD are sporadic. A small number of familial cases have been described, allowing greater understanding of the abnormal host protein (PrP) gene in pathogenesis. The age of onset for CJD is 57–62 years. Equal numbers of males and females are afflicted. CJD may progress in just a few weeks from dementia and myoclonus to akinetic mutism and death in 4 months. Although prion diseases are not contagious through usual human contact, person-to-person spread can occur with direct inoculation or transplantation of infectious material such as dural, liver, and corneal transplants; use of dura mater in embolization procedures; use

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of prion-contaminated growth hormone or pituitary gonadotropin from human cadavers; and contaminated neurosurgical equipment. Nearly 100 cases of iatrogenic CJD have occurred in patients who received cadaveric human growth hormone.120 Other known prion disease that affect humans are Gerstmamm–Straussler–Scheinker Syndrome, kuru, and fatal familial insomnia. These, along with CJD and variant CJD, which will be discussed below, share similar neuropathologic features that include neuronal loss, glial cell proliferation, little or no inflammatory response, accumulation of an abnormal host protein (PrP) and presence of small vacuoles in the neuropil. These vacuoles produce a spongiform appearance, leading to the descriptive name of bovine spongiform encephalopathy (BSE), a prion disease in cattle. Numerous other prion diseases, also known as transmissible spongiform encephalopathies, have been described in animals: scrapie in sheep, feline spongiform encephalopathy, transmissible mink encephalopathy, and chronic wasting disease of deer and elk. BSE, commonly known as mad-cow disease, is a uniformly fatal neurodegenerative disease in cattle. The affected cows are sometimes referred to as ‘downer cows’ because they are unable to walk. The largest known outbreak occurred beginning in 1980 in the United Kingdom, where almost 200 000 cattle were infected and almost 5 million cattle were slaughtered in an attempt to eradicate the disease. An exhaustive epidemiologic investigation concluded that normally herbivorous cattle were being fed infected remains of other cattle in the form of meat and bone meal which had been contaminated with bovine brain and spinal cord. Other contributing theories were that a change in British law allowed lower sterilization temperatures for protein meal and that the use of organic solvents in feed preparation had been abandoned. Cattle farming entails using protein supplements as well as antibiotics and hormones. Soya bean meal is used worldwide as a protein supplement, but because soya beans grow poorly in Europe, cattle farmers turned to less expensive forms of protein. During the mid l990s, cases of what was initially presumed to be CJD began to appear in teenagers and young adults in the UK. However, the early clinical presentation differed from that of classic CJD, beginning with persistent and prominent behavioral and psychiatric disturbances which ranged from anxiety and depression to frank psychosis with visual and auditory hallucinations. These patients were minimally responsive to psychiatric medication. Painful neurologic symptoms such as dysesthesia also occurred early in disease. Onset of hard neurologic signs such as gait disturbance, slurring, and tremor followed several months into the illness. Chorea, dystonia, and myoclonus were seen late in the course. Survival time was longer (14 months on average) in these cases than in classic CJD and median age was much younger (28 years). By late 1998, a total of 39 cases had been diagnosed. A comparison of biochemical properties of PrP from brains of

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BSE-infected cattle and patients with this new form of CJD led to the realization that there was a new variant of CJD (vCJD).121–123 Although the exact incubation period from BSE prion exposure to the onset of symptoms of vCJD is not known, it can be measured in years. MRI brain scanning in more than 75% of vCJD patients shows a prominent, symmetrical pulvinar high signal on T2-weighted and/or proton-density-weighted images. This pulvinar sign is not seen in patients with classic CJD.124 The electroencephalogram is diffusely abnormal and non-specific. Neuropathologic findings in vCJD differ markedly from those of classic CJD and most resemble the findings in bovine spongiform encephalopathy (BSE). Post-mortem brain examinations from vCJD patients show multiple microscopic, abnormal aggregates surrounded by holes, resulting in a daisy-like appearance described as ‘florid plaques.’ Immunohistochemical analysis of brain tissue shows marked accumulation of protease-resistant prion protein. Lymphoreticular involvement, such as in the tonsils, Peyer patches and appendix, occurs in vCJD (but not CJD). Therefore, a tonsil biopsy showing a characteristic prion protein by Western blot and immunhistochemistry can help establish the diagnosis of vCJD. Tonsil biopsy has shown 100% specificity and sensitivity in the diagnosis of vCJD.125 In 2002, a 22-year-old Florida resident developed symptoms consistent with vCJD. Symptoms began with depression and memory loss that interfered with the patient’s job. Within a month, the patient developed involuntary muscle movement, gait disturbance and incontinence. The mother of the patient, a UK resident, took the patient to England where the patient continued to deteriorate, developing confusion, hallucinations, speech abnormalities, bradykinesia, and spasticity. He was referred to the National Prion Clinic in the UK. A Western blot analysis of a tonsil biopsy indicated a protease-resistant prion protein (PrP-res) with the characteristic pattern of vCJD, and other analyses were consistent with 105 other vCJD cases in the UK.126 A total of 208 patients from 11 countries have been diagnosed with vCJD between the first case report in 1996 and June 2008. The majority (167) have been from the UK, but a total of 3 cases occurred in US residents. Two of the US residents were likely exposed while living in the UK, the third was likely exposed while living in Saudi Arabia. The Centers for Disease Control and Prevention reports that every case of human vCJD had a history of exposure within a country where there were BSE-infected cattle. The majority of persons with vCJD became infected through consumption of cattle products, but three UK cases have been linked to receiving blood from an asymptomatic, infected donor.127 Strong laboratory and epidemiologic evidence suggest that vCJD and BSE are causally linked.128 Reports of vCJD in humans in the UK following a large epidemic of BSE in cattle with a lag period consistent with the incubation period of prions strongly suggests that vCJD results from bovine

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to human transmission of BSE.129 Most vCJD cases (128 of 138) have occurred in the UK where the highest number of BSE cattle infections have occurred. By 1993, the peak of the BSE epidemic, several hundred thousand BSEinfected cattle might have entered the human food chain. The BSE epidemic in the UK peaked in 1993, and since then the number of BSE cases in cattle has been steadily declining. Fewer cases of cattle BSE may be attributable to bans, beginning in 1988, on use of animal protein in feed. Treatment To date, all treatment is experimental. Supportive care with antipsychotic medication and sedatives has not been particularly effective for patients with vCJD. Quinacrine, which may prevent conversion of normal prion protein to abnormal prion protein, is currently being evaluated. Pentosan polysulphate may also affect prion production and replication. Flupirtine may have some benefit on cognitive function.130 Other strategies such as compounds that interact with the abnormal prion structure or immunologic approaches to reduce brain amyloid accumulation are being studied. Gender Differences No preponderance in either sex has been reported for vCJD. In other prion diseases, only kuru, a progressive cerebellar ataxia ending in dementia and death related to ritual cannibalism, is known to be more prevalent in women among the Fore tribe in Papua New Guinea.131 Approximately 15% of human prion diseases are familial and autosomal dominant. Capability already exists for genetic testing of inherited mutations and polymorphisms in disease-causing genes before clinical disease is present. Ethical issues regarding pre-natal testing will arise for pregnant women with family histories of dementia-associated prion disease. Pre-implantation genetic diagnosis, performed on a single cell from a 3-day-old embryo, is not yet widely available, but is likely to become so. These are difficult issues, yet to be resolved. Geneticists, physicians, medical ethicists, and their patients will have much to consider regarding pre-natal testing for inherited disease.

References   1. Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis. 1995;1:7–15.   2. Reintjes R, Dedushaj I, Gjini A, et al. Tularemia outbreak investigation in Kosovo: case control and environmental studies. Emerg Infect Dis. 2002;8:69–73.   3. Gayer M, Legros D, Formenty P, et al. Conflict and emerging infectious diseases. Emerg Infect Dis. 2007;13:1625–1631.   4. Shirley SM, Kark S. Amassing efforts against alien invasive species in Europe. PLos Biol. 2006;4:e279.   5. Jamieson DJ, Jernigan DB, Ellis JE, et al. Emerging infections and pregnancy: West Nile virus, monkeypox, severe acute respiratory syndrome, and bioterrorism. Clin Perinatol. 2005;32:765–776.

  6. Magnus JH, Greene ME, Kishor S. Infectious disease and gender [conference summary]. Emerg. Infect. Dis. 2004 Nov. Available from www.cdc.gov/ncidod/EID/ vol10no11/04-0622_06.htm   7. Pinto da Cunha 1997. In: Pan American Health Organization. Ethnicity and Health. Washington, DC: PAHO;2002.   8. Cono J, Cragan JD, Jamieson DJ, et al. Prophylaxis and treatment of pregnant women for emerging infections and bioterrorism emergencies. Emerg Infect Dis. 2006;12(11):1631–1637.   9. Sanz E, Gómez-López T, Martínez-Quintas MJ. Perception of teratogenic risk of common medicines. Eur J Obstet Gynecol Reprod Biol. 2001;95:127–131. 10. Jamieson DJ, Ellis JE, Jernigan DB, et al. Emerging infectious disease outbreaks: old lessons and new challenges for obstetrician-gynecologists. Am J Obstet Gynecol. 2006;194:1546–1555. 11. Centers for Disease Control and Prevention. Updated recommendations for antimicrobial prophylaxis among asymptomatic pregnant women after exposure to Bacillus anthracis. MMWR Morb Mortal Wkly Rep. 2001;50(43):960. 12. Sawatsky B, Ranadheera C, Weingartl H, et al. Hendra and Nipah virus. In: CT Mettenleiter, F Sobrino, eds. Animal Viruses: Molecular Biology. Norfolk, UK: Caister Academic Press; 2008. 13. Paton NI, Leo YS, Zaki SR, et al. Outbreak of Nipah-virus infection among abattoir workers in Singapore. Lancet. 1999; 354:1253–1256. 14. Chua KB, Koh CL, Hooi PS, et al. Isolation of Nipah virus from Malaysian Island flying-foxes. Microbes Infect. 2002;4:145–151. 15. Anon. Nipah encephalitis outbreak over wide area of western Bangladesh. Health Sci Bull. 2004;2(1):7–11. 16. Anon. Nipah virus outbreak from date palm juice. Health Sci Bull. 2005;3(4):1–5. 17. Sejvar JJ, Hossain J, Saha SK, et al. Long-term neurological and functional outcome in Nipah virus infection. Ann Neurol. 2007;62:235. 18. Sarji SA, Abdullah BJ, Goh KJ, et al. MR imaging features of Nipah encephalitis. AJR 2000;175:437. 19. Wong KT, Shieh WJ, Kumar S, et al. Nipah virus infection: pathology and pathogenesis of an emerging paramyxoviral zoonosis. Am J Pathol. 2002;161:2153. 20. Charrel RN, de Lamballerie X, Raoult D. Chikungunya outbreaks – the globalization of vectorborne diseases. N Engl J Med. 2007;356(8):769–771. 21. Parola P, de Lamballerie X, Jourdan J, et al. Novel Chikungunya virus variant in travelers returning form Indian Ocean islands. Emerg Infect Dis. 2006;12:1493–1499. 22. Laras K, Sukri NC, Larasati RP, et al. Tracking the re-emergence of epidemic chikungunya virus in Indonesia. Trans R Soc Trop Med Hyg. 2005;99:128–141. 23. Schuffenecker I, Iteman I, Michaut A, et al. Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak. PLoS Med. 2006;3:e263. 24. Deller JJ, Russell PK. Chikungunya disease. Am J Trop Med Hyg. 1968;17:1007–1011. 25. Kennedy AC, Fleming J, Solomon L. Chikungunya viral arthropathy: a clinical description. J Rheumatol. 1980;7:231–236. 26. Fourie ED, Morrison JGL. Rheumatoid arthritis syndrome after chikungunya fever. S Afr Med J. 1979;56:130–132. 27. Parida MM, Santhosh SR, Dash PK, et al. Rapid and real-time detection of chikungunya virus by reverse transcription loopmediated isothermal amplification assay. J Clin Microbiol. 2007;45:351–357.

C hapter 4 5     Gender Differences in Emerging Infectious Diseases l

28. Carey DE, Myers RM, DeRanitz CM, et al. The 1964 chikungunya epidemic at Vellore, South India, including observations about concurrent dengue. Trans R Soc Trop Med Hyg. 1969;63:434–435. 29. Gerardin P, Barau G, Michault A, et al. Multidisciplinary prospective study of mother-to-child chikungunya virus infections on the island of La Reunion. PLoS Med. 2008;5(3):e60. 30. Ramful D, Carbonnier M, Pasquet M, et al. Mother-to-child transmission of chikungunya virus infection. Pediatr Infect Dis J. 2007;26(9):811–815. 31. Lenglet Y, Barau G, Robillard PY, et al. J Gynecol Obstet Biol Reprod (Paris). 2006;35(6):578–583. 32. Parmenter CA, Yates TL, Parmenter RR, et al. Statistical sensitivity for detection of spatial and temporal patterns in rodent population densities. Emerg Infect Dis. 1999;5(1):118–125. 33. Ma RM, Xiao H, Jing XT, et al. Hemorrhagic fever with renal syndrome presenting with intrauterine fetal death. A case report. J Reprod Med. 2003;48(8):661–664. 34. Howard MJ, Doyle TJ, Koster FT, et al. Hantavirus pulmonary syndrome in pregnancy. Clin Infect Dis. 1999;29(6):1538–1544. 35. Jezek Z, Fenner F. Human Monkeypox. New York, NY: Karger; 1988. 36. Heymann DL, Szczeniowski M, Esteves K. Re-emergence of monkeypox in Africa: a review of the past six years. Br Med Bull. 1998;54:693–702. 37. Hutin YJ, Williams RJ, Malfait P, et al. Outbreak of human monkeypox, Democratic Republic of Congo, 1996 to 1997. Emerg Infect Dis. 2001;7:434–438. 38. Reed KD, Melski JW, Graham MB, et al. The detection of monkeypox in humans in the Western Hemisphere. N Engl J Med. 2004;350:342–350. 39. Ligon BL. Monkeypox: a review of the history and emergence in the Western hemisphere. Semin Pediatr Infect Dis. 2004;15(4):280–287. 40. DeClercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 2002;55:1–28. 41. Peterson LR, Marfin AA, Gubler DJ. West Nile virus. JAMA. 2003;290(4):524–528. 42. Nash D, Mostashari F, Fine A, et al. The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med. 2001;344:1807–1814. 43. Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med. 2002;137:173–179. 44. Tsai TF, Popovici F, Cernescu C, et al. West Nile encephalitis epidemic in southeastern Romania. Lancet. 1998;352:767–771. 45. Bode AV, Sejvar JJ, Pape WJ, et al. West Nile virus disease: a descriptive study of 228 patients hospitalized in a 4-county region of Colorado in 2003. Clin Infect Dis. 2006;42:1234–1240. 46. Centers for Disease Control and Prevention. West Nile virus infections in organ transplant recipients – New York and Pennsylvania August–September 2005. MMWR Morb Mortal Wkly Rep. 2005;54:1021–1023. 47. Centers for Disease Control and Prevention. West Nile virus activity – United States, November 20–25, 2003. MMWR Morb Mortal Wkly Rep. 2003;52:1160. 48. Kerdpanich A, Watanaveeradej V, Samakoses R, et al. Perinatal dengue infection. Southeast Asian J Trop Med Public Health. 2001;32:488–493. 49. Centers for Disease Control and Prevention. Intrauterine West Nile virus infection – New York 2002. MMWR Morb Mortal Wkly Rep. 2002;51(50):1135–1136.

513

50. Chapa JB, Ahn JT, DiGiovanni LM, et al. West Nile virus encephalitis during pregnancy. Obstet Gynecol. 2003;102(2): 229–231. 51. O’Leary DR, Kuhn S, Kniss KL, et al. Birth outcomes following West Nile virus infection of pregnant women in the United States: 2003–2004. Pediatrics. 2006;117:e537–e545. 52. Centers for Disease Control and Prevention. Interim guidelines for the evaluation of infants born to mothers infected with West Nile virus during pregnancy. MMWR Morb Mortal Wkly Rep. 2004;53(7):154–157. 53. Centers for Disease Control and Prevention. Possible West Nile virus transmission to an infant through breast-feeding – Michigan. MMWR Morb Mortal Wkly Rep. 2002;51(39):877–888. 54. Dolan M, Wong M, Regnery R, et al. Syndrome of Rochalimae henselae adenitis suggesting cat scratch disease. Ann Intern Med. 1993;118:331–336. 55. Maguina C, Garcia P, Gotuzzo E, Cordero L, Spach D. Bartonellosis (Carrion’s Disease) in the modern era. Clin Infect Dis. 2001;33:772–779. 56. Anderson BE, Neuman MA. Bartonella spp. as emerging human pathogens. Clin Microbiol Rev. 1997;10(2):203–219. 57. Jackson LA, Perkins BA, Wenger JD. Cat scratch disease in the United States: an analysis of three national databases. Am J Public Health. 1993;83(12):1707–1711. 58. Maurin M, Raoult D. Bartonella (Rochalimae) quintana infections. Clin Microbiol Rev. 1996;9:275–292. 59. Raoult D, Fournier PE, Drancourt M, et al. Diagnosis of 22 new cases of Bartonella endocarditis. Ann Intern Med. 1996; 125:646–652. 60. Kreisel D, Pasque MK, Damiano RJ, et al. Bartonella speciesinduced prosthetic valve endocarditis associated with rapid progression of valvular stenosis. J Thorac Cardiovasc Surg. 2005; 130:567–568. 61. Kemper C, Lombard C, Deresinski S, et al. Visceral bacillary epithelioid angiomatosis: possible manifestations of disseminated cat scratch disease in the immunocompromised host: a report of two cases. Am J Med. 1990;89:216–222. 62. Spach DH, Koehler JE. Bartonella-associated infections. Infect Dis Clin North Am. 1998;12:137–155. 63. Perkocha L, Geaghan B, Yen T, et al. Clinical and pathological features of bacillary peliosis hepatis in association with human immunodeficiency virus infection. N Engl J Med. 1990;323: 1581–1586. 64. Huarcaya E, Maguina C, Best I, et al. Immunological response in cases of complicated and uncomplicated bartonellosis during pregnancy. Rev Inst Med Trop Sao Paulo. 2007;49(5):335–337. 65. Raoult D, Fournier PE, Vandnesch F, et al. Outcome and treatment of Bartonella endocarditis. Arch Intern Med. 2003; 163:226–230. 66. Rolain J, Brouqui P, Koehler J, et al. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother. 2004;48:1921–1933. 67. Black RE, Brown KH, Becker S, et al. Contamination of weaning foods and transmission of enterotoxigenic Escherichia coli diarrhoea in children in rural Bangladesh. Trans R Soc Trop Med Hyg. 1982;76:259–264. 68. Devasia RA, Jones TF, Ward J, et al. Endemically acquired foodborne outbreak of enterotoxin-producing Escherichia coli serotype 0169:H41. Am J Med. 2006;119:168. 69. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food – selected

514

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81. 82. 83.

84.

85.

86.

87.

s ecti o n 8     Infectious Disease l

sites, United States, 2003. MMWR Morb. Mortal. Wkly. Rep. 53 (2004) 338. Johnson KE, Thorpe CM, Sears CL. The emerging importance of non-0157 Shiga toxin producing Escherichia coli. Clin Infect Dis. 2006;43:1587–1595. Cody SH, Glynn MK, Farrar JA, et al. An outbreak of Escherichia coli 0157:H7 infection from unpasteurized commercial apple juice. Ann Intern Med. 1999;130:202–209. Frenzen PD, Drake A, Angulo FJ. Economic cost of illness due to Escherichia coli 0157 infections in the United States. Food Prot. 2005;68(12):2623–2630. Slutsker L, Ries AA, Greene KD, et al. Escherichia coli 0157:H7 diarrhea in the United States: clinical and epidemiologic features. Ann Intern Med. 1997;126:505–513. Centers for Disease Control and Prevention. Investigation of outbreak of human infections caused by E. coli 0157:H7. Atlanta, GA: CDC; July 15, 2008. Waters JR, Sharp JC, Dev VJ. Infection caused by E. coli 0157 in Alberta, Canada, and in Scotland: a five-year review, 1987–1991. Clin Infect Dis. 1994;19:834–843. Boyce TG, Swerdlow DL, Griffin PM. Current concepts: Escherichia coli 0157:H7 and the hemolytic-uremic syndrome. N Engl J Med. 1995;333:364–368. Elliott EJ, Robins-Browne RM, O’Loughlin EV, et al. Nationwide study of haemolytic uraemic syndrome: clinical, microbiological, and epidemiological features. Arch Dis Child. 2001;85:125–131. Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of E. coli 0157 infections. N Engl J Med. 2000;342:1930–1936. Clemens JD, Rao MR, Chakraborty J, et al. Life-threatening enterotoxigenic E. coli diarrhea in Bangladeshi infants and children. Pediatrics. 1997;100(6):e2. Clemens JD, Stanton BF, Stoll B. Breast-feeding as a determinant of severity in shigellosis: evidence for protection throughout the first three years of life in Bangladeshi children. Am J Epidemiol. 1986;123:710–720. Enright MC. The evolution of a resistant pathogen – the age of MRSA. Curr Opin Pharmacol. 2003;3:474–479. Smith MA, Mathewson JJ, Ulert IA, et al. Contaminated stethoscopes revisited. Arch Intern Med. 1996;156:82–84. Boyce JM, Havill NL, Otter JA, et al. Widespread environmental contamination associated with patients with diarrhea and methicillin-resistant S. aureus colonization of the gastrointestinal tract. Infect Control Hosp Epidemiol. 2007;28:1142–1147. Saravolatz LD, Markowitz N, Arking L, et al. Methicillinresistant S. aureus. Epidemiologic observations during a community-acquired outbreak. Ann Intern Med. 1982;96:11–16. Baba T, Takeuchi F, Kuroda M, et al. Genome and virulence determinants of high virulence CA-MRSA. Lancet. 2002;359(9320):1819–1827. King MD, Humphrey BJ, Wang YF, et al. Emergence of community acquired MRSA USA300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med. 2006;114:309–317. Fridkin SK, Hageman JC, Morrison M, et al. Methicillinresistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;352:1436–1444.

88. Frazee BW, Lynn J, Charlebois ED, Lambert L, et al. High prevalence of methicillin-resistant Staphylococcus aureus in emergency department skin and soft tissue infections. Ann Emerg Med. 2005;45(3):311–320. 89. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillinresistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006;355(7):666–674. 90. Diep BA, Chambers HF, Graber CJ, et al. Emergence of multidrug-resistant, community-associated methicillin-resistant S. aureus clone USA300 in men who have sex with men. Ann Intern Med. 2008;148:249–257. 91. Mathews WC, Caperna JC, Barber RE, et al. Incidence of and risk factors for clinically significant MRSA infection in a cohort of HIV-infected adults. J Acquir Immune Defic Syndr. 2005;40:155–160. 92. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant S. aureus infection from methicillin-susceptible S. aureus infection: a prospective investigation. Clin Infect Dis. 2007;44:471–482. 93. Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin resistant S. aureus – Minnesota and North Dakota, 1997–1999. MMWR Morb Mortal Wkly Rep. 1999;48:707. 94. Centers for Disease Control and Prevention. Methicillinresistant Staphylococcus aureus skin infections among tattoo recipients – Ohio, Kentucky, and Vermont 2004–2005. MMWR Morb Mortal Wkly Rep. 2006;55(24):677. 95. Centers for Disease Control and Prevention. Public health dispatch: Outbreaks of community-associated methicillinresistant Staphylococcus aureus skin infections – Los Angeles County, California, 2002–2003. MMWR Morb Mortal Wkly Rep. 2003;52(05):88. 96. Nguyen DM, Mascola L, Brancoft E. Recurring methicillin-resistant Staphylococcus aureus infections in a football team. Emerg Infect Dis. 2005;11(4):526–532. 97. Huang SS, Platt R. Risk of methicillin-resistant S. aureus infection after previous infection or colonization. Clin Infect Dis. 2003;36:281–285. 98. Dominguez TJ. It’s not a spider bite, it’s communityacquired methicillin-resistant S. aureus. J Am Board Fam Pract. 2004;17:220–226. 99. Miller LG, Perdrea-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillinresistant S. aureus in Los Angeles. N Engl J Med. 2005;352: 1445–1453. 100. Siberry GK, Tekle T, Carroll K, et al. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis. 2003;37:1257–1260. 101. Trucksis M, Hooper DC, Wolfson JS. Emerging resistance to fluoroquinolones in staphylococci: an alert. Ann Intern Med. 1991;114:424–426. 102. Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Ann Intern Med. 2003;138:135–142. 103. Stevens DL, Herr D, Lampiris H, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis. 2002;34:1481–1490.

C hapter 4 5     Gender Differences in Emerging Infectious Diseases l

104. Soriano A, Marco F, Martinez J, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of MRSA bacteremia. Clin Infect Dis. 2008;46(2):193–200. 105. Schairer J, Sankri-Tarbichi AG, Fairfax MR, et al. Methicillinresistant Staphylococcus aureus infection with intermediate sensitivity to vancomycin: a case report and literature review. J Intensive Care Med. 2008 Aug 12, [Epub ahead of print]. 106. Weis F, Beiras-Fernandez A, Schelling G. Daptomycin, a lipopeptide antibiotic in clinical practice. Curr Opin Investig Drugs. 2008;9(8):879–884. 107. Tigecycline, Med. Lett. Drugs Ther. 47 (2005) 73–74. 108. Batts DH, Lavin BS, Eliopoulos GM. Quinupristin/dalfopristin and linezolid: spectrum of activity and potential roles in therapy – a status report. Curr Clin Top Infect Dis. 2001;21:227–251. 109. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis. 2005;40:374–380. 110. Sader HS, Fritsche TR, Jones RN. Antimicrobial activity of ceftaroline and ME1036 tested against clinical strains of CMRSA. Antimicrob Agents Chemother. 2008;52(3):1153–1155. 111. Fritsche TR, Rhomberg PR, Sader HS, et al. In vitro activity of omiganan pentahydrochloride tested against vancomycin-tolerant, -intermediate and -resistant S. aureus. Diagn Microbiol Infect Dis. 2008;60(4):399–403. 112. Weems JJ, Steinberg JP, Filler S, et al. Phase II randomized, double-blind, multicenter study comparing the safety and pharmacokinetics of tefibazumab to placebo for treatment of Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2006;50:2751–2755. 113. Chen KT, Huard RC, Della-Latta P, et al. Prevalence of methicillin-sensitive and methicillin-resistant Staphylococcus aureus in pregnant women. Obstet Gynecol. 2006;108:482–487. 114. M. Reusch, P. Ghosh, C. Ham, et al. Prevalence of MRSA colonization in peripartum mothers and their newborn infants. Scand. J. Infect. Dis. 40 (8) 667–671. 115. Andrews WW, Schelonka R, Waites K, et al. Genital tract methicillin-resistant Staphylococcus aureus: risk of vertical transmission in pregnant women. Obstet Gynecol. 2008;111(1):113–118. 116. Saiman L, O’Keefe M, Graham PL, et al. Hospital transmission of CA-MRSA among postpartum women. Clin Infect Dis. 2003;37:1313–1319.

515

117. Behari P, Englund J, Alcasid G, et al. Transmission of methicillin-resistant Staphylococcus aureus to preterm infants through breast milk. Infect Control Hosp Epidemiol. 2004;25(9):778–780. 118. Laibi VR, Sheffield JS, Roberts S, et al. Clinical presentation of CA-MRSA in pregnancy. Obstet Gynecol. 2005;106:461–465. 119. Pruziner SB. Novel proteinacious infectious particles cause scrapie. Science. 1982;216:136–144. 120. Brown P, Preece MA, Will RG. Friendly fire in medicine: hormones, homografts and Creutzfeldt–Jakob disease. Lancet. 1992;340:24–27. 121. Collinge J. Variant Creutzfeldt–Jacob disease. Lancet. 1999;354(9175):317–323. 122. Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt–Jakob disease in the UK. Lancet. 1996;347:921–925. 123. Spencer MD, Knight RS, Will RG. First hundred cases of variant Creutzfeldt–Jakob disease: retrospective case note review of early psychiatric and neurological features. BMJ. 2002;324:1479–1482. 124. Zeidler M, Sellar RJ, Collie DA, et al. The pulivinar sign on magnetic resonance imaging in variant Creutfeldt–Jakob disease. Lancet. 2000;355:1412–1418. 125. Hill AF, Butterworth RJ, Joiner S, et al. Investigation of variant Creutzfeldt–Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet. 1999;353:183–189. 126. Department of Health. Monthly Creutzfeldt–Jakob disease statistics. London: DoH; October 2002. 127. Centers for Disease Control and Prevention. Fact Sheet: Variant CJD. Atlanta, GA: CDC; 2007. 128. Belay ED, Potter ME, Schonberger LB. Relationship between transmissible spongiform encephalopathies in animals and humans. Task Force Report for the Council for Agricultural Science and Technology. Washington, DC: Council for Agricultural Science and Technology. 2000:136. 129. Hill AF, Desbruslais M, Joiner S, et al. The same prion strain causes vCJD and BSE. Nature. 1997;389:448–450. 130. Otto M, Cepek L, Ratzka P, et al. Efficacy of flupirtine on cognitive function in patients with CJD: a double-blind study. Neurology. 2004;62(5):714–718. 131. Gajdusek DC. Unconventional viruses and origin and disappearance of kuru. Science. 1977;197:943–960.

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Sexually Transmitted Infections in Men and Women Anne M. Rompalo, and Khalil G. Ghanem The Johns Hopkins University School of Medicine, Department of Infectious Diseases, Baltimore, MD, USA

Introduction

differences are most pronounced in less industrialized countries. In general, most people report having only one recent sexual partner, despite substantial regional variation in the prevalence of multiple partnerships which is generally higher in industrialized countries. However, the data show pronounced asymmetry between men and women. Worldwide, men report more multiple partnerships than do women; only in some industrialized countries are the proportions of men and women who report multiple partnerships more-or-less equal.1 In a systematic review of factors that shape young people’s sexual behavior,3 gender stereotypes were noted as crucial in determining social expectations and, in turn, behavior. In general, men are expected to be highly heterosexually active, and women chaste. Vaginal penetration is perceived to be important in determining masculinity and marks the transition from boyhood to manhood. Men are expected to seek physical pleasure, but women desiring sex can be branded ‘loose’ or cheap’.4–7 Where romantic love is expected to precede marriage, sex for young women must be linked to romance, and they are expected to be ‘swept off their feet’ into sexual intercourse, in a way that is not logical, planned, or rational.7–9 Men, on the other hand, may scheme and plot to obtain sex, for example, by deceiving women into thinking the relationship is a serious one when it is not.10,11 Paradoxically, despite the stigmatizing effect for women in carrying condoms or using other contraception, women, not men, are generally considered responsible for pregnancy prevention.6,10,12 The data generated from both of these recent reports demonstrated a striking gender difference in sexual behavior. Furthermore, women might be disadvantaged in protecting their sexual health if their partner is older than them, of higher status than them,13,14 or if they are beholden to

Beyond clinical manifestations and infected anatomic sites, little is known about gender and biologic sex effects for sexually transmitted infections (STIs). This chapter will discuss the current state of knowledge of the association of biologic sex with the manifestations, complications, and epidemiology of STIs. Although the response to treatment appears similar in men and women, women are at risk for more severe complications from STIs than are men, which include chronic pelvic pain, ectopic pregnancy, infertility, and neonatal transmission of pathogens.

Gender differences in behavioral susceptibility Men and women have sex for different reasons and in different ways in different settings. Recent research on sexual and reproductive behavior1 from 59 countries found substantial diversity in sexual behavior by gender and region, reflecting powerful social and economic influences. Such influences include shifts in poverty, education and employment, increased migration between and within countries, globalization of mass media, access to family planning services, and public health HIV/STI prevention strategies.2 Almost everywhere, sexual activity begins for most men and women in the later teenage years (ages 15–19), but regional and sex variations between men and women are substantial.1 For women, median age at first intercourse is low in regions where early marriage is the norm, such as in South Asia and parts of Africa. For men, age at first intercourse is, in general, not linked to age at marriage. Gender

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a man for favors, goods, or money in return for sex.15,16 Women’s power to maintain monogamous relationships might be diminished in locations in which they outnumber men with whom they might have sex. This may occur as a result of the age structures of populations and patterns of age mixing, or where cultural practices such as polygyny are prevalent17–19 and where high levels of imprisonment of black men distort sex ratios in predominantly black communities – as in the United States for example.20 Gender differences are also noted for self-perceived health risk. A recent Swedish study was designed to compare different areas of adolescent behaviors and selfperceived health with the aim of identifying age and gender differences. In all age groups, girls had significantly more problems regarding self-perceived health, i.e., general health, abdominal pain, headache, feeling depressed, and suicidal thoughts, than boys.21 This could contribute to delay in diagnoses and therapeutic interventions among girls and women with STIs.

Gender differences in biological susceptibility Biologic Factors: Men In men, the biological risk factors associated with STIs remain relatively constant throughout life. Early adolescence begins between the ages of 11 and 15 among men, whereas it begins between the ages of 9 and13 for women. Little is known regarding the biological susceptibility of males to STIs over their lifespan with regard to hormonal influences or physiologic immune aging. Male circumcision status is one of the most important characteristics associated with variable risk of STIs and will be the focus of this discussion. The foreskin contains large numbers of dendritic cells, which are a target cell for HIV. The inner surface of the foreskin is nonkeratinized and may be vulnerable to viral infections such as herpes simplex virus or human papilloma virus. The foreskin may also act as a reservoir for sexually transmitted pathogens that could lead to urethritis. The glans of a circumcised penis has a thicker cornified epithelium that is more resistant to ulcerations from either infection or trauma during sexual intercourse, thus making it a better barrier for infectious agents.

Biologic Factors: Women Endogenous Hormonal Effects The female reproductive tract (FRT) has evolved to maintain a difficult balance of supporting reproduction and protecting against deleterious pathogen invasion.22 These roles appear diametrically opposed immunologically. The immune system of the lower genital tract is tasked with maintaining tolerance to commensal organisms, providing

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at least transient tolerance to allogeneic sperm, and protecting against pathogenic microorganisms. To support conception and fetal development, the FRT must tolerate allogeneic sperm in both the lower and upper genital tract as well as an immunologically distinct fetus in the upper genital tract. Both require transient downregulation of immunologic response to foreign antigen exposure. Pregnancy is well known to produce a state of transient immunosuppression. The cyclical decrease in immunologic markers in the lower genital tract in the periovulatory period coincident with the estrogen surge, however, is less well understood.24 In human studies that use immunologic markers, there is some consistency in hormonal effects on lower genital tract immunity: a decline in cervical immune responses around the time of ovulation. Studies that quantitate immunoglobulin and cytokine levels in cervical mucus of pregnant women have shown increased levels of IgA, IgG, and IL-1.25 Other studies have shown that immunoglobulin and cytokine levels (IL-10, IL-6, and IL1-) in non-pregnant women increase approximately 3 days before ovulation corresponding to the time of estrogen surge.24 Al-Harthi et al. measured a number of cytokines in the genital tract and in peripheral blood.25 Levels of IL-8 in plasma and IL-6 and IL-1 in the vagina were elevated during the follicular phase when both estrogen and progesterone levels are low. Among adolescents, a negative correlation between estradiol and both IgA, IL-2, and IL-10 levels in cervical secretions has been observed.26 In adult women, cervical IL-10 and IL-12 concentrations reached a nadir at ovulation in cycling women, and were highest among women using combined oral contraceptives (COCs).27 Of note, the correlation between plasma and cervical IL-10 and IL-12 was poor, with higher levels observed in cervical secretions suggesting that local production of genital tract cytokines predominates.28 These data emphasize the need for more epidemiologic research using tissue-specific sampling. Anatomically the FRT is composed of an array of epithelial cell types, several communicating compartments, and a unique microbiological balance all of which are physiologically influenced by hormonal flux.29 Furthermore, biological factors that may increase female susceptibility to STIs vary with age. The cellular morphology of the cervix and vagina vary over a woman’s lifetime and are directly influenced by hormonal changes. At birth, the neonatal vagina is lined with the stratified squamous epithelium of adulthood as a result of intra-uterine exposure to maternal estrogen. This epithelium is susceptible to trichomonas and candidal infections but resistant to chlamydial and gonococcal infections.30 When this maternal estrogen wanes, usually during the first month of life, the stratified squamous epithelium is replaced by a thin, atrophic columnar epithelium which remains until menarche and which will support the growth of both Chlamydia trachomatis and Neisseria gonorrhea. Colonization of the neonatal vagina with Trichomonas vaginalis can spontaneously resolve as the epithelial lining

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of the vagina is replaced with columnar cells.31 At puberty, estrogen stimulation returns to stimulate a thicker, glycogencontaining stratified squamous epithelium that covers the vaginal vault to the squamocolumnar junction on the cervix and also that is less susceptible to chlamydial and gonococcal infections.32 The cervix consists primarily of dense collagenous connective tissue. The cervical canal consists of columnar epithelium but the part of the ectocervix that projects (sometimes referred to as ectocervix) into the vagina is covered by stratified squamous, nonkeratinizing epithelium. The columnar epithelium of the cervical canal, or endocervix, may extend out beyond the external os where it forms small patches known as physiological eversion, or ectopy, or ectropion. Cervical ectopy is a common physiological process in adolescence, as well as during pregnancy and in response to hormonal contraceptive use. A larger surface area of columnar epithelium is exposed to potential infectious inoculum when ectopy is present, and so the size of ectopy is believed to correlate with the risk of cervical chlamydial and gonococcal infections.33–35 With age, the uterus elongates and the squamocolumnar junction migrates into the cervical canal.36 The external surface of the portio vaginalis of the cervix is covered by stratified squamous epithelium identical to that of the vagina. At menopause, a sharp decline in estrogen levels effects atrophic changes in the vagina, with thinning of the epithelium, decreased lubrication, and narrowing and shortening of the vaginal canal. Sexually active postmenopausal women experience less pronounced changes.37 The estrogen stimulation associated with puberty also affects the vaginal flora. Prepubescent girls have vaginal flora predominately composed of anaerobic rods and cocci and low levels of lactobacilli.32,38 At puberty, glycogen is deposited on the vaginal epithelium under estrogenic control. The vaginal epithelial cells metabolize the glycogen to form glucose. Lactobacilli that are part of the normal vaginal flora use the glucose for nutrients and produce lactic acid, which keeps the vagina at an acidic pH. In addition to producing acid, some species of lactobacilli produce hydrogen peroxide (H2O2), which may play a crucial role in protecting against overgrowth of pathogens in the vagina, leading to bacterial vaginosis, and which also acts as a natural microbicide with the vaginal ecosystem, especially important in killing HIV. As estrogen declines during menopause, there is also a decline in glycogen production and vascularity in the vagina. Physiological hormonal changes throughout a woman’s lifespan also affect the production and consistency of cervical mucus, which also may serve as a defense against infection.39 Cervical mucus is abundant through the first month of life, becomes scant with loss of maternal estrogen, and becomes copious around puberty. The mucus secreted at adolescence, unlike that of older adolescents or adult women, is easily penetrated by organisms and sperm.

Once monthly menstrual cycles are established, maximal secretion and minimal viscosity occurs during midcycle or the periovulatory phase. A thick, viscous cervical mucus acts as a functional barrier against attachment of pathogens to epithelial surfaces and against the ascent of organisms into the uterus and fallopian tubes. It may also provide a substrate for antibacterial enzymes, antibodies, and leukocytes.30 Adolescent girls also experience opening of the endocervical canal at 9 or 10 years of age. Given their immunological naivety, their easily penetrable cervical mucus, and the opening of the cervical canal, sexually active adolescent girls have major biological predisposition for ascent of pathogens into the upper reproductive tract and a higher incidence of pelvic inflammatory disease.30,39 The fluctuating steroid hormones – estradiol, estrone, estrone-sulfate, and progesterone – that fluctuate across the menstrual cycle also impact normal physiologic variation in the vagina. Several studies examined vaginal tissue, fluid, and microbial flora in asymptomatic, non-contracepting women at three stages of the menstrual cycle: menstrual phase (days 1–5), pre-ovulatory phase (days 7–12), and postovulatory phase (days 19–24). The volume of vaginal discharge increased and the amount of cervical mucus decreased over the menstrual cycle.40,41 There are problems with these studies, however. Most studies use day since last menstrual period in the context of a ‘normal 28-day cycle’ to measure stage of menstrual cycle, generally using a bivariate categorization of ‘early’ (follicular/proliferative) and ‘late’ (luteal/secretory) stages. There is a high degree of inter-individual variability in menstrual cycle length; therefore in the absence of a hormonal measure of ovulation (e.g., luteinizing hormone), misclassification using the day of cycle as a proxy for menstrual stage limits the power to detect true associations with sex steroid fluctuation. Efforts to improve measurement of sexual behavior and stage of menstrual cycle are ongoing, and will improve the validity of future epidemiologic studies. Exogenous Hormonal Effects The effects of oral contraceptives (OCs) and depot medroxyprogesterone acetate (DMPA) on cervical and vaginal mucosa and vaginal flora have been described, but findings on the relationship of their use to the incidence of genital tract infections are contradictory. The use of OCs causes an increase in cervical ectopy34,42 and small changes in vaginal flora but has minimal effect on vaginal epithelium and vaginal and cervical discharge.43 In contrast, women using DMPA experience hypoestrogenism, which causes a decrease in peroxide-producing Lactobacilli colonization and a slight thinning of the vaginal epithelium.44 Mahmoud et al.45 measured antichlamydial activity of cervical secretions collected from women using combined oral contraceptives. COC users had a significantly higher Chlamydia inclusion count (i.e., lower antichlamydial activity) compared to non-COC users independent of the stage

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of the menstrual cycle. These data would suggest that COC users would be at an increased risk of chlamydial infection, however the epidemiologic data to support this hypothesis have been inconsistent. Existing prospective studies suggest an increased risk of cervical chlamydial infection among oral contraceptive and DMPA users compared to nonusers. Six prospective studies have evaluated the association between use of OCs and risk of C. trachomatis. Three of these report a harmful association and three show no significant risks. Several biological mechanisms have been posited to explain the increased susceptibility to C. trachomatis infection resulting from hormonal contraception. The most widely proposed mechanism is the hormone-induced increase in cervical ectopy, resulting in increased exposure of susceptible columnar cells to chlamydial infection. However, when ectopy was directly measured, no increase in chlamydial infection was observed.35 If COC use increases the risk of CT acquisition yet decreases the risk of CT clearance, left truncation resulting from unknown duration of prevalent infection could result in important selection bias that could explain the inconsistency of the cross-sectional literature in assessment of the association of COC use and CT infection. Three prospective studies have evaluated the risk of Chlamydial infection associated with DMPA use. Each reported a significant association between DMPA and increased risk of chlamydial infection. Women using DMPA have also been reported to have increased incidence of trichomoniasis and pelvic inflammatory disease.46 Several prospective studies were conducted to evaluate the risk of gonococcal cervicitis in hormonal contraceptive users. In a study of 818 women recruited from sexually transmitted diseases clinics in Birmingham, AL, hormonal contraception increased the risk of gonococcal cervicitis by 70%.47 Another study of 948 Kenyan commercial sex workers did not reveal an increased risk of gonococcal infection among hormonal contraceptive users (either depot medroxyprogesterone acetate or combined oral contraceptive pills).46 Finally, a prospective study of 819 women in Baltimore, MD who were followed for 1 year revealed that only depot medroxyprogesterone acetate was significantly associated with a nearly four-fold increased risk of both chlamydial and gonococcal cervical infections.48 Current consensus is that there is little evidence of an association between OC use and the acquisition of gonococcal infections. Studies of highly effective contraception and risk of trichomoniasis are inconclusive. The single study of DMPA and trichomoniasis yielded a borderline statistically significant protective effect.49 Similarly, prospective and cross-sectional studies on the effect of OC use and risk of human papillomavirus (HPV) provide inconsistent findings. In contrast, data supporting a moderate positive association between cervical cancer and long-term oral contraceptive use in women with HPV are more consistent,50,51 although this association is not found in all studies. No prospective studies have evaluated

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the association between OC use or DMPA use and HSV incidence. Previous research has suggested that the association between OC use and cervical infection may be mediated through cervical ectopy, which is commonly associated with OC use. More recent studies suggest that cervical ectopy does not appear to be the primary mediator of increased acquisition of cervical infection among hormonal contraceptive users.46 Potential proposed mechanisms for an association between cervical ectopy and increased STI acquisition are that both estrogen and progesterone enhance the growth and persistence of C. trachomatis infection in animal models, suppression of local immune response by sex hormones, and changes in vaginal flora associated with the hypoestrogenic effect as an outcome of DMPA administration.46 Newer formulations of hormonal methods – the combined estrogen-progestin-releasing patch, ring, or injectables progestin-only methods including pills, injectables other than DMPA, or implants – have not been evaluated in prospective studies as to the risk of STI acquisition. Pregnancy Dramatic hormonal and anatomic changes occur during pregnancy that may have important effects on STI acquisition, pathogenesis, and disease manifestations. During pregnancy the placenta produces large amounts of estrogen and progesterone. The anatomy of the female genital tract also undergoes dramatic changes related to the growing fetus and the concomitant hormonal surge. Vaginal walls become thickened and engorged with blood, and the glycogen content of the vagina increases with a resulting decrease in vaginal pH. The columnar epithelial cells of the endocervix extend to the ectocervix. This tissue is friable and bleeds easily which may increase susceptibility to infection but this is not well studied.36 The attachment of the chorion to the endometrial decidua with obliteration of the uterine cavity after the 12th week of pregnancy may obstruct the route for ascending intraluminal spread of gonococci.52 After the 16th week of pregnancy, the fetal membranes rest over the internal cervical opening, and infection of the membranes (chorioamnionitis), caused by a variety of organisms, is more common.53 Immunologic rejection of the fetus does not normally occur during pregnancy most likely due to suppressed maternal immune function. This immunosuppression may in turn affect the natural history of many infectious diseases. High levels of estrogens seen during pregnancy may depress cell-mediated immunity, impair the activity of natural killer cells, and suppress some aspects of neutrophil function.54 However, there are no convincing data that the risks of gonorrhea, syphilis, bacterial vaginosis, or PID are altered during pregnancy. The data associating increased risk for C. trachomatis are mixed.52,53 HPV prevalence appears to increase during pregnancy,46,54–57 with a ‘catch-up’ clearance

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in the early post-partum period.55,58 These findings during pregnancy are not uniformly observed.59,60 An increase in HPV acquisition during pregnancy is unlikely to explain the increased HPV prevalence, and it is hypothesized that the observations reflect increases in HPV viral load to levels above the limit of detection resulting from hormonemediated immunosuppression.22 One study demonstrated a nearly eight-fold increased odds of genital HSV-DNA shedding among pregnant women.61 There are no prospective studies demonstrating increased risk of HSV acquisition during pregnancy. Menopause There are few studies on the prevalence of risk factors for STIs other than HIV in menopausal and postmenopausal women.62,63 The low levels of estrogen following menopause can result in atrophic vaginitis, which may increase susceptibility to STIs and increase vaginal transmission of HIV.64

Sexually transmitted bacterial infections Neisseria gonorrhoeae Neisseria gonorrhoeae is the etiologic agent of gonorrhea and its related clinical syndromes which include urethritis, cervicitis, salpingitis, bacteremia, arthritis, and others.65 Humans are the only natural host for gonococci and these bacteria survive only a short time outside the human body. N. gonorrhoeae is a Gram-negative diplococcus that infects mucus-secreting epithelial cells. It is oxidase-positive, nonmotile, does not form spores, divides by binary fission every 20 to 30 minutes, and utilizes glucose. It grows best on selective media, such as Thayer–Martin medium. Since it does not tolerate drying, specimens collected for culture are best plated immediately and incubated at 36 °C in a 3–5% CO2 environment. Nucleic acid amplification tests are now available that have excellent sensitivity and specificity and allow less invasive collection of specimens for adequate test performance. Immediate physical contact with mucosal surfaces of an infected person, usually a sexual partner, is required for transmission.65 Gonorrhea attaches to different types of epithelial cells via a number of different structures on its surface. N. gonorrhoeae has the ability to alter its surface structures, particularly pilin, lipooligosaccharide antigens and less frequently protein 1 antigens, which help it evade the host response. It is ingested by the cell and can cause asymptomatic or symptomatic infection. Gonorrhea is the second most commonly reported notifiable disease in the United States. Although the national rate of gonorrhea declined 74% from 1975 through 1997 as a result of national control efforts, cases of gonorrhea increased recently for the second consecutive year with

358 366 cases in 2006.66 Increases in quinolone-resistant N. gonorrhoeae (QRNG) in 2006 led to changes in national treatment guidelines that limit the recommended treatment to cephalosporins. Prior to 1996, rates of gonorrhea among men were higher than rates among women. For the sixth consecutive year, however, gonorrhea rates among women are slightly higher than among men. In 2006 the gonorrhea rate among women was 124.3 and the rate among men was 116.8 cases per 100 000 population. Currently gonorrhea rates continue to be highest among adolescents and young adults. The highest rate is among 20- to 24-year-olds overall with the highest rate among women in the 15- to 19-yearold groups, and among men in the 20- to 24-year-old group. Men with urethral gonorrhea can develop overt, symptomatic urethritis within 2–7 days after inoculation. Symptoms may include purulent urethral discharge often accompanied by dysuria. On physical examination the discharge may appear mucopurulent but often it can be clear or cloudy. Asymptomatic infection does occur and may be more common than previously believed due to the availability of urine screening tests. Asymptomatic infection has been linked to specific gonococcal phenotypes and represents a reservoir that perpetuates transmission from men to women. Complications of gonococcal infections are rare in men but may include epididymitis, inguinal lymphadenitits, penile edema, periurethral abscess or fistula, accessory or Tyson’s gland infection, balanitis, and urethral stricture. Epididymitis can present with unilateral testicular pain and testicular swelling and is usually associated with overt or subclinical urethritis. Women with genital gonococcal infections present with symptomatic disease far less frequently than do men. Women may have gonococcal cervicitis and report symptoms in only 50% of cases. Symptoms may occur within 10 days of infection, but the exact incubation period for women remains unclear. When symptoms occur they may be nonspecific and include abnormal vaginal discharge, intermenstrual bleeding, dysuria, lower abdominal pain or dyspareunia. On physical examination, the cervix may appear edematous with mucopurulent or purulent discharge and easily-induced friability. As with men, women can develop urethritis and 40–90% of women with cervical gonococcal infection have urethral co-infection.67 Women with total abdominal hysterectomies can develop urethral infections after sexual exposure to an infected partner. Symptoms may include dysuria although most infections are asymptomatic. Accessory gland infections can also occur involving the Skene’s or Bartholin glands. Often the infection is unilateral and occlusion of the gland’s duct may result in abscess formation.68 Pelvic inflammatory disease refers to an ascending infection to the endometrium and/or fallopian tubes.65 Symptoms include lower abdominal pain, discharge, dyspareunia, intermenstrual bleeding, and fever. However, silent or asymptomatic PID can occur. The clinical diagnosis of PID is imprecise, but exam findings include uterine, adnexal

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tenderness, or cervical motion tenderness. Cervicitis may or may not be present. Long-term sequelae of PID include chronic pelvic pain, tubal infertility, and ectopic pregnancy. Gonococcal infection in women may be influenced by the hormonal changes. Several reports beginning in the 1950s suggested that there was an increased risk of diagnosing N. gonorrhoeae in women shortly after the beginning of menstruation.69 Several hypotheses were suggested: menstrual blood providing nutritional supplementation enhancing the growth of the organism, favorable characteristics of the cervical mucus, hormonally mediated increased adherence of the organism, or the presence of vaginal flora disruptions (e.g. bacterial vaginosis) enhancing gonococcal infection. Several prospective studies were conducted to evaluate the risk of gonococcal cervicitis in hormonal contraceptive users. In a study of 818 women recruited from sexually transmitted diseases clinics in Birmingham, AL, hormonal contraception increased the risk of gonococcal cervicitis by 70%.47 Another study of 948 Kenyan commercial sex workers did not reveal an increased risk of gonococcal infection among hormonal contraceptive users (either depot medroxyprogesterone acetate or combined oral contraceptive pills).46 Finally, a prospective study of 819 women in Baltimore, MD who were followed for 1 year revealed that only depot medroxyprogesterone acetate was significantly associated with a nearly four-fold increased risk of both chlamydial and gonococcal cervical infections.48 There are no convincing data that the risk of gonorrhea during pregnancy is altered. Both men and women may develop anorectal gonococcal infection if they engage in receptive anal intercourse.68 In 35–50% of women with gonococcal cervicitis who do not acknowledge rectal sexual contact, however, the rectal mucosa may be co-infected.66 This may be a result of perineal contamination with infected cervical secretions. Most rectal gonorrhea cases are asymptomatic, but occasionally severe proctitis may result. Symptoms, if present, include anal irritation, painful defecation, constipation, rectal bleeding and/or discharge, and tenesmus. Evaluation with an anoscope is recommended with symptomatic patients and signs of infection may include purulent discharge, erythema or easily induced bleeding as well as normal mucosa. Pharyngeal gonococcal infection is most often asymptomatic and exudative pharyngitis is rare.69 Disseminated gonoccocal infection (DGI) occurs infrequently, in only 0.5–3% of cases. Gonoccocal strains that are resistant to killing by normal human serum have a propensity to produce bacteremia. DGI occurs more frequently in women and often with 7 days of menses. Clinical manifestations include skin lesions, arthralgias, tenosynovitis, arthritis, hepatitis, myocarditis, and rarely endocarditis and meningitis. Typical skin lesions are acrally distributed, sparse, and appear as a pustular lesion on an erythematous base. Synovial cultures are positive in only 50% of septic arthritis cases. Treatment of gonococcal infections is currently limited to cephalosporin regimens.70 Current 2007 updated

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recommended treatment regimens for gonococcal infections of the cervix, urethra, and rectum include ceftriaxone 250 mg IM in a single dose or cefixime 400 mg orally in a single dose with treatment for chlamydia if chlamydial infection is not ruled out. Other single-dose cephalosporin therapies that are considered alternative treatment regimens for uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime 500 mg IM; or cefoxitin 2 g IM, administered with probenecid 1 g orally; or cefotaxime 500 mg IM. Some evidence indicates that cefpodoxime 400 mg and cefuroxime axetil 1 g might be oral alternatives. Uncomplicated gonococcal infections of the pharynx should be treated with ceftriaxone 125 mg IM in a single dose along with treatment for chlamydia.

Chlamydia Trachomatis In the United States, Chlamydia trachomatis infections are the most commonly reported notifiable disease.69 Recent studies also demonstrate the high prevalence of chlamydial infections in the general US population. In the most recent National Health and Nutrition Examination Survey which was conducted from 1999 to 2002, chlamydia prevalence among participants (aged 14–39 years) was 2.2%.71Among young adults (18–26 years of age) participating in the National Longitudinal Study of Adolescent Health from 2001 to 2002, chlamydia prevalence was 4.2%.72 As of 2006, over 1 million chlamydia infections were reported to the CDC. The increase in reported chlamydial infections over the last decade may reflect the expansion of chlamydia screening activities, use of increasingly sensitive diagnostic tests, an increased emphasis on case reporting from providers and laboratories, improvements in the information systems for reporting, and, possibly, true increases in disease. However, routine screening programs are available mainly for women and many women who are at risk are still not being tested. This may reflect lack of awareness among some healthcare providers and limited resources available to support screening. Chlamydia screening and reporting are likely to continue to expand further in response to the Healthcare Effectiveness Data and Information Set (HEDIS) measure for chlamydia screening of sexually active women 15 through 25 years of age who receive medical care through commercial or Medicaid managed care organizations.73 Among women, the highest age-specific rates of reported chlamydia in 2006 were among those 15–19 years of age (2862.7 cases per 100 000 females) and 20–24 years of age (2797.0 cases per 100 000 females). These increased rates in women may, in part, reflect increased screening in this group. Age-specific rates among men, while substantially lower than the rates among women, were highest in the 20to 24-year-old age group (856.9 cases per 100 000 males).66 C. trachomatis is an obligate intracellular bacterium which has DNA and RNA, bacterial ribosomes, a Gramnegative-like cell wall and it is susceptible to antibiotics.74

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It requires 36 to 48 hours to complete its life cycle, but knowledge regarding the replication cycle is still incomplete. The organism generally causes superficial mucosal infection of columnar epithelial cells, and this infection is often chronic lasting months to years. In men, C. trachomatis can cause a mucopurulent urethritis but over 50% are asymptomatic.75,76 The exact incubation period in men is unknown but most likely between 7 and 14 days in symptomatic infection. Symptoms when present include urethral discharge and dysuria. Complications are infrequent but include epididymitis. Up to 70% of sexually transmitted cases of epididymitis are due to C. trachomatis. Symptoms may include epididymal, testicular, and/or scrotal pain and fever. The role for chlamydial infection in male sterility is unclear and the risk of prostatitis is unknown. In women, 70–80% of chlamydial cervical infections are without associated symptoms or signs. When present, symptoms are non-specific. The most common signs include mucopurulent discharge and hypertrophic ectopy, which refers to an area of ectopy that is edematous, congested, and bleeds easily.75 Although chlamydial infections in women are usually asymptomatic, they may result in pelvic inflammatory disease (PID), which is a major cause of infertility, ectopic pregnancy, and chronic pelvic pain. Data from a randomized controlled trial of chlamydia screening in a managed care setting suggested that screening programs can lead to a reduction in the incidence of PID by as much as 60%.77 As with other inflammatory STDs, chlamydial infection can facilitate the transmission of HIV infection. In addition, pregnant women infected with chlamydia can pass the infection to their infants during delivery, potentially resulting in neonatal ophthalmia and pneumonia. Due to the large burden of disease and risks associated with infection, CDC recommends screening all sexually active women younger than 26 years of age for chlamydia annually.70 Syndromes seen in both men and women include conjunctivitis which can be a result of autoinoculation from infected genitalia in adults, but also can be acquired by neonates by passage through an infected birth canal. Conjunctiva in adults often has a follicular appearances and nonpurulent discharge whereas purulent conjunctivitis is seen in the neonate 5–14 days after vaginal delivery.75 Rectal infections due to chlamydia are frequently asymptomatic although rectal pain, discharge, and tenesmus may occur. Infections can be seen in persons practicing receptive anal intercourse and concomitant infection of the rectum occurs in about 25–30% of women with cervical chlamydial infection.76 Reactive arthritis from C. trachomatis is more common in men than women despite a similar occurrence of reactive arthritis from enteric infections and is associated with HLA-B27. A characteristic syndrome of conjunctivitis, urethritis, oligoarthritis, and skin lesions which include keratoderma blenorrhagica and circinate balanitis occurs

3–6 weeks after the trigger infection. Chlamydial antigens and DNA have been demonstrated within joints.76 The diagnosis of chlamydial infections has been made much easier with the advent of nucleic acid amplification tests (NAATs). Culture can be performed but is expensive and technically difficult. Non-culture tests rely on detection of bacterial products, such as proteins or nucleic acid, in patient samples. Non-amplified tests require adequate number of organisms to be present which is between 1000 and 10 000. NAATs markedly amplify target nucleic acids, require only 1 to 10 organisms in the sample, and increase the sensitivity to over 90% for cervical and urethral swabs while maintaining over 99% specificity. NAATs can be used on first-catch urine specimens from men and women and from self-collected vaginal swabs from women.74 Recommended treatment of uncomplicated chlamydial infection for both men and women include azithromycin 1.0 g orally in a single dose or doxycycline 100 mg given orally twice a day for 7 days.70 First line recommended therapy for pregnant women includes azithromycin 1.0 g in a single dose or amoxicillin 500 mg orally three times a day for 7 days.70

Syphilis Data from the general US population of 18- to 49-year-olds collected in the most recent National Health and Nutrition Examination Study 2001–2004 showed that prevalence of syphilis seroreactivity was low (0.71%).78 Although the rate of primary and secondary (P&S) syphilis in the United States declined 89.7% between 1990 and 2000, the rate of P&S syphilis increased between 2001 and 2006. Overall increases in rates between 2001 and 2006 were observed primarily among men (from 3.0 cases per 100 000 population to 5.7 cases per 100 000 population). After persistent declines since 1990, the rate of P&S syphilis among women increased from 0.8 cases per 100 000 population in 2004 to 0.9 cases per 100 000 population in 2005 to 1.0 case per 100 000 population in 2006.66 Untreated syphilis is a chronic disease that can be interrupted by periods of active clinical stages. The disease is often described clinically in four stages: primary, secondary, latent, and tertiary disease. Primary Syphilis The classic chancre, which develops at the site of inoculation, begins as a painless papule. It quickly erodes, becomes indurated, and forms an ulcer with a clean base. Multiple ulcers can occur. However, 60% of lesions that occur are described as atypical, and the absence of a primary skin lesion is also common.79–81 Many factors can influence the presentation of the chancre, such as the immune status of the patient, current topical or oral antibiotic use, and secondary bacterial infection. Regional lymphadenopathy occurs

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with moderately enlarged, painless, rubbery bilateral lymph nodes. Chancres that occur on the cervix, in the mouth or anal canal may have atypical appearances and have been described as granulomatous plaques or masses. The chancre usually heals within 3–6 weeks, with a range of 1–12 weeks, and usually does not scar. Women are less likely than men to present during primary syphilis probably because women are less likely than men to notice the painless ulcer.80 Secondary Syphilis Clinical manifestations of secondary or disseminated syphilis are protean.79–82 Constitutional symptoms include malaise, headache, pharyngitis, fever, and myalgias. Generalized lymphadenopathy occurs during the secondary stage in over 85% of patients. A skin rash may develop that may be generalized or localized, mild or florid eruptions. It may be an evanescent macular rash that can easily be overlooked by the patient or clinician. The classic secondary rash evolves into a symmetric macular, papular, and/or pustular eruption. The papules are red or reddish brown and discrete. They may become scaly. The rash can be confused with pityriasis rosea or psoriasis but it is usually nonpruritic and involves the palms and soles in 60% to over 80% of patients. It may persist for weeks to months.81,82 Other secondary manifestations include mucous patches, which are flat patches involving the mouth, pharynx, larynx, and genitals can be found in 5% to 30% of patients. Some mucous patches may be small, superficial, ulcerated areas with grayish borders that resemble painless aphthous ulcers or plaques. Condylomata lata develop in 5–25% of patients. These lesions are moist, heaped, wart-like papules. Unlike the primary chancre that occurs at the site of sexual contact, these lesions develop in warm intertriginous areas, such as the gluteal folds, perineum, nasolabial folds, axillae, between the fingers and toes, under the breast, between the scrotum, and the thigh. They are teeming with spirochetes and very contagious.79,82 Patchy or moth-eaten alopecia occurs in some patients, which is reversible with treatment. Subclinical hepatitis, detected by laboratory studies showing elevated liver enzymes, can occur in up to 25% of patients.82 Iritis, anterior uveitis, and glomerulonephritis or nephritic syndrome has been reported and is most likely due to deposition of circulating immune complexes that contain treponemal outer membrane proteins and human fibronectin, antibody to these substances, and complement.82 Latent Syphilis During the latent stage of syphilis, no clinical manifestations occur. The only evidence that infection is present is a positive serologic test for syphilis. Latent syphilis is categorized into early latent syphilis, which is syphilis of less than one year’s duration, and late latent syphilis, which is syphilis of greater than or equal to one year’s duration. During

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the pre-penicillin era, 25% of patients whose infection had become latent had recrudescence of active, secondary syphilis within the first year of infection.79 Thus the demarcation between early and late phases of latent infection developed. In addition, patients with early latent syphilis are considered to be more contagious to their sexual contacts and are treated with shorter courses of penicillin therapy. Syphilis of unknown duration with no clinical manifestations is usually categorized into late latent disease. Patients who progress to late latent syphilis should be treated with longer courses of antibiotics, with penicillin being the drug of choice.70 Tertiary Syphilis Approximately one-third of patients in the late latent syphilis stage progress to end-stage or tertiary syphilis.79 Tertiary syphilis manifestations are usually described in three categories: neurosyphilis, benign late syphilis, and cardiovascular syphilis. It must be stressed that neurosyphilis may appear during any stage of the disease, since central nervous system invasion by spirochetes occurs early in infection. Clinical manifestations of neurosyphilis that may appear early or late include asymptomatic neurosyphilis, meningeal involvement (acute meningitis), meningovascular involvement, and parenchymatous disease (paresis, tabes dorsalis, and optic atrophy). Late benign syphilis presents as gummatous lesions that can occur in skeletal, spinal, and mucosal areas such as the eyes and viscera. Gummas of the lung, stomach, liver, genitals, breast, brain, and heart have been reported. The average onset of late benign syphilis is 4–12 years. In cardiovascular tertiary syphilis, aortic, coronary ostial, valvular, and myocardial lesions have been described but the most common pathological lesion is endarteritis of the aortic vasovasorum.82 Treponema pallidum bacteria are thought to spread to the heart early in the disease process and lodge in the aortic wall where they may remain dormant for years. The spirochetes appear to have a predilection for the vasa vasorum where they produce transmural inflammatory lesions that are rich in perivascular lymphocytes and plasma cells, resulting in endarteritis. All three layers of the aortic wall can be affected. The aortic media may develop patchy necrosis with focal scarring and destruction of elastic tissue resulting in subsequent aortic dilation and aneurysm formation. The average appearance of cardiovascular tertiary syphilis is about 15–30 years after initial infection. Women having any stage of syphilis can transmit the infection to their offspring, with the risk being highest in primary and secondary syphilis.82 Therefore, a serologic test for syphilis should be performed on all pregnant women at the first prenatal visit. Women who are at high risk for syphilis, live in areas of high syphilis morbidity, are previously untested, or have positive serology in the first trimester should be screened again early in the third trimester (28 weeks gestation) and at delivery. Some states require all women to be screened at delivery. Infants should

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not be discharged from the hospital unless the syphilis serologic status of the mother has been determined at least once during pregnancy and preferably again at delivery. Any woman who delivers a stillborn infant should be tested for syphilis.70

Chancroid Chancroid is an acute infection manifested by deep genital ulcerations and by the frequent occurrence of inguinal adenopathy, often with bubo formation. The etiologic agent is Haemophilus ducreyi, which is a Gram-negative coccobacillus. Transmission is exclusively via sexual contact, with an incubation period of 3–10 days.83 In the United States, chancroid usually occurs in discrete outbreaks, although the disease is endemic in some areas and it is a cofactor for HIV transmission. Approximately 10% of persons who have chancroid that was acquired in the United States are coinfected with Treponema pallidum or HSV; this percentage is higher in persons who have acquired chancroid outside the United States.83 The epidemiology of chancroid has a striking gender difference, with 90% of reported cases occurring in men.83 The lesions begin as tender papules, which then erode within 24 hours to become painful, soft, nonindurated ulcers. Men present with ulcers and inguinal swelling or pain which may be accompanied by bubo formation and rarely with urethral discharge. Women may present with dysuria, pain, bleeding, vaginal discharge, or painful vulvo-vaginal ulcers. Women may have an unapparent carrier state or overlooked lesions and are less likely than men to progress from the papule stage to pustules when experimentally inoculated with Haemophilus ducreyi. Diagnosis requires selective media but culture has a reported sensitivity of 40–89%. Serology is not useful and PCR is not commercially available. Treatment currently recommended includes azithromycin, 1.0 g given once orally, ceftriaxone 250 mg given once IM, or ciprofloxacin 500 mg given orally twice a day for 3 days.70

Sexually transmitted viral infections other than HIV Human Papillomavirus (HPV) HPV causes a variety of lesions of the skin and mucous membranes including common warts of the skin, plantar warts, genital warts (sometimes called condyloma acuminata), squamous intraepithelial lesions, and invasive anogenital carcinoma of the cervix, vagina, vulva, penis, anal canal, and perineal areas. Of the over 100 types of HPV, approximately 30 infect the anogenital area and are transmitted principally through sexual contact. Anogenital HPV types are divided into those associated with high risk development of malignancies (e.g., HPV types 16, 18, 31, 33, 35,

39, 45, 51, 52, etc.) and those associated with low risk of malignancy development (e.g., HPV types 6, 11, 42, 43, 44, etc.). HPV 16, 18 are the most oncogenic or highest risk of these types. Low-risk types are commonly associated with visible genital warts. The prevalence of HPV infection is high. According to population-based estimates from the National Health and Nutrition Examination Survey, 26.8% of women ages 14– 59 had subclinical infection detectable by DNA testing of self-collected vaginal swabs. Incidence is difficult to determine.84 Annual incidence of all types of genital HPV infection is estimated to be 6.2 million in the United States. It is also estimated that 80% of sexually active women will have been infected with genital HPV by age 50. Limited data for young men show similar incidence rates. The prevalence of genital warts is estimated at 1% and incidence is estimated to be approximately 0.3% per year overall. Risk factors for HPV acquisition in women include young age (25 years), early age at first intercourse (16 years or younger), multiple sexual partners, and having a male partner who has had multiple sex partners. Similar risk factors have been found for penile HPV in men.85 Prior HPV infection at other sites does not appear to offer protection, and there does not appear to be significant cross-protection between genital HPV types. Recent evidence from several studies demonstrates that condoms prevent subclinical HPV infection and may be effective in preventing actual disease manifestations.86,87 Vertical transmission rarely results in recurrent respiratory papillomatosis due to HPV 6/11 in infants and young children. Cesarean section has not been shown to effectively reduce transmission to neonates. Cervical carcinoma is the most important sequela of genital high-risk HPV infection in women. In 2007, an estimated 11 150 cases of cervical cancer occurred with 3670 related deaths.88 Worldwide, almost 500 000 estimated cervical cancers occurred with over 270 000 associated deaths. Cancer rates at other anogenital sites such as the penis, vulva, vagina, and anus are 8- to 10-fold lower, although anal cancer incidence in HIV-positive individuals, especially men who have sex with men is high. Risk factors for persistence or progression of HPV infection to neoplasia include diminished cellular immunity and immunosuppression for any cause. Hormonal influences related to pregnancy and oral contraceptives, smoking, folate deficiency, other STIs such as C. trachomatis and herpes simplex virus infection have been associated with cervical cancer in some studies. Recommendations for Pap screening in women have been developed by a number of nationally recognized expert groups. According to the CDC, Pap screening should begin no sooner than 3 years after onset of vaginal intercourse; no later than age 21.70,89 Exceptions include known or suspected history of sexual abuse, HIV infection, or immune compromise. Women age 30 or older (with three consecutive satisfactory normal Paps) may be screened every

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2–3 years. Another option is a combination of Pap screening with a test for high-risk HPV. Those with negative combined tests should be screened with combined tests no more frequently than every 3 years. Exceptions to these guidelines include DES exposure, HIV infection, or immune compromise. Pap screening may be discontinued in women who have had a total hysterectomy for benign disease and no history of CIN 2 or 3 or at age 70 with three or more consecutive satisfactory normal Paps and no abnormal Paps within the past 10 years. Exceptions include any history of cervical cancer, DES exposure, or HIV infection. The Bethesda System for cervical cytology uses categories of low grade squamous intraepithelial lesions (LSIL) and high-grade SIL (HSIL). Atypical squamous cells of undetermined significant (ASCUS) and atypical squamous cells cannot rule out high grade lesion (ASC-H) are less specific, but potentially important indicators of disease. Atypical glandular cells (AGC) can also be observed on cytology. There is no need for more frequent Pap tests in the case of external genital warts. Limitations of Pap tests include unsatisfactory results (requiring a repeat visit and specimen) up to 20% of the time and variable sensitivity (50–70% for a single Pap test, which is the rationale for serial testing). Liquid media-based tests (e.g., Thinprep, SurePath) and computer-assisted reading may enhance sensitivity, but reduce specificity.88 Perhaps the most exciting progress in prevention of cervical cancer is the development of the HPV vaccines. Gardasil (Merck) is a prophylactic quadrivalent vaccine that was licensed in June 2006 for the prevention of genital warts and cervical disease. It is composed of non-infectious virus-like particles, types 6, 11, 16, and 18. It is licensed for females between the ages of 9 and 26 years old. Trials are currently being conducted among males but efficacy in this population is still unknown. A second vaccine (Cervarix Glaxo Smith Kline) is currently under FDA review. The Advisory Committee on Immunization Practices (ACIP) and the American Cancer Society (ACS) recommend routine administration of the HPV vaccine for girls between 11 and 12 years of age.89,90 It may be given as young as 9 years of age and catch-up vaccination for girls 13–18 years old is recommended. For 19–26-year-old women the ACIP recommends catch-up vaccination as well. The recommended dosing schedule is 0, 2, and 6 months but a minimum of 4 weeks between the first and second doses and a minimum of 12 weeks between the second and third doses is recommended if the 0, 2, and 6-month schedule cannot be followed. There is no need to restart the series if a dose is missed.

Herpes Simplex Virus (HSV) There are two types of HSV which can cause genital infections: HSV-1 and HSV-2. HSV-1 is typically acquired in the orolabial area and presents as vesicles or ulcers commonly referred to as ‘cold sores’ or ‘fever blisters.’ HSV-1

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can be transmitted to the genital area of a person who does not already have HSV-1 through oral sex. Most genital herpes infections are caused by HSV-2. Both types establish lifelong infection characterized by latency in the dorsal root ganglion with the ability for recurrent clinical disease and asymptomatic shedding. It is estimated that at least one million new cases of genital herpes occur in the US each year and that over 80% of these infections have not been diagnosed. According to the most recent 1999-2004 NHANES, 17% of persons ages 14–49 have HSV-2 antibodies.91 Seroprevalence of HSV-1 was 58% which reflected a decrease from 62% in the 1988– 1994 NHANES. Among persons infected with HSV-1 but not with HSV-2, a higher percentage reported having been diagnosed with genital herpes in 1999–2004 compared with 1988–1994. Seroprevalence of HSV-1 decreased but the incidence of genital herpes caused by HSV-1 may be increasing.91 Gender has not been associated with HSV-1 seropositivity, but women consistently have been found to have a higher rate of HSV-2 seropositivity than men. The reasons for the differential rates are unclear, but may result from the higher rate of male-to-female transmission compared to female-to-male transmission and a higher frequency of recurrent genital HSV lesions in men in some studies.92,93 Most studies evaluating the effects of sex hormones on HSV susceptibility and progression have focused on HSV-2. In a cross-sectional study of 273 women who were seropositive for HSV-2, women using either depotmedroxyprogesterone acetate and combined oral contraceptives were more likely to experience HSV-2 shedding.61 Data are conflicting since a longitudinal study of women initiating hormonal contraception did not reveal increased HSV-2 shedding.94 The data on hormonal contraception and HSV-2 acquisition are much more limited. Hormonal contraception increased the risk of genital ulcer disease (GUD) acquisition in a study of 302 Kenyan commercial sex workers, but HSV2 was likely responsible for only 50% of the genital ulcers.87 In another prospective study of 948 Kenyan commercial sex workers, neither depot-medroxyprogesterone acetate nor combined oral contraceptive use increased incident GUD acquisition.95 Among pregnant women, one study demonstrated a nearly eight-fold increased odds of genital HSV-DNA shedding.61 There are no prospective studies demonstrating increased risk of HSV acquisition during pregnancy. An intriguing association between sex hormones and HSV-2 was noted in the data from the glycoprotein-Dsubunit vaccine trials. Overall, this vaccine was not found to be protective against acquisition of HSV infection.96 However, in subgroup analyses, women who were initially seronegative for both HSV-1 and HSV-2 were protected against incident herpes infection after receiving the vaccine but no similar association was noted in men. Whether this finding can be attributed to the effect of sex hormones on the immune response to the vaccine is unclear but

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interesting. Evaluation of a new HSV-2 vaccine among HSV-1 and HSV-2 seronegative women is under way. The projected US rate of neonatal herpes is 33 per 100 000 live births; most (85%) of neonatal herpes cases are projected to occur in infants whose mothers are either HSV-seronegative or seropositive for HSV-1 only.97 In vaginal delivery, transmission occurs in 1% of recurrent genital herpes and up to 30–50% of infections acquired around the time of delivery. Risk factors for HSV transmission to the infant include: new infection, primary infection, lack of type-specific antibodies, and scalp electrodes.98 According to the American College of Obstetrics and Gynecology recommendations, women with active recurrent genital herpes should be offered suppressive viral therapy at or beyond 36 weeks of gestation.99 Abdominal delivery (cesarean section) is recommended when prodromal symptoms or active lesions occur at the onset of labor, regardless of whether this is a primary or recurrent outbreak. Data regarding interventions to reduce vertical transmission in the specific setting of primary herpes are limited. A meta-analysis of five studies found a significant reduction in clinical recurrences at delivery when women were given acyclovir from 36 weeks of gestation to delivery with an associated decrease in cesarean sections related to clinical herpes recurrences.100 Cesarean delivery is not recommended for women with a history of HSV infection but no active genital disease during labor. Routine antepartum genital HSV cultures in asymptomatic patients with recurrent disease are not recommended and routine HSV screening of pregnant women is currently not recommended. Prevention must center on avoiding acquisition of HSV in late pregnancy. The new type-specific serologies may be of use in determining risk status and management of HSV in pregnancy in particular for women with a clinical diagnosis of genital herpes, a history of atypical recurrent genital lesions, or a past or present partner with a history of genital herpes.70

Other organisms and syndromes Trichomonas vaginalis Globally, Trichomonas vaginalis infection is the most common curable STI. T. vaginalis is a pathogenic protozoan parasite of the human urogenital tract. The epidemiology of this STI is not as well recognized due to limited diagnostic techniques, absence of screening programs, and lack of disease reporting. Recently, however, T. vaginalis infection has been associated with a range of adverse reproductive health outcomes, including preterm birth,101 post-hysterectomy infection,102 atypical pelvic inflammatory disease,103,104 infertility,105,106 and HIV-1 acquisition.107,108 Utilization of polymerase chain reaction-based diagnostics has enhanced our understanding of the epidemiology of T. vaginalis both at the population level and in sexual partners. High rates of

asymptomatic infection in male partners of infected females and subsequent re-infection have significant implications for control programs. Up to one-third of females with trichomoniasis are thought to be asymptomatic, many women develop symptoms and signs of vaginal discharge, vulvar irritation, and inflammation. Some women complain of lower abdominal pain and dysuria.109 Men with T. vaginalis infection are largely asymptomatic, but 5–15% of men with urethritis not caused by gonorrhea (non-gonococcal urethritis or NGU) have been found to have trichomoniasis. Furthermore, trichomonas infection in men has been associated with prostatitis, epididymitis, and infertility.110 Diagnostic modalities available for trichomonas infection include vaginal saline wet mount microscopy, culture, rapid antigen testing, and nucleic acid amplification and detection.111 Recommended therapy includes 2 g of oral metronidazole in a single dose or 2 g of tinidazole orally in a single dose.70

Pelvic Inflammatory Disease (PID) Each year in the United States it is estimated that more than 1 million women experience an episode of acute PID, that more than 100 000 women become infertile as a result of PID, and a large proportion of the ectopic pregnancies occurring every year are due to the consequences of PID.70 PID is a syndrome characterized by infection of the upper female genital tract which can include the uterus, fallopian tubes, ovaries, and peritoneum. Infection spreads from an infection in the cervix and vagina. The etiology of PID is polymicrobial. It is firmly associated with infections caused by Neisseria gonorrhea and Chlamydia trachomatis. In studies of women with PID, N. gonorrhoeae has been recovered from the cervix in 30–80% of women, and C. trachomatis has been recovered from the cervix in 20–40% as well as from the endometrium and/or fallopian tubes.112–114 Other organisms associated with PID include Mycoplasma hominis, Mycoplasma genitalium, Ureaplamsa urealyticum, anaerobic and aerobic Gram-negative organisms such as Bacteroides spp., E. coli, and Gram-positive organisms such as streptococcus spp.115 When symptoms are present, they may include lower abdominal pain, cramping, dysuria, intermittent or post-coital bleeding, vaginal discharge, and fever. Often asymptomatic or atypical presentation can occur in the setting of upper tract inflammation with or without documented infection, such as dyspareunia, irregular bleeding, urinary or gastrointestinal symptoms. Mild abdominal or uterine tenderness on exam has been associated with asymptomatic endometritis. Approximately 25% of women with a single episode of symptomatic PID will experience sequelae, including ectopic pregnancy, infertility or chronic pelvic pain.116 Diagnosis may at times be challenging, but the CDC recommends empiric treatment of PID if uterine or adnexal

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tenderness or cervical motion tenderness is present on pelvic examination. Treatment regimens, depending on severity of infection, can be oral or parenteral and are aimed to cover gonorrhea, Chlamydia, and anaerobic organisms.70

Epididymitis A variety of inflammatory conditions target the epididymis, including bacterial, viral, and fungal infections as well as idiopathic inflammation.117 Acute epididymitis is characterized by inflammation of the epididymis, characterized by symptoms of pain and swelling, generally occurring on one side and developing over several days. Clinical signs may include positive urine cultures, fever, erythema of the scrotal skin, leukocytosis, urethritis, hydrocele, and involvement of the adjacent testis. Up to 80% of all cases of epididymitis may be bacterial in origin, though large epidemiologic studies have identified a clear bacterial etiology in fewer than 25% of subjects with clinical signs of epididymitis.118 Transmission of C. trachomatis is felt to be responsible for infectious epididymitis in patients 35 years old or younger, though the majority of men in this age range with epididymitis (up to 90%) have no objective laboratory evidence of C. trachomatis on urethral swab polymerase chain reaction.119 In patients older than 35, coliform bacteria are the most common pathogens isolated in infectious epididymitis, with E. coli accounting for the majority of cases. Other reports have sporadically implicated other bacteria that may be found in epididymitis, including U. urealyticum, Corynebacterium sp., Mycoplasma sp.120

References 1. Wellings K, Collumbien M, Slaymaker E, et al. Sexual behaviour in context: a global perspective. Lancet 2006; 368:1706–28. 2. Gerressu M, Stephenson JM. Sexual behaviour in young people. Curr Opin Infect Dis 2008;21:37–41. 3. Marston C, King E. Factors that shape young people’s sexual behaviour. Lancet 2006;368:1581–86. 4. Wood K, Maforah F, Jewkes R. He forced me to love him: putting violence on adolescent sexual health agendas. Soc Sci Med 1998;47:233–42. 5. Ankomah A. Condom use in sexual exchange relationships among young single adults in Ghana. AIDS Educ Prev 1998;10:303–16. 6. Ascencio MV. Sex, and Sexuality Among New York’s Puerto Rican Youth. London: Lynne Rienner; 2002. 7. Schiffer J, Madrigal J. The Sexual Construction of Latino Youth: Implications for the Spread of HIV/AIDS. New York, NY: The Haworth Higpanic/Latino Press; 2000. 8. De la Cuesta C. Taking love seriously: the context of adolescent pregnancy in Columbia. J Transcult Nurs 2001;12:180–92. 9. Yeh C. Sexual risk taking among Taiwanese youth. Publ Health Nurs 2002;19:68–75. 10. Farrer J. Opening Up: Youth Sex Culture and Market Reform in Shanghai. Chicago, IL: University of Chicago Press; 2002.

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11. Eyre SL, Hoffman V, Millstein SG. The gamesmanship of sex: a model based on African American adolescent accounts. Med Anthropol Q 1998;12:467–89. 12. McKernon S. Managing condom use and non-use: a study of condom uses among clients of a sexual health clinic. Venereol 1996;9:233–38. 13. Bajos N, Marquet J. Research on HIV sexual risk: social relations-based approach in a cross-cultural perspective. Soc Sci Med 2000;50:1533–46. 14. Kordoutis PS, Loumakou M, Sarafidou JO. Heterosexual relationship characteristics, condom use and safe sex practices. AIDS Care 2000;12:767–82. 15. Soler H, Quadagno D, Sly DF, Riehman KS, Eberstein IW, Harrison DF. Relationship dynamics, ethnicity and condom use among low-income women. Fam Plann Perspect 2000;32:82–88, 101. 16. Pulerwitz J, Amaro H, De Jong W, Gortmaker SL, Rudd R. Relationship power, condom use and HIV risk among women in the USA. AIDS Care 2002;14:789–800. 17. Mufune P. Changing patterns of sexuality in northern Namibia: implications for the transmission of HIV/AIDS. Culture Health Sexuality 2003;5(5):425–38. 18. Halton K, Ratcliffe AA, Morison L, West B, Shaw M. Herpes simplex 2 risks among women in a polygynous setting in rural West Africa. AIDS 2003;17:97–103. 19. Slap GB, Lot L, Huang B, Daniyam CA, Zink TM. Sexual behaviour of adolescents in Nigeria: cross sectional survey of secondary school students. BMJ 2003;326:15–20. 20. Adimora AA, Schoenbach VJ. Contextual factors and the black-white disparity in heterosexual HIV transmission. Epidemiology 2002;13:707–12. 21. Holmberg LI, Hellgerg D. Age-related gender differences of relevance for health in Swedish adolescents. Int J Adolesc Med Health 2007;19:447–57. 22. K. Ghanem, P. Gravitt, Sex steroids and risk of female genital tract infection, in: S.L. Klein, C. Roberts (Eds.), Sex Hormones and Immunity to Infection. Springer Science  Business Media, New York, NY, in press. 23. Kutteh WH, Moldoveanu Z, Mestecky J. Mucosal immunity in the female reproductive tract: correlation of immunoglobulins, cytokines, and reproductive hormones in human cervical mucus around the time of ovulation. AIDS Res Hum Retroviruses 1998;14(Suppl. 1):S51–5. 24. Kutteh WH, Franklin RD. Quantification of immunoglobulins and cytokines in human cervical mucus during each trimester of pregnancy. Am J Obstet Gynecol 2001;184:865–72, discussion 872-4. 25. Al-Harthi L, Wright DJ, Anderson D, et al. The impact of the ovulatory cycle on cytokine production: evaluation of systemic, cervicovaginal, and salivary compartments. J Interferon Cytokine Res 2000;20:719–24. 26. Shrier LA, Bowman FP, Lin M, Crowley-Nowick PA. Mucosal immunity of the adolescent female genital tract. J Adolesc Health 2003;32:183–86. 27. Gravitt P, Hildesheim A, Herrero R, et al. Correlates of IL-10 and IL-12 concentrations in cervical secretions. J Clin Immunol 2003;23:175–83. 28. Castle PE, Hildesheim A, Bowman FP, et al. Cervical concentrations of interleukin-10 and interleukin-12 do not correlate with plasma levels. J Clin Immunol 2002;22(1):23–27.

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29. McCree DH, Rompalo AM. Biological and behavioral risk factors associated with STDs/HIV in women. Implications for behavioral Interventions. In: SO Aral, JM Douglas, JA Lipshutz, eds. Behavioral Interventions for Prevention and Control of Sexually Transmitted Diseases. New York, NY: Springer Science  Business Media; 2007:310–24. 30. Bolan G, Ehrhardt AA, Wasserheit JN, et al. Gender perspectives and STDs. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 3rd ed. New York, NY: McGraw–Hill; 1998:117–27. 31. Hobbs MM, Sena AC, Swugard J, Schwebke JR, et al. Trichomonas vaginalis and trichomoniasis. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 4th ed. New York, NY: McGraw–Hill; 2008:771–93. 32. Hammerschlag MR, Alpert S, Rosner I, et al. Microbiology of the vagina in children: normal and potentially pathogenic organisms. Pediatrics 1978;62:57–62. 33. Draper DL, Donegan EA, James JF, Sweet RL, Brooks GF. Scanning electron microscopy of attachment of Neisserial gonorrhoeae colony phenotypes to surfaces of human genital epithelia. Am J Obstet Gynecol 1980;138:818–26. 34. Harrison HR, Costin M, Meder JB, et al. Cervical Chlamydia trachomatic infection in university women: relationships to history, contraception, ectopy, and cervicitis. Am J Obstet Gynecol 1985;153:244–51. 35. Jacobson DL, Peralta L, Farmer M, Graham N, Gaydos C, Zenilman J. Relationship of hormonal contraception and cervical ectopy as measured by computerized planimetry to chlamydial infection in adolescents. Sex Transm Dis 2000;27:313–19. 36. Singer A. The uterine cervix from adolescence to menopause. Br J Obstet Gynecol 1975;82:81–99. 37. Mooradian AD, Greiff V. Sexuality in older women. Arch Intern Med 1990;150:1033–38. 38. Mardh PA, Soltesz LV. In vitro interactions between lactobacilli and other microorganisms occurring in the vaginal flora. Scand J Infect Dis 1983;40(Suppl.):47–51. 39. Cohen M, Black JR, Proctor RA, Sparling PF. Host defenses and the vaginal mucosa: a re-evaluation. Scand J Urol Nephrol 1984;86(Suppl.):13–22. 40. Eschenbach DA, Thwin SS, Patton DL, et al. Influence of the normal menstrual cycle on vaginal tissue, discharge, and microflora. Clin Infect Dis 2000;30(6):901–97. 41. Patton DL, Thwin SS, Meier A, et al. Epithelial cell layer thickness and immune cell populations in the normal human vagina at different stages of the menstrual cycle. Am J Obstet Gynecol 2000;183(4):967–73. 42. Critchlow CW, Wolner-Hanssen P, Eschenbach DA, et al. Determinants of cervical ectopia and of cervicitis: age, oral contraception, specific cervical infection, smoking and douching. Am J Obstet Gynecol 1995;173:534–43. 43. Scwebke JR, Weiss H. Influence of the normal menstrual cycle on vaginal microflora. Clin Infect Dis 2001;32:325. 44. Miller L, Patton DL, Meier A, et al. Depomedroxyprogesteroneinduced hypoestrogenism and changes in vaginal flora and epithelium. Obstet Gynecol 2001;96:431–39. 45. Mahmoud EA, Hamad EE, Olsson SE, Mardh PA. Antichlamydial activity of cervical secretion in different phases of the menstrual cycle and influence of hormonal contraceptives. Contraception 1994;49(3):265–74.

46. Baeten JM, Nyange PM, Richardson BA, et al. Hormonal contraception and risk of sexually transmitted disease acquisition: results from a prospective study. Am J Obstet Gynecol 2001;185(2):380–85. 47. Louv WC, Austin H, Perlman J, Alexander WJ. Oral contraceptive use and the risk of chlamydial and gonococcal infections. Am J Obstet Gynecol 1989;160(2):396–402. 48. Morrison CS, Bright P, Wong EL, et al. Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections. Sex Transm Dis 2004;31(9):561–67. 49. Kleinschmidt I, Rees H, Delany S, et al. Injectable projestin contraceptive use and risk of HIV infection in a South African family planning cohort. Contraception 2007;75:461–67. 50. Moreno V, Bosch FX, Munoz N, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infections: the IARC multicentric case-control study. Lancet 2002;359:1085–92. 51. Berrington A, Jha P, Peto J, et al. Oral contraceptives and cervical cancer. Lancet 2002;360:410. 52. Hitti J, Watts DH, et al. Bacterial sexually transmitted infections in pregnancy. In: KK Holmes, PE Sparling, PA Mardh, eds. Sexually Transmitted Diseases, 4th ed. New York, NY: McGraw–Hill; 2008:1528–61. 53. Brunham RC, Martin DH, Hubbard TW, et al. Depression of the lymphocyte transformation response to microbial antigens and to phytohemagglutinin durng pregnancy. J Clin Invest 1983;72:1629–38. 54. Banura C, Franceschi S, Doorn LJ, et al. Infection with human papillomavirus and HIV among young women in Kampala, Uganda. J Infect Dis 2008;197(4):555–62. 55. Fife KH, Katz BP, Brizendine EJ, Brown DR. Cervical human papillomavirus deoxyribonucleic acid persists throughout pregnancy and decreases in the postpartum period. Am J Obstet Gynecol 1999;180(5):1110–14. 56. Hernandez-Giron C, Smith JS, Lorincz A, et al. High-risk human papillomavirus detection and related risk factors among pregnant and nonpregnant women in Mexico. Sex Transm Dis 2005;32(10):613–18. 57. Ziegler A, Kastner C, Chang-Claude J. Analysis of pregnancy and other factors on detection of human papilloma virus (HPV) infection using weighted estimating equations for follow-up data. Stat Med 2003;22(13):2217–33. 58. Nobbenhuis MA, Helmerhorst TJ, van den Brule AJ, et al. High-risk human papillomavirus clearance in pregnant women: trends for lower clearance during pregnancy with a catch-up postpartum. Br J Cancer 2002;87(1):75–80. 59. de Roda Husman AM, Walboomers JM, Hopman E, et al. HPV prevalence in cytomorphologically normal cervical scrapes of pregnant women as determined by PCR: the agerelated pattern. J Med Virol 1995;46(2):97–102. 60. Kemp EA, Hakenewerth AM, Laurent SL, Gravitt PE, Stoerker J. Human papillomavirus prevalence in pregnancy. Obstet Gynecol 1992;79(5):649–56. 61. Mostad SB, Kreiss JK, Ryncarz AJ, et al. Cervical shedding of herpes simplex virus in human immunodeficiency virusinfected women: effects of hormonal contraception, pregnancy, and vitamin A deficiency. J Infect Dis 2000;181(1):58–63. 62. Nafashima T. A high prevalence of chlamydial cervicitis in postmenopausal women. Am J Obstet Gynecol 1987;156:31–32.

C h a p t e r 4 6     Sexually Transmitted Infections in Men and Women l

63. Goldmeier D, Ridgway GL, Oriel JD. Chlamydial vulvoginitis in postmenopausal women. Lancet 1981;2: 476–77. 64. Peterman TA, Stoneburner RL, Allen JR, et al. Risk of human immunodeficiency virus transmission from heterosexual adults with transfusion-associated infections. JAMA 1988;259:55–58. 65. A.M. Rompalo, Gonorrhea. National Network of HIV/STD Prevention Training Centers. Core Curriculae August 2007. http://depts.washington.edu/nnptc/core_training/clinical/ index.html. 66. CDC, Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance, 2006. Atlanta, GA: US Department of Health and Human Services; 2007. 67. Barlow D, Phillips I. Gonorrhea in women: diagnostic, clinical and laboratory aspects. Lancet 1978;1:761–69. 68. Hook EW III, Handsfield HH, et al. Gonococcal infections in the adult. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 4th ed. New York, NY: McGraw–Hill; 2008:628–45. 69. Putkonen T, Ebeling K. Gonococci and the menstrual cycle. J Vener Dis Inf 1950;31(10):263–67. 70. CDC, Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2006. MMWR Morb Mortal Wkly Rep 2006;55(No.RR-11):38. 71. Datta SD, Sternberg M, Johnson RE, et al. Gonorrhea and chlamydia in the United States among persons 14 to 39 years of age, 1999 to 2002. Ann Intern Med 2007;147(2):89–96. 72. Miller WC, Ford CA, Morris M, et al. Prevalence of chlamydial and gonococcal infections among young adults in the United States. JAMA 2004;291(18):2229–36. 73. National Committee for Quality Assurance (NCQA). HEDIS 2000: Technical Specifications, Washington, DC;1999:68-70, 285-6. 74. Schachter J, Stephens RS, et al. Biology of Chlamydia trachomatis. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 4th ed. New York, NY: McGraw–Hill; 2008:555–74. 75. W.M. Geisler, Chlamydia. National Network of HIV/STD Prevention Training Centers. Core Curriculae August 2007. http://depts.washington.edu/nnptc/core_training/clinical/ index.html. 76. Stamm WE, et al. Chlamydia trachomatis infections of the adult. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 4th ed. New York, NY: McGraw–Hill; 2008:575–93. 77. Scholes D, Stergachis A, Heidrich FE, Andrilla H, Holmes KK, Stamm WE. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med 1996;34(21):1362–66. 78. Gottlieb SL, Pope V, Sternberg MR, et al. Prevalence of syphilis seroreactivity in the United States: data from the National Health and Nutrition Examination Surveys (NHANES) 2001– 2004. Sex Transm Dis 2008;35(5):507–11. 79. Sparling PF, Scwart MN, Musher Dm, Healy BP, et al. Clinical manifestation of syphilis. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 4th ed. New York, NY: McGraw–Hill; 2008:661–84. 80. Rompalo AM, Joesoef MR, O’Donnell JA, et al. Clinical manifestations of early syphilis by HIV status and gender:

81.

82.

83.

84.

85.

86.

87.

88. 89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

529

results of the syphilis and HV study. Sex Transm Dis 2001;28:156–65. G.A. Bolan, Syphilis. National Network of HIV/STD Prevention Training Centers. Core Curriculae 2003. http:// depts.washington.edu/nnptc/core_training/clinical/index.html. Tramont EC. Treponema pallidum (Syphilis). In: GL Mandell, JE Bennett, R Dolin, eds. Principles and Practices of Infectious Diseases, 6th ed. Philadelphia, PA: Elsevier; 2005:2768–84. C.L. Heaton, Chancroid. National Network of HIV/STD Prevention Training Centers. Core Curriculae 2003. http:// depts.washington.edu/nnptc/core_training/clinical/index.html. Allsworth JE, Lewis VA, Peipert JF. Viral sexually transmitted infections and bacterial vaginosis: 2001–2004 national health and nutrition examination survey data. Sex Transm Dis 2008 Jul 2, Epub ahead of print. Svare EI, Kjaer SK, Worm AM, et al. Risk factors for genital HPV DNA in men resemble those found in women: a study of male attendees at a Danish STD clinic. Sex Transm Infect 2002;78:215–18. Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 2006;354(25):2645–54. Hernandez BY, Wilkens LR, Zhu X, et al. Transmission of human papillomavirus in heterosexual couples. Emerg Infect Dis 2008;14(6):888–94. www.cdc.gov/std/hvp. (Accessed 2008.) American Academy of Pediatrics, Committee on Infectious Diseases. Prevention of human papillomavirus infections: provisional recommendations for immunization of girls and women with quadrivalent human papillomavirus vaccine. Pediatrics 2007;120:666–68. Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007;56:1–23. Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006;296(8):964–73. Corey L, Wald A, et al. Genital herpes. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 4th ed. New York: McGraw–Hill; 2008:399–437. Benedetti JK, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994;121:847–54. Wang CC, McClelland RS, Overbaugh J, et al. The effect of hormonal contraception on genital tract shedding of HIV-1. AIDS 2004;18:205–9. Baeten JM, Benki S, Chohan V, et al. Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women. AIDS 2007;21: 1771–77. Stanberry LR, Spruance SL, Cunningham AL, et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med 2002;347:1652–61. Brown ZA, Gardella C, Wald A, Morrow RA, Corey L. Genital herpes complicating pregnancy. Obstet Gynecol 2005;106(4):845–56. Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol 2007;31(1):19–25.

530

s e c t i o n 8     Infectious Disease l

99. ACOG practice bulletin. Management of herpes in pregnancy. Number 8 October 1999. Clinical management guidelines for obstetrician-gynecologists. Int. J. Gynecol. Obstet. 68 (2) (2000) 165–173. 100. Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev 2008(1), CD004946.. 101. Cotch MF, Pastorek JG 2nd, Nugent RP, et al. Trichomonas vaginalis associated with low birth weight and preterm delivery. The Vaginal Infections and Prematurity Study Group. Sex Transm Dis 1997;24:353–60. 102. Soper DE, Bump RC, Hurt WG. Bacterial vaginosis and trichomoniasis vaginitis are risk factors for cuff cellulitis after abdominal hysterectomy. AmJ Obstet Gynecol 1990;163:1016–21. 103. Minkoff H, Grunebaum AN, Schwarz RH, et al. Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy. Am J Obstet Gynecol 1984;150:965–72. 104. Moodley P, Wilkinson D, Connolly C, Moodley J, Sturm AW. Trichomonas vaginalis is associated with pelvic inflammatory disease in women infected with human immunodeficiency virus. Clin Infect Dis 2002;34:519–22. 105. Sherman KJ, Chow WH, Daling JR, Weiss NS. Sexually transmitted diseases and the risk of tubal pregnancy. J Reprod Med 1988;33:30–34. 106. Grodstein F, Goldman MB, Cramer DW. Relation of tubal infertility to history of sexually transmitted diseases. Am J Epidemiol 1993;137:577–84. 107. Miller M, Liao Y, Gomez AM, Gaydos CA, D’Mellow D. Prevalence and incidence of Trichomonas vaginalis infection among African American women in New York City who use drugs: associations and coinfections. J Infect Dis 2008;197:503–9. 108. Van Der Pol B, Kwok C, Pierre-Louis B, et al. Trichomonas vaginalis infection and human immunodeficiency virus acquisition in African women. J Infect Dis 2008;197:548–54.

109. Van Der Pol B, Williams JA, Orr DP, et al. Prevalence, incidence, natural history, and response to treatment of Trichomonas vaginalis infection among adolescent women. J Infect Dis 2005;192:2039–44. 110. Krieger JN. Trichomoniasis in men: old questions and new data. Sex Transm Dis 1995;22:83–96. 111. Gaydos CA. Rapid tests for sexually transmitted diseases. Curr Infect Dis Rep 2006;8:115–24. 112. Toney JF. Pelvic Inflammatory Disease: National Network of HIV/STD Prevention Training Centers; 2002, Core Curriculaehttp://depts.washington.edu/nnptc/core_training/ clinical/index.html. 113. Paavonen J, Westrom L, Eschenbach DA, et al. Pelvic inflammatory disease. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 4th ed. New York, NY: McGraw–Hill; 2008:1018–50. 114. Mardh PA. An overview of infectious agents of salpingitis, their biology and recent advances in methods of detection. Am J Obstet Gynecol 1980;138:933–51. 115. Hebb JK, Cohen CR, Astete SG, Bukusi EA, Totten PA. Detection of novel organisms associated with salpingitis, by use of 16S rDNA polymerase chain reaction. J Infect Dis 2004;190:2109–20. 116. Westrom L. Effect of pelvic inflammatory disease on fertility. Am J Obstet Gynecol 1975;121:707–13. 117. Tracy CR, Steers WD, Costabile R. Diagnosis and management of epididymitis. Urol Clin North Am 2008;35:101–10. 118. Mittemeyer BT, Lennox KW, Borski AA. Epididymitis: a review of 610 cases. J Urol 1966;95:390–92. 119. Berger RE, Alexander ER, Harnisch JP, et al. Etiology, manifestations, and therapy of acute epididymitis: prospective study of 50 cases. J Urol 1979;121:750–54. 120. Geisler WM, Krieger JN, et al. Epididymitis. In: KK Holmes, PF Sparling, WE Stamm, eds. Sexually Transmitted Diseases, 4th ed. New York, NY: McGraw–Hill; 2008:1127–46.

Chapter

47

Infections in Pregnancy Emilia Mia Sordillo1, and Bruce Polsky2 1 Attending, Medicine and Pathology, Medical Director, Microbiology, and Molecular Diagnostics, St Luke’s–Roosevelt Hospital Center, Department of Clinical Pathology; Associate Professor of Clinical Medicine and Clinical Pathology and Cell Biology. College of Physicians and Surgeons, Columbia University, New York, NY, USA 2 St Luke’s–Roosevelt Hospital Center, Department of Medicine, and Chief, Division of Infectious Diseases, New York, NY, USA

Introduction and significance

other organisms associated with ­chorioamnionitis may cause stillbirth in up to 15% of ­pregnancies overall, with the greatest risk earlier in pregnancy. Among stillbirths at less than 28 weeks gestation, infection was estimated to be the cause in 19%, in comparison with 8% for stillbirths between 28 and 36 weeks, and 2% for stillbirths at more than 37 weeks.7 In the United States fetal mortality rates for less than 28 weeks gestation, the period most likely to be associated with infection, have not declined since 1990, and the 2003 rate (3.21/1000 live births  fetal deaths) was even greater than the 1985 rate (2.01/1000). Black women were at the highest risk. The highest rate, 13.9/1000 live births plus fetal deaths, occurred in black women.8 Globally, the World Health Organization estimates that perinatally acquired infection is responsible for more than 25% of deaths in newborns.9

Maternal and infant morbidity and mortality are obvious consequences of many intrapartum and peripartum infections, but even infections that produce few observable maternal symptoms can dramatically affect fetal intra-uterine growth and development. Despite advances in peripartum care, maternal morbidity and mortality associated with infections in pregnancy are increasing even in developed countries. Recently published data1,2 from the Center for Disease Control’s Pregnancy Mortality Surveillance System indicates that although maternal mortality from hemorrhage, embolism, and anesthesia has declined in the United States, the proportion of maternal deaths due to infections has increased. During 1991–7 infection accounted for 13.2% of pregnancy-related deaths overall and 36.3% of abortion-related deaths. The greatest infection risk is found in blacks, older women, women without prenatal care,1 and women with multiple pregnancy.2 In the United States pregnancy rates are stable or increasing in these groups.3 Infection is also a major cause of morbidity and mortality for the fetus and newborn. Many perinatal infections are associated with intra-uterine growth retardation and low birthweight, or cause fetal and neonatal brain injury.4 Infections, particularly bacterial vaginosis and chorioamnionitis, can result in preterm delivery of live-born infants (delivery before 37 weeks gestation), or stillbirth. Evidence of intra-uterine infection has been reported in up to 70% of spontaneous births occurring at less than 30 weeks gestation, and 30–40% after that time.5 Notably, the rate of preterm birth in developed countries is rising, and in the United States increased from 9.5% in 1981, to 12.7% in 2005.6 In developed countries, infections due to Treponema pallidum (syphilis), Toxoplasma gondii, Listeria monocytogenes, parvovirus B19, HIV, group B streptococcus, Mycoplasma spp., Ureaplasma urealyticum, Chlamydia trachomatis, and Principles of Gender-Specific Medicine

Mechanisms of increased susceptibility to infection in pregnancy A multitude of immunologic, endocrinologic, metabolic, physiologic, and anatomic changes influence the likelihood and course of many infections during pregnancy. Some of these changes are intrinsic, and occur in all normal pregnancies, while others occur to varying degrees in normal and abnormal pregnancies.

Changes in Immune Function Changes in the immune response to infection are an inadvertent byproduct of the alterations in maternal immune function that are essential in order to initiate and sustain pregnancy. In a normal pregnancy, the maternal immune system must allow implantation and subsequent ­development of a fetal ‘hemi-allograft’. When evaluating 531

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changes in immune response during pregnancy, there are two ­important caveats: first, that systemic changes reflected in the peripheral blood are not completely representative of the dominant local changes at the maternal–fetal interface; and, second, that immune function is dynamic, and can vary during the course of pregnancy. In particular, changes in the placenta reflect this variation. ‘Type 1’ to ‘Type 2’ Shift The current concept of a ‘type 1’ to ‘type 2’ shift in maternal immune function during pregnancy is based on a model of changes in T-helper lymphocyte function initially proposed by Wegmann and colleagues, and subsequently modified to include more recently recognized facets of the immune response (Table 47.1). Examples of infections for which ‘type 1’ immunity has been shown to be protective include leishmaniasis, salmonellosis, listeriosis, mycobacterial infections, and infections with fungal ­organisms such as Candida, Coccidioides, Cryptococcus, and Aspergillus. Certain bacteria, such as Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus agalactiae (group B streptococcus), and Streptococcus pyogenes (Group A streptococcus), also engender a primarily ‘type 1’ response.10 Wegmann and coworkers hypothesized that functional maternal immunosuppression in pregnancy was the consequence of a shift from a T-helper 1 (Th1, IFN--secreting cell) to a T-helper 2 (Th2, Interleukin-4–IL-4–secreting cell)- response.11 The basis for this hypothesis included clinical observations, for example, changes in severity of some

immune-mediated conditions during pregnancy, such as improvement of rheumatoid arthritis but worsening of systemic lupus erythematosis, and findings in women with recurrent miscarriage, and evidence from studies of pregnancy in inbred mice. Subsequently, secretion of the Th1-cytokine, IFN-, has been shown to promote phagocytosis and killing of intracellular pathogens, while IL-4 and related Th2cell-produced cytokines such as IL-10 and IL-13 stimulate B cell proliferation, class switching, and antibody production. Thus, a shift from a Th1- to a Th2-dominant immune response correlates with increased susceptibility to viral and other intracellular pathogens such as Listeria monocytogenes, Mycobacterium tuberculosis, Toxoplasma gondii, and Leishmania, as well as the increased antibody production and physiologic hypergammaglobulinemia seen in pregnancy.10 However, findings in normal early human pregnancy indicate there is also a generalized inflammatory response that appears necessary for successful implantation. Leukocytosis, increased monocyte priming and phagocytosis, production of the proinflammatory cytokines IL-6 and TNF, and increased C-reactive protein are observed.12 Endotoxin receptors are increased.13 These findings are consistent with activation of the innate immune response, and contribute to the intact response to most extracellular bacteria, but increased susceptibility to endotoxin and Gram-negative sepsis observed in pregnancy. The current understanding of immune responses in pregnancy also incorporates more recently recognized regulatory T cell subpopulations such as Th3, Tr1, and Treg cells,14,15

Table 47.1  ‘Type 1’ to ‘Type 2’ shift in pregnancy Cell type

Manifestations

Effect

T cells

↓ Th1 (IFN--producing)

Suppression

↑ Th2 (IL-4-producing) ↑ Treg NK cells

Peripheral blood

Suppression

↓ IFN-, cytotoxic activity ↓ ‘type 1’(decreased IL-18R  NK cells) ↑ ‘type 2’(increased ST2L  NK cells) Uterus ↑ NK3 cells (TGF-producing) Monocytes

↑ Numbers, phagocytosis, respiratory burst

‘Alternative’ activation

↑ CD14 endotoxin receptor expression ↑ IL-12 secretion Granulocytes

↑ Numbers, phagocytosis, respiratory burst

Activation

Dendritic cells

↓ CD86, HLA-DR expression

Suppression

↓ IL-12 production ↑ IL-10 production

C h a p t e r 4 7     Infections in Pregnancy l

and the regulatory role of cells of the innate immune ­system, such as monocytes,13 NK cells,12,15 and dendritic cells.16 Treg cells, which can inhibit allograft rejection, antitumor response, and contribute to persistence of intracellular pathogens such as Leishmania, express the CD25 cell marker. The number of circulating maternal Tregs increases throughout pregnancy, then slowly declines postpartum. Increased numbers of CD4  CD25  Treg cells are found in human maternal decidua, possibly in response to increased progesterone or other pregnancy hormones.14 Changes in the NK cell population also occur early, by the 12th week of pregnancy, and much earlier than the Th2 shift, which is more apparent in the third trimester. The ‘type 1 to type 2 shift’ in the NK cell population is evidenced by changes in cell markers including decreased IL-18 receptor expression, increased ST2L expression, and by decreased IFN- production;12 the type 2, IL-10–producing but IFN-nonproducing ‘NK2’ cells are increased.15 A regulatory NK cell population important for allograft tolerance has recently been described, and there appears to be a similar role for regulatory NK cells in protecting the fetus. A unique, immunosuppressive population of regulatory NK cells has been reported in the uterus of pregnant women. These cells are recruited to the endometrium from the peripheral blood, and proliferate and differentiate to TGF--producing, immunosuppressive NK3 cells in the decidual microenvironment. These cells have an inhibitory receptor that recognizes placentally expressed class I antigens such as HLA-C, HLA-G, and HLA-E, to inhibit maternal NK cell activity.15 A shift in pregnancy to favor ‘type 2’ responses can also be demonstrated in circulating dendritic cells, and in monocytes and granulocytes. In pregnancy, CD86, HLA-DR dendritic cells are decreased in the third trimester, and are biased to secrete IL-10 rather than IL-12, favoring a Th2 phenotype.16 Monocytes and granulocytes, which are the primary effector cells of the innate immune system, increase in number beginning in the first trimester, and have an activated phenotype, as demonstrated in vitro by enhanced phagocytosis and respiratory burst activity. Monocyte expression of the endotoxin receptor CD14 is increased, as is the endotoxin-induced production of IL12.13 In late gestation, monocytes and granulocytes concentrate in the decidua, and increase production of cytokines. Cytokine expression is further increased in labor, and may act to promote labor. The underlying activation of granulocytes and monocytes, and their potential enhanced cytokine response to microbial pathogens, may explain the association between infection and preterm birth. In a ‘type 2’ cytokine environment, monocyte activation is shifted from a ‘classical’ to an ‘alternative’ activation pattern When exposed to the type 2 cytokines IL-4, IL-10, and TGF-, monocytes express receptors with broad specificity for foreign antigens, such as macrophage mannose receptor, resulting in increased endocytosis and antigen presentation. By contrast, functions enhanced by ­exposure to type 1

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Table 47.2  Immunomodulating factors produced by the placenta Cell receptors/antigens  

 class I HLA-antigens, primarily HLA-G, but also HLA-C, HLA-E, HLA-F   l soluble HLA-G isoforms, primarily HLA-G5 and HLA-G6   l  Toll-like receptors (TLRs) l

Cytokines      

  IL-10   IL-4 l  Macrophage colony-stimulating factor (M-CSF)   l  Vascular endothelial growth factor (VEGF)   l  IFN-   l  Transforming growth factor-beta (TGF) l l

Hormones        

  Progesterone   Estradiol l  Corticotrophin releasing hormone l  Human placental lactogen l l

Syncytiotrophoblast debris/microparticles

cytokines such as nitric oxide production, cytotoxicity and lysis of microorganisms, are reduced.18 ‘Alternatively-activated’ monocytes can further promote the ‘type 2’ environment by inducing differentiation of naïve T cells into Th2 cells. Immune Modulation by the Placenta Development of the placenta occurs concurrently with changes in the immune response, and the placenta plays a role as an immune-modulating organ. As the placenta ­develops, it changes not only structurally, but also in expression of glycoproteins, cytokines, and hormones, with related local and systemic effects on immune function (Table 47.2). Early in pregnancy, local effects predominate. One important feature of the placenta is its expression of unique class I HLA-antigens, primarily HLA-G, but also HLA-C, HLA-E, and HLA-F; the placenta does not produce HLA-A, HLA-B or HLA-D. HLA-G expression by trophoblast cells can be activated by IL-10, which also downregulates expression of the classical class I and II HLA antigens. HLA-G interacts with uterine macrophages and NK cells to stimulate local production of angiogenic factors and cytokines including IFN-, and is immunosuppressive to CD8 and CD4 T cells.12 The trophoblast also secretes the soluble isoforms HLA-G5 and HLA-G6, which can be detected in amniotic fluid and serum from women in all three trimesters.19 These soluble isoforms have been shown to inhibit NK cell and CD8 T cell-mediated lysis and to suppress CD4 T cell proliferation in vitro (reviewed by Carosella20,21). HLA-G may also play a role in presentation

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of viral antigens.22 It is noteworthy that Herpes simplex virus and human cytomegalovirus can disrupt placental HLA-G expression.22,23 The placenta produces a number of cytokines that have local immunomodulatory effects, and can also enter the maternal circulation. These cytokines include the immunosuppressive, Th2-enhancing cytokines IL-424 and IL10,25 plus TGF-,26,27 which enhances generation of Tregs and alternative activation of monocytes. TGF-1 has been found in amniotic fluid, and at increased levels in the blood of women between 21 and 36 weeks gestation.28 Placentally produced cytokines that support monocyte activation include macrophage colony-stimulating factor, vascular endothelial growth factor, and pregnancy-specific glycoproteins such as PSG1a.29 Later in pregnancy, increased placental production of progesterone, estradiol, corticotrophin-releasing hormone, human placental lactogen, and other pregnancy-related hormones further contributes to the systemic Th1 to Th2 shift and to enhancement of the monocyte response (reviewed in Sacks13). The placenta also sheds syncytiothrophoblast debris, including subcellular microparticles that are released into the maternal circulation. In co-culture experiments, these microparticles stimulate PBMCs through monocyte and dendritic cell uptake, resulting in production of TNF and IL-12, but minimal IL-18 or IFN-, and promoting the type 2 bias.12 Pregnancy-associated tissues, such as amniotic epithelial cells, decidual inflammatory cells, and placenta express toll-like receptors (TLRs), particularly TLR2, TLR4,30 and TLR3.31 The TLRs are pattern-recognition receptors that recognize repeating sequences on the surface of microorganisms. Expression of TLRs is inhibited by estrogen and enhanced by higher progesterone levels. Some evidence suggests that TLR2 expression is altered in placental samples in acute chorioamnionitis.32 In cultures of cells derived from normal first-trimester trophoblast, cross-linking of TLR4 promotes cytokine expression, but ligation of TLR2 results in apoptotic cell death. One interpretation is that stimulation through TLRs could be a way in which intra-uterine infections lead to preterm labor, intra-uterine growth retardation, spontaneous abortion, and preeclampsia.33 However, data regarding the role of these receptors in the context of pregnancy are still limited.

Endocrinologic and Metabolic Changes Steroid Hormones In pregnancy, increased levels of the steroid hormones cortisol, estrogen, and, in particular, progesterone, are found locally in the uterus and placenta and in the circulation.34 These pregnancy-associated steroids modulate the generation, survival, and activity of various immune cells. Most of the available data come from murine models. In mice, pregnancy steroids induce thymic involution, marked by shrinkage of the cortex with loss of CD4  CD8 cells,

and concurrent expansion of the medulla with production of Th2 cells (reviewed by Clarke and Kendall35). Progesterone has a major influence on lymphocyte production, acting through intracellular receptors in thymic epithelium,36 and by downregulating production of B cells in the bone marrow.37 Steroid hormones also decrease the number of ­circulating lymphocytes by inducing apoptotic cell death. Although there is limited direct evidence from human pregnancy, similar effects have been described in many other animals, suggesting these mechanisms are conserved.38 Glucocorticoids and progesterone influence the function of T lymphocytes by stimulating IL-4 and IL-10, but suppressing IFN- and IL-12 production.39,40 In vitro, progesterone can influence even established Th1 clones to shift to produce Th2 cytokines.41 Progesterone also acts indirectly by stimulation of progesterone-responsive tissues to produce P-induced blocking factor (PIBF), which induces production of the Th2 cytokines, leukemia inhibitory factor, and MCSF, increases B cell antibody production, suppresses NK function, inhibits cytotoxicity by blocking degranulation and perforin release, and inhibits transformation into lymphocyteactivated killer cells.42,43 Progesterone acts on the uterus to enhance homing of NK cells, and upregulates placental expression of HLA-G and TLRs.33 Estrogens contribute to modulation of the immune response by stimulating proliferation of a different cell population, the CD4  CD25 Treg cells.44 The steroid hormones also promote alternative activation of monocytes, and the shift towards antigen presentation and immune tolerance.18 The impact of the changes in immune response due to progesterone and estrogen has been shown in several models. Pregnancy-related sex steroids have been shown to influence susceptibility to infection with Listeria monocytogenes and Toxoplasma gondii (reviewed by Roberts et al.45). In rodent models, higher estrogen levels or estrogen treatment increased susceptibility to Neisseria gonorrhoeae, Mycoplasma hominis, and Ureaplasma urealyticum.46,47 In mice, progesterone administration increases mortality from infection with herpes simplex virus type 2 (HSV-2). In rats, progesterone treatment before infection with Chlamydia trachomatis increases susceptibility to uterine infection, and prevents clearance of the organism resulting in a persistent infection; concurrent estrogen treatment limited the degree of inflammatory response.48 Other Pregnancy-Related Hormones In addition to steroid hormones, a number of placental products including corticotrophin-releasing hormone, human chorionic gonadotropin, and human placental lactogen can also suppress lymphocyte function, and activate monocytes.13 Prolactin, which increases during pregnancy, helps suppress cell-mediated immunity, augments B cell function and survival, in part through modulation of Th2 cytokines, and helps to mediate the effects of estrogen.49 A relationship between prolactin levels and susceptibility to parasitic infections, particularly malaria, has been proposed.

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Diabetes Mellitus Diabetes mellitus (DM) in pregnancy may be pre-existing, either insulin-dependent (0.5%) or non-insulin dependent (2%), or may be gestational (3–6%) and a consequence of the pregnancy itself. Non-insulin-dependent and gestational diabetes both occur with greater frequency in non-whites.50 Underlying hepatitis B infection has been reported as a risk for development of gestational DM even in women with low weight and body mass.51 In pregnancy, circulating insulin antagonists including cortisol, prolactin, human placental lactogen, and leptin contribute to increased insulin resistance, with worsening of preexisting diabetes. Medical complications including infection are more frequent in pregnant women with diabetes, although most risk occurs in women with preexisting diabetes.52 Overall, there is a four-fold increased risk of infection pre-and post-partum in insulin-dependent diabetic pregnant women.53 Examples of increased risk include colonization and infection with group B streptococcus and post-cesarean wound infections.54,55 Unfortunately, the older literature does not always clearly distinguish between risk for pregnant women with preexisting DM and risk in women without DM prior to pregnancy, and increased risk cannot always be extrapolated for gestational diabetes. For example, solely gestational DM may not represent an increased risk for perinatal infection with group B streptococcus.56 By contrast, the risk of urinary tract infection, particularly due to Gram-positive organisms, is increased in pregnant women with both preexisting and gestational DM. The frequency of urinary tract infections is decreased by good glucose control.57 The risk of periodontal disease is also increased in all diabetic pregnant women, with a rate of 4.8% to 9.0% in gestational diabetes, and an even higher prevalence of 30.5% in women with preexisting diabetes.58

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and Porphyromonas gingivalis. As a consequence of these changes, pregnant women are more likely to develop gingivitis. Although the mechanism has not been elucidated, maternal peridontitis has been associated with preterm birth and low birthweight. The level of risk correlates with the severity of the periodontal disease (reviewed by Krejci61).

Anatomic Changes Some of the anatomic changes that occur during pregnancy are associated with altered risk of infection. Most prominent among these are changes in the urinary tract and the development of pregnancy-specific tissues such as the placenta.

Uterine Decidual and Syncytiotrophoblast Production of IDO The amino acid tryptophan appears to be an important proliferation signal for T lymphocytes. Tryptophan is metabolized by the enzyme indoleamine 2,3-dioxygenase (IDO). Increased IDO activity causes a local decrease in tryptophan, and a local suppression of Th1 activity. IDO is produced by tissue macrophages in response to IFN-, by dendritic cells in response to stimulation by Treg cells,59 and by the decidua and the fetal syncytiotrophoblast.60

Urinary Tract Asymptomatic bacteriuria occurs in 4–6% of both pregnant and non-pregnant women, but pregnancy-associated anatomic, functional, and hormonal changes in the urinary tract (Table 47.3) increase infection risk.62–64 Many assessments of risk have used 100 000 colony forming units (CFU)/ml as the definition of bacteriuria for midstream urine specimens collected from asymptomatic patients; lower counts may be significant in patients with symptoms, or if urine is collected by catheterization, or for Gram-positive bacteria or yeast. Glucosuria, increased urine pH due to bicarbonate excretion, stasis due to bladder muscle relaxation, and increased bladder volume encourage bacterial growth in the urine. In pregnancy, the risk of cystitis is 30–60% in women with asymptomatic bacteriuria when colony counts are 100 000 CFU/ml. After 20 weeks gestation, pyelonephritis is a common complication of UTI due to ureteral obstruction and urinary stasis. Dilatation of the ureters in response to hormonal changes such as increased progesterone, or possibly to estrogen or relaxin, is apparent in some women as early as the 7th week of gestation. Hormonal factors also cause decreased ureteral peristalsis, which may progress to intermittent atony in later pregnancy. Additional mechanical dilation of the ureters occurs in mid- and late pregnancy due to the enlarging uterus. The dilated ureters may contain over 200 ml of urine.62 Dextro-rotation of the uterus places the right kidney at greater risk.63 The vast majority of UTI are caused by Escherichia coli, although Gram-positive pathogens are increased in women with DM. Treatment of asymptomatic bacteriuria decreases the risk of subsequent pyelonephritis to 1–4%.65

Gingival Hyperplasia In pregnancy, increased estrogen, progesterone, and chorionic gonadotropin cause swelling of endothelial cells and pericytes in the gingival microvasculature, causing the gums to become soft, swollen, and hyperemic. Concurrently, there is a marked increase in the proportion of anaerobic species, particularly Bacteroides melanogenicus, Prevotella ­ intermedia,

Respiratory System Pregnancy causes a progressive decrease in the expiratory reserve volume and residual volume, and thus the functional reserve capacity and total lung capacity. Although these changes are not thought to increase the risk of contracting pneumonia, a decreased respiratory reserve increases the risk of respiratory failure and complications for mother and

Physiologic Changes

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Table 47.3  Anatomic and functional changes in the urinary tract and infection risk Kidney

Renal calyces and ureters

Bladder

Alteration

Consequence

↑ GFR

↑ Excretion of protein, amino acids, glucose

↑ Renal plasma flow

↑ Urine output

Glucosuria

May ↑ bacteriuria and UTI

↑ Bicarbonate wasting

Compensatory respiratory alkalosis, may ↓ buffering capacity

Progesterone-related dilation

Physiologic hydronephrosis and hydroureter in 80%, R  L

Ureteral muscle relaxation

↓ Peristalsis

Compression by the enlarging uterus

Postural urine flow in late pregnancy, ↑ susceptibility to pyelonephritis

Smooth muscle relaxation, bladder atony

Urinary stasis and ↑ UTI risk

Compression by the enlarging uterus

↑ bladder pressure,↑ vesicoureteral reflux and ↑ susceptibility to pyelonephritis

fetus.66 Respiratory compromise from pneumonia decreases the maternal ability to meet the increased oxygen requirements needed to support a fetus. Additionally, the increased minute ventilation in pregnancy leads to a decreased PaCO2 with a compensatory decreased serum bicarbonate (compensated respiratory alkalosis). As a consequence, even slight CO2 retention is poorly tolerated, and may contribute to increased maternal morbidity and mortality from pneumonia, particularly during the third trimester.67 In addition, the compensatory decrease in serum bicarbonate increases vulnerability to metabolic acidosis from sepsis or other causes. Pneumonia caused by viral pathogens, particularly varicella, influenza, measles, and the coronavirus associated with severe acute respiratory syndrome (SARS), and by Coccidioides immitis, are associated with more severe outcomes in pregnant women. Bronchitis-­bronchiolitis and pneumonia are also associated with a higher rate of preterm birth.68 In the third trimester, relaxation of the gastroesophageal sphincter, delayed gastric emptying, and increased intra-abdominal pressure increases the risk of aspiration and aspiration-related pneumonia. Placenta and other Pregnancy-Associated Tissues The presence of the placenta and other pregnancy­associated tissues is a risk for certain infections, such as choriamnionitis, and for other infections associated with the puerperal period. The placenta can also be a focus of infection because of specific organism tropism, best described for Plasmodium falciparum malaria. When P. falciparum infection occurs in pregnancy, the parasite expresses specific proteins that mediate the binding of infected erythrocytes to chondroitin sulfate A produced by the placenta. Large numbers of parasitized erythrocytes can be sequestered in the placenta.

The placenta may also serve as a nidus for infection in listeriosis. Evidence from a guinea pig model indicates that, once infected, the placenta serves as a source for reseeding other maternal organs. In mammals, L. monocytogenes infection may be difficult to clear until the placenta is expelled.69

Infections for which pregnancy alters maternal susceptibility or course Some infections occurring during pregnancy primarily have consequences for the mother, and only secondarily affect the fetus. These infections are unlikely to be transmitted to the fetus, and if promptly treated do not increase the likelihood of adverse outcome for the infant. Other pregnancyassociated infections that mostly affect the mother are those that occur during the puerperium, the period including labor and the following six weeks, and are a direct consequence of the birth process or its management.

Urinary Tract Infection Cystitis occurs in 1–2 % of pregnancies. Although anatomic and physiologic changes increase the risk of urinary tract infection (UTI) in pregnant women, the major factor influencing the likelihood of infection is the presence of asymptomatic bacteriuria early in pregnancy. Other underlying conditions that concurrently increase the risk for UTI include insulin-dependent and non-insulin-­dependent diabetes mellitus, the acquired immunodeficiency syndrome, and previous urologic abnormalities. Other reported risk factors include a history of previous UTI or

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sickle cell ­ hemoglobinopathy (early pregnancy) and lower ­socioeconomic and educational status, previous Chlamydial infection, and illicit drug use (after 20 weeks gestation).62,70 As in non-pregnant women, most UTIs are caused by gut flora, generally the Enterobactericeae and particularly E. coli, although Gram-positive pathogens are increased in women with DM. Treatment of asymptomatic bacteriuria dramatically decreases the risk of infection, and screening of women at 12–16 weeks gestation with a urine culture is recommended. The value of repeated screening is unknown, but the risk of UTI and pyelonephritis are reportedly very low in women with a negative initial culture. In women with a positive culture, the current recommendations are to treat even in the absence of symptoms. Although single dose therapy has been used, with the exception of single dose fosfomycin, treatment for 3–7 days is more effective. After treatment, pregnant women should be screened periodically for recurrent bacteriuria.71 The reported sensitivity of leukocyte esterase/nitrate dipsticks is very variable (50–92%) even in large studies,72 suggesting that in this known high risk group screening by urine culture is preferable. A similar regimen and followup is recommended for women with bacteriuria who also have symptoms of cystitis such as frequency, urgency, and dysuria. Antibiotics recommended for treatment of UTI that are considered safe for use in pregnancy are listed in Table 47.4. Because of increasing resistance, treatment should be modified based on susceptibility results unless the bacteriuria has cleared with empiric therapy. Women with recurrent UTI may benefit from a single postcoital antibiotic dose, or may require daily suppression with nitrofurantoin or cephalexin. If group B streptococci are isolated, intrapartum penicillin prophylaxis is required even if the patient is screen negative at a later date. Short-term antibiotic therapy is unlikely to have adverse effects on the fetus. Nitrofurantoin has been associated with hemolytic anemia in G-6-PD deficient women, and rarely with pneumonitis. Sulfonamides may be associated with hyperbilirubinemia, but this is unlikely to be significant during a short course of treatment. Acute pyelonephritis follows UTI or asymptomatic bacteriuria in up to 25% of pregnant patients if untreated. Pyelonephritis is more likely in the second and third trimesters, but over 20% of cases occur in the first trimester.73 Symptoms include fever and flank tenderness, often accompanied by rigors, nausea, vomiting, and costovertebral angle pain and tenderness, usually associated with pyuria. In pregnant women, pyelonephritis may be complicated by preterm labor, septic shock or acute respiratory distress syndrome,70 possibly reflecting an increased sensitivity to endotoxin in pregnancy. Pulmonary injury is most likely to occur in sicker patients who have tachycardia and high fever, in cases of fluid overload, or when beta-agonists are given for tocolysis.74 In a recent prospective series, pulmonary insufficiency occurred in 7% of pregnant women with

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Table 47.4  Antibiotic regimens for treatment of asymptomatic bacteriuria and UTI in pregnancy Antimicrobial Asymptomatic bacteriuria and cystitis

Amoxicillin 500 mg orally three times/day

Ampicillin 250 mg orally four times/day Cephalothin or cephalexin 250 mg orally four times/day Fosfomycin one 3 g sachet orally Nitrofurantoin 100 mg orally twice/day Trimethoprim/sulfamethoxazole 160/800 mg orally twice/day Pyelonephritis

Ampicillin 2 g intravenously every 6 h Plus gentamicin 5–7 mg/kg intravenously once daily Cefazolin 1–2 g intravenously every 8 h Cefotaxime 1–2 g intravenously every 8 h Ceftriaxone 1–2 g intravenously once daily Ceftazidime 1–2 g intravenously every 8 h

Other agents

Amoxicillin/clavulanate 500  mg orally every 8 h Aztreonam 1–2 g intravenously every 6–8 h

pyelonephritis.73 In general, pregnant women with pyelonephritis should be hospitalized for initial management, and monitored for development of these complications. Initial treatment should include intravenous antimicrobials and careful intravenous hydration, with modification of ­therapy based on culture results. Suggested initial regimens are listed in Table 47.4. Over 70% of infections are caused by E. coli. Gram-positive organisms, particularly group B streptococcus increase in importance in later pregnancy, and in some series cause more than 10% of infections in later pregnancy.73 Penicillin, ampicillin or amoxicillin should be used for treatment of infections caused by group B streptococci. Group B streptococci remain susceptible to penicillin, and testing is not needed except in cases of penicillin allergy, when susceptibility to clindamycin and erythromycin should be determined. By contrast, resistance in Gramnegative organisms is increasing, particularly to ­ampicillin and trimethoprim/sulfamethoxazole. A review of 3871 urine culture isolates from women aged 16–45 years collected from July 2005 through June 2008 in our Hospital Center indicated that 90% of enterococcal isolates were susceptible to ampicillin, and 84% of S. aureus isolates were methicillin-susceptible. By contrast, susceptibility of E. coli was only 53% to ampicillin, 70% to cephalothin and

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trimethoprim/sulfamethoxazole, and 96% to nitrofurantoin. As might be expected, resistance in all cases was higher in isolates from women aged 31–45 years than from women aged 16–30 years. Of note, susceptibility to amoxicillin/clavulanate and intravenous antimicrobials commonly used in pregnancy was high (Table 47.5). Susceptibilities of isolates collected specifically from patients in obstetrics/gynecology locations were similar to those for isolates from all women aged 16–45 years, with the exception that enterococcal isolates were 100% ampicillin-susceptible, and E. coli isolates were 100% susceptible to nitrofurantoin. Because GFR is increased by 30–50% in pregnancy, doses of some drugs such as aminoglycosides and ceftriaxone must be adjusted accordingly;75 for aminoglycosides, serum drug levels are helpful. Other agents, such as cefazolin, do not require dose adjustment. Nitrofurantoin should not be used in pyelonephritis, as it has limited parenchymal penetration. Once afebrile, if oral intake is good and there is no diarrhea, treatment may be changed to oral antibiotics to complete a 10–14 day course.76 A urine culture should be performed 1–2 weeks after treatment is completed. Women who do not improve within 48 hours of initial antibiotic treatment should be evaluated for possible obstruction or abscess. Women who have had pyelonephritis or with recurrent UTI should receive preventive antibiotic treatment. Daily suppression with nitrofurantoin73 or cephalexin, or a postcoital dose70 until 4–6 weeks postpartum has been recommended. Evidence from randomized controlled trials support the efficacy of adjunctive measures such as increased intake of cranberry and blueberry products in prevention of UTI in women with recurrent infections.77

Pneumonia Pneumonia occurs in up to 1% of pregnancies,66 and is poorly tolerated due to increased oxygen requirements, and decreased buffering capacity with decreased ability to compensate for acidemia. Because of the greater affinity of fetal hemoglobin for oxygen, the fetus is relatively protected until maternal oxygen saturation becomes 90% (PaO2   65 mmHg). Before antibiotics, mortality was 30% in pregnant women with pneumonia, and now is about 4%,78 but remains the third most common cause of death in this group.79 Mortality is highest in the third trimester. Streptococcus pneumoniae and varicella zoster are the most common causes of severe pneumonia in pregnancy. Bacterial Pneumonia With the exception of aspiration pneumonia in the third trimester, susceptibility to bacterial pneumonia does not appear to be increased by pregnancy itself. However, other medical conditions, particularly asthma and anemia, substantially increase the risk of bacterial pneumonia, and corticosteroid treatment for enhancement of fetal lung maturity appears to increase the risk of nosocomial pneumonia.80 In community-acquired pneumonia, the most common bacterial pathogens are similar to those causing disease in non-pregnant adults, and include pneumococcus, Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Haemophilus influenzae. However, up to 1 in 5 pregnant women admitted with bacterial pneumonia requires intensive care management,81 and 10–20% require intubation and mechanical ventilation.80 The frequency of complications such as bacteremia (16%) and empyema (8%) is also increased. Clinical symptoms are similar to those in

Table 47.5  Susceptibility of urinary tract isolates of E. coli to commonly used antibiotics Antimicrobial Oral

Solely parenteral agents

Women aged 16–30 years

Women aged 31–45 years

Ampicillin

57%

46%

Amoxicillin/clavulanate

93%

90%

Cephalothin

74%

64%

Nitrofurantoin

98%

94%

Trimethoprim/ sulfamethoxazole

74%

64%

Aztreonam

99%

100%

Cefazolin

93%

89%

Cefotetan

99%

99%

Ceftriaxone,ceftazidime, cefotaxime

99%

99%

Gentamicin

95%

93%

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non-pregnant women, and include fever, cough, pleuritic chest pain, rigors, and chills. All pregnant women with a possible diagnosis of pneumonia should undergo chest radiography, and should be admitted at least initially for observation and intravenous antibiotics. The applicability of guidelines from the American Thoracic Society and British Thoracic Society for assessment of disease severity in pregnant women is unknown. Standard therapy for bacterial communityacquired pneumonia with ceftriaxone and azithromycin should be given. Vancomycin may be added in locales with decreased pneumococcal susceptibility to penicillin and ceftriaxone. Patients with suspected nosocomial pneumonia should be treated with intravenous antibiotics based on resistance patterns for local nosocomial isolates. Viral Pneumonia Viral pneumonia may be particularly severe in pregnancy. Varicella and influenza are the most frequent causes. Approximately 1 in 10 unvaccinated pregnant women will be susceptible to primary varicella. Varicella pneumonia usually occurs 3–5 days after onset of the rash, presenting with oral lesions, increased dyspnea, cough with bloodtinged respiratory secretions, and pleuritic chest pain. The risk of varicella pneumonia is increased in smokers, in women with underlying lung disease or immunosuppression, in women with more than 100 skin lesions, in women infected later in pregnancy, or when varicella has been acquired from a household contact.82 Chest radiography demonstrates interstitial, nodular lesions with a ground-glass appearance, or local infiltrates, and should be performed in women who develop consistent symptoms. Although varicella pneumonia occurs at the same rate as in non-pregnant adults, disease is more severe and mortality rates may be 35–40%.83,84 Maternal and fetal outcomes are improved by treatment with intravenous acyclovir 10 mg/kg every 8 hours. Mortality is highest when varicella pneumonia occurs in the third trimester.82 When there is a known exposure, administration of Varicella Zoster Immune Globulin (VZIG) within 96 hours can prevent or attenuate infection. Varicella infection may also be transmitted to the fetus, and is discussed later in this chapter. Illness due to influenza in pregnancy is increased 10-fold over non-pregnant women without other illnesses. The risk of influenza pneumonia is also increased in pregnancy.85 In the 1918–1919 pandemic, the mortality rate for pregnant women with influenza pneumonia was 50%. Although the safety of amantidine and neuraminidase inhibitors is unknown in pregnancy, they should be given in severe illness. The influenza vaccine is considered safe for use in pregnancy, and immunization is recommended for prevention of illness due to influenza. Although there is limited experience with infection due to SARS-coronavirus in pregnant women, the experience

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from the Hong Kong outbreak suggests a fatality rate of 25%. Half of the affected women received intensive care, and one-third required mechanical ventilation. More than half of the women in their first trimester had spontaneous fetal loss. Of the five women who presented after 24 weeks gestation, four delivered pre-term.86 Tuberculosis Pregnancy-related tuberculosis has increased in the United States and other developed countries because of demographic changes, including an increase in immigrants with underlying infection, or at risk for acquisition of tuberculosis in immigrant communities.87 In contrast to older literature, recent studies do not show an increased risk in pregnant women of developing active tuberculosis,87,88 and morbidity and mortality were not increased when pregnant women received appropriate antituberculosis treatment.89 However, late diagnosis or incomplete treatment are associated with increased morbidity and mortality.87 Treatment of tuberculosis is similar for pregnant and nonpregnant adults, with the exception that streptomycin, kanamycin, amikacin, capreomycin, and fluoroquinolones should not be used in pregnant women unless no other treatment options are available. Streptomycin has been clearly documented to cause congenital deafness. Pyridoxine (25 mg day) supplementation is required when isoniazid is given.90 Fungal Pneumonia In the first two trimesters of pregnancy, Coccidioides immitis causes a mild influenza-like illness and pneumonia, but in the third trimester of pregnancy the risk for dissemination is increased.91–93 Immunologic and hormonal changes during pregnancy and the postpartum period are thought responsible for increased frequency and severity of disease. Disseminated disease is associated with a very high mortality rate, and treatment with amphotericin B is recommended.

Puerperal Infections Fever In the puerperal period, spiking fever greater than 39 °C (102.2 °F) is usually caused by infection with bacteria, particularly Streptococcus pyogenes (group A beta-­hemolytic streptococcus), the classic cause of childbed fever, or Streptococcus agalactiae (group B beta-hemolytic streptococcus). Infections with group A streptococci can be complicated by toxic shock syndrome.94 Persistent low-grade fever also suggests bacterial infection. Endometritis Postpartum abdominal pain, tenderness, and fever, suggest the diagnosis of endometritis, an infection of the decidua,

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myometrium, and surrounding tissues. Bacteremia with chills or rigors may occur. Other findings, such as foulsmelling lochia and leukocytosis, may be observed in women without endometritis and are not diagnostic. Most severe endometritis occurs ‘early,’ within the first 48 hours after delivery. ‘Late’-onset endometritis can appear up to 6 weeks postpartum, but symptoms are generally milder.95 For the most part, endometritis is an ‘ascending’ infection, caused by microorganisms colonizing the vagina such as the beta-hemolytic streptococci, other streptococci, enterococci, S. aureus, Gram-negative enteric bacteria such as E. coli, Klebsiella, and Proteus species, anaerobic organisms such as Bacteroides, Prevotella, Fusobacterium, and Clostridium species, and Chlamydia trachomatis, Mycoplasma species, Ureaplasm urealyticum, and Neisseria gonorrhoeae. In the United States, endometritis is rare after vaginal delivery (1.3%), but the risk more than triples after interventions such as internal fetal monitoring, multiple cervical examinations, or after prolonged rupture of the membranes. Intrapartum chorioamnionitis raises the risk to 13%.96 The duration of membrane rupture before delivery increases the risks of both chorioamnionitis and endometritis, which more than double after 12 hours and 16 hours, respectively.97 Intrapartum chorioamnionitis can also occur preterm, or in women with intact membranes,98 and organisms such as Haemophilus influenzae, Streptococcus pneumoniae, and Listeria monocytogenes, should also be considered.99 Cesarean delivery is the greatest risk factor for endometritis. Prior to widespread perioperative antibiotic prophylaxis, endometritis occurred in up to 50% of patients. Administration of a first- or second-­generation cephalosporin intraoperatively after clamping of the umbilical cord decreases the rate to 12–17%.100 Andrews and colleagues have reported that addition of intravenous azithromycin to cefotetan or cefoxitin prophylaxis further decreased the rate of pos-cesarean endometritis to about 2%, even in a high-risk population.101 The benefit of azithromycin presumably relates to its activity against Ureaplasma urealyticum or mycoplasma, which have been associated with a three-fold increased risk of endometritis. Endometritis occurs rarely after voluntary termination of pregnancy. When prophylactic antibiotics are administered, endometritis is a complication in about 0.5% of suction procedures, 1.5% of dilatation and curettage procedures, and 5% of uterine instillations. Reports of endometritis after medical abortion are very rare, and endometritis or genital tract infection have been reported in fewer than 0.013% of women treated with mifespristone.102 Reports linking toxic shock syndrome and infection with Clostridium sordellii and Clostridium perfringens after medical abortion103,104 now appear to be linked to impairment of local innate immunity due to intravaginal use of the prostaglandin E2-pharmacomimetic misoprostol, but not to mifespristone.105

When endometritis is suspected, a pelvic examination should be performed and aerobic cultures obtained from the endocervical canal. Blood cultures may be positive in up to 20% of women.99 In post-cesarean infections, initial treatment should include coverage for anaerobic organisms in addition to aerobic Gram-positive and Gram-negative bacteria, then modified based on culture results. Based on a meta-analysis of 39 clinical trials, the preferred regimen is clindamycin 900 mg plus gentamicin 1.5 mg/kg intravenously every 8 hours.94 Clindamycin 2700 mg plus gentamicin 5 mg/kg intravenously as a single daily dose has been shown to be equally effective.106 When fever persists after 48 hours, or enterococcal infection is suspected, addition of ampicillin 2 g intravenously every 6 hours or vancomycin is recommended.107 Once the patient is afebrile, further treatment with oral antibiotics does not appear necessary. Persistence of fever and discomfort after 48 hours may signal the presence of a focus requiring debridement or drainage, such as pelvic abscess or an infected hematoma, or the presence of pelvic thrombophlebitis. Computerized tomography of the pelvis can be helpful in identifying these complications. Wound Infections The risk of wound infection following cesarean delivery ranges from 3% to 15%,108 and is greatest in overweight and obese patients, after emergency cesarean delivery or membrane rupture more than 6 hours before delivery,109 or if a subcutaneous hematoma develops.108 The risk of wound infection increases more than nine-fold in women who are both obese and diabetic.55 Intraoperative antimicrobial use to prevent endometritis concurrently decreases wound infections, to fewer than 2%.100,101 Abscesses of the abdominal incision may form by the fourth postoperative day. Potential organisms include any that may have been present in the amniotic fluid at the time of delivery, methicillin-resistant staphylococci and nosocomial Gram­negative organisms. Necrotizing fasciitis is a very rare complication of pregnancy, and in a large series of 5048 women undergoing cesarean section occurred in only nine.110 All the infections were polymicrobial; no clear-cut risk factors could be identified. Necrotizing fasciitis can also occur at the site of an episiotomy or tear. Cultures should be obtained from infected wounds, and necrotic tissue must be debrided. Abscesses should be drained and the pus sent for aerobic and anaerobic culture. Antibiotic management should include coverage for group A streptococci, methicillin-resistant S. aureus and Gram­negative organisms. Initial treatment of abscesses and necrotizing fasciitis also requires anti-anaerobic coverage. When an anaerobic infection is detected in a patient receiving clindamycin, an agent with broader anti-anaerobic coverage such as metronidazole or imipenem/cilastatin should be used.

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Mastitis Mastitis, or infection of the mammary glands, is common, and occurs in 5–33% of breast feeding women.111 Almost all cases appear in the first 3 months, and very rarely at weaning. In a small percentage, mastitis is complicated by breast abscess or recurrent mastitis. Risk factors for mastitis include older maternal age, fatigue, employment outside the home, trauma to the skin or nipple, ineffective nursing technique, and milk stasis. The presenting symptoms are chills, rigors, and fever, in conjunction with unilateral breast tenderness, erythema, and decreased milk production. Most mastitis is caused by S. aureus, which may be transmitted to the mother from an infant nasally colonized before hospital discharge, followed by streptococci and E. coli. Prevention includes proper positioning of the infant and nursing technique. Initial treatment includes an antistaphylococcal oral antibiotic such as dicloxacillin or cephalothin, after cultures of expressed milk have been obtained. If fever persists, coverage should be modified for activity against methicillinresistant S. aureus. Women should be treated for 10 days. If an abscess has formed it should be drained by ultrasoundguided needle aspiration, or surgically. Prevention of Puerperal Infection Prevention of puerperal infection includes strict adherence to Infection Control guidelines, particularly hand hygiene. In 1847, Semmelweiss described his experience in the maternity ward of the Vienna Hospital, which demonstrated that hand disinfection before examination of pregnant patients dramatically decreased mortality from childbed fever.112 As the increased risk of endometritis associated with multiple exams and interventions such as fetal monitoring suggests, appropriate hand hygiene remains an essential measure to prevent nosocomial and iatrogenic infections.

Hepatitis E Hepatitis E virus (HEV) is a nonenveloped, single-stranded RNA virus transmitted by the fecal–oral route that is a major cause of endemic hepatitis in Asia, the Middle East, Africa, and Central America. Like hepatitis A, HEV may cause fulminant hepatitis, encephalopathy, and death. However, in contrast to hepatitis A, B, or C, pregnancy is a major risk factor for severe infection due to hepatitis E virus in endemic areas. The increased rates of fulminant infection and death in pregnancy have been attributed to pregnancy-associated changes in immune function, and also to a direct effect of steroid hormones on viral regulatory elements controlling viral replication. In a study of Asian women with acute HEV, HEV viral load was more than 10fold higher in pregnant than in non-pregnant women at similar stages of disease.113 The severity of infection appears to be exacerbated by folate deficiency, which commonly

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complicates pregnancy in underdeveloped countries. Acute maternal infection in the second and third trimester is associated with pre-term birth, perinatal infant death, and acute neonatal infection with HEV, but infants who survive the initial period recover fully.114,115

Intestinal Parasitosis and Biliary Ascariasis Infestation by intestinal parasites is common in pregnant women in the non-developed world. The extent of infection and types of infecting parasite vary according to region and socioeconomic conditions. A 2006 study in Venezuela found that 74% of women were affected by intestinal parasites, most commonly Ascaris lumbricoides (57%), Trichuris trichuria (36%), Giardia lamblia (14%), Entamoeba histolytica (12%), Necator americanus (8%), Enterobius vermicularis (6%), and Strongyloides stercoralis (3%). Pregnant women with intestinal parasites are more likely to be anemic,116 but anemia may be the consequence of other confounding conditions rather than the parasite load. In most cases, pregnancy is not otherwise known to alter the course of the parasitic infection. An exception is infection with A. lumbricoides, which in pregnancy is more likely to cause biliary ascariasis. Biliary ascariasis may present as acute cholecystitis, cholangitis, biliary cholic, acute pancreatitis or hepatic abscess. Conservative treatment with bowel rest, antispasmodics, and antibiotics is successful in 68–80% cases, but the presence of dead worms, stones or strictures may prevent migration of the worms back to the duodenum, necessitating surgery. Animal models suggest the increased susceptibility to biliary ascariasis in pregnancy is due to relaxation of the sphincter of Oddi and decreased intestinal motility due to smooth muscle dysfunction as a consequence of increased progesterone and estrogen, particularly in the second and third trimesters.117

Malaria Malarial infection causes increased maternal and perinatal infant morbidity and mortality, and it is associated with maternal anemia, low birthweight, and preterm birth. In high transmission areas, most women have partial protection due to previous infections, and severe maternal anemia and low birthweight babies are the primary complications. In low transmission areas, particularly in Asia and Latin American, women are less likely to have preexisting immunity, infections are more likely to be severe, and the risk of fatal infection is higher.118 Severe malaria in pregnancy is caused by Plasmodium falciparum. During pregnancy, even women from endemic areas who would be expected to have developed some clinical immunity to malaria can develop high parasitemias. Some evidence suggests that changes in maternal spleen function decrease parasite clearance and increase maternal susceptibility even within the first 8 weeks. However, the

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major factor influencing the severity of malaria in pregnancy is the sequestration of parasitized erythrocytes by the placenta. By the 10th to the 12th week of pregnancy, the placenta expresses chondroitin sulfate A (CSA), and can support the clonal expansion of a subpopulation of parasites that express an antigen able to bind to CSA.119 The placenta can sequester a large number of parasitized erythrocytes, including late trophozoite and schizont stages that are not seen in the peripheral blood. Sequestration occurs throughout the intervillous space of the placenta, and is not limited to the vascular wall.120 Binding to other antigens may occur, but appears to be less important. The parasitized cells can also circulate, but the detectable parasitemia underestimates the placental parasite load, and examination of peripheral blood can be falsely negative. The risk associated with malaria

in pregnancy is greatest during the first pregnancy. After several pregnancies, the mother develops specific ‘anti­adhesion’ antibodies directed against the malarial antigens expressed by placental variants.121,122 In placental malaria, the intervillous spaces contain parasitized erythrocytes, and increased numbers of monocytes and macrophages (Figure 47.1). These phagocytic cells often contain hemozin pigment, which may also be present as free pigment or in fibrin deposits, and may also contain ingested parasitized erythrocytes (erythrophagocytosis) (Figure 47.2). The pigment deposits persist after the parasites have been cleared. The presence of both parasitized erythrocytes and hemozoin pigment indicate a chronic infection. When placental monocytes and macrophages are increased, changes in the placental cytokine balance are thought to contribute to poor outcome.120 Malaria parasites

Figure 47.1  Placental malaria, H&E. Left: Sequestration of P. falciparum-infected erythrocytes in the intervillous space (maternal blood), and infiltration by monocytes and macrophages. The monocytic cells release proinflammatory cytokines including IFN- and IL-2. Right: There are multiple infected maternal erythrocytes in the intervillous space. By contrast, the fetal erythrocytes within the capillaries of the villous are not infected.

Figure 47.2  Placental malaria, H&E. Left and right: placental macrophages containing phagocytosed parasitized erythrocytes and brown hemozoin pigment. Some immune functions, such as production of chemokines and differentiation to dendritic cells, are impaired in cells containing large amounts of hemozoin pigment.

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do not cross the placenta to infect the fetus, although leakage of maternal cells into the fetal circulation at parturition could potentially lead to infection of the infant. Other plasmodium species do not adhere to placental receptors, and infection does not have the same clinical impact, although chronic infection with P. vivax is associated with maternal anemia, and low birthweight. Other factors that may increase susceptibility to malaria in pregnancy include sustained increases in cortisol and prolactin levels,123 and HIV infection. HIV infection decreases the response to the variant-specific antigens responsible for binding to CSA, decreases the lymphoproliferative responses to malarial antigens, and impairs the cytokine response. In non-pregnant adults, the level of parasitemia is inversely correlated with the CD4 count.124 In malaria endemic areas, preventive measures include insecticide-treated nets to prevent mosquito bites, and intermittent preventive therapy in pregnancy. Intermittent treatment with at least two doses of sulfadoxine-pyramethamine in the second and third trimesters is recommended by the WHO. Women with HIV infection may require additional

doses. Use of chloroquine for prophylaxis is no longer recommended due to resistance.125 Currently, the only antimalarials known to be safe for treatment during the first trimester of pregnancy are quinine, proguanil, chloroquine, and clindamycin. Artemisininbased combination therapies (ACTs) are not recommended in the first trimester unless no other alternative is available. Recommendations for malaria treatment in pregnancy are available from the CDC and the WHO (summarized in Table 47.6).

Schistosomiasis Schistosomiasis is a common parasitic infection in the developing world, and affects about 40 million women of childbearing age, mostly in sub-Saharan Africa (S. haematobium and S. mansonii) and the western Pacific (S. japonicum). In contrast to infection with malaria, pregnancy-related changes in immunity or parasite-specific antigen expression do not seem to be factors in the course of disease. However, schistosomiasis can adversely affect

Table 47.6  Recommendations for malaria treatment in pregnancy Uncomplicated falciparum malaria   First trimester Chloroquine-susceptible: Chloroquine phosphate, 600 mg base (1000 mg salt) orally, followed by 300 mg base orally at 6, 24, and 48 hours for a total dose of 1500 mg base Hydroxychloroquine, 620 mg base (800 mg salt) orally, followed by 310 mg base orally at 6, 24, and 48 hours for a total dose of 1550 mg base Chloroquine-resistant: Quinine 10 mg/kg plus clindamycin 5 mg/kg three times per day,  7 days Artesunate 2 mg/kg per day plus clindamycin 5 mg/kg three times per day,  7 days l  Second or third trimester Artesunate 2 mg/kg per day plus clindamycin 5 mg/kg three times per day,  7 days Quinine 10 mg/kg plus clindamycin 5 mg/kg three times per day,  7 days l

Severe malaria  Quinidine gluconate 6.25 mg base loading dose over 1–2 hours followed by 0.0125 mg base/kg continuous infusion, plus clindamycin for at least 24 hours, and until parasitemia is 1%. Treatment may be completed with oral quinine plus clindamycin. Treat patients for 3 days if disease was acquired in Africa or South America, and for 7 days if acquired in South-East Asia l  Artesunate 2 mg/kg per day plus clindamycin 5 mg/kg three times per day,  7 days l

Other antimalarial agents  Artemisinin combination treatments (ACTs) , such as arthemether–lumefantrine, artesunate– ­amodiaquine, artesunate–mefloquine, and artesunate–sulfadoxine-pyramethamine, have been used extensively outside the United States, but should be avoided during the first trimester l  Atovaquone-proguanil tablets, 250 mg atovaquone/100 mg proguanil each,  4 tablets orally per day  3 days l

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pregnancy outcome, such as low birthweight (japonicum) and preterm delivery (haematobium). Potential pathogenic mechanisms include maternal iron deficiency anemia due to direct blood loss in the stool (mansonii, japonicum) or urine (haematobium), or associated with chronic disease, and inflammation in response to placental infection by immature worms and eggs with consequent cytokine production. In S. haematobium infection, stimulation of cytokine production following binding of circulating antigen to placental TLRs has been proposed. Similar outcomes can be shown in animal models. After experimental infection of rats with S. mansonii; infected rats have fewer pregnancies, fewer surviving pups, higher maternal death rates, higher spontaneous abortion rates, and lower pup weights at birth and in early infancy. Analogous findings are obtained after infection in pigs, and congenital transmission has also been described.126 The WHO considers pregnant women with schistosomiasis to be high-risk, and recommends treatment. If treated early in the disease course, hepatic, gastrointestinal, and urinary tract pathology is reversible. Praziquantel is listed as a pregnancy class B agent, but no adverse effects have been reported in 20 years of post-market monitoring.

Infections in which fetal transmission or other fetal morbidity is the primary concern For some infections during pregnancy, the mother is minimally, if at all, affected, but transmission to the fetus is a major concern, and the consequences of fetal infection can be devastating. In many infections, growth of the fetus may be affected (intra-uterine growth retardation) or the infant may be delivered prematurely (miscarriage or preterm birth), even in the absence of congenital infection.

‘Torch’ Agents Toxoplasmosis Toxoplasmosis is a zoonotic parasitic infection caused by infection with Toxoplasma gondii. Cats are the definitive hosts for this parasite; humans are intermediate hosts and are infected by cat exposure, or by ingestion of raw or undercooked meat, infected water, or contaminated soil.127 Cats are less likely to be infected in Asia, and the risk from direct cat exposure is less likely than in the United States and Europe.128 Congenital toxoplasmosis usually occurs in association with primary infection during pregnancy, although congenital transmission has been reported from chronically infected mothers, even in the absence of ­immunocompromise.129,130 T. gondii actively invades cells, and can cross biological barriers, including the placenta and

blood–brain barrier. Congenital toxoplasmosis causes a disseminated infection in the fetus, and T. gondii DNA can be detected in amniotic fluid, blood, cerebrospinal fluid, and other fetal tissues. The incubation period of toxoplasmosis is 4 to 21 days. Most cases are asymptomatic in the mother, or present only with localized lymphadenopathy or symptoms of mononucleosis. An evaluation for possible congenital toxoplasmosis includes maternal serology, and molecular amplification testing for T. gondii DNA from amniotic fluid. Maternal IgM antibody appears within 1–2 weeks after infection, followed by IgA and IgE. The IgM response peaks at 2 months, and generally wanes after 6–9 months; the IgG response peaks after 4 months. Some authors suggest that in pregnant seroconverters, testing IgA and IgE levels, and the binding avidity of IgG, IgA, and IgE may be helpful, since avidity increases during infection, and low avidity suggests a more recent infection. Congenital infection should be treated before birth, with the best outcomes reported if treatment is initiated within 4 weeks of seroconversion. Treatment should include sulfadiazine plus pyramethamine until birth; clindamycin should be used in early pregnancy. The risk of primary toxoplasmosis in pregnancy can be minimized by avoiding consumption of raw or undercooked meat, washing hands and utensils thoroughly after contact with raw meat, washing all uncooked vegetables, wearing gloves when in contact with soil, and washing hands thoroughly immediately thereafter. Cats should be kept indoors. Pregnant women should not change cat litter, and should wash their hands immediately after contact with cats. Rubella Rubella (German measles) is a generally mild childhood illness that causes devastating congenital infection in infants of non-immune mothers, particularly when infection is acquired in the first trimester. After the availability of vaccine in 1969, the number of rubella cases declined in the United States, and by 1979, the characteristic 6- to 9-year epidemic cycle of rubella was no longer evident. Congenital transmission has been eliminated in the United States since 2005, and substantial progress towards elimination in the Western Hemisphere and worldwide has been made due to aggressive vaccination programs.131 Rubella virus is transmitted by respiratory tract aerosols, and enters the susceptible host through the nasopharyngeal epithelium. The virus is transported via the blood to the lymph nodes and spleen, and replicates in reticuloendothelial cells. Six to 20 days after the initial infection, the virus reenters the blood and disseminates widely, and the rash appears shortly thereafter. Virus is shed from the nasopharynx beginning 3–8 days after exposure, and for 6–14 days after onset of the rash, accounting for an extended period of infectivity. In most younger children,

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rubella is a mild illness, causing a low-grade fever that lasts for less than 24 hours, a maculopapular rash over the face and neck that lasts 2 or 3 days, and malaise. Many children are completely asymptomatic, although rare cases of rubella encephalitis have been reported. In older children, adolescents, and adults, rubella symptoms may include several days of fever, headache, malaise, coryza and conjunctivitis. Illness may be complicated by cervical adenopathy, which can precede the rash by several days, and by arthralgia or arthritis, which occurs in up to 70% of older girls and women. Thrombocytopenic purpura may also occur rarely. During pregnancy, rubella infection is transmitted transplacentally, and can cause a disseminated infection, resulting in miscarriage, stillbirth or damage to various fetal organs (the congenital rubella syndrome). Rubella infection causes cell death, inhibition of mitosis, and vascular endothelial damage, and its impact is greatest during organogenesis. When infection occurs during the first trimester of pregnancy, 50–90% of fetuses will be affected, but the percentage of affected infants declines progressively during the second trimester.132 The classic findings in congenital rubella include cataracts/congenital glaucoma, congenital heart disease (most commonly patent ductus arteriosus or peripheral pulmonary artery stenosis), hearing impairment, and pigmentary retinopathy, but all organ systems can be affected. Congenital rubella infection also causes encephalitis, mental retardation, pneumonia, hepatitis, thrombocytopenia, growth plate defects, diabetes mellitus, and thyroiditis.133 Congenitally infected babies excrete rubella virus at birth and for months, and are highly infectious. Rubella is a vaccine-preventable illness, and live attenuated rubella virus vaccines have been available and in use for over 40 years. Currently, two doses of combined measles–mumps–rubella (MMR) vaccine are recommended in the current schedule for children and adolescents. Susceptible women of childbearing age should be vaccinated. Although extensive postvaccination surveillance has not turned up any instance of congenital rubella following inadvertent vaccine administration to pregnant women, current recommendations are that women known to be pregnant should not be vaccinated, and conception should be avoided for 28 days after receipt of a rubella-containing vaccine. Adult women can develop acute transient arthralgia and arthritis after vaccination, but evidence does not support an association with chronic joint problems. Subclinical thrombocytopenia may be observed after vaccination. Cytomegalovirus Infection with human cytomegalovirus (HCMV or HHV-5) is a common congenital viral infection, affecting at least 1% of live-born infants in developed countries. Most severe fetal infections occur during primary maternal infection, with a congenital transmission rate of about 40%. Of these infants,

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10–15% will be symptomatic at birth and an additional 5–10% will develop late neurologic findings.134 Primary CMV infection during the third trimester has the highest rate of congenital transmission. In early pregnancy, spontaneous abortion can occur, often accompanied by evidence of placental infection, even without signs of fetal infection. Congenital infection can also follow reactivation of endogenous maternal CMV infection, or if the mother is reinfected with a new strain, but at a lower rate, presumably because of partial maternal immunity.135 The risk of congenital infection in non-primary infection had previously been estimated at about 1%,135 but a recent prospective study found a much higher rate of almost 20%.134 It is now recognized that over 60% of congenitally infected infants have mothers with previous immunity to CMV, but with evidence of secondary infection during pregnancy. Most of these infants are asymptomatic at birth but are at risk for late neurologic disease.136 HCMV infects many cell types, including fibroblasts, epithelial and endothelial cells, macrophages, and muscle cells, and latency is established once the primary infection is controlled. The consequence is that congenital HCMV may cause symptoms in virtually any organ system, most commonly the central nervous system, liver, spleen, gastrointestinal tract, and hematopoietic system. Disease may be mild or fulminant, with infant mortality rates of 25%. Findings typical of congenital HCMV infection include intra-uterine growth retardation, jaundice, hepatospenomegaly, enteritis, pneumonitis with respiratory distress, rash, chorioretinitis, pancytopenia., and central nervous system findings such as meningoencephalitis, calcifications, microcephaly, ventriculomegaly, ocular abnormalities, and cerebellar hypoplasia. Related symptoms include lethargy, seizures, and cognitive and motor deficits. Hearing loss affects 50–60% of infants with other findings of HCMV at birth, and 10–15% of infants who appear asymptomatic. Other deficits such as mental retardation, and visual and motor impairment are less common in infants who are asymptomatic at birth.136,137 In primary maternal HCMV infection, maternal viremia leads to placental infection, and subsequent hematogenous dissemination to the fetus. Maternal leukocytes transmit infection, either by migration later in pregnancy and direct contact with fetal endothelium, or indirectly by contact with uterine endothelial cells, which are in contact with cells of the cytotrophoblast. In cases of congenital transmission from mothers with recurrent CMV, local immunosuppression in the uterus is thought to allow HCMV reactivation in uterine macrophages, which then infect invading cytotrophoblast cells, allowing viral spread to the fetus. In an infected fetus, HCMV can be detected in blood, and viremia persists for months after birth. Congenital HCMV should be considered in mothers who develop primary or secondary CMV infection. Primary maternal HCMV infection is documented by ­ positive

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viral culture, or by molecular testing. Seroconversion is ­suggestive, but IgM antibodies can remain positive for up to 18 months, thus may not reflect acute infection. Secondary infection is suggested by a significant increase in IgG titer, or by the presence of IgM. Because IgM assays can give false-positive results, routine serologic screening has not been recommended during pregnancy in the absence of maternal symptoms or findings on ultrasonography. In a newborn infant, a diagnosis of congenital infection can be made by detecting the virus in sputum or urine. Large amounts of virus are shed and culture is nearly 100% sensitive and specific in this setting. Molecular methods are not needed. However, antenatal diagnosis can be more difficult. Fetal blood sampling for CMV-specific IgM antibody is no longer recommended because of risks associated with cordocentesis, and because specific anti-CMV IgM may not develop until late in pregnancy. Assays of amniotic fluid for virus are preferred. In amniotic fluid, detection of HCMV by conventional or shell vial culture methods has been the gold standard for prenatal diagnosis, but molecular detection is more sensitive (90% vs. 80% by amniotic fluid culture) and is still highly specific. Detection of even small amounts of HCMV DNA correlates with congenital infection at birth. The importance of quantitative HCMV DNA testing is less clear, since levels do not correlate with structural abnormalities on ultrasound or with symptomatic versus asymptomatic infection at birth in all studies.135 When amniotic fluid is tested by virus culture, and assays for viral DNA, Immediate-Early mRNA, and pp67 (late expression) mRNA, obtaining positive results in two or more assays has a positive predictive value of 96.7–100% for congenital infection. Conversely, inability to detect HCMV in two or more assays has a negative predictive value of 84–93%. Unfortunately, antenatal testing procedures are limited by the risk of false-negative results when performed too early. The sensitivity of prenatal diagnosis increases from 50% to 76.2% and 91.3%, when 8, 9–12 and 13 weeks, respectively, elapse between the maternal infection and testing.135 At least 5–7 weeks are required after fetal infection for viral dissemination, followed by viral replication in the kidney and excretion of virus into the amniotic fluid via the fetal urine. Thus testing is not considered reliable before the 21st week of gestation, or less than 6 weeks after maternal infection. Contamination with maternal blood or tissue can also occur, leading to false-positive results.136 Because of these limitations, recommendations have been to limit prenatal diagnosis only to those mothers with known or highly suspected primary HCMV infection and/or in the presence of fetal ultrasonographic abnormalities. There is no FDA-approved antiviral agent for treatment of congenital CMV infection. Treatment of symptomatic infants diagnosed at birth with intravenous ganciclovir 6 mg/kg every 12 hours for 6 weeks benefited infants with pneumonia and prevented hearing loss.138 The efficacy

of antenatal ganciclovir for prevention of sequelae due to ­congenital HCMV infection has not been conclusively demonstrated. In a prospective clinical trial performed in Italy, treatment of pregnant women with confirmed primary CMV with CMV-specific immune globulin decreased the rate of symptomatic congenital infection at birth to 3%, in contrast to 50% in the untreated group.137 HCMV may also be transmitted after birth via breast milk. Postnatally acquired HCMV does not appear to be associated with neurologic or cognitive abnormalities, or other increased morbidity, except in cases of coincident congenital HIV infection.136 Most transmission of HCMV occurs by contact with blood or body secretions such as saliva, urine, feces, semen, vaginal secretions, breast milk or tears from an infected person. Risk reduction includes limiting potential exposure by practicing monogamy, avoiding contact with saliva and urine, particularly of toddlers and very young children, and following handwashing and general good hygiene practices. Herpes Simplex Virus (HSV) HSV infection is more severe in pregnancy. Recurrences are more frequent, more severe, and last longer, and primary infection may lead to severe illness with a maternal mortality rate of about 50% if disseminated infection occurs.139 Because seropositivity is high in the general population, only a small number of women have a true primary HSV infection during pregnancy. Severe primary disease is most likely in women who develop gingivostomatitis or vulvovaginitis, particularly when infection occurs in the third trimester,140 and is associated with disseminated skin lesions and evidence of multiorgan involvement including hepatitis and encephalitis. Maternal HSV infection is also associated with congenital infection, which affects 1 in 3200 to 1 in 5000 newborns. Maternal antibody is protective, and influences the rate of transmission, which decreases from 50% for primary maternal infection, to 33% for a non-primary first episode (infection with HSV-1 or HSV-2 in a woman with serologic evidence of previous infection with the other type), to 3% for recurrent HSV infection. Intra-uterine infection accounts for only 5% of congenital HSV infections. The greatest risk of intra-uterine HSV transmission occurs with primary disseminated maternal infection in the first 20 weeks of pregnancy, but intrauterine infections have also been reported in association with recurrent maternal infection during that period.141 Intra-uterine infection may be a consequence either of viremia or ascending infection. Most intra-uterine infections are caused by HSV-2. Several factors may be contributory, including a greater background seropositivity to HSV-1, smaller likelihood of recurrent infection due to HSV-1, and greater resistance to HSV-1 infection by placental syncytiotrophoblast cells which lack receptors for HSV-1 entry. As

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with other intra-uterine infections, risks include pregnancy loss and congenital malformations. Classically, infants with intra-uterine HSV infection develop severe skin (vesicles, scarring), eye (microphthalmia, chorioretinitis, cataracts), and brain (microcephaly, hydrocephaly, intracranial calcifications, encepahlomalacia, seizures) lesions. Limb hypoplasia similar to that seen in congenital varicella syndrome has also been reported. Transmission at the time of delivery accounts for the majority (90%) of congenital HSV infections. Because the infant is most commonly infected with HSV by contact with maternal lesions during passage through the birth canal, transmission can be avoided by treatment of women with recurrent HSV with acyclovir at term, and by cesarean delivery if lesions are present. Cesarean delivery reduces the risk of neonatal HSV by 85%. Although lesions are almost always very painful during primary infection, symptoms are usually less severe in recurrent infections. Some patients may even be asymptomatic, particularly if lesions are limited to the cervix and vagina. Thus, careful examination of the external genitalia and the cervix must be performed when the mother enters labor. Neonates may have infection only of the skin, eyes, mouth, or more serious CNS or disseminated infection, which are associated with infant mortality (15% and 57%, respectively) and residual neurologic impairment. Type-specific serologic testing early in pregnancy is useful to determine susceptibility to infection, risk for recurrence (greater for HSV-2 infections), and to help distinguish primary vs. recurrent infection and the associated risk of congenital transmission for women who become symptomatic later in pregnancy. In primary or recurrent infection, the diagnosis can be confirmed rapidly by direct fluorescent antibody testing, or shell vial and conventional viral culture of material from maternal lesions. Molecular methods such as PCR for HSV DNA are generally not required when lesions are present. HSV infections in pregnant women should be treated in the same way as in nonpregnant women, with the caveat that of antiviral agents, acyclovir has been used most often and does not appear to be associated with any teratogenic effects. Regimens include acyclovir 400 mg orally three times per day or acyclovir 200 mg orally 5 times per day for 7–10 days (primary infections) or 5 days (recurrent infections). Suppression of HSV recurrences with acyclovir 400 mg orally three times per day, beginning in the 36th week of pregnancy has been shown to reduce both recurrences around the time of delivery, and the need for cesarean section.142 Valacyclovir also appears safe in pregnancy, but has been used less extensively. The best measure to reduce congenital HSV infection is prevention of transmission to the mother. Steps to prevent a primary infection in the mother or infection with a new HSV strain from an HSV-infected contact include minimizing exposure by avoiding intercourse during outbreaks, the

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use of condoms, avoidance of oro-labial contact, and by antiviral treatment for the HSV-infected partner.

Parvovirus Parvovirus B19 causes the childhood illness erythema infectiosum (fifth disease). In adults, particularly women, infection can be associated with acute and sometimes persistent symmetrical arthritis of the wrists, ankles, and knees. Patients with underlying diseases may develop more severe symptoms, such as transient aplastic crisis in patients with sickle cell anemia, or refractory anemia and thrombocytopenia in immunocompromised individuals. Infection during the second trimester of pregnancy can cause fetal anemia, hydrops, and death, even when maternal infection is mild or asymptomatic. Immunity to parvovirus is based primarily on neutralizing antibody, and pregnancy does not appear to affect susceptibility to infection or the course of the disease in the mother. Data from the United States and Europe indicate that up to one half of women are susceptible at the time of pregnancy, and 1.5% (in endemic periods) to 13% (during epidemics) of previously seronegative women of childbearing age are infected with parvovirus annually.143 Viremia develops 4–14 days after exposure to parvovirus, and may produce symptoms of headache, fever, malaise, and coryza, or may be asymptomatic in up to 50% of individuals. Infection of bone marrow erythrocyte progenitor cells (the precursors of erythroblasts and megakaryocytes) causes formation of giant pronormoblasts, cytoplasmic vacuoles, and large eosinophilic nuclear inclusion bodies, followed by cell death and an acute drop in peripheral reticulocytes, causing anemia. Leukopenia and thrombocytopenia may also occur. The pathogenic effects of infection in other cells, such as mature erythrocytes, synovium, placenta, fetal myocardium and endothelium, are less clear. Transmission to the fetus occurs in about one-third of maternal infections. When infection occurs between weeks 11 and 23, during the period of hepatic hematopoiesis, the fetus can develop severe fetal anemia, leading to high output cardiac failure and non-immune hydrops because of the short lifespan of fetal erythrocytes, and the three- to fourfold increase in erythrocytes needed to accommodate fetal growth during this period. Estimates from retrospective case series place the overall risk of fetal hydrops following parvovirus infection from 1% to 4%, and as much as 7% when infection occurs between 13 and 20 weeks gestational age. Death from hydrops occurs in 50–90% of untreated cases within 2–4 weeks after maternal infection.144 Treatment includes intra-uterine transfusion, which improves survival to 85% in the cases of severe hydrops.145,146 Early studies suggested that the overall outcome after maternal parvovirus infection is good for liveborn infants,147 and growth and general health are normal.148 However, in a recent

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follow-up study of 24 infants treated with transfusions for hydrops, 3 of the 16 surviving children (32%) had developmental delays not attributable to other etiologies.149 Parvovirus binds to susceptible cells through globoside or P-antigen, and individuals lacking P-antigens cannot be infected by the virus. However, P-antigen expression is not sufficient for viral entry into the cell, which requires the presence of a functional co-receptor such as the 51 integrin,150 or possibly Ku80.151 Placental expression of P-antigen, which is highest early in pregnancy and gradually declines to become undetectable in the third trimester, may influence the likelihood of maternal–fetal transmission. A virally encoded phosphoprotein, NS1, controls viral transcription and replication, and causes host cell death, both by direct toxicity and by promoting cell cycle arrest and apoptosis. The NS1 protein also causes release of placental proinflammatory cytokines that are associated with a poor pregnancy outcome. In immunocompetent subjects, virus-specific IgM appears within 4 days of symptoms, or 21–24 days after exposure, and controls viremia. Specific IgG appears within 7–10 days and is associated with immune complex formation, the development of arthropathy, and the characteristic lacy, red ‘slapped cheek’ rash, and the recovery of reticulocytes and resolution of anemia. Diagnosis of maternal parvovirus infection is primarily based on serology. Virusspecific IgM persists from 2 up to 6 months; commercially available assays are sensitive and specific. Molecular methods, such as real-time PCR for parvovirus B19 DNA, or in situ hybridization, should be used to evaluate fetal but not maternal specimens, since viral DNA can persist in asymptomatic individuals.152 Parvovirus B19 cannot be cultured by routine methods. Once maternal infection has been diagnosed, the fetus should be monitored weekly by ultrasonography for 14–16 weeks for increased peak systolic flow velocity of the middle cerebral artery, which is a sensitive marker for fetal anemia. Development of hydrops is manifested by combinations of generalized edema, subcutaneous edema, ascites, pleural effusion, pericardial effusion, placental edema, and polyhydramnios. The optimal stage for intervention by fetal transfusion has not been established. Recently, third trimester fetal loss in the absence of fetal hydrops, but associated with parvovirus B19 DNA in placental tissues has been reported. Fetal loss occurred most often at 4–6 weeks, but could occur up to 12 weeks, after infection. In these cases, maternal infection was asymptomatic, and serologic response was delayed or absent. The cause of death in these infants was not clear at autopsy. Most parvovirus infections occur in the winter and spring, with epidemics at 3–5 year intervals. Respiratory secretions from an infected person are very contagious. In the immunocompetent, secretions are only infectious before appearance of the rash or arthropathy, but immunocompromised individuals unable to make antibody cannot

clear the virus and are infectious for an extended period. Hand and respiratory hygiene are recommended for prevention. Except in healthcare settings, isolation or restriction of activities has not been recommended by the CDC, since a diagnosis is usually made once the characteristic rash has appeared, and the individual is no longer infectious. Most pregnant women acquire infection in a family setting. Because parvovirus B19 is a small, non-enveloped single-stranded DNA virus, it is stable to current blood decontamination methods, and can also be transmitted through contaminated blood products. A recombinant vaccine (Medimmune) to VP1 and VP2 capsid proteins is under evaluation. The benefit of intravenous immunoglobulin for prophylaxis after exposure has not been systematically evaluated. Other recently described members of the Parvoviridae found in human specimens include three Erythrovirus strains (A6, K71 and V9) which are closely related to B19, two novel parvoviruses, PARV4 and PARV5, and human bocavirus. Only limited information is available about the role of these strains in clinical disease.

Varicella Zoster As described earlier in this chapter, chickenpox (varicella zoster virus, VZV) during pregnancy can be associated with a more severe course of disease, and varicella pneumonia presents a risk for maternal ventilatory failure and associated high mortality. There is also a risk to the developing fetus, usually as a consequence of maternal viremia. When infection occurs during the first 24 weeks of pregnancy, congenital varicella will develop in almost 2%, manifested by dermatomal skin lesions (cicatricial scars, skin loss), low birthweight, eye (microphthalmia, enophthalmia, chorioretinitis, cataracts, nystagmus, anisocoria, optic atrophy) and brain lesions (cortical atrophy, spinal cord atrophy, limb paresis, microcephaly, seizures, Horner’s syndrome, encephalitis, dysphagia), and skeletal anomalies such as limb hypoplasia. Almost one-third of infants with congenital varicella die within a few months. The fetus is unable to mount a cell-mediated immune-response to VZV infection, and zoster-like reactivations with associated encephalitis are thought to cause the typical lesions of congenital varicella. Neonatal varicella occurs in infants whose mothers are infected in the 3 weeks prior to delivery. Infants infected 2– 3 weeks prior to delivery develop chickenpox, but generally do well since some maternal IgG will have developed and been transferred to the infant. Infants of mothers infected closer to delivery (maternal rash in the 5 days prior to delivery or just after) will not have acquired maternal antibody. These infants have 17–30% chance of developing fulminant disseminated infection, with a 20% risk of death.153 Infections with VZV occur due to transplacental infection following maternal viremia, ascending infection during birth, or respiratory infection after birth. Maternal shingles

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does not appear to be associated with risk of congenital infection, and maternal antibodies appear to be protective. The diagnosis of maternal varicella can generally be made clinically, and confirmed rapidly by direct fluorescent antibody testing, or shell vial and conventional viral culture of material from maternal lesions. Serology and culture are less reliable in congenital varicella, and molecular methods such as PCR for viral DNA may be needed for differentiation from HSV-2 or coxsackie B virus, which may present similarly. Amniotic fluid can be tested antenatally, but should be limited to cases in which fetal ultrasound examination demonstrates findings consistent with the diagnosis, since a positive amniotic fluid result may be obtained in the absence of fetal malformations. Active immunization of women before pregnancy is recommended. Since the varicella vaccine contains a live, although attenuated, virus, women should wait at least 4 weeks after vaccination before becoming pregnant, and vaccine should not be given to women who are already pregnant. Exposed, susceptible pregnant women should receive Varicella Zoster Immune Globulin (VZIG) 125 U/10 kg (maximum 625 U) intramuscularly within 72–96 hours. Little information is available about the use of acyclovir for prophylaxis after maternal exposure or for prevention of congenital varicella syndrome, but may be of benefit. Higher doses of acyclovir (800 mg orally five times per day) are required. Timing also appears to be an issue, and treatment on the 7th day after exposure is recommended.82

Classical Sexually Transmitted Infections (STIs) Many women continue to have intercourse even late in pregnancy, and thus are at continued risk of acquiring an STI. Data from the CDC indicate that more than 15% of new STIs in women of child-bearing age occur during pregnancy. STIs are discussed elsewhere in this volume, and this discussion focuses primarily on the impact of STIs on pregnancy and congenital infection. Screening and treatment guidelines have been established by the CDC154 and by the American College of Obstetricians and Gynecologists.155 Chlamydia Infection with Chlamydia trachomatis (CT) may be the most commonly diagnosed bacterial STI in pregnancy. CT is a frequent cause of cervicitis, endometritis, salpingitis, peritonitis, reactive arthritis, Reiter syndrome, and infertility associated with pelvic infection. Most epidemiologic data suggests that women with previous pelvic infections, whether symptomatic or asymptomatic, are at risk for ectopic pregnancy. CT is transmitted to the infant during passage through the birth canal in 30–50% of infected women. In neonates, CT causes conjunctivitis, pharyngitis, pneumonia, and genital tract infection. CT conjunctivitis is not prevented by neonatal prophylaxis and requires prolonged treatment to prevent blindness.

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All pregnant women should be tested at the first ­prenatal visit. If positive, they should be treated and retested 3 weeks later. All women less than 25 years or at increased risk (new partners, multiple partners, previous STD, or in areas with a high prevalence) should be retested in the third trimester. Women should be screened using nucleic acid amplification tests for urine, vaginal, and cervical specimens. Direct fluorescent antibody tests or culture are recommended for rectal specimens, although nucleic acid amplification tests are more sensitive and have been validated in some laboratories. Treatment with azithromycin 1 g orally as a single dose is preferred. Doxycycline should not be administered in pregnancy. Gonorrhea Pregnant women with Neisseria gonorrhoeae infection may have localized infection such as cervicitis, urethritis, pharyngitis, or proctitis, but also appear to be at a somewhat increased risk for disseminated infection. Maternal infection is associated with a three-fold increased risk of preterm birth. Maternal genital infection may result in neonatal gonococcal conjunctivitis, pharyngitis, and neonatal sepsis and disseminated infection. Because of the risk of blindness in infants who develop conjunctivitis due to gonococcal infection, silver nitrate or antibiotic ointment are routinely administered for ophthalmic prophylaxis. Screening in the first and third trimester is recommended for women at high risk of infection, such as those with new partners, multiple partners, a previous STI, or in areas with a high prevalence of gonococcal infection. In pregnant women, diagnosis by nucleic amplification methods is preferred although culture should be used for rectal and pharyngeal specimens. The preferred treatment for localized infection is ceftriaxone 125 mg intramuscularly or cefixime 400 mg orally as a single dose. Azithromycin 2 g orally may be used in cases of cephalosporin allergy. Disseminated infection requires higher doses and more prolonged treated, dependent on the site of infection. Diagnosis of infection in the infant should generally use culture methods. Syphilis Pregnancy does not alter the clinical course of syphilis in pregnant women, but there is a high risk of transmission of syphilis to the fetus at all stages of syphilis. The risk is greatest (60%) in primary and secondary syphilis, but remains high (40%) in early latent infection, and in latent maternal infection up to 4 years duration (10%). The risk of transmission becomes minimal in women infected for periods longer than 4 years.156 Syphilis causes spontaneous abortion, preterm birth, congenital malformations, and long-term neurologic deficits. Fetal abnormalities appear to be a consequence of the

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immune response to treponemal organisms, and conversely, due to limited fetal inflammatory responses there are few signs of clinical disease in the fetus before 18 weeks gestation. As a consequence, there are few if any sequelae when treatment is instituted promptly for disease detected early in pregnancy. Syphilis is a disseminated infection, and untreated infection in a fetus after 18 weeks gestation leads to multiorgan disease. Hepatic involvement occurs early, and is associated with decreased fetal erythrocyte production and anemia, which can be followed by output failure with ascites, hydrops, and sometimes death. Infants viable at birth may have jaundice with petechiae or purpura, diffuse adenopathy, rhinitis (snuffles), pneumonia, myocarditis, and nephrosis. Syphilitic infection also alters placental function due to changes in the villi, which become thickened and club-shaped with evidence of vascular insufficiency due to endarteritis and stromal proliferation. All pregnant women should be screened for syphilis with a treponemal or nontreponemal serologic test at the first prenatal visit, and preferably again at delivery. Women at high risk should also be screened at 28 weeks gestation. Women should be treated with benzathine penicillin, 2.4 million units intramuscularly as a single dose for early syphilis, and as a weekly dose for 3 weeks for syphilis greater than 1 year in duration. Penicillin-allergic women should be desensitized. The nontreponemal test should be repeated at 28–32 weeks gestation and at delivery, and at 6 and 12 months after treatment for primary or secondary syphilis, and at 6, 12, and 24 months after treatment for late latent syphilis. Bacterial Vaginosis and Trichomoniasis Bacterial vaginosis (BV) and Trichomonas vaginalis (TV) infection occur almost exclusively in sexually active women. Sexual transmission has not been established for BV, and no single agent appears to be responsible for development of this syndrome, although multiple bacterial species have been evaluated. Both BV and TV infection cause increased vaginal secretions, often with an unpleasant odor. Women may complain of itching or dysuria, or be asymptomatic. In pregnancy, BV and TV infection have been associated with increased risk of preterm birth. Screening for BV at the first prenatal visit is recommended for asymptomatic pregnant women, but only if there is a history of preterm birth. Diagnosis is based on clinical findings and the presence of ‘clue cells’ on wet mount. Treatment with either metronidazole 500 mg orally twice daily or 250 mg orally three times daily, or with clindamycin 300 mg orally twice daily, may be given for a total of 7 days. Routine screening of asymptomatic women without a history of prior preterm birth is not recommended.157 Prospective trials have yielded conflicting results regarding the benefit of treatment for asymptomatic women for prevention of preterm birth. A meta-analysis of 17 trials, of which three included women

considered high risk because of previous preterm birth, suggested there was no significant effect of antibiotic treatment on preterm birth.158 Routine screening for TV infection is not currently recommended. Genital Warts Genital warts may proliferate and grow larger and more friable during pregnancy, and may progress to neoplasm. Large lesions may interfere with delivery. In addition, human papilloma virus (HPV) types 6 and 11 can cause respiratory papillomatosis in infants and children. It is unknown whether infection is transmitted transplacentally or perinatally, and cesarean delivery is not recommended to prevent transmission. Imiqiumod, podophyllin, and podophyllotoxin should not be used during pregnancy. If treatment is needed, the lesions should be treated with cryotherapy, trichloracetic acid, or surgery.

HIV The CDC recommends that all women should be screened for HIV infection early in pregnancy, and again before 36 weeks if at high isk, unless testing is declined (‘opt-out approach’). Universal testing is recommended, since some studies have found that more than one-third of women whose HIV infections were first detected during pregnancy were not aware of, or did not report, risk factors for HIV infection before testing.159 Rapid HIV testing is recommended for women whose HIV status is unknown at the time of labor onset. Recommendations for optimal management of HIVinfected pregnant women are updated regularly. The most recent Public Health Service recommendations (2008),160 plus available data regarding safety of various antiretrovirals in pregnancy and management suggestions for various common clinical scenarios, are available at www.AIDSinfo. nih.gov. The 2008 recommendations are summarized in Table 47.7. These guidelines primarily address prevention of transmission of HIV-1; little information is available regarding management of HIV-2-infected mothers. The goal of HIV management in pregnancy is to maximize the health of the mother, and to prevent maternal–fetal transmission of HIV. Initial evaluation of the HIV-infected pregnant woman should include an assessment of immune function and the need for prophylaxis against opportunistic infections. Treatment of pregnant women is complicated by the need to avoid drugs with teratogenic potential, particularly in the first trimester. Efavirenz, in particular, has been associated with central nervous system defects in animal studies and in some case reports, and an alternative agent substituted whenever possible even for women already taking a regimen that includes it. However, HAART should be offered to all HIV-positive women, since antiretroviral therapy has been shown to reduce congenital HIV transmission even when the mother’s viral load is less than 1000 ­copies/ml.161 Whenever

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Table 47.7  Measures for prevention of mother-to-child HIV transmission Newly diagnosed or previously untreated Women with HIV RNA  1000 copies/ml l  Resistance testing prior to initiation of treatment l  Zidovudine-containing HAART – if possible delay until after first trimester Women with HIV RNA 1000 copies/ml l  Zidovudine-containing HAART – if possible delay until after first trimester l  Consider discontinuing HAART postnatally; if NNRTI was used, stop NNRTI prior to NRTI to prevent emergence of NNRTI resistance Previously known HIV infection On HAART, mother chooses to continue l  Zidovudine-containing HAART regimen l  Fetal ultrasound second trimester for malformations if fetal exposure to efavirenz in the first ­trimester l  Resistance testing if persistently detectable HIV RNA On HAART, mother chooses to stop l  Intrapartum/postpartum zidovudine l  Fetal ultrasound second trimester for malformations if fetal exposure to efavirenz in the first ­trimester ALL HIV-infected pregnant women   Monitor CD4 cell count at initial visit and every 3 months  Measure HIV RNA at initial visit, 2–6 weeks after starting or changing HAART, monthly until undetectable, then every 2 months, and at 34–36 weeks gestation l  Avoid efavirenz in first trimester 3 l  Avoid nevirapine in women with CD4 250 cells/mm l  Monitor for hepatic dysfunction. Check transaminases and electrolytes monthly in the last ­trimester. l  Monitor women on protease inhibitors for glucose intolerance l  Fetal ultrasound first trimester to confirm gestational age l  Intravenous zidovudine should be given during labor even to women with evidence of resistance by genotyping l  Scheduled cesarean delivery if HIV RNA 1000 copies/ml near delivery l  Avoid artificial rupture of membranes, invasive monitoring, and forceps or vacuum extractor during delivery l  Avoid methergine (ergot) in women receiving protease inhibitors or efavirenz l  6 week zidovudine prophylaxis of infants dosed by gestational age; consider additional agents if high maternal viral load or ­resistance. Should be started within 6–12 hours after birth l  Woman does not breastfeed l l

possible, women exposed to HAART during pregnancy should be entered in the Antiretroviral Pregnancy Registry (www.APRegistry.com). Infants of untreated mothers have a 15–40% risk of congenital HIV transmission. HIV transmission can be minimized by administration of HAART combined with intrapartum and postpartum zidovudine. Intrapartum prophylaxis alone is not sufficient; although 30% of transmission occurs intrapartum, estimates are that 50% occurs in the period just prior to delivery, and 20% before 36 weeks. The period between 28 and 36 weeks gestation accounts for a significant proportion of transmission.162 The risk for peripartum transmission is increased in preterm birth, and with prolonged rupture of the membranes. Elective cesarean delivery may reduce the risk of HIV transmission by as much as 50–70%, but is associated with increased risk of maternal complications including endometritis, sepsis, and

pneumonia. Cesarean delivery is primarily recommended for women with persistently elevated viral load, or whose viral load is unknown. In addition to reducing the risk of HIV transmission to the infant, antiretroviral therapy of the mother reduces the risk of infant death.163 Combination antiretroviral therapy is the current standard of care,160 although a number of regimens including zidovudine (AZT) alone, AZT plus lamivudine (3TC), and nevirapine alone for various durations during pregnancy, labor, and to the infant after birth have demonstrated at least partial efficacy.164,165 Combination therapy including a protease inhibitor decreased congenital HIV transmission to 1.2% in comparison to 20% in infants of untreated women.166 Regimens should generally include AZT since passage across the placenta is excellent. Dosing recommendations for AZT are given in Table 47.8. HAART prophylaxis should be started by the 28th week of ­gestation

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Table 47.8  Intrapartum and postpartum dosing of zidovudine Maternal/intrapartum All HIV-positive mothers: l  2 mg/kg body weight intravenously over 1 hour, followed by continuous infusion of 1 mg/kg body weight per hour l  Begin with labor onset, treat until delivery Neonatal/postpartum Term infants (35 weeks): l  2 mg/kg body weight per dose given orally, OR l  1.5 mg/kg body weight per dose given intravenously, begun within 6–12 hours or sooner after birth, then given every 6 hours l  Begin at birth, treat through age 6 weeks 30 weeks up to 35 weeks: l  2 mg/kg body weight per dose given orally, OR l  1.5 mg/kg body weight per dose given intravenously, begun within 6–12 hours or sooner after birth, then given every 12 hours; increased to every 8 hours at age 2 weeks l  Begin at birth, treat through age 6 weeks   30 weeks: l  2 mg per kg body weight per dose given orally, OR l  1.5 mg per kg body weight per dose given intravenously, begun within 6–12 hours or sooner after birth, then given every 12 hours; increased to every 8 hours at age 4 weeks l  Begin at birth, treat through age 6 weeks

in women who are not already receiving antiretroviral ­therapy. Resistance testing is recommended when therapy is initiated and for women whose viral load remains elevated. Antiretrovirals that should be avoided in pregnancy include efavirenz (teratogenicity), nevirapine (hepatic dysfunction in women with CD4 250 cells/mm3), and stavudine plus didanosine (lactic acidosis). Pregnant women receiving protease inhibitors may require increased doses in the third trimester. Early intra-uterine infection with HIV is associated with intra-uterine growth retardation, microcephaly, and craniofacial abnormalities. In several cohort studies, infants of HIV-infected mothers have been shown to have increased morbidity and mortality whether or not they are infected with HIV, although the risk is highest in infants who are infected at birth or within the first 6 weeks of life. Maternal morbidity and mortality, absolute CD4 T cell count of 350 cells/mm3, and increased maternal viral load are predictors of infant morbidity and mortality. Infants most often present with pneumonia and sepsis.167,168 Breastfeeding contributes to transmission in 30–50% infants, and HIV-positive mothers should be advised not to breastfeed, even if receiving HAART. HIV-positive women with chronic hepatitis B co-infection may benefit from a regimen that includes tenofovir plus 3TC or emtricitabine (FTC). These women must be monitored for hepatic toxicity. If antiretroviral therapy is discontinued postpartum, there is a risk of hepatitis flare.

Hepatitis A,B,C Hepatitis A Hepatitis A (HAV) is a very common infection caused by a small, non-enveloped RNA virus that is easily spread by a fecal–oral route. The incubation period is 15–50 days. Initial symptoms are flu-like, with fever, myalgias, and headache, followed by elevation of serum hepatic transaminases and jaundice. Fulminant infection may be accompanied by coagulopathy and signs of acute liver failure. HAV infection is rare in pregnancy in developed countries, occurring in about 1/1000.169 Findings from a retrospective study suggest the risk of preterm labor and other pregnancy complications is increased when acute maternal HAV infection occurs in the second or third trimester.170 HAV infection is diagnosed by detection of anti-HAV IgM in serum. The therapy is supportive, with bed rest, IV fluids, antiemetics, and vitamin K for coagulopathy. Perinatal transmission occurs during travel through birth canal. Prevention of HAV infection includes administration of inactivated vaccine, which is safe in pregnancy, to women traveling or at high risk, and intramuscular immunoglobulin if a known exposure occurs. Hepatitis B Hepatitis B virus (HBV) is a double stranded DNA virus that replicates using a reverse transcription step. Most transmission occurs through contact with blood and body fluids, and sexual transmission is well-recognized. The ­incubation

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period is 2 to 4 months. Acute or active HBV infection is diagnosed by detection of hepatitis B surface antigen (HBsAg) in serum. In addition to acute hepatitis, HBV infection carries the risk of chronic infection (5–10% of infections) with subsequent cirrhosis and liver dysfunction and the risk of hepatocellular carcinoma, which develops in up to 50% of chronic carriers. The risk of chronic infection is inversely related to the age of the individual when infection is acquired, and infants infected at birth have a 90% likelihood of developing chronic disease. Acute HBV infection complicates 1–2 per 1000 pregnancies, and chronic HBV is found in 1% of pregnancies. The risk of transmission to the fetus is greatest when maternal acute HBV infection is acquired in the second (10%) and third (70%) trimesters, since these mothers are most likely to be shedding HBV at delivery. Mothers who are both HBeAg and HBsAg are most infectious. More than 95% of transmission to the infant occurs during labor and delivery. In the United States prior to routine screening and treatment of newborns, 4% of all acute and 25% of all chronic HBV infections were acquired in the ­ perinatal period.169 Because infants who acquire HBV are very likely to develop chronic infection, the CDC recommends that women at high risk for acquisition of HBV infection should receive HBV vaccine, which is safe in pregnancy. Women exposed to HBV, and infants of mothers who are HBsAg, or who were diagnosed with HBV infection in pregnancy, should receive prophylaxis with HBV vaccine and hepatitis B immune globulin (HBIG). Some evidence suggests that administration of HBIG to HBeAg/HBsAg women in the third trimester of pregnancy can prevent transmission of HBV to infants who acquire infection in utero rather during the birth process.171 All women should be tested for HBsAg at the first prenatal visit in each pregnancy, even if previously tested or vaccinated. Women who have not previously been screened or who are at high risk for hepatitis B (multiple partners, STD, intravenous drug use, HbsAg partner, clinical hepatitis) should be screened at delivery. Women at risk who are not seropositive should be vaccinated. Hepatitis C Hepatitis C virus (HCV) is an enveloped, single stranded RNA virus transmitted through transfusion or other contact with blood. Sexual transmission may occur but has not clearly been documented. HCV becomes chronic in 50% infections, and has a high association with hepatocellular carcinoma. Between 2 and 5% of pregnant women in the United States are infected with HCV.169 Diagnosis of HCV is based on serologic testing, followed by confirmatory serologic testing or qualitative molecular testing for viral RNA. Pregnancy does not appear to modify the course of HCV in the mother. Acute HCV during pregnancy appears to be associated with

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some increased risk of preterm delivery, and infants are susceptible to infection during delivery because of exposure to infectious virus during the birth process. Vertical transmission occurs in 7% infants whose mothers are HCV RNApositive, but not from mothers who are HCV RNA-negative. Cesarean delivery may not decrease transmission of HCV.172 All pregnant women with a history of IV drug use, blood transfusion or organ transplantation before 1992 should be screened for hepatitis C infection with a serologic assay. Use of interferon (causes fetal growth retardation) and ribavirin (teratogenic effects) is contraindicated in pregnancy.

Group B streptococcus Studies in the United States and Europe have found that between 10 and 30% of women of child-bearing age are colonized by group B streptococcus (GBS). Most pregnant women are asymptomatic, although a small number develop GBS urinary tract infection, chorioamnionitis or endometritis. Without prophylaxis, colonization can be demonstrated in over 40% of infants born to colonized mothers.173 The majority of vertical transmission occurs during labor and passage through the birth canal. Intra-uterine infection of the fetus appears to follow ascending spread of GBS from the vagina. A small number of infants may be infected after swallowing infected amniotic fluid. GBS-infected infants may present with sepsis, pneumonia, meningitis, osteomyelitis or septic arthritis. Delivery at 37 weeks gestation, or prolonged membrane rupture, or maternal intrapartum temperature 99.5 °F (37.5 °C) increase the risk of early-onset GBS disease by 6.5 times. Prior to implementation of the 2002 guidelines for universal screening and intrapartum treatment supported by the CDC,174 the American College of Obstetrician sand Gynecologists (ACOG), and the American Academy of Pediatrics, the attack rate for Group B streptococcal ­neonatal sepsis and meningitis in the United States was 2 per 1000, with a 50% mortality.175 During the 3 years (2003–2005) following implementation of the CDC guidelines, there was a 70% decrease in the rate of early (infants aged 0–6 days) neonatal infection, although the overall rate of invasive group B streptococcal disease increased. Intrapartum prophylaxis did not affect the rate of late (infants aged 7–89 days) infection. The major benefit of prophylaxis has been observed in white infants. By contrast, rates in black infants rose by 70% during 2003–2005.176 In general, the incidence of invasive group B streptococcal infection is twice as high in blacks as in whites, and the relative risk is 4 to 5 times as high in infants and pregnant women.177 Per the 2002 guidelines, all pregnant women should be screened between 35 and 37 weeks gestation, or at labor if not yet screened. Women screened early should be retested after 4 weeks if they have not delivered. Specimens should be obtained from both the rectum and vagina, and tested for GBS, either by a culture method using a

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s­ elective ­ enrichment broth, or by a nucleic acid amplification method. Women with GBS UTI do not need to be rescreened. The 2002 recommendations are summarized in Table 47.9. Per the guidelines, an infant who was 38 weeks gestation, appears healthy, and whose mother received at least 4 hours of intrapartum prophylaxis before delivery may be discharged home after 24 hours if there are no other outstanding concerns, and a person who can comply with home observation will be present. There are efforts under way to develop a vaccine to prevent invasive GBS disease. Recent CDC surveillance data suggests that a pentavalent conjugate vaccine including types Ia, Ib, II, III, and V, could prevent up to 96% of neonatal disease in the United States.177

Listeriosis Infection with the Gram-positive bacillus Listeria ­monocytogenes is most often food-borne. It is reported to have the highest mortality rate of any food-borne pathogen, even when appropriate antibiotic therapy is given.178 Because it is an intracellular pathogen, and is dependent on T cell-immunity for resolution of infection, serious ­ illness occurs in individuals with compromised cell-mediated immunity. Up to one-third of reported cases of listeriosis occur in pregnant women, most frequently in the third trimester.179 Although infection may cause maternal septicemia, most often it is apparent only as a flu-like illness, or as premature labor or decreased fetal movements. The initial site of infection after ingestion is usually the intestine, followed by translocation and spread to the liver and spleen where replication occurs. Although the primary mode of infection of the placenta and gravid uterus is hematogenous, ascending infection from the vagina may also occur. Listeria, like other Gram-positive organisms, binds immune cells through TLR-2; TLR-2 receptors are also present on amniotic epithelial cells, decidual inflammatory cells, and placenta. Binding of Listeria to pregnancy-associated tissues may be mediated in part through the TLRs expressed by these cells, or might contribute to apoptotic cell death of placental tissues. Once the uterus is infected, the organism evades non-specific innate and specific cell-mediated immune responses. Invasion factors such as listeriolysin O and phospholipase C allow the bacteria to escape from phagocytic vacuoles by forming pores in cell membranes, and causing lysis of the vacuole. Listeria is able to replicate in the cell cytosol, and to use intracellular actin polymerization to propel bacteria from one cell to another cell with minimal exposure to the extracellular environment.178 Listeria also expresses surface proteins called internalins that enable the organism to invade nonphagocytic cells including placental syncytiotrophoblast and villous cytotrophoblast cells, as well as intestinal cells.180

The outcome of placental infection is pregnancy loss, fetal death, preterm birth or stillbirth.181 A newborn exposed to Listeria may develop septicemia or meningoencephalitis. In some outbreaks, up to 63% of pregnancies complicated by maternal listeriosis terminated in fetal or neonatal death. Empiric treatment with ampicillin or ­ amoxicillin may improve outcome.181

Emerging infections Dengue Dengue hemorrhagic fever (DHF) is a serious complication of infection with the mosquito-borne dengue fever virus, and is more likely to follow a primary dengue infection in pregnant than in nonpregnant women. DHF may be confused with pre-eclampsia, because of the symptoms of thrombocytopenia, liver dysfunction, capillary leak, edema, ascites, and decreased urine output.182 Most pregnant women with dengue present in the third ­ trimester. Dengue infection in the first trimester of pregnancy may be complicated by spontaneous abortion, and in the third trimester by premature delivery, and by severe and prolonged bleeding during surgical deliveries. The incidence of fetal death is increased. In DHF, increased vascular permeability and endothelial leakage damage the placenta, and may allow vertical transmission of virus. Fetal malformations do not appear to be associated with maternal infection.183 However, exposure in utero may predispose the infant to DHF. Treatment is supportive, with intravenous fluid replacement and platelet transfusions as needed.182 Pregnant women should avoid travel to areas of ongoing dengue transmission, particularly in the third trimester.

West Nile Virus (WNV) West Nile virus is a mosquito-borne flavivirus that infects humans, other mammals including horses, dogs, cats, alpacas, and non-mammalian species such as birds and ­alligators. Many species of mosquito can transmit the virus. Infection of the placenta and transmission to the fetal has been shown in a murine model,184 and vertical transmission of WNV with subsequent encephalitis was found in 3 of 72 live-born infants.185 However, a study by the same authors of birth outcomes following WNV infection in pregnant women in the United States has not clearly demonstrated the relationship to developmental abnormalities. Reports of outcomes ­ following WNV infection during pregnancy have included cases of fetal growth retardation,186 and a more dramatic case of chorioretinal scarring and brain abnormalities, including lissencephaly and severe white matter loss, in an infant born to a mother infected with WNV during the second trimester.187

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Table 47.9  Intrapartum prophylaxis for prevention of early-onset GBS infection Screen   All pregnant women between 35 and 37 weeks gestation, unless GBS bacteriuria has been detected

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Treat   Women whose culture results are unknown but who have risk factors: Delivery at 37 weeks gestation Prolonged membrane rupture 18 hours Maternal intrapartum temperature 38.0 °C ■  Women with GBS bacteriuria during the current pregnancy ■  Women who previously gave birth to an infant with invasive GBS ■

Do not treat   Women with negative cultures obtained during the 5 weeks prior to delivery l  GBS-colonized women undergoing planned cesarean deliveries who have not begun labor or had rupture of membranes

■



Regimens   Recommended l  Penicillin G, 5 million units intravenously  1 dose, followed by 2.5 million units intravenously every 4 hours until delivery ■  Alternative l  Ampicillin 2 g intravenously  1 dose, followed by 1 g intravenously every 4 hours until delivery ■  Penicillin allergy l  Low risk for anaphylaxis:   Cefazolin 2 g intravenously  1 dose, followed by 1 g intravenously every 8 hours until delivery l  High risk for anaphylaxis: GBS susceptible to erythromycin   Erythromycin 500 mg intravenously every 6 hours until delivery GBS susceptible to clindamycin  Clindamycin 900 mg intravenously every 8 hours until delivery GBS resistant to erythromycin and clindamycin   Vancomycin 1 g intravenously every 12 hours until delivery ■



l

l

l

l

Adapted from CDC, Prevention of perinatal group B Streptococcal disease. MMWR 2002;51(RR11);1-22.

Viral Hemorrhagic Fevers Viral hemorrhagic fevers including Lassa fever and Ebola appear to be more severe during pregnancy, and mortality is higher. For pregnant women infected with Lassa fever, the risk of death is highest in the third trimester. The placenta is thought to be a site for viral replication, and women improve rapidly after delivery or termination of pregnancy.188 In Ebola virus infection, the risk of death is similar in all trimesters, and pregnant women are more likely to have hemorrhagic and neurologic complications.189

Lymphocytic Choriomeningitis Virus (LCMV) LCMV is an arenavirus that is the cause of a zoonotic infection acquired from contact with rodents or their waste. In adults, infection causes fever, malaise, myalgias, anorexia, nausea, vomiting, pharyngitis, and adenopathy. CNS disease occurs after a period of improvement. Intra-uterine LCMV infection can cause fetal death, hydrocephalus, microcephaly or macrocephaly, chorioretinitis, and neurologic sequelae such as psychomotor retardation and deafness. Neurologic findings are highly variable, and may correlate with developmental stage at the time of infection.

The diagnosis is made serologically.190,191 Pregnant women should avoid rodents and their excreta.

Human Granulocytic Anaplasmosis (HGA, Previously Called Human Granulocytic Ehrlichiosis) Only a few cases of infection in pregnant women by Anaplasma phagocytophilum (previously Ehrlichia phagocytophilum) have been described. In sheep and cows, infection in late pregnancy has been reported to cause stillbirth, abortion, and congenital infection. When recognized and treated, there do not appear to be adverse consequences in human pregnancy. In a recent report reviewing nine cases of HGA in women between 10 and 39 weeks gestation, pregnancy did not affect the severity of illness. Congenital infection was found in only one case, and all patients were treated successfully with either doxycycline or rifampin.192

Clostridium Difficile Infection (CDI) Disease due to the anaerobic bacterium Clostridium difficile is most often manifested as diarrhea that may progress to

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fulminant colitis, sepsis, and death. CDI usually occurs as a healthcare-associated infection, particularly in patients with disturbed bowel flora because of preceding antibiotic use or, rarely, inflammatory bowel disease. Prior to 2005, CDI was reported infrequently in pregnant women. However, in 2005–2006, 10 women with severe CDI were reported to the CDC.193 Two of these women were infected by an apparently new hyper-virulent epidemic strain designated PCR ribotype 027.3 or North American Pulsed-Field type 1 (NAP1), which hyper-produces toxins A and B, and an additional product, binary toxin. Three of the pregnancies ended in stillbirths. Six women developed toxic megacolon, and five of those underwent colectomy. Three women ultimately died. Most of the women had not previously been admitted to the hospital, and in at least one case there was no known prior antimicrobial treatment, leading to a concern that pregnancy might be a predisposing factor for severe CDI. Th-1 cytokines have been proposed to play a role in resolution of CDI, and one hypothesis suggests that the decreased Th-1 response later in pregnancy might coincide with an increased susceptibility to CDI. Four additional cases of peripartum CDI, in two cases with the ‘hyper-­virulent’ strain, have been reported recently.194

Potential agents of bioterrorism Smallpox The last case of naturally occurring smallpox was reported from Somalia in 1977, but smallpox remains a concern because of its potential use as an agent of bioterrorism. In historical studies, mortality rates have generally been much higher in pregnant women, reportedly up to 63%.195 A recent review of four large studies over the period from 1868 through 1962 found an overall case fatality rate in pregnant women of 34.3%, with risk increasing from an overall 22.9% in the first trimester to 40.5% in the third trimester.196 Pregnant women are also more likely to develop hemorrhagic smallpox. Vaccination offers considerable protection against mortality, and the risk of death from smallpox infection appears to be 10-fold higher in unvaccinated as compared to previously vaccinated pregnant women.195,196 Acute maternal smallpox also has a devastating affect on pregnancy outcome, causing spontaneous abortion and premature termination of pregnancy. The overall proportion of abortion or preterm birth was 39.9%,196 but has been reported to be up to 60–75%.195 Over half of live births born to mothers infected in the second half of pregnancy die within the two weeks after delivery, and most within the first 72 hours. The risk of miscarriage and preterm birth were similarly elevated even in women with mild cases of smallpox. Prior vaccination does not appear to improve pregnancy outcome.196

Cellular immunity appears to be the most important aspect of the immune response determining outcome, since neutralizing antibodies develop early in primary infections and do not influence lesion size or affect survival. Animal models in non-pregnant inbred mice of experimental poxvirus infections with vaccinia or the murine poxvirus ectromelia have shown that a ‘type 1’ immune response and production of Th1 cytokines promote resistance to smallpox, but a ‘type 2’ response enhances pathogenesis.195 Smallpox vaccination of pregnant women is recommended only in the setting of a potential outbreak, since vaccination just before conception or during pregnancy can result, in rare instances, in fetal vaccinia. The risk is very small, and only about 50 cases have been documented, despite massive smallpox vaccination during eradication efforts.197 For the 376 women in the US military enrolled in the National Smallpox Vaccine in Pregnancy Registry from 2003 through 2006, the rates of pregnancy loss (11.9%), preterm birth (10.7%), and birth defects (2.8%), were not increased, and there were no cases of fetal vaccinia.198

Issues regarding antibiotic management in pregnancy Because most antimicrobial agents cross the placenta, drugs that could potentially have adverse effects on the fetus should be avoided in other than life-saving circumstances. An agent with a known safety profile should be used whenever possible. Currently, the FDA categorizes antimicrobials for use in pregnancy based on evidence of safety and risk as Category A (Studies of use by pregnant women without known adverse effects on fetus), Category B (Appear safe in animal studies, limited studies in pregnant women or appear safe in human studies although some problem in studies of pregnant animals), Category C (Little or no evidence regarding safety or harm in pregnant women), Category D (Evidence of harm in some cases, but benefit may outweigh risk in some circumstances), Category X (Risk is high, unlikely to be outweighed by benefit). The Food and Drug Administration (FDA) plans to change this classification system in the near future to be more clinically descriptive. Most antibiotics are pregnancy Category B, such as the penicillins, including beta lactam/beta-lactamase inhibitor combinations, cephalosporins, aztreonam, nitrofurantoin, clindamycin, and aminoglycosides, and these drugs are generally considered safe in pregnancy. Sulfonamides and trimethoprim should be avoided when other agents are available. These drugs affect folate metabolism, potentially affecting first trimester neural tube development, and in the third trimester, sulfonamides can lead to neonatal

C h a p t e r 4 7     Infections in Pregnancy l

Table 47.10  Guidelines for vaccination of pregnant women No contraindications   Inactivated influenza   Hepatitis B l  Tetanus-diphtheria (Td) l  Meningococcal (MPSV4) l  Rabies l l

Presumed low risk: use if high likelihood of disease exposure   Hepatitis A   Pneumococcal polysaccharide (PPV23) l  Inactivated polio vaccine l  Tetanus, diphtheria, pertussis (Tdap) l l

Unknown risk: use only if very high likelihood of disease exposure   Anthrax   Vaccinia (smallpox) l  Japanese encephalitis l  Yellow fever l l

Contraindicated   Human papillomavirus   Attenuated influenza l  Measles l  Mumps l  Rubella l  Attenuated polio vaccine l  Varicella l  Zoster l  BCG l l

Adapted from CDC and ACIP Guidelines, updated May 2007.

h­ yperbilirubinemia and kernicterus. In G6PD-deficient women, sulfonamides can cause hemolytic anemia that may be poorly tolerated in pregnancy. Ceftriaxone is also known to displace bilirubin from albumin, but this does not appear to limit its use in pregnant women. Because GFR is increased by 30–50% in pregnancy, doses of some drugs such as aminoglycosides and ceftriaxone may require adjustment.75 Monitoring serum levels may assist with dosing of vancomycin and aminoglycosides.

Vaccination There are no known risks to vaccination of pregnant women with bacterial vaccines or toxoids or with inactivated virus vaccine. Attenuated live vaccines should be avoided, since there is a potential risk for dissemination to the fetus. Accidental vaccination with a live-virus vaccine is not considered an indication for pregnancy termination. Guidelines from the CDC were updated in 2007 (see Table 47.10).

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References   1. Berg CJ, Chang J, Callaghan WM, Whitehead SJ. Pregnancyrelated mortality in the United States, 1991–1997. Obstet Gynecol 2003;101:289–96.   2. MacKay AP, Berg CJ, King JC, Duran C, Chang J. Pregnancyrelated mortality among women with multifetal pregnancies. Obstet Gynecol 2006;107:563–68.   3. Martin JA, Hamilton BE, Sutton PD, et al. Centers for Disease Control and Prevention National Center for Health Statistics, National Vital Statistics System. Birth: final data for 2005. Natl Vital Stat Rep 2007;56(6):1–103.   4. Ledger WJ. Perinatal infections and fetal/neonatal brain injury. Curr Opin Obstet Gynecol 2008;20:120–24.   5. Shim SS, Romero R, Hong JS, et al. Clinical significance of intraamniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 2004;191:1339–45.   6. Goldenberg RI, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:73–82.   7. Gibbs RS. The origins of stillbirth: infectious diseases. Semin Perinatol 2002;26(1):75–78.   8. MacDorman MF, Hoyert DL, Martin JA, Munson ML, Hamilton BE. Fetal and perinatal mortality, United States, 2003. Natl Vital Stat Rep 2007;55(6):1–17.   9. Zupan J, Ohman EA. Neonatal and Perinatal Mortality: Country, Regional and Global Estimates. Geneva: World Health Organization; 2006, www.who.int/making_pregnancy_ safer/publications/neonatal.pdf. 10. Spellberg B, Edwards JE Jr. Type 1/Type 2 immunity in infectious diseases. Clin Infect Dis 2001;32:76–102. 11. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenom? Immunol Today 1993;14:353–56. 12. Sargent IL, Borzychowski AM, Redman CWG. NK cells and human pregnancy – an inflammatory view. Trends Immunol 2006;27:399–404. 13. Sacks G, Sargent I, Redman C. An innate view of human pregnancy. Immunol Today 1999;20:114–18. 14. Mellor AL, Munn D. Policing pregnancy: tregs help keep the peace. Trends Immunol 2004;25:563–65. 15. Saito S, Nakashima A, Myojo-Higuma S, Shiozaki A. The balance between cytotoxic NK cells and regulatory NK cells in human pregnancy. J Reprod Immunol 2008;77:14–22. 16. Bachy V, Williams DJ, Ibrahim MAA. Altered dendritic cell function in normal pregnancy. J Reprod Immunol 2008;78:11–21. 17. Christiaens I, Zaragoza DB, Guilbert L, Robertson SA, Mitchell BF, Olson DM. Inflammatory processes in preterm and term parturition. J Reprod Immunol 2008;79:50–57. 18. Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 1999;10:137–42. 19. Hunt JS, Jadhav L, Chu W, Geraghty DE, Ober C. Soluble HLA-G circulates in maternal blood during pregnancy. Am J Obstet Gynecol 2000;183:682–88. 20. Carosella ED, Rouas-Freiss N, Paul P, Dausset J. HLA-G: a tolerance molecule from the major histocompatability complex. Immunol Today 1999;20:60–62.

558

s e c t i o n 8     Infectious Disease l

21. Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N. HLA-G molecules: from maternal-fetal tolerance to tissue acceptance. Adv Immunol 2003;81:199–252. 22. Lin A, Xu H, Yan W. Modulation of HLA expression in human cytomegalovirus immune evasion. Cell Mol Immunol 2007;4:91–98. 23. Schust DJ, Tortorella D, Ploegh HL. HLA-G and HLA-C at the feto-maternal interface: lessons learned from pathogenic viruses. Semin Cancer Biol 1999;9:37–46. 24. Moraes-Pinto MI, Vince GS, Flanagan BF, Hart CA, Johnson PM. Localization of IL-4 and IL-4 receptors in the human term placenta, deciduas, and amniochorionic membranes. Immunology 1997;90:87–94. 25. Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ, Fisher SJ. Human placental cytotrophoblasts produce the cytokine interleukin 10. J Exp Med 1996;184:539–48. 26. Dungy LJ, Siddiqi TA, Khan S. Transforming growth factorbeta 1 expression during placental development. Am J Obstet Gynecol 1991;165:853–57. 27. Ando N, Hirahara F, Fukushima J, et al. Minaguchi H. Differential gene expression of TGF-beta isoforms and TGF-beta receptors during the first trimester of pregnancy at the human maternal-fetal interface. Am J Reprod Immunol 1998;40:48–56. 28. Ayatollahi M, Geramizadeh B, Yazdani M, Azarpira N. Effect of the immunoregulatory cytokines on successful pregnancy depends upon the control of graft rejection mechanisms. Transplant Proc 2007;39:244–45. 29. Motrán CC, Lopez Diaz F, Gruppi A, Slavinn D, Chatton B, Bocco JL. Human pregnancy-specific glycoprotein 1a (PSG1a) induces alternative activation in human and mouse monocytes and suppresses the accessory cell-dependent T cell proliferation. J Leukoc Biol 2002;72:512–21. 30. Holmlund U, Cebers G, Dahlfors AR, et al. Expression and regulation of the pattern recognition receptors Toll-like receptor-2 and Toll-like receptor-4 in the human placenta. Immunology 2002;107:145–51. 31. Abrahams VM, Mor G. Toll-like receptors and their role in the trophoblast. Placenta 2005;26:540–47. Review. 32. Rindsjö E, Holmlund U, Sverremark-Ekström E, Papadpgiannakis N, Scheynius A. Toll-like receptor-2 expression in normal and pathologic human placenta. Hum Pathol 2007;38:468–73. 33. Aflatoonian R, Fazeli A. Toll-like receptors in female reproductive tract and their menstrual cycle-dependent expression. J Reprod Immunol 2008;77:7–13. 34. Forest MG. Pituitary gonadotrophin and sex steroid secretion during the first two years of life. In: MM Grumbach, PC Sizonenko, ML Aubert, eds. Control of the Onset of Puberty. Baltimore, MD: Williams and Wilkins; 1990. 35. Clarke AG, Kendall MD. The thymus in pregnancy: the interplay of neural, endocrine and immune influences. Immunol Today 1994;15:545–52. 36. Medina KL, Kincade PW. Pregnancy-related steroids are potential negative regulators of B lymphopoiesis. Proc Natl Acad Sci U S A 1994;91:5382–86. 37. Medina KL, Smithson G, Kincade PW. Suppression of B lymphopoiesis during normal pregnancy. J Exp Med 1993;178:1507–15.

38. Lutton B, Callard I. Evolution of reproductive-immune ­interactions. Integ Compar Biol 2006;46:1060–71. 39. Piccinni MP, Scaletti C, Maggi E, Romagnani S. Role of hormone-controlled Th1-and Th2-type cytokines in successful pregnancy. J Neuroimmunol 2000;109:30–33. 40. Ehring GR, Kerschbaum HH, Eder C, et al. A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K channels, Ca2 signaling, and gene expression in T lymphocytes. J Exp Med 1998;188:1593–602. 41. Piccinni MP, Giudizi MG, Biagiotti R, et al. Progesterone favors the development of human T helper cells in producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 1995;155:128–33. 42. Arck P, Hansen PJ, Mulac Jericevic B, Piccinni MP, SzekeresBartho J. Progesterone during pregnancy: endocrine-immune cross-talk in mammalian species and the role of stress. Am J Reprod Immunol 2007;58:268–79. 43. Druckmann R, Druckmann MA. Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol 2005;97:389–96. 44. Polanczyk MJ, Carson BD, Subramanian S, et al. Cutting edge: estrogen drives expansion of the CD4CD25 regulatory T cell compartment. J Immunol 2004;173:2227–30. 45. Roberts CW, Walker W, Alexander J. Sex-associated steroids and immunity to protozoan parasites. Clin Micro Rev 2001;14:473–88. 46. Furr PM, Taylor-Robinson D. Oestradiol-induced infection of the genital tract of female mice by Mycoplasma hominis. J Gen Microbiol 1989;135:2743–49. 47. Furr PM, Taylor-Robinson D. The establishment and persistence of Ureaplasma urealyticum in oestradiol-treated female mice. J Med Microbiol 1989;29:111–14. 48. Kaushic C, Zhou F, Murdin AD, Wira CR. Effects of estradiol and progesterone on susceptibility and early immune responses to Chlamydia trachomatis infection in the female genital tract. Infect Immun 2000;28:4297–316. 49. MacMurray RW. Estrogen, prolactin, and autoimmunity: actions and interactions. Int Immunopharmacol 2001;1:995–1008. 50. Kapoor N, Sankaran S, Hyer S, Shehata H. Diabetes in pregnancy: a review of current evidence. Curr Opin Obstet Gynecol 2007;19:586–90. 51. Lao TT, Chan BC, Leung WC, Ho LF, Tse KY. Maternal hepatitis B infection and gestational diabetes mellitus. J Hepatol 2007;47:46–50. 52. Lucas MJ. Diabetes complicating pregnancy. Obstet Gynecol Clin North Am 2001;28:513–36. 53. Stamler EF, Cruz ML, Mimouni F, et al. High infectious morbidity in pregnant women with insulin-dependent diabetes: an understated complication. Am J Obstet Gynecol 1990;163:1217–21. 54. Chaim W, Bashiri A, Bar-David J, Shoham-Vardi I, Mazor M. Prevalence and clinical significance of postpartum endometritis and wound infection. Infect Dis Obstet Gynecol 2000;8:77–82. 55. Schneid-Kofman N, Sheiner E, Levy A, Holcberg G. Risk factors for wound infection following cesarean deliveries. Int J Gynaecol Obstet 2005;90:10–15. 56. Piper JM, Georgiou S, Xenakis EM, Langer O. Group B streptococcus infection rate unchanged by gestational diabetes. Obstet Gynecol 1999;93:292–96.

C h a p t e r 4 7     Infections in Pregnancy l

57. Ovalle A, Levancini M. Urinary tract infections in pregnancy. Curr Opinion Urol 2001;11:55–59. 58. Novak KF, Taylor GW, Dawson DR, Ferguson JE 2nd, Novak MJ. Periodontitis, and gestational diabetes mellitus: exploring the link in NHANES III. J Publ Health Dent, Summer 2006;66:163–68. 59. Fallarino F, Grohman U, Hwang KW, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206–12. 60. Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol 2006;7:241–46. 61. Krejci CB, Bissada NF. Women’s health issues and their relationship to periodontitis. J Am Dent Assoc 2002;133:323–29. 62. Patterson TF, Andriole VT. Detection, significance, and therapy of bacteriuria in pregnancy. Infect Dis Clin North Am 1997;11:593–608. 63. Connolly A, Thorp JM. Urinary tract infections in pregnancy. Urol Clin North Am 1999;26:779–87. 64. Macejko AM, Schaeffer AJ. Asymptomatic bacteriuria and symptomatic urinary tract infections during pregnancy. Urol Clin North Am 2007;34:35–42. 65. Smaill F. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev 2007(2), CD000490. Review. 66. Ramsey PS, Ramin KD. Pneumonia in pregnancy. Obstet Gynecol Clin North Am 2001;28:553–59. 67. Cole DE, Taylor TL, McCullough DM, Shoff CT, Derdak S. Acute respiratory distress syndrome in pregnancy. Crit Care Med 2005;33(Suppl. 10):S269–78. 68. Bánhidy F, Acs N, Puhó EH, Czeizel AE. Maternal acute respiratory infectious diseases during pregnancy and birth outcomes. Eur J Epidemiol 2008;23:29–35. 69. Bakardjiev AI, Theriot JA, Portnoy DA. Listeria monocytogenes traffics from maternal organs to the placenta and back. PLoS Pathog 2006;2:e66. 70. Gilstrap LC, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol Clin North Am 2001;28:581–91. 71. Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40:643–54. 72. Rouse DJ, Andrews WW, Goldenberg RL, Owen J. Screening and treatment of asymptomatic bacteriuria of pregnancy to prevent pyelonephritis: a cost effectiveness and cost–benefit analysis. Obstet Gynecol 1995;86:119–23. 73. Hill JB, Sheffield JS, McIntire DD, Wendel GD. Acute pyelonephritis in pregnancy. Obstet Gynecol 2005;105:18–23. 74. Towers CV, Kaminskas CM, Garite TJ, Nageotte MP, Dorchester W. Pulmonary injury associated with antepartum pyelonephritis: can patients at risk be identified? Am J Obstet Gynecol 1991;164:974–78. 75. Popovi J, Gruji Z, Sabo A. Influence of pregnancy on ceftriaxone, cefazolin, gentamicin pharmacokinetics. J Clin Pharm Ther 2007;32:595–602. 76. Le J, Briggs GG, McKeown A, Bustillo G. Urinary tract infections during pregnancy. Ann Pharmacother 2004;38:1692– 16701. Review. 77. Jepson RG, Craig JC. A systematic review of the evidence for cranberries and blueberries in UTI prevention. Mol Nutr Food Res 2007;51:738–45.

559

78. Madinger NE, Greenspoon JS, Ellrodt AG. Pneumonia during pregnancy: has modern technology improved maternal and fetal outcome?  Am J Obstet Gynecol 1989;161:657–62. 79. Rigby FB, Patorek JG. Pneumonia during pregnancy. Clin Obstet Gynecol 1996;39:107–19. 80. Goodnight WH, Sper DE. Pneumonia in pregnancy. Crit Care Med 2005;33(Suppl. 10):S390–97. 81. Zeeman GG, Wendel GD, Cunningham FG. A blueprint for obstetrical critical care. Am J Obstet Gynecol 2003;188:532–36. 82. Tan MP, Koren G. Chickenpox in pregnancy: revisited. Reprod Toxicol 2006;21:410–20. 83. Chapman S, Duff P. Varicella in pregnancy. Semin Perinatol 1993;17:403–9. 84. Haake DA, Zakowski PC, Haake DL. Early treatment with acyclovir for varicella pneumonia in otherwise healthy adults. Rev Infect Dis 1990;12:788–98. 85. Mullooly JP, Barker WH, Nolan TF. Risk of acute respiratory disease among pregnant women during influenza A epidemics. Public Health Rep 1986;101:205–11. 86. Wong SF, Chow KM, Leung TN, et al. Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am J Obstet Gynecol 2004;191:292–97. 87. Ormerod P. Tuberculosis in pregnancy and the puerperium. Thorax 2001;56:494–99. 88. Espinal MA, Reingold AL, Lavandera M. Effect of pregnancy on risk of developing active tuberculosis. J Infect Dis 1996;173:488–91. 89. Tripathy SN, Tripathy SN. Tuberculosis, and pregnancy. Int J Gynaecol Obstet 2003;80:247–53. 90. Centers for Disease Control and Prevention. Treatment of tuberculosis. MMWR 2003;52(No. RR-11):1–77. 91. Stevens DA. Coccidioidomycosis. N Engl J Med 1995;332:1077–82. 92. Rosenstein NE, Emery KW, Werner SB, et al. Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995–1996. Clin Infect Dis 2001;32:708–15. 93. Hooper JE, Lu Q, Pepkowitz SH. Disseminated coccidioidomycosis in pregnancy. Arch Pathol Lab Med 2007;131:652–55. 94. Udagawa H, Oshio Y, Shimuzu Y. Serious group A streptococcal infection around delivery. Obstet Gynecol 1999;94:153–57. 95. French LM, Smaill FM. Antibiotic regimens for endometritis after delivery. Cochrane Database Syst Rev 2004;4, CD001067. Review. 96. Maberry MC, Gilstrap LC 3rd, Bawdon R, Little BB, Dax J. Anaerobic coverage for intra-amnionic infection: maternal and perinatal impact. Am J Perinatol 1991;8:338–41. 97. Tran SH, Cheng YW, Kaimal AJ, Caughey AB. Length of rupture of membranes in the setting of premature of membranes at term and infectious maternal morbidity. Am J Obstet Gynecol 2008;198(700):e1–e5. 98. Bobitt JR, Hayslip CC, Damato JD. Amniotic fluid infection as determined by transabdominal amniocentesis in patients with intact membranes in premature labor. Am J Obstet Gynecol 1981;140:947–952. 99. Ledger WJ. Post-partum endomyometritis diagnosis and treatment: a review. J Obstet Gynaecol Res 2003;29:364–373.

560

s e c t i o n 8     Infectious Disease l

100. Smaill F, Hoffmeyr GJ. Antibiotic prophylaxis for cesarean section. Cochrane Database Syst Rev 2002;3, CD000933. Review. 101. Tita ATN, Hauth JC, Grimes A, Owen J, Stamm AM, Andrews WW. Decreasing incidence of postcesarean endometritis with extended-spectrum antibiotic prophylaxis. Obstet Gynecol 2008;11:51–56. 102. Shannon C, Brothers LP, Philip NM, Winikoff B. Infection after medical abortion: a review of the literature. Contraception 2004;70:183–190. 103. Fischer M, Bhatnagar J, Guarner J, et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 2005;353:2352–2360. 104. Cohen AL, Bhatnagar J, Reagan S, et al. Toxic shock ­associated with Clostridium sordellii and Clostridium perfringens after medical and spontaneous abortion. Obstet Gynecol 2007;110:1027–1033. 105. Aronoff DM, Hao Y, Chung J, et al. Misoprostol impairs female reproductive immunity against Clostridium sordelli. J Immunol 2008;180:8222–8230. 106. Livingston JC, Llata E, Rhinehart E, et al. Gentamicin and clindamycin therapy in postpartum endometritis: the efficacy of daily dosing versus dosing every 8 hours. Am J Obstet Gynecol 2003;188:149–152. 107. Brumfield CG, Hauth JC, Andrews WW. Puerperal infection after cesarean delivery: evaluation of a standardized protocol. Am J Obstet Gynecol 2000;182:1147–1151. 108. Olsen MA, Butler AM, Willers DM, Devkota P, Gross GA, Fraser VJ. Risk factors for surgical site infection after low transverse cesarean section. Infect Control Hosp Epidemiol 2008;29:477–484. 109. Martens MG, Kolrud BL, Faro S, Maccato M, Hammill H. Development of wound infection or separation after cesarean delivery, prospective evaluation of 2431 cases. J Reprod Med 1995;40:171–175. 110. Goepfert AR, Guinn DA, Andrews WW, Hauth JC. Necrotizing fasciitis after cesarean delivery. Obstet Gynecol 1997;89:409–412. 111. Michie C, Lockie F, Lynn W. The challenge of mastitis. Arch Dis Child 2003;88:818–821. 112. I. Semmelweis, The Etiology, the Concept, and the Prophylaxis of Childbed Fever: Classics of Obstetrics and Gynecology Library [translated by Frank P. Murphy]. New York: Division of Gryphon Editions; 1990:355–400. 113. Kar P, Jilani N, Husain SA, et al. Does hepatitis E viral load and genotypes influence the final outcome of acute liver failure during pregnancy?  Am J Gastroenterol 2008;103:2495–2501. 114. Kumar RM, Uduman S, Rana S, Kochiyil JK, Usmani A, Thomas L. Seroprevalence and mother-to-infant transmission of hepatitis E virus among pregnant women in the United Arab Emirates. Eur J Obstet Gynecol Reprod Biol 2001;100:9–15. 115. Patra S, Kumar A, Trivedi SS, Puri M, Sarin SK. Maternal and fetal outcomes in pregnant women with acute hepatitis E infection. Ann Intern Med 2007;147:28–33. 116. Rodriguez-Morales AJ, Barbella RA, Case C, et al. Intestinal parasitic infections among pregnant women in Venezuela. Infect Dis Obstet Gynecol 2006:231–325. 117. Shah OJ, Robanni I, Khan F, Zargar SA, Javid G. Management of biliary ascariasis in pregnancy. World J Surg 2005;29:1294–1298.

118. Menéndez C, D’Allessandro U, ter Kuile FO. Reducing the burden of malaria in pregnancy by preventive strategies. Lancet Infect Dis 2007;7:126–135. Review. 119. Beeson JG, Rogerson SJ, Cooke BM. Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria. Nat Med 2000;6:86–90. 120. Rogersonn SJ, Hviid L, Duffy PE, Leke RFG, Taylor DW. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis 2007;7:105–117. 121. Duffy PE, Fried M. Malaria during pregnancy: parasites, antibodies, and chondroitan sulphate A. Biochem Soc Trans 1999;27:478–482. 122. Gamain B, Smith JD, Viebig NK, Gysin J, Scherf A. Pregnancy-associated malaria: parasite binding, natural immunity and vaccine development. Int J Parasitol 2007;37:273–283. 123. Bouyou MK, Adegnika AA, Agnandi ST, et al. Cortisol and susceptibility to malaria during pregnancy. Microbes Infect 2005;7(11-12):1217–1223. 124. Ned RM, Moore JM, Chaisavaneeyakorn S, Udhayakumar V. Modulation of immune responses during HIV-malaria coinfection in pregnancy. Trends Parasitol 2005;21:284–291. 125. Newman RD, Robalo M, Quakyi I. Malaria during pregnancy: epidemiology, current prevention strategies, and future directions. Emerg Infect Dis [serial on the Internet] 2004 November;1, Available from www.cdc. gov/ncidod/EID/vol10no11/04-0624_09.htm. 126. Friedman JF, Mital P, Kanzaria HK, Olds GR, Kurtis JD. Schistosomiasis and pregnancy. Parasitol 2007;23:159–164. 127. Rorman E, Zamir CS, Rilkis I, Ben-David H. Congenital toxoplasmosis – prenatal aspects of Toxoplasma gondii infection. Reprod Toxicol 2006;21:458–472. 128. Sukthana Y. Toxoplasmosis: beyond animals to humans. Trends Parasitol 2006;22:137–142. 129. Silveira C, Ferreira R, Muccioli C, Nussenblatt R, Belfort R. Toxoplasmosis transmitted to a newborn from the mother infected 20 years earlier. Am J Opthalmol 2003;136:370–371. 130. Kodjikian L, Hoigne I, Adam O, et al. Vertical transmission of toxoplasmosis from a chronically infected immunocompetent woman. Pediatr Infect Dis J 2004;23:272–274. 131. Castillo-Solorzano C, Marsigli C, Bravo Alcantara P, et al. Progress toward elimination of rubella and congenital rubella syndrome – the Americas, 2003–2008. MMWR 2008;57(43):1176–1179. 132. Miller E, Cradock-Watson JE, Pollock TM. Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet 1982;ii:781–784. 133. Plotkin SA. The history of rubella and rubella vaccination leading to elimination. Clin Infect Dis 2006;43(Suppl. 3):S164–S168. 134. Rahav G, Gabbay R, Ornoy A, et al. Primary versus nonprimary cytomegalovirus infection during pregnancy, Israel. Emerg Infect Dis 2007;13:1791–1793. 135. Revello MG, Gerna G. Pathogenesis and prenatal diagnosis of human cytomegalovirus infection. J Clin Virol 2004;29:71–83. 136. Ornoy A, Diav-Citrin O. Fetal effects of primary and secondary cytomegalovirus infection in pregnancy. Reprod Toxicol 2006;21:399–409.

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137. Schleiss MR. Congenital cytomegalovirus infection: update on management strategies. Curr Treat Opt Neurol 2008;10:186–192. 138. Bale JF, Mier L, Petheram SJ. Congenital cytomegalovirus infection. Curr Treat Opt Neurol 2002;4:225–230. 139. Sauerbrei A, Wutler P. Herpes simples and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Herpes simplex virus infections. Med Microbial Immunol 2007;196:89–94. 140. Peacock JE, Sarubbi FA. Disseminated Herpes simplex infection during pregnancy. Obstet Gynecol 1983;61(Suppl. 3):13S–18S. 141. Hutto C, Arvin A, Jacobs R, et al. Intrauterine herpes simplex virus infection. J Pediatr 1987;110:97–101. 142. Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev 2008:1, CD004946. Review. 143. Jensen IP, Thorsen P, Jeune B, Moller BR, Vesterqaard BF. An epidemic of parvovirus B19 in a population of 3,596 pregnant women: a study of sociodemographic and medical risk factors. BJOG 2000;107:637–643. 144. Tolvesnstam T, Papadogiannakis N, Norbek O, Petersson K, Broliden K. Frequency of human parvovirus B19 infection in intrauterine fetal death. Lancet 2001;357:1494–1497. 145. Rodis JF, Borgida AF, Wilson M, et al. Management of parvovirus infection in pregnancy and outcomes of hydrops: a survey of members of the Society of Perinatal Obstetricians. Am J Obstet Gynecol 1998;179:985–988. 146. Enders M, Weidner A, Zoellner I, Searle K, Enders G. Fetal morbidity and mortality after acute parvovirus B19 infection in pregnancy: prospective evaluation of 1018 cases. Prenat Diagn 2004;24:513–518. 147. Miller E, Fairley CK, Cohen BJ, Seng C. Immediate and long term outcome of human parvovirus B19 infection in pregnancy. Br J Obstet Gynaecol 1998;105:174–188. 148. Rodis JF, Rodner C, Hansen AA, Borgida AF, Deoliveira I, Shulman Rosengren S. Long term outcome of children following maternal human parvovirus B19 infection. Obstet Gynecol 1998;91:125–128. 149. Nagel HTC, de Haan TR, Vandenbussche FPHA, Oepkes D, Walter FJ. Long-term outcome after fetal transfusion for hydrops associated with parvovirus infection. Obstetr Gynecol 2007;109:42–47. 150. Weigel-Kelley KA, Yoder MC, Srivastava A. Alpha5-beta1 integrin as a cellular coreceptor for human parvovirus B19: requirement of functional activation of 1 integrin for viral entry. Blood 2003;102:3927–3933. 151. Munakata Y, Saito-ito T, Kumura-Ishii K, et al. Ku80 autoantigen as a cellular coreceptor for human parvovirus B19 infection. Blood 2005;106:3449–3456. 152. Söderlund-Venermo M, Hokynar K, Nieminen J, Rautakorpi H, Hedman K. Persistence of human parvovirus B19 in human tissues. Pathol Biol (Paris) 2002;50:307–316. 153. Sauerbrei A, Wutler P. Herpes simples and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2. Varicella-zoster virus infections. Med Microbial Immunol 2007;196:95–102. 154. Workowski A, Berman SM. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2006. MMWR 2006;55(No. RR-11).

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155. American College of Obstetricians and Gynecologists: ACOG Committee Opinion. Primary and preventive care: periodic assessments. Obstet Gynecol 2003;102:1117–1124. 156. Johnson HL, Erbelding EJ, Ghanem KG. Sexually transmitted infections during pregnancy. Curr Infect Dis Rep 2007;9:125–133. 157. US Preventive Services Task Force. Screening for bacterial vaginosis in pregnancy to prevent preterm delivery: US Preventive Services Task Force recommendation statement. Ann Intern Med 2008;148:214–222. 158. Simcox R, Sin W-TA, Seed PT, Briley A, Shennan AH. Prophylactic antibiotics for the prevention of preterm birth in women at risk: a meta-analysis. Austral N Z J Obstet Gynaecol 2007;47:368–377. 159. Favia A, Fiore JR, Pastore G. Newly diagnosed HIV-1 infections in pregnancy: evidences from a cohort study in southeastern Italy. Eur J Epidemiol 2004;19:391–393. 160. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008;1-139. Available at www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL. pdf. (Accessed December 06, 2009.) 161. Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads 1000 copies/ml. J Infect Dis 2001;183:539–545. 162. Lallemant M, Jourdain G, Le Couer S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N Engl J Med 2000;343:982–991. 163. Jamieson DJ, Clark J, Koutis AP, et al. Reommendations for human immunodeficiency virus screening, prophylaxis, and treatment for pregnant women in the United States. Am J Obstet Gynecol 2007;197(Suppl. 3):S26–S32. 164. Suksomboon N, Poolsup N, Ket-Aim S. Systematic review of the efficacy of antiretroviral therapies for reducing the risk of mother to chills transmission of HIV infection. J Clin Pharm Ther 2007;32:293–311. 165. Volmink J, Siegfrid NL, van der Merwe L, Brocklehurst P. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev 2007;1, CD003510. Review. 166. Cooper ER, Charurat M, Mofenson L, et al. Women and Infant’s Transmission Study Group. J Acquir Immune Defic Syndr 2002;29:484–494. 167. Kuhn L, Kasonde P, Sinkala M, et al. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis 2005;41:1654–1661. 168. Chilongozi D, Wang L, Brown L, et al. HIVNT 024 Study Team. Morbidity and mortality among a cohort of human immunodeficiency virus type 1-infected and -unifected pregnant women and their infants from Malawi, Zambia and Tanzania. Pediatr Infect Dis J 2008;27:808–814. 169. Magriples U. Hepatitis in pregnancy. Semin Perinatol 1998;22:112–117. 170. Elinav E, Ben-Dov IZ, Shapira Y, et al. Acute hepatitis a infection in pregnancy is associated with high rates of

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s e c t i o n 8     Infectious Disease l

­gestational complications and preterm labor. Gastroenterol 2006;130:1129–1134. 171. Xiao XM, Li AZ, Chen X, Zhu YK, Miao J. Prevention of vertical hepatitis B transmission by hepatitis B immunoglobulin in the third trimester of pregnancy. Int J Gynecol Obstet 2007;96:167–170. 172. McMenamin MB, Jackson AD, Lambert J, et al. Obstetric management of hepatitis C-positive mothers: analysis of vertical transmission in 5559 mother-infant pairs. Am J Obstet Gynecol 2008;199(315):e1–e5. 173. Sensini A, Tissi L, Verducci N, et al. Carriage of group B Streptococcus in pregnant women and newborns: a 2-year study at Perugia General Hospital. Clin Microbiol Infect 1997;3:324–328. 174. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Centers for Disease Control and Prevention. Prevention of perinatal group B Streptococcal disease. MMWR 2002;51(RR11):1–22. 175. Larsen JW, Sever JL, Group B. streptococcus and pregnancy: a review. Am J Obstet Gynecol 2008;198:440–448. 176. Centers for Disease Control and Prevention. Perinatal group B streptococcal disease after universal screening recommendations – United States, 2003–2005. MMWR 2007;56(28):701–705. 177. Phares CR, Lynfield R, Farley MM, et al. Epidemiology of invasive group B streptococcal disease in the United States 1999–2005. JAMA 2008;299:2056–2065. 178. Orndorff PE, Hamrick TS, Smoak IW, Havell EA. Host and bacterial factors in listeriosis pathogenesis. Vet Microbiol 2006;144:1–15. 179. Gellin BG, Broome CV, Bibb WF, Weaver RE, Gaventa S, Macola L. The epidemiology of listeriosis in the United States – 1986. Listeriosis Study Group. Am J Epidemiol 1991;133:392–401. 180. Seveau S, Pizarro-Cerda J, Cossart P. Molecular mechanisms exploited by Listeria monocytogenes during host cell invasion. Microbes Infect 2007;9:1167–1175. 181. Craig S, Permezel M, Doyle L, Mildenhall L, Garland S. Perinatal infection with Listeria monocytogenes. Aust N Z J Obstet Gynaecol 1996;36:286–290. 182. Malhotra N, Chanana C, Kumar S. Dengue infection in pregnancy. Int J Gynecol Obstet 2006;94:131–132. 183. Waduge R, Malavige GN, Pradeepan M, Wijeyaratne CN, Fernando S, Seneviratne SL. Dengue infections during pregnancy: a case series from Sri Lanka and review of the literature. J Clin Virol 2006;37:27–33. 184. Julander JG, Winger QA, Rickfords LF, et al. West Nile virus infection of the placenta. Virology 2006;347:175–182.

185. O’Leary DR, Kuhn S, Kniss KL, et al. Birth outcomes following West Nile Virus infection of pregnant women in the United States: 2003–2004. Pediatrics 2006;117:e537–e545. 186. Chapa JB, Ahn JT, DiGiovanni LM, Ismail MA. West Niles encephalitis virus during pregnancy. Obstet Gynecol 2003;102:229–231. 187. Alpert SG, Fergerson J, Noël L-P. Intrauterine West Nile virus: ocular and systemic findings. Am J Ophthalmol 2003;136:733–735. 188. Price ME, Fisher-Hoch SP, Craven RB, McCormick JB. A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy. BMJ 1988;297:584–587. 189. Mupapa K, Mukundu W, Bwaka MA, et al. Ebola hemorrhagic fever and pregnancy. J Infect Dis 1999;179(Suppl. 1):S11–S12. 190. Barton LL, Peters CJ, Ksiazek TG. Lymphocytic choriomeningitis virus: an unrecognized teratogenic pathogen. Emerg Infect Dis 1995;1:152–153. 191. Bonthius DJ, Wright R, Tseng B, et al. Congenital lymphocytic choriomeningitis virus infection: spectrum of disease. Ann Neurol 2007;62:347–355. 192. Dhand A, Nadelman RB, Aguero-Rosenfeld M, Haddad FA, Stokes DP, Horowitz HW. Human granulocytic anaplasmosis during pregnancy: case series and literature review. Clin Infect Dis 2007;45:589–593. 193. Rouphael NG, O’Donnell JA, Bhatnagar J, et al. Clostridium difficile-associated diarrhea: an emerging threat to pregnant women. Am J Obstet Gynecol. 2008;198(635):e1–e6. 194. Garey KW, Jiang Z-D, Yadav Y, Mullins B, Wong K, DuPont HL. Peripartum Clostridium difficile infection: case series and review of the literature. Am J Obstet Gynecol 2008(199):332–337. 195. Hassett DE. Smallpox infections during pregnancy, lessons on pathogenesis from nonpregnant animal models of infection. J Reprod Immunol 2003(60):13–24. 196. Nishiura H. Smallpox during pregnancy and maternal outcomes. Emerg Infect Dis 2006;12:1119–1121. 197. Napolitano PG, Ryan MA, Grabenstein JD. Pregnancy discovered after smallpox vaccination: Is vaccinia immune globulin appropriate?  Am J Obstet Gynecol 2004;191:1863–1867. 198. Ryan MA, Seward JFand the Smallpox Vaccine in Pregnancy Registry Team. Pregnancy, birth, and infant health outcomes from the National Smallpox Vaccine in Pregnancy Registry, 2003–2006. Clin Infect Dis 2008;46(Suppl. 3):S221–S226.

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Adult Immunization in Women and Men SALLY L. HODDER, DEBRA CHEW, AND SHOBHA SWAMINATHAN New Jersey Medical School of the University of Medicine and Dentistry of New Jersey, Department of Medicine, Newark, NJ, USA

INTRODUCTION

HUMAN PAPILLOMAVIRUS G Epidemiology of Human Papillomavirus (HPV) Infections in Men and Women

Immunization is one of the most successful and costeffective strategies for the prevention of infectious disease and was voted a top public health advance of the twentieth century by the public health community.1 Today we have vaccines that not only decrease incidence of the acute diseases such as hepatitis B or human papilloma virus (HPV), but consequently also decrease the serious sequelae of those infections, including hepatocellular carcinoma and cervical cancer. Never has gender medicine been so evident as in the development programs of the human papilloma vaccines. Early trials were targeted to woman (not men), despite the fact that interruption of viral disease transmission requires immunization to a large proportion of the population in order to achieve herd immunity. Moreover, HPV is associated with morbidity and mortality in men. While the major impact of immunization has historically been in children, important new vaccines target adults. This chapter reviews recent vaccine developments for adults including HPV, varicella zoster, influenza, hepatitis A and hepatitis B. Several vaccines for bacterial disease, including pneumococcus, pertussis (as a component of the tetanus and diphtheria vaccine), and meningococcus are also included. At the conclusion of this chapter is a discussion of immunization issues and pregnancy. Childhood vaccines (e.g., rotovirus, polio) and vaccines for travelers (e.g., yellow fever, typhoid, and Japanese encephalitis vaccines) are not discussed. For comprehensive current recommendations for adult immunization in the United States, readers are urged to consult the Centers for Disease Control and Prevention.

Principles of Gender-Specific Medicine

In the United States HPV infection is extremely common, with at least 50% of sexually active men and women ⬎50 years acquiring HPV at some point in their lives.2 Estimated HPV incidence in the US is 6.2 million cases per year2 with 74% of new infections occurring among individuals 15–24 years of age.3 In the National Health and Nutrition Examination Survey (NHANES) conducted in 2003–2004, overall HPV prevalence as determined by polymerase chain reaction performed on self-collected vaginal swabs was 26.8% in the sample consisting of women aged 14–59 years.4 HPV prevalence in the NHANES sample was highest (44.8%) among those women aged 20–24 years. Worldwide, there is an enormous burden of HPV infection, however prevalence estimates vary by geographic location.5 There are more than 100 types of human and animal papillomaviruses; approximately 30 of those types infect the human anogenital tract6,7 and those types have been further classified into ‘high risk’ and ‘low risk’ types based on associations of invasive cancer versus genital warts or benign lesions. HPV-associated cancers often occur at the squamocolumnar junction of the anus and the cervix, hence the strong association with cervical cancer in women and anal cancer in both men and women. In a study of HPV prevalence in cervical cancers from women in 25 countries, HPV 16 was found in more than 57% of the samples while HPV 18 was demonstrable in 16.6% of samples.8 Roughly 3500 new cases of vulvar cancer occur annually in the US;9 HPV types 16 and 18 are associated with 80% of lesions.10

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Anal cancer rates in the US are increasing in both men and women, and have doubled in incidence from 1973 to 2000.11 HPV types 16 and 18 account for the majority of isolates in persons with high grade anal dysplasia.12 Other cancers that have been associated with HPV infection include penile and oropharyngeal cancer as well as squamous cell carcinoma of the esophagus.13 Noteworthy, is a particular strong association between HPV type 16 and tonsillar carcinoma.14 HIV infection merits special consideration in any discussion of HPV epidemiology as HIV-infected persons have a greater risk for development of HPV-associated dysplasia compared with persons who are not HIV infected. In a recently published study of 470 HIV-infected and 185 HIVuninfected women from the Women’s Interagency HIV Study (WIHS), HIV-infected women were more likely (80%) to have anal and/or cervical HPV infection than their HIVnegative counterparts.15 Moreover, HIV-infected women more commonly than HIV-negative women had low grade anal intraepithelial neoplasia (12% vs. 5% respectively) and high grade intraepithelial neoplasia (9% vs. 1% respectively). Overall, squamous cell anal cancer occurs in 70/100 000 HIV-infected men who have sex with men (MSM), similar to the incidence of cervical cancer in US women prior to the introduction of cervical pap smear screening.16 In a recent study of men from Rome by Pierangeli et al., HIV-infected men were more likely than HIV-negative men to have highrisk HPV types, 48% vs. 33% respectively.17 In summary, HIV-infection has been linked to development of HPVassociated cellular dysplasia and current recommendations suggest periodic cervical pap smears in women and anal pap smears in men who have sex with men. However, given the increasing incidence of anal dysplasia and anal cancer in HIV-infected women, it may be prudent to procure screening anal pap smears in all HIV-infected persons.

HPV Vaccine History and Efficacy To fully understand the basis of the HPV vaccine, one must consider the structure of the virus. HPV consists of circular, double-stranded DNA molecule coding for a limited number of proteins that are categorized as early proteins or late proteins. The early proteins include E6, a protein that destroys p53 tumor suppressor protein,18 and E7, a protein that acts to abolish the effect of retinoblastoma tumor suppressor protein.19 The late proteins L1 and L2 combine to constitute the symmetrical outer coat, or viral capsid of HPV. In the early 1990s, the observation was made that L1 protein produced in an in vitro system aggregated into capsomeres and formed viral-like particles that were demonstrated to be immunogenic and serve as the basis for current HPV vaccines.20–22 The viral-like particles had the distinct advantage of stimulating antibody production but were devoid of HPV DNA and the oncogenic potential that the presence of the DNA conferred.

There are currently two HPV vaccines, Cervarix (GlaxoSmithKline Biologicals) and Gardasil (Merck and Company, Inc.), and though both vaccines consist of HPV L1 protein viral-like particles, these two vaccines have important differences. Cervarix is a bivalent vaccine targeted to HPV-16 and HPV-18 (the two HPV types responsible for 70% of cervical cancer) while Gardasil is a quadrivalent vaccine targeted to HPV-16 and HPV18 as well as HPV-6 and 11 (responsible for 75–90% of genital warts).23 To date only Gardasil is FDA licensed (approved for girls and women aged 9–26 years), though both Cervarix and Gardasil are approved in Europe as well as other areas of the world. Cervarix is produced via Trichoplusia ni (HI-5) insect cell line infected with an L1 recombinant baculovirus while Gardasil relies on yeast cells to express L1.23 Both vaccines require three deltoid injections over 6 months, however, the second dose of Cervarix is administered at 1 month while the second dose of Gardasil is administered at 2 months. There are also important differences in the adjuvants used. Gardasil uses a traditional aluminum salt adjuvant while Cervarix uses a monophosphosphoryl lipid A, a non-toxic form of lipopolysaccharide with aluminum hydroxide which induces immune responses by toll-like receptor molecules. Recent studies have demonstrated higher neutralizing antibody levels for HPV 16 and 18 with Cervarix compared with Gardasil (2009 International Papillomavirus Conference, Malmo, Sweden24); however, the clinical implications of higher antibody levels are unclear at this time. With regard to clinical studies, it is interesting that Gardasil studies were initially only performed in women (not men). Two Phase III Gardasil trials (Females United to Unilaterally Reduce Endo/Ectocervical Disease [FUTURE] I and II) enrolled 17 622 young women. In FUTURE I, among 5455 women randomized to either Gardasil or placebo and followed a mean of 3 years, vaccine efficacy (by per-protocol analysis) was 100% for the co-primary endpoints of incident genital warts, vulvar, or vaginal intraepithelial neoplasia or cancer and incident cervical intraepithelial neoplasia associated with vaccine types. However, in an intent-to-treat analysis that included women with prevalent HPV infection or disease, reductions in vulvar or vaginal perianal lesions were 34% (95% CI 15–49%) and cervical lesions (regardless of HPV type) were decreased 20% (95% CI 8–31%), suggesting that optimal prevention requires vaccination before incident infection of relevant serotypes has occurred.25 Similar results were found in the FUTURE II where 12 167 women (aged 15–26 years) were randomized to Gardasil or placebo. Vaccine efficacy for a composite primary endpoint of Grade 2 or 3 intraepithelial neoplasia, adenocarcinoma in situ, or cervical cancer related to HPV 16 or 18 was 98% (95% CI 86–100%) in the per-protocol susceptible populations without evidence of HPV-16 or 18 infection through 1 month after the third vaccine dose. Vaccine efficacy was again observed to be lower (44% with 95% CI 26-58) in

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the intent-to-treat population that included all randomized women regardless of HPV infection status at enrollment.26 Regarding Cervarix clinical trial results, a Phase III trial randomized 18 644 women aged 15–25 years to receive either HPV16/18 vaccine or Hepatitis A as the ‘control’ vaccine. During a mean follow-up period of 14.8 months, vaccine efficacy against CIN 2 or greater was 90.4% (95% CI 53.4–99.3) using a modified intent-to-treat analysis.27 Noteworthy when comparing Phase III trials of Cervarix and Gardasil is that often differing methods of analysis were used: according to protocol analyses include those individuals without evidence of HPV infection one month after completing the vaccine series; modified intent-to-treat excluded from analysis women who were infected with a vaccine type at enrollment; intent-to-treat included all enrolled women in the analysis even if they had evidence of a vaccine type HPV. In a study of young men aged 10–18 years, Cervirax proved immunogenic with 100% of study participants completing the three vaccine series having antibodies to HPV 16/18 one month after the third dose.28 Ninety-seven percent of participants completed the three-dose series; pain, redness, and swelling were the most frequent adverse events. Recently, results of Gardasil in men were presented. In a study of 4056 men, aged 16–26 years, who were not infected with any of the HPV types contained in the vaccine, efficacy was 90.4% (95% CI 69.2–98.1) against HPV-6/11/16/18 related genital lesions, 89.4% (95% CI 65.5–97.9) against condyloma.29 In a sample of 5088 female subjects receiving Gardasil 83.9% reported injection site pain, 2.8% severe pain, 2% swelling and 0.9% erythema.30 Serious adverse events occurred in ⬍0.1% of vacinees with similar proportions in vaccine and placebo groups.30 Syncope due to vasovagal reactions has been observed31 and constitutes a commonly reported adverse event30 such that patients should be observed for 15 minutes after receiving the vaccine.

HPV Vaccine Current Recommendations Currently Gardasil is approved in the United States for girls and women 9–26 years for prevention of the following HPV diseases: cervical, vulvar, vaginal cancer caused by HPV types 16 and 18, genital warts caused by HPV types 6 and 11, and precancerous or dysplastic lesions caused by HPV-6/11/16/18 including CIN grade2/3 and cervical adenocarcinoma in situ, CIN grade 1, vulvar or vaginal intraepithelial neoplasia grades 2 and 3. Gardasil is administered intramuscularly in the deltoid area as 3 separate 0.5 ml doses at time 0, 2 months, and 6 months after the initial dose.32 The Advisory Committee on Immunization Practices (ACIP) recommends vaccinating girls 11–12 years with ‘catch-up’ immunization recommended for those 13–26 years who did not receive the vaccine.30 Ideally, girls should be immunized before sexual debut and, therefore,

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Gardasil has been approved for girls as young as 9 years of age. Studies indicate that protection lasts for at least 5 years.30 There is not a recommendation for a booster dose at this time, though studies are ongoing to determine duration of protection. Currently, there is not an FDA approved indication for administration of any HPV vaccine in men or boys. However, studies in males are ongoing and initial results were recently presented (see above).

HPV Vaccine Contraindications and Precautions The Advisory Committee on Immunization Practices30 advises that HPV vaccine is contraindicated in individuals with severe allergic reaction after a previous dose or to a vaccine component such as yeast.30 However, surveillance studies have indicated that the HPV vaccine poses minimal risk for anaphylaxis in persons with histories of allergic reactions to baker’s yeast.33 With regard to pregnancy, Gardasil is classified as Category B based on a lack of fetal harm in rats, and though adverse fetal events have not been associated with the vaccine, Gardasil is not recommended for use in pregnancy.30

ZOSTER IMMUNIZATION Epidemiology of Herpes Zoster in Men and Women Primary varicella-zoster virus (VZV) infection typically occurs in childhood and may result in clinical chickenpox; however, reactivation of latent VZV within the dorsal root ganglia decades later leads to herpes zoster, a dermatomal vesicular eruption often associated with painful postherpetic neuralgia. The clinical course of acute zoster is variable. The rash usually lasts 7–10 days with complete healing within 2–4 weeks. Post-herpetic neuralgia (PHN) is manifested by persistent pain that may last months or years following rash resolution and occurs in 10–18% of patients with zoster.34 Other complications associated with zoster include herpes zoster ophthalmicus, occurring in 10–25% of persons with zoster, and which can result in loss of vision and other complications of the eye.35,36 Reactivation of VZV in the geniculate ganglion of the facial nerve results in the uncommon Ramsay Hunt syndrome, a peripheral facial nerve palsy accompanied by zoster vesicles on the ear, hard palate, or tongue.37 Uncommonly, herpes zoster is associated with neurologic complications that include myelitis, aseptic meningitis, meningoencephalitis, cranial palsies, motor weakness in noncranial nerve distributions called zoster paresis, autonomic dysfunction causing urinary retention, and rarely acute focal stroke-like neurologic deficits termed granulomatous angiitis.38 Immunocompromised persons are at increased risk for cutaneous and visceral dissemination and neurologic zoster complications.39

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Approximately 1 in 3 persons will develop zoster during their lifetime, resulting in an estimated 1 million episodes in the United States annually.40 In the United States, approximately 99.5% of the population age 40 years and older has serologic evidence of prior VZV infection, thus predisposing almost all older adults to develop zoster.41 Among varicella vaccine recipients, zoster may also develop from reactivation of the attenuated Oka/Merck VZV strain in the vaccine, and although longer follow-up is needed, studies suggest this risk to be considerably lower than the incidence of zoster following wild-type VZV infection.42–44 Age is the most important risk factor for development of zoster. Zoster incidence has been shown to increase with age by a factor of ⬎10 with much of the increase in incidence beginning around 50–60 years old.45 It is estimated that 50% of persons who live to age 85 years will have experienced zoster.46,47 Several studies have also demonstrated a higher incidence of zoster among women after controlling for age, other zoster risk factors such as immunodeficiency and co-morbidities, and gender differences in medical consultation rate.48–50 In a large, randomized controlled vaccine trial in the US, the incidence of confirmed zoster cases was 11% higher among women in a cohort of immunocompetent persons 60 years and older.48 However, some researchers did not find a difference in incidence by gender.46,51 The epidemiology of zoster is directly related to the biology underlying the virus–host relation that allows reactivation of latent VZV. As cell mediated immunity plays a key role in controlling the development of zoster and its severity, persons who are immunocompromised with deficiencies in cell mediated immunity (such as among persons with hematologic malignancies and solid tumors, stem cell transplants and solid organ transplants, and HIV infection) have a substantially higher incidence of zoster and its severe manifestations.52–62

Zoster Vaccine History In May 2006, a vaccine for prevention of zoster was licensed in the United States for use in persons 60 years and older. The licensed US zoster vaccine (Zostavax, Merck & Co., Inc.) is a lyophilized preparation of a live, attenuated strain of VZV, the same strain used in the varicella vaccines (Varivax, Proquad). However, the zoster vaccine’s minimum potency is at least 14 times the potency of Varivax. The Oka VZV strain in the vaccine was initially isolated in Japan in the early 1970s from a healthy child who had varicella, and then attenuated through sequential passage of the virus in cell cultures.40

Zoster Vaccine Efficacy The zoster vaccine was licensed in the US based on results of a large, double-blind, randomized, placebo-controlled vaccine trial in the US, termed the Shingles Prevention Study,

involving over 38 000 healthy adults 60 years and older who had a history of varicella or at least 30 years of residence in the continental US (as a marker of previous infection). The vaccine was partially efficacious in reducing the risk for developing zoster by 51.3% (p ⬍0.001), 66.5% efficacious (p ⬍0.001) for preventing PHN, and 61.1% efficacious in reducing the burden of illness caused by zoster (p ⬍0.001). There were no significant differences by sex in vaccine efficacy at reducing zoster, PHN or burden of illness.48

Zoster Vaccine Current Recommendations One dose of zoster vaccine is routinely recommended for all persons 60 and older who have no contraindications, including persons who report a previous episode of zoster or who have chronic medical conditions. Although zoster vaccination is not recommended for persons of any age who have received varicella vaccine, healthcare providers do not need to ask patients about their history of varicella or conduct serologic testing for varicella immunity before administration of zoster vaccine.40

Zoster Vaccine Contraindications Zoster vaccine is contraindicated for the following persons: (1) those who have a history of anaphylactic reaction to any component of the vaccine, including gelatin and neomycin; (2) persons with primary or acquired immunodeficiency (including persons with leukemia, lymphomas, or other malignant neoplasms affecting the bone marrow or lymphatic system, persons with HIV or AIDS (though a trial is ongoing of HIV-infected persons to assess safety of Zostavax), persons on immunosuppressive therapy including high-dose corticosteroids, persons with clinical or laboratory evidence of other unspecified cellular immunodeficiency, persons undergoing hematopoietic stem cell transplantation, persons receiving recombinant human immune mediators and immune modulators); and (3) pregnant women, though these women are unlikely to be in the vaccine target age group.40

INFLUENZA VACCINE Epidemiology of Influenza in Men and Women in the US Influenza, caused by infection with influenza type A or B virus, remains a leading cause of illness and mortality worldwide, causing epidemics of varying severity each year. Influenza A causes moderate to severe illness and affects all age groups. Influenza B generally causes milder disease than type A and primarily affects children. Influenza A virus is classified into subtypes based on its two surface antigens: hemagglutinin and neuraminidase. Antigenic changes in these surface antigens from point

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mutations during viral replication give rise to new influenza variants. The impact of these alterations depends on the degree to which pre-existing immunity is present in the population at risk. Major antigenic shifts occurring through genetic recombination with other Influenza A viruses allow the emergence of new viral subtypes into an overall population that possesses no immunity, thus having the potential to cause world-wide pandemics. The greatest recorded pandemic, the 1918–1919 pandemic of ‘Spanish’ influenza, alone caused an estimated 21 million deaths worldwide.63 The recent emergence of influenza A Avian H5N1 flu and the novel H1N1 flu viruses in 2009 have heightened the awareness and preparedness for the threat of a future influenza pandemic and the need for ongoing active surveillance. Uncomplicated influenza typically causes an acute, selflimited febrile illness, characterized by the abrupt onset of fever, nonproductive cough, sore throat, malaise, myalgia, and headache. Complications of influenza include primary influenza viral pneumonia and secondary bacterial infection such as pneumonia, sinusitis, and otitis media, and uncommonly is associated with encephalitis, transverse myelitis, Guillain-Barré syndrome, myocarditis, pericarditis, myositis, and Reye syndrome.63,64 The typical incubation period averages 2 days (range from 1–4 days); the infectious period begins the day before symptom onset through 5–10 days after illness onset.63 Influenza is highly contagious, with an attack rate as high as 40% during influenza outbreaks.65 The virus is transmitted person to person via large droplets and via direct and indirect contact with contaminated respiratory secretions.66 In the US, peak influenza activity is from December to March, but may occur earlier or later, as evidenced by the emergence of novel H1N1 in April of 2009. Excess morbidity and mortality typically accompanies influenza epidemics, not only from influenza and pneumonia but also from underlying chronic diseases, such as cardiovascular and pulmonary conditions, that can be exacerbated by influenza. In the US each year, influenza contributes to approximately 36 000 excess deaths, primarily among the elderly.67,68 An average of more 200 000 hospitalizations occur each year related to influenza, more than 57% of which are among persons younger than 65 years old.69 Influenza also results in more severe disease and significant mortality in individuals with immunodeficiency and underlying chronic medical conditions and women in the second and third trimester of pregnancy.65–67,70,71 While older adults have the highest mortality rate, children have the highest attack rate, and typically serve as a major source of transmission within communities.67,68,72–74

Influenza Vaccine History Despite more than 60 years of influenza vaccine research, to date, vaccines must be annually produced. Each year viral strains are selected on the basis of global surveillance

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of circulating strains and their likelihood to cause disease in the upcoming flu season. Thus, flu vaccines must be given annually to provide optimal protection against circulating influenza viruses. Clearly, a priority in influenza vaccine science should be development of a vaccine to ‘conserved’ antigenic domains that are less likely to undergo frequent mutation. Two influenza vaccines are available in the United States; both are formulated to contain three inactivated viruses, one each of influenza A (H1N1) virus, A (H3N2) virus, and influenza B. Trivalent inactivated influenza vaccine (TIV) has been available since 1943 and cannot transmit influenza. TIV is administered by the intramuscular route, and is licensed for use in persons 6 months and older, including those who have chronic medical conditions that confer a higher risk of influenza complications.64 Live attenuated influenza vaccine (LAIV) was approved for use in the US in 2003. Unlike TIV, LAIV contains live (though attenuated) viruses and thus has the potential to cause mild flu-like illness. Additionally, the vaccine is administered intranasally; half of the dose is sprayed into each nostril. The viruses are cold-adapted and replicate effectively in the mucosa of the nasopharynx, offering the potential advantage of inducing mucosal immunity. LAIV is licensed for use only in healthy, nonpregnant persons 2– 49 years of age; its safety has not been established in persons with underlying chronic medical conditions. Shedding of LAIV has occurred in vaccinated adults and particularly in children, though infrequently; however, all transmitted viruses have retained their attenuated phenotype and genotype.64,75,76

Influenza Vaccine Efficacy TIV has been shown to be effective in preventing influenza among healthy adults under 65 years of age, with protection levels of 70–90% when there is a good antigenic match between the vaccine strain and circulating virus.77–80 Among healthy adults ⬍65 years old, recent studies show that the vaccine has been 90% effective in reducing hospitalizations due to pneumonia and influenza.81 Older adults, however, typically have a diminished immune response to influenza vaccination compared to healthy younger adults. One randomized controlled trial among persons 60 and older demonstrated a 58% vaccine efficacy against influenza respiratory illness, but reduced efficacy among those 70 years and older.82 Among nursing home residents, TIV has been found to be 30–40% effective in preventing influenza respiratory illness.82,83 Although the vaccine is not highly effective in preventing clinical illness among the elderly, the vaccine is up to 70% effective in preventing influenza and pneumonia-related hospitalization and up to 80% effective in preventing influenza-related deaths among the elderly.83,85–87 There have been no documented differences in vaccine efficacy by gender.

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LAIV efficacy has been evaluated in groups of healthy children and healthy adults. In a large randomized, doubleblind, placebo-controlled trial enrolling over 4500 adults aged 18–64, the vaccine effectively reduced severe febrile upper respiratory tract illnesses, work absenteeism, healthcare visits, and medication use during influenza outbreak periods. This study was conducted during the 1997–98 influenza season when the vaccine and circulating Type A strains were not antigenically well matched.88 Studies comparing the efficacy of TIV to LAIV have been limited. One randomized, double-blind, placebocontrolled challenge study among 92 healthy adults found the vaccines to have comparable efficacy in this study population.89

Influenza Vaccine Current Recommendations Routine vaccination is targeted to those individuals at highest risk for influenza-related hospitalizations and death, and is recommended annually to: (1) all persons 50 years of age and older; (2) children aged 6 months to 18 years; (3) persons at risk for medical complications, including chronic pulmonary and cardiovascular diseases, metabolic disorders including diabetes mellitus, renal dysfunction, hemoglobinopathy such as sickle cell disease, immunosuppression, including HIV infection, any condition such as cognitive dysfunction, spinal cord injury, seizure disorder or other neuromuscular disorder that can compromise respiratory function of handling of respiratory secretions; and (4) residents of nursing homes and long-term care facilities. In 2008, CDC ACIP expanded its vaccination recommendation among children to include those 5–18 years old based on the evidence that influenza negatively impacts various indicators, such as school absenteeism, increased antibiotic use, medical care visits, and parental work loss.64 Routine annual vaccination is also targeted to individuals who can transmit influenza to groups at highest risk for complications, and include: (1) healthcare providers (LAIV should not be administered to healthcare workers who have contact with severely immunosuppressed persons); (2) healthy household contacts (including children and caregivers) of high-risk persons; and (3) healthy household contacts (including children and caregivers) of children under 59 months old.64 Vaccination is also recommended for pregnant women (with TIV only), travelers, and the general population for anyone who wishes to reduce the likelihood of becoming ill from influenza.64

Influenza Vaccine Contraindications TIV is contraindicated in the following: (1) persons with a severe allergic reaction to a vaccine component (e.g., egg) or following a prior dose of the vaccine and; (2) persons with a moderate or severe acute illness.64

LAIV is contraindicated in the following: (1) persons with a history of severe allergy to vaccine component (e.g., egg); (2) persons younger than 2 years of age or age 50 years and older; (3) persons with chronic medical conditions, including asthma, reactive airway disease, and other chronic pulmonary or cardiovascular conditions, metabolic disease such as diabetes, renal disease, or hemoglobinopathy; known or suspected immunosuppression; (4) children or adolescents receiving long-term therapy with aspirin or other salicylates, because of the association of Reye syndrome with wild-type influenza infection; (5) pregnant women; and (6) persons with a history of Guillain-Barré syndrome.64

HEPATITIS B VACCINE (HBV) Epidemiology of HBV Infections in Men and Women The prevalence of disease caused by the hepatitis B virus (HBV) varies worldwide with a relatively low prevalence of 0.1–2.0 % in developed nations as compared to rates of almost 20% in China and countries of sub-Saharan Africa.90 Infection is acquired through mucosal or percutaneous exposure to infectious blood or body fluids. Infections acquired perinatally have a 90% risk of becoming chronic infections; those acquired between 1 and 5 years of age have a 10–20% of becoming chronic. This contrasts to the infections acquired in adulthood that are spontaneously cleared, leaving a small proportion (5%) that progress to chronic HBV infection. Implementation of routine HBV vaccination has dramatically changed the prevalence of the disease, with a 78% decrease in incident infections in the US from 1990 to 2005.91 Chronic HBV infection places patients at increased risk for cirrhosis of the liver and hepatocellular carcinoma. Although among adults hepatitis C virus infection results in a higher percentage of infections becoming chronic, HBV infection remains the most common worldwide cause of hepatocellular carcinoma.92 Interestingly, men seem to be at a higher risk of developing chronic hepatitis B virus infection after exposure as compared to their female counterparts,93–95 and also had higher rates of development of hepatocellular carcinoma.94 Hepatitis B virus belongs to the family Hepadnaviridae (hepatotrophic virus). It is a 42nm complex virus containing a double-stranded DNA coiled in a sphere enclosing the viral core. The primary site of infection is the liver where the virus produces multiple large quantities of spherical particles that were first identified in the blood as Australia Antigen particles; later known as hepatitis B surface antigen (HBsAg). Presence of HBsAg indicates active HBV infection and if detectable for ⱖ6 months, is indicative of chronic HBV infection. On the other hand, clearance of infection is accompanied by the development of antibody

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to HBsAg also known as hepatitis B surface Antibody (HBsAb) or anti-HBsAg. Several populations have been identified as being at high-risk of HBV infections, such as: multiple sexual partners (both heterosexual and MSM), injection drug use, household contacts of known HBV cases, hemodialysis patients, developmentally challenged residents of long-term care facilities, travel to HBV endemic area and HIV infection.91

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Hepatitis B Current Recommendations The CDC recommends HBV vaccination for all high-risk adults and for all adults seeking HBV vaccine. These highrisk individuals include susceptible partners of HBsAg positive patients, persons with multiple sexual partners, MSM, injection drug users, persons with HIV infection, hemodialysis patients, healthcare workers, travelers to HBV endemic areas, and persons with chronic liver disease.92

Hepatitis B Vaccine There are currently two single-antigen vaccines, Recombivax HB and Engerix-B, approved for use in the United States. In addition, HBV vaccine is also available in combination: (a) Twinrix (HBV and HAV), used in adults, (b) Comvax (HBV and Hemophilus influenza) and (c) Pediarix (HBV, diphtheria and tetanus toxoids, pertussis and inactivated poliovirus) approved for use in children. For all these vaccines, HBsAg is used as the immunizing antigen. Although there are multiple serotypes available worldwide, development of anti-HBsAg to any of the types confers cross-serotype immunity. In the United States, recombinant technology is used to express HBsAg which is in turn used in the vaccines. Alternatively, HBsAg can also be isolated from the serum of infected persons. However, due to the possible risk of acquiring other infectious diseases, this method is no longer used for HBV vaccine preparation in the US.

Hepatitis B Vaccine Efficacy The vaccine is given in three doses administered intramuscularly at 0, 1, and 6 months, preferably in the deltoid muscle or in the lateral aspect of the thigh in children. Administration of the vaccine subcutaneously in adipose tissue can adversely affect the immunogenicity of the vaccine96 and hence long needles may be needed for overweight persons. Administration of all three doses results in protective immunity in over 90% of adults.97 Vaccine efficacy can be measured by the levels of antibody titer in the serum after the third dose of vaccine. Patients are considered immune when these titers are ⱖ 10 IU/ml; there is a high risk of vaccine failure when levels decline below this level.98 Although not routinely recommended, antibody titers may be measured in select high-risk groups of patients such as healthcare workers, men who have sex with men (MSM), HIV-infected persons, and hemodialysis patients. For titers less than 10 IU/ml after completion of three vaccine doses, there are two options available: (1) a fourth dose or (2) a three-injection revaccination series. Administration of the forth dose increased the rate of protective immunity to approximately 65%99 and repeating the entire series resulted in protective antibody titers between 70 and 100%.98,100 Studies have also shown that once protective titers are attained, they persist for years and hence booster vaccination is not recommended.98,101

HEPATITIS A VACCINE Epidemiology of Hepatitis A in Men and Women Hepatitis A is an acute, generally self-limiting illness caused by the picornavirus hepatitis A. In the United States, person-to-person transmission via the fecal–oral route (especially among close household contacts102 and in conditions of overcrowding with suboptimal hygiene) is the primary means of transmission, though commonsource outbreaks through contaminated food and water also occur.103 Food can be contaminated either at the source such as with shellfish exposure to contaminated water104 or as a result of an infected food handler coming in contact with the food. The incubation period of the illness varies from 2 to 7 weeks, and clinical presentation is usually that of a mild and self-limited illness with frequently reported malaise and fatigue. Physical signs may include presence of tea colored urine, pale colored stools, icterus and pruritis, a sign of cholestasis. Patients frequently have tender hepatomegaly and some may have mild splenomegaly. Most patients demonstrate a spontaneous resolution of symptoms within 2 months of presentation.105 Rarely, patients with hepatitis A can progress to fulminant hepatic failure and death. Prior reports have suggested that the case fatality rate from hepatitis A virus infections was 0.01 to 0.03%,106 with higher mortality associated with older age, although none of the infections resulted in chronic hepatitis A virus infection.107 Historically this disease primarily affected children and young adults.103 In addition, men were noted to have higher rates of hepatitis A virus.108 However, with the advent of hepatitis A vaccination, rates have declined in all age groups.109 According to the CDC, there has been a sharp decline in the number of reported cases of hepatitis A in the United States from 10 616 cases in 2001 to 3579 cases in 2006.110 Current estimates place the rates of acute hepatitis A virus infections at 1.0/100 000 among children aged ⬍5 years to 1.8/100 000 among persons aged 5–24 years.109 Differences among rates of infection between the two sexes have also declined and by 2005 both sexes had comparable rates of infections (1.7/100 000 among men as compared to 1.3/100 000 in women). A special note must be made of the additional risk for hepatitis A among men who have

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sex with men (MSM). There have been reports of increased rates of hepatitis A among MSM populations and these outbreaks vary from the traditional hepatitis A outbreaks because they are sexually transmitted and hence do not follow the normal seasonal variations of non-MSM hepatitis A outbreaks.111,112

Hepatitis A Vaccine History Protection against hepatitis A viral infections can be conferred either by active immunization or passive immunization with immune globulin via the transfer of protective antibodies.113 Currently, regimens are available both for pre- and post-exposure prophylaxis. Once administered, immune globulin confers protective levels of antibody for approximately 3–5 months, depending on the antibody dose, and is most effective when administered early in the incubation period of the illness. An immune globulin dose of 0.02 ml/kg IM usually confers protection for ⬍3 months while a dose of 0.06 ml/kg confers protection for 3–5 months.103 In contrast to the time-limited protection of immune globulin, recovery from HAV infection confers lifelong immunity and results in much higher titers of protective antibody than those achieved via either passive immunization using immune globulin or active immunization with vaccines. Seroprevalence studies of populations demonstrate correlation of seroprevalence with age, i.e., older groups of people have higher seroprevalence rates than younger aged populations. Many inactivated hepatitis A vaccines have been studied for efficacy in clinical trials. Currently there are two single antigen hepatitis A vaccines approved for commercial use: Havrix114 and Vaqta.115 In addition, there is also a combination vaccine, Twinrix,116 for both hepatitis A and B. All hepatitis A vaccines are inactivated vaccines with single antigen. No preservative is added in the Vaqta formulation as compared to both Havrix and Twinrx, which contain a preservative (not thimerosal).114–116

Hepatitis A Vaccine Efficacy Administration of HAV is recommended as a two dose series given 6 months apart. Efficacy studies of the vaccine in various populations have shown that the vaccine is highly immunogenic.117,118 Administration of the first dose confers detectable levels of antibody in most of the individuals within one month.117 The booster dose of HAV vaccine ensures extremely high levels of protective antibody and this level is projected to persist for ⬎20 years, possibly conferring life-long immunity.117,119 The vaccine is highly immunogenic in all age groups and titers have been detected at over 6 years after the last administered dose. No gender-specific differences have been observed in antibody response rates among vaccine recipients. The effectiveness of the vaccine is also apparent with the marked decrease in

the incidence of new cases with HAV since the advent in 2001 of universal vaccination of children, a group traditionally at high risk of infection.

Hepatitis A Current Recommendations Current guidelines recommend routine vaccination using the two-dose schedule for children, groups at high risk for HAV including travelers to countries with endemic hepatitis A, MSM, injection and non-injection drug uses, persons with occupational risk, persons with clotting-factor disorders, and persons with chronic liver disease, as well as any person who desires immunization.103 Wiedermann et al. estimate that based on the levels of titers obtained after two doses of hepatitis A vaccine, protective antibody titers are likely to be present for about 30 years or longer.120 Hence, booster dosing beyond the two approved doses is not currently recommended. Hepatitis A vaccine is not approved for administration for post-exposure prophylaxis. For patients deemed to be at high risk of infection, such as close household contact of an index case, members of school or day care centers, post-exposure prophylaxis may be given with immune globulin. Vaccination may also be given to these individuals if they also have an underlying indication to be vaccinated and have previously not been immunized against HAV.

Hepatitis A Contraindications Contraindications to hepatitis A vaccine include severe allergic reactions to previous doses or to vaccine components.103

PNEUMOCOCCAL VACCINE Epidemiology of Pneumococcal Infection and Disease in Men and Women Pneumococcal disease caused by the bacterial pathogen Streptococcus pneumoniae results in widespread illness and death in the United States and worldwide among children and adults. The organism colonizes the upper respiratory tract and is transmitted as a result of direct person-to-person contact via respiratory droplets and by autoinoculation in persons carrying the bacteria in their upper respiratory tract. In the US and Europe, S. pneumoniae is the leading bacterial cause of pneumonia, meningitis, and otitis media. Each year in the US it is estimated that as many as 175 000 hospitalizations from pneumococcal pneumonia occur, and pneumococcal disease accounts for more than 500 000 cases of pneumonia, 50 000 cases of pneumococcal bacteremia, and about 3000 cases of pneumococcal meningitis.121–123 Pneumococci account for up to 35% of adult communityacquired pneumonia requiring hospitalization and up to

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50% of nosocomial pneumonia.124,125 An estimated 40 000 deaths occur annually in the US, with the highest mortality occurring among the elderly and patients with underlying medical conditions.121,122 The case-fatality rate for pneumococcal pneumonia is 5–7% (higher among the elderly); 15–20% (up to 60% among the elderly) for pneumococcal bacteremia, and 30–40% (up to 80% among the elderly) for pneumococcal meningitis.126–129 Incidence of invasive pneumococcal disease is greatest among children younger than 2 years of age and increased among the elderly 65 years and older and among persons with underlying medical conditions. However, recent data from the US suggest that the incidence of pneumococcal disease is decreasing as a result of widespread use of protein-conjugate pneumococcal vaccine in children since its licensure in 2000.130 The majority of invasive pneumococcal disease is caused by a limited number of serotypes of pneumococci. Ninety serotypes of pneumococci have been distinguished by variations in the bacteria’s polysaccharide capsule. The polysaccharide capsule of the organism constitutes its major virulence factor, and antibodies directed against the capsular polysaccharide protect against infection. Serotype prevalence differs by age and geographic region, but the 10 most common serotypes are estimated to account for approximately 62% of invasive disease worldwide.131

Pneumococcal Vaccine History Two kinds of pneumococcal vaccine are available in the United States. The 23 valent pneumococcal polysaccharide vaccines or PPSV23 (Pneumovax 23, Merck & Co., Inc. or Pnu-Immune 23, Wyeth–Ayerst Laboratories) are effective in preventing invasive pneumococcal disease among older children and adults. PPSV23 was licensed in the US in 1983 and replaced an earlier 14 valent formulation that was licensed in 1977. The 23 valent vaccines contain 25 μg of capsular polysaccharides from each of 23 common serotypes of S. pneumoniae (serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F) that represent at least 85–90% of the serotypes that cause invasive pneumococcal infections among children and adults in the US.132–134 PPV23 also contains the six serotypes that most frequently cause invasive drug resistant pneumococcal infections in the US.135,136 Since polysaccharide vaccines fail to elicit a protective immune response among infants and very young children, PPSV23 vaccines do not protect children under 2 years of age, the age group with the highest rate of disease. Protein conjugate pneumococcal vaccine (Prevnar, Wyeth Lederle Vaccines) or PCV7 was licensed in 2000 for pediatric use for children aged 2 and under. PCV7 contains lesser amounts of capsular material from seven pneumococcal serotypes that are most commonly implicated in disease of children.134,137

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Pneumococcal Vaccine Efficacy The 23-valent pneumococcal polysaccharide vaccine has been shown to be effective in preventing pneumococcal invasive disease, with levels of protection of 56–81% in various case-control vaccine studies.138–141 There have been no documented differences in vaccine efficacy by gender. PPSV23 was effective was among healthy persons aged 65 and older and among specific patient groups (e.g. persons with diabetes mellitus, coronary vascular disease, congestive heart failure, chronic pulmonary disease and anatomic asplenia), but not for certain groups of immunocompromised patients.133 Despite its effectiveness against invasive disease, the PPSV23 vaccine has been less effective in preventing nonbacteremic pneumococcal pneumonia. In two post-licensure randomized controlled trials conducted in the US among the elderly and those with high-risk medical conditions, there was no difference in the incidence of nonbacteremic pneumococcal pneumonia between the vaccinated and nonvaccinated study groups.142,143 A metaanalysis evaluating pneumococcal vaccine efficacy did not demonstrate a protective effect for non-bacteremic pneumonia among persons in high-risk groups.144

Pneumococcal Vaccine Current Recommendations for Adults The 23 valent pneumococcal polysaccharide vaccine is recommended to: (1) all persons aged 65 years and older; (2) adults 19–64 years of age who have a chronic illness, including chronic cardiovascular disease (e.g., congestive heart failure or cardiomyopathies), chronic pulmonary disease (e.g., COPD, or emphysema, or asthma; diabetes mellitus, alcoholism, chronic liver disease, and cerebrospinal fluid leaks; (3) adults 19–64 years of age who have functional or anatomic asplenia (e.g., sickle cell disease or splenectomy); (4) adults 19–64 years old who are cigarette smokers; (5) immunocompromised adults and children aged 2 and older (e.g. persons with HIV infection, leukemia, lymphoma, Hodgkin’s disease, multiple myeloma, generalized malignancy, chronic renal failure, nephrotic syndrome, conditions associated with immunosuppression such as organ or bone marrow transplantation or receipt of immunsuppressive chemotherapy and systemic corticosteroids).123,145 CDC revised its recommendations for PPSV23 to include adult cigarette smokers and persons with asthma due to their increased risk for invasive pneumococcal disease.145 Routine revaccination of immunocompetent persons previously vaccinated with PPSV23 is not recommended. However revaccination once is recommended 5 years from receipt of first dose of pneumococcal vaccine in persons who are likely to have a rapid decline in pneumococcal antibody levels. These persons include those with functional or anatomic asplenia, immunosuppression, including

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those with chronic renal failure and nephrotic syndrome, and persons 65 years of age and older if they received initial vaccination prior to age 65 if at least 5 years have elapsed since first dose.123

TETANUS/DIPTHERIA/PERTUSSIS Epidemiology of Tetanus, Diphtheria, and Pertussis in Men and Women in the US Tetanus is caused by Clostridium tetani, an anaerobic Gram-positive bacillus that is found in the soil and the intestines of many animals. The disease is caused by toxins that bind irreversibly to receptors at the neuromuscular junction. This results in persistent muscular spasms that can vary in intensity and duration without loss of consciousness. There can also be involvement of the autonomic nervous system causing overstimulation of the sympathetic nervous system. Per published estimates by the WHO, there has been a decline in the number of reported cases of tetanus worldwide from 114 248 in 1980 to 14 529 in 2006. Within the United States, there were 129 case of tetanus reported between 1998 and 2000, most of which were attributable to traumatic injuries.146 However, worldwide, even in 2007, there were 17 012 cases reported.147 One of the biggest concerns with tetanus is the incidence of maternal and neonatal tetanus. The WHO estimated that in 2007 there were approximately 6067 cases of neonatal tetanus worldwide.148 Pertussis is a respiratory illness characterized by paroxysms of cough occurring over a period of days to weeks caused by Bordetella pertussis, a Gram-negative coccobacillus. It is primarily a toxin-mediated disease. The incubation period can vary from less than one week to more than three weeks. The initial presenting symptoms can be non-specific and can range from mild catarrhal illness, malaise and low-grade fever, gradually progressing to a persistent non-productive cough characteristic of the name ‘whooping cough’. Clinical presentation is usually most severe in infants and the presentation can vary in adults, where the diagnosis is frequently missed. The disease can result in complications such as pneumonia, otitis media, and aspirations from frequent coughing. The World Health Organization reported that in 2006 there were 115 924 cases of pertussis worldwide; a sharp decline from the 1 982 384 cases reported in 1980.149 This decrease is attributed to an increase in global immunizations from 26% in 1980 to 90% in 2006. However, in the United States there has been a rising trend in the number of reported cases of pertussis for the same time period. The Centers for Disease Control (CDC) reported 25 827 new cases of pertussis in 2004, the highest number of cases since 1959,150 though reasons for this increase are unclear and are being investigated.

Diphtheria is caused by a non-sporulating, nonencapsulated, non-motile Gram-positive bacillus, Corynebacterium diphtheriae. It can cause an illness that locally can result in respiratory system involvement with pharyngitis and tracheobronchitis and also cause toxin-mediated disease more distally resulting in cardiac and neurologic toxicity. Death can occur as a result of asphyxiation of the diphtheroid membrane in the pharynx, cardiac arrest or from neuritis with resultant palsies. Diphtheria presents very rarely in the United States. According to the CDC, between 1998 and 2006 there only seven cases reported.151 Prior to that three small outbreaks were reported between 1972 and 1982 that were related to overcrowding and poor hygiene.152

Tetanus/Diphtheria/Pertussis Vaccine History Currently, there are two Tdap vaccines licensed for use among adults in the United States: Boostrix and Adacel (11 through 64 years).153 Boostrix is manufactured by GlaxoSmithKline Biologicals and was approved for booster immunization among persons aged 10 through 64 years of age in December 2008.154 Adacel, manufactured by Sanofi Pasteur, is approved for use in people age 11–64 years.155 The pertussis antigen components are derived from antigens of Bordetella pertussis grown in culture. There are three antigens in the vaccine: PT, FHA, and PRN are extracted, purified and adsorbed onto various components. The tetanus and diphtheria toxins are produced by growing Clostridium tetani and Corynebacterium diphtheria respectively and extracting the toxins. The three components of the vaccine are then combined with additives to formulate the final compound.

Tetanus/Diphtheria/Pertussis Vaccine Efficacy The vaccines were approved based on the results of various clinical trials that showed efficacy of the various components of the vaccine. Pichiero et al.’s large multi-center study showed that almost 98% of subjects developed protective immunity against tetanus and diphtheria, although lower antibody titers were noted for the pertussis antigens.156 These data were supported in other trials with over 2000 patients that showed patients developed protective antibody titers to tetanus and diphtheria toxins in over 98% and participants also developed titers against the three pertussis antigens in varying degrees from 77 to 97%.157–159

Tetanus/Diphtheria/Pertussis Current Recommendations The Tdap vaccine is routinely recommended as a booster for all adults between the ages of 19 and 64 every 10 years.160 The dose is 0.5 ml administered intramuscularly. If vaccination is required as part of trauma or wound care, the CDC recommends using Tdap instead of the dT vaccine

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especially when the Tdap vaccine has not previously been administered. For adults without documented completion of three injections of Tdap as part of primary series of vaccination, CDC recommends re-administering the series with Tdap vaccination.161 A special note needs to be made for adults anticipating being in or currently in contact with infants. These individuals should have received Tdap within the 10 years prior to help reduce the risk of pertussis for the infant. The Tdap can be safely administered as early as within two years of the last dT vaccine,162 although local adverse reactions are fewer when administered after five years of the prior dose.160 In addition, all healthcare workers in contact with patient contact should receive a Tdap vaccine every 10 years.160

Contraindications The Tdap vaccine is contraindicated for individuals with a history of any form of serious allergic reaction to any component of the vaccine. In addition, for persons with a history of serious neurological complications such as prolonged seizures or coma that are attributable to the pertussis component should not be given the Tdap and instead may receive the Td vaccine.160

MENINGOCOCCAL VACCINE Epidemiology of Meningococcal Disease in Men and Women in the US Meningococcal infections are caused by Neisseria meningitidis, a Gram-negative diplococcus. According to the Centers for Disease Control approximately 1400–2800 cases of meningococcal disease occur every year in the United States with a relatively high case fatality rate of about 10–14%.163 In addition to increased mortality, N. meningitidis also causes a significant increase in morbidity as noted by high rates of deafness, neurological sequelae, limb loss etc.164 Infants less than one year old remain at highest risk of infection with a rate of 9.1/100 000 populations. However, almost 62% of all meningococcal infections occur in persons over 11 years of age.165 Transmission occurs through close contact of the susceptible host with infected droplet particles. N. meningitidis can cause both the more commonly known meningitis and disseminated meningococcemia.166 In the US, the majority of infections have been sporadic cases. However, a few epidemics in select populations such as college communities and day care centers have been reported.167,168 Apart from these locations, select populations remain at increased risk of meningococcal disease, including persons with splenectomy or functional asplenia169 and those with deficiency of the terminal common complement pathway.170 In addition,

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overcrowding171 and both active172 and passive smoking173 increase meningococcal disease risk. Neisseria meningitidis produces a polysaccharide capsule that is very useful in identifying the various subtypes responsible for clinical disease. Presently, there are 13 serogroups (A, B, C, D, X, Y, Z, E, W-135; H, I, K and L) identifiable by sero-agglutination. The CDC performed laboratory surveillance of 217 meningitis cases between 1989 and 1991 and serological details were available for 261 (79%) of the cases. Forty-six percent and 45% were caused by serogroups B and C respectively, with the remainder being caused by serogroups W-135, Y, A, and a few other non-typeable strains.174 Noteworthy is that there has been a shift in the epidemiology of meningococcal disease with an increase in the incidence of serogroup Y disease.175 The reason for this shift in epidemiology remains uncertain; however, it is postulated that it may in part be related to an older population with resultant waning immunity.175 This hypothesis, however, remains to be confirmed. Worldwide, most infections are caused by serotypes A, B, C, Y and W-135.

Meningococcal Vaccine History and Efficacy There are currently two commercially available vaccines approved for use in the United States: (1) meningococcal polysaccharide vaccine (MPSV4 or Menomune), and (2) meningococcal conjugate vaccine (MCV4 or Menactra). Both vaccines offer protection against the four commonest serogroups responsible for meningococcal disease (groups A, C, Y and W-135). MENOMMUNUE (MPSV4) This is a quadrivalent polysaccharide vaccine approved for subcutaneous use and available since the 1970s. It is the only vaccine approved for use in patients over the age of 55. This vaccine has demonstrated clinical and immunological protection against types A and C and immunological efficacy against types Y and W-135. Studies have shown that the antibody titers developed in response to the vaccine are specific to the group although no cross-protection exists. However the duration of immunity conferred by the polysaccharide vaccine depends on the age when the vaccine was first administered, with the lowest response observed in those children vaccinated before the age of 4. The vaccine is routinely given as a single subcutaneous dose of 0.5 ml. Among adults, revaccination within 3–5 years may be considered for select populations such as persons remaining in endemic areas and for those who remain at high risk of acquiring meningococcal infections.165 The need for revaccination stems from the mechanism of immunogenicity of this vaccine. This is a polysaccharide vaccine and hence a mature B-cell lymphocyte response is elicited. This type of response lacks the capacity to develop an

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anamnestic response and also results in a shorter duration of protection as compared to conjugate vaccine. MENACTRA (MCV4) This quadrivalent conjugate vaccine is a combination vaccine for intramuscular use and is the preferred vaccine for persons 2–55 years of age. This vaccine is prepared using four meningococcal groups (A, C, Y and W-135) conjugated with the diphtheria toxoid protein carrier. The capsular polysaccharide of the selected strains are conjugated to selected proteins (in this case, diphtheria toxoid). This conjugation changes the type of host immune response from a primarily humoral response as noted on the MPSV4 vaccine to a T-cell-dependent cellular immunity. This offers two distinct advantages: (1) longer duration of protection, thereby possibly reducing need for booster doses or revaccination and (2) anamnestic response; resulting in a stronger response upon exposure to the antigens.165

Meningococcal Vaccine Current Recommendations Meningococcal vaccine is recommended for the following groups: (1) routinely for young adolescents (11–12 years) or at high school entry (15 years); (2) persons at increased risk such as college freshmen living in dormitories, military recruits, microbiologists exposed to N. meningitidis, travelers to or residence in hyperendemic or epidemic areas of the world, persons with terminal complement component deficiency or asplenia, and during meningococcal outbreaks. Vaccination for adults 20–55 years is not routinely recommended. On another note, HIV-infected persons are at slightly increased risk of meningococcal infections. However, there are limited data regarding the efficacy of the vaccine in this population. Hence, only patients who wish to be vaccinated can be given the vaccine.

Meningococcal Vaccine Contraindications The vaccine is contraindicated only in cases of history of severe allergic or anaphylactic reaction to the vaccine or any of its components. However, caution needs to be used if administered in the setting of moderate to severe illnesses. 176 Persons with a history of Guillain-Barré syndrome (GBS) might be at increased risk for GBS after MCV4 vaccination; therefore, a history of GBS is a precaution to administration of MCV4.177

IMMUNIZATION ISSUES FOR PREGNANT WOMEN Pregnancy presents a condition unique to women and can contribute to a significant increase in morbidity and mortality both for the women and their offspring. This is

especially true with regards to many vaccine-preventable illnesses such as influenza,178 tetanus, varicella etc. Among issues that require consideration in this population is a balance between the potential risks of vaccine-related complications versus the possible benefit of immunization in the setting of pregnancy and extending into the first few months of life for the newborn infant. Ideally, it is desirable for a woman planning a pregnancy to seek medical consultation prior to planned conception in order to ensure that most recommended vaccinations are completed prior to conception, thereby providing optimal protection while minimizing any possible risk to the fetus. However, women frequently present for medical care after conception, therefore it is important to offer those immunizations that can protect both the mother and the fetus from potential pathogens while avoiding vaccines that may have associated risks for either the mother or fetus. Generally, an inactivated vaccine or a toxoid is considered safe in pregnancy and can be administered in the second or third trimester. On the other hand, live vaccines are contraindicated during pregnancy unless specifically indicated. The potential risks associated with vaccinating a pregnant woman can be summarized under the following categories: ■

■ ■

Inadvertent infection of the unborn fetus as a result of the vaccine Possible teratogenicity of the vaccine Lack of efficacy of the vaccine.

Hepatitis A The safety of hepatitis A vaccination among pregnant women has not been established. However, it is an inactivated vaccine and has been used in pregnancy without reported adverse outcomes. Conversely, hepatitis A infection in a pregnant woman can cause significant viremia, placing the woman at increased risk for severe systemic infection, spontaneous abortion and premature delivery.179 Hence, if a pregnant woman has had close contact with a person infected with hepatitis A, passive immunization with hepatitis A immune globulin should be considered along with hepatitis A vaccine.103 In addition, a second dose of the vaccine should be administered six months later.

Hepatitis B Current HBV vaccines contain inactivated virus particles and should pose no harm to the fetus. Furthermore, pregnant women who acquire acute hepatitis B virus infection during pregnancy have almost a 60% risk of the infection being transmitted to the fetus,180 especially when acquired close to delivery. In some cases, fulminant infections of the mother, rates of spontaneous abortion can exceed 70%.181 Hence HBV vaccination should be routinely considered in

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some susceptible pregnant women especially those considered to be high risk such as those having more than one sex partner during the previous 6 months, previously treated for an STD, recent or current injection drug use, or having had an HBsAg-positive sex partner.182

Human Papilloma Virus Vaccine With regard to pregnancy, Gardasil is classified as Category B based on a lack of fetal harm in rats, and though adverse fetal events have not been associated with the vaccine, Gardasil is not recommended for use in pregnancy.30

Influenza Pregnant women with influenza virus infection have higher rates of morbidity and mortality.178,183,184 These rates are especially higher when the infection is acquired later in the pregnancy especially in the second and third trimesters and may be related to increased rates of acute cardiopulmonary complications.185 This increase in the rates of influenza associated complications has led to the CDC’s recommendation that all pregnant women be vaccinated against influenza virus using the inactivated vaccine.186 There are two vaccines currently approved for influenza vaccination: Trivalent inactivated influenza vaccine (TIV) and live, attenuated influenza vaccine (LAIV). During preparation of TIV only subvirion and purified surface antigen preparations are used in the United States and hence this vaccine poses no risk of infection for the pregnant woman and her unborn fetus. Although there are limited data documenting the effectiveness of influenza vaccination among pregnant women, studies have documented detectable levels of antibodies after vaccination.185,187 These antibodies have also been detected in neonates; however these levels decline rapidly and by 6 months of age most infants have no detectable levels of antibody.187 LAIV is not currently licensed for use in pregnant women. However, according to the CDC, pregnant women do not need to avoid contact with persons who may have been vaccinated with the LAIV.186

Measles, Mumps and Rubella The primary purpose of immunity to measles and rubella is to prevent fetal complications such as congenital rubella and also to reduce the maternal complications such as pneumonia associated with primary infection in pregnancy. Studies have shown that measles infection during pregnancy can result in premature labor and an increased risk of both fetal and neonatal loss. In addition, there is also a higher than expected rate of maternal complications such as pneumonitis and hepatitis.188 Rubella virus is one of the most teratogenic viruses and congenital rubella infection characterized by deafness, cataracts and congenital

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heart disease can be seen in up to 50% of affected fetuses. However, MMR is a live vaccine and is as such contraindicated for use both in pregnant women and also for women who may become pregnant within one month of the administration of the vaccine.189 Hence, women who are considering becoming pregnant should be screened for the presence of protective antibodies especially against rubella, and if found to be susceptible, vaccination should be recommended prior to conception and they should be counseled to avoid pregnancy for 28 days after vaccination. It is important to note that infants born to HIV-infected women have significantly lower titers of protective measles antibody placing these infants at risk for measles earlier in life than infants born to HIV-uninfected mothers.190,191 Studies have also reported that infants born to mothers who have been vaccinated have lower measles titers than mothers with immunity acquired from natural infection.192,193 All of these factors need to be considered when screening pregnant women for measles and making recommendations for them and their infants.

Meningococcal Vaccination Meningococcal infection is primarily an infection of young adults and although infection in pregnancy is rare; it can result in increased complications in the pregnant woman. Of the currently available vaccines, tetravalent meningococcal polysaccharide vaccine and tetravalent meningococcal conjugate vaccine, neither has been licensed for use in pregnant women.163 However, limited data regarding the use of the tetravalent meningococcal polysaccharide vaccine in pregnant women has shown no increase in adverse outcomes194 and hence can be considered in select situations if clinically indicated. No data are available regarding the safety and efficacy of the tetravalent meningococcal conjugate vaccine in pregnancy.

Pneumococcal Vaccine Women of childbearing age who fall into one of the high risk categories (i.e., asplenia, deficiencies in terminal complement components, etc.) should undergo pneumococcal vaccination before conception. Currently guidelines do not recommend routine screening of pregnant women for colonization with S. pneumoniae; however, if it is isolated, should not be ignored. Pneumococcal vaccination is not routinely recommended in pregnancy and the safety of the pneumococcal polysaccharide vaccine has not been established in the first trimester of pregnancy. However, studies have shown that vaccination in third trimester is effective and can produce protective antibodies in the neonates.195,196 These studies also suggest that based on the levels of protective anti-pneumococcal antibodies in the cord blood at birth, there may also be detectable antibodies in the infants until 4 months of age.

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Tetanus–Diphtheria Obstetric tetanus can occur during pregnancy and for up to six weeks after delivery or termination of pregnancy. It frequently occurs as a result of contamination of wounds during delivery and can result in high case fatality rates of 15 to over 50%. Neonatal infection occurs as a result of contamination of the umbilical stump and case fatality rates ranging from 10 to 100% have been reported. In 2006, there were 41 cases of tetanus reported in United States, however none were in women aged 30–39 years and there were no cases of neonatal tetanus.197 There are two vaccines currently available: Td and TdaP. For pregnant women who have been vaccinated with Td more than 10 years prior to presentation, it is recommended that they be vaccinated against Td during pregnancy. The goal of this immunization is not only to confer protection to the mother but to also confer passive immunity to the neonate. Studies have shown that if given two doses of the tetanus toxoid at least 4–6 weeks before delivery, neonatal levels of antibody are high enough to confer protection for a few years until active immunization of the neonate confers lasting immunity. In addition, this vaccine also confers protection both to the mother and the neonate against diphtheria. Td vaccines however lack one component present in Tdap vaccines, i.e. the pertussis component. Tdap vaccines have been labeled as pregnancy Category C because there are not adequate numbers of controlled trials to demonstrate safety of the vaccines and hence are not routinely recommended in pregnancy. Alternatively, Tdap can be administered in the immediate postpartum prior to being discharged from the healthcare facility. On the other hand, if the pregnant woman has been vaccinated with Td within the past 10 years, it is recommended that Tdap be administered in the postpartum period; with a minimum interval between the two vaccinations being at least 2 years in order to reduce the risk of adverse reactions to the vaccine. Although there are no controlled studies evaluating the safety of Tdap during pregnancy, there are many cases of pregnant women receiving Tdap vaccine with no adverse effect reported. Hence, if Tdap is inadvertently administered during pregnancy or if pregnancy occurs soon after vaccination with Tdap, no further intervention is routinely recommended. The dosage of Tdap or Td is 0.5 ml administered intramuscularly.

Varicella Varicella zoster virus is highly infectious and infection in the mother is associated with complications for the pregnant woman and the unborn fetus. Pregnant women have been reported to be at increased risk for complications such as varicella pneumonia, which if untreated can result in fatality rates as high as 40%.198 There is also an increased risk of transmission of the virus to the fetus and newborn resulting in neonatal varicella or herpes zoster infection

during infancy. Infections acquired in the first trimester of pregnancy can result in congenital varicella syndrome characterized by low birthweight, cutaneous scarring, limb hypoplasia, microcephaly, cortical atrophy, mental retardation, and early death.198,199 Infections acquired in the second and third trimesters of pregnancy could result in neonatal or zoster infections in infancy. However, when an infection develops in the pregnant mother from 5 days before to 2 days after delivery, it results in severe neonatal varicella infection due to the lack of protective maternal antibodies in the neonate. The varicella zoster vaccine is a live vaccine and therefore is not recommended in pregnancy.200 Hence, screening for the presence of protective antibody prior to conception is ideal and vaccination of susceptible women by giving two doses 4–8 weeks apart is recommended. Women need to be advised to not become pregnant for 4 weeks after administration of the vaccine. However, if pregnancy occurs within 4 weeks of vaccine administration, the woman should be counseled regarding potential side effects from the vaccine. The virus is a live attenuate vaccine and as such has less virulence that the wild strain that causes the infection. Based on the pregnancy database for the vaccine, there has not been an increase in reported cases of congenital varicella syndrome or birth defects attributable to this vaccine. Due to their higher risk for severe varicella and complications, post exposure prophylaxis with varicella zoster immune globulin (VZIG) should be considered for susceptible non-immune pregnant women. While VZIG prevents complications of varicella in the mother, it has not been found to prevent viremia and complications of varicella infection, including congenital varicella syndrome or neonatal varicella in the fetus. VariZIG is the VZIG product currently used in the US under Investigational New Drug Application Expanded Access Protocol. The CDC-recommended dose of VariZIG is 125 units/10 kg of body weight, up to a maximum of 625 units (5 vials).201 CDC also recommends prenatal assessment of women for evidence of varicella immunity. For pregnant women, evidence of immunity includes: (1) documentation of two doses of varicella vaccine; (2) serologic tests showing immunity to varicella or; (3) receipt from a healthcare provider of a diagnosis of or documented history of chickenpox or herpes zoster.201

References 1. CDC, Centers for Disease Control and Prevention. Ten great public health achievements – United States, 1900–1999. MMWR Morb Mortal Wkly Rep 1999;48:241–43. 2. CDC, Centers for Disease Control and Prevention, Fact Sheet: Genital HPV, 2007. 3. Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health 2004;36(1):6–10.

CHAPTER 48 4. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA 2007;297:813–9. 5. Clifford GM, Gallus S, Herrero R, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency Research on Cancer HPV Prevalence Surveys: a pooled analysis. Lancet 2005;366:991–8. 6. De Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology 2004;324:17–27. 7. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518–27. 8. Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The International Perspective. Int J Cancer 2004;111(2):278–85. 9. Jemal A, Siegel R, Ward E, et al. Cancer statistics. Cancer J Clin 2007;57:43–66. 10. Hillemanns P, Wang X. Integration of HPV-16 and HPV18 DNA in vulvar intraepithelial neoplasia. Gynecol Oncol 2006;100:276–82. 11. Johnson LG, Madeleine MM, Newcomer LM, Schwartz SM, Daling JR. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000. Cancer 2004;101(2):281–8. 12. Sobhani I, Vuagnat A, Walker F, et al. Prevalence of high-grade dysplasia and cancer in the anal canal in human papillomavirus-infected individuals. Gastroenterology 2001;120:857–66. 13. Monk BJ, Tewari KS. The spectrum and clinical sequelae of human papillomavirus infection. Gynecol Oncol 2007;107:S6–S13. 14. Mellin H, Friesland Lewensohn SR, Dalianis T, MunckWikland E. Human papillomavirus in tonsillar cancer: clinical correlates, risk of relapse, and survival. Int J Cancer 2000;89(3):300–4. 15. Hessol N, Holly EA, Efird JT, Minkoff H, Schowalter K, et al. Anal intraepithelial neoplasia in a multisite study of HIV-infected and high-risk HIV-uninfected woman. AIDS 2009;23:59–70. 16. Chiao EY, Krown SE, Stier EA, Schrag D. A populationbased analysis of temporal trends in the incidence of squamous anal cancer in relation to the HIVepidemic. J Acquir Immune Defic Syndrome 2005;40:451–5. 17. Pierangeli A, Scagnolari C, Degener AM, et al. Type-specific human papillomavirus-DNA in anal infection in HIV-positive men. AIDS 2008;22:1929–35. 18. Scheffner M, Wemess BA, Hulbregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by Human Papilloma Virus Types 16 and 18 promotes degradation of p53. Cell 1990;63:1129–36. 19. Dyson N, Howley PM, Munger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989;243:934–7. 20. Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991;185:251–7. 21. Kirnbauer R, Booy F, Ch N, Lowy DR, Schiller JT. Papilloma L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A 1992;89:12180–4.

●

Adult Immunization in Women and Men

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22. Rose RC, Bonnez W, Reichman RC, Garcea RL. Expression of human papillomavirus type 11 L1 protein in insect cells in vivo and in vitro assembly of virus-like particles. J Virol 1992;67:1936–44. 23. Schiller JT, Castellsague X, Villa LL, Hildesheim A. An update of prophylactic human papillomavirus L1 virus-like particle vaccine clinical trial results. Vaccine 2008;26S:K53–K61. 24. Einstein MH. on behalf of the HPV-010 Study Group. Immune response after primary vaccination course: a comparative trial of two HPV prophylactic vaccines. Presentation Number O-01.02. 2009 International Papillomavirus Conference, Malmo, Sweden; May 2009. 25. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928–43. 26. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–27. 27. Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III doubleblind, randomized controlled trial. Lancet 2007;369:2161–70. 28. Petaja T, Keranen H, Karppa T, et al. Immunogenicity and safety of human papillomavirus (HPV)-16/18 as04-adjuvanted vaccine in healthy boys aged 10–18 years. J Adolesc Health 2009;44:33–40. 29. Giuliano A, Palefsky J. Quadravalent HPV vaccine efficacy against male genital disease and infection. Presentation Number O-01.07. 2009 International Papillomavirus Conference, Malmo, Sweden, May 2009. 30. CDC, Centers for Disease Control and Prevention. Quadrivalent human papillomavirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-02). 31. CDC, Centers for Disease Control and Prevention. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-15). 32. Prescribing Information. Gardasil [Human Papillomavirus Quadrivalent (Types 6,11,16,18) Vaccine, Recombinant]. Merck & Co., Inc., Whitehouse Station, NJ; September 2008. 33. DiMiceli L, Pool V, Kelso JM, Shadomy SV, Iskender J. Vaccination of yeast sensitive individuals: review of safety data in the US Vaccine Adverse Event Reporting System (VAERS). Vaccine 2006;24:703–7. 34. Yawn BP, Saddier S, Wollan P, Sauver JS, Kurland M, Sy L. A population-based study of the incidence and complications of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007;82:1341–9. 35. Scott FT, Leedham-Green ME, Barrett-Muir WY, et al. A study of zoster and the development of postherpetic neuralgia in East London. J Med Virol 2003(Suppl. 1):S24–30. 36. Ragozzino MW, Melton LJ 3rd, Kurland LLT, Chu CP, Perry HO. Population-based study of herpes zoster and its sequelae. Medicine 1982;61:310–16. 37. Sweeney CJ, Gilden DH. Ramsay Hundt syndrome. J Neruol Neurosurg Psychiatry 2001;71:149–54. 38. Gilden DH, Kleinschmidt-DeMasters BK, LaGuarda JJ, Mahalingam R, Cohrs RJ. Neurologic complications of

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41.

42.

43. 44.

45. 46.

47. 48.

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50.

51. 52.

53.

54.

55. 56.

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Infectious Disease

the reactivation of varicella-zoster virus. N Engl J Med 2000;342:635–45. Gnann JW, Whitley RJ. Natural history and treatment of varicella-zoster virus in high-risk populations. J Hosp Infect 1991;18:317–29. CDC, Centers for Disease Control and Prevention. Prevention of herpes zoster. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008;57(RR-05). Kilgore PE, Kruszon-Moran D, Seward JF, et al. Varicella in Americans from NHANES III: implications for control through routine immunization. J Med Virol 2003;70(Suppl. 1):S111–18. Takayama N, Takayama M, Takita J. Herpes zoster in healthy children immunized with varicella vaccine. Pediatr Infect Dis J 2000;19:169–70. Gershon AA. Live-attenuated varicella vaccine. Infect Dis Clin North Am 2001;15:65–81. Black S, Shrinefield H, Ray P, et al. Postmarketing evaluation of the safety and effectiveness of varicella vaccine. Pediatr Infect Dis J 1999;18:1041–6. Hope-Simpson RE. Postherpetic neuralgia. J R Coll Gen Pract 1975;25:571–5. Brisson M, Edmunds WJ, Law B, et al. Epidemiology of varicella zoster virus infection in Canada and the United Kingdom. Epidemiol Infect 2001;127:305–14. Schmader K. Herpes zoster in older adults. Clin Infect Dis 2001;32:1481–6. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271–84. Opstelten W, Van Essen GA, Schellevis F, Verheij TJ, Moons K. Gender as an independent risk factor for herpes zoster: a population-based prospective. Ann Epidemiol 2006;1006(16):692–5. Fleming DM, Cross KW, Cobb WA, Champion RS. Gender difference in the incidence of zoster. Epidemiol Infect 2004;132:1–5. Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med 1995;155:1605–9. Rusthoven JJ, Ahlgren P, Elhakim T, et al. Varicella-zoster infection in adult cancer patients. A population study. Arch Intern Med 1988;148:1561–66. Rusthoven JJ. The risk of varicella-zoster infections in different patient populations: a critical review. Transfus Med Rev 1994;8:96–116. Goffinet DR, Glatstein EJ, Merigan TC. Herpes zostervaricella infections and lymphoma. Ann Intern Med 1972;76:235–40. Schimpff S, Serpick A, Stoler B, et al. Varicella-zoster infection in patients with cancer. Ann Intern Med 1972;76:241–54. Wilson JF, Marsa GW, Johnson RE. Herpes zoster in Hodgkin’s disease. Clinical, histologic, and immunologic correlations. Cancer 1972;29:461–65. Arvin AM. Varicella-zoster virus: pathogenesis, immunity, and clinical management in hematopoietic cell transplant recipients. Biol Blood Marrow Transplant 2000;6:219–30. Schuchter LM, Wingard JR, Piantadosi S, Burns WH, Santos GW, Saral R. Herpes zoster infection after autologous bone marrow transplatation. Blood 1989;74:1424–7.

59. Gourishankar S, McDermid JC, Jhangri GS, Preiksaitis JK. Herpes zoster infection following solid organ transplantation: incidence, risk factors, and outcomes in the current immunosuppressive era. Am J Transplant 2004;4:108–15. 60. Veenstra J, Krol A, van Praag RM, et al. Herpes zoster, immunological deterioration and disease progression in HIV1 infection.. AIDS 1995;9:1153–8. 61. Gebo KA, Kalyani R, Moore RD, Polydefkis M. The incidence of, risk factors for, and sequelae of herpes zoster among HIV patients in the HAART era. J Acquir Immune Defic Syndr 2005;40:169–74. 62. Gershon AA, Mervish N, LaRussa P, et al. Varicella-zoster virus infection in children with underlying human immunodeficiency virus infection. J Infect Dis 1997;176:1496–500, 33. 63. Treanor JJ. Influenza virus, Ch 153. In: GL Mandell, JE Bennett, R Dolin, eds. Principles and Practice of Infectious Diseases, fifth ed. Philadelphia, PA: Churchill Livingstone; 2000:1823–49. 64. CDC, Centers for Disease Control and Prevention. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008;57(RR-07):1–60. 65. Monto AS, Kioumehr F. The Tecumseh study of respiratory illness. IX. Occurrence of influenza in the community, 19661971. Am J Epidemiol 1975;102:553–9. 66. Brankston G, Gitterman L, Hirji Z, Lemieux C, Gardam M. Transmission of influenza A in human beings. Lancet Infect Dis 2007;7:257–65. 67. Barker WH, Mullooly JP. Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 1980;112:798–811. 68. Barker WH. Excess pneumonia and influenza associated hospitalization during influenza epidemics in the United States, 1970–78. Am J Public Health 1986;76:761–5. 69. Thompson WW, Shay DK, Weintraub E, et al. Influenzaassociated hospitalizations in the United States. JAMA 2004;292:1333–40. 70. Mullooly JP, Bridges CB, Thompson WW, et al. Influenzaand RSV-associated hospitalizations among adults. Vaccine 2007;25:846–55. 71. Irving WL, James DK, Stephenson T, et al. Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. BJOG 2000;107:1282–9. 72. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179–86. 73. O’Brien MA, Uyeki TM, Shay DK, et al. Incidence of outpatient visits and hospitalizations related to influenza in infants and young children. Pediatrics 2004;113:585–93. 74. Neuzil KM, Wright PF, Mitchel EF Jr, Griffin MR. The burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr 2000;137:856–64. 75. King JC Jr., Fast PE, Zangwill KM, et al. Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus- infected and noninfected children. Pediatr Infect Dis J 2001;20:1124–31. 76. Buonaguiro DA, O’Neill RE, Shutyak L, et al. Genetic and phenotypic stability of cold-adapted influenza viruses in a trivalent

CHAPTER 48

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

vaccine administered to children in a day care setting. Virology 2006;347:296–306. Bridges CB, Thompson WW, Meltzer MI, et al. Effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial. JAMA 2000;284:1655–63. Jefferson TO, Rivetti D, DiPietrantonj C, et al. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2007;2, CD001269. Nichol KL, Lind A, Margolis KL, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med 1995;333:889–93. Campbell DS, Rumley MH. Cost-effectiveness of the influenza vaccine in a healthy, working-age population. J Occup Environ Med 1997;39:408–14. Hak E, Buskens E, Nichol KL, et al. Clinical effectiveness of influenza vaccination in persons younger than 65 years with high-risk medical conditions: the PRISMA study. Arch Intern Med 2005;165:274–80. Govaert TM, Thijs CT, Masurel N, et al. The efficacy of influenza vaccination in elderly individuals. A randomized doubleblind placebo-controlled trial. JAMA 1994;272:1661–5. Monto AS, Hornbuckle K, Ohmit SE. Influenza vaccine effectiveness among elderly nursing home residents: a cohort study. Am J Epidemiol 2001;154:155–60. Ohmit SE, Arden NH, Monto AS. Effectiveness of inactivated influenza vaccine among nursing home residents during an influenza A (H3N2) epidemic. J Am Geriatr Soc 1999;47:165–71. Jefferson T, Rivetti D, Rudin M, et al. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet 2005;366:1165–74. Patriarca PA, Weber JA, Parker RA, et al. Efficacy of influenza vaccine in nursing homes. Reduction in illness and complications during an influenza A (H3N2) epidemic. JAMA 1985;253:1136–9. Nichol KL, Nordin JD, Nelson DB, et al. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med 2007;357:1373–81. Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA 1999;282:137–44. Treanor JJ, Kotloff K, Betts RF, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine 1999;18:899–906. Custer B, Sullivan SD, Hazlet TK, Iloeje U, Veenstra DL, Kowdley KV. Global epidemiology of hepatitis B virus. J Clin Gastroenterol 2004;38(10 Suppl. 3):S158–S168. CDC, Centers for Disease Control and Prevention. Comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. Part II: Immunization of Adults. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-16):1–25. Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004;127(5 Suppl. 1):S5–S16.

●

Adult Immunization in Women and Men

579

93. Tsay PK, Tai DI, Chen YM, et al. Impact of gender, viral transmission and aging in the prevalence of hepatitis B surface antigen. Chang Gung Med J 2009;32(2):155–64. 94. Lee CM, Lu SN, Changchien CS, et al. Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection. Cancer 1999;86(7):1143–50. 95. Behal R, Jain R, Behal KK, Bhagoliwal A, Aggarwal N, Dhole TN. Seroprevalence and risk factors for hepatitis B virus infection among general population in Northern India. Arq Gastroenterol 2008;45(2):137–40. 96. CDC, Centers for Disease Control and Prevention. Suboptimal response to hepatitis B vaccine given by injection into the buttock. MMWR Morb Mortal Wkly Rep 1985;34(8):105–13. 97. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 1980;303(15):833–41. 98. Hadler SC, Francis DP, Maynard JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl J Med 1986;315(4):209–14. 99. Clemens R, Sänger R, Kruppenbacher J, et al. Booster immunization of low- and non-responders after a standard three dose hepatitis B vaccine schedule – results of a post-marketing surveillance. Vaccine 1997;15(4):349–52. 100. Craven DE, Awdeh ZL, Kunches LM, et al. Nonresponsiveness to hepatitis B vaccine in health care workers. Results of revaccination and genetic typings. Ann Intern Med 1986;105(3):356–60. 101. West DJ, Calandra DB. Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination. Vaccine 1996;14(11):1019–27. 102. CDC, Centers for Disease Control and Prevention. Foodborne transmission of hepatitis A – Massachusetts, 2001. MMWR Morb Mortal Wkly Rep 2003;52(24):565–7. 103. CDC, Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-07):1–23. 104. Halliday ML, Kang LY, Zhou TK, et al. An epidemic of hepatitis A attributable to the ingestion of raw clams in Shanghai, China. J Infect Dis 1991;164(5):852–9. 105. Tong MJ, el-Farra NS, Grew MI. Clinical manifestations of hepatitis A: recent experience in a community teaching hospital. J Infect Dis 1995;171(Suppl. 1):S15–S18. 106. Melnick JL. History and epidemiology of hepatitis A virus. J Infect Dis 1995;171(Suppl. 1):S2–S8. 107. Forbes A, Williams R. Changing epidemiology and clinical aspects of hepatitis A. Br Med Bull 1990;46:303–18. 108. CDC, Centers for Disease Control and Prevention. Surveillance for acute viral hepatitis – United States, 2005. MMWR Summ Surv 2007;56(SS-03):1–24. 109. Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United States in the era of vaccination. JAMA 2005;294:194–201. 110. CDC, Centers for Disease Control and Prevention. Viral hepatitis surveillance: estimates of disease burden from viral hepatitis. Atlanta, GA: US Department of Health and Human Services; CDC, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention (proposed); 2006.

580

SECTION 8

●

Infectious Disease

111. Tjon G, Xiridou M, Coutinho R, Bruisten S. Different transmission patterns of hepatitis A virus for two main risk groups as evidenced by molecular cluster analysis. J Med Virol 2007;79(5):488–94. 112. Stene-Johansen K, Tjon G, Schreier E, et al. Molecular epidemiological studies show that hepatitis A virus is endemic among active homosexual men in Europe. J Med Virol 2007;79(4):356–65. 113. CDC, Centers for Disease Prevention and Control. Prevention of hepatitis A through active or passive immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1999;48(RR-12):1–37. 114. Prescribing Information, Havrix [Hepatitis A Vaccine], GlaxoSmithKline Biologicals, Rixensart, Belgium, May 2009. 115. Prescribing Information, Vaqta [Hepatitis A Vaccine, Inactivated], Merck & Co., Inc., Whitehouse Station, NJ, 2007. 116. Prescribing Information, Twinrix [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine], GlaxoSmithKline Biologicals, Rixensart, Belgium, May 2009. 117. Clemens R, Safary A, Hepburn A, Roche C, Stanbury WJ, André FE. Clinical experience with an inactivated hepatitis A vaccine. J Infect Dis 1995;171(Suppl. 1):S44–S49. 118. McMahon BJ, Williams J, Bulkow L, et al. Immunogenicity of an inactivated hepatitis A vaccine in Alaska Native children and Native and non-Native adults. J Infect Dis 1995;171(3):676–9. 119. Van Damme P, Van Herck K. A review of the long-term protection after hepatitis A and B vaccination. Travel Med Infect Dis 2007;5(2):79–84, Epub 2006 Jun 19. 120. Wiedermann G, Kundi M, Ambrosch F. Estimated persistence of anti-HAV antibodies after single dose and booster hepatitis A vaccination (0–6 schedule). Acta Trop 1998;69:121–5. 121. CDC, Centers for Disease Control and Prevention. Pneumococcal polysaccharide vaccine usage, United States. MMWR Morb Mortal Wkly Rep 1984;33:273–276, 281. 122. Williams WW, Hickson MA, Kane MA, Kendal AP, Spika JS, Hinman AR. Immunization policies and vaccine coverage among adults: the risk for missed opportunities. Ann Intern Med 1988;108:616–25. 123. CDC, Centers for Disease Control and Prevention. Prevention of pneumococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(RR-08):1–24. 124. Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: 5-year prospective study. Rev Infect Dis 1989;11:586–99. 125. Fang GD, Fine M, Orloff J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases. Medicine 1990;69:307–16. 126. Istre GR, Tarpay M, Anderson M, Pryor A, Welch D. Pneumococcus Study Group. Invasive disease due to Streptococcus pneumoniae in an area with a high rate of relative penicillin resistance. J Infect Dis 1987;156:732–5. 127. Breiman RF, Spika JS, Navarro VJ, Darden PM, Darby CP. Pneumococcal bacteremia in Charleston County, South Carolina: a decade later. Arch Intern Med 1990; 150:1401–5.

128. Bennett NM, Buffington J, LaForce FM. Pneumococcal bacteremia in Monroe County, New York. Am J Public Health 1992;82:1513–16. 129. Wenger JD, Hightower AW, Facklam RR, Gaventa S, Broome CV. Bacterial Meningitis Study Group. Bacterial meningitis in the United States, 1986: report of a multistate surveillance study. J Infect Dis 1990;162:1316–23. 130. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003;348:1737–46. 131. Kalin M. Pneumococcal serotypes and their clinical relevance. Thorax 1998;53:159–62. 132. Robbins JB, Austrian R, Lee CJ, et al. Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis 1983;148:1136–59. 133. Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. JAMA 1993;270:1826–31. 134. Butler JC, Breiman RF, Lipman HB, Hofmann J, Facklam RR. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978–1994: implications for development of a conjugate vaccine. J Infect Dis 1995;171:885–9. 135. Hofmann J, Cetron MS, Farley MM, et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995;333:481–6. 136. Butler JC, Hofmann J, Cetron MS, Elliott JA, Facklam RR, Breiman RF. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention’s Pneumococcal Sentinel Surveillance System. J Infect Dis 1996;174:986–93. 137. CDC, Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2000;49(RR-09):1–35. 138. Shapiro ED, Clemens JD. A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections. Ann Intern Med 1984;101:325–30. 139. Sims RV, Steinmann WC, McConville JH, King LR, Zwick WC, Schwartz JS. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med 1988;108:653–7. 140. Shapiro ED, Berg AT, Austrian R, et al. The protective efficacy of polyvalent pneumococcal polyscaccharide vaccine. N Engl J Med 1991;325:1453–60. 141. Farr BM, Johnston Bl, Cobb DK, et al. Preventing pneumococcal bacteremia in patients at risk: results of a matched case-control study. Arch Intern Med 1995;155:2336–40. 142. Broome CV. Efficacy of pneumococcal polysaccharide vaccines. Rev Infect Dis 1981;3(Suppl.):S82–S96. 143. Simberkoff MS, Cross AP, Al-Ibrahim M, et al. Efficacy of pneumococcal vaccine in high-risk patients: results of a Veterans Administration cooperative study. N Engl J Med 1986;315:1318–27.

CHAPTER 48 144. Fine MJ, Smith MA, Carson CA, et al. Efficacy of pneumococcal vaccination in adults: a meta-analysis of randomized controlled trials. Arch Intern Med 1994;154:2666–77. 145. CDC, Centers for Disease Control and Prevention. Provisional recommendations for use of pneumococcal vaccines. Advisory Committee on Immunization Practices (ACIP). Posted December 8, 2008. www.cdc.gov/vaccines/ recs/provisional/downloads/pneumo-oct-2008-508.pdf. 146. CDC, Centers for Disease Control and Prevention. Tetanus surveillance – United States, 1998–2000. MMWR Surv Summ 2003;52(SS-03):1–8. 147. World Health Organization, Immunization surveillance, assessment and monitoring: Tetanus. www.who.int/immunization_ monitoring/diseases/tetanus/en/index.html. (Accessed May 21, 2009.) 148. World Health Organization, Immunization surveillance, assessment and monitoring: Neonatal tetanus. www.who .int/immunization_monitoring/diseases/neonatal_tetanus/en/ index.html. (Accessed May 21, 2009.) 149. World Health Organization, Department of Immunizations, Vaccines and Biologicals. Vaccine-Preventable Diseases: Monitoring System. 2007 Global Summary. Geneva: WHO; 2007. 150. CDC, Centers for Disease Control and Prevention. Pertussis. In: W Atkinson, S Wolfe, J Hamborsky, L McIntyre, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases, eleventh ed. Washington DC: Public Health Foundation; 2009. 151. CDC, Centers for Disease Control and Prevention. Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008;57(RR-04):1–47, 51; erratum in MMWR Morb Mortal Wkly Rep 2008;57(26):723. 152. Harnisch JP, Tronca E, Nolan CM, Turck M, Holmes KK. Diphtheria among alcoholic urban adults. A decade of experience in Seattle. Ann Intern Med 1989;111(1):71–82. 153. CDC, Centers for Disease Control and Prevention. FDA approval of expanded age indication for a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine. MMWR Morb Mortal Wkly Rep 2009;58(14):374–5. 154. Prescribing Information. BOOSTRIX [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed]. GlaxoSmithKline Biologicals, Research Triangle Park, NJ. December 2008. 155. Prescribing Information. Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed]. Sanofi Pasteur Ltd, Swiftwater, PA, January 2009. 156. Pichichero ME, Rennels MB, Edwards KM, et al. Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents and adults. JAMA 2005;293(24):3003–11, Epub 2005 Jun 2. 157. Blatter M, Friedland LR, Weston WM, Li P, Howe B. Immunogenicity and safety of a tetanus toxoid, reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19–64 years of age. Vaccine 2009;27(5):765–72, Epub 2008 Nov 27. 158. Bartels I, Jüngert J, Lugauer S, Stehr K, Heininger U. Immunogenicity and reactogenicity of a single dose of

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

●

Adult Immunization in Women and Men

581

a diphtheria–tetanus–acellular pertussis component vaccine (DTaP) compared to a diphtheria--tetanus toxoid (Td) and a diphtheria toxoid vaccine (d) in adults. Vaccine 2001;19(23–24):3137–45. Van der Wielen M, Van Damme P, Joossenss E, François G, Meurice F, Ramalho AA. randomised controlled trial with a diphtheria-tetanus-acellular pertussis (dTpa) vaccine in adults. Vaccine 2000;18(20):2075–82. CDC, Centers for Disease Control and Prevention. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP) and Recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for Use of Tdap among Health-Care Personnel. MMWR Recomm Rep 2006;55(RR-17):1–33. CDC, Centers for Disease Control and Prevention. Diphtheria, tetanus, and pertussis: Recommendations for vaccine use and other preventive measures. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1991;40(RR-10). Halperin SA, Sweet L, Baxendale D, et al. How soon after a prior tetanus–diphtheria vaccination can one give adult formulation tetanus–diphtheria–acellular pertussis vaccine? Pediatr Infect Dis J 2006;25(3):195–200. CDC, Centers of Disease Control and Prevention. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(RR-07):15. Edwards MS, Baker CJ. Complications and sequelae of meningococcal infections in children. J Pediatr 1981;99(4):540–545. CDC, Centers for Disease Control and Prevention. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(RR-07):15. CDC, Centers for Disease Control and Prevention. Control and Prevention of Meningococcal Disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(RR-05):1–51. Imrey PB, Jackson LA, Ludwinski PH, et al. Outbreak of serogroup C meningococcal disease associated with campus bar patronage. Am J Epidemiol 1996;143(6):624–30. Jackson LA, Schuchat A, Reeves MW, Wenger JD, Serogroup C. meningococcal outbreaks in the United States. An emerging threat. JAMA 1995;273(5):383–9. Locker GJ, Wagner A, Peter A, et al. Lethal Waterhouse– Friderichsen syndrome in posttraumatic asplenia. J Trauma 1995;39(4):784–6. Morris JT, Kelly WJ. Recurrence of neisserial meningococcemia due to deficiency of terminal complement component. South Med J 1992;85(10):1030–1. Baker M, McNicholas A, Garrett N, et al. Household crowding a major risk factor for epidemic meningococcal disease in Auckland children. Pediatr Infect Dis J 2000;19(10):983–90. Blackwell CC, Weir DM, James VS, et al. Secretor status, smoking and carriage of Neisseria meningitidis. Epidemiol Infect 1990;104(2):203–9.

582

SECTION 8

●

Infectious Disease

173. Stanwell-Smith RE, Stuart JM, Hughes AO, Robinson P, Griffin MB, Cartwright K. Smoking, the environment and meningococcal disease: a case control study. Epidemiol Infect 1994;112(2):315–28. 174. CDC, Centers for Disease Control and Prevention. Labbased surveillance for meningococcal disease – US, 1989– 91. MMWR Surv Summ 1993;42(SS-02):21–30. 175. Rosenstein NE, Perkins BA, Stephens DS, et al. The changing epidemiology of meningococcal disease in the United States, 1992–1996. J Infect Dis 1999;180(6):1894–901. 176. CDC, Center for Disease Control and Prevention. Guide to Vaccine Contraindications and Precautions. http://cdc .gov/vaccines/recs/vac-admin/downloads/contraindicationsguide-508.pdf. (Accessed May 29, 2009.) 177. CDC, Centers for Disease Control and Prevention. Decision not to recommend routine vaccination of all children aged 2–10 years with quadrivalent meningococcal conjugate vaccine (MCV4). Report from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008;57(17):462–5. 178. Irving WL, James DK, Stephenson T, et al. Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. BJOG 2000;107(10):1282–9. 179. Elinav E, Ben-Dov IZ, Shapira Y, et al. Acute hepatitis A infection in pregnancy is associated with high rates of gestational complications and preterm labor. Gastroenterology 2006;130(4):1129–34. 180. Sookoian S. Liver diseases during pregnany: acute viral hepatitis. Ann Hepatol 2006;5(3):231–6. 181. Burk RD, Hwang LY, Ho GYF, et al. Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load. J Infect Dis 1994;170:14–18. 182. CDC, Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. Part 1: Immunization of Infants, Children, and Adolescents. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(RR-16):12, 14. 183. Harris JW. Influenza occurring in pregnant women: a statistical study of thirteen hundred and fifty cases. JAMA 1919;72:978–80. 184. Freeman DW, Barno A. Deaths from Asian influenza associated with pregnancy. Am J Obstet Gynecol 1959;78:1172–5. 185. Sumaya CV, Gibbs RS. Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity in mother and infant. J Infect Dis 1979;140:141–6. 186. CDC, Centers for Disease Control and Prevention. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008;57(RR-07):1–60.

187. Munoz FM, Greisinger AJ, Wehmanen OA, et al. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2005;192:1098–6. 188. Atmar RL, Englund JA, Hammill H. Complications of measles during pregnancy. Clin Infect Dis 1992;14(1):217–26. 189. CDC, Centers for Disease Control and Prevention. Notice to readers: Revised ACIP recommendation for avoiding pregnancy after receiving a rubella-containing vaccine. MMWR Morbid Mortal Wkly Rep 2001;50(49):1117. 190. Embree JE, et al. Increased risk of early measles in infants of human immunodeficiency virus type 1-seropositive mothers. J Infect Dis 1992;165(2):262–7. 191. Scott S, Moss WJ, Cousens S, et al. The influence of HIV-1 exposure and infection on levels of passively acquired antibodies to measles virus in Zambian infants. Clin Infect Dis 2007;45(11):1417–24, Epub 2007 Oct 22. 192. Maldonado YA, Lawrence EC, DeHovitz R, Hartzell H, Albrecht P. Early loss of passive measles antibody in infants of mothers with vaccine-induced immunity. Pediatrics 1995;96(3 Pt 1):447–50. 193. De Serres G, Joly JR, Fauvel M, Meyer F, Mâsse B, Boulianne N. Passive immunity against measles during the first 8 months of life of infants born to vaccinated mothers or to mothers who sustained measles. Vaccine 1997;15(6–7):620–3. 194. McCormick JB, Gusmao HH, Nakamura S, et al. Antibody response to serogroup A and C meningococcal polysaccharide vaccines in infants born of mothers vaccinated during pregnancy. J Clin Invest 1980;65:1141. 195. Quiambao BP, Nohynek H, Käyhty H, et al. Maternal immunization with pneumococcal polysaccharide vaccine in the Philippines. Vaccine 2003;21(24):3451–4. 196. Quiambao BP, Nohynek HM, Käyhty H, et al. Immunogenicity and reactogenicity of 23-valent pneumococcal polysaccharide vaccine among pregnant Filipino women and placental transfer of antibodies. Vaccine 2007;25(22):4470–7, Epub 2007 Mar 28. 197. CDC, Centers for Disease Control and Prevention. Summary of Notifiable Diseases – United States, 2006. MMWR Morb Mortal Wkly Rep 2008;55(53):1–94. 198. McCarter-Spaulding DE. Review Varicella infection in pregnancy. Obstet Gynecol Neonatal Nurs 2001;30(6):667–73. 199. Balducci J, Rodis JF, Rosengren S, Vintzileos AM, Spivey G, Vosseller C. Pregnancy outcome following first-trimester varicella infection. Obstet Gynecol 1992;79:5–6. 200. CDC, Centers for Disease Control and Prevention. Prevention of varicella. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Issue Series Title: MMWR Recomm Rep 2007;56(RR-04):16, 24–6,29–32. 201. CDC, Centers for Disease Control and Prevention. Prevention of varicella. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-04):1–40.

Section 9

Immunology

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Introduction ROBERT G. LAHITA Sex hormones, sex chromatin, the role of hormones on T regulation, on apoptosis and on the levels of cytokines are the subject of this very interesting section. Nowhere is the role of gender more obvious than in the immune and rheumatic diseases. Sex steroids play an important role in the maturation of organ systems that affect animals throughout life and are therefore important to the health of most vertebrates. Even though the most obvious effects occur at puberty in the development of secondary sexual characteristics, hormones affect major developmental changes before parturition and even later in life. Diverse biologic functions including behavior, intelligence, sexual preference, physical stature, and the immune system are likely targets for these hormones. Although the effects of sex steroids on the immune system are profound and long-lasting, the effects such hormones have on the maturation of various cell systems and how that influences susceptibility to disease remains unknown. Sex chromatin also has a role in the diseases of the immune system, but knowledge of the role of genes and sexual preference for a certain illness is unknown. In this section we will explore these phenomena and some of the known observations found with sex steroids. Hormones may act through alteration of cytokine levels, the control of cell populations through processes like apoptosis or the alteration of very basic molecular mechanisms. Autoimmune diseases are somewhat affected by sex hormones because in some instances disease activity is made worse when levels of steroids like estrogens are high. However, hormones do not explain a skew of disease towards males or females. Recent studies of autoimmunity in males may provide us with new understanding of some of these phenomena, but more work needs to be done. Many theories have been proposed to explain the predominance of autoimmune disease in females. These include the metabolism of sex hormones studied in diseases like systemic lupus erythematosus or rheumatoid arthritis or perhaps the role of the X chromosome. Selected aspects of immune gender interactions are given here with specific emphasis on new material involving cytokines, estrogen receptors, prolactin and various concerns like the role and utility of oral contraceptives and altered immune function in pregnancy. The effects of gender on the immune system are anything but subtle, but they are elusive. The molecular mechanisms involved in immune regulation and the basic role of estrogen and estrogen receptors are given in the chapter by Abdou and Rider. While no specific anomaly can be responsible for all effects on immune disease, you will see that sex has a significant effect on basic molecular mechanisms. Abdou and Rider discuss the dimorphic sexual nature of the immune response. Topics like the synthesis of immunoglobulin, the varying classes of immune cells, and the response

to antigens for different genders is an important area. Hilary Sanfey discusses gender and tissue transplantation in a particularly interesting chapter. Many examples of gender specificity in the transplant process, like the issue of liver failure, illustrate the importance of gender and transplantation. In my own chapter, I report the influence of male and female metabolism and the various changes of sex steroid metabolism in diseased patients in the hope that they might explain the change of activity within a disease. The primary observation that there are metabolic differences within certain of the autoimmune diseases is important. While the etiologies of these diseases are unknown, they are affected by sex hormones. I also explore the observations of autoimmunity in men. Pregnancy is discussed by Laskin and colleagues as a special time for women with immune disease in both a good and bad sense. The effects that pregnancy brings to patients who are ill, depend on the nature of the illness. This is certainly the case for many women with rheumatoid arthritis and multiple sclerosis where remissions are found during pregnancy. The case is different for illnesses like SLE. Laskin also goes into the entire area of coagulation and immune regulation as affected by gender. The immune system is affected by gonadotropins such as prolactin as well as sex steroids, and this is covered in a brilliant chapter by Sara Walker. Only now do we appreciate the effects of sex steroids and cytokines such as prolactin on B cell function. Dr Cutolo details his experiences with sex hormones and cytokine inhibitors; specifically the tumor necrosis factor inhibitors, and how they cause an increase in aromatases that produce a concomitant increase of estradiol in those being treated with the TNF inhibitor drugs. Dr Petri tackles the issue of exogenous estrogens such as the oral contraceptives and their role in the autoimmune diseases. She cites the literature regarding their safety in diseases like rheumatoid arthritis and lupus where their use has been shown to be risk-free. This of course presupposes that patients taking these agents do not have a procoagulant state such as the antiphospholipid syndrome or some other risk factor that would prevent their use. Sex steroids are potent modulators of immunity in all animal systems. They are very important in patients with diseases such as rheumatoid arthritis and SLE, but they are not involved in the etiopathogenesis and their roles are unclear. What continues to be intriguing is the gender specificity of many diseases of the immune system for either males or females. The role of sex hormones in the maturation of the immune system and their effect on the development of organs like the brain could explain both the gender differences and some of the abnormalities found in these systems. It is impossible to discuss every aspect of this changing landscape in this section, but it is possible to stimulate interest in a very important and under-explored part of immunology.

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Gender Differences in Autoimmune Diseases: Immune Mechanisms and Clinical Applications Nabih I. Abdou1, and Virginia Rider2 1 Clinical Professor of Medicine, University of Missouri School of Medicine and Center for Rheumatic Disease and Center for Allergy and Immunology, Kansas City, MO, USA 2 Professor of Biology, Pittsburg State University, Department of Biology, Pittsburg, KS, USA

(SLE).3 Their original observation demonstrated alteration of estrogen metabolism in SLE. They studied estrogen metabolism in 10 patients with SLE and 29 normal controls. They measured urinary estrogen metabolites after injection of tritiated thymidine-labeled estradiol. SLE patients had increased 16–hydroxylation of estrone. In SLE males only 16 alpha-hydroxyestrone was elevated whereas in SLE females both 16-alpha hydroxyestrone and estriol were elevated. These observations support the concept that some SLE patients have abnormal estradiol metabolism resulting in increased estrogenic activity.3

General remarks In this short analytical review, we will update and add new information to complement and extend our previous reviews on gender differences in autoimmunity.1,2 We will start with general remarks on what is new in sex hormones and autoimmunity. We will then discuss genes and sex differences with respect to autoimmune diseases, immune mediators, and signals that are under the influence of sex hormones, and update the information on estrogen receptors (ER), both ER and ER. We will discuss immune modulation following activation and/or blocking of estrogen receptors and the subsequent expression of the autoimmune state. We selected, in this chapter, recent work that dealt with hormones and gender differences in autoimmunity. We will discuss the interplay between sex hormones and the cellular– humoral–cytokine factors that could influence the expression of autoimmune diseases. Specific autoimmune diseases with female predominance will be discussed with emphasis on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren syndrome (SS), and neurologic diseases, particularly those with established animal models. Current and future applications of the basic information in the field of hormones and gender will be outlined with emphasis on possible future therapeutic applications in autoimmune diseases with female predominance.

Genes and Sex Work by Kotzin’s group4 has demonstrated that there are five genes to be regulated by either estradiol or dihydrotestosterone and contribute to autoimmunity in an in vivo lupus animal model, the NZBxNZW F1 mice. Most of the genes were expressed in the antigen-presenting cells in female mice and were the result of transcriptional modification by sex hormones.4

Mediators and Signals Type I interferon plays an important role in the initiation and progression of autoimmune diseases. In lupus, disease activity usually correlates with ‘the interferon signature’ of gene expression in peripheral blood mononuclear cells. Abrogation of INF- signaling results in abrogation of lupus disease activity. Lupus mice deficient in INF- receptor failed to develop antinuclear antibody and renal disease.5 Gender differences in autoimmune diseases in the human have been studied by dissecting the effect of 17-estradiol (E2) on NF-B signaling. High concentration of E2 modulates NF-B signaling and affects T cell survival in human

Specific remarks in autoimmunity Sex Hormones The original observation of Lahita et al. opened the field of the role of hormones in systemic lupus erythematosus Principles of Gender-Specific Medicine

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T cells via ER. This would suggest that the hormonal effects could underline the gender differences in autoimmune diseases.6 However, these effects could not be generalized to all autoimmune diseases since high levels of estrogen, as occur during pregnancy, can induce disease activity in SLE while in rheumatoid arthritis (RA) symptoms usually improve with increasing estrogen. We, therefore, need to know more about the molecular basis of individual autoimmune diseases and whether the inflammatory auto­ immune mechanisms are via the Th1 or Th2 pathway in the various autoimmune diseases. Gender differences in autoimmunity could be mediated by the expression of certain receptors and signals in T cells. Recently, it has been reported that peroxisome proliferatoractivated receptor (PPAR) mediates inflammatory responses by activating NF-B and C-JUN in immune cells. PPAR is more abundant in male as compared to female CD4 T cells and androgen augments its activation. Ablation of PPAR gene selectively removed NF-B and C-JUN activity in male T lymphocytes resulting in increased production of interferon-gamma (IFN-) and TNF and downregulation of Th2 cytokines. The authors suggested that males are less prone to develop Th1-mediated autoimmunity because their T cells express higher levels PPAR.7

Estrogen Receptors (ER) Selective estrogen receptor blockers modulate the binding of estrogen to its receptor by their tertiary structure. They have a profound effect in modulating bone by affecting osteoporosis and are useful in the treatment of estrogen receptorpositive carcinoma of the breast.8 Estrogen receptor blockers such as Faslodex (fulvestrant) have been studied extensively in our lab. Fulvestrant blocked estrogen receptor activation of calcineurin and CD154 in human lupus T cells.9,10 The blockade by fulvestrant was hormone-specific to the lupus T cells but not to normal healthy controls’ T cells.9,10 Potential differences in signaling between the two known estrogen receptors, ER and ER have been easier to study by creating mouse models with one type of ER deficiency. This allowed investigators to dissect the role of each receptor in modulating the various immune functions. Decreased ER in macrophages resulted in stimulation of CD4 T cells. However, E2 acting via ER, increased proinflammatory cytokine expression, enhanced proliferative and INF- production by CD4 T cells.11 Estrogen receptor alpha plays a role in conducting or promoting lupus disease activity in lupus mice. Estrogen receptor-alpha deficiency attenuates lupus in NZB/NZW mice.12 Disruption of ER in female lupus-prone mice attenuated glomerulonephritis and increased survival and retarded the development of antihistone/DNA antibodies or the development of antidouble-stranded DNA IgG.12 Results from several investigators indicated that ER promotes lupus by inducing IFN- and cytokines.11,12 Estrogen receptor-alpha

deficiency in male autoimmune mice increased their survival and decreased anti-DNA antibodies.12 These results indicate that disrupting estrogen receptor-alpha in autoimmune prone lupus mice may prevent or be beneficial in the treatment for lupus.12 Isolation and characterization of ER was reported by Gustafsson in 199913 and is under extensive studies to clarify its role in human biology.14 There are no clear and consistent data – so far – in the literature to implicate ER in autoimmune diseases. It is premature to assign a clear role for ER in human or in animal models of autoimmune diseases.15,16 The majority of studies of the physiology of ER focused on the cardiovascular system and used ER knockout mice. Estrogen action as an anti-inflammatory agent is possibly mediated by ER. Estrogen receptor-beta agonist (ER--041) was shown to have an anti-inflammatory effect in rheumatoid arthritis and Crohn’s disease in Phase I clinical trials.17 These studies were based on the clinical observation that rheumatoid arthritis patients remit during pregnancy and the disease peeks after menopause. Moreover, rheumatoid arthritis patients receiving aromatase inhibitors that interfere with estrogen production could show arthritis flares. Estrogen receptor-beta agonist is selective and is not a pan-antiinflammatory agent. It did not stimulate the uterus or breast, or inhibit ovulation or slow bone loss.18 In a recent study using a cell line expressing ER, it was found that estradiol treatment significantly reduced the activation of proinflammatory genes by TNF-.18 Similar findings were reported by using selective ER compounds18 indicating that these compounds have anti-inflammatory properties in immune cells. The antiinflammatory effects were achieved by transcriptional repression of proinflammatory genes and could be considered for future testing in therapeutic trials in which female predominance in autoimmunity is present and for whom estrogen, via its receptor, could play a role in the disease pathogenesis.

Cells T Regulatory (Treg) Cells in SLE Treg cells play a critical role in suppressing autoreactive clones. Tregs downregulate lupus disease activity and could prevent lupus flares.19 About 30 years ago, we reported that Treg suppressor cells are deficient in human SLE patients with active disease.19 Treg function inversely correlated with SLE disease activity.19 Possible mechanisms of Treg abnormality in active SLE were found to be due to Treg antibody.20 Recent work from several laboratories documented the deficiency of Treg (CD4 CD25high) cells in active SLE.21 The increased Treg correlated with increased Foxp3 mRNA, protein expression and disease inactivity.21 Estrogen was shown to upregulate Foxp3 and CD4 CD25 in estrogen-treated and pregnant mice,22 indicating that estrogen regulates Foxp3 expression. Our recent work indicates that administering estrogen receptor blocker (fulvestrant) to human females

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with moderately active SLE results in improved clinical disease as measured by SLE disease activity (SLEDAI).23 We anticipated that improved disease activity would correlate with increased Foxp3 expression. Our unpublished observations show a trend for increased Foxp3 mRNA in the patients receiving fulvestrant compared with the placebo arm (unpublished). Work by other investigators has clearly shown that estrogens (17-estradiol, E2) augmented Foxp3 expression in vitro and in vivo in naive mice.24 Recent studies suggest that Treg cells could be used therapeutically to treat autoimmunity. CD4 Foxp3 T cells specific for autoantigen can be converted to Foxp3 T regulatory cells when stimulated with TGF-. The generated TGF--inducted Tregs are effective in preventing autoimmunity.25 Moreover, in a murine lupus model of autoimmunity in which peptide-induced immune tolerance was achieved, it was shown that CD8 T cell-mediated suppression was dependent on the expression of Foxp3.26 The latter was induced in vitro by TGF- in the presence of IL-2. By blocking Foxp3, the ability of CD8 T inhibitory cells to inhibit anti-DNA production was eliminated.26 Estrogen and Apoptosis Estrogens may regulate immune cell survival through the Fas/FasL pathway. Estrogen treatment of women increased FasL expression in monocytes through the binding of the estrogen receptor to the estrogen recognizing elements and AP-1 motif present at the FasL promoter.27 Furthermore, estrogens induced apoptosis only in monocytes expressing ER but not in monocytes expressing ER.27 Recent work by others, however, has demonstrated the upregulation of Bcl-2 (survival marker) through ERK phosphorylation and was associated with survival of human macrophages in an estrogen microenvironment.28 Our previous work has shown that E2 in vitro decreased apoptosis and TNF- production of lupus blood mononuclear cells of cycling women.29 Th-1 Cells Transsexual men are an unusual experimental model for testing chemokine profiles after administration of female sex hormones. Men given estrogens plus antiandrogens showed upregulation of the expression of Th1 associated chemokine receptors and a decrease in natural killer cell numbers. Women given androgens showed upregulation of mitogeninduced IFN-/IL-4 ratio and TNF production. No significant changes were noted in CD4 lymphocyte numbers nor in serum IgG, IgM or in antithyroperoxidase levels.30 Dendritic Cells 17-estradiol (E2) promotes the differentiation of functional dendritic cells (CD11C, CD11b dendritic cells). The latter differentiation was inhibited by the ER blocker ICI 182,780 indicating that E2 effect is mediated via estrogen receptors. Dendritic cells upon activation with E2 upregulated their

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capacity to present self and foreign antigens to CD4 T cells and thus could influence the autoimmune response.31 Dendritic cells exposed to estradiol in vivo produced more INF- in response to IL-12 and IL-18 indicating that estradiol enhanced innate immunity by enhancing INF- production by dendritic cells.32 Recently it was reported that estradiol or exogenous estrogen receptor ligands differentially regulate GM-CSFmediated dendritic cell differentiation.33 Seventeen-beta estradiol facilitated the differentiation of bone marrow precursor cells into functional dendritic cells with increased expression of costimulatory molecules CD40 and CD86, enhanced production of IL-12 in response to toll-like receptor ligands CpG and LPS.

Innate Immunity Sex hormones could regulate cells and mediators of the innate immune system and therefore could indirectly play a key role in the inflammatory response of autoimmune diseases. Progesterone was shown to inhibit toll-like receptor (TLR) 7 and 9 induced IFN- production by human and mouse plasmacytoid dendritic cells. This would block the development and impair innate antiviral immunity in females.34 This observation will broaden the scope by which sex steroid hormones regulate immune responses, not only at the level of gene transcription but also by regulating pattern recognition receptor signaling. The latter regulatory mechanism will provide new approaches in studying the interaction between sex steroids, innate immunity, and autoimmunity. The influence of innate immunity in autoimmune diseases is highlighted by the recent finding that toll-like receptor 7 ligands could induce higher levels of interferon alpha in females and thus play a critical role in the progression of SLE.35 Exogenous 17-estradiol and estrogen receptor antagonism, however, did not affect TLR-7 induced IFN- production.35 TLR and Mannan-binding lectin (MBL) play an important role in preventing sepsis in SLE patients.36 This natural protection is not influenced by estrogen. Statins, however, in addition to being lipid-lowering drugs, could potentiate TLR expression and signaling and thus play a role in sepsis prevention.37

Sex Hormones and Specific Autoimmune Diseases The balance between androgens and estrogens in clinical autoimmunity has been the interest of many clinical immunologists, particularly in rheumatoid arthritis (RA) and SLE.38,39 The imbalance between the hormones has been speculated to be secondary to inflammatory cytokines such as TNF-. The latter can stimulate the aromatase activity resulting in inducing alteration in androgen suppressor activity and estrogen enhancing activity of the autoimmune response.39

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Specific autoimmune diseases with gender differences Systemic Lupus Erythematosus (SLE) In SLE, altered serum hydroxylated estrogens have been reported.3 Moreover, 17-estradiol was shown in SLE to enhance the expression of markers of cell growth and proliferation, whereas testosterone induced markers for enhanced apoptosis.40 The enhancing role of estrogen was shown to be exerted by activating NF-B pathway.40 These observations were shown in synovial tissue in RA and skin of SLE patients.40,41 The results in RA and SLE would justify clinical trials using androgens (testosterone, dehydroxy-epiandrosterone or dehydrotestosterone) in RA and antiestrogens (estrogen receptor blockers or selective estrogen receptor modulators) in SLE.42 It remains to be seen if estrogen receptor antagonism would lead to infertility or other undesirable side effects in women.

Oral Contraceptives and SLE The majority of lupus patients who have a mildly active or inactive disease have no flares after taking combined (estrogen and progesterone) oral contraceptive.43–45 There are a few uncontrolled case reports or in certain open trials indicating flares in lupus after receiving high doses of estrogens.46,47 The safety of oral contraception, however, in moderately active or severe lupus has not been tested in a controlled double-blind protocol.

Estrogen Receptor Blockers in SLE Because serum or plasma levels of estrogen in SLE do not differ from age and sex-matched normal controls,2 we initiated a study to characterize and quantitate estrogen receptors (ER) in SLE peripheral blood mononuclear cells and B cell lines derived from SLE patients.48 Our original work did not show quantitative differences between SLE and normals.48,49 Moreover, the binding affinity of the estrogen receptor to estrogen was the same in SLE and controls.50 We extended the in vitro work of estrogen receptors in lupus to in vivo work using the estrogen receptor modulatorblocker fulvestrant (Faslodex) in human SLE in young cycling females with moderately active SLE.23 Our results, which were from a double-blind placebo-controlled trial on 20 lupus patients, have clearly shown that by blocking the estrogen receptor in vivo by fulvestrant there was a significant decrease in the SLEDAI scores compared to controls. Fulvestranttreated lupus patients also showed a decreased need for treatment with steroids and azathioprine but those differences were not significant owing to the small sample size. Blocking the estrogen receptors for one year in the same patients did not significantly change antinuclear antibody, antidoublestranded DNA or total hemolytic complement levels.23 There were no side effects from the fulvestrant. There were no changes in the bone density within the one-year follow-up

of the lupus patients receiving the fulvestrant. Results from the same study showed upregulation of estrogen serum levels and cumulative increase of fulvestrant serum levels in patients receiving the estrogen receptor blocker.23 Preli­minary work in progress from the same study indicates that there is a trend towards increased Foxp3 mRNA in patients who received fulvestrant versus the controls. The observations indicate that by blocking the estrogen receptor in vivo an increase in serum estrogen levels is noted. This increase is most likely secondary to a feedback mechanism mediated by blocking in vivo the ER.23 The molecular mechanisms leading to gender differences in human SLE have been investigated and recently reviewed by us.51 In a recent report, SLE predominance in women was attributed to demethylation of CD40 ligand on CD4 T cells. The demethylation on the inactive X chromosome in women with lupus resulted in the overexpression of CD40 ligand on CD4 T cells.25 This would lead to enhanced T–B cell collaboration with subsequent overproduction of autoantibodies. In our laboratory, overexpression of CD40L was observed following activation of lupus T cells with estrogen. Such overexpression was blocked by the estrogen receptor blocker (fulvestrant).9

Rheumatoid Arthritis (RA) Rheumatoid arthritis occurs in women three to four times more than in men. The mechanisms of gender differences in rheumatoid arthritis are unclear. Interleukin-1 and TNF are implicated in the pathogenesis of RA. Recent work has demonstrated that 17-estradiol (E2) induced IL-1 mRNA expression in rheumatoid fibroblast-like cell line as well as in primary synovial cells from RA patients.52 The induction of IL-1 by E2 was ER-dependent, and was the result of dissociation of corepressor, histone deacetylase, from ER. This resulted in augmentation of SP1 transcriptional activity through GC-rich region within the IL-1 gene promoter.52 Work by Cutolo and colleagues shed some light on the role of estrogen in rheumatoid arthritis.38 They proposed that estrogens upregulate humoral immunity whereas androgens and progesterone downregulate the same response. They indicated that several factors play a role in estrogen regulation of the immune system, including androgen/estrogen ratio, sex hormones circadian levels, increased activity of aromatase by inflammatory cytokines such as TNF-, IL1, IL6, and increased availability of 17-estradiol. The authors speculated that the better response of male rheumatoid arthritis patients to anti-TNF therapy could be due to these hormonal levels in the synovial fluid.38

Sjögren Syndrome (SS) Sjögren syndrome is 13 times more prevalent in females when compared to males with SS. Aromatase-deficient mice with abnormal hydroxylation of estradiol spontaneously develop a lymphoproliferative autoimmune disease resembling Sjögren’s syndrome.53 Estrogen deficiency

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could result in an autoimmune exocrinopathy that resembles Sjögren’s syndrome in healthy mice.54 Ovariectomy in healthy C57 BL/6 mice resulted in a significant increase in apoptotic epithelial cells in the salivary gland cells that was associated with increased -fodrin cleavage. The latter is an important autoantigen in Sjögren’s syndrome. Extension of the in vivo work to in vitro studies using cultured mouse or human salivary gland cells from donors that were treated with tamoxifen showed evidence of a cleavage product of 120 Kd -fodrin. Moreover, transfer of -fodrin reactive T cells into ovariectomized severe combined immune deficiency mice resulted in the development in the recipients of autoimmune exocrinopathy similar to Sjögren’s syndrome.54 This would indicate that estrogen deficiency could influence autoantigen cleavage and might result in autoimmune exocrinopathy in postmenopausal women.54

Neurologic Diseases Gender differences in autoimmunity had been studied extensively in experimental allergic encephalomyelitis (EAE), a model for multiple sclerosis in whom females are more prone to develop the disease. The focus of the work in EAE encompassed all parameters of the immune system: cellular, humoral, cytokines, chemokines, and genes. Cytokines and several proinflammatory mediators have been investigated. One of the recent cytokines, IL-13, that is produced by activated T cells has several effects, including inhibition of production of inflammatory cytokines, upregulation of MHC Class II expression on monocytes, induction of anti CD40 dependent IgG/IgE class switch, and IgG, IgM synthesis by B cells.55 Recent work has shown that the difference in EAE susceptibility in females is influenced by genderspecific proinflammatory effects of IL-13, mediated in part through upregulation of Th1 inducing cytokines and MHC II or CD11b macrophages.56 It seems – in order to induce an efficient autoimmune response – there should be stable contact between CD4 T cells and dendritic cells. This latter contact could be inhibited by T regulatory cells.57 In myasthenia gravis (MG), a classical clinical model of a neurologic human autoimmune disease, we earlier reported evidence of altered cell population in the thymus of females with MG.58 Recent reports indicated the increased expression of ER on thymocytes, and increased both ER and ER on T cells from peripheral blood mononuclear cells of MG patients.59 The increased estrogen receptor expression in MG was pronounced on CD4 subsets and was presumed to be due to excess proinflammatory cytokines.59

Future applications and concluding remarks The role of sex steroids in autoimmune diseases with female predominance was discussed in this chapter. It is anticipated that future work will result in rapid progress in

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this field. Future investigations need to define the effects of hormone agonists and antagonists on various gene signals using microassay technology, defining high and low affinity hormone receptors, the cell types of the immune system that binds to estrogen, the status of steroid metabolism in patients with autoimmune diseases with female predominance, and the downstream events with respect to signal transduction and the hormonal profile at the tissue or cellular levels. It is hoped that by understanding the molecular events of the immune–endocrine system that new alternative strategies will be considered and implemented for therapy of autoimmune patients with female predominance. This area of basic and clinical research in autoimmune diseases started to gain momentum after cross-talks and exchange of ideas between molecular biologists, basic-clinical immunologists, rheumatologists, and endocrinologists.

Acknowledgements We thank our patients who contributed and participated in the studies referred to in this chapter. We thank our research coordinator, Cindy Greenwell; laboratory technologist, Phyllis Smotherman; and transcriptionist, Hope Schreck. Several graduate students and medical residents and fellows contributed to our research work. The work was supported by NIH grant AI49272, AstraZeneca Pharmaceuticals who sponsored the Faslodex trial, grants from Saint Luke’s Foundation, and Evans Family endowment funds. All studies quoted in this chapter have been approved by Saint Luke’s Hospital Review Board and were registered under #IRUSFULV0031.

References 1. Rider V, Abdou NI. Gender differences in autoimmunity: molecular mechanisms for estrogen effects in systemic lupus erythematosus. Int Immunopharmacol Rev 2001;1:1009–24. 2. Rider V, Abdou NI. Sexual dimorphism and the immune system. In: MJ Legato, ed. Principles of Gender-Specific Medicine. New York, NY: Elsevier Academic Press; 2004:1071–81. 3. Lahita RG, Bradlow HL, Kunkel HG, Fishman J. Alterations of estrogen metabolism in systemic lupus erythematosus. Arthritis Rheum 1979;22:1195–98. 4. Gubbels Bupp MR, Jørgensen TN, Kotzin BL. Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus. Genes Immun 2007;10:47–56. 5. Jørgensen TN, Roper E, Thurman JM, Marrack P, Kotzin BL. Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 x NZW)F(1) mice. Genes Immun 2007;8:653–62. 6. Hirano S, Furutama D, Hanafusa T. Physiologically high concentrations of 17-estradiol enhance NF-B activity in human T cells. Am J Physiol 2007;292:1465–71. 7. Dunn SE, Ousman SS, Sobel RA, et al. Peroxisome proliferator-activated receptor (PPAR) expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J Exp Med 2007;204:321–30.

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  8. Riggs BL, Hartman LC. Selective estrogen-receptor modulators – mechanisms of action and application to clinical practice. N Engl J Med 2003;348:618–29.   9. Rider V, Jones S, Evans M, Bassiri H, Afsar Z, Abdou NI. Estrogen increases CD40 ligand expression in T cells from women with systemic lupus erythematosus. J Rheumatol 2001; 28:2644–49. 10. Rider V, Foster RT, Evans MJ, Suenaga R, Abdou NI. Gender differences in autoimmunity: estrogen increases calcineurin A2 expression in systemic lupus erythematosus. Clin Immunol Immunopathol 1998;89:171–80. 11. Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB, Estes DM. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4 T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4 T cells independent of antigen presentation. J Immunol 2005;175:5716–23. 12. Bynoté KK, Hackenberg JM, Korach KS, Lubahn DB, Lane PH, Gould KA. Estrogen receptor-alpha deficiency attenuates autoimmune disease in (NZBxNZW)F1 mice. Genes Immun 2008;10:137–52. 13. Gustafsson JA. Estrogen receptor  – a new dimension in estrogen mechanism of action. J Endocrinol 1999;163:379–83. 14. Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006;116:561–70. 15. Harris HA. Estrogen receptor-beta: recent lessons from in vivo studies. Mol Endocrinol 2007;21:1–13. 16. Imamov O, Shim GJ, Warner M, Gustafsson JA. Estro­gen receptor beta in health and disease. Biol Reprod 2005;73: 866–71. 17. Harris H. Estrogen receptor beta: a new target for anti-inflammatory therapy? Arthritis Rheumatol 2005;10, (Abstr.). 18. Cvoro A, Tatomer D, Tee MK, Zogovic T, Harris HA, Leitman DC. Selective estrogen receptor- agonists repress transcription of proinflammatory genes. J Immunol 2008;180: 630–36. 19. Sagawa A, Abdou NI. Suppressor-cell dysfunction in systemic lupus erythematosus. Cells involved and in vitro correction. J Clin Invest 1978;62:789–96. 20. Sagawa A, Abdou NI. Suppressor cell antibody in systemic lupus erythematosus. Possible mechanisms for suppressor cell dysfunction. J Clin Immunol 1979;63:536–43. 21. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4  CD25 high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 2007;178: 2579–88. 22. Polanczyk M, Hopke C, Huan J, Vandenbark AA, Offner H. Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 2005; 170:85–92. 23. Abdou NI, Rider V, Greenwell C, Li X, Kimler BF. Fulvestrant (Faslodex), an estrogen selective receptor downregulator, in therapy of women with systemic lupus erythematosus. Clinical, serologic, bone density, and T cell activation marker studies: a double-blind placebo-controlled trial. J Rheumatol 2008;35:797–803. 24. Polanczyk MJ, Carson BD, Subramanian S, et al. Cutting edge: estrogen drives expansion of the CD4  CD25 regulatory T cell compartment. J Immunol 2004;173:2227–30.

25. Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 2007;179:6352–58. 26. Singh RP, La Cava A, Wong M, Ebling F, Hahn BH. CD8 T cell-mediated suppression of autoimmunity in a murine lupus model of peptide-induced immune tolerance depends on Foxp3 expression. J Immunol 2007;178:7649–57. 27. Mor G, Sapi E, Abrahams VM, et al. Interaction of the estrogen receptors with the Fas ligand promoter in human monocytes. J Immunol 2003;170:114–22. 28. Subramanian M, Shaha C. Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. J Immunol 2007;179:2330–38. 29. Evans M, MacLaughlin S, Marvin RD, Abdou NI. Estrogen decreases in vitro apoptosis of peripheral blood mononuclear cells from women with normal menstrual cycles and decreases TNF- production in SLE but not in normal cultures. Clin Immunol Immunopathol 1997;82:258–62. 30. Giltay EJ, Fonk JC, von Blomberg BM, Drexhage HA, Schalkwijk C, Gooren LJ. In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. J Clin Endocrinol Metab 2000;85:1648–57. 31. Paharkova-Vatchkova V, Maldonado R, Kovats S. Estrogen preferentially promotes the differentiation of CD11c CD11b (intermediate) dendritic cells from bone marrow precursors. J Immunol 2004;172:1426–36. 32. Siracusa MC, Overstreet MG, Housseau F, Scott AL, Klein SL. 17beta-estradiol alters the activity of conventional and IFN-producing killer dendritic cells. J Immunol 2008;180:1423–31. 33. Carreras E, Turner S, Paharkova-Vatchkova V, et al. Estradiol acts directly on bone marrow myeloid progenitors to differentially regulate GM-CSF or Flt3 ligand-mediated dendritic cell differentiation. J Immunol 2008;180:727–38. 34. Hughes GC, Thomas S, Li C, Kaja MK, Clark EA. Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J Immunol 2008;180:2029–33. 35. Berghöfer B, Frommer T, Haley G, Fink L, Bein G, Hackstein H. TLR7 ligand induce higher INF- production in females. J Immunol 2006;177:2088–96. 36. Mok MY, Ip WK, Lau CS, Lo Y, Wong WH, Lau YL. Mannose-binding lectin and susceptibility to infection in Chinese patients with systemic lupus erythematosus. J Rheumatol 2007;34:1270–76. 37. Methe H, Kim JO, Kofler S, Nabauer M, Weis M. Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14 monocytes. Arterioscler Thromb Vasc Biol 2005;25:1439–45. 38. Cutolo M, Capellino S, Sulli A, et al. Estrogens and immune diseases. Ann N Y Acad Sci 2006;1089:538–47. 39. Castagnetta L, Granata OM, Traina A, et al. Role for sex steroids in autoimmune diseases. A working hypothesis and supporting data. Ann N Y Acad Sci 2002;966:193–203. 40. Cutolo M, Sulli A, Capellino S, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 2004;13:635–38. 41. Castagnetta LA, Carruba G, Granata OM, et al. Increased estrogen formation and estrogen to androgen ratio in the

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42. 43.

44.

45.

46. 47.

48.

49.

50.

synovial fluid of patients with rheumatoid arthritis. J Rheumatol 2003;30:2597–605. Cutolo M. Sex hormone adjuvant therapy in rheumatoid arthritis. Rheum Dis Clin N Am 2000;26:881–95. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraception in women with systemic lupus erythematosus. N Engl J Med 2005;353:2550–58. Sánchez-Guerrero J, Uribe AG, Jiménez-Santana L, et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med 2005;353:2539–49. Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 2005;142:953–62. Abdou NI. Is it safe for lupus patients to take estrogen? It depends. J Clin Rheumatol 2007;13:1. Jungers P, Dougados M, Pélissier C, et al. Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum 1982;25:618–23. Suenaga R, Evans MJ, Mitamura K, Rider V, Abdou NI. Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 1998;25: 1305–12. Suenaga R, Rider V, Evans MJ, Abdou NI. In vitro-activated T cells from SLE patients and normal donors express estrogen receptor alpha proteins which bind to the human estrogen response element. Lupus 2001;10:116–22. Rider V, Li X, Peterson G, Dawson J, Kimler BF, Abdou NI. Differential expression of estrogen receptors in women with systemic lupus erythematosus. J Rheumatol 2006;33: 1093–101.

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51. Rider V, Abdou NI. Hormones: epigenetic contributors to gender biased autoimmunity. In: M Zouali, ed. Epigenetics in Autoimmune Diseases. London: Wiley; 2009:310–36. 52. Itoh Y, Hayashi H, Miyazawa K, et al. 17beta-estradiol induces IL-1alpha gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor alpha (ERalpha) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ERalpha. J Immunol 2007;178:3059–66. 53. Shim GJ, Warner M, Kim HJ, et al. Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjögren’s syndrome. Proc Natl Acad Sci 2004;101:12628–33. 54. Ishimaru N, Arakaki R, Watanabe M, Kobayashi M, Miyazaki K, Hayashi Y. Development of autoimmune exocrinopathy resembling Sjögren’s syndrome in estrogen-deficient mice of healthy background. Am J Pathol 2003;163:1481–90. 55. Minty A, Chalon P, Derocq JM, et al. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature 1993;362:248–50. 56. Sinha S, Kaler LJ, Proctor TM, Teuscher C, Vandenbark AA, Offner H. IL-13 mediated gender difference in susceptibility to autoimmune encephalomyelitis. J Immunol 2008;180:2679–85. 57. Tadokoro CE, Shakhar G, Shen S, et al. Regulatory T cells inhibit stable contacts between CD4 T cells and dendritic cells in vivo. J Exp Med 2006;203:505–11. 58. Abdou NI, Lisak RP, Zweiman B, Abrahamsohn I, Penn AS. The thymus in myasthenia gravis: evidence of altered cell population. N Engl J Med 1974;291:1271–78. 59. Nancy P, Berrih-Aknin S. Differential estrogen receptor expression in autoimmune myasthenia gravis. Endocrinology 2005;146:2345–53.

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Hormones and Cytokines: Gender-Specific Effects Maurizio Cutolo University of Genoa, Research Laboratories and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, Genoa, Italy

Involvement of sex hormones and cytokines in autoimmune rheumatic diseases

contrast to the reduced androgen levels typically found in RA patients.2 Physiological, pathological, and therapeutic conditions that can change the serum estrogen milieu and/or peripheral conversion rate include the menstrual cycle, pregnancy, postpartum period, menopause, old age, chronic stress, altered circadian rhythms (i.e. cortisol/melatonin), inflammatory cytokines, use of corticosteroids, oral contraceptives, and steroid hormonal replacement that alter androgen/estrogen ratios.2,7,8 At physiological concentrations, 17-estradiol and a combination of downstream estrogens stabilized or increased immune stimuli-induced TNF secretion.9 These effects were dependent on the presence of physiological concentrations of cortisol and therefore were related to cortisol’s circadian rhythms.10 Sex hormones can exert local actions (intracrine) in the tissues in which they are formed or enter the circulation. Both T and 17-estradiol seem to exert dose- and timedependent effects on cell growth and apoptosis.2,3 These effects, as well as important influences on gene promoters of Th1/Th2 cytokines and the recently discovered increase in SF estrogen concentrations, suggest that estrogens are important in inciting and perpetuating RA.9,10 Recent data suggest that the sex hormone milieu and B cell receptor signaling, not antigenic specificity, correlate with the differentiation pathway of B cells. Although both marginal zone and follicular B cells produce anti-DNA antibodies in murine models of SLE, it has been unclear whether these distinct B cell subsets make identical or different antibodies. Single-cell analysis has demonstrated that the same DNA-reactive B cells can mature to either subset, depending on the hormonal environment. Anti-DNA B cells in estradiol-treated mice become marginal zone cells while identical cells from prolactin-treated mice become follicular

Evidences indicate that during the fertile age, women are more often affected by autoimmune rheumatic diseases than men.1 Rheumatic disorders with autoimmune involvement such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are thought to result from the combination of several predisposing factors, including relationships between epitopes of the trigger agent (i.e., virus) and histocompatibility antigens (i.e., HLA), latitude effects, the status of the stress response system, including the hypothalamic–pituitary–adrenocortical axis (HPA), the sympathetic nervous system (SNS), and gonadal hormones (hypothalamic–pituitary–gonadal axis, HPG).2–4 Pre- and postmenopausal concentrations of circulating sex hormones further influence the occurrence of rheumatic diseases. Obviously, sex hormones play important roles as modulators of disease onset and perpetuation of disease. Like cortisol, sex hormones have circadian rhythms.5 Sex hormones are involved in the immune response, and estrogens enhance humoral immunity whereas androgens and progesterone (and glucocorticoids) function as natural immunosuppressors.2,6 Low concentrations of gonadal and adrenal androgens [testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS)], as well as a reduced ratio of androgens to estrogens, have been detected in serum and body fluids (blood, synovial fluid (SF), saliva) of male and female RA patients, as well as SLE patients. This finding supports a possible pathogenic role for decreased levels of the immunosuppressive androgens.6 In contrast, serum estrogen levels are normal in RA and this lack of a significant change is in strict

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cells. Therefore, even the B cell receptor signaling pathway is influenced by the hormonal environment. These observations have important implications for the pathogenesis and treatment of autoimmune diseases.11 These developments have opened new research avenues. The association between persistent fetal–maternal microchimerism and the development of autoimmune diseases has attracted special interest.12 In analogy to allogeneic organ transplantation, fetal–maternal (and maternal–fetal) microchimerism may play an important role in immunologic tolerance of the fetal semi-allograft. The female preponderance for autoimmune diseases may therefore be understood as a consequence of increased allogeneic cell traffic in females (compared to males) and the increased risk for long-term microchimerism, both of which may lead to abnormal autoimmunity. Under an evolutionary viewpoint the occurrence of autoimmune diseases, in general, can be seen as the price to be paid for successful reproduction. Women, who are exposed to cell traffic, appear to pay the higher price, reflected in a larger occurrence of autoimmunity.

Peripheral sex hormone metabolism in autoimmune diseases Several findings suggest that conversion of upstream androgen precursors to 17-estradiol is accelerated in RA and SLE patients. 17-estradiol, the aromatic product of the gonadal steroid metabolic pathway and the result of peripheral conversion from the adrenal androgen DHEA, has as its upstream precursors hormones such as DHEA, testosterone, and progesterone. In fact, many studies and reviews in the last 20 years have shown reduced serum concentrations of DHEAS, testosterone, and progesterone in both male and female RA and SLE patients.13,14 These data strongly support the existence of accelerated peripheral metabolic conversion of upstream androgen precursors to 17-estradiol. The discovery of very high estrogen concentrations in synovial fluid from RA patients of both sexes can be explained by the results of recent studies showing that inflammatory cytokines (i.e. TNF-, IL-1, IL-6) are increased in RA synovitis and can markedly stimulate aromatase activity in peripheral tissues15,16 (Figure 50.1). The aromatase enzyme complex is involved in the peripheral conversion of androgens (testosterone and androstenedione) to estrogens (estrone and estradiol, respectively). In tissues rich in macrophages, a significant correlation was found between aromatase activity and IL-6 production. Aromatase has been found also in synoviocytes.17 Therefore, the increased aromatase activity induced by locally produced inflammatory cytokines (i.e. TNF-, IL-1, IL-6) might explain the relatively low androgens and high estrogens in

Synovial tissue

Androstenedione TNF-α IL-1 IL-6

Testosterone

P450 Arom

Aromatase

TNF-α IL-1 IL-6

Synovial fluid Estrogen Estrogens

Estradiol IL-6

Androgens

Figure 50.1  Increased concentrations of estrogens and low androgen concentrations are observed in synovial fluid of RA patients of both sexes. The proinflammatory cytokines (i.e. TNF-, IL-1, IL-6) induce aromatases in synovial tissue, thereby accelerating the metabolic conversion of androgens to estrogens.

synovial RA fluids, as well as the effects of these hormones on synovial cells, as reported from this laboratory.18 The role of local concentrations of sex hormones at the level of inflammatory foci is of great value in explaining the effects exerted by these hormones on the immuneinflammatory reaction. Men with RA have a higher than normal frequency of low testosterone levels. Interestingly, in a recent study, DHEAS and estrone concentrations were lower and studio was higher in male RA patients compared with healthy controls.19 In this study, estrone did not correlate with any disease variable but estradiol did have strong positive correlation with all measured indices of inflammation. Men with RA had aberrations in all sex hormones analyzed, although only estradiol consistently correlated with inflammation. The low levels of estrone and DHEAS may reflect a shift in adrenal steroidogenesis toward the glucocorticoid pathway, whereas the high estradiol levels seemed to be caused by increased conversion of estrone to estradiol as an effect of 17-hydroxysteroid dehydrogenase. In SLE patients, aromatase activity in skin and subcutaneous tissue showed a tendency to be increased compared to control subjects. Aromatase activity in SLE patients varied inversely with disease activity, and the patients had decreased serum levels of androgen and increased levels of estrogen.20 Therefore, tissue aromatase activity showed significant direct correlation with concentrations of circulating estrogen in SLE patients. These data suggest that abnormal regulation of aromatase activity (i. e., increased activity) could partially explain the abnormalities of peripheral estrogen synthesis (i.e., increased availability of 17-estradiol and possible metabolites) that have been found in SLE, as well as the altered serum sex hormone levels and ratio (i.e., decreased androgens and DHEAS in SLE).

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Recently, Straub suggested that urinary excretion of hydroxyestrogens (namely, 16-hydroxyestrone and 2– hydroxyestrogens) reflected production in the tissues, since no respective hydroxylase activity is expected in the urine.21 On the other hand, as recently reviewed, peripheral estrogen hydroxylation was increased in both men and women with SLE. The estrogenic metabolites have been reported to increase B cell differentiation and activate T cells.22 Elevated serum levels of 16-hydroxyestrone, already described in SLE patients, indicate that men with disease differ from women with disease to the extent that only 16hydroxyestrone was elevated in men, whereas women had elevations of both 16-hydroxyestrone and estriol.23 These data suggest that abnormal patterns of 17-estradiol metabolism lead to increased estrogenic activity in SLE patients. In the synovial fluids of RA patients, the increased estrogen concentrations observed in both sexes consist mainly of hydroxylated forms, in particular 16-hydroxyestrone, an endogenous hormone that encourages mitogenesis and cell proliferation.24 In these studies, the molar ratio of free estrogens/free androgens was elevated significantly in RA synovial fluids. The serum levels of 17-estradiol were not typically outside of the physiologic ranges in RA or in SLE patients of both sexes, and the alterations in estrogen metabolism were again observed in both male and female patients.24–26 17-estradiol is thought to play dual pro- and anti-inflammatory roles in chronic inflammatory diseases, related to low and high concentrations, respectively. Therefore, it is possible that the phenomenon might simply depend on different dose-related rates of peripheral 17-estradiol conversion to pro- or anti-inflammatory metabolites such as 16-hydroxyestrone or naturally occurring antagonists (i.e. 2–hydroxyestrogens), respectively.10

Sex hormones and cytokines Macrophage release of proinflammatory cytokines (TNF-, IL-6) can be modulated by estrogen in different ways. In a recent study, estrogen was found to alter proinflammatory cytokine release from activated monocytes and/or macrophages, in particular through modulation of CD16 expression.27 Recent studies showed that 16-hydroxyestrone was far more potent than 17-estradiol in exerting an influence on cell proliferative activities. More recently, we tested the effects of 17-estradiol and testosterone on differentiation into activated macrophages of cultured human myeloid monocytic cells (THP-1) in order to evaluate the influence of both hormones on cell proliferation and apoptosis.7 Effects were evaluated using activity of NF-B, a complex of molecules that affects cellular activation. Testosterone was found to exert proapoptotic effects and reduce macrophage proliferation, whereas 17-estradiol induced the opposite effects by interfering with NF-B activities. These

results supported the hypothesis that sex hormones modulate cell growth and apoptosis. In another investigation, 17-estradiol was found to increase IgG and IgM production by peripheral blood mononuclear cells (PBMC) from SLE patients, resulting in elevated levels of polyclonal IgG (including IgG anti-ds DNA) by enhancing B cell activity via interleukin 10 (IL-10).20 It would be of great interest to replicate these results in the presence of 16-hydroxyestrone as well as naturally occurring 2–hydroxylated antiestrogen. It was reported recently that disease activity in SLE patients had negative correlation with urinary concentration of 2–hydroxylated estrogens.21 In addition, interesting changes of serum estrogens that correlated with cytokine variations have been found during pregnancy in SLE patients.28,29 The major hormonal alteration observed during SLE pregnancies was an unexpected lack of an increase in serum estrogen levels and, to a lesser extent, increased serum progesterone levels, during the second trimester and especially during the third trimester of gestation. The failure of the hormones to increase was likely due to placental compromise. In addition, a lower than expected increase of IL-6 in the third trimester of gestation and persistently high levels of IL-10 during pregnancy seem to be the major alterations of the cytokine milieu in the peripheral circulation of pregnant SLE patients. In conclusion, these variations of steroid hormones and cytokines may result in suppressed activation of humoral immune responses, probably due to a change in the estrogen/androgen balance. In turn, the disordered balance of hormones could account for the increased immunosuppressive effect exerted by cytokines on disease activity during the third trimester. A recent study evaluated whether patients with SLE experience a decrease in disease activity after natural meno­pause.30 Differences in disease activity scores and the number of visits to a rheumatologist’s office were only significant when the fourth year before menopause was compared with the fourth year after menopause.29 Disease activity was mild during the premenopausal and postmenopausal periods in women with SLE and a modest decrease, noted especially in maximum disease activity, was observed after natural menopause.30

Conclusions Sex hormones can exert local actions (intracrine) in the tissues in which they are formed and an accelerated peripheral metabolic conversion of upstream androgen precursors to 17-estradiol and even conversion to more estrogenic metabolites is observed in RA and SLE patients. The circadian rhythms of cortisol and melatonin circadian rhythms are altered, at least in RA, and these alterations also partially involve circadian synthesis and levels of sex hormones.31

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Local effects of sex hormones in autoimmune rheumatic diseases seem to consist mainly of modulation of cell proliferation and cytokine production and may also affect the development and activation of specific mature B cell subsets.32 In this respect, it is interesting that male patients with RA seem to profit more from anti-TNF- treatment strategies than do female patients.33 In fact, blockade of TNF-induced upregulation of aromatase would particularly increase the level of androgens in male as compared with female patients with RA, and this can lead to the better clinical outcome that has already been reported in male patients. Certainly, endogenous and exogenous hormones have great potential to affect the immune system and can change activity of autoimmune diseases, and it is worthwhile to continue to seek novel and improved applications of hormonal or/and antihormonal immunotherapy (i.e. antiestrogens, receptor modulators, anta­ gonist metabolites, androgenic compounds) to treating this family of diseases.34 In conclusion, sex hormones play a role in the genesis of autoimmunity and future research may provide a therapeutic approach that is capable of altering disease pathogenesis, rather than targeting disease sequelae.35–37

References   1. Kvien TK, Uhlig T, Odegard S, Heiberg MS. Epidemiological aspects of rheumatoid arthritis: the sex ratio. Ann N Y Acad Sci 2006;1069:212–22.   2. Bijlsma JW, Masi A, Straub RH, et al. Neuroendocrine immune system involvement in rheumatology. Ann N Y Acad Sci 2006;1069:xviii–xxiv.   3. Cutolo M, Capellino S, Sulli A, et al. Estrogens and autoimmune diseases. Ann N Y Acad Sci 2006;1089:538–47.   4. Straub RH, Cutolo M. Does stress influence the course of rheumatic diseases? Clin Exp Rheumatol 2006;24:225–28.   5. Cutolo M, Otsa K, Aakre O, et al. Nocturnal hormones and clinical rhythms in rheumatoid arthritis. Ann N Y Acad Sci 2005;1051:372–78.   6. Cutolo M, Capellino S, Montagna P, et al. Sex hormone modulation of cell growth and apoptosis of the human monocytic/ macrophage cell line. Arthr Res Ther 2005;7:R1124–32.   7. Cutolo M, Villaggio B, Otsa K, et al. Altered circadian rhythms in rheumatoid arthritis patients play a role in the disease’s symptoms. Autoimmunol Rev 2005;4:497–502.   8. Straub RH, Buttgereit F, Cutolo M. Benefit of pregnancy in inflammatory arthritis. Ann Rheum Dis 2005;64:801–3.   9. Janele D, Lang T, Capellino S, et al. Effects of testosterone, 17-estradiol, and downstream estrogens on cytokine secretion from human leukocytes in the presence and absence of cortisol. Ann N Y Acad Sci 2005;1069:168–82. 10. Cutolo M. Estrogen metabolites: increasing evidence for their role in rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 2004;31:419–21. 11. Venkatesh J, Peeva E, Xu X, Diamond B. Cutting edge: hormonal milieu, not antigenic specificity, determines the mature phenotype of autoreactive B cells. J Immunol 2006;176:3311–14. 12. Gleicher N, Barad DH. Gender as risk factor for autoimmune diseases. J Autoimmun 2007;28:1–6.

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13. Bijlsma JWJ, Straub RH, Masi AT, et al. Neuroendocrine immune mechanisms in rheumatic diseases. Trends Immunol 2002;23:59–61. 14. Lahita RG, Bradlow HL, Ginzler E, et al. Low plasma androgens in women with systemic lupus eryuthematosus. Arthritis Rheum 1987;30:241–48. 15. Macdiarmid F, Wang DF, Duncan LG. Stimulation of aromatase activity in breast fibroblasts by tumor necrosis factor . Mol Cell Endocrinol 1994;106:17–21. 16. Purohit A, Ghilchic MW, Duncan L. Aromatase activity and interleukin-6 production by normal and malignant breast tissues. J Clin Endocrinol Metabol 1995;80:3052–58. 17. Le Bail J, Liagre B, Vergne P, et al. Aromatase in synovial cells from postmenopausal women. Steroids 2001;66:749–55. 18. Castagnetta L, Cutolo M, Granata O, et al. Endocrine end-points in rheumatoid arthritis. Ann N Y Acad Sci 1999;876:180–92. 19. Tengstrand B, Carlstron K, Fellander-Tsai L, et al. Abnormal levels of serum dehydroepiandrosterone, estrone, and estradiol in men with rheumatoid arthritis: high correlation between serum estradiol and current degree of inflammation. J Rheumatol 2003;30:2338–43. 20. Folomeev M, Dougados M, Beaune J, et al. Plasma sex hormones and aromatase activity in tissues of patients with systemic lupus erythematosus. Lupus 1992;1:191–95. 21. Weidler C, Harle P, Schedel J, et al. Patients with rheumatoid arthritis and systemic lupus erythematosus have increased renal excretion of mitogenic estrogens in relation to endogenous antiestrogens. J Rheumatol 2004;31:489–95. 22. Kanda N, Tsuchida T, Tamaki K. Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum 1999;42:328–37. 23. Lahita RG, Bradlow HL, Kunkel HG, et al. Alterations of estrogen metabolism in systemic lupus erythematosus. Arthritis Rheum 1979;22:1195–98. 24. Capellino S, Montagna P, Villaggio B, Sulli A, Straub RH, Cutolo M. Hydroxylated estrogen metabolites influence proliferation of cultured human monocytes: possible role in synovial tissue hyperplasia. Clin Exp Rheumatol 2008;26:903–9. 25. Castagnetta L, Carruba G, Cutolo M, et al. Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. J Rheumatol 2003;30:2597–605. 26. McMurray RW, May W. Sex hormones and systemic lupus arythematosus:review and meta-analysis. Arthritis Rheum 2003;48:2100–10. 27. Kramer PR, Kramer SF, Guan G. 17 beta-estradiol regulates cytokine release through modulation of CD16 expression in monocytes and monocyte-derived macrophages. Arthritis Rheum 2004;50:1967–75. 28. Doria A, Cutolo M, Ghirardello A, et al. Hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum 2002;47:202–9. 29. Doria A, Ghirardello A, Punzi L, et al. Pregnancy, cytokines and disease activity in systemic lupus erythematosus. Arthritis Rheum 2004;51:989–95. 30. Sanchez-Guerrero J, Villegas A, Mendoza A, et al. Disease activity during the premenopausal and postmenopausal periods

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in women with systemic lupus erythematosus. Am J Med 2001;11:464–68. 31. Cutolo M, Straub RH, Buttgereit F. Circadian rhythms of nocturnal hormones in rheumatoid arthritis: translation from bench to bedside. Ann Rheum Dis 2008;67:905–8. 32. Cutolo M, Capellino S, Straub RH. Oestrogens in rheumatic diseases: friend or foe? Rheumatology (Oxford) 2008;47 (Suppl. iii):2–5. 33. Straub RH, Pongratz G, Cutolo M, et al. Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti-tumor necrosis factor therapy in rheumatoid arthritis. Arthritis Rheum 2008;58:976–84.

34. Atzeni F, Sarzi-Puttini P, DePortu S, Cutolo M, Carrabba M, Straub RH. In etanercept-treated psoriatic arthritis patients clinical improvement correlated with an increase of serum cortisol relative to other adrenal hormones. Clin Exp Rheumatol 2008;26:103–8. 35. Cutolo M, Straub RH. Circadian rhythms in arthritis: hormonal effects on the immune/inflammatory reaction. Autoimmun Rev 2008;7:223–28. 36. Cutolo M, Straub RH. Stress as a risk factor in the pathogenesis of rheumatoid arthritis. Neuroimmunomodulation 2006;13:277–82. 37. Cutolo M. Sex and rheumatoid arthritis: mouse model versus human disease. Arthritis Rheum 2007;56:1–3.

Chapter

51

Prolactin and Autoimmunity Sara E. Walker Emeritus Professor of Medicine, University of Missouri School of Medicine, Department of Internal Medicine, Columbia, MO, USA

Prolactin

potential of IRF-1 to promote autoimmunity was demonstrated when type II collagen-induced arthritis was induced in mice that were IRF-1 deficient (/) or IRF-1 positive (/). Disease was reduced in the IRF-1 / mice compared to the / mice.11

Prolactin and the Immune System Prolactin, a peptide hormone, has the potential to stimulate the immune system and has been implicated as a factor that can activate autoimmune diseases.1 The importance of prolactin as an immune stimulator and the relationships between prolactin, estrogen, and autoimmunity have been addressed in recent reviews.2–4 Prolactin is produced in the anterior pituitary as well as extrapituitary sites such as the brain and lymphocytes5 and is a cytokine, with comparable structural motifs and similar receptor structures and signal transduction pathways. Prolactin receptors are distributed throughout the immune system6 and are included in a novel receptor family that includes receptors for IL-2, IL-3, IL-4, IL-6, IL-7, growth hormone, and erythropoietin.7 Prolactin can influence the immune system through the thymus,8 inducing IL-2 receptors on lymphocytes.9 Lymphocytes synthesize and release a biologically active form of prolactin10 that acts as an autocrine and paracrine growth factor. Treatment with corticosteroids can suppress production of prolactin, leading to the hypothesis that reduction of circulating prolactin accounts for some of the immunosuppressive actions of this class of drugs. Dexamethasone decreases circulating prolactin and inhibits gene expression of both pituitary prolactin and lymphocyte prolactin.6 Th1 cytokines are involved in initiating autoimmunity, and Th2 cytokines contribute to production of antibodies by B cells. The transcription factor gene, interferon regulatory factor-1 (IRF-1), which is exquisitely sensitive to prolactin, is an important regulator of T cell and B cell differentiation and maturation. IRF-1 is required for Th1 immune responses. Prolactin, which stimulates IRF-1, can regulate expression of Th1 cytokines such as IFN- and IL-15. The

Principles of Gender-Specific Medicine

Prolactin and Animal Models Nonautoimmune Models In rodents, prolactin influences the immune system at almost every level12,13 and has a key role in maintaining normal immune function and sustaining life. Rats that were deprived completely of prolactin by hypophysectomy and injections of antiprolactin antibody became anergic and anemic and died within 8 weeks. Replacement injections of either prolactin or growth hormone stimulated expression of the c-myc growth promoting gene and reversed involution of the spleen and thymus.14 High levels of circulating prolactin stimulate immune responses in mice. When hyperprolactinemia was created by either implanting syngeneic pituitary glands or injecting exogenous prolactin, primary humoral antibody responses were increased.15 Low levels of prolactin in cysteaminetreated mice were associated with thymic atrophy and immune suppression.16 NZB/NZW Mice Sex hormones play an important role in regulating the severity of disease in the F1 hybrid New Zealand Black (NZB) x New Zealand White (NZW) (NZB/NZW) mouse, a model of systemic lupus erythematosus (SLE) that spontaneously develops antibodies to double-stranded DNA (anti-ds DNA) and dies early with immune complex glomerulonephritis. Disease in females starts early and progresses rapidly, and

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Copyright 2010 20 , Elsevier Inc. All rights reserved.

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the females die on the average 4 months earlier than the males, which have an indolent form of SLE.17 Of interest, serum estradiol and prolactin concentrations in the NZB/ NZW model are comparable to mice that do not develop autoimmune disease18,19 and females do not have abnormal estrogen metabolism that would alter 2-hydroxylated or 16hydroxylated products.20 Hyperprolactinemia in NZB/NZW mice resulted in premature death from autoimmune renal disease. Female NZB/ NZW mice that were made chronically hyperprolactinemic by grafts of two syngeneic pituitary glands developed premature glomerulonephritis and early mortality. In contrast, mice treated with the prolactin-lowering drug bromocriptine had delayed appearance of anti-ds DNA and significantly prolonged lifespans.21 Neidhart22 treated mature NZB/NZW females from the age of 36 weeks with a dose of bromocriptine (5 mg/kg/day) that suppressed serum prolactin to undetectable levels. After 12 weeks of treatment, autoantibodies were not suppressed but proteinuria was delayed. No mice treated with bromocriptine had histological evidence of glomerulonephritis, but glomerulonephritis was found in 70% of NZB/NZW controls. The effects of very high levels of prolactin were studied in female NZB/NZW recipients of four transplanted pituitary glands. As early as 12 weeks after implantation, 80% of recipients had hypergammaglobulinemia and anti-ds DNA.23 Male NZB/NZW mice also responded to hyperprolactinemia with accelerated disease.24 Naturally occurring hyperprolactinemia, which is expected during gestation, was detrimental in parous NZB/NZW dams that had whelped and suckled two litters. Females that experienced prolonged pseudopregnancy, which is associated with persisting hyperprolactinemia, also had accelerated disease.25

Estrogen–Prolactin Interactions Estrogen Treatment with estrogen accelerates disease in weanling NZB/NZW mice. In early experiments, castrated NZB/ NZW mice received pharmacologic doses of hormones in the form of crystalline implants containing 6–7 mg of 17-estradiol. Autoantibody production was stimulated in implant recipients of both sexes, and the hormone-treated mice died prematurely.26–30 Surgical oophorectomy affected autoantibodies but was not shown to change lifespans. Estrogen implants in the early experiments,26,28,29 released extremely high concentrations of circulating estradiol and the implanted mice died from estrogen toxicity.27,31 Newer dosing regimes,18,32 however, mimicked naturally occurring levels of estrogen and these treatments did shorten longevity in NZB/NZW hybrids and first-generation offspring of NZB/NZW x NZB backcross mice. Gender, and possibly female hormones, affected severity of disease in SLE models developed by Wakeland,33,34in which specific lupus susceptibility genes were introduced

into C57BL/6 mice by congenic matings. Bicongenic B6.NZMc1/c7 females expressed both the Sle 1 gene (high titers of antinuclear antibodies) and the Sle 3 gene (glomerulonephritis) and developed severe disease and very high levels of anti-ds DNA. It therefore appeared that the effects of female gender promoted the phylogenetic expression of specific genes. BALB/c mice do not have overt autoimmune disease but do develop autoantibodies with increased age.35 BALB/c mice of both sexes were implanted with capsules containing 2–3 mg 17-estradiol and immunized 3 months later with the 16/6 idiotype of human anti-ds DNA. The mice responded with high titers of anti-ds DNA antibodies,36 thereby demonstrating the propensity of estrogen to stimulate the autoimmune response in this susceptible murine model. The autoimmune-promoting effects of estrogen were substantiated when treatment with either tamoxifen or antiestradiol antibody decreased the severity of subsequent proteinuria and protected against immune complex deposits in renal glomeruli.37 Diamond and associates38 generated transgenic BALB/c mice that expressed the gamma2b heavy chain of a nephritogenic anti-DNA antibody and used this model to study the effects of estrogen on B cells. These mice are normally able to maintain tolerance by deleting DNA-reactive B cells that arise in the immature repertoire, but long-term treatment with a physiologic dose of estradiol was associated with the development of circulating anti-DNA antibodies and glomerular immune complexes. Estradiol was thought to have stimulated autoimmunity by increasing the resistance of transitional B cells to apoptosis through upregulation of the anti-apoptotic protein, Bcl-2, and the inhibitory signaling molecules CD22 and SHP-1. In estradiol-treated transgenic mice, there was a 10-fold increase in marginal zone cells. Marginal zone B cells were activated to secrete high affinity and potentially pathogenic anti-DNA antibodies, and were not susceptible to regulation by T cells.39–41 Treatment of the transgenic mice with the estrogen receptor blocker tamoxifen prevented the appearance of lupus. When tamoxifen was given in conjunction with estradiol, autoreactive B cells expanded but were anergic and the mice did not develop anti-DNA antibodies or glomerular IgG deposits.41 Estrogen-Prolactin Interactions Estrogen is a potent stimulus for production of pituitary prolactin in rodents, and estrogen stimulates autoimmunity in the NZB/NZW lupus model. Nevertheless, there is experimental evidence in both NZB/NZW mice (predestined to develop SLE) and transgenic BALB/c mice (prone to develop SLE) that the presence of prolactin is necessary in order for estrogen to exert its stimulatory effects on autoimmune disease. Female NZB/NZW mice treated with very high doses of ethinyl estradiol or 17-estradiol, in the same doses used by the earliest investigators,26,27 developed pituitary adenomas

C h a p t e r 5 1   Prolactin and Autoimmunity l

and extremely high serum prolactin levels, up to 91 times greater than controls.31 The primary cause of death was estrogen toxicity, manifested as fulminant endometritis and severe lower urinary tract obstruction with bladder stones. The results of this experiment confirmed the sensitivity of the mouse to estrogenic stimulation of prolactin production, with pronounced hyperplasia and formation of adenomas in the anterior pituitary. It is possible that estrogen-induced elevation of prolactin contributed to the apparent stimulation of autoimmune disease in the NZB/NZW mice that received pharmacologic doses of estrogen in early experiments. Elbourne42 treated NZB/ZW mice with estrogen to produce high physiologic levels of the hormone. When these animals were given pituitary implants to create hyperprolactinemia, the combination of high estrogen and high prolactin was associated with accelerated albuminuria and very early appearance of antibodies to DNA (75% positive at 16 weeks of age). In contrast, comparable high estrogentreated mice that received bromocriptine instead of pituitary implants had delayed autoimmune disease. The high estrogen–low prolactin mice had delayed appearance of albuminuria and anti-DNA (10% positive at 16 weeks of age). The importance of prolactin as a stimulator of autoimmunity was demonstrated in studies of the transgenic R2A gamma 2b BALB/c mouse model.39 Lupus autoantibodies developed when these mice were oophorectomized to remove the major source of estrogen and treated with a prolactin dose that caused a two-fold increase in circulating prolactin. The T1/T2 ratio was inverted, Bcl-2 was increased, and the total number of B cells was increased. A second group of lupus-susceptible transgenic BALB/c mice was given both estrogen and bromocriptine in order to determine if estrogen could stimulate lupus in the presence of extremely low concentrations of prolactin. Bromocriptine did not block the appearance of DNA-reactive B cells, but the cells that did develop were functionally inactive. It therefore appeared that a sufficient amount of circulating prolactin was required in order for estrogen to stimulate lupus in a mouse with a permissive genetic background.43,44 In contrast to its actions in transgenic BALB/c mice, prolactin did not stimulate lupus in R4A gamma 2b C57Bl/6 mice. Because animals with the C57Bl background did not respond, it was concluded that the stimulatory effects of prolactin were genetically determined. The importance of genetic background was further substantiated when C57BL/6 mice carrying the transgene were bred with Sle3/5 C57BL/6 mice. The C57BL/6 offspring, which carried both the Sle3/5 lupus susceptibility interval and R4A-gamma2b, developed increased titers of anti-DNA antibodies and glomerular deposits of IgG.45 Of interest, the prolactin-stimulating effects of 17-estradiol were not shared by chlordecone, an organochloride pesticide with estrogenic effect. Chlordecone did stimulate the onset of disease activity in oophorectomized NZB/NZW females. Mice treated with chlordecone had dose-related

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suppression of serum prolactin concentrations, a finding suggesting that this compound did not require prolactin to stimulate disease.46 In summary, estrogen and prolactin both play important roles in the autoimmune disease, SLE. In experimental models of lupus, either hormone is capable of augmenting autoimmunity. When the effects of very high doses of estrogen were tested in mice, the experimental results were obscured by estrogen toxicity, which led to early death unrelated to autoimmune disease. Pharmacologic doses of estrogen stimulated the formation of pituitary adenomas and extremely high amounts of circulating prolactin. In lupusprone mice, the immune-enhancing properties of estrogen were impeded by very low concentrations of prolactin. Therefore, prolactin is necessary in order for estrogen to stimulate the autoimmune process (reviewed by Grimaldi47).

Prolactin and human autoimmune disease Effects of Prolactin Stimulation of the Immune System Healthy women who were made temporarily hyperprolactinemic by treatment with domperidone had transient increases in theophylline-sensitive T cells. CD4 lymphocytes decreased, and mitogenic responses to concanavalin A increased.48 Findings in subjects with longstanding increases of serum prolactin above the norm, however, were not consistent. Cytokine levels were normal,49 surveys of lymphocyte subsets were either normal,50 or displayed increased CD4 51 and natural killer (NK) cell activity was either decreased52 or normal.53 Giving bromocriptine treatment to inhibit pituitary secretion of prolactin and reduce serum prolactin concentrations resulted in normalization of increased numbers of CD4TQ1 cells51 and increased efficiency and recycling capacity of NK cells.52 Hyperprolactinemia can stimulate autoantibodies in individuals without clinical autoimmune disease. Pontiroli et al54 studied 71 hyperprolactinemic women, of whom 30 had evidence of prolactinomas by tomography. Three had antibodies directed against the pituitary, 2 had antithyroid antibodies, and 3 had antibodies to gastric parietal cells. In another series, women with prolactinomas had antimicrosomal antibodies and antithyroglobulin, each occurring in 21% of subjects. These antibodies were found in 8% and 5% of normal women, respectively. The occurrence of antithyroglobulin antibodies was 19% in hyperprolactinemic men compared with 2% in normal men.55 Reactivity against a number of autoantigens was found in a survey of 33 hyperprolactinemic women; 82% had imaging studies showing pituitary adenomas. Twenty-five (76%) of the women had at least one autoantibody, and 8 had seven or more different autoantibodies. The most common antibody specificities were directed

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against single-stranded DNA, ds DNA, Sm, pyruvate dehydrogenase, and SSA/Ro. The subjects did not have clinical evidence of autoimmune disease.56 Another survey found anticardiolipin antibodies in 5 of 23 (22%) of women and men with serum prolactin concentrations above the norm.57 Our laboratory surveyed sera from individuals with no clinical diagnosis of rheumatic disease, submitted to the University of Iowa Medicine Endocrine Laboratory. Eight of 24 (33%) sera from hyperprolactinemic women (serum prolactin 26–253 ng/ml, normal 0–20 ng/ml) had positive fluorescent antinuclear antibody (FANA) tests, and 3 of these women had either anti-Scl 70, anti-SSB/La, or the Sm determinants B/B’ and C. Fifteen hyperprolactinemic men, including 8 with prolactinomas, were also tested. Eight (53%) had positive FANA tests. In comparison, FANA tests were positive in 3 of 15 (20%) age-matched men with normal prolactin concentrations (p 0.01).13 Hyperprolactinemia Preceding Autoimmune Disease In at least 7 cases, hyperprolactinemia has been documented before the onset of autoimmune disease. Elevated serum prolactin was found in one patient 5 years before the appearance of Graves’ disease, and idiopathic hyperprolactinemia was present in another individual 2 years before dermatomyositis was diagnosed.58 Two patients were hyperprolactinemic 12 years before the diagnosis of primary Sjögren’s syndrome.59 High serum prolactin was present in 3 women at intervals of 3 months, 16 months, and 10 years before SLE was diagnosed. Lupus was expressed in these patients by prominent photosensitivity and malar rash, without clinical evidence of involvement of the kidney or central nervous system.60 Hyperprolactinemia in Nonrheumatic Autoimmune Diseases Serum prolactin concentrations above the norm have been reported in autoimmune diseases,61 some of which are not traditionally included in the category of rheumatologic disease. Experimental autoimmune encephalitis in animals, which resembles multiple sclerosis in humans, was associated with elevated levels of prolactin. Bromocriptine treatment protected the animals from developing encephalitis (reviewed by Shuster62). The role of prolactin in the pathogenesis of multiple sclerosis, however, is less clear. In the human disease, one-third of patients with multiple sclerosis had prolactin elevations,63 secretion of prolactin was hyperresponsive following injection with thyroid-releasing hormone,64 and prolactin levels were increased in early stages of a multiple sclerosis flare.63 Hyperprolactinemia was reported in a small series of patients with multiple sclerosis65 and in the optic neuromyelitis variant, in which Asian patients had prominent optic nerve involvement and high cell counts and excessive protein in cerebrospinal fluid.66 In

contrast, a survey of 132 multiple sclerosis patients found no difference in mean serum prolactin concentrations and no difference in response to metoclopramide stimulation between the affected individuals and controls. Prolactin levels did not correlate with disease activity or classification.67 A case control study comparing 43 multiple sclerosis patients with 43 age- and sex-matched controls showed no difference in serum prolactin concentrations between the groups.68 Bromocriptine treatment was not successful in an open-label trial in which 5 mg/day was given to 18 multiple sclerosis patients. After one year, disease had progressed in 14 of the 15 subjects who completed the study.69 A report of two women with myasthenia gravis and thymic hyperplasia suggested an association between myasthenia and hyperprolactinemia. Both subjects were found to be hyperprolactinemic 4 and 14 years after the appearance of myasthenia gravis. One was treated with bromocriptine and her myasthenia improved substantially after the serum prolactin value became normal. Subsequently, 192 myasthenic subjects were tested. In women, mean serum prolactin was increased significantly compared to control values and there was a strong positive correlation with levels of anti-acetylcholine receptor antibodies.70 It was postulated that bromocriptine-lowering agents might prove helpful in treating myasthenia gravis.71 Four patients with autoimmune Addison’s disease were hyperprolactinemic, and it was thought that deficient corticosteroids caused prolactin to rise above the norm.72 Thyroid disease with autoimmune features is also associated with elevated prolactin. In a series of 92 hyperprolactinemic women, 33 had evidence of a primary thyroid disorder. Antibodies to thyroglobulin were found in 26%, hyperplasia in 14%, and thyroid nodules in 3%.73 In a series of 14 subjects with untreated hyperprolactinemia, 57.1% had antithyroglobulin antibodies.74 Prolactin has been associated with ocular disease, and an interesting study suggested that prolactin was produced locally in the inflamed eye. Aqueous humor was analyzed in 14 patients with previously documented anterior uveitis and the mean prolactin concentration was 1.9 ng/ml  1 standard deviation (SD), a value that exceeded the mean control value of 0.5  0.5 (p 0.001). In contrast, serum prolactin levels did not differ between the two groups.75 Bromocriptine was used with success to treat four uveitis patients.76 In another series, 14 patients with severe iridocyclitis responded to treatment with cyclosporine given in combination with bromocriptine, 2.5 mg three times daily.77 The treated individuals were not reported to be hyperprolactinemic before treatment started.

Autoimmune Diseases with Prolactin Concentrations above the Norm Hyperprolactinemia in Rheumatic Diseases Increasing reports of autoimmune disease associated with hyperprolactinemia have led to the supposition that prolactin

C h a p t e r 5 1   Prolactin and Autoimmunity l

has a role in the pathogenesis of these disorders.78 Table 78.1 describes groups of patients with specific rheumatologic diseases who had significant serum prolactin elevations in comparison with a normal control population. Hyperprolactinemia was found in 36% of patients with reactive arthritis,79 and 4 patients with reactive arthritis responded to treatment with bromocriptine in doses of 2.5 or 5 mg/day.80 In contrast, ankylosing spondylitis was said to be associated with normal serum prolactin, although the values were not given.81–83 Rovensky et al.84 studied 18 men with ankylosing spondylitis and found normal resting prolactin levels, with normal prolactin response to hypoglycemic stimulation. Repeated surveys of subjects with scleroderma have suggested that there is an association of this disease with hyperprolactinemia, and it now appears that many of these patients have evidence of prolactinomas. Five groups of women with scleroderma had elevated prolactin levels.85–88 When 44 scleroderma patients were assessed using the NB2 cell bioactivity assay, a subgroup of six hyperprolactinemic subjects was identified. There was no correlation between basal prolactin levels and systemic sclerosis subgroup, erythrocyte sedimentation rate, C-reactive protein, or level of disease activity.89 A survey of 30 women with the disease did not find significant basal hyperprolactinemia.90 Instead, scleroderma was associated with an overactive prolactin response to metaclopramide, suggesting that central dopaminergic

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tone was increased. Pituitary microadenomas were diagnosed by computerized tomography in 80% of the subjects. Identification of prolactin-like proteins in acinar epithelial cells of Sjögren’s syndrome patients raised the possibility that local production of PRL contributes to local inflammation,91 and hyperprolactinemia has been reported in primary Sjögren’s syndrome. In an early survey, 5 of 11 (46%) affected individuals with Sjögren’s syndrome were hyperprolactinemic.92 In a second study, 55 patients with primary Sjögren’s syndrome had higher mean serum prolactin compared with 110 normal controls. Prolactin levels were highest in those diagnosed before the age of 45 years. Two patients were found to have primary Sjögren’s syndrome 12 years after hyperprolactinemia was first detected. Both had unusually aggressive disease with systemic features.93 A survey of 49 patients in Egypt confirmed an association between hyperprolactinemia and Sjögren’s syndrome; 16.3% of the subjects had serum prolactin levels above the norm.94 The risk of rheumatoid arthritis (RA) is increased in women who breastfeed after the first pregnancy, and it was suggested that the propensity to develop RA was related to immune-stimulating prolactin surges that accompany suckling.95 Prolactin secretion was reported as either normal or upregulated in RA.96 The proinflammatory cytokine macrophage inflammatory protein-1alpha is produced by cells involved in the inflammatory rheumatoid process and may

Table 51.1  Hyperprolactinemia in rheumatic diseases Diagnosis

Sex

N (% HPRL)a

PRL (disease)

PRL (controls)

p

Ref.

Reactive arthritis Scleroderma

F,M F F F M F PMF F,M F,M F,M M M F F F F F AD F,M

25 (36) 17 (59) 24 (35) 44 (85) 8 (62) 12 (ND) 22 (ND) 11 (46) 55 (4) 49 (16.3) 91 (40) 29 (7) 60 (0) 8 (38) 11 (0) 8 (0) 16 (25) 22 (0)

16.4  14.1b 19.2  2.1c 16.8  9.1b 48.6  18.0b 16.3  12.8b 24.9  11.8b 22.9  9.5b 25.2  20b 271.5  209.2b 14.5  11.7b 249  16b 13.1  1.6c 225.6  104.6b 10.9  1.9d 8.9  4.0b 7.8  2.4b 12.6  6.9b 19.3  ND

8.7  4.5 8.1  1.1 11.6  4.5 14.1  5.2 6.4  5.4 15.8  3.6 14.3  3.8 10.4  7.2 205.9  ND 7.9  9.7 189  85 7.5  0.5 175  68.5 5.8  1.3 4.6  1.7 4.6  1.7 9.1  2.1 9.8  ND

0.05 0.01 0.001 0.01 0.05 0.019 0.001 0.04 0.02 0.01 0.0015 0.001 0.05 0.048 0.006 0.006 0.05 0.009

79 85 86 87 87 88 88 92 93 94 102 103 104 114 115 115 118 119

Sjögren’s syndrome

Rheumatoid arthritis

Chronic juvenile arthritis

Behçet’s syndrome

Abbreviations: N, number of subjects in the study group; HPRL, hyperprolactinemic; PRL, mean prolactin level; p, mean serum prolactin concentration in study group vs. mean serum prolactin concentration in control group; Ref., reference; PMF, postmenopausal female; ND, no data; AD, active disease. a Normal values for serum prolactin concentrations were 20 ng/ml [refs 79, 92, 94, 103], 1.4–14.6 g/l [ref. 85], 2.6–20.6 ng/ml [ref. 86], 48.6  18.0 g/l (females) and 16.3  12.8 g/l (males) [ref. 87], 500 mIU/l [ref. 93], 109–224 mU/l [ref. 102], 3–12 g/l [ref. 114], and 1.2–29.9 (females) and 2.6–18.8 ng/ml (males) [ref. 118]. ND refs 88,104,115,119. b Mean  standard deviation. c Mean  standard error of the mean. d Not defined as representing standard deviation or standard error of the mean

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stimulate pituitary production of prolactin.97 Furthermore, the prolactin gene is close to the HLA region on the short arm of chromosome 6 and an interaction may exist between prolactin and the HLA DR4 gene, which predisposes to RA.95 These circumstances suggest that prolactin may have a role in initiating or sustaining inflammation in RA, but it is not clear whether the pathogenic stimulation is produced by prolactin of lymphocyte origin as well as pituitary prolactin. Prolactin has been identified in tissue extracts from ankle joints of rats with acute adjuvant arthritis.98 It is produced in the rheumatoid joint by fibroblast-like synovial cells and lymphocytes that infiltrate the synovium, where it appears to stimulate collagenase activity and act as a growth factor for lymphocytes. In vitro application of bromocriptine to RA synovial cells and infiltrating lymphocytes suppressed the expression of mRNA for prolactin and for tumor necrosis factor-alpha (TNF-).99 Prolactin expression in leukocytes is directed by a promoter located upstream of the pituitary promoter. The leukocyte promoter is activated in myeloid leukemic cells by the proinflammatory cytokine TNF-.100 This finding is of interest because TNF plays an important role in inflammation in RA, and treatments designed to inactivate TNF are effective in treating the disease.101 It would be anticipated that circulating levels of prolactin would be high in RA, but this is not always true. Mateo et al.102 did find that 40% of men with RA had serum prolactin that exceeded the population norm, and the subjects’ serum prolactin concentration had positive correlations with duration and functional stage of disease. A study of 29 men with RA revealed that prolactin was elevated compared to normal controls,103 whereas a survey of 60 women with RA did not find hyperprolactinemic subjects. The mean prolactin concentration in the women with RA was significantly greater compared to controls.104 Orbach et al.105 reported that 6% of RA patients had prolactin levels above the norm. In five separate studies, RA was associated with prolactin levels that were within normal limits and comparable to normal controls.74,84,106–108 One group of investigators found that women with RA had a substandard response to hypoglycemic stimulation, with failure to adequately elevate serum prolactin in response to hypoglycemia.84 Eijsbouts et al.108 tested 20 patients with active, recently diagnosed RA who were not receiving disease modifying antirheumatic drugs. Basal prolactin concentrations in RA were comparable to controls, and the untreated patients had suppressed prolactin responses to hypoglycemia. After 6 months of treatment with diseasemodifying therapy (sulfasalazine, which could be changed to methotrexate if needed), prolactin responses to hypoglycemia increased to normal in the RA patients. Other investigators found that serum prolactin was significantly lower in men and women with RA compared to controls.109,110 In many instances, therefore, RA was associated with normal or low levels of circulating prolactin and prolactin suppressive treatment111,112 did not uniformly improve the disease. It therefore appeared that prolactin does not

stimulate RA. In fact, an earlier study showed that excessive circulating prolactin could be beneficial. Thirteen patients with rheumatic disease who were thought to have RA were treated with intramuscular ovine prolactin in an uncontrolled study. Seven improved rapidly, 3 had moderate improvement, and 3 did not improve.113 Table 51.1 shows that serum prolactin concentrations were elevated in prepubertal girls (mean age 8.2 years) who had juvenile chronic arthritis and positive antinuclear antibody tests. Prolactin values in these girls were elevated significantly, compared with seronegative girls with juvenile chronic arthritis and age-matched controls.114 In another survey, younger girls (mean age 4.5 years) with antinuclear antibody-positive pauciarticular juvenile chronic arthritis had increased serum prolactin compared to controls. Serum IL-6 was increased significantly in the children with juvenile chronic arthritis and spondyloarthropathy, and there was positive correlation between concentrations of circulating prolactin and IL-6.115 Although two surveys found normal prolactin concentrations in Behçet’s disease,116,117 a recent determination revealed an association between active disease and hyperprolactinemia (Table 51.1). Thirty-two Behçet’s patients were classified as having active or inactive disease. The 14 individuals with active Behçet’s disease had significantly higher mean prolactin levels compared to controls, and 4 were hyperprolactinemic. Circulating prolactin levels had positive correlation with the erythrocyte sedimentation rate (p  0.05) and C-reactive protein (p  0.05).118 There were no hyperprolactinemic subjects among 21 Portuguese patients with Behçet’s disease recruited from a uveitis clinic, but mean serum prolactin levels were higher than controls in the affected individuals (p  0.009) and in those with complete manifestations of the disease (p  0.02).119 Hyperprolactinemia has not been identified in groups of patients with fibromyalgia. Twenty-one hyperprolactinemic women were tested for tender points, and 15 (71%) met American College of Rheumatology criteria for the classification of fibromyalgia.120 On the other hand, detailed studies of hormonal status in 12 premenopausal women with primary fibromyalgia showed that both serum prolactin and prolactin responses to hypoglycemia were similar to healthy premenopausal controls.121

Prolactin and Systemic Lupus Erythematosus Effects of Prolactin in SLE Peripheral blood monocytic cells (PBMC) isolated from SLE patients with active disease had increased basal expression of CD69, an early cell surface activation marker, on unstimulated cells. Adding prolactin to SLE PBMC nonspecifically stimulated with concanavalin A did not increase CD69 expression. However, the addition of antiprolactin antibodies to similarly stimulated cells cultured without prolactin did block autocrine and paracrine actions of prolactin

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and resulted in significantly decreased CD69 expression. It was concluded that prolactin produced by SLE PBMC had a major role in activating immune cells in SLE, and this activation took place between the steps of antigen presentation and subsequent non-antigen specific co-stimulatory activation.122 Takizawa et al.123 studied PBMC from healthy volunteers and found that adding prolactin increased the expression of CD69 on phytohemagglutinin-stimulated CD8 T lymphocytes, but optimal concentrations of hormone (up to 2 g/ ml) were required to achieve this effect. Hyperprolactinemia in SLE There is currently great interest in the influences of prolactin on SLE, and numerous surveys conducted in different parts of the world have consistently shown an increased occurrence of hyperprolactinemia in human SLE. Twelve percent of serum samples submitted to an antinuclear antibody reference laboratory had abnormally elevated prolactin concentrations. Hyperprolactinemia was clustered in two groups: (1) sera from women 50 years of age who were anti DNA positive (20% hyperprolactinemic) and were thought to have SLE, and (2) sera from women 50 years old with antibodies to both Ro and La. The expected incidence of hyperprolactinemia was 1.3%.124 Eight men with SLE had serum prolactin above the mean,125 and 5 pregnant lupus patients had prolactin levels greater than the expected values for gestation.126 In 12 additional groups, 12–69.7% of SLE subjects had serum prolactin levels that exceeded the population norm74,127–137 (Table 51.2). Other surveys produced evidence that prolactin levels were not elevated consistently in SLE. Ostendorf

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et al.138 found that only 4 women (2%) in a cohort of 182 SLE patients had elevated prolactin, and Munoz et al.139 reported decreases in serum prolactin in 14 women with SLE during the luteal phase. Current evidence supports the contention that elevated prolactin concentrations correlate with clinical and/or serologic evidence of active disease.127,129,132,134–137,140–144 A study of 78 unselected patients with SLE found active lupus in 29 instances. Prolactin concentrations measured by immunoradiometric assay and biologic assay were significantly greater in the active patients compared with those who had inactive disease, and the Toronto SLE Disease Activity Index (SLEDAI) scores had positive correlation with the prolactin levels. Increased prevalence of malar rash and central nervous system manifestations were significantly more common in the hyperprolactinemic patients compared to those with normal levels of circulating prolactin.134 A survey that compared 60 SLE patients with 47 normal healthy subjects showed that anti-ds DNA correlated in a positive manner with serum prolactin, and hyperprolactinemia was associated with fatigue, fever, anemia, elevated erythrocyte sedimentation rate, decreased C3, and renal manifestations of SLE.135 Miranda et al.144 classified 26 SLE patients as having mild, moderate, or severely active lupus glomerulonephritis. The individuals with severe renal activity had mean serum prolactin 24.7 ng/ml, and this value was significantly greater than mean serum prolactin (18.6) in the patients with mild renal activity (p 0.05). Additional studies that supported the association of hyperprolactinemia and active SLE have appeared since the first edition of this book.137,140–142,145 Elevated serum prolactin measured by radioimmunoassay did correlate with

Table 51.2  Hyperprolactinemia in systemic lupus erythematosus Sex F,M F,M F F,M F,M F,M F F,M F,M F F,M F,M

a

N (%HPRL) 46 (22) 82 (19.5) 20 (30) 83 (15.9) 30 (40) 34 (31) 36 (28) 78 (26.9) 60 (28.3) 43(69.7) 26 (12) 38 (ND)

PRL, SLE b

17.2 (3.6–188) ND (5–58)b 19.4  15.6c ND (5–57)b 19.4  11.3c 20  2d 17.1  12.9c 15.2  19.1c 17.4  15.1c 23.6  5.9c 21.3  12.6c 24.4  3.1e

PRL, controls

P

Year

Ref.

8.4 (2.0–17.5) ND 9.5  6.8 ND 12.0  7.5 ND 9.9  3.5 8.9  3.2 6.3  3.2 6.4  2.2 12.5  6.5 11.2  1.2

ND ND 0.05 ND 0.01 ND 0.01 ND 0.0001 0.0001 0.006 0.05

1992 1994 1996 1996 1997 1997 1998 2001 2001 2003 2005 2007

127 128 129 130 131 132 133 134 135 136 74 137

Abbreviations: N, number of subjects in the study group; HPRL, hyperprolactinemic, PRL, prolactin concentration; p, mean prolactin concentration in the study group vs. mean prolactin concentration in the control group; Ref., reference; ND, no data. a Normal values for serum prolactin concentrations were 2–20 ng/ml [refs 127,134,136], 5–20 ng/ml [refs 128,133], 25 ng/ml [ref. 129], 20 ng/ml [refs 130–132], 20 ng/ml (females) and 15 ng/ml (males) [ref. 135], 30 ng/ml (females) and 30 ng/ml (males) [ref. 74], ND ref. 137. b Parentheses enclose range. c Mean  standard deviation. d Mean  standard error of the mean. e Not defined as representing standard deviation or standard error of the mean.

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anti-ds DNA and decreased lymphocyte subsets137 and with clinical and serological evidence of active disease.141 Active disease did not correlate with the biologic activity of prolactin as measured using the traditional Nb2 cell assay, but lupus activity did correlate positively with results of two homologous in vitro bioassays for prolactin activity, the HPL-9 bioassay on human embryonic kidney-derived 293 cells transfected with the cDNA encoding the long isoform of human prolactin receptor and the prolactin-responsive lactogenic hormone response element, and a proliferative assay that had been used to characterize the relative bioactivity of wild-type prolactin.142 SLE activity correlated with little (free) serum prolactin, the 23 kDa single-chain polypeptide which makes up approximately 80% of total circulating prolactin. Measurements of free serum prolactin and prolactin fractions collected after gel filtration chromatography showed strong positive correlation between circulating free prolactin and the SLEDAI score (r  0.314, p 0.001). The subjects with elevated free prolactin were more likely to have serological evidence of active SLE compared to those with normal serum free prolactin. There was negative correlation between the SLEDAI and percentage of big big prolactin (100 kDa), a fraction that likely represents free prolactin complexed with IgG, and can be composed of prolactin complexed with antiprolactin antibody.140 Big big prolactin has reduced bioactivity towards its receptor and is associated with asymptomatic hyperprolactinemia. In a study of 55 hyperlactinemic women with macroprolactinemia who were not identified as having autoimmune disease, none had sustained amenorrhea and only one had galactorrhea.146 Big big prolactin, therefore, is believed to have low in vivo biological activity compared with little prolactin. It is possible that investigators who found no association between serum prolactin and lupus activity105,128,130–132 were working with subjects whose elevated prolactin concentrations included relatively high percentages of big big prolactin. Careful follow-up of a woman with severe SLE provided convincing evidence that her disease activity correlated with circulating prolactin levels. At the age of 14 years, she was diagnosed with anti-ds DNA-positive lupus that was later complicated by type IV lupus nephritis and antiphospholipid syndrome. The serum prolactin level did not exceed 21.5 ng/ml, but the SLEDAI score did parallel prolactin over a 4-year period.147 A 31-year-old woman who had both SLE and a prolactinoma experienced flares of her disease when her serum prolactin was increased, and her disease improved after she was treated with bromocriptine. Prolactin levels had positive correlation with anti-DNA (r  0.55, p 0.05), and prolactin correlated negatively with serum complement activity (r  0.33, p 0.05).148 In juvenile SLE, one study found no relationship between serum prolactin and disease. Prolactin did not differ between 37 children with SLE and 51 healthy children.149 Another survey of 33 prepubertal children revealed hyperprolactinemia in 3 (9%). All three hyperprolactinemic children had

central nervous system complications of SLE (one with psychosis, two with cognitive dysfunction). In contrast, only 10% of patients with normal prolactin had central nervous system involvement.150 Reuman151 described a 13-year-old girl who developed polyarthralgia, irregular menstrual periods, and obsessive–compulsive symptoms. She was found to have clinical and serologic abnormalities of SLE, modest hyperprolactinemia with values up to 91 ng/ml (normal 20 ng/ml), and a poorly demarcated pituitary adenoma. Her joint symptoms and obsessive–compulsive symptoms improved following surgical removal of the adenoma and treatment with bromocriptine. Hyperprolactinemia in Lupus Pregnancy It is expected that maternal prolactin will be increased during pregnancy, but Jara-Quezada et al.126 reported undue elevations of serum prolactin in five pregnant women with SLE as well as an association between hyperprolactinemia and and clinical lupus activity during pregnancy. In a series of 15 pregnant SLE patients, prolactin levels during the second and third trimester were significantly higher compared to the control group of nine healthy pregnant primaparous women. Furthermore, there was a strong correlation between serum prolactin, the SLAM measure of active SLE, lupus anticoagulant, and poor fetalmaternal outcome, especially preterm birth.152 The studies of Leanos-Miranda et al.153 in 91 pregnant women with SLE revealed that antiprolactin antibodies were present in 13%. These women had total serum prolactin values that were greater than pregnant SLE patients without antiprolactin, yet severe lupus flares during gestation were limited to those who did not have prolactin antibodies. Nephritis and vasculitis occurred in 21 patients, and these complications were limited to women who did not have antibodies to prolactin. Premature birth and/or intrauterine growth retardation were significantly more common in infants born to women without the antibodies. Therefore, antiprolactin antibodies, which are associated with macroprolactinemia and could negate the effects of prolactin, appeared to be protective and predictive of relatively good outcomes because they were associated with significantly fewer maternal and fetal complications. Causes of Hyperprolactinemia in SLE The source of excessive circulating prolactin in SLE has not been determined. Secretion is diurnal and is affected by the menstrual cycle. Drugs, hypothyroidism, pregnancy, and renal insufficiency are recognized causes of hyperprolactinemia and should be considered in patients tested for the hormone.154 Both the anterior pituitary and activated lymphocytes are likely sources of excessive circulating prolactin in SLE. Certainly, the anterior pituitary contributes much of the circulating hormone. Many factors unrelated to SLE can influence pituitary secretion of prolactin. Prolactin is a stress hormone

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and levels rise in response to mental or physical stress and are affected by the menstrual cycle. The techniques used to obtain blood for testing are clearly important. In a study of 79 SLE patients, blood was obtained under uniform conditions 2–3 hours after awakening and three samples were taken at 30-minute intervals. Prolactin concentrations were highest in the first blood sample, and persistent hyperprolactinemia was found in all three samples in 37% of SLE patients. In healthy controls, 18% were persistently hyperprolactinemic.155 Prolactinomas are not rare in SLE and have been reported in at least 46 SLE patients.148,151,155–159 In six known instances, SLE improved with bromocriptine therapy148,151,155–157 and 11 patients had flares when bromocriptine was stopped.148,155,156,158 Of interest, the hyperprolactinemia noted in many SLE patients, including those with prolactinomas, was not extraordinarily high. In SLE–prolactinoma patients, diurnal secretion of prolactin is abolished and the relatively constant secretion of even modestly increased quantities of prolactin may be a key factor in stimulating autoimmunity. It has been suggested that low levels of homovanillic acid in SLE reflect impaired dopamine turnover and altered dopaminergic tone, which can affect pituitary prolactin secretion.160 Koller et al.161 examined 11 patients with newly diagnosed and untreated SLE following simultaneous injection of corticotrophin-, growth hormone-, thyrotropin-, and gonadotropin-releasing hormones in order to test pituitary reserve, and results were consistent with normal hypothalamic-pituitary axis. Lymphocytes from SLE patients actively secrete prolactin162 in excessive amounts and it has been postulated that measurable prolactin of lymphocyte origin circulates in these individuals. The prolactin secreted by peripheral blood monocytic cells (PBMC) from SLE patients has increased bioactivity compared to that from healthy normal control cells, and lymphocyte-derived prolactin could stimulate function of the hypothalamic dopaminergic system.163 Circulating antibodies to prolactin contribute to hyperprolactinemia in SLE. These antibodies were identified in 5% of 259 consecutive SLE patients.164 Among individuals with hyperprolactinemia and SLE, 41% had macroprolactinemia consisting of circulating IgG-prolactin complexes, thought to represent prolactin–antiprolactin. The presence of antiprolactin antibodies in individuals with hyperprolactinemia was not positively correlated with increased SLE activity. Rather, antibody-positive individuals had low indices of active SLE.165 The attenuation of disease could have resulted from antiprolactin antibodies interfering with prolactin binding to receptors on lymphocytes, leading to functional inactivation of prolactin and decreased lymphocyte proliferation. Antiprolactin antibodies could also interfere with feedback mechanisms involved in regulation of pituitary secretion of prolactin. Prolactin bound to anti-prolactin has the potential to present a falsely low concentration of circulating prolactin to the hypothalamus

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and anterior pituitary, resulting in compensatory oversecretion of the hormone. High-molecular weight immunoglobulin–prolactin complexes may be retained within the vascular system so that the bound prolactin has limited access to targets in the central nervous system and the immune system.166 A longitudinal study of a pregnant woman with SLE showed that bioactive 150 kDa prolactin (big big prolactin) was the predominant circulating form of prolactin. In contrast, healthy pregnant women had circulating monomeric prolactin. When the SLE patient’s serum was injected into rats, the IgG–prolactin complex was cleared more slowly than serum that contained predominantly monomeric prolactin.167 Lymphocytic hypophysitis is a rare inflammatory disease of the pituitary in which the gland is inflamed, enlarged, and infiltrated by lymphocytes. The disorder may cause sellar compression, hypopituitarism, diabetes insipidus, and hyperprolactinoma.168 The hyperprolactinemia is thought to result from compression of the pituitary stalk by the suprasellar pituitary mass, resulting in decreased delivery of dopamine (the inhibitor of prolactin secretion) to the anterior pituitary and unrestrained secretion of prolactin. It has been proposed that increased prolactin concentrations also occur because: the inflammatory process interferes with production of hypothalamic dopamine, massive cell destruction causes escape of prolactin into the circulation, antibodies to prolactinsecreting cells directly stimulate prolactin secretion, and prolactin is released from the immune cells infiltrating the anterior pituitary gland.169 Lymphocytic hypophysitis has been reported in at least two individuals with SLE who had symptomatic pituitary masses that were initially thought to be adenomas.170,171 Characteristics of lymphocytic hypophysitis on MRI imaging are strong, homogenous, and symmetrical enhancement of the anterior pituitary and lack of erosive changes of the floor of the sella. Imaging may not differentiate lymphocytic hypophysitis from an atypical adenoma, and histological examination is needed to make a definite diagnosis.168 It is anticipated that future imaging studies of the pituitary will lead to a better understanding of the occurrence of pituitary tumors and inflammatory masses that could disturb circulating levels of prolactin in SLE patients.

Prolactin-lowering therapy for autoimmune diseases Rationale Properties of Bromocriptine Some autoimmune diseases respond favorably to treatment with prolactin suppressing drugs such as bromocriptine, an ergot derivative with potent dopamine receptor agonist activity that selectively inhibits secretion of prolactin from the anterior pituitary.172 Favorable responses to prolactinsuppressing drugs support the contention that prolactin can

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stimulate autoimmunity. Bromocriptine therapy causes a prompt and marked decrease in serum prolactin and is used to treat prolactinomas, acromegaly, symptomatic hyperprolactinemia, and parkinsonism. Undesirable side-effects include nausea, orthostatic hypotension, headache, fatigue, abdominal cramps, nasal congestion, and constipation. Serious adverse events have been almost completely limited to those instances in which bromocriptine was either used to suppress postpartum lactation or given in high doses to treat Parkinson’s disease.173–175 Immunosuppressive Properties of Bromocriptine It is generally believed that bromocriptine has immunosuppressive properties that result from its ability to lower circulating prolactin of pituitary origin.176,177 Macrophages taken from bromocriptine-treated mice had deficient production of interferon-gamma that was reversed by treating the animals with ovine prolactin.178 Bromocriptine has been shown to directly suppress the immune system in vitro. Bromocriptine suppressed early stages of human T cell activation179 and inhibited proliferation and immunoglobulin production in mitogen-stimulated human B cells.180 Neidhart22 provided convincing evidence that the immunosuppressive effects of bromocriptine in an animal model of autoimmune disease were related to the ability of this drug to suppress pituitary secretion of prolactin. Bromocriptine did suppress proliferation of mitogen-stimulated mouse splenocytes. The lowest suppressive concentration of bromocriptine, however, was 200 ng/ml. In contrast, the circulating level of bromocriptine in autoimmune NZB/NZW mice that were treated successfully with bromocriptine was 2–6 ng/ml. In the presence of this low level of circulating bromocriptine, the mice had amelioration of autoimmune disease with reduced severity of renal disease. The bromocriptine concentration that suppressed in vitro immune responsiveness was 33–100 times greater than the serum bromocriptine concentration in the treated autoimmune mice, and it was concluded that suppression of autoimmune disease was achieved by cutting off pituitary prolactin secretion and not by directly suppressing lymphocyte proliferation. Prevention of Autoimmune Disease in Experimental Animals Prophylactic treatment with bromocriptine decreased the occurrence of experimental autoimmune uveitis in female Lewis rats181 and inhibited experimental allergic encephalomyelitis and adjuvant arthritis.182–185 Treatment with bromocriptine, started at 6 weeks of age, ameliorated the severity of spontaneous SLE in female NZB/NZW mice. A bromocriptine dose was used that had been shown to suppress circulating prolactin to 8 ng/ml in swim-stressed NZB/NZW females, compared with 76 ng/ml in untreated stressed female controls. Treatment began before the overt appearance of autoimmune

disease and continued throughout the lifespans of the mice. At the age of 24 weeks, anti-ds DNA antibodies were decreased in treated mice compared to controls. Survival was prolonged significantly in the bromocriptine-treated group compared to controls.21 The protective effects of bromocriptine were confirmed in a second set of experiments, in which oophorectomized NZB/NZW mice that received bromocriptine from the age of 6 weeks developed autoimmune disease of intermediate severity. Concurrent treatment with high-dose estrogen did not accelerate disease in bromocriptine-treated mice, a result implying that prolactin was a more important determinant of disease severity than estrogen in NZB/NZW mice.42 Treatment of Established Autoimmune Disease in Experimental Animals In experimental animal models, bromocriptine treatment was effective after clinical signs of disease appeared. Experimental autoimmune encephalitis was suppressed in Lewis rats that received bromocriptine either one week after immunization or after clinical signs appeared.186,187 The spontaneously diabetic BB rat had decreased severity of disease following treatment with both bromocriptine and cyclosporine,185,188 whereas nonobese diabetic mice had varying responses to bromocriptine therapy. Early treatment from the age of 21 days reduced the incidence of diabetes.189 In contrast, long-term treatment with a higher dose of bromocriptine accelerated the onset of diabetes and increased islet inflammation.190 Bromocriptine suppressed the severity of spontaneous periarteritis in aged Sprague– Dawley rats.185 BALB/c mice with two separate autoimmune states – either SLE induced by injected human anti-ds DNA monoclonal antibody or antiphospholipid syndrome induced by injected monoclonal mouse anti-cardiolipin antibody – responded favorably to bromocriptine treatment. The SLE mice had decreased glomerular deposition of immunoglobulin, and mice with antiphospholipid syndrome responded with decreased activated partial thromboplastin time and fewer resorbed fetuses.191 Neidhart185 reported that a prolactin-suppressing dose of bromocriptine was beneficial in mature NZB/NZW female mice. Treatment was started at 36 weeks of age, when the mice were expected to have clinical SLE, and proteinuria and histologic evidence of glomerulonephritis were suppressed.

Treatment of Autoimmune Diseases in Humans Hedner and Bynke192 reported success with bromocriptine treatment of four individuals with inflammatory eye disease (iridocyclitis and ankylosing spondylitis, iritis with reactive arthritis, idiopathic unilateral iridocyclitis). The doses were 2.5–5 mg/day. Bromocriptine was used because the patients had hyperprolactinemia, galactorrhea, or Parkinson’s disease. The eye disease resolved, and had been present for 4–12 months at the time of the report. In another series, 14

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individuals with severe corticosteroid-resistant uveitis that threatened sight received bromocriptine, 7.5–10 mg/day, in combination with cyclosporine A (starting dose, 4 mg/kg). Serum prolactin levels were suppressed below 2 ng/ml, and visual acuity improved markedly in 8 patients.193 A double-blind study of 15 patients with recurrent anterior uveitis was designed so that 7 subjects were randomized to receive bromocriptine, 5 mg/day, and 8 subjects received placebo for 48 weeks. Two bromocriptine-treated patients stopped treatment and 5 controls left the study because of recurrences. A conclusion was not reached concerning the effectiveness of bromocriptine treatment.194 Although prolactin-suppressive treatment was effective in treating experimental autoimmune encephalitis and diabetes mellitus182–189 in experimental animals, this form of therapy was not successful in humans with multiple sclerosis or diabetes mellitus. An open-label study of bromocriptine treatment in multiple sclerosis gave disappointing results. Patients with either relapsing–remitting or chronicprogressive forms of multiple sclerosis received 5 mg/day. Clinical relapses, new lesions on magnetic resonance imaging of the brain and brain stem, and increased visual or auditory evoked responses showed progression in 14 of the 15 subjects who completed one year of treatment.195 In obese individuals with type 2 diabetes mellitus, bromocriptine was given to 15 subjects while 7 controls received placebo in a double-blind study that lasted 16 weeks. The bromocriptine-treated group had favorable response in the form of small but significant decreases of fasting glucose levels and hemoglobin A1c. There were, however, no changes in body composition, body fat distribution, oral glucose tolerance, insulin-mediated glucose disposal, or endogenous glucose production.196 The inefficacy of bromocriptine in treating type 2 diabetes mellitus was confirmed by the findings of Wasada et al.197 Atkinson et al.198 reported there was no advantage in combining bromocriptine with cyclosporine A in treating newly diagnosed insulin-dependent diabetics. Dramatic response to bromocriptine treatment was reported for four men with severe reactive arthritis following enteritis caused by Salmonella typhi or Shigella flexerni. Doses of either 2.5 or 5.0 mg/day resulted in decreased numbers of affected joints after 1–8 days of therapy.199 The hypothesis that lowering serum prolactin would effectively treat RA was tested in two open-label studies. Nine postmenopausal women took bromocriptine in doses up to 30 mg/day (mean dose 19.7 mg/day) for 90 days. Prolactin decreased to undetectable levels in 8 of the subjects, and 4 had improvement in RA according to American College of Rheumatology criteria. IL-2 production was suppressed in phytohemaglutinin-stimulated peripheral blood mononuclear cells from the treated patients.111 Another prolactin-lowering dopamine agonist, quinagolide (150 g/ day), was given to 4 men and 5 women for 24 weeks. Serum prolactin levels were normal before treatment and decreased to levels below detection within 4 weeks

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of starting treatment. There was a tendency for gradual improvement in the Richie articular index, and 2 patients met EULAR criteria for moderate response. There was no improvement in objective variables such as the erythrocyte sedimentation rate and C-reactive protein, and it was concluded that quinagolide treatment of RA was ineffective.112

Treatment of SLE with Prolactin-Lowering Drugs The first case report of successful use of bromocriptine treatment in a case of active SLE appeared in 1990200(L. Schanberg, personal communication). A woman with SLE who was not reported to be hyperprolactinemic had central nervous system lupus and was resistant to conventional therapy. She improved after treatment with bromocriptine and intravenous IgG. In two instances, the disease flared after bromocriptine was discontinued. Four women with chronic, symptomatic hyperprolactinemia developed mild SLE characterized by photosensitivity, malar rash, arthralgias, and positive fluorescent antinuclear antibody tests with titers 1:320–1:640. Two had antibodies to ds-DNA, but none had real involvement. Three had pituitary microadenomas and were either untreated or were treated intermittently with bromocriptine. They had moderately high prolactin concentrations that ranged from 55 to 217 (normal 0–20 ng/ml). One hyperprolactinemic patient with SLE and a prolactinoma was treated with bromocriptine and no corticosteroids. When the serum prolactin was lowered, she had resolution of facial rash, fatigue, and arthralgias.154 Seven lupus patients with active but not organthreatening SLE were treated in an open-label study with bromocriptine, 3.75–7.5 mg/day. One patient had a microprolactinoma and borderline hyperprolactinemia (20.6, normal 2–18.5 ng/ml), but the other study participants had normal prolactin concentrations at entry. The dose for each subject was chosen to achieve suppression of serum prolactin 3 ng/ml. The treatment period was 6 months, and 6 of the 7 patients had improvement in the SLE Activity Measure (SLAM) and the SLEDAI. Raynaud’s phenomenon, arthralgias, and arthritis improved. Serum IgG fell transiently during treatment, but changes in IgM, antids DNA, C3, and C4 were not significant. Three of the 4 patients who took prednisone at entry were able to reduce the dose during treatment. After bromocriptine was discontinued, subjects were followed on protocol for 5 months. Five patients became hyperprolactinemic. Constitutional, cutaneous, neuromotor, and articular manifestations of SLE increased in all 7 patients and all had increased SLAM scales and SLEDAI scores. In 6 individuals, changes in medication were needed to control lupus activity.201 Three patients asked to resume bromocriptine therapy at the end of the study. One woman became hyperprolactinemic after stopping bromocriptine. The drug was later restarted at her request. Her disease remained quiescent during a follow-up

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period of 3 years.13 The patients experienced improvement in mood states during the treatment period, as measured by the Symptom Questionnaire survey. Total distress scores improved, and this improvement correlated positively with improvement in both the SLAM and SLEADI. The angerhostility measure decreased during bromocriptine therapy. Improvement in this measure did not correlate with improved disease activity, and this observation raised the question that bromocriptine exerted favorable psychotropic effects.202 The double-blind study of Alvarez-Nemegyei et al.203 showed that treatment with a fixed low dose of bromocriptine for one year reduced the expected number of lupus flares. Thirty-six of 66 consecutive patients with SLE were randomized to receive a daily dose of 2.5 mg and 30 controls received placebo. Patients were entered into the study without regard to disease activity, although those with organ failure were excluded. Modest hyperprolactinemia was found at entry in 51% of subjects in the bromocriptine treatment group and 40% of the controls. Subjects were followed prospectively for 2–17 months (mean, 12.5 months). Serum prolactin was reduced significantly in the treatment group and there was evidence of clinical improvement after 5 months of treatment. The mean number of flares/patient/ month in treated subjects was reduced to 0.08  1 vs. 0.18  0.2 in controls (p  0.03). In a separate study, patients with active SLE were randomized to receive either daily bromocriptine, in a dose designed to suppress serum prolactin to a concentration 1 ng/ml, or hydroxychloroquine, 6 mg/kg. Patients were selected so that at entry they did have active SLE but did not have either life-threatening disease or progressive disease that involved a major organ. Treatment was given for one year. Preliminary data from 24 patients were encouraging. In 11 bromocriptine-treated patients the SLAM decreased from (mean  SEM) 14.0  1.1 at entry to 7.5  0.8 (p 0.05) after one year of treatment. In 13 SLE patients randomized to receive hydroxychloroquine, SLAM decreased from 13.4  1.3 at entry to 9.0  1.4 (p 0.001). Prednisone doses, the numbers of patients who started and stopped prednisone, and numbers of patients who left the study were similar in both treatment groups.204 Continued analyses of the complete data set following completion of the study showed that SLE activity improved in both the bromocriptine treatment group and the hydroxychloroquine treatment group (SE Walker, unpublished data). Hrycek et al.205,206 found that benefits of prolactinsuppressive treatment were not limited to the use of bromocriptine. Low-dose quinagolide was given to 20 SLE patients and 17 healthy controls. The SLEDAI decreased significantly during therapy, as did prolactin and circulating IL-6. In 25 SLE patients who were treated with low-dose quinagolide (12.5–50 g/day), SLEDAI, serum prolactin, and IL-6 decreased significantly after 3 months of treatment vs. values at entry.

Prolactin-Lowering Treatment in SLE Pregnancy Prolactin that is elevated above the expected level in pregnancy can be predictive of maternal and fetal complications in SLE,152 and treatment with bromocriptine for 2 weeks postpartum was beneficial for women with SLE.207 A recent trial examined the protective role of bromocriptine therapy in SLE pregnancy. Bromocriptine is recognized as safe for use during pregnancy and is not teratogenic,208although it should be used with caution if there are risks of clotting, such as cigarette use and antiphospholipid antibodies.209 Jara et al.210 treated 10 pregnant SLE patients with bromocriptine, 2.5 mg/day plus prednisone, 10 mg/day, and a second group of 10 pregnant SLE patients received prednisone, 10 mg/ day. Subjects were treated from 25 to 35 weeks of gestation. Serum prolactin was suppressed by bromocriptine, and at 30 and 35 weeks of gestation mean prolactin in the bromocriptine-prednisone group was significantly lower compared to the group that received only prednisone. Treatment with bromocriptine plus prednisone was associated with 8 births at term, no flares of SLE, and no premature rupture of the membranes, whereas women in the group treated only with prednisone had 5 births at term, 3 individuals with flares, and 3 with premature rupture of the membranes.

Suggestions for further investigations What is the incidence of pituitary prolactinomas in patients with autoimmune diseases? How many of those with apparent prolactinomas have autoimmune hypophysis? Do those with prolactinomas respond more readily to treatment with a dopamine agonist, whereas those with autoimmune hypophysitis respond better to corticosteroid therapy? Do SLE patients deserve a course of daily, low-dose prolactin suppressive treatment, even if the circulating level of prolactin is not elevated? Should a course of bromocriptine be given to all pregnant women who do have SLE and do not have factors predisposing to clotting?

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References 1. Walker SE, Jacobson JD. Roles of prolactin and gonadotropin-releasing hormone in rheumatic diseases. Rheum Dis Clin North Am 2000;26:713–36. 2. Hooghe R, Dogusan Z, Martens N, Velkenier B, HooghePeters EL. Effects of prolactin on signal transduction and gene expression: possible relevance for systemic lupus erythematosus. Lupus 2001;10:719–27. 3. Vera-Lastra O, Jara LJ, Espinoza LR. Prolactin and autoimmunity. Autoimmun Rev 2002;1:360–64.

C h a p t e r 5 1   Prolactin and Autoimmunity l

4. McMurray RW, May W. Sex hormones and systemic lupus erythematosus. Arthritis Rheum 2003;48:2100–10. 5. Ben-Jonathan N, Mershon JL, Allen DL, Steimetz RM. Extra pituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr Rev 1996;17:639–69. 6. Weigent DA. Immunoregulatory properties of growth hormone and prolactin. Pharmacol Ther 1996;69:237–57. 7. Thoreau E, Petridou B, Kelly PA, Djiane J, Mornon JP. Structural symmetry of the extracellular domain of the cytokine/growth hormone/prolactin receptor family and interferon receptors revealed by hydrophobic cluster analysis. FEBS Lett 1991;282:26–31. 8. Dardenne M, Savino W, Gagnerault M-C, Iton T, Bach J-F. Neuroendocrine control of thymic hormonal production. I. Prolactin stimulates in vivo and in vitro the production of thymulin by human and murine thymic epithelial cells. Endocrinology 1989;125:3–12. 9. Mukherjee P, Mastro AM, Hymer WC. Prolactin induction of interleukin-2 on rat splenic lymphocytes. Endocrinology 1990;126:88–94. 10. Montgomery DW, Shen GK, Ulrich ED, Steiner LL, Parrish PR, Zukoski CF. Human thymocytes express a prolactin-like messenger ribonucleic acid and synthesize bioactive prolactin-like protein. Endocrinology 1992;131:3016–19. 11. Tada Y, Ho A, Matsuyama T. Reduced incidence and severity of antigen-induced autoimmune diseases in mice lacking interferon regulatory factor-1. J Exp Med 1997;185:231–38. 12. Yu-Lee L-Y. Molecular actions of prolactin in the immune system. Proc Soc Exp Biol Med 1997;215:35–52. 13. Walker SE, McMurray RW, Houri JM, et al. Effects of prolactin in stimulating disease activity in systemic lupus erythematosus. Proc N Y Acad Sci 1998;840:762–72. 14. Berczi I, Nagy E, de Toledo SM, Matusik RJ, Friesen HG. Pituitary hormones regulate c-myc and DNA synthesis in lymphoid tissue. J Immunol 1990;146:2201–6. 15. Cross RJ, Campbell JL, Roszman TL. Potentiation of antibody responsiveness after the transplantation of a syngeneic pituitary gland. J Neuroimmunol 1989;25:29–35. 16. Bryant HU, Holaday JW, Bernton EW. Cysteamine produces dose-related bidirectional immunomodulatory effects in mice. J Pharmacol Exp Ther 1989;249:424–29. 17. Andrews BS, Eisenberg RA, Theofilopoulos AN et al. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 1978;148:1198–215. 18. Brick JE, Wilson DA, Walker SE. Hormonal modulation of responses to thymus-independent and thymus-dependent antigens in autoimmune NZB/W mice. J Immunol 1985;134:3693–98. 19. Walker SE, Besch-Williford CL, Keisler DH. Accelerated deaths from systemic lupus erythematosus in NZB x NZW F1 mice treated with the testosterone-blocking drug flutamide. J Lab Clin Med 1994;124:401–7. 20. Baer AN, Green FA. Estrogen metabolism in the (New Zealand black x New Zealand white) F1 murine model of systemic lupus erythematosus. Arthritis Rheum 1990;33:107–12. 21. McMurray R, Keisler D, Kanuckel K, Izui S, Walker SE. Prolactin influences autoimmune disease activity in the female B/W mouse. J Immunol 1991;147:3780–87. 22. Neidhart M. Bromocriptine has little direct effect on lymphocytes, the immunomodulatory effect being mediated by

23. 24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

609

the suppression of prolactin secretion. Biomed Pharmacother 1997;51:118–25. Walker SE, Allen SH, McMurray RW. Prolactin and autoimmune disease. Trends Endocrinol Metab 1993;4:147–51. McMurray R, Keisler D, Izui S, Walker SE. Hyperprolactinemia in male NZB/NZW (B/W) F1 mice; Accelerated autoimmune disease with normal circulating testosterone. Clin Immunol Immunopathol 1994;71:338–43. McMurray RW, Keisler D, Izui S, Walker SE. Effects of parturition, suckling and pseudopregnancy on variables of disease activity in the B/W mouse model of systemic lupus erythematosus. J Rheumatol 1993;20:1143–51. Roubinian JR, Talal N, Greenspan JS, Goodman JR, Siiteri PK. Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice. J Exp Med 1978;147:1568–83. Melez KA, Reeves JP, Steinberg AD. Modification of murine lupus by sex hormones. Ann Immunologie (Paris) 1978;129C:707–14. Roubinian J, Talal N, Siiteri PK, Sadakian JA. Sex hormone modulation of autoimmunity in NZB/NZW mice. Arthritis Rheum 1979;22:1162–69. Steinberg AD, Melez KA, Raveche ES, et al. Approach to the study of the role of sex hormones in autoimmunity. Arthritis Rheum 1979;22:1170–76. Siiteri PK, Jones LA, Roubinian J, Talal N. Sex steroids and the immune system. I. Sex difference in autoimmune disease in NZB/NZW hybrid mice. J Steroid Biochem 1980;12:425–32. Walker SE, McMurray RW, Besch-Williford CL, Keisler DH. Premature death with bladder outlet obstruction and hyperprolactinemia in New Zealand black X New Zealand white mice treated with ethinyl estradiol and 17 beta-estradiol. Arthritis Rheum 1992;35:1387–92. Carlsten H, Tarkowski A. Histocompatibility complex gene products and exposure to oestrogen: two independent disease accelerating factors in murine lupus. Scand J Immunol 1993;83:341–47. Mohan C, Morel L, Yang P, et al. Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies. J Clin Invest 1999;103:1685–95. Morel L, Mohan C, Ying Y, et al. Multiplex inheritance of component phenotypes in a murine model of lupus. Mamm Genome 1999;10:176–81. Van Griensven M, Bergijk EC, Baelde JJ, Bruun JA. Differential effects of sex hormones on autoantibody production and proteinuria in chronic graft-versus-host disease-induced experimental lupus nephritis. Clin Exp Immunol 1997;107:254–60. Blank M, Mendlovic S, Fricke H, Mozes E, Talal N, Shoenfeld Y. Sex hormone involvement in the induction of experimental systemic lupus erythematosus by a pathogenic anti-DNA idiotype in naive mice. J Rheumatol 1990;17:311–17. Dayan M, Zinger H, Kalush F, Mor G, Amir Y. The beneficial effects of treatment with Tamoxifen and anti-oestradiol antibody on experimental systemic lupus erythematosus are associated with cytokine modulations. Immunology 1997; 90:101–8. Offen D, Spatz L, Escowitz H, Factor S, Diamond B. Induction of tolerance to an IgG autoantibody. Proc Natl Acad Sci U S A 1992;89:8332–36.

610

s e c t i o n 9     Immunology l

39. Bynoe MS, Grimaldi CM, Diamond B. Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. Proc Natl Acad Sci U S A 2000;97:2703–8. 40. Grimaldi CM, Hicks R, Diamond B. B cell selection and susceptibility to autoimmunity. J Immunol 2005;174:1775–81. 41. Grimaldi CM, Michael DJ, Diamond B. Cutting edge: expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. J Immunol 2007;167:1886–90. 42. Elbourne KB, Keisler D, McMurray RW. Differential effects of estrogen and prolactin on autoimmune disease in the NZB/ NZW F1 mouse model of systemic lupus erythematosus. Lupus 1998;7:420–27. 43. Peeva E, Michael D, Cleary J, Rice J, Chen X, Diamond B. Prolactin modulates the naïve B cell repertoire. J Clin Invest 2003;111:275–83. 44. Peeva E, Venkatesh J, Michael D, Diamond B. Prolactin as a modulator of B cell function: implications for SLE. Biomed Pharmacother 2004;58:310–19. 45. Peeva E, Gonzalez J, Hicks R, Diamond B. Cutting edge: Lupus susceptibility interval Sle3/5 confers responsiveness to prolactin in C57BL/6 mice. J Immunol 2005;177:1401–5. 46. Wang F, Roberts SM, Butfiloski EJ, Sobel ES. Diminished prolactin from chlordecone treatment in ovariectomized (NZB x NZW)F1 mice. Int Immunopharmacol 2007;7:1808–12. 47. Grimaldi CM. Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells. Curr Opin Rheumatol 2006;18:456–60. 48. Rovensky J, Buc M, Jojda Z, et al. Effect of domperidone-induced hyperprolactinemia on selected immune parameters in healthy women. Arch Immunol Ther Exp (Warsz) 1995;43:221–27. 49. Clodi M, Svoboda T, Kotzmann H, et al. Effect of elevated serum prolactin concentrations on cytokine production and natural killer cell activity. Neuroendocrinology 1992;56:775–79. 50. Koller M, Kotzmann H, Clodi M, Riedo M, Lugar A. Effect of elevated serum prolactin concentrations on the immunophenotype of human lymphocytes, mitogen-induced proliferation and phagocytic activity of polymorphonuclear cells. Eur J Clin Invest 1997;27:662–66. 51. Gerli R, Riccardi C, Nicoletti I, et al. Phenotypic and functional abnormalities of T lymphocytes in pathological hyperprolactinemia. J Clin Immunol 1987;7:463–70. 52. Vidaller A, Guadarrama F, Llorente L, et al. Hyperprolactinemia inhibits natural killer (NK) cell function in vivo and its bromocriptine treatment not only corrects it but makes it more efficient. J Clin Immunol 1982;12:210–15. 53. Matera L, Ciccarelli E, Cesano A, Veglia F, Minola C, Camanni F. Natural killer activity in hyperprolactinemic patients. Immunopharmacology 1989;18:143–46. 54. Pontiroli AE, Falsetti L, Bottazzo G. Clinical, endocrine, roentgenographic, immune characterization of hyperprolactinemic women. Int J Fertil 1987;32:81–85. 55. Ishibashi M, Kuzuya N, Sawada S, Kitamura K, Kamoi K, Yamazi T. Anti-thyroid antibodies in patients with hyperprolactinemia. Endocrinol Jpn 1991;38:517–22. 56. Buskila D, Berezin M, Gur H, et al. Autoantibody profile in the sera of women with hyperprolactinemia. J Autoimmunity 1995;8:415–24.

57. Toubi E, Gabriel D, Golan TD. High association between hyperprolactinemia and anticardiolipin antibodies. J Rheumatol 1997;24:1451, letter. 58. Kawai T, Katoh K, Tani K. Hyperprolactinemia preceding development of autoimmune disease. J Rheumatol 1996;23:1483–84. 59. Haga HJ, Rygh T. The prevalence of hyperprolactinemia in patients with primary Sjogren’s syndrome. J Rheumatol 1999;26:1291–95. 60. McMurray RW, Allen SH, Braun AL, Rodríguez F, Walker SE. Longstanding hyperprolactinemia associated with systemic lupus erythematosus: possible hormonal stimulation of an autoimmune disease. J Rheumatol 1994;21:843–50. 61. Orbach H, Shoenfeld Y. Hyperproalctinemia and autoimmune diseases. Autoimmunity Rev 2007;6:536–42. 62. Shuster EA. Hormonal influences in multiple sclerosis. In: M Rodroguez, ed. Advances in Multiple Sclerosis and Experimental Demyelinating Diseases. Current Topics in Microbiology and Immunology. Berlin: Springer-Verlag; 2008:267–311. 63. Draca S, Levic Z. The possible role of prolactin in the immunopathogenesis of multiple sclerosis. Med Hypotheses 1996;47:89–92. 64. Azar ST, Yamout B. Prolactin secretion is increased in patients with multiple sclerosis. Endocr Res 1999;25:207–14. 65. Grinsted L, Heltberg A, Hagen C, Djursing H. Serum sex hormone and gonadotropin concentrations in premenopausal women with multiple slerosis. J Intern Med 1989;226:241–44. 66. Yamasaki K, Horiuchi I, Minohara M, et al. Hyperprolactinemia in multiple sclerosis. Intern Med 2000;39:296–99. 67. Heesen C, Gold SM, Bruhn M, Hench AM, Schulz K-H. Prolactin stimulation in multiple sclerosis – an indicator of disease subtypes and activity? Endocr Res 2002;28:9–28. 68. Harirchian MH, Sahraian MA, Shirani A. Serum prolactin level in patients with multiple sclerosis: a case control study. Med Sci Monit 2006;12:CR177–80. 69. Bissay V, De Klippel N, Herroelen L, et al. Bromocriptine therapy in multiple sclerosis: an open label pilot study. Clin Neuropharmacol 1994;17:473–76. 70. Tsinzerling N, Pirskanen R, Matell G, et al. Raised prolactin levels in myasthenia gravis: two case reports and a study of two patient populations. Acta Neurol Scand 2006;114:346–49. 71. Yang M, Huang L, Liu W, Sheng Z, Xie H, Liao E. Prolactin may be a promising therapeutic target for myasthenia gravis: hypothesis and importance. Med Hypotheses 2007;70:1017–20. 72. Lever EG, McKerron CG. Auto-immune Addison’s disease associated with hyperprolactinaemia. Clin Endocrinol (Oxf) 1984;21:451–57. 73. Ferrari C, Boghen M, Paracchi A, et al. Thyroid autoimmunity in hyperprolactinemic disorders. Acta Endocrinol 1983;104:35–41. 74. Kramer CK, Tourinho TF, de Castro WP, Oliveria MD. Association between systemic lupus erythematosus, rheumatoid arthritis, hyperprolactinemia and thyroid autoantibodies. Arch Med Res 2005;36:54–58. 75. Pleyer U, Gupta D, Weidle EG, Lisch W, Zierhut M, Thiel HJ. Elevated prolactin levels in human aqueous humor of patients with anterior uveitis. Graefe’s Arch Clin Exp Ophthalmol 1991;229:447–51.

C h a p t e r 5 1   Prolactin and Autoimmunity l

76. Hedner LP, Bynke G. Endogenous iridocyclitis relieved during treatment with bromocriptine. Am J Ophthalmol 1985;100:618–19. 77. Palestine AG, Nussenblatt RB, Gelato M. Therapy for human autoimmune uveitis with low-dose cyclosporine plus bromocriptine. Transpl Proc Suppl 1988;20:131–35. 78. De Bellis A, Bizarro A, Bellastella A. Role of prolactin in autoimmune diseases. In: SE Walker, LJ Jara, eds. Endocrine Manifestations of Systemic Autoimmune Diseases vol. 9. Amsterdam: Elsevier; 2008:29–43. 79. Jara LJ, Silveira LH, Cuellar ML, Pineda CJ, Scopelitis E, Espinoza LR. Hyperprolactinemia in Reiter’s syndrome. J Rheumatol 1994;21:1292–97. 80. Jara LJ, Silveira LH, Cuellar ML, et al. An acute remission of Reiter’s syndrome in male patients treated with bromocriptine. J Rheumatol 1992;19:747–50. 81. Jimenez-Balderas FJ, Tapia-Serrano R, Madero-Cervera JI, Murrieta S, Mintz G. Ovarian function studies in active ankylosing spondylitis in women. Clinical response to estrogen therapy. J Rheumatol 1990;17:497–502. 82. Gordon D, Beastall GH, Thomson JA, Sturrock RD. Androgenic status and sexual function in males with rheumatoid arthritis and ankylosing spondylitis. Quart. J. Med. 1986;60:671–79. 83. Tapia-Serrano R, Jimenez-Balderas FJ, Murrieta S, BravoGatica C, Guerra R, Mintz G. Testicular function in active ankylosing spondylitis. Therapeutic response to human chorionic gonadotrophin. J Rheumatol 1991;18:841–48. 84. Rovensky J, Imrich R, Malis F, et al. Prolactin and growth hormone resonses to hypoglycemia in patients with rheumatoid arthritis and ankylosing spondylitis. J Rheumatol 2004;12:2418–21. 85. Kucharz EJ, Jarczyk R, Jonderko G, Rubisz-Brzezinska J, Brzezinska-Wcislo L. High serum level of prolactin in patients with systemic sclerosis. Clin Rheumatol 1996;15:314. 86. Shahin AA, Abdoh D, Abdelrazik M. Prolactin and thyroid hormones in patients with systemic sclerosis: correlations with disease manifestations and activity. Z. Rheumatol. 61 703–709. 87. Czuwara-Ladykowska J, Sicinska J, Olszewska M, et al. Prolactin synthesis by lymphocytes from patients with systemic sclerosis. Biomed Pharmacother 2006;60:152–55. 88. Mirone L, Barini A, Barini A. Androgen and prolactin (Prl) levels in systemic sclerosis (SSc). Relationship to disease severity. Ann N Y Acad Sci 2006;1069:257–62. 89. La Montagna G, Meli R, Criscuolo T, D’Angelo S, Valentín G. Bioactivity of prolactin in systemic sclerosis. Clin Exp Rheumatol 2004;22:145–50. 90. Vera-Lastra O, Jara LJ, Medina G, et al. Functional hyperprolactinemia and hypophyseal microadenoma in systemic sclerosis. J Rheumatol 2006;33:1108–12. 91. Steinfeld S, Rommes S, Francois C, et al. Big prolactin 60 kDa is overexpressed in salivary glandular epithelial cells from patients with Sjögren’s syndrome. Lab Invest 2000;80:239–47. 92. Gutierrez MA, Anaya J, Scopelitis E, et al. Hyperprolactinaemia in primary Sjögren’s syndrome. Ann Rheum Dis 1994;53:425– 28, letter. 93. Haga HJ, Rygh T. The prevalence of hyperprolactinemia in patients with primary Sjögren’s syndrome. J Rheumatol 1999;26:1291–95.

611

94. El Miedany YM, Ahmed I, Moustafa H, El Baddini M. Hyperprolactinemia in Sjögren’s syndrome: a patient subset or a disease manifestation? Joint Bone Spine 2004;71:203–8. 95. Brennan P, Ollier B, Worthington J, Hajeer A, Silman A. Are both genetic and reproductive associations with rheumatoid arthritis linked to prolactin? Lancet 1996;348:106–9. 96. Eijsbouts A, van den Hoogen F, Laan R, et al. Similar response of adrenocorticotrophic hormone, cortisol and prolactin to surgery in rheumatoid arthritis and osteoarthritis. Br J Rheumatol 1998;37:1138–39. 97. Kullich WC, Klein G. High levels of macrophage inflammatory protein-1alpha correlate with prolactin in female patients with acute rheumatoid arthritis. Clin Rheumatol 1998;17:263–64. 98. Elhassan AM, Adem A, Suliman IA, Mustafa A, Lindgren JU. Prolactin, growth hormone, IGF-1 in ankles and plasma of adjuvant arthritic rats. Scand J Rheumatol 1999;28:368–73. 99. Nagafuchi H, Suzuki N, Kaneko A, Asai T, Sakane T. Prolactin locally produced by synovium infiltrating T lymphocytes induces excessive synovial cell functions in patients with rheumatoid arthritis. J Rheumatol 1999;26:1890–900. 100. Gerlo S, Verdood P, Kooijman R. Tumor necrosis factoralpha activates the extrapituitary PRL promoter in myelokd leukemic cells. J Neuroimmunol 2006;172:206–10. 101. Moreland LF, Emery P, eds. TNF-alpha Inhibiton in the Treatment of Rheumatoid Arthritis. London: Martin Dunitz, Taylor & Francis Group; 2003. 102. Mateo L, Nolla JM, Bonnin MR, Navarro MA, RoigEscoffet D. High serum prolactin levels in men with rheumatoid arthritis. J Rheumatol 1998;25:2077–82. 103. Seriolo B, Ferretti V, Sulli A, Fasciolo D, Cutolo M. Serum prolactin concentrations in male patients with rheumatoid arthritis. Ann N Y Acad Sci 2002;966:258–62. 104. Ram S, Blumberg D, Newton P, Anderson NR, Gama R. Raised serum prolactin in rheumatoid arthritis: genuine or laboratory artifact? Rheumatology 2004;43:1271–74. 105. Orbach H, Zandman-Goddard G, Amital H, et al. Novel biomarkers in autoimmune diseases. Prolactin, ferritin, vitamin D, TPA levels in autoimmune diseases. Ann N Y Acad Sci 2007;1109:385–400. 106. Templ E, Koeller M, Riedl M, Wagner O, Graninger W, Luger A. Anterior pituitary function in patients with newly diagnosed rheumatoid arthritis. Br J Rheumatol 1996;35:350–56. 107. Gutierrez MA, Garcia ME, Rodríguez JA, Mardonez G, Jacobelli S, Rivero S. Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation. J Rheumatol 1999;26:277–81. 108. Eijsbouts AMM, van den Hoogen FHJ, Laan RFJM, Sweep CGJ, Hermus ARMM, van de Putte LBA. Decreased prolactin response to hypoglycaemia in patients with rheumatoid arthritis: correlation with disease activity. Ann Rheum Dis 2005;64:433–37. 109. Nagy E, Chalmers IM, Barager FD, Friesen HG, Berczi I. Prolactin deficiency in rheumatoid arthritis. J Rheumatol 1991;18:1662–68. 110. Cutolo M, Balleari E, Giusti M, Monachesi M, Accardo S. Sex hormone status in women suffering from rheumatoid arthritis. J Rheumatol 1986;13:1019–23.

612

s e c t i o n 9     Immunology l

111. Figueroa FE, Carrion F, Martinez ME, Rivero S, Mamani I. Bromocriptine induces immunological changes related to disease parameters in rheumatoid arthritis. Br J Rheumatol 1997:1022–27. 112. Eijsbouts A, van den Hoogen F, Laan RFJM, Hermus ARMM, Sweep FCGJ, van de Putte L. Treatment of rheumatoid arthritis with the dopamine agonist quinagolide. J Rheumatol 1999;26:2284–85. 113. Ingvarsson CG. Prolactin in rheumatoid arthritis. (A therapeutic test.). Acta Rheum Scand 1969;15:4–17. 114. McMurray RW, Allen SH, Pepmueller PH, Keisler D, Cassidy JT. Elevated serum prolactin levels in children with juvenile rheumatoid arthritis and antinuclear antibody seropositivity. J Rheumatol 1995;22:1577–80. 115. Picco P, Gattorno M, Buoncompagni A, Facchetti P, Rossi G, Pistoia V. Prolactin and interleukin 6 in prepubertal girls with juvenile chronic arthritis. J Rheumatol 1998;25:347–51. 116. Keser G, Oksel F, Ozgen G, Aksu K, Doganavsargil E. Serum prolactin levels in Behçet’s syndrome. Clin Rhematol 1999;18:351–52. 117. Apaydin KC, Duranoglu Y, Ozgurel Y, Saka O. Serum prolactin levels in Behçet’s disease. Jpn J Ophthalmol 2000;44:442–45. 118. Atasoy M, Karatay S, Yildirim K, Kadi M, Erdem T, Senel K. The relationship between serum prolactin levels and disease activity in patients with Behçet’s disease. Cell Biochem Funct 2006;24:353–56. 119. Proenca H, Ferreira M, Miranda A, Castanheira-Dinis A, Monteiro-Grillo M. Serum prolactin levels and Behcet disease. Eur J Ophthalmol 2007;17:404–7. 120. Buskila D, Fefer P, Harman-Boehm I, et al. Assessment of nonarticular tenderness and prevalence of fibromyalgia in hyperprolactinemic women. J Rheumatol 1993;20:2112–15. 121. Adler GK, Kinsley BT, Hurwitz S, Mossey CJ, Goldenberg DL. Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome. Am J Med 1999;106:534–43. 122. Chavez-Rueda K, Legorreta-Haquet MV, Cervera-Castillo H, et al. Proalctine effect on CD69 and CD154 expression by CD4 cells from systemic lupus erythematosus patients. Clin Exp Rheumatol 2005;23:769–77. 123. Takizawa K, Kitani S, Takeuchi F, Yamamoto K. Enhanced expression of CD69 and CD25 antigen on human peripheral blood mononuclear cells by prolactin. Endocr J 2005;52:635–41. 124. Allen SH, Sharp GC, Wang G, et al. Prolactin levels and antinuclear antibody profiles in women tested for connective tissue disease. Lupus 1996;5:30–37. 125. Lavalle C, Loto E, Paniagua R, et al. Correlation study between prolactin and androgens in male patients with systemic lupus erythematosus. J Rheumatol 1987;14:268–72. 126. Jara-Quezada L, Grae A, Lavalle C. Prolactin and gonadal hormones during pregnancy in systemic lupus erythematosus. J Rheumatol 1991;18:349–53. 127. Jara LJ, Gomez-Sanchez C, Silveira LH, Martinez-Oxuna P, Vasey FB, Espinoza LR. Hyperprolactinemia in systemic lupus erythematosus: association with disease activity. Am J Med Sci 1992;303:222–26. 128. Pauzner R, Urowitz MB, Gladman DD, Gough JM. Prolactin in systemic lupus eythematosus. J Rheumatol 1994;21:2064–67.

129. Neidhart M. Elevated serum prolactin or elevated prolactin/ cortisol ratio are associated with autoimmune processes in systemic lupus erythematosus and other connective tissue diseases. J Rheumatol 1996;23:476–81. 130. Buskila D, Lorber M, Neumann L, Flusser D, Shoenfeld Y. No correlation between prolactin levels and clinical activity in patients with systemic lupus erythematosus. J Rheumatol 1996;23:629–32. 131. Huang C-M, Chou C-T. Hyperprolactinemia in systemic lupus erythematosus. Chin Med J (Taipei) 1997;59:37–41. 132. Rovensky J, Jurankova E, Rauova L, et al. Relationship between endocrine, immune, clinical variables in patients with systemic lupus erythematosus. J Rheumatol 1997;24:2330–34. 133. Jimena P, Aguirre MA, Lopez-Curbelo A, de Andres M, Garcia-Courtay C, Cuadrado MJ. Prolactin levels in patients with systemic lupus erythematosus: a case controlled study. Lupus 1998;7:383–86. 134. Pacilio M, Migliaresi S, Meli R, Ambrosone L, Bigliardo B, Di Carlo R. Elevated bioactive prolactin levels in systemic lupus erythematosus–association with disease activity. J Rheumatol 2001;28:2166–221. 135. Jacobi AM, Rohde W, Ventz M, Riemekasten G, Burmester GR, Hiepe F. Enhanced serum prolactin (PRL) in patients with systemic lupus erythematosus: PRL levels are related to the disease activity. Lupus 2001;10:554–61. 136. Vera-Lastra O, Mendez C, Jara LJ, et al. Correlation of prolactin serum concentrations with clinical activity and remission in patients with systemic lupus erythematosus. Effect of conventional treatment. J Rheumatol 2003;30:2140–46. 137. Rastin M, Hatef MR, Tabasi N, Sheikh A, Abbasi JM, Mahmoudi M. Sex hormones and peripheral white blood cell subsets in systemic lupus erythematosus patients. Iranian J Immunol 2007;4:110–15. 138. Ostendorf B, Fischer R, Santen R, et al. Hyperprolactinemia in systemic lupus erythematosus. Scand J Rheumatol 1996;25:97–102. 139. Munoz JA, Gil A, Lopez-Dupla JM, Vazquez JJ, GonzalezGancedo P. Sex hormones in chronic systemic lupus eythematosus. Correlation with clinical and biological parameters. Ann Med Interne 1994;145:459–63. 140. Leanos-Miranda A, Cardenas-Mondragon G. Serum free prolactin concentrations in patients with systemic lupus erythematosus are associated with lupus activity. Rheumatology 2005;45:97–101. 141. Rezaieyazdi Z, Hesamifard A. Correlation beween serum proalctin levels and lupus activity. Rheumatol Int 2006;26:1036–39. 142. Cardenas-Mondragon G, Ulloa-Aguirre A, Isordia-Salas I, Goffin V, Leanos-Miranda A. Elevated serum bioactive prolactin concentrations in patients with systemic lupus erythematosus are associated with disease activity as disclosed by homologous receptor bioasays. J Rheumatol 2007;34:1514–21. 143. Chavez-Rueda K, Legorreta-Haquet VM, Cervera-Castillo H, et al. Effect of prolactin on lymphocyte activation from systemic lupus erythematosus patients. Ann N Y Acad Sci 2007;1008:157–65. 144. Miranda JM, Prieto RE, Paniagua R, et al. Clinical significance of serum and urine prolactin levels in lupus glomerulonephritis. Lupus 1998;7:387–91.

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145. Garcia M, Colombani-Viadl ME, Zylbersztein CC, et al. Analysis of molecular heterogeneity of prolactin in human systemic lupus erythematosus. Lupus 2004;13:575–83. 146. Leslie H, Courtney CH, Bell PM, et al. Laboratory and clinincal experience in 55 patients with macroprolactinemia identified by a simple polylethylene glocol precipitation method. J Clin Endocrinol Metab 2001;86:2743–46. 147. Sugiura K, Muro Y, Watanabe A, Tomita Y. A case of systemic lupus erythematosus: continued association of circulating prolactin levels with disease activity over a 4-year follow-up period. Mod Rheumatol 2005;15:230–32. 148. Funauchi M, Ikoma S, Enomoto H, et al. Prolactin modulates the disease activity of systemic lupus erythematosus accompanied by prolactinoma. Clin Exp Rheumatol 1988;16:479–82. 149. Athreya BH, Rafferty JH, Sehgal GS, Lahita RH. Adenohypophyseal and sex hormones in pediatric rheumatic diseases. J Rheumatol 1993;20:725–30. 150. El-Garf A, Salah S, Shaarawy M, Zaki S, Anwer S. Prolactin hormone in juvenile systemic lupus erythematosus: a possible relationship to disease activity and CNS manifestations. J Rheumatol 1996;23:374–77. 151. Reuman PD. First reported pediatric case of systemic lupus erythematosus associated with prolactinoma. Arthritis Rheum 2004;50:3616–18. 152. Jara LJ, Pacheco-Reyes H, Medina G, Angeles U, Cruz-Cruz P, Saavedra MA. Prolactin levels are associated with lupus activity, lupus anticoagulant, poor outcome in pregnancy. Ann N Y Acad Sci 2007;1108:218–26. 153. Leanos-Miranda A, Cardenas-Mondragon G, Ulloa-Aguirre A, Isordia-Salas I, Parra A, Ramirez-Peredo J. Anti-prolactin autoantibodies in pregnant women with systemic lupus erythematosus: maternal and fetal outcome. Lupus 2007;16:342–49. 154. McMurray RW, Allen SH, Braun A, Rodriguez F, Walker SE. Longstanding hyperprolactinemia associated with systemic lupus erythematosus: possible hormonal stimulation of an autoimmune disease. J Rheumatol 1994;21:843–50. 155. Dostal C, Moszkorzova L, Musilova L, Lacinova Z, Marek J, Zvarova J. Serum prolactin stress values in patients with systemic lupus erythematosus. Clin Rheumatol 2002;25:602–5, Letter. 156. Compan-Gonzalez DA, Martinez-Aguilar NE, VargasCamano ME, et al. Hyperprolactinemia and autoimmunity. Rev Alerg Mex 1996;43:128–42. 157. Radis CD, Callis KP. Systemic lupus erythematosus with membranous glomerulonephritis and transverse myelitis associated with anabolic steroid use. Arthritis Rheum 1997;40:1899–902. 158. Jara LJ, Acala M, Vera-Lastra W, et al. Hyperprolactinemia secondary to microadenoma and systemic lupus erythematosus: an analysis of 36 cases. Arthritis Rheum 2003:S586, Abstract. 159. Li M, Keiser HD, Peeva E. Prolactinoma and systemic lupus erythematosus: do serum prolactin levels matter?. Clin Rheumatol 2006;25:602–5. 160. Ferreira C, Paes M, Gouveia A, Ferreira E, Papua F, Fiuza T. Plasma homovanillic acid and prolactin in systemic lupus erythematosus. Lupus 1998;7:392–97. 161. Koller MD, Templ E, Riedl M, et al. Pituitary function in patients with newly diagnosed untreated systemic lupus erythematosus. Ann Rheum Dis 2004;63:1677–80.

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162. Gutierrez MA, Molina JF, Jara LJ, et al. Prolactin and systemic lupus erythematosus: prolactin secretion by SLE lymphocytes and proliferative (autocrine) activity. Lupus 1995;4:348–52. 163. Mendez I, Alcocer-Varela J, Parra A, et al. Neuroendocrine dopaminergic regulation of prolactin release in systemic lupus erythematosus: a possible role of lymphocyte-derived prolactin. Lupus 2004;13:45–53. 164. Leanos-Miranda A, Pascoe-Lira D, Chavez-Rueda KA, Blanco-Favela F. Antiprolactin autoantibodies in systemic lupus erythematosus: frequency and correlation with prolactinemia and disease activity. J Rheumatol 2001;28:1546–53. 165. Leanos A, Pascoe D, Fraga A, Blanco-Favela F. Anti-PRL autoantibodies in systemic lupus erythematosus patients with associated hyperprolactinemia. Arthritis Rheum 1998;7:398–403. 166. Theunissen C, De Schepper J, Schiettecatte J, Verdood P, Hooghe-Peeters EL, Velkeniers B. Macroprolactinemia: clinical significance and characterization of the condition. Acta Clin Belgica 2005;60:190–97. 167. Leanos-Miranda A, Pascoe-Lira D, Chavez-Rueda KA, Blanco-Favela F. Persistence of macroprolactinemia due to antiprolactin autoantibody before, during, after pregnancy in a woman with systemic lupus erythematosus. J Clin Endocrinol Metab 2001;86:2619–24. 168. Caturegli P, Newschaffer C, Olivi A, Pomper MD, Burger PC, Rose NR. Autoimmune hypophysitis. Endocrine Rev 2005;26:599–614. 169. De Bellis A, Bizzarro A, Pivonello R, Lombardi G, Bellastella A. Prolactin and autoimmunity. Pituitary 2005;8:25–30. 170. Katano H, Umemura A, Kamiya K, Kanai H, Yamada K. Visual disturbance by lymphocytic hypophysitis in a nonpregnant woman with systemic lupus erythematosus. Lupus 1998;7:554–56. 171. Ji JD, Lee SY, Choi SJ, Lee YH, Song GG. Lymphocytic hypophysitis in a patient with systemic lupus erythematosus. Clin Exp Rheum 2000;18:117–80. 172. Walker SE. Effectiveness of bromocriptine in the treatment of autoimmune diseases. In: L Matera, R Rapaport, eds. Growth and Lactogenic Hormones. Neuroimmune Biologyvol. 2. New York: Elsevier; 2002:287–96. 173. Parkes D. Bromocriptine. N Engl J Med 1979;301:873–78. 174. Vance ML, Evans WS, Thorner MO. Bromocriptine, Diagnosis and treatment: drugs five years later. Ann Intern Med 1984;100:78–91. 175. McMurray RW. Bromocriptine in rheumatic and autoimmune diseases. Semin Arthritis Rheum 2001;31:21–32. 176. Hiestand PC, Mekler P, Nordmann R, Grieder A, Permmongkol C. Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporine. Proc Natl Acad Sci U S A 1986;83:2599–603. 177. Nagy E, Berczi I, Wren GE, Asa SL, Kovacs K. Immunomodulation by bromocriptine. Immunopharmacology 1983;6:231–43. 178. Bernton EW, Metzler MS, Holaday JW. Suppression of macrophage activation and T-lymphocyte function in hypoproalactinemic mice. Science 1988;239:401–4. 179. Morikawa K, Oseko F, Morikawa S. Immunosuppressive activity of bromocriptine on human T lymphocyte function in vitro. Clin. Exp. Immunol. 194; 95; 514–518.

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s e c t i o n 9     Immunology l

180. Morikawa K, Oseko F, Morikawa S. Immunosuppressive property of bromocriptine on human B lymphocyte function in vitro. Clin Exp Immunol 1993;93:200–5. 181. Palestine AG, Muellenbert-Coulombre CG, Kim MK, Gelato MD, Nussenblatt RB. Bromocriptine and low dose cyclosporine in the treatment of experimental autoimmune uveitis in the rat. J Clin Invest 1987;79:1078–81. 182. Neidhart M. Synergism between long-acting bromocryptine microcapsules and cyclosporine A in the prevention of various autoimmune diseases in rats. Experientia 1996;52:892–99. 183. Riskind PN, Massacesi L, Doolittle TH, Hauser SL. The role of prolactin in autoimmune demyelination: suppression of experimental allergic encephalomyelitis by bromocriptine. Ann Neurol 1991;29:542–47. 184. Berczi B, Nagy E, Asa SL, Kovacs K. The influence of pituitary hormones on adjuvant arthritis. Arthritis Rheum 1984;27:682–88. 185. Neidhart M. Bromocriptine microcapsules inhibit ornithine decarboxylase activity induced by Freund’s complete adjuvant in lymphoid tissues of male rats. Endocrinology 1989;125:2846–52. 186. Dijkstra CD, Roupe van der Voort E, De Groot CJA, Uitdehaad BMJ, Polman CJ, Berkenbosch F. The therapeutic effect of bromocriptine on acute and chronic experimental allergic encephalomyelitis. Ann Neurol 1992;31:450–51. 187. Dijkstra CD, Rouppe van der Voort E, De Groot CJA et al. Therapeutic effect of the D2-dopamine agonist bromocriptine on acute and relapsing experimental allergic encephalomyelitis. Psychoneuroendocrinology 1994;19:135–42. 188. Mahon JL, Gunn HC, Stobie K et al. The effect of bromocriptine and cyclosporine on spontaneous diabetes in BB rats. Transplant Proc 1988;20(Suppl.):197–200. 189. Hawkins TA, Gala RR, Dunbar JC. Prolactin modulates the incidence of diabetes in male and female NOD mice. Autoimmunity 1994;18:155–62. 190. Durant S, Alves V, Couland J et al. Attempts to pharmacologically modulate prolactin levels and type 1 autoimmune diabetes in the non-obese diabetic (NOD) mouse. J Autoimmun 1985;8:875–85. 191. Blank M, Krause I, Buskila D et al. Bromocriptine immunomodulation of experimental SLE and primary anti-phospholipid syndrome via induction of nonspecific T suppressor cells. Cell Immunol 1995;162:114–22. 192. Hedner LP, Bynke G. Endogenous iridocyclitis relieved during treatment with bromocriptine. Am J Ophthalmol 1985;100:618–19. 193. Palestine AG, Nussenblatt RB, Gelato M. Therapy for human autoimmune uveitis with low-dose cyclosporine plus bromocriptine. Transpl Proc 1988;20:131–35. 194. Schaaf L, Zierhut M, Baur EM et al. Bromocriptine in patients with chronic autoimmune-associated disorders. Klin Wochenschr 1991;69:943. 195. Bissay V, De Klipel N, Herroelen L et al. Bromocriptine therapy in multiple sclerosis: an open label pilot study. Clin Neuropharmacol 1994;17:473–76.

196. Pijl H, Ohashi S, Matsuda M et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care 2000;23:1154–61. 197. Wasada T, Kawahara R, Iwamoto Y. Lack of evidence for bromocriptine effect on glucose tolerance, insulin resistance, body fat stores in obese type 2 diabetic patients. Diabetes Care 2000;23:1040. 198. Atkinson PR, Mahon JL, Dupre J et al. Interaction of bromocriptine and cyclosporine in insulin dependent diabetes mellitus: results from the Canadian open study. J Autoimmun 1990;3:793–97. 199. Bravo G, Zazueta B, Lavalle C. An acute remission of Reiter’s syndrome in male patients treated with bromocriptine. J Rheumatol 1992;19:747–50. 200. Rabinovich CE, Schanberg LE, Kredich DW. Intravenous immunoglobulin and bromocriptine in the treatment of refractory neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 1990;33:R22, Abstract. 201. McMurray RW, Weidensaul D, Allen SH, Walker SE. Efficacy of bromocriptine in an open label therapeutic trial for systemic lupus erythematosus. J Rheumatol 1995;22:2084–91. 202. Walker SE, Smarr KL, Parker JC, Weidensaul DN, Nelson W, McMurray RW. Psychological state and disease activity in patients with SLE treated with bromocriptine. Lupus 2000;9:527–33. 203. Alvarez-Nemeguei J, Cobarrubias-Cobbs A, Escalante-Triay F, Sosa-Munoz J, Miranda JM, Jara LJ. Bromocriptine in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled study. Lupus 1998;7:414–19. 204. Walker SE, Reddy GH, Miller D et al. Treatment of active systemic lupus erythematosus (SLE) with the prolactin (PRL) lowering drug, bromocriptine (BC): comparison with hydroxychloroquine (HC) in a randomized, blinded one-year study. Arthritis Rheum 1999;42:S282, Abstract. 205. Hrycek A, Cieslik P, Tustanowski J, Nowak S, Jedynak P. Selected serum cytokines in systemic lupus erythematosus treated with quinagolide. Lupus 2001;10(6):424–30. 206. Hrycek A, Pochopien-Kenig G, Scieszka J. Selected acute phase proteins and interleukin-6 in systemic lupus erythematosus patients treated with low doses of quinagolide. Autoimmunity 2007;40:217–22. 207. Molitch M. Medical management of prolacin-secreting pituitary adenomas. Pituitary 2002;5:55–65. 208. Yang XY, Liang LQ, Xu HS et al. Efficacy of oral bromocriptine in protecting the postpartum systemic lupus erythematosus patients from disease relapse. Zhonghua Nei Ke Za Zhi 2003;42:621–24. 209. Dargaud Y, Pariset C, Pinede L et al. Multiple arterial thromboses in a patient with primary antiphospholipid syndrome receiving a bromocriptine therapy. Lupus 2004;13: 957–60. 210. Jara LJ, Cruz-Cruz P, Saavedra MA et al. Bromocriptine during pregnancy in systemic lupus erythematosus: a pilot clinical trial. Ann N Y Acad Sci 2007;1110:297–304.

Chapter

52

Sex Hormones and Immune Function Robert G. Lahita Chairman of the Department of Medicine, Newark Beth Israel Medical Center, Newark, NJ; Professor of Medicine, New Jersey Medical School, Newark, NJ, USA

cytokine production1 and consequently disease susceptibility and outcome. Differences are noted with both humoral and cellular immunity. Female subjects had a 30% lower innate immune response, independent of the HLA region TNF locus. TNF was measured after LPS-stimulated whole blood culture.2 In relation to humoral immunity, many studies have shown sex differences with regard to vaccines. Clinical efficacy varies with the sex of the individual.3 The reasons for the sex differences in antibody response are uncertain. Women develop antibodies faster, reject transplants faster, and live longer than men. Females have a relative increase in CD4 T cells compared to males.4 Females have a greater Th2 response than males.5 Clear evidence of an effect of sex hormones on the Th1/Th2 balance is found in pregnancy6 and with the use of exogenous hormones.7,8 Peripheral blood lymphocytes studied at different times in the menstrual cycle show that they downregulate Th1 profile of the immune response during the luteal phase. Thus interferon-related genes are amongst the downregulated genes.9 In Fisher 344 rats macrophages from females produce larger amounts of PG-E2 and thromboxane B2.10 Prostaglandin synthesis is also increased in female peritoneal macrophages. This was observed in cells stimulated with LPS. Moreover, this was seen best in cells taken during the luteal and not the follicular phase of the menstrual cycles.11 The cellular response is also dimorphic. Removal of androgen in mice produces an increase in size and cellularity of primary and peripheral lymphoid organs and enhances immune responses.12 Thymus atrophy occurs in the presence of testosterone and this atrophy represents apoptosis in response to sex hormones.13–15 With the castration of young male animals there is expansion of bone marrow derived B cells. Cell-mediated

Introduction The entire area of steroid biochemistry and metabolism remains one of the most controversial in both endocrinology and immunology. The convergence of these two disciplines can be difficult because there is little known about the effects that phenomena in one specialized area have on the other. In this chapter the metabolic changes found in a variety of autoimmune diseases are described. The full importance of these changes, where they occur, and their effects on the immune system are not fully known. Various changes of cytokines in response to shifting levels of sex steroids are known to occur, but at the level of a particular organ like the ovary or the liver such responses may only be apparent over long periods of time. Such changes at the ‘local’ level have effects on the host, but the complexity of these effects and careful study of the initial stimulus is the material of future research and presently only speculation.

An overview of sex hormones and the immune system The immune system is sexually dimorphic. The differences between female and male immune responses under normal as well as pathological conditions are attributed to estrogens, androgens, and progestogens. Androgens are suppressive to the immune system while estrogens are stimulatory. Estrogens are also important since females have higher levels of Ia antigen, greater antibody response to antigen, and a higher incidence of autoimmune diseases. This sexual dimorphism is common to many species, from worms to mammals. In general, gender hormones modify

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immunity Th1 and humoral or Th2 immunity is certainly driven by sex hormones. Pregnant women are naturally of a Th2 profile and are vulnerable to infections that normally require cell-mediated immune attack.16 The protection afforded the fetus (from Th1 effects) may be the result of progesterone.17,18 In a collaborative review,19 women are more likely than men to develop a Th2 profile when challenged with infection. Autoimmune diseases like SLE and Sjögren syndrome are more Th2 in character. IL4 can be produced in large amount from cultured blood mononuclear cells.20 Huber showed that testosterone promoted interferon- production from CD4 cells (Th1) whereas estrogen promoted Il-4 (Th2).21 Exogenous exposure of cells to sex steroids also has effects. Diethylstilbestrol (DES) exposure gives credence to the overall importance of prenatal hormone exposure and its effects. From testicular cancer in young men to cervical and vaginal cancers, the risk is increased dramatically.22,23 Breast cancer risk is also increased in these previously exposed women.

Androgens Male sex steroids are very important to the immune system. Androgens have many effects on immune function and the effects are observed in both humans and animals. The most important effect is that of immunosuppression because of in vitro observations of their effects on normal lymphocytes from humans and because of their effects on the disease manifestations of inbred autoimmune mice with the disease SLE.24 Graft rejection in rodents is delayed by the injection of testosterone. Resistance to certain viral infections can be reduced while in some cases it is enhanced when androgens are given at certain doses.25,26 A consistent effect of androgens is the immunosuppression of chickens through the retardation of the function and development of the bursa of fabricius.27–30 Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from humans with SLE31 and also inhibits pokeweed mitogen stimulation of B cell differentiation. This occurs through the downregulation of IL-6 and the inhibition of B cell activity. Androgens also have an effect on the pluripotential stem cells of the bone marrow: namely the accelerated proliferation and differentiation of such stem cells into compartments of cells that include lymphoid elements. The important effects of androgens on immune maturation are reflected by the discovery of receptors for estrogen and dihydrotestosterone, a 5-reduced metabolite of testosterone in the thymus,32–34 and these receptors are on thymocytes.30 Androgen receptors are also found on lymphocytes, specifically CD8 cells, but the data are inconsistent.35,36 Androgens inhibit B and T cell maturation, reduce B cell synthesis of immunoglobulins, and suppress the phytohemagglutinin-induced blast transformation of lymphocytes.37,38 The androgens are also

modifiers of the regulatory genes that influence the function of structural genes.39 For example, guinea pig mammary epithelial Ia antigens are increased in number through the effects of estrogens and prolactin and are decreased by testosterone.40 The wide range of effects that this steroid has on immune function might be due to variable androgen sensitivity of certain cell groups and the in vivo conversion of androgens to estrogens through well-recognized pathways.

Estrogens The estrogens are very important because unlike the androgens they have a decided effect on upregulating immune function. Female mice make more antibodies to foreign antigens than do males and this difference is reported for a variety of antigens.41 Estrogens, depending on dose and condition, are both immunosuppressors and immunostimulants. The steroid 17-estradiol prolongs first and second set skin grafts in mice after X-irradiation and inhibits corneal graft acceptance in preimmunized rabbits.42 In general, however, skin allograft rejection is naturally better in females than in males.43 Estrogens regulate immunity by way of the thymus in rodents44 and decrease the overall thymic population of small lymphocytes. Estrogen given prior to bone marrow transplantation causes an increase of graft failure. Estradiol and diethylstilbestrol (in concentrations of 10–50 mg/ml) are known to reduce the phytohemagglutinin and concanavalin-A response of lymphocytes in vitro.45 The mixed lymphocyte reaction is also enhanced by estradiol. Enhanced lymphocyte activity is observed at 200 ng/ml, whereas the effects are diminished with doses as high as 2000 ng/ml (thymidine incorporation). Estrogens also deplete thymus hormones and are known to produce a relative lymphopenia when given in excessive amount. Perhaps in vivo this is illustrated by the fluctuant lymphocyte responses observed during normal menses,26 pregnancy, and during the use of oral contraceptives.46 Estrogens have an effect on thymus cell activity,13,30,47,48 because castrated male and certain female mice display hyperplastic spleens and thymuses after challenge with thymic-dependent antigens, indicating an effect of the estrogens on programmed cell death and the persistence and expansion of lymphocyte subpopulations. Moreover, castration of males leads to accelerated allograft rejection. Although syngeneic grafts of ovaries in males and grafts of testes in females have no significant effect on allograft rejection.49 Sustained levels of estrogens in mice lead to a marked reduction in natural killer cell activity. In summary, estrogens have been found to have many effects on immune function. Estrogens are detrimental to all animals with an autoimmune disease like SLE, as observed in both mice and dogs. Tamoxifen, an estrogen receptor antagonist, and antiestradiol antibody have beneficial effects on experimental SLE. There is also an estrogen benefit from cytokine regulation.50 Men with prostatic cancer who are given diethylstilbestrol

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have markedly depressed cell-mediated immunity. Using normal lymphocytes, estradiol treatment of pokeweedmitogen-treated B cells shows an increase in plaque-forming cells (in vitro).48,51,52 Estrogen receptors are found on CD8 and CD4 T lymphocytes in some studies from mice and men.35,53,54 In that regard, there are studies to show that CD4 T-helper cells increase after estrogen therapy55 while other studies show estrogens as an inhibitor of CD8 suppressor T cells. An increase of T-helper cells could result in an increase of polyclonal B cell immunoglobulin production. Apoptosis is inhibited in vitro using peripheral blood mononuclear cells from women with normal menses and there is some evidence that conditions like endometriosis are really estrogen mediated failures of apoptosis. Estradiol decreases TNF in SLE cells but not those from normal people.56

Progestogens Sex steroids like progesterone, the hormone of pregnancy, have been considered as therapeutic agents in diseases like SLE. Progesterone is an immunosuppressive hormone,6,48,57 and levels of this hormone rise during pregnancy when the placenta assumes an active role in its synthesis and secretion. A large concentration of 10–15 mg/ml of progesterone inhibits lymphocyte responses to phytohemagglutinin and to concanavalin A in vitro. Analogs like 20-hydroxyprogesterone have similar effects.58 Progesterone has been known to increase the relative amounts of CD8 suppressor cells in humans and to decrease them in mice. In addition, progesterone has been considered as one cause of the many suppressive effects found in pregnant females. Suppression of the clinical manifestations of MS and RA might be related to levels of this steroid.

Normal estrogen and androgen metabolism Estrogens The metabolism of the sex hormone is an important aspect of normal physiology. Estradiol is quickly converted to estrone that can be metabolized in one of two ways. Estrone can be hydroxylated in one direction to 16–alpha hydroxyestrone or estriol; more feminizing estrogens than the catechol estrogens. Alternatively, the estrone can be directed towards one of the catechol (less feminizing) estrogens 2–hydroxy or 2– methoxy estrone (Figure 52.1). The change appears to have some importance to the normal physiology of the individual and the levels of the final products depends on the substrate amounts of estradiol. In the female, the metabolism has profound effects on the immune system whereas in the male the lesser amounts of estradiol and its effects are unknown. Elevation of the 16–hydroxylated estrogens in the male results in feminizing effects like gynecomastia or decreased

Metabolism of Estradiol O

HO

OH

HO

Estradiol (E2)

HO

O

OH

OH

OH

HO Estriol (E3)

16αHydroxy estrone (16αOHE1)

Estrone (E1)

O

O CH3O

HO HO

OH 2-Hydroxy estrone (2 OHE1)

2-Methoxy estrone (2 MeOE1)

Figure 52.1  The metabolism of estradiol is reversible towards estrone. Estrone can be metabolized in the direction of either the very feminizing 16–alpha hydroxyestrone or towards the catechol estrogens like 2–methoxy estrone. In the disease systemic lupus erythematosus the metabolism of estrogen is directed primarily toward the 16 metabolites.

libido. Estrone hydroxylation toward the catechol estrogens in the female has predictable effects related to less feminizing hormones, such as oligomenorrhea or osteoporosis. Many environmental factors affect the direction of estrone metabolism. These include smoking, diet, and normal physiologic changes such as pregnancy. Smoking cigarettes and dietary changes increase the metabolism of estrone toward the 2–hydroxylated less feminizing compounds, whereas pregnancy shifts the hydroxylation of estrone toward the very feminizing compounds (Figure 52.2). One estrogen, 16-hydroxyestrone, is feminizing, highly uterotropic, and modestly bound to cytosol receptors and testosterone-estradiol-binding globulin (TEBG)59 (Table 52.1). Radioimmunoassay failed to show uniformly elevated levels of 16-hydroxyestrone in all active SLE patients.60 This suggests that a conjugated form of this steroid is active or that there are other estrogen metabolites of importance to SLE that are not apparent. Enzymatic systems in mice favor the formation of such compounds, although nothing is known about lupus mice with regard to the metabolism of estrone. Clinical studies on the steroid 16-hydroxyestrone showed that it had interesting properties in vivo that might explain its possible role in disease; these include covalent binding of this steroid to erythrocytes and lymphocytes via a Heyn’s rearrangement in vivo and the possibility that such covalent binding might occur at the level of the estrogen receptor or the T cell receptor and result in alteration of immune function.61,62 Studies of family members of SLE patients indicated that elevated hydroxylation of estradiol was commonly observed in nonaffected first-degree relatives as well as patients.63

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The estrogen estriol is certainly not as potent an estrogen as estradiol, the most feminizing of estrogens. Indeed estriol acts as a weak estrogen when injected into animals and when injected with estradiol acts as an antiestrogen. Some evidence actually suggests that estriol acts as a protection from the very feminizing effects of estradiol.64 Normal women ingesting oral contraceptives have enhanced binding of l6-hydroxyestrone to various cell proteins. Specific antiestrogen-protein adduct immunoglobulins are isolated from normal and SLE patients ingesting oral contraceptives which means that these adducts are common. This finding suggested a common pathway to adduct formation in all women who ingest large amounts of estradiol or for one reason or another have an endogenous source of high estrogen levels.65 Males with SLE were also reported who had hormone protein adduct-specific IgG in their sera. Estrogen metabolism and disease Estradiol

Estrone Increased by Pregnancy

Increased by Thyroid hormone Vegeterian diet Athletic activitty Cigerettes Naloxone 2 OH metabolites

16-alpha metabolites Associated with Systemic lupus erythematosus Breast cancer Liver disease

Associated with Osteoporosis

Figure 52.2  The overall metabolism of estrogen. In diseases like lupus or liver disease, the hydroxylation of estrone is directed toward the 16 metabolites. There are many factors that increase the hydroxylation toward the 2–hydroxyl metabolites, which are less feminizing.

Table 52.1  The different biologic activities of both the feminizing estrogens and the non-feminizing estrogens 2-hydroxy Ulterotropic activity TEBG binding Receptor binding LH secretion Prolactin secretion

Catechols Negative Positive Positive Upregulated Downregulated

Patients with rheumatoid arthritis also metabolize estrogen in synovial fluid66 and some inhibitors of TNF raise levels of plasma estrogens for unknown reasons.67

Androgens Androgens are of particular importance to the autoimmune diseases. The one illness which has been extensively studied is systemic lupus erythematosus (SLE).68 Early reasons proposed for SLE in the male included low levels of androgen and high levels of estrogen69,70 (Figure 52.3). However, most studies indicate that young men with SLE are hormonally normal and that estrogen : androgen ratios are minimally elevated, if at all. Furthermore, data from the studies of men with SLE do not help to explain the large numbers of women who predominate with the disease. Androgen studies in women with SLE have been of particular interest. Androgen metabolism in SLE females reveals a difference in the overall metabolism of androgens when compared to men with SLE. The oxidation of testosterone at C17 in SLE females is increased. Males with SLE have both normal oxidation of testosterone and normal plasma androgen levels71 (Figures 52.4 and 52.5). Several studies of women with active SLE revealed that they had decreased plasma levels of androgen54,72,73 (Figure 52.6). This observation is found in Klinefelter patients (XXY) as well as women with lupus. These study subjects all had normal thyroid function, an absence of renal and liver disease, and were not taking corticosteroids. Low plasma androgens in women with SLE and early animal work prompted the hypothesis that androgen replacement therapy in this disease would work. Clinical studies involving the use of DHEA as a therapy for lupus were a result of this observation but are to date unproductive. Testosterone is oxidized to androstenedione, converted to dehyroepiandrosterone, and then sulfated.74 Both testosterone and androstenedione can be metabolized to estrone and estradiol. After the male hormones are aromatized to estrogens they can then enter the pathways for estrone hydroxylation. Specific cytokine levels change in response to levels of certain sex steroids. By this mechanism it is

• Low male incidence

16-hydroxy Very feminizing Positive Negative Positive Downregulated Upregulated

TEBG, or testosterone binding globulin; LH, leuteotrophic hormone.

• Low androgens in females with SLE

After puberty (1:10 M:F)

Low plasma androgens (Jungers et al.73; Lahita et al.74) Increased oxidation of testosterone in females with SLE (Lahita et al.72)

Figure 52.3  Evidence of a role for androgen in the disease systemic lupus erythematosus in the human.

C h a p t e r 5 2     Sex Hormones and Immune Function

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l

thought that certain sex steroid levels affect the T cell populations and determine anti-inflammatory versus proinflammatory cytokine profiles.75 Sex steroids affect the severity of SLE31,47,76 but do not explain the high female prevalence. As we can see from other conditions and emerging data, the effects of sex steroids on conditions like fibromyalgia or Hashimoto’s thyroiditis are also important. However, a direct relationship of both androgen and estrogen metabolites on the severity of the disease,

OH

O

H a b O

O

Androstenedione

Testosterone

O

OH

HO

the production of antibodies, or the appearance of certain clinical signs in SLE has not been established. Rheumatoid arthritis is also associated with hormone changes.77,78 In many cases of rheumatoid arthritis low androgen levels have been described. In many cases of rheumatoid arthritis the signs and symptoms of disease coincide with the menstrual cycle, an observation that has also been made anecdotally in lupus patients.79 Several observations about rheumatoid arthritis are startling and unexplained. These include the remission of RA in the pregnant female and also the response of many patients and animal models to exogenous estrogen.80–82 Exacerbations of rheumatoid arthritis occur during certain times in the menstrual cycle and this is one of the few diseases where this observation is made. There are data from Sjögren syndrome to show that the levels of androgens in the tears of patients with the disease are low.83 The significance of this finding is not known. The antiphospholipid syndrome, an autoimmune disease that produces a procoagulant condition in most patients, has no apparent predilection for sex. The disease affects more women than men in its secondary form; however the primary condition does not favor either sex.

Clinical Aspects

HO Estradiol

Estrone

Figure 52.4  The interrelationship between androgen and estrogen metabolism. Estrone is further metabolized towards the 16–or 2–hydroxyl pathways. Testosterone is oxidized to androstenedione, which then has an option to become dehyroepiandrosterone.

Males with SLE The age of onset of the disease is more evenly distributed in males, since one-fourth are diagnosed after age 50 years.84 The hormonal metabolic studies data suggest 1000

Males O = On steroids

800

** p = 0.06 * p = < 0.001 *

70

60

500

50

500

400

40

400

300

30

300

20

200

100

10

100

0

0

200

60

50

Testosterone

80

600

N = 6 23 19 44 Normal

Normal SLE males males

Normal SLE females females

Figure 52.5  The oxidation of testosterone at C-17 is increased in females with systemic lupus erythematosus (SLE), but not in males.

µg/dL (DS)

700

90

40

=T = ∆4 = DHEA = DS

900

(∆4, DHEA) ng/dL

Testosterone extent (%) oxidation

100

Females

** *

*

*

12 11 13 13

22 24 24 20

Inactive SLE

Active SLE

Figure 52.6  The overall levels of plasma testosterone in women with systemic lupus erythematosus (SLE) decreases with clinical activity. These patients are not taking prednisone at the time of measurement.

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that an increase in feminizing 16–hydroxylated estrogenic metabolites is found in SLE males, although no phenotypic evidence of hyperestrogenism is found.63,85–88 The BXSB mouse develops SLE-like disease in non-hormone-dependent fashion. The presence of the Y chromosome is most important in this strain. A group of human male relatives has been described who resemble the mouse strain BXSB in that ‘male-predominant’ families exist in which SLE occurs in males in preference to females.89 In one interesting study of males with lupus, females that have a male relative with lupus were more likely to have renal disease.90 Men with SLE are in some series reported to be clinically different.31,76,91 While several male studies show no clinical difference in severity of disease between women and men, others have suggested that men have a more severe form of the disease.92 For example, increased pleuropericardial disease and peripheral neuropathy are said to be more common in males. Men were found to have more discoid lupus erythematosus and papular nodular mucinosis.93 In a Spanish series of 261 SLE patients 11.5% were males, and they had less arthritis, more serositis, and a greater propensity for discoid rashes. A recent database on males from Malta also found more cardiorespiratory problems in men94 and a Taiwan study suggested that men have a significantly lower Fc R distribution on monocytes and neutrophils and high prolactin levels that might have a role in the pathogenesis of lupus in this sex.95 All of these data are collected from small numbers of men and such things as statistical bias might be significant. Sex hormone profiles indicate that men with lupus have significantly higher levels of gonadotropins (FSH, LH) than controls. A small percentage of patients (14%) in one study had low testosterone and elevated LH levels.96 The patients with the low androgens had more central nervous system disease and serositis when compared to controls. Finally, the prolactin to testosterone levels correlated with the SLEDAI scores in these men. Studies of Russian male lupus patients are perhaps the most insightful.97,98 The investigators describe elevated leutinizing hormone and follicle-stimulating hormone in SLE males; a lower trochanteric index (1.89 vs. 2.00 for normal men), which is indicative of a lack of androgen effect on bone growth; severe aortic insufficiency and sacroileitis (12% of all men); and overall a greater incidence of severe vascular diseases like Reynaud’s phenomenon and digital vasculitis. The Russian investigators found more severe disease in men, with 63% dying from end-stage renal disease. The only significant increases in Russian men with SLE are the incidences of nephritis, Reynaud’s phenomenon, and malar rash. Finally, the Russian study also includes male SLE patients with profound impotence. The causes of such impotence in young SLE males remain unknown. Elderly men who present with SLE are also found to have low androgen levels and are hypogonadal.99 Such males might respond to androgen therapy.

Hypogonadism Patients with Klinefelter syndrome can also have a variety of rheumatic diseases like SLE and scleroderma.100–103 Such males commonly have gynecomastia, infertility, a female fat phenotype, and the usual sequelae of hypogonadism. These Klinefelter males have met the ARA criteria for SLE both serologically and clinically. The incidence of SLE or any other autoimmune disease is not increased in patients with Klinefelter syndrome, even though this is frequently stated. Patients with SLE and Klinefelter syndrome together have the estrogen and androgen metabolism of females with SLE,104 but low levels of both sex steroid classes. This is the reason that the Klinefelter syndrome is a hypergonadotropin state. When SLE does occur in young Klinefelter males it can be treated with the synthetic androgens usually given to such males. Androgens such as methyl testosterone as tablet, androgen patch or gel can alleviate the symptoms of the disease in Klinefelter males but do not alter the amount or type of autoantibody. The man with Klinefelter syndrome and SLE oxidizes testosterone in exaggerated fashion, like women with SLE. This increased oxidation is not found in the SLE male with a normal XY karyotype. The hypergonadotropic state of men with Klinefelter syndrome and SLE has not been adequately investigated at this time and may have some role in the etiopathogenesis of the disease. Patients with hypogonadism have manifested all of the metabolic abnormalities found in patients who do not have hypergonadotropin syndromes. Patients with Klinefelter syndrome described with connective tissue diseases like rheumatoid arthritis, lupus, and other conditions have the same hydroxylation profiles as women with the disease. Most Klinefelter patients have an increase of estrone hydroxylation toward estriol and increased oxidation of testosterone at C17. In these patients there is neither elevated estrogen nor androgen and the gonadotropins are high. The principal clinical manifestations in these patients include cardiopulmonary disease. At least two of these patients were known to have multiple estrogen-dependent illnesses like porphyria, lupus, and chronic active liver disease.

Use of hormones to alter disease states Females: Clinical Oral Contraceptives and Postmenopausal Hormone Replacement in the Rheumatic Diseases Most of these studies will be discussed in Chapter 54. Data from the mouse and human have shown that unopposed estrogens exacerbate SLE. The data from human studies however are largely in vitro or derived from anecdotal studies of patients on oral contraceptives. Most studies involving oral contraceptives and SLE or hormone replacement therapy in postmenopausal women with SLE suggest that

C h a p t e r 5 2     Sex Hormones and Immune Function l

the disease worsens with these agents.105–107 However, these studies are inconclusive and difficult because of the variability of the human illness, the designate endpoints of therapy, the steroids chosen, and the lack of a double-blinded study. Recent data strongly suggest that use of hormone replacement therapy (HRT) predisposes women to the development of SLE.108 The results of the contraceptive/hormone replacement trial, a double-blinded control study to look at oral contraceptive use and HRT in women with lupus, is in progress and data should be available shortly. Current epidemiological studies do not support the idea that female hormones increase the risk of developing SLE.81,107 Sex steroids have been considered for use in inflammatory diseases like gout and osteoarthritis because estrogens suppress neutrophil function and that is the reason109,110 that gout is uncommon in premenopausal women.111 The overall gender-related mechanism for the selectivity of one sex for a disease over another continues to evade explanation and there is debate about this from some quarters.112 Estrogens may be effective in the treatment of rheumatoid arthritis, and several clinical studies have argued both for113–115 and against their use.116 The mechanism of suppression of inflammation in cases of rheumatoid arthritis may give some significant insight into the pathogenesis of this common disease and is based on two observations: first is that patients improve when pregnant, and second that oral contraceptives may have a protective effect. Menopause is an interesting time for most lupus patients. For many years patients who reached the menopause were known by most clinicians to improve. These conclusions were without data until recently, when menopause has been conclusively shown to be associated with remission of illness.117 Most authors conclude that a ‘modest’ decrease of activity occurs in those women reaching the menopause.118 Hyperestrogenism Hyperestrogenic conditions are associated with autoantibodies in both normal males and females. In the human female periods of hormonal change such as pregnancy and the normal menses are associated with changes in immune function. These changes are also observed in mice. Clinical syndromes such as insulin-resistant diabetes mellitus, hirsutism, and cystic ovaries are found in patients with autoantibodies.47,119 Polycystic ovary disease may be considered autoimmune and autoantibodies could result from the unopposed actions of plasma estrogen.120 More recently autoantibodies have been described in patients with endometriosis, and patients have been referred as those with a lupus-like illness.121–123 This may be of particular interest since the uterus and the ovaries of humans and animals are a source of cytokines.124

Androgens as a Treatment for Lupus Therapy of SLE with anabolic steroids like Danazol or cyproterone acetate is not effective therapy for either murine

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or human SLE.123,125–127 However, the use of hormones like Danazol in idiopathic thrombocytopenic purpura increases platelet numbers and coagulation factors like Factor VIII. This suggests a role for certain patients with SLE. Other androgens are under study, like 19–nortestosterone, have also had limited use in the treatment of SLE in women. Doses used were 100 mg/ml per week intramuscularly. While the overall condition of female patients improved, and patients admitted increased energy, loss of joint pains, and resolution of systemic abnormalities such as skin rashes or anemia, we noted no significant change of serologies. Anti-DNA and ANA titers remained elevated. Most curious in this treatment group was an overall worsening of lupus symptoms in male patients.128 These findings in men on 19–nortestosterone correlated with lowered endogenous testosterone levels and elevated estradiol levels. Another steroid, cyproterone acetate, a potent antigonadotrophic agent,128 resulted in resolution of some systemic abnormalities, such as oral ulcers, after 50 mg daily for a mean of 63 months. As with other androgens, no improvement in serologic features was observed. Another approach to the treatment of lupus involves the use of gonadotropic hormone-releasing hormone agonists. These agents are used effectively to treat endometriosis and prostate carcinoma. Data about their use in SLE are inconclusive because of small numbers studied.129–131 One androgen, studied extensively in women, is dehyroepiandrosterone (DHEA).132,133 This drug, at doses of 200 mg per day in tablet form, results in clinical improvement as measured by standard indices and it is steroid-sparing, that is to say that the total dose of prednisone might be lowered with its use.133 This drug suppresses cytokine levels such as IL-4, 5 and 6, and increases IL-2 during treatment. Natural killer cell activity also increases with this agent.134–136

Sex hormones, behavior, and autoimmune diseases Sex steroids are important to the development of various organs, and a major one is the brain. Recent attention is directed to cerebral development, cerebral dominance, and the incidence of autoimmune disease.137,138 Some studies say that patients with autoimmune disease are predominantly left-handed, indicating dominance of the right cerebral hemisphere. This variation is reported in patients with SLE138–142 and other diseases of the immune system. Neuronal migration is under the influence of steroids like testosterone, and new data suggest that SLE mice have aberrant neuronal migration patterns consistent with those observed in humans with learning disabilities like dyslexia. Handedness in patients with SLE is more directed to the left than in the normal population. The finding of increased

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learning disabilities like developmental dyslexia in patients with SLE, their unaffected male offspring, and unaffected male siblings has been confirmed by several groups and is a subject of considerable interest.

Fibromyalgia There are other related conditions that are found almost exclusively in women.143–146 Such symptoms do occur in men but with rarity. A link to sex hormone levels has not been established. Fibromyalgia is a chronic painful condition which is real. It is not associated with any abnormal serology or elevation in acute phase reactants. In fact is likely that fibromyalgia is an endocrine disorder regulated by sex steroids like estrogen and testosterone which each affect serotonin, but this is hypothesis. The ratio of men to women is not known but it could be that women predominate at a ratio of 50 to 1. The condition is one that involves specific points of pain that are elicited on physical exam and are associated with a lack of sleep. The condition is often confused with the associated connective tissue disorder and often patients are over-treated because of this confusion. For example, a patient who has normal serological tests and a diagnosis of systemic lupus erythematosus might have her trigger points mistaken for a flare of her disease. A physician who fails to follow the serological course of such a patient or fails to recognize the appropriate trigger points for fibromyalgia might increase the corticosteroid dose according to the patient’s clinical complaints of pain. This would result in a patient who is ingesting large amounts of corticosteroid, with all of the attendant side effects of that drug, who really needs an analgesic and a pharmacological aid to sleep. While the etiology of fibromyalgia is unknown, it is believed to include a disorder of stage 4 REM sleep.145 Once the patient is able to sleep, the symptoms and signs of fibromyalgia often abate. It is therefore important to give patients sleep testing in order to document the sleep disorder objectively. Once this is accomplished the patient can be treated with agents that induce sleep, such as tricyclic antidepressants, gamma hydroxybuteric acid or others, along with non-narcotic analgesics. The use of the analgesics in non-PRN form is very effective in the relief of pain. Aerobic exercise is also encouraged in order to gradually begin a normal sleep cycle. There is no experience in the use of hormones to treat fibromyalgia; however the observation that females who are postmenopausal, those who withdraw from estrogen replacement therapy, and those who have estrogen-dependent illnesses like lupus get more fibromyalgia would suggest that these steroids might be useful.146,147 The effects on serotonin of estrogen or androgen withdrawal would be important to research in this illness.

References 1. Temple SE, Pham K, Glendenning P, Phillips M, Waterer GW. Endotoxin induced TNF and IL-10 mRNA production is higher in male than female donors: correlation with elevated expression of TLR4. Cell Immunol 2008;251:69–71. 2. Meyer JM, Han J, Moxley G. Tumor necrosis factor markers show sex-influenced association with rheumatoid arthritis. Arthritis Rheum 2001;44:286–295. 3. Cook IF. Sexual dimorphism of humoral immunity with human vaccines. Vaccine 2008;26:3551–3555. 4. Lisse IM, Aaby P, Whittle H, Jensen H, Engelmann M, Christensen LB. T lymphocyte subsets in West African children: impact of age, sex and season. J Pediatr 1997;130:77–81. 5. Giron-Gonzalez JA, Moral FJ, Elvira J. et al. Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared with women, Eur. J. Endocrinol. 143: 31–36. 6. Beagley KW, Gockel CM. Regulation of innate and adaptive immunity by the female sex hormones estradiol and progesterone. FEMS Immunol Med Microbiology 2003;38:13–22. 7. Giltay EJ, Fonk JCM, VonBlomberg BME, Drexhage HA, Schalkwijk C, Gooren LJG. In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. J Clin Endocrinol Metab 2000;85:1648–1657. 8. Verthelyi D. Sex hormones as immunomodulation in health and disease. Immunopharmacology 2001;1:983–993. 9. Dosiou C, Lathi RB, Tulac S, Joseph-Huang ST, Giudice LC. Interferon related and other immune genes are downregulated in peripheral blood leukocytes in the luteal phase of the menstrual cycle. J Clin Endocrinol Metab 2008;89:2501–2504. 10. Du JT, Vennos E, Ramey E, Ramwell PW. Sex differences in arachidonate cyclo-oxygenase products in elicited rat peritoneal macrophages. Biochim Biophys Acta 1984;794:256–260. 11. Leslie CA, Dubey DP. Increased PGE2 from human monocytes isolated in the luteal phase of the menstrual cycle. Implications for immunity. Prostaglandins 1994;47:41–54. 12. Roden AC, Moser MT, Tri SD, et al. Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol 2004;173:6098–6108. 13. Olsen NJ, Watson MB, Henderson GS, Kovacs WJ. Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice. Endocrinology 1991;129:2471–2476. 14. Olsen NJ, Zhou P, Ong H, Kovac WJ. Testosterone induces expression of transforming growth factor-beta in the murine thymus. J Steroid Biochem Molec Biol 1993;45:327–332. 15. Nelson JF, Felicio LS, Osterburg HH, Finch CE. Differential contributions of ovarian and extraovarian factors to age-related reductions in plasma estradiol and progesterone during the estrous cycle of C57BL mice. Endocrinology 1992;130:805–810. 16. Harris RE. Coccidiomycosis complicating a pregnancy: report of 3 cases and review of the literature. Obstet Gynecol 1996;28:401–405. 17. M. Marzi, A. Vigano, D. Trabattoni et al. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy, Clin. Exp. Immunol. 106 127–133.

C h a p t e r 5 2     Sex Hormones and Immune Function l

18. Ostensen M, Aune B, Husby G. Effect of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand J Rheumatol 1983;12:69–72. 19. Whitacre CC, Reingold SC, O’Looney PA. A gender gap in autoimmunity. Science 1990;283:1277–1278. 20. Hamano N, Terada N, Maesako K, et al. Effect of female hormones on the production of IL-4 and IL-13 from peripheral blood mononuclear cells, Acta Otolaryngol (Suppl) 537 27–31. 21. Huber SA, Kupperman J, Newell MK. Estradiol prevents and testosterone promotes Fas-dependent apoptosis in CD4 Th2 cells by altering Bcl 2 expression. Lupus 1999;8:384–387. 22. Depue RH, Pike MC, Henderson BE. Estrogen exposure during gestation and the risk of testicular cancer. J Natl Cancer Inst 1983;71:1151–1155. 23. Swerdlow AJ, De Stavola BL, Swanick MA, Macanochie NE. Risk of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetioloogy. Lancet 1997;350:1723–1728. 24. Ahmed SA, Dauphinee M, Talal N. Effects of short term administration of sex hormones on normal and autoimmune mice. J Immunol 1985;134:204–210. 25. Yohn DS. Sex related resistance in hamsters to adenovirus oncogenesis. Prog Exp Tumor Res 1973;18:138. 26. Bjune G. In vitro lymphocyte responses to PHA show covariation with the menstrual cycle. Immunol Abstr 1979:51. 27. Verheul HA, Tittes EV, Kelder J, Schuurs AH. Effects of steroids with different endocrine profiles on the development, morphology and function of the bursa of Fabricius in chickens. J Steroid Biochem 1986;25:665–675. 28. Hirota Y, Suzuki T, Bito Y. The B-cell development independent of bursa of Fabricius but dependent upon the thymus in chickens treated with testosterone propionate. Immunology 1980;39:37–46. 29. Meyer RK, Rao MA, Aspinall RL. Inhibition of the development of the bursa of Fabricius in the embryos of the common fowl by 19-nortestosterone. Endocrinology 1959;64:890. 30. Stimson WH, Hunter IC. Estrogen induced immunoregulation mediated through the thymus. J Clin Lab Immunol 1980;4:27–33. 31. Blank M, Mendlovic S, Fricke H, Mozes E, Talal N, Shoenfeld Y. Sex hormone involvement in the induction of experimental systemic lupus erythematosus by a pathogenic anti-DNA idio­ type in naive mice. J Rheumatol 1990;17:311–317. 32. Grossman CJ, Sholitan LJ, Roselle G. Estradiol regulation of thymic lymphocyte function in the rat: mediation by serum thymic factors. J Steroid Biochem 1982;16:683–690. 33. Grossman CJ, Sholitan LJ, Blaha GC, Nathan P. Rat thymic estrogen receptor II. Physiologic properties. J Steroid Biochem 1989;11:1241. 34. Sholitan LJ, Grossman CJ, Taylor BB. Rat thymic homogenates convert testosterone to androgenic metabolites. J Steroid Biochem 1980;13:1365. 35. Cohen JHM, Danel L, Cordier G, Saez S, Revillard J. Sex steroid receptors in peripheral T cells: absence of androgen receptors and restriction of estrogen receptors to OKT8 positive cells [abstract]. J Immunol 1983;131:2767–2771. 36. Raveche ES, Vigersky RA, Rice MK, Steinberg AD. Murine thymic androgen receptors. J Immunopharmacol 1980;2:425.

623

37. Dunkel L, Taino VM, Savilahti E, Eskola J. Effect of endogenous androgens on lymphocyte subpopulations. Lancet 1985;I:440–441. 38. Weinstein Y, Isakov Y. Effects of testosterone metabolites and of anabolic androgens on the bone marrow and thymus in castrated female mice. Immunopharm 1983;5:229–237. 39. Lubahn DB, Joseph DR, Sar M, et al. The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate. Mol Endocrinol 1988;2:1265–1275. 40. Klareskog L, Forsum U, Peterson PA. Hormonal regulation of the expression of Ia antigens on mammary gland epithelia. Eur J Immunol 1980;10:958–963. 41. Terres G, Morrison SL, Habicht GL. A quantitative difference in the immune response between male and female mice. Proc Exp Biol Med 1968;27:664. 42. Thompson JS, Crawford MK, Reilly R, Stevenson C. Estrogenic hormones in immune responses in normal and X irradiated mice. J Immunol 1957;98:331. 43. Waltman SR, Brude RM, Benios J. Prevention of corneal rejection by estrogens. Transplantation 1971;11:194. 44. Brodie JY, Hunter IC, Stimson WH, Green B. 1980 Specific estradiol binding in cytosols from the thymus glands of normal and hormone-treated male rats. Thymus 1980;1:337. 45. Wyle FA, Kent JR. Immunosuppression by sex steroid hormones. I. The effect upon PHA- and PPD-stimulated lymphocytes. Clin Exper Immunol 1977;27:407–415. 46. Satoh PS, Fleming WE, Johnstone KA, Ozmun JM. Active E rosette formation in women taking oral contraceptives. N Engl J Med 1977;296:254. 47. Golsteyn EJ, Fritzler MJ. The role of the thymus-hypothalamus–pituitary–gonadal axis in normal immune processes and autoimmunity. J Rheumatol 1987;14:982–990. 48. O’Hearn M, Stites DP. Inhibition of murine suppressor cell_ function by progesterone. Cell Immunol 1983;77:340–348. 49. Sasson S, Mayer M. Effect of androgenic steroids on rat thymus and thymocytes in suspension. J Steroid Biochem 1981;14:509–518. 50. Buskila D, Berezin M, Gur H, et al. Autoantibody profile in the sera of women with hyperprolactinemia. J Autoimmun 1985;8:415–424. 51. Paavonen T, Aronen H, Pyrhonen S, Hajba A, Andersson LC. The effects of anti-estrogen therapy on lymphocyte functions in breast cancer patients. APMIS 1991;99:163–170. 52. Sthoeger Z, Chiorazzi N, Lahita RG. Regulation of the immune response by sex steroids. J Immunol 1988;141:91–98. 53. Danel L, Sovweine G, Monier JC, Saez S. Specific estrogen binding sites in human lymphoid cells and thymic cells. J Steroid Biochem 1983;18:559. 54. Jungers P, Pelissier C, Bach JF, Nahoul K. Les androgènes plasmatiques chez les femmes atteintes de lupus erythemateux disseminé (LED). Pathol Biol (Paris) 1980;28:391–392. 55. Stimson WH. Estrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset. Scand J Immunol 1988;28:345–350. 56. Evans MJ, MacLaughlin S, Marvin RD, Abdou NI. Estrogen decreases in vitro apoptosis of peripheral blood mononuclear cells from women with normal menstrual cycles and

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decreases TNF-alpha production in SLE but not in normal cultures. Clin Immunol Immunopathol 1997;82:258–262. Clemens LE, Siiteri PK, Stites DP. Mechanisms of immunosuppression of progesterone on maternal lymphocyte activation during pregnancy. J Immunol 1979;122:1978–1985. Mori T, Kobayashi H, Nishimoto H. Inhibitory effect of progesterone and 20-hydroxy-pregn-4-en-3-one on the phytohemagglutinin-induced transformation of human lymphocytes. Am J. Obstet Gynecol 1977;127:151. J. Fishman, C. Martucci, Biological properties of 16-alpha hydroxyestrone: implicationso in estrogen physiology and pathophysiology, J. Clin. Endocrinol. Metab. 51 611–615. Ikegawa S, Lahita RG, Fishman J. Concentration of 16 alpha hydroxyestrone in human plasma as measured by a specific RIA. J Steroid Biochem 1983;18:329–332. Bucala R, Fishman J, Cerami A. The reaction of 16- hydroxyestrone with erythrocytes in vitro and in vivo. Eur J Biochem 1984;140:593–598. Bucala R, Fishman J, Cerami A. Formation of co-valent adducts bewteen cortisol and 16-alpha-hydroxyestrone and protein, possible role in pathogenesis of cortisol topxicity and SLE. Proc Natl Acad Sci 1983;79:3320. Lahita RG, Bradlow HL, Fishman J, Kunkel HG. Estrogen metabolism in systemic lupus erythematosus: patients and family members. Arthritis Rheum 1982;25:843–846. Melamed M, Castano E, Notides AC, Sasson S. Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol. Mol Endocrinol 2008;11:1868–1878. Bucala R, Lahita RG, Fishman J, Cerami A. Anti-estrogen antibodies in users of oral contraceptives and in patients with systemic lupus erythematosus [abstract]. Clin Exper Immunol 1987;67:167–175. Cutolo M, Accardo S, Villaggio B, et al. Evidence for the presence of androgen receptors in the synovial tissue of rheumatoid arthritis patients and healthy controls. Arthritis Rheum 1992;35:1007–1015. Cutolo M, Sulli A, Capellino S, et al. Anti-TNF and sex hormones. Ann N Y Acad Sci 2006;1069:391–400. Lahita RG. Sex steroids and SLE: metabolism of androgens to estrogens [Editorial]. Lupus 1992;1:125–127. Inman RD. Immunologic sex differences and the female preponderance in systemic lupus erythematosus. Arthritis Rheum 1978;21:849–852. Inman RD, Jovanovic L, Markenson JA. Systemic lupus erythematosus in men: genetic and endocrine features. Arch Intern Med 1982;142:1813–1815. Lahita RG, Bradlow HL, Kunkel HG, Fishman J. Increased oxidation of testosterone in systemic lupus erythematosus. Arthritis Rheum 1983;26:1517–1521. Jungers P, Nahoul K, Pelissier C. Low plasma androgens in women with active or quiescent SLE. Arthritis Rheum 1982;25:454–457. Lahita RG, Bradlow HL, Ginzler E, Pang S, New M. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 1987;30:241–248. Spencer NFL, Poynter ME, Hennebold JD, Mu HH, Daynes RA. Does DHEAS restore immune competence in aged animals through its capacity to function as a natural modulator of peroxisome activities? In: FL Bellino, RD Daynes, PJ Hornsby, DH Lavren, JE Nestler, eds.

75.

76.

77. 78.

79. 80.

81.

82.

83.

84. 85.

86.

87.

88.

89. 90.

91. 92.

93.

Dehydroepiandrosterone (DHEA) and Aging. New York, NY: New York Academy of Sciences; 1996:200–216. Zietz B, Reber T, Oertel M, Gluck T, Scholmerich J, Straub RH. Altered function of the hypothalamic stress axes in patients with moderately active systemic lupus erythematosus. II. Dissociation between androstenedione, cortisol, or dehydroepiandrosterone and interleukin 6 or tumor necrosis factor. J Rheumatol 2000;27:911–918. Ansar Ahmed S, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action, Am. J. Pathol. 121 531–551. Cutolo M, Accardo S. Sex hormones and rheumatoid arthritis. Clin Exp Rheum 1991;9:641–646. Rhodes K, Scott A, Markham RL, Monk-Jones ME. Immunological sex differences. A study of patients with rheumatoid arthritis, their relatives and controls. Ann Rheum Dis 1969;28:104. Latman N. Relation of menstrual cycle to the symptoms of rheumatoid arthritis. Am J Med 1983;74:957–960. Bijllsma JWJ, Huber-Bruning O, Thijssen JHH. Effect of estrogen treatment on clinical and laboratory manifestation of rheumatoid arthritis. Ann Rheum Dis 1987;46:777–779. Liang MH, Karlson EW. Female hormone therapy and the risk of developing or exacerbating systemic lupus erythematosus or rheumatoid arthritis. Proc Assoc Am Phys 1996;108:25–28. Spector TD, Brennan P, Harris P, Studd JWW, Silman AJ. Does estrogen replacement therapy protect against rheumatoid arthritis? J Rheum 1991;18:1473–1476. Sullivan DA, Kelleher RS, Vaerman JP, Hann LE. Androgen regulation of secretory component synthesis by lacrimal gland acinar cells in vitro. J Immunol 1990;145:4238–4244. Stahl N, Decker J. Androgenic status of males with SLE, Arthritis Rheum, 21 665–668. Alarcon-Segovia D, Alarcon-Riquelme ME. Etiopathogenesis of systemic lupus erythematosus: A tale of three troikas. In: RG Lahita, ed. Systemic Lupus Erythematosus. San Diego, CA: Academic Press; 2002:55–66. Lahita RG, Bradlow HL, Kunkel HG, Fishman J. Increased 16 alpha hydroxylation of estradiol in systemic lupus erythematosus. J Clin Endocrinol Metab 1981;53:174–178. Lahita RG, Bradlow HL, Kunkel HG, Fishman J. Alterations of estrogen metabolism in SLE. Arthritis Rheum 1979;22: 1195–1198. Lahita RG, Bucala R, Bradlow HL, Fishman J. Determination of 16-hydroxyestrone by radioimmunoassay in systemic lupus erythematosus. Arthritis Rheum 1985;28:1122–1127. Lahita RG, Chiorazzi N, Gibofsky A. Familial systemic lupus erythematosus in males. Arthritis Rheum 1983;26:39. Stein CM, Olson JM, Gray-McGuire C, et al. Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives. Arthritis Rheum 2002;46:428–435. Hughes GR. Current understanding of systemic lupus erythematosus. Inflammation 1984;8(Suppl.):S75–S79. Sthoeger ZM, Geltner D, Rider A, Bentwich Z. Systemic lupus erythematosus in 49 Israeli males: a retrospective study. Clin Exp Rheum 1987;5:233–240. Anisman H, Baines MG, Berczi I, et al. Neuroimmune mechanisms in health and disease: 2. Disease. Can Med Assoc J 1996;155:1075–1082.

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94. Camilleri F, Mallia C. Male SLE, patients in Malta. Adv Exp Med Biol 1999;455:173–179. 95. Chang DM, Chang CC, Kuo SY, Chu SJ, Chang ML. The clinical features and prognosis of male lupus in Taiwan. Lupus 1998;7:462–468. 96. Mok CC, Lau CS. Profile of sex hormones in male patients with systemic lupus erythematosus. Lupus 2000;9:252–257. 97. Alekberova Z, Kotelnikova G, Folomeev M. Aortic defects in systemic lupus erythematosus. Terapeuticheskii Arkhiv 1989;61(5):35–38. 98. Alekberova ZS, Folomeev MI. Sexual dimorphism in rheumatic diseases. Revmatologiia (Mosk) 1985;2:58–61. 99. Lahita RG. Sex, and age in systemic lupus erythematosus. In: RG Lahita, ed. Systemic Lupus Erythematosus. New York, NY: John Wiley and Sons; 1986:523–539. 100. Aoki N. Klinefelter’s syndrome, autoimmunity, and associated endocrinopathies. Intern Med 1999;38:838–839. 101. Fam A, Izsak M, Saiphoo C. SLE, and Klinefelter’s syndrome. Arthritis Rheum 1980;23:124. 102. French MAH, Hughes P. Systemic lupus erythematosus and Klinefelter’s syndrome. Ann Rheum Dis 1983;42:471–473. 103. Kobayashi S, Shimamoto T, Taniguchi O, Hashimoto H, Hirose S. Klinefelter’s syndrome associated with progressive systemic sclerosis: report of a case and review of the literature. Clin Rheumatol 1991;10:84–86. 104. Lahita RG, Bradlow HL. Klinefelter’s syndrome: hormone metabolism in hypogonadal males with systemic lupus erythematosus. J Rheumatol 1987;14(Suppl. 13):154–157. 105. Asherson RA, Harris NE, Gharavi AE, Hughes GRV. Systemic lupus erythematosus, antiphospholipid antibodies, chorea and oral contraceptives. Arthritis Rheum 1986;29: 1535–1536. 106. T.A. Chapel, R.E. Burns, Oral contraceptives and exacerbations of SLE, Am J Obstet Gynecol 110 366. 107. Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Gilkeson GS. Hormonal and reproductive risk factors for development of systemic lupus erythematosus: results of a population-based, case-control study. Arthritis Rheum 2002;46:1830–1839. 108. Sanchez-Guerrero J, Karlson E, Liang MH, et al. Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum 1997;40:804–808. 109. Buyon J, Korchack HM, Rutherford LE. Female hormones reduce neutrophil responsiveness in vitro. Arthritis Rheum 1984;27:623–630. 110. Bodel P, Dillard GM, Kaplan SS, Malawista SE. Antiinflammatory effects of estradiol on human blood leukocytes. J Lab Clin Med 1972;80:373–384. 111. Mikkelson WM, Dodge NJ, Vlakenberg H. The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia. Am J Med 1965;39:242. 112. Lockshin MD. Invited review: sex ratio and rheumatic disease. J Appl Physiol 2001;91:2366–2373. 113. Linos A, Worthing JW, O’Fallon WM, Kurland LT. The epidemiology of rheumatoid arthritis in Rochester. Minnesota: a study of its incidence, prevalence, and mortality. Am J Epidem 1989;111:87–98. 114. Linos A, O’Fallon WM, Worthington JW, Kurland LT. Case control study of rheumatoid arthritis and prior use of oral contraceptives. Lancet 1983;1:1299.

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115. Linos A, Worthing JW, O’Fallon WM, Kurland LT. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of its incidence, prevalence, and mortality. Am J Epidem 1989;111:87–98. 116. Oka M, Vainio U. Effect of pregnancy on the prognosis and serology of rheumatoid arthritis. Acta Rheum Scand 1966;12:47. 117. Mok CC, Lau CS, Ho CT, Wong RW. Do flares of systemic lupus erythematosus decline after menopause? Scand J Rheumatol 1999;28:357–362. 118. Sanchez-Guerrero J, Villegas A, Mendoza-Fuentes A, et al. Disease activity during the premenopausal and postmenopausal periods in women with systemic lupus erythematosus. Am J Med 2001;111:464–468. 119. DeClue TJ, Shah SC, Marchese M, Malone JI. Insulin resistance and hyperinsulinemia induce hyperandrogenism in a young type B insulin resistant female. J Clin Endocrinol Metab 1991;72:1308–1311. 120. Harrison LC, Dean B, Peluso I, Clark S, Ward G. Insulin resistance, acanthosis nigricans, and polycystic ovaries associated with a circulating inhibitor of postbinding insulin action. J Clin Endocrinol Metab 1985;60:1047–1052. 121. Dmowski WP, Gebel HM, Rawlins RG. Immunological aspects of endometriosis. Obstet Gynecol Clin North Am 1989;16(1):93–103. 122. Dmowski WP, Steele RW, Baker GF. Deficient cellular immunity in endometriosis. Am J Obstet Gynecol 1981;141:377. 123. Braun DP, Gebel H, Rotman C, Rana N, Dmowski WP. The development of cytotoxicity in peritoneal macrophages from women with endometriosis. Fertil Steril 1992;57(6):1203–1210. 124. Tung KSK, Smith S, Teuscher C. Murine autoimmune oophoritis, epididymoorchitis and gastritis induced by day 3 thymectomy: Immunopathology. Am J Pathol 1987;26:293. 125. Dmowski WP. Danazol: a synthetic steroid with diverse biologic effects. J Reprod Med 1990;35:69–74, discussion 74–75. 126. Olsen NJ, Kovacs WJ. Case report: testosterone treatment of systemic lupus erythematosus in a patient with Klinefelter’s syndrome. Am J Med Sci 1995;310:158–160. 127. Agnello V, Pariser K, Gell J. Preliminary observation on Danazol therapy of systemic lupus: effects on DNA antibodies, thrombocytopenia and complement. J Rheumatol 1983;10:682–687. 128. Jungers P, Liote F, Dehaine V, Dougados M, Viriot J, Pelissier C, et al. Hormonal contraception and lupus. Ann Med Interne (Paris) 1990;141(3):253–256. 129. Ivanova AV, Shardina LA. Benediktov II. [Gonadotropic and sex hormones in women with systemic lupus erythematosus]. Revmatologiia. (Mosk) 1989:3–8. 130. S.T. Vilarinho, L.T. Costallat, Evaluation of the hypothalamic–pituitary–gonadal axis in males with systemic lupus erythematosus, J. Rheumatol. 25 1097–1103 131. El-Roeiy A, Dmowski WP, Gleicher N. Effect of danazol and GnRH agonists (GnRH-a) on the immune system in endometriosis [abstract]. Soc Gynecol Invest 1988:283. 132. Van VR, Engleman EG, McGuire JL. Dehydroepiandrosterone in systemic lupus erythematosus. Results of a double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheum 1995;38:1826–1831. 133. Van VR, McGuire JL. Studies of dehydroepiandrosterone (DHEA) as a therapeutic agent in systemic lupus erythematosus. Ann Med Interne (Paris) 1996;147:290–296.

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134. Araneo BA, Daynes RA. Dehydroepiandrosterone functions as more than an antiglucocorticoid in preserving immunocompetence after thermal injury. Endocrinology 1995;136:393–401. 135. Daynes RA, Dudley DJ, Araneo BA. Regulation of murine lymphokine production in vivo II. Dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells. J Immunol 1990;20:793–802. 136. Daynes RA, Araneo BA. Programming of lymphocyte responses to activation: extrinsic factors, provided microenvironementally, confer fllexibility and compartmentalization to T cell function. Chem Immunol 1992;54:1–20. 137. Nandy K, Harbous L, Bennet D, Bennet M. Correlation between learning disorder and elevated brain reactive antibodies in aged C57B1/6 and young NZB mice. Life Sciences 1983;33:1499. 138. Sherman GF, Galaburda AM, Geschwind N. Ectopic neurons in the brain of the autoimmune mouse: aneuropathophysiologic model of dyslexia?. Neuropath Proc 1983;275:6. 139. Lahita RG. Systemic, lupus erythematosus: learning disability in the male offspring of female patients and relationship to laterality, Psychoneuroendocrinology 13 385–396. 140. Wood LC, Cooper DS. Autoimmune thyroid disease, lefthand­edness, and developmental dyslexia (1989) unpublished work.

141. Wyckoff PM, Miller LC, Tucker LB, Schaller JG. Neuropsychological assessment of children and adolescents with systemic lupus erythematosus. Lupus 1995;4:217–220. 142. Boone KB, Swerdloff RS, Miller BL, Geschwind DH, Razani J, Lee A, et al. Neuropsychological profiles of adults with Klinefelter syndrome. J Int Neuropsychol Soc 2001;7(4):446–456. 143. Alarcon GS. Arthralgias, myalgias, facial erythema, and a positive ANA: not necessarily SLE. Cleve Clin J Med 1997;64:361–364. 144. Bennet RM. Confounding features of the fibromyalgia syndrome: a current perspective of differential diagnosis. J Rheum 1995;19:58–61. 145. Bennet RM, Clark SR, Campbell SM. Somatomedin-C levels in patients with the fibromyalgia syndrome: a possible link between sleep and muscle pain. Arthritis Rheum 1992;35:1113–1116. 146. Carette S, Dessureault M, Belanger A. Fibromyalgia, and sex hormones. J Rheum 1992;19:831–832. 147. Ferraccioli G, Cavalieri F, Salaffi F. Neuroendocrinologic findings in primary fibromyalgia (soft tissue chronic pain syndrome) and in other chronic rheumatic conditions (rheumatoid arthritis, low back pain. J Rheum 1990; 17:869–73.

Chapter

53

Pregnancy and Autoimmune Rheumatic Disease Carl A. Laskin1, Christine A. Clark2, and Karen A. Spitzer3 1

LifeQuest Centre for Reproductive Medicine; Departments of Medicine (Rheumatology), Obstetrics & Gynecology and Immunology, University of Toronto, Toronto, ON, Canada 2 Candidate, Mount Sinai Hospital, University of Toronto, LifeQuest Centre for Reproductive Medicine, Toronto, Ontario, Canada 3 University of Toronto, LifeQuest Centre for Reproductive Medicine, Toronto, Ontario, Canada

Pregnancy and the rheumatic diseases

Immune function in the connective tissue diseases and pregnancy

Rheumatic diseases occur most often in women, ranging from an incidence of 9:1 (female : male) in systemic lupus erythematosus (SLE) to 3:1 in rheumatoid arthritis (RA). It follows logically that physiological states characterized by hyperestrogenicity would likely have an effect on disease activity. Pregnancy may therefore exacerbate disease or be associated with disease amelioration, if not remission.1 Medical issues associated with pregnancy may be rather complicated due to the multisystemic nature of rheumatic disorders,2 presenting many challenges for the attending physicians, whether general internists, rheumatologists, or obstetricians. Of particular concern are the medications used to treat these patients. Although some medications may be completely safe in pregnancy, it may be necessary, depending on the drug, to discontinue certain agents from 3 weeks to 2 years prior to conception. Under ideal circumstances, any patient with an underlying medical problem should be assessed prior to a pregnancy in order that the pregnancy can be undertaken electively and as safely as possible. On too many occasions a patient may first present in a medical office pregnant either with active disease or on unsafe medications. Critical decisions must be made at these times that may be difficult emotionally and ethically. Among the rheumatic diseases that could be addressed in this chapter, many are simply too uncommon to warrant detailed discussion. Therefore, those disorders that are more likely to be encountered by the clinician will be discussed.

Principles of Gender-Specific Medicine

Most rheumatic diseases are characterized by abnormalities in immunoregulation due to an imbalance in immune suppressor activity. Pregnancy and the accompanying hormonal changes may have a significant effect on disease manifestations, either amelioration or exacerbation. Circulating autoantibodies are the primary marker of most connective tissue diseases (CTD), which may either be causative of or merely associated with tissue damage. These autoantibodies may bind with antigens on cell surfaces resulting in tissue destruction. As an alternative to this cytotoxic mechanism, the autoantibody may bind with antigen to form either a circulating or in situ immune complex or fix complement, thereby initiating an inflammatory response when fixed in tissues, which then results in damage (immune complex mechanism). The clinical manifestations vary according to the site of tissue injury, which, in turn, varies according to the disease entity. This may lead to inflammatory synovitis as in RA or a multisystem disorder as in SLE.3 During pregnancy a number of alterations in immune function occur affecting lymphocyte function, humoral immunity, and the inflammatory response. Awareness of these changes is of paramount importance in the assessment of a patient with a known or possible CTD. Human pregnancy is associated with an increase in immune suppressor activity leading to a decrease in humoral B cell function. In many autoimmune diseases there is dysregulation of the immune response leading to an impairment of suppressor activity resulting in polyclonal B cell activation. Therefore

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the superimposition of pregnancy on the immunoregulatory abnormalities present in a woman with a CTD will alter the immune environment and may even correct the abnormalities existing in the CTD. Regardless, the interaction of these two altered immune states must be appreciated in order to account for changes in disease activity.

implantation period, and premature and term labor. Th1 activity plays an important role in the promotion of the Th2 response, regulation of the placentation process, defense against infections, and initiation of delivery. The new paradigm should more properly be thought of as ‘Th1–Th2 cooperation’ rather than a Th2-dominant phenomenon.

A brief outline of the immunology of implantation, pregnancy, and labor and delivery The fundamental theory of the establishment of pregnancy has been the Th1/Th2 paradigm.1 Helper-T cell clones can be divided into two phenotypes that secrete a distinct cytokine pattern (Table 53.1).4 During pregnancy, there is an overall suppression of Th1-mediated cellular immunity and an enhancement of Th2-mediated humoral immunity. The maintenance of pregnancy requires the downregulation of the pro-inflammatory Th1 cytokines (tissue necrosis factor-alpha [TNF-], interferon gamma [IFN-], and interleukin-2 [IL-2]) and the upregulation of anti-inflammatory Th2 cytokines (IL-4, IL-6, and IL-10). During embryo implantation, uterine epithelial cells surrounding the blastocyst undergo apoptosis. These apoptotic cells are then taken up by macrophages found in excess at the implantation site. The uptake of the apoptotic cells into the macrophages promotes the secretion of Th2 cytokines and suppresses the release of Th1 cytokines including TNF- from the macrophages. The Th2-rich anti-inflammatory environment surrounds and protects the developing embryo. Therefore pregnancy appears to be a Th2 phenomenon. Recent data, however, suggest that this paradigm may be overly simplistic. Although TNF- and IFN- have been implicated in failed implantation or early pregnancy loss, it now appears that small quantities of these cytokines may be necessary for the successful implantation of the embryo. Moreover, it may be that Th1 activity both accompanies and predominates over Th2-mediated events during the early

Management of reproductive issues in the rheumatic diseases As with any woman with an underlying medical problem, pregnancy should ideally be elective. Planning minimizes the risks not only of disease complications to mother and fetus but also of birth defects due to medication. Prior to becoming pregnant, the patient should be assessed by an internist with specific notice taken of the manifestations of the underlying disease, the past history of exacerbations, and past and current medications. The attending physician will then be able to document (a) the clinical profile; (b) the laboratory profile; (c) the frequency and pattern of the most recent disease flare; and (d) the current medications. Clinical profile: This profile is constructed from the history and physical examination. In addition, the past history is utilized to record how the disease initially presented and the usual manifestations of a flare. Laboratory profile: The laboratory tests that best reflect the patient’s disease status are used as indicators of disease activity during a pregnancy. The profile is constructed from the current laboratory tests and any relevant serology, as well as noting which laboratory variables are associated with disease activity. Most recent disease flare: It is important to determine and document the most recent exacerbation of the disease as well as the severity. The timing of a pregnancy will determine the safety of such an undertaking. Appropriate counseling of the patient can then be undertaken. This information should be incorporated into the patient’s clinical profile. Medications: A detailed history of current medications is essential to provide appropriate counseling to the patient regarding the timing of a pregnancy. Many antirheumatic drugs are unsafe in pregnancy, and because many are also long acting, they may have to be discontinued months prior to conception.

n

n

n

n

Table 53.1  Distribution of cytokine production between helper cell clones, Th1 and Th24 Th1

Th2

IFN- IL-2 TNF- TNF- GM-CSF IL-3 IL-10

IL-3 IL-4 L-5 IL-6 IL-10 IL-13 TNF GM-CSF

IFN: interferon; IL: interleukin; TNF: tumor necrosis factor; GM-CSF:granulocyte macrophage colony-factor.

Systemic lupus erythematosus SLE is a multisystem autoimmune disorder characterized by diverse clinical and laboratory abnormalities, with a variable disease course. The disease predominantly affects young women in childbearing years but may occur in any

C h a p t e r 5 3    Pregnancy and Autoimmune Rheumatic Disease l

age group. The prevalence has been reported from 15 to 50 per 100 000 population but varies considerably according to race and ethnic background. Clinical manifestations are the result of inflammation of multiple organ systems including skin, joints, kidneys, nervous system, and serosal membranes. Diagnosis and management of SLE is often difficult due to heterogeneity of the clinical and laboratory manifestations. Most clinicians rely upon the American College of Rheumatology (ACR) 1982 classification criteria to assist in the assessment of patients with an established or possible diagnosis of lupus.5 Genetic factors have been documented with a strong association with MHC components HLA-DR2 and -DR36 Apart from the minor organ manifestations of arthritis and dermatitis, clinical evidence of renal involvement is found in 50–66% of patients with SLE. The World Health Organization has recognized six classes of lupus glomerulonephritis.7 The prognosis varies according to the severity of involvement with mesangial and membranous glomerulonephritis having a better prognosis than proliferative disease. Central nervous system involvement may present with neurologic and/or psychiatric manifestations. Laboratory findings in SLE include cytopenias, abnormal renal function tests, hypergammaglobulinemia, and a number of circulating autoantibodies. Among the most significant autoantibodies is anti-dsDNA antibody, which may be both pathogenic and a marker of disease activity. In addition, depressed complement levels correlate with disease activity.

Systemic Lupus and Fertility Although studies indicate no difference in fertility rates in women with SLE compared to the general population, one must interpret these findings with caution.8 Any active inflammatory disorder impacts the pituitary–ovarian axis leading to anovulation. In addition, the adverse effects of certain medications such as cyclophosphamide may severely compromise gonadal function. Therefore, under these circumstances, fertility rates will be affected. There are women with well-controlled SLE who may require fertility treatment often in the form of ovulation induction therapy. This treatment requires the use of high doses of exogenous follicle stimulating hormone (FSH) leading to a hyperestrogenic state. The hyperestrogenicity may exacerbate lupus. There are several studies of ovulation induction therapy in women with SLE.9–12 For the most part, the women have fared well although some complications associated with disease exacerbation have occurred, but since the studies are small, no conclusions can be drawn. Although such therapy is not contraindicated in women with SLE, it is advisable to initiate ovulation induction only in those individuals whose disease is under excellent control for an extended period such as 6 months. In addition, the patient must be assessed for disease activity and advisability of entering a pregnancy.

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The Pre-Pregnancy Evaluation Whenever possible, women with SLE contemplating pregnancy should be evaluated prior to conception for the status of their disease and its activity. The clinician should determine the patient’s clinical and laboratory profile, date of most recent flare of the disease, and current medications. Using a methodical approach the physician may grasp the subtle nuances of the underlying disease permitting better distinction of disease activity and the physiological or pathophysiological changes associated with pregnancy. Pregnancy in any woman with an underlying medical problem should be managed by both an internist/subspecialist and obstetrician/perinatologist. In the case of SLE, that internist should be a rheumatologist or at the very least an internist familiar with the management of lupus. The prepregnancy evaluation should be undertaken by an internist/ rheumatologist and a recommendation made to the patient regarding the medical management plan. It is often necessary to delay a pregnancy until the disease comes under better control or while medications are changed to those more compatible with pregnancy. Appropriate counseling regarding the potential effect of the disease on the pregnancy and neonate, and similarly the effect of the pregnancy on the disease should be undertaken.

The Effect of Pregnancy on SLE There is some consistency in the response of SLE to pregnancy but some patients do not ‘behave’ as expected. As early as 1952, it was noted that some women with SLE flare during pregnancy.13 Other studies have also noted an increase in flares during pregnancy.14–17 The more recent literature, however, notes that the frequency of disease exacerbation during pregnancy and postpartum is less than that reported earlier.18,19 In a case–control prospective study comparing pregnant and non-pregnant women with similar manifestations of SLE, Lockshin et al. found no increase in flares during pregnancy.20,21 In contrast, Petri concluded that pregnancy was associated with an increased rate of disease flares in her population with a frequency of 1.63 per person years compared to 0.64–0.65 in a postpartum group or in non-pregnant controls.22 Ruiz-Irastorza et al. observed findings similar to Petri with a 65% flare rate during pregnancy compared to 42% in the controls group.23 Recent studies by Cortes-Hernandez et al. found that 33% of their lupus patients flared during pregnancy, with 26% in the second trimester and 51% post partum.24 The major predictors of a flare were the discontinuation of antimalarial treatment, a history of more than three flares before the pregnancy, and a SLEDAI score (a standardized measure of lupus disease activity) 5 during these flares. In one study of 46 women with SLE who underwent 61 pregnancies, Urowitz et al. observed no increased frequency of lupus flares, using the SLEDAI, during pregnancy compared with controls.25

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Indeed there was a reduced chance of flare during a pregnancy if the patient had inactive disease for 6 months prior to conception. Clearly there is a lack of consensus among these studies. This may be due to dissimilar entry criteria, differing definitions of a flare, distinct patient populations, and differing control groups.22,23 The incidence of adverse pregnancy outcomes in women with SLE is increased. In a retrospective analysis, 555 women with SLE had an adverse outcome apart from manifestations of SLE compared to a group of 600 000 controls.26 These outcomes included hypertension, renal disease, preterm delivery, non-elective cesarean section, postpartum hemorrhage, and delivery-related deep venous thrombosis. Clark et al. noted 38.9% of women with SLE had a preterm delivery (before 37 weeks gestation) in a group of 72 pregnancies27 The observation of preterm delivery was associated with disease activity and the presence of IgG anti-cardiolipin antibody. Renal disease may flare during a pregnancy, which may be related to insufficient steroid dosage in treatment.23 Studies have been inconsistent in finding deterioration in renal function associated with pregnancy.18,26,28–32 Tozman et al. noted no recurrence of renal disease in 11 of 18 patients with similar findings by Jungers et al. and Huong et al. All noted that the best prognosis was associated with remission of the disease at pregnancy onset. Furthermore, they all noted a higher risk of pre-eclampsia and premature birth than expected. In contrast, others noted an increase of renal flare in pregnancy.30,31 These authors also conclude that the only predictor of a favorable maternal outcome in a pregnancy is quiescence of renal disease. In contrast to renal disease, there is very little studied with respect to central nervous system (CNS) disease. Suffice it to say that moderate to severely active lupus is a high-risk situation for both mother and fetus.31

serum urate can be seen in active SLE. Knowledge of your patient and how her disease has manifested itself in the past will assist immeasurably in correctly assessing this difficult diagnostic situation.

Effect of SLE on Pregnancy Adverse pregnancy outcome is more common in SLE than in any other rheumatic disease. Appropriate pre-pregnancy evaluation and counseling maximizes the probability of a successful outcome for both the mother and the neonate. Maintaining the viability of the pregnancy requires close collaboration between the obstetrician/perinatologist and internist/rheumatologist.

Spontaneous Abortion, Prematurity, and Stillbirth It has been reported in the past that the incidence of fetal wastage in SLE pregnancies approximated 50%, which included miscarriage, prematurity, and stillbirth.14,17,22,23,25,34–36 However, a recent analysis of longterm data indicated that the spontaneous abortion rate in SLE has declined from 50% to less than 20% over the past 40 years (Figure 53.1).37 Among the risk factors associated with adverse outcomes are antiphospholipid antibodies, hypocomplementemia, and hypertension during pregnancy.24 Although some have noted that infants born to mothers with lupus are small for gestational age, others have not observed this even in cases where placental size is reduced. The increased frequency of fetal loss in SLE may be due to several factors: (i) active lupus resulting in decidual vasculitis which in turn compromises placental blood flow 45 General population

40

Pre-eclampsia and Active SLE

35 % Pregnancy loss

It is a major diagnostic challenge to distinguish preeclampsia from a lupus flare during pregnancy. Pre-eclampsia occurs in approximately 13% of lupus pregnancies and can be as high as 66% in those with renal disease.21,33 Defining the clinical and laboratory profile of the patient before pregnancy will often assist in distinguishing these two conditions. If there are clinical features of active lupus and positive serology, this is likely a lupus flare. Depressed complement levels are characteristic of active lupus whereas elevated complement levels are seen in pregnancy and do not change in pre-eclampsia. Although proteinuria may be seen both in pre-eclampsia and lupus nephritis, the presence of an active sediment is a feature of active nephritis and not pre-eclampsia. Elevated liver function tests and uric acid with thrombocytopenia and decreased urinary excretion of calcium are characteristic of pre-eclampsia whereas thrombocytopenia alone or, if there is renal insufficiency, elevated

SLE Linear regression 95% CI

30 25 20 15 10 5 60–65 66–70 71–75 76–80 81–85 86–90 91–95 96–00 2000–

Year

Figure 53.1  Change in rate of fetal loss in SLE pregnancies and in the US general population over the past 40 years.37 Data were grouped into 5-year periods (except for the first period, 1963–1965, and the last period, 2000–2003). Redrawn from Clark, Spitzer, and Laskin, 2005, Figure 1, p. 1710, by permission of the Journal of Rheumatology.

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depriving the fetus; (ii) trophoblast-reactive lymphocytotoxic antibodies; (iii) anti-Ro/SSA or anti-La/SSB antibodies with their associated compromise of the fetal cardiac conduction system; and (iv) antiphospholipid antibodies with resulting placental vascular thrombosis and insufficiency culminating in ischemic pregnancy loss.

Antiphospholipid Antibodies and Pregnancy Antiphospholipid antibodies (aPL) in low to moderate titer may be seen in 40–60% of lupus patients with active disease. The aPL family of antibodies includes IgG or IgM anti-cardiolipin antibodies (aCL) and a non-specific in vitro inhibitor of coagulation often referred to as the lupus anticoagulant (LAC). Although the mere presence of aPL in a woman with lupus may not be associated with any particular manifestation, there may be an increased risk of adverse pregnancy outcome in such individuals. A review of 10 studies comprising 554 women with SLE observed fetal loss more frequently in the presence of aPL (39–59%) compared to those without aPL (16–20%).38 In addition, aPL have been associated with pre-eclampsia and placental abruption.39–42 Women with SLE and aPL and the associated clinical manifestations including thromboembolism and pregnancy wastage, are classified with secondary antiphospholipid syndrome (APS). Those with only aPL and an associated clinical feature are classified as primary APS since they lack any other feature of SLE. LAC and aCL have often been used interchangeably to indicate the presence of aPL. While there is certainly a correlation between these two antibodies, they are not identical. Lockshin et al. reported that while both the LAC and aCL were associated with fetal loss, higher levels of aCL appear to be more predictive of fetal distress or fetal death among pregnant women with SLE.42 However, other recent observations by Clark et al. have shown that the LAC may have a higher association with pregnancy loss and adverse outcome than aCL.43 The risk of fetal loss in women with circulating aPL has lately become controversial. Although some studies suggest that the presence of aCL or features of the antiphospholipid syndrome (APS) are associated with increased risk of pregnancy loss in women with SLE, others have not found this to be the case.36,44–51 Questions have arisen regarding the association of aPL with early vs. late pregnancy loss; the significance of IgM and IgA isotypes of aCL,52 and whether the presence of LAC or aCL in women with no history of thromboembolism or adverse pregnancy outcome, is sufficient indication for intervention. Treatment for pregnant women with APS, whether primary or secondary, has also become somewhat controversial. Although initial studies supported the use of prednisone and aspirin to promote live birth in a woman with a history of pregnancy loss and aPL, a double-blind, randomized controlled trial failed to show a benefit beyond placebo.53,54 Heparin and aspirin have become the accepted

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treatment for the prevention of pregnancy loss in women with APS,55–60 although studies supporting the use of such therapy prior to 2000 contrast with those performed after that date where ASA alone was found to be at least as efficacious as heparin with ASA.55–61

The Neonate In general, term births from women with SLE are at no greater risk of congenital anomalies than those born to mothers without SLE. The major exception is those babies born to mothers possessing anti-Ro (SSA) and/or anti-La (SSB) antibodies. Although abnormalities occur in only 1–2% of the neonates, the manifestations form collectively the neonatal lupus syndrome. Transient serologic abnormalities, skin lesions, and cardiac anomalies including congenital heart block characterize the syndrome,62–64 which results from the transplancental passage of maternal IgG anti-Ro/La antibody and usually resolves by 8–9 months of age. The antibody may be found in up to 25–30% of women with SLE but may also be an isolated finding in the general population. Once a woman with anti-Ro/La antibodies has given birth to an infant with congenital heart block, the risk in a subsequent pregnancy is about 15%.62

The Management of SLE during Pregnancy Ideally, lupus should be inactive when pregnancy is contemplated. Should the disease flare during pregnancy, treatment must be instituted immediately using the safest, most effective regimen. Prednisone has few adverse effects on the fetus and should be used if necessary. Other drugs with very good safety profiles in SLE include some non-steroidal anti-inflammatory drugs (NSAIDs, naproxen, ibuprofen), antimalarials, and azathioprine. Monitoring During Pregnancy Both the obstetrician and internist should concurrently follow pregnant women with SLE. Efforts should be coordinated to avoid duplication of laboratory tests and inappropriate, overly liberal consultation with other medical specialties. Maternal clinical evaluation in addition to appropriate laboratory testing determines disease activity. If the patient’s serology is concordant with disease activity, then rising anti-dsDNA antibody and falling complement levels will be the markers of a disease flare. Be aware that complement levels in pregnancy are typically elevated so a falling level should be noted, not just a low level. Validated measures of disease activity usually restricted to research protocols can be adapted for use in the clinic.65,66 Labor and Delivery The obstetrician should make the decision regarding the mode of delivery. Most patients with SLE deliver vaginally.

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Corticosteroid supplementation should be administered at labor or prior to a cesarean section in women currently or recently using such medications. Of note, there is no rationale for prophylactically increasing the dose of corticosteroids to prevent a postpartum flare of the disease.65 Breastfeeding The major concern in nursing the neonate is exposure to certain medications that may enter the breast milk. The underlying disease is not an issue in terms of the safety of the infant, but there is some conflicting evidence suggesting an association of disease exacerbation with hyperprolactinemia.65–68 If the disease is active, caution must be exercised due to some medications with which the mother may be treated. Prednisone (up to 30–40 mg/day), hydroxychloroquine, and short acting non-steroidal agents (naproxen, ibuprofen) are considered compatible with breastfeeding. Contraception At one time combined oral contraceptives (estrogencontaining agents) were considered to be at least relatively contraindicated in women with SLE.69–71 This may still be the case in those with aPL as there appears to be increased risk in those patients of thromboembolism.72 However, in those lacking aPL the controversies have been limited to patients with some degree of disease activity. Two recent studies clarified this issue. Neither found any association between combined oral contraceptive use and exacerbation of SLE, providing the woman has stable disease.73,74

Rheumatoid arthritis Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease targeting the joints. Its etiology is unknown but a peculiar host response to a viral infection continues to be hypothesized.75 The disease appears to have no racial predilection and can be considered relatively common, affecting 1% of the population with a female to male ratio of 3:1. Although RA can affect any age group, most patients present between 20 and 60 years of age. The typical clinical picture is a symmetric, inflammatory polyarthritis mainly affecting small to medium-sized synovial joints. Early morning stiffness or gelling, and constitutional symptoms of fatigue and malaise, accompany active disease. The disease is characterized by exacerbations and remissions.76 Extra-articular manifestations attest to the systemic nature of the disease process. Laboratory findings include a normocytic, normochromic anemia as well as abnormalities in a number of acute phase reactants such as elevated platelet count and erythrocyte sedimentation rate (ESR), and hypergammaglobulinemia. Leukopenia is a manifestation of RA with hypersplenism,

or Felty’s syndrome. The classic autoantibody is an IgM anti-immunoglobulin or rheumatoid factor and is detected in the serum of 75–80% of patients with RA. The antinuclear factor (ANA) and several other autoantibodies are often found in Felty’s syndrome. Synovial fluid is characterized by an inflammatory exudate with polymorphonuclear cells and lymphocytes. Radiographic changes range from soft tissue swelling to erosive destruction of the articular surfaces of joints. RA is diagnosed based upon the clinical and laboratory features outlined above. The ACR has revised the classification criteria for RA emphasizing the objective finding of synovitis for a minimum of 6 weeks, ruling out other conditions.75,76

Effect of Hormones and Pregnancy on RA RA is a hormone-sensitive disease. Numerous studies have shown a relationship between the use of oral contraceptives (OC) and RA.77–79 In some studies a protective effect of the higher estrogen containing OC was observed, particularly if used in younger age groups.80 However, the use of OC does not affect the long-term outcome of RA should it develop.78 Prolactin levels may exacerbate RA but breastfeeding for longer than 12 months may actually protect against development of the disease.81 In contrast, breastfeeding for less than 12 months before the onset of RA is associated with an increased risk of developing RA and should it develop, the disease may be more aggressive.82 Karlson et al. also reported that an early age at menarche and irregular menstrual cycles appear to be risk factors for the development of RA.81 There are very few diseases other than RA so dramatically affected by pregnancy. Remission of the disease occurs in almost 80% of pregnant women with RA, usually occurring in the first trimester but is also seen even into the second and third trimesters.83,84 This observation was noted in 1938 when Hench described a marked improvement in rheumatoid disease in 33 of 34 pregnancies occurring in 20 women with RA.85 Since that time, many others have described this tendency in RA.84,86 In addition, there is evidence suggesting that pregnancy may exert a protective effect against the development of RA.87,88 In contrast to the remitting effects of pregnancy on RA, most patients flare 6 weeks to 6 months post partum.89 In addition to confirming this observation, Spector and Da Silva noted an increased risk of developing RA during the postpartum period.90 As mentioned above, some studies even suggest that a postpartum flare and the new onset of RA may be associated with breast-feeding. Barrett et al. found that women breastfeeding for the first time had increased disease activity 6 months postpartum.82,91 It is hypothesized that high levels of the proinflammatory hormone prolactin plays a critical role in the increased incidence of postpartum flares of RA and the onset of new disease.

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Not all patients experience the expected remission during pregnancy. Barrett et al. found that greater than 25% of women with RA continued to have significant disability during pregnancy. Surprisingly, in this prospective study, only 16% of 140 women with RA were in complete remission during pregnancy.92 Recent studies suggest that the effects of pregnancy on the clinical manifestations of RA may be more variable than originally accepted. There has been little success in predicting with any degree of certainty which women with RA will go into a remission during pregnancy. Factors that may be implicated in the variability of effect include disease duration, functional class, and rheumatoid factor positivity but none of these has been shown to have any predictive value. Although remission is expected by the end of the first trimester, there is still a small but significant number of women who show no improvement and indeed, require further intervention during pregnancy to control disease.

Possible Mechanisms of Remission during Pregnancy and Flares Post Partum The remission-inducing effect of pregnancy on RA continues to be the subject of a great deal of creative research. Initially it was hypothesized that the increase in blood cortisol levels during pregnancy was responsible for the induction of remission in pregnant women with RA.85,93 This theory has since been discredited because it has been shown that there is no correlation between the change in RA disease activity during pregnancy and plasma cortisol concentrations.89 Furthermore, plasma cortisol levels normalize within 5 days post partum yet RA flares do not usually occur for another 4–6 weeks. Non-hormonal plasma constituents may possibly play a role in remission induction in RA during pregnancy. Pregnancy zone proteins (PZP) have a suppressive effect on the inflammatory activity of polymorphonuclear leukocytes. It is interesting that the timing of amelioration of RA during pregnancy is associated with the rise of PZP levels. In addition, the lack of improvement in 20–25% of women with RA during a pregnancy may be due to the inability of these individuals to synthesize sufficient amounts of PZP.84,94 The expansion of T regulatory cells with suppressor activity and decreased B cell response in pregnancy (Th2 response) may counter the lack of suppressor activity seen in RA (Th1 response).76,83,95 Therefore the amelioration of RA in pregnancy may be a downregulation of a Th1 response rather than an upregulation of a Th2 response.95 Alternatively, the shift to Th2 cytokines during pregnancy may underlie the amelioration of RA and the shift back to a Th1 cytokine profile is responsible for the postpartum flare.96–99 An intriguing hypothesis has been proposed by Adams et al.100 The hypothesis is based upon the recent observation that placental apoptotic syncytiotrophoblastic debris is extruded into the maternal circulation constituting the

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primary event. This debris contains intracellular fetal HLA Class II molecules. The second event is the uptake of this debris by immature maternal dendritic cells, which then present fetal HLA Class II peptides. The HLA molecules also present HLA self-peptides. In pregnancy, this process should induce immune tolerance of fetal antigens. In RA, the simultaneous presentation of fetal and self HLA peptides by tolerogenic dendritic cells during pregnancy may be the underlying mechanism of amelioration of disease activity. With the disappearance of the apoptotic syncytiotrophoblastic debris postpartum, the remission can no longer be sustained and there is a recurrence of rheumatoid disease activity. This novel hypothesis requires further investigation. Yan et al. from this same group of investigators found that, in pregnancy, rheumatoid disease activity was correlated with maternal serum levels of fetal DNA.101 As the fetal DNA levels increased throughout pregnancy, the disease was either markedly improved or remained in remission. Post partum, as fetal DNA levels decreased, disease activity returned.

Effect of RA on Pregnancy Investigations regarding the effect of RA on pregnancy, as opposed to pregnancy on RA, are less well established. Indeed, there is little adverse disease effect on pregnancy with most issues being related to specific medications. Kaplan and Diamond noted that RA appears to have no significant impact on the patient’s ability to have a normal pregnancy, delivery, and infant.102 Nelson et al. found no increase in infertility in patients with RA, although there was diminished fecundability (the probability of conceiving within one menstrual cycle).103 In a prospective case–control study this group also observed no increase in adverse pregnancy outcomes in women who later developed RA.104 Notwithstanding these observations, women with an active inflammatory systemic disease often have menstrual irregularities with interruption of the pituitary–ovarian axis. This might lead to anovulation with subsequent subfertility. Upon establishing disease control these endocrine abnormalities reverse, with normalization of the menstrual cycle accompanied by ovulation and return of fertility.

Management of RA during Pregnancy The therapeutic objective in both the pregnant and nonpregnant RA patient is to control inflammation, leading to reduction of pain, restoration of function, and prevention of deformity and damage. This is accomplished using a combination of drug therapy, patient education, physiotherapy, and occupational therapy. Ideally the patient should defer pregnancy until she is well controlled on a treatment regimen deemed safe in pregnancy. A pre-pregnancy consultation will assist in this assessment allowing the woman to initiate a pregnancy electively with

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a safe management plan in place. In RA, the major issues when contemplating pregnancy are mostly related to medications. Non-steroidal agents can be used in pregnancy with certain caveats (see below). Naproxen and ibuprofen have a good safety profile in pregnancy. Corticosteroids are not contraindicated but pre-pregnancy counseling for the patient is necessary regarding a moderately increased risk of orofacial cleft in the fetus.105 Antimalarial agents such as hydroxychloroquine have become widely accepted in the treatment of the pregnant woman with RA.106–111 Sulfasalazine can usually be continued during pregnancy with little if any risk to the mother and fetus.107,112,113 It is worthwhile noting that males on sulfasalazine often manifest oligospermia, reversible upon discontinuation of the drug. Immunosuppressive agents such as azathioprine have shown a good safety track record in pregnancy whereas methotrexate should be discontinued 3 months prior to conception.107 Even in males, it is recommended that methotrexate be discontinued 3 months prior to conception.113 The question regarding tumor necrosis factor alpha (TNF-) inhibitors has become very controversial recently114 and at present, the use of such agents including etanercept and infliximab must be viewed as relatively contraindicated during a pregnancy. Because most women with RA experience remission or at least a significant improvement in disease activity during pregnancy, medications can often be discontinued. For those with active disease during pregnancy, treatment must be directed at controlling inflammation while balancing the risk to the fetus with the benefits to the mother’s health. In those women with active disease during pregnancy, the use of prednisone to control moderate to severe disease activity may be unavoidable. Postpartum flare requires aggressive and timely treatment. If the mother is nursing, the drugs of choice for disease control are naproxen, ibuprofen, and prednisone. Antimalarials and sulfasalazine are also deemed safe for breastfeeding. The safety of TNF- inhibitors for nursing mothers has not been established. A review of currently available data suggests that etanercept should be avoided during pregnancy and breastfeeding.115 One case report found clinically significant levels of infliximab in a 6-week-old, breastfed newborn. As the investigators were unable to demonstrate infliximab in the breast milk, they concluded that its presence was the result of transplacental transfer and cautioned against maternal use during pregnancy as both short- and long-term effects on the infant as the result of exposure in utero are unknown.116 General therapeutic measures such as appropriate bedrest, physiotherapy, occupational therapy, and nutrition remain as mainstays in the treatment of active RA.

Issues Surrounding Labor and Delivery Although there are few issues surrounding labor and delivery in women with RA, the usual issues with respect to surgery remain, particularly if rheumatoid disease involves the

cervical spine with atlanto-axial subluxation and its attendant anesthetic risks. Recent population-based studies noted an increase risk of cesarean section, prematurity, and longer hospitalizations at birth among infants born to mothers with RA. These problems may actually be due to disease manifestations or maternal drug therapy.117,118 There is a growing trend, especially in European hospitals, to establish practice guidelines with respect to the management of pregnant women with RA.119

Family Planning Although there is no evidence indicating that RA adversely affects fertility or the ability to carry a pregnancy, counseling regarding medication safety during pregnancy remains the most significant issue when planning a pregnancy in a couple with RA. There are adverse effects on fertility among anti-inflammatory agents and certain immunosuppressants in both men and women.120 Pregnancy itself is not harmful to the potential mother with RA or her infant but she must be cognizant of the emotional and physical stress associated in caring for a newborn.

Seronegative spondyloarthropathies This group of diseases is distinguished from RA by the absence of rheumatoid factor, or seronegativity. Among the diseases included in this category are ankylosing spondylitis (AS), reactive arthritis (formerly Reiter’s syndrome), psoriatic arthritis (PsA), and arthritis associated with inflammatory bowel disease or enteropathic arthritis.121 The common articular features of this group of disorders are sacroiliitis, spondylitis, seronegative polyarthritis, and dactylitis. It is intriguing to note the strong familial aggregation of these disorders both within each entity and among all the entities in the group. The finding of a strong association with HLA B27 supports the interrelationship of these diseases. The diagnosis of a seronegative arthropathy is based upon clinical features including both articular and extra-articular, and the radiologic findings of sacroiliitis and spondylitis. Other than a negative rheumatoid factor, the laboratory findings are not very helpful: the ESR is usually normal. HLA typing may be helpful in dealing with a diagnostic challenge. Other than PsA, seronegative disorders are more common in men than women, which distinguishes them from most other rheumatic diseases. The diagnosis of AS in a woman is often missed due to the milder nature of the disease process compared to that seen in men.122

Spondyloarthropathies and Pregnancy There are few studies on the interaction of seronegative diseases and pregnancy. In his report of 14 patients with AS,

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Hart concluded there was no change in the progress of the disease and childbirth had little or no effect on its course,123 Others have observed that pregnancy has no ameliorating effect on AS and there is no adverse effect of the disease on the pregnancy.124 The course of AS is independent of pregnancy, with each running a separate course. Flares during pregnancy occur but are likely the natural history of the disease rather than a relationship to pregnancy. In contrast, the majority of pregnant patients with PsA show an improvement in both skin and joint disease125,126 and like RA, remission during pregnancy in PsA is relatively common (up to 70% of patients), and there is frequently a postpartum flare. Treatment of AS as well as other seronegative diseases may involve the use of non-steroidal agents such as naproxen or ibuprofen. These agents can be used in pregnancy safely until week 32 when they must be discontinued. Corticosteroids may also be used and can be continued throughout pregnancy. Physical therapy is particularly helpful in treating sacroiliitis and spondylitis. In the pregnant woman, postural and breathing exercises may be especially important.

Scleroderma (progressive systemic sclerosis) Progressive systemic sclerosis (PSS) is a relatively uncommon disease characterized by fibrosis and a vasculopathy in skin, joints, and internal organs.125,127 The incidence of the disease is only 2–12 cases per million population annually, with a global distribution. Women are affected 3–4 times more than men, with most patients presenting between 30 and 50 years of age. The main pathologic lesion is vascular with a concentric proliferation of the intima and fibrosis of the adventitia of small arteries and arterioles.127 The most common clinical feature of PSS is Raynaud’s phenomenon, which may predate other features by years. Skin and joint involvement is common as is dysphagia due to esophageal dysmotility. Renal involvement is the leading cause of death in PSS, typically manifested as the sudden onset of malignant hypertension. Poor prognostic signs in this disease include the presence of renal disease and pulmonary hypertension.128 Laboratory features of PSS are anemia due to chronic illness, microangiopathic hemolysis in cases of rapidly progressive renal failure, an elevated ESR, hypergammaglobulinemia, and a positive ANA. The diagnosis of PSS, however, is based on clinical features.129

Effect of Scleroderma on Pregnancy There are few reports on scleroderma and pregnancy probably because it is such a rare disease, and it usually presents in postmenopausal women. Although there was some concern regarding an increase in infertility in women with PSS,

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Steen and Medsger were unable to confirm this when compared to controls.130–132 An increased incidence of spontaneous abortions in women with PSS was observed in a case–control study, which included healthy controls.132 Fourteen percent of pregnancies resulted in fetal demise usually in the first trimester and in women destined to develop PSS.133 In addition, patients with PSS have higher rates of perinatal death and a greater frequency of small for gestational age neonates compared with a general population. However, even in women with severe PSS, successful pregnancies can occur if the complications of the disease are adequately treated in a timely fashion.134,135

Effect of Pregnancy on Scleroderma Early literature reported patients with diffuse PSS having an exacerbation of their disease during pregnancy to the point of maternal death.136,137 However, in a later study using a questionnaire, authors reported that maternal complications were no more frequent than patients with RA or in normal controls.131 A prospective study of 67 pregnancies demonstrated that in 61% symptoms remained stable, 20% of pregnancies improved, and the remainder noted worsening.133 If PSS progresses rapidly with cardiac or renal involvement, the effect of pregnancy may aggravate matters significantly.137–141 Esophagitis is often exacerbated by PSS. Raynaud’s phenomenon on the other hand usually improves during pregnancy due the peripheral vasodilation characteristic of pregnancy.138 Many patients do well during pregnancy, but for some, disease exacerbation may be precipitated by pregnancy. Pregnant women with PSS must be monitored closely by the internist/rheumatologist and obstetrician, with particular attention paid to blood pressure and renal function.

Treatment of Scleroderma There is no specific treatment for scleroderma. Treatment modalities are directed towards suppression of the microvascular abnormalities and the process underlying the progressive fibrosis characteristic of this condition.125 To date, there are no pharmacologic or biologic agents that have demonstrated significant efficacy to warrant their recommendation in this condition. Management of scleroderma must be supportive and attempt to be preventative of disease progression whether the patient is pregnant or not. Supportive measures may include patient education, avoidance of exposure to cold and compliance with a physiotherapy program to preserve hand function and thereby minimize contractures. Skin treatment in pregnancy is aimed at symptomatic relief of pruritis and the prevention of digital ulcers due to Raynaud’s phenomenon. The usual treatment of Raynaud’s phenomenon with calcium channel blocking agents such as nifedipine can also be used in pregnancy. In most pregnant women with Raynaud’s phenomenon, the problem is

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usually ameliorated by the generalized vasodilatation associated with pregnancy. Systemic treatment of organ involvement is often necessary with medications selected to be safe in pregnancy. Antihypertensive agents such as alpha-methyldopa and calcium channel antagonists such as nifedipine are considered compatible with pregnancy and may be used to treat hypertension. If renal failure is present, dialysis may be required. In the case of severe cardiac, pulmonary or renal disease, termination of the pregnancy is recommended. Should myositis occur, corticosteroids are useful. Esophageal dysmotility leading to gastric reflux is common in scleroderma. It is a common problem in general in pregnancy and may be quite disabling when the woman also has scleroderma. Treatment with antacids, H2-blocking agents, and metoclopramide are often effective and may be used in pregnancy. The most effective therapy is proton pump inhibition. A multicenter prospective controlled study concluded that proton pump inhibitors do not represent a major teratogenic risk,142 but the recommendation is still to use such agents only when the potential benefits outweigh the risks (US Food and Drug Administration, FDA, Category C-‘Risk cannot be ruled out’, Table 53.2). The Teratogen Information System, TERIS, concludes that the doses required during pregnancy would be unlikely to pose a risk to the fetus. Pre-delivery anesthesia consultation may be beneficial owing to the special challenges inherent in scleroderma. Certain physical limitations may be present due to contractures of the skin, hips, and extremities. Ideally, during delivery the environment should be kept warm, including the provision of intravenous fluids. The patient should wear thermal socks and the application of warm compresses should be used to minimize problems of Raynaud’s phenomenon, which can occur during labor and delivery.138 Postpartum management involves monitoring the patient’s blood pressure, which may be a harbinger of a renal crisis. A pregnant woman with scleroderma usually experiences a good outcome medically and obstetrically. Owing to the rarity of this condition and the dearth of published literature concerning pregnancy in scleroderma, it is still not clear whether there is a higher frequency of pregnancy loss or adverse pregnancy outcome.130,134,143 However, the adverse outcomes described in earlier literature do not seem to be as frequent today. Nonetheless, owing to the medical issues as well as the possibility of prematurity and small for Table 53.2  FDA classification of drugs in pregnancy Class A B C D X

Controlled studies show no risk No evidence of risk in humans Risk cannot be ruled out Positive evidence of risk Contraindicated in pregnancy

gestational age neonate, women with scleroderma should attend a high-risk pregnancy unit and be managed by a perinatologist. Pre-pregnancy evaluation and planning as well as close medical and obstetrical monitoring to enable early and aggressive therapeutic intervention should promote a higher probability of a successful pregnancy outcome for both mother and neonate.

Pharmacologic treatment of rheumatic disease and reproduction The assessment of any pregnant patient with rheumatic disease or those contemplating pregnancy must include consideration of current medications and, in some cases, previous exposure to specific pharmacologic agents. Although most drugs may be safe while the man and woman are attempting to conceive, some must be discontinued during pregnancy and yet others require discontinuation some time prior to conception.

Non-steroidal Anti-inflammatory Drugs (NSAIDs) NSAIDs are commonly used in the treatment of the arthritis manifested in many rheumatic diseases. Many are now available over the counter, making it of paramount importance that the obstetrician and internist be aware of all medications consumed by the patient whether prescribed or self-administered. Most NSAIDs are safe to use for couples attempting to conceive. However, for women, some agents can inhibit follicular rupture, preventing the release of the oocyte and thereby contributing to subfertility.144,145 This is not a common phenomenon, occurring in about 10% of women taking such agents (personal observations). In addition, NSAIDs may inhibit the motility of the fallopian tubes and by extension, the passage of the oocyte down the tubes.146,147 Although these issues might arise with the use of any NSAID due to the inhibition of cyclooxygenase, the most widely studied agent is indomethacin.148,149 During pregnancy, naproxen and ibuprofen are the two most commonly used NSAIDs. Indeed, there is too little in the literature regarding any other drug in this class other than indomethacin to have any knowledge regarding their safety profiles. When considering naproxen and ibuprofen in pregnancy, the fetal risk category is B but is reclassified as C when used in high doses. Peripartum there is concern with respect to the neonate regarding intracranial hemorrhage, premature closure of the ductus arteriosus, and impaired renal function leading to a decrease in amniotic fluid volume. The patient should be informed that NSAIDs will start being tapered by week 25 and completely discontinued by week 32 at the latest (6–8 weeks prior to the expected date of delivery).

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A population-based study in Denmark indicated that there might be some association with the use of NSAIDs and early pregnancy loss.150 However, the study fails to indicate the reason for the use of the drugs or if there was an underlying disorder that might predispose to pregnancy loss. It is interesting to note that in women with RA, in whom the use of NSAIDs would be quite extensive, there does not appear to be any increased incidence of pregnancy loss. Clearly, further studies need to be undertaken to support or refute the Danish observation. Aspirin (ASA) has become a commonly used drug in pregnancy.151 Despite a continuing lack of consensus, it has been variously recommended as a pre-treatment for ovulation induction, for the promotion of implantation in in vitro fertilization cycles, and for the prevention of pregnancy loss.152–154 It has been shown to provide moderate but consistent reductions in the relative risk of pre-eclampsia and preterm delivery.155 ASA appears to be a safe agent to use in pregnancy with the exception of a reported increased incidence of gastroschisis in the offspring of women taking ASA in the first trimester.156,157 Regardless of the very low frequency of this side effect (1/1 000 compared to 1/10 000 in the general population), patients should still be counseled regarding the potential association prior to initiating ASA therapy during pregnancy. ASA is also capable of prolonging labor and may cause an increase in antepartum and postpartum bleeding. It is actually for the latter reasons that it has an FDA classification of C/D when used in the third trimester. To avoid the issues surrounding labor and delivery, discontinuation of ASA 4 weeks prior to the expected date of delivery should be implemented. The American Academy of Pediatrics (AAP) considers ASA, naproxen, and ibuprofen compatible with breastfeeding but as always, the lowest effective dose should be used.

Anticoagulants The patient with APS and previous thrombosis should receive anticoagulation treatment throughout their pregnancy and during the postpartum period.158 As discussed earlier, data supporting the use of heparin treatment in women with pregnancy loss and APL with no history of thrombosis are inconclusive and evidence-based standards of care both during the peripartum and postpartum periods are lacking.159 Once the decision to use heparin has been made, low-molecular weight heparin (LMWH) is perceived to be more desirable than unfractionated heparin (UFH), despite a Cochrane Review recommending the use of unfractionated heparin160 as LMWH carries less of a risk of osteoporosis and thrombocytopenia and can be administered once daily (161). Two small studies comparing UFH and LMWH did not show differences in efficacy but larger prospective data are needed.162,163 LMWH treatment over the duration of a pregnancy can be associated with osteopenia and therefore calcium and vitamin D supplementation should be recommended during pregnancy.164,165

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Antimalarial Agents Antimalarials are used extensively in both RA and SLE. The major side effect is retinal toxicity, which requires ophthalmologic monitoring every 6–12 months. The favored antimalarial is hydroxychloroquine (FDA Category C), which appears to have a lower incidence of retinal toxicity. Numerous studies have attested to the safety of antimalarials in pregnancy.106,166,167 All of the investigators have commented that the risk of a flare of disease far outweighs any risk of fetal toxicity. In a follow-up study of the children born to mothers on hydroxychloroquine during pregnancy, Klinger et al. found no evidence of retinal toxicity, prompting these authors to conclude that there appears to be little or no risk of ocular toxicity in children exposed to hydroxychloroquine in utero.168 This observation has been confirmed by Motta et al.169 The AAP has categorized hydroxychloroquine to be safe in the nursing mother.

Corticosteroids Corticosteroids are commonly used in the treatment of most rheumatic diseases and are associated with a rapid or relatively rapid therapeutic response. In RA most patients achieve a response using low doses of prednisone (5–10 mg/day). In SLE, prednisone doses are usually higher, with minor organ disease requiring 10–40 mg/day and major organ manifestations treated with 40–80 mg/day. In all cases, the lowest effective dose of prednisone should be used. The use of prednisone in pregnancy is associated with few adverse side effects on the fetus. Maternal side effects are dose-related. The commonest side effects are hypertension and gestational diabetes mellitus. In a double-blind, randomized controlled trial, Laskin et al. observed an incidence of gestational diabetes mellitus of 15% and hypertension 13% in the prednisone-treated group compared to 5% in the placebo group for either condition.54 The cushingoid side effects and osteopenia occur similarly to that seen in the non-pregnant state. Fetal side effects are few and uncommon. Orofacial clefting in the offspring of mothers treated with corticosteroids during the first trimester has been reported.105,170 The results in these studies have been supported by the findings in a recent meta-analysis where the prevalence of orofacial clefting in prednisone-exposed infants was 1/400 compared to 1/800 in the general population.171 In spite of the low risk of this potential side effect, any pregnant woman on corticosteroids should be counseled appropriately. Premature birth has been described in pregnant women treated with corticosteroids. In a randomized trial referred to above, Laskin et al. found premature births before 37 weeks gestation in 62% of the prednisone-treated group compared to 11% in the placebo group.54 The neonates were all appropriate size for gestational age. Prednisone is classified as D

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when used in the first trimester. The physician must weigh potential risks versus benefits when prescribing these agents. The AAP considers prednisone to be compatible with breastfeeding. There appears to be minimal exposure with maternal doses at 30–40 mg/day.

Sulfasalazine Sulfasalazine (SSZ) is used with reasonable success in RA, spondyloarthropathies, and inflammatory bowel disease. The drug appears to be safe in pregnancy with most of the evidence gathered from its use in Crohn’s disease.172–175 Although there are no reported issues with respect to female fertility, males treated with SSZ are often found to have low sperm counts and motility. The oligoasthenaspermia is reversible but requires at least 2 months avoidance of SSA.172,176 Owing to a report of bloody diarrhea in an infant breastfed by a woman on SSA, the AAP recommends caution when nursing on SSA.177,178

Azathioprine Azathioprine (AZA) is used in many rheumatic diseases for its immunosuppressive properties and as a steroid-sparing agent. Among all immunosuppressive agents, AZA appears to be the safest in pregnancy. The placenta reportedly forms a relative barrier to AZA and its metabolites.179 In a recent study of 189 women exposed to AZA compared to 230 controls not exposed to any teratogens during pregnancy, outcomes associated with AZA included increased rates of spontaneous abortions, intra-uterine growth restriction (IUGR), and prematurity,180 but no increase in the occurrence of major malformations. However, as larger studies are required to confirm these results, AZA continues to be a Class D drug. With few data available regarding the safety of AZA in breastfeeding, the AAP has recommended that mothers avoiding nursing while being treated with this agent.

accumulates leading to toxicity.183 The AAP categorizes MTX as contraindicated in nursing mothers.

Cyclophosphamide Cyclophosphamide (CTX) is a cytotoxic, alkylating agent used in the treatment of severe major organ involvement in SLE and specific vasculitides. It has been categorized as a Class D drug by the FDA. CTX is embryotoxic and associated with many anomalies upon exposure in the first trimester. However, it does not appear to be associated with abnormalities if used in the second and third trimesters. Regardless, the drug should not be used in pregnancy unless there is a life-threatening problem and even then restricted to use late in the pregnancy. CTX is contraindicated in the nursing mother owing to the risk of neutropenia, immunosuppression, growth disturbances, and potential carcinogenesis in the neonate.173,174,183

Cyclosporine Cyclosporine A (CSA, FDA Classification C) is used to treat certain manifestations of SLE renal disease. Most of the literature surrounding the use of CSA in pregnancy deals with renal transplantation. There appears to be little evidence that CSA crosses the placenta to any significance184–186 and current data indicate that it is probably safe in pregnancy with no specific anomalies described.187–189 Adverse pregnancy outcomes such as prematurity and IUGR likely have more to do with the underlying disease process than treatment with CSA.190 CSA is excreted in breast milk and is associated with immunosuppression, neutropenia, and growth disturbances in the neonate. The AAP categorizes CSA as contraindicated in the nursing mother.

Mycophenolate Methotrexate Methotrexate (MTX), a drug used with good success in RA, is a folic acid antagonist. Use in pregnancy has been associated with spontaneous abortions due to embryotoxicity. The drug has definite association with numerous fetal anomalies as well as IUGR.181–183 MTX is not to be used in pregnancy and has an FDA Category X rating. Owing to MTX binding to tissues, it is recommended that it be discontinued at least 3 months prior to conception. A similar recommendation applies to men taking MTX but evidence is lacking to support such a recommendation.182 However, until the situation is clarified, it is recommended that both men and women avoid pregnancy for at least 3 months after discontinuing MTX.181–183 MTX is only excreted in breast milk to a very small degree. However, it binds to neonatal tissues and therefore

Mycophenolate mofetil (MMF) is a purine biosynthesis inhibitor. Its use in pregnancy is accompanied by several congenital anomalies and spontaneous abortions.187,191–193 These findings have been noted not only in animal studies but also in humans. In addition, a possible characteristic phenotype has been described.192 Although MMF does not appear to impact male fertility, paternal exposure may be associated with congenital anomalies.191 Recommendations in women regarding discontinuation of MMF prior to conception vary from 3 to 12 weeks. It would appear that avoidance of this drug by females at least 6 weeks prior to conceiving may be the most appropriate whereas for males, the recommendation is 12 weeks’ avoidance. This is an FDA Class D drug and should be avoided in pregnancy. Since MMF is excreted into breast milk, it should not be administered to nursing mothers.

C h a p t e r 5 3    Pregnancy and Autoimmune Rheumatic Disease l

Leflunomide Leflunomide, a pyrimidine synthesis inhibitor, is used in the treatment of RA. The active metabolite has a half-life of 2 weeks. Owing to teratogenicity and embryotoxicity in animals when administered in human-equivalent doses, the drug is FDA Class X and is contraindicated in pregnancy. If pregnancy is contemplated, there is an elimination or washout protocol that should be undertaken by both men and women exposed to the drug. It may take up to 2 years after the last dosing before reaching undetectable levels. The elimination protocol is likely ineffective should the woman already be pregnant. It is therefore recommended that under such circumstances, the woman should be advised to terminate the pregnancy. Evidence regarding the transfer of leflunomide into breast milk is insufficient, and until conclusive results are obtained, breastfeeding is therefore not recommended.120

TNF- Antagonists The two most commonly used anti-TNF- agents are etanercept and infliximab, both of which are FDA Category B drugs and both of which are used in the treatment of RA, with infliximab being used most frequently in spondyloarthropathies. At present the data reported in the literature are very controversial.187,194–199 While a review of 131 women directly exposed to infliximab during pregnancy found no increase in proportion of live births, miscarriages, or therapeutic terminations compared to the US general population,199 a case report documented a possible causal relationship between maternal use of etanercept during pregnancy and the VATER or VACTERL complex of congenital anomalies (vertebral anomalies; anal atresia; cardiac defect; tracheoesophageal fistula; renal abnormalities; and limb abnormalities) occurring in the neonates.196 Further studies into this association must be undertaken before a clear recommendation regarding the use of anti-TNF- agents in pregnancy can be offered. At present, the common recommendation is to discontinue the agents once the woman is pregnant. Only in those cases where the mother’s health is in jeopardy might anti-TNF- agents be considered. However, all patients must be counseled regarding the potential fetal toxicity of these agents and the fact that very little is known about their use in pregnancy and lactation. Other biologics such as rituximab, adalimumab, anakinra and abatacept, fall into a similar category as etanercept and infliximab except even less is known about their effects in pregnancy.200,201 There is insufficient information regarding these agents in the nursing mother, although one group of investigators, unable to demonstrate infliximab in the breast milk, concluded that its presence in a 6-week-old neonate was due to transplacental transfer. The maternal use of TNF- antagonists should continue to be restricted until the short- and long-term

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effects on the infant resulting from exposure in utero and in breast milk have been more completely elucidated.116

Conclusion Management of pregnancy in women with rheumatic disease requires the physician to have a detailed knowledge of the patient’s disease history, including her typical clinical manifestations, laboratory markers, and flare indicators. Ideally, a pregnancy should be planned with the patient to ensure conception occurs during a period of clinical quiescence after appropriate withdrawal of any fetotoxic agents. With improvements in disease management and perinatal monitoring, in addition to collaboration between rheumatologists and perinatologists, there is now a good prognosis for both mother and fetus for the majority of women with rheumatic disease.

References 1. Doria A, Iaccarino L, Arienti S, et al. Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases. Reprod Toxicol 2006;22:234–241. 2. Laskin CA. Pregnancy and the rheumatic diseases. In: GN Burrow, TP Duffy, JA Copel, eds. Medical Complications During Pregnancy, sixth ed. Philadelphia, PA: Elsevier Saunders; 2004:429–449. 3. Lahita RG, Chiorazzi N, Reeves WH, eds. Textbook of the Autoimmune Diseases. Philadelphia, PA: Lippincott Williams & Wilkins; 2000. 4. Roitt IM, Delves PJ. Roitt’s Essential Immunology, tenth ed. London: Blackwell Science; 2001, 182. 5. Tan EM, Cohen AS, Tan EM, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–1277. 6. Arnett FC. The genetics of human lupus. In: DJ Wallace, BH Hahn, eds. Dubois’ Lupus Erythematosus, fifth ed. Baltimore, MD: Williams & Wilkins; 1997:77–117. 7. Gladman DD, Urowitz MB, Cole E, Ritchie S, Chang CH, Churg J. Kidney biopsy in SLE. 1: clinical-morphologic correlations. Q J Med 1989;73:1125–1133. 8. Fraga A, Mintz G, Orozco J. Sterility and fertility rates, fetal wastage and maternal morbidity in systemic lupus erythematosus. J Rheumatol 1974;1:283–288. 9. Sanchez-Guerrero J, Karlson EW, Liang MH, Hunter DJ, Speizer FE, Colditz GA. Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum 1997;40:804–808. 10. Huong DL, Wechsler B, Piette JC. Risks of ovulation induction therapy in systemic lupus erythematosus. Br J Rheumatol 1996;35:1184–1186. 11. Huong DL, Wechsler B, Vauthier-Brouzes D, et al. Importance of planning ovulation in systemic lupus erythematosus and antiphospholipid syndrome: a single center retrospective study of 21 cases and 114 cycles. Semin Arthritis Rheum 2002;32:174–188.

640

s e c t i o n 9     Immunology l

12. Guballa N, Sammaritano L, Schwartzman S, Buyon J, Lockshin MD. Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome. Arthritis Rheum 2002;43:550–556. 13. Ellis FA, Bereston ES. Lupus erythematosus associated with pregnancy and menopause. AMA Arch Dermatol Syphilol 1952;69:170–176. 14. Garsenstein M, Pollak VE, Kark RM. Systemic lupus erythematosus and pregnancy. N Engl J Med 1962;267:165–169. 15. Mund A, Simson J, Rothfield N. Effect of pregnancy on the course of systemic lupus erythematosus. JAMA 1963;183:917–920. 16. Zurier RB. Systemic lupus erythematosus and pregnancy. Clin Rheum Dis 1975;1:613–616. 17. Grigor RR, Shervington PC, Hughes GRV, Hawkins DF. Outcome of pregnancy in systemic lupus erythematosus, Proc. R. Soc. Med. 70 99–100. 18. Tozman EC, Urowitz MB, Gladman DD. Systemic lupus erythematosus and pregnancy. J Rheumatol 1980;7:624–632. 19. Zulman MI, Talal N, Hoffman GS, Epstein WV. Problems associated with the management of pregnancies in patients with systemic lupus erythematosus. J Rheumatol 1980;7:37–49. 20. Lockshin MD, Reinitz E, Druzin ML, Murrman M, Estes D. Lupus pregnancy: case control study demonstrating absence of lupus exacerbations during and after pregnancy. Am J Med 1984;77:893–898. 21. Lockshin MD. Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis Rheum 1989;32:665–670. 22. Petri M. Hopkins lupus pregnancy center: 1987–1996. Rheum Dis Clin North Am 1997;23:1–13. 23. Ruiz-Irastortza G, Lima F, Alves J, et al. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol 1996;35:133–138. 24. Cortes-Hernandez J, Ordi-Ros J, Paredes F, Casellas M, Castillo F, Vilardell-Tarres M. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective stud of 103 pregnancies. Rheumatology (Oxford) 2002;41:643–650. 25. Urowitz MB, Gladman DD, Farewell VT, Stewart J, McDonald J. Lupus and pregnancy studies. Arthritis Rheum 1993;36:1392–1397. 26. Yasmeen S, Wilkins EE, Field NT, Sheikh RA, Gilbert WM. Pregnancy outcomes in women with systemic lupus erythematosus. J Maternal Fetal Med 2001;10:91–96. 27. Clark CA, Spitzer KA, Nadler JN, Laskin CA. Preterm deliveries in women with systemic lupus erythematosus. J Rheumatol 2003;30:2127–2132. 28. Jungers P, Dougados M, Pelissier C, et al. Lupus nephropathy and pregnancy. Arch Intern Med 1982;142:771–776. 29. Huong DL, Wechsler B, Vauthier-Brouzes D, et al. Pregnancy in past or present lupus nephritis: a study of 32 pregnancies from a single centre. Ann Rheum Dis 2001;60:599–604. 30. Bobrie G, Liote F, Houillier P, et al. Pregnancy in lupus nephritis and related disorders. Am J Kidney Dis 1987;9:339–343. 31. Moroni G, Quaglini S, Banfi G, et al. Pregnancy in lupus nephritis. Am J Kidney Dis 2002;40:713–720. 32. Tandon A, Ibaniz D, Gladman DD, Urowitz MB. The effect of pregnancy on lupus nephritis. Arthritis Rheum 2004;50:3941–3946. 33. Nossent HC, Swaak TJ. Systemic lupus erythematosus. VI. Analysis of the interrelationship with pregnancy. J Rheumatol 1990;17:771–776.

34. Morris WI. Pregnancy in rheumatoid arthritis and systemic lupus erythematosus. Aust N Z J Obstet Gynecol 1969;9:136–144. 35. Friedman EA, Rutherford JW. Pregnancy and lupus erythematosus. Obstet Gynecol 1956;8:601–610. 36. Lima F, Buchanan NMM, Kamashta MA, Kerslake S, Hughes GR. Obstetric outcome in systemic lupus erythematosus. Semin Arthritis Rheum 1995;25:184–192. 37. Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J Rheumatol 2005;32:1709–1712. 38. McNeill HP, Chesterman CN, Krilis SA. Immunology and clinical importance of antiphospholipid antibodies. Adv Immunol 1991;8:425–426. 39. Tseng CE, Buyon JP. Neonatal lupus syndrome. Rheumatic Dis Clin North Am 1997;23:31–54. 40. Elias M, Eldor A. Thromboembolism in patients with the ‘lupus’ type circulating anticoagulant. Arch Intern Med 1984;144:510–515. 41. Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980;92:156–159. 42. Lockshin MD, Druzin ML, Goei S, et al. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 1985;313:152–156. 43. Clark-Soloninka CA, Spitzer KA, Nadler JN, Laskin CA. Evaluation of screening 590 plasma samples for the lupus anticoagulant using a panel of four tests. Arthritis Rheum 1998;41(Suppl.):S168. 44. Martinez-Rueda JO, Arce-Salinas CA, Kraus A, AlcocerVarela J, Alarcon-Segovia D. Factors associated with fetal loss in severe systemic lupus erythematosus. Lupus 1996;5:113–119. 45. Hanly JG, Gladman DD, Rose TH, Laskin CA, Urowitz MB. Lupus pregnancy: a prospective study of placental changes. Arthritis Rheum 1998;31:358–366. 46. Abramowsky CR, Vegas ME, Swinehart G, Gyves MT. Decidual vasculopathy of the placenta in lupus erythematosus. N Engl J Med 1980;303:668–672. 47. Guzman E, Schulman H, Bracero L, Rochelson B, Farmakides G, Coury A. Uterine-umbilical artery Doppler velocimetry in pregnant women with systemic lupus erythematosus. J Ultrasound Med 1992;11:275–281. 48. Carreras LO, Defreyn G, Machin SJ, et al. Arterial thrombosis, intrauterine death and ‘lupus’ anticoagulant: Detection of immunoglobulin interfering with prostacyclin formation. Lancet 1981;1:244–246. 49. Geis W, Branch DW. Obstetric implications of antiphospholipid antibodies: pregnancy loss and other complications. Clin Obstet Gynecol 2001;44:2–10. 50. Out HJ, Bruinsem HW, Chrustuaebs GCML, et al. A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies. Am J Obstet Gynecol 1992;167:26–32. 51. Vinatier D, Dufour P, Cosson M, Houpeau JL. Antiphos­ pholipid syndrome and recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol 2001;96:37–50. 52. Soloninka CA, Laskin CA, Wither J, Wong D, Bombardier C, Raboud J. Clinical utility and specificity of anticardiolipin antibodies. J Rheumatol 1991;18:1849–1855.

C h a p t e r 5 3    Pregnancy and Autoimmune Rheumatic Disease l

53. Lubbe WFF, Butler WS, Palmer SJ, Liggins GC. Fetal survival after prednisone suppression of maternal lupus anticoagulant. Lancet 1983;2:1361–1363. 54. Laskin CA, Bombardier C, Hannah M, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997;337:148–153. 55. Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipids antibodies (or antiphospholipid antibodies). Br Med J 1997;314:253–57. 56. Huong DL, Wechsler B, Bletry O, Vauthier-Brouzes D, Lefebvre G, Piette JC. A study of 75 pregnancies in patients with antiphospholipid syndrome. J Rheumatol 2001;28:2025–30. 57. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002;100:408–13. 58. Shehata HA, Nelson-Piercy C, Khamashta MA. Management of pregnancy in antiphospholipid syndrome. Rheum Dis Clin North Am 2001;27:643–59. 59. Laskin CA, Spitzer KA, Clark CA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol 2009;36:279–87. 60. Bresnihan B, Grigor RR, Oliver M, et al. Immunological mechanism for spontaneous abortion in systemic lupus erythematosus. Lancet 1997;2:1205–7. 61. Empson M, Lassere M, Craig JC, Scott JR. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol 2002;100:135–44. 62. Escobar MC, Gomez-Puerta JA, Albert D, Ferrer Q, Girona J. Recurrent congenital heart block in neonatal lupus. Clin Rheumatol 2006;26:1161–63. 63. Brucato A, Doria A, Frassi M, et al. Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study. Lupus 2002;11:716–21. 64. Lee LA, Harmon CE, Huff C, Norris DA, Weston WL. The demonstration of SSA/Ro antigen in human fetal tissues and in neonatal and adult skin. J Invest Dermatol 1985;85:143–46. 65. Ruiz-Irastorza G, Lima F, Alvers J, et al. Increaed rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol 1996;35:133–38. 66. Urowitz MB, Gladman DD. Measures of disease activity and damage in SLE. Baillière’s Clin Rheumatol 1998;12:405–13. 67. Mok CC, Wong RW, Lau CS. Exacerbation of systemic lupus erythematosus by breast feeding. Lupus 1998;7:569–70. 68. Ostensen M. Sex hormones and pregnancy in rheumatoid arthritis and systemic lupus erythematosus. Ann N Y Acad Sci 1999;876:131–43. 69. Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Gilkeson GS. Hormonal and reproductive risk factors for development of systemic lupus erythematosus: results of a populationbased, case-control study. Arthritis Rheum 2002;46:1830–39. 70. Gill D. Rheumatic complaints of women using antiovulatory drugs. J Chron Dis 1968;21:435–44. 71. Dubois EL, Strain L, Ehn M, Bernstein G, Friou GJ. LE cells after oral contraceptives. Lancet 1968;2:679. 72. Chapel TA, Burns RE. Oral contraceptives and exacerbation of lupus erythematosus. Am J Obstet Gynecol 1971;110:366–69.

641

73. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med 2005;353:2550–58. 74. Sanchez-Guerrero J, Uribe AG, Jimenez-Santana L, et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med 2005;353:2539–49. 75. Firestein G. Etiology and pathogenesis of rheumatoid arthritis. In: WN Kelley, ED Harris, S Ruddy, CB Sledge, eds. Textbook of Rheumatology, 5th ed. vol. I. Philadelphia, PA: WB Saunders; 1997. 76. Harris ED Jr. Clinical features of rheumatoid arthritis. In: WN Kelley, ED Harris, S Ruddy, CB Sledge, eds. Textbook of Rheumatology, fifth ed. vol. I. Philadelphia, PA: WB Saunders; 1997. 77. Merlino LA, Cerhan JR, Cirswell LA, Mikuls TR, Saag KG. Estrogen and other female reproductive risk factors are not strongly associated with the development of rheumatoid arthritis in elderly women. Semin Arthritis Rheum 2003;33:72–82. 78. Drossaers-Bakker KW, Zwinderman AH, van Zeben D, Breedveld FC, Hazes JM. Pregnancy and oral contraceptive use do not significantly influence outcome in long term rheumatoid arthritis. Ann Rheum Dis 2002;61:405–8. 79. Bhatia SS, Majkam DS, Kitelson JM, Norris JM, et al. Rheumatoid factor seropositivity is inversely associated with oral contraceptive use in women without rheumatoid arthritis. Ann Rheum Dis 2007;66:267–69. 80. Doran MF, Crowson CS, O’Fallon WM, Gabriel SE. The effect or oral contraceptives and estrogen replacement therapy on the risk of rheumatoid arthritis: a population based study. J Rheumatol 2004;31:207–13. 81. Karlson EW, Mandl LA, Hankinson SE, Grodstein F. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses’ Health Study. Arthritis Rheum 2004;50:3458–67. 82. Jorgensen C, Piot MC, Bologna C, Sany J. Oral contraception, parity, breast feeding, and severity of rheumatoid arthritis. Ann Rheum Dis 1996;55:94–98. 83. Ostensen M, Villiger PM. Immnunology of pregnancy-pregnancy as a remission inducing agent in rheumatoid arthiritis. Transplant Immunol 2002;9:155–60. 84. Persellin RH. The effect of pregnancy on rheumatoid arthritis. Bull Rheum Dis 1976-1977;27:922–27. 85. Hench PS. The amelioration effect of pregnancy on chronic atrophic (infectious) rheumatoid arthritis, fibrositis and intermittent hydrarthrosis. Proc Mayo Clinic 1938;13:161. 86. Bulmash JM. Rheumatoid arthritis and pregnancy. Obstet Gynecol Ann 1979;8:223–76. 87. Hazes JMW, Dukmans BAC, Vandenbroucke JP, de Vries RR, Cats A. Pregnancy and the risk of developing rheumatoid arthritis. Arthritis Rheum 1990;33:1770–75. 88. Silman A, Kay A, Brennan P. Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis Rheum 1992;35:152–55. 89. Nelson JL, Ostensen M. Pregnancy and rheumatoid arthritis. Rheum Dis Clin North Am 1997;23:195–221. 90. Spector TD, Da Silva JAP. Pregnancy and rheumatoid arthritis: an overview. Am J Reprod Immunol 1992;28:222–25. 91. Barret JH, Brennan P, Fiddler M, Silman A. Breast-feeding and postpartum relapse in women with rheumatoid and inflammatory arthritis. Arthritis Rheum 2000;43:1010–15.

642

s e c t i o n 9     Immunology l

92. Barrett JH, Brennan P, Fiddler M, Silman AJ. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum 2000;42:1219–27. 93. Plotz CM, Goldenberg A. Rheumatoid arthritis. In: JJ Ravinsky, AF Gutman, eds. Medical, Surgical and Gynecological Complications of Pregnancy, second ed. Baltimore, MD: Williams & Wilkins; 1965. 94. Neely NT, Persellin RH. Activity of rheumatoid arthritis during pregnancy. Texas Med 1977;73:59–63. 95. Ostensen M, Villiger PM. The remission of rheumatoid arthritis during pregnancy. Semin Immunopathol 2007;29:185–91. 96. Shimoaka Y, Hidaka Y, Tada H, et al. Changes in cytokine production during and after normal pregnancy. Am J Reprod Immunol 2000;44:143–47. 97. Elenkov IJ, Wilder RL, Bakalov VK, et al. IL-12, TNFalpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metabol 2001; 86:4933–38. 98. Weetman AP. The immunology of pregnancy. Thyroid 1989 1999;9:643–46. 99. Van Roon JA, Bijlsma JW, Lafeber FP. Suppression of inflammation and joint destruction in rheumatoid arthritis may require a concerted action of Th2 cytokines. Curr Opin Invest Drugs 2002;3:1011–16. 100. Adams KM, Yan Z, Stevens AM, Nelson JL. The changing maternal ‘self’ hypothesis: a mechanism for maternal tolerance of the fetus. Placenta 2007;28:378–82. 101. Yan A, Lambet NC, Ostensen M, Adams KM, Guthrie KA, Nelson JL. Prospective study of fetal DNA in serum and disease activity during pregnancy in women with inflammatory arthritis. Arthritis Rheum 2006;54:2069–73. 102. Kaplan D, Diamond H. Rheumatoid arthritis and pregnancy. Clin Obstet Gynecol 1965;8:286–303. 103. Nelson JL, Koepsell RD, Dugowson CE, Voigt LF, Daling JR, Hansen JA. Fecundity before disease onset in women with rheumatoid arthritis. Arthritis Rheum 1993;36:7–14. 104. Nelson JL, Voigt LF, Koepsell TD, Dugowson CE, Daling JR. Pregnancy outcome in women with rheumatoid arthritis before disease onset. J Rheumatology 1992;19:18–21. 105. Carmichael SL, Shaw GM, Ma C, et al. and the National Birth Defects Prevention Study. Maternal corticosteroid use and orofacial cleft. Am J Obstet Gynecol 2007; 197:el-585–87. 106. Al-Herz A, Schulzer M, Esdaile JM. Survey of antimalarial use in lupus pregnancy and lactation. J Rheumatol 2002;29:700–6. 107. Ostensen M, Ramsey-Goldman R. Treatment of inflammatory rheumatic disorders in pregnancy: what are the safest treatment options?. Drug Safety 1998;19:389–410. 108. Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 2003;48:3207–11. 109. Levy RA, Vilela VS, Cataldo MJ, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double blind and placebo controlled study. Lupus 2001;10:401–4.

110. Borden MB, Parke AL. Antimalarial drugs in systemic lupus erythematosus: use in pregnancy. Drug Safety 2001;24:1055–63. 111. Parke A, West B. Hydroxychloroquine in pregnant patients with systemic lupus erythematosus. J Rheumatol 1996;23:1715–18. 112. Rains CP, Noble S, Faulds D. Sulfasalazine. A review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis. Drugs 1995;50:137–56. 113. Janseen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy and lactation. Arch Intern Med 2000;160:610–19. 114. Carter JD, Ladhani A, Ricca L, Valeriano J, Vasey FB. A safety assessment of TNF antagonists during pregnancy: a review of the FDA database. J Rheumatol 2009;36:635–41. 115. Romero-Mate A, Garcia-Domoso C, Cordoba-Guijarro S. Efficacy and safety of etanercept in psoriasis/psoriatic arthritis: an updated review. Am J Clin Dermatol 2007;8:143–53. 116. E.A. Vasiliauskas, J.A. Church, N. Silverman, M. Barry, S.R. Targan, M.C. Dubinsky, Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn, Clin. Gastroenterol. Hepatol. 4 1255–1258. 117. Reed SD, Voltan TA, Svec MA. Pregnancy outcomes in women with rheumatoid arthritis in Washington State. Maternal Child Health J 2006;10:361–66. 118. Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006;54:899–907. 119. Vroom F, van der Laar MA, van Roon EN, Brouwers JR, de Jong-van den Berg LT. Treatment of pregnancy and nonpregnant rheumatic patients: a survey among Dutch rheumatologists. J Clin Pharm Ther 2009;833:39–44. 120. Ostensen M. Antirheumatic therapy and reproduction. The influence on fertility, pregnancy and breast feeding. Z Rheumatol 2006;65:222–24. 121. Benjamin R, Parham P. HLA-B27 and disease: a consequence of inadvertent antigen presentation. Rheum Dis Clin North Am 1992;18:11–21. 122. Moll JMH. The place of psoriatic arthritis in the spondarthritides. Baillière’s Clin Rheumatol 1994;8:395–417. 123. Hart FD. Discussion on medical diseases in pregnancy. Proc R Soc Med 1959;52:767–74. 124. Ostensen M, Husby G. Ankylosing spondylitis and pregnancy. Rheum Dis Clin North Am 1989;15:241–54. 125. Ostensen M. The effect of pregnancy on ankylosing spondylitis, psoriatic arthritis, and juvenile rheumatoid arthritis. Am J Reprod Immunol 1992;28:235–37. 126. Gladman DD. Natural history of psoriatic arthritis. Baillière’s Clin Rheumatol 1994;8:379–94. 127. Seibold JR. Scleroderma. In: WN Kelley, ED Harris, S Ruddy, CB Sledge, eds. Textbook of Rheumatology, fifth ed.Vol. I. Philadelphia, PA: WB Saunders; 1997. 128. Lee P, Langevitz P, Alderdice CA, et al. Mortality in systemic sclerosis (scleroderma). Q J Med 1992;82:139–48. 129. Masi A. for Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581–90.

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130. Silman AJ, Black C. Increased incidence of spontaneous abortion and infertility in women with scleroderma before disease onset: a controlled study. Ann Rheum Dis 1988;47:441–44. 131. Englert H, Brennan P, McNeil D, Black C, Silman AJ. Reproductive function prior to disease onset in women with scleroderma. J Rheumatol 1992;19:1575–79. 132. Steen VD, Medsger TA Jr. Fertility and pregnancy outcome in women with systemic sclerosis. Arthritis Rheum 1999;42:763–68. 133. Steen VD, Brodeur M, Conte C. Prospective pregnancy (PG) study in women with systemic sclerosis (Ssc). Arthritis Rheum 1996;39(Supp. 9):S151. 134. Giordano M, Valentini G, Lupoli S, Giordano A. Pregnancy and systemic sclerosis. Arthritis Rheum 1985;28:237–38. 135. Steen VD. Scleroderma and pregnancy. Rheum Dis Clin North Am 1997;23:133–47. 136. Sampaio-Barros PD, Samara AM, Marques Neto JF. Gynaecologic history in systemic sclerosis. Clin Rheumatol 2000;19:184–87. 137. Spiera H, Krakoff L, Fishbane-Mayer J. Successful pregnancy after scleroderma hypertensive renal crisis. J Rheumatol 1989;16:1587–98. 138. Avrech OM, Golanm A, Panskym M, Langerm R, Caspi E. Raynaud’s phenomenon and peripheral gangrene complicating scleroderma in pregnancy – diagnosis and management. Br J Obstet Gynaecol 1992;99:850–51. 139. Black CM. Systemic sclerosis and pregnancy. Baillière’s Clin Rheumatol 1990;4:105–24. 140. Maymon R, Fejgin M. Scleroderma in pregnancy. Obstet Gynecol Surv 1989;44:530–34. 141. Brown AN, Bolster MB. Scleroderma renal crisis in pregnancy associated with massive proteinuria. Clin Exper Rheumatol 2003;21:114–16. 142. Diav-Citrin O, Arnon J, Shechtman S et al. The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study. Aliment Pharmacol Ther 2005;21:269–75. 143. Steen VD, Conte C, Day N, Ramsey-Goldman R, Medsger TA Jr. Pregnancy in women with systemic sclerosis. Arthritis Rheum 1989;32:151–57. 144. Stone S, Khamashta MA, Nelson-Piercy C. Nonsteroidal anti-inflammatory drugs and reversible female infertility: is there a link?. Drug Safety 2002;25:545–51. 145. Killick S, Elstein M. Pharmacologic production of luteinized unruptured follicles by prostaglandin synthetase inhibitors. Fertil Steril 1987;47:773–77. 146. Elder MG, Myatt L, Chaudhuri G. The role of prostaglandins in the spontaneous motility of the fallopian tube. Fertil Steril 1997;28:86–90. 147. Laszlo A, Nadasy GL, Monos E, Zsolnai B. Effect of pharmacological agents on the activity of the circular and longitudinal smooth muscle layers of human fallopian tube ampullar segments. Acta Physiol Hungarica 1988;72:123–33. 148. Sookvanichsilp N, Pulbutr P. Anti-implantation effects of indomethacin and celecoxib in rats. Contraception 2002;65:373–78. 149. Lim H, Paria BC, Das SK et al. Mulitple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 1997;91:197–208. 150. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users

151. 152.

153.

154.

155.

156.

157.

158.

159.

160.

161. 162.

163.

164.

165.

166. 167.

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of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. Br Med J 2001;322:266–70. James AH, Brancazio LR, Price T. Aspirin and reproductive outcomes. Obstet Gynecol Surv 2008;63:49–57. Bromer JG, Cetinkaya MB, Arici A. Pretreatments before the induction of ovulation in assisted reproduction technologies: evidence-based medicine in 2007. Ann N Y Acad Sci 2008;1127:31–40. Frattarelli JL, McWilliams GD, Hill MJ, Miller KA, Scott RT Jr. Low-dose aspirin use does not improve in vitro fertilization outcomes in poor responders. Fertil Steril 2008;89:1113–17. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Human Reprod 2006;21:2216–22. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA and the PARIS Collaborative Group. Antiplatelet gents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007;369:1791–98. Kozer E, Nikrar S, Costei A, Boskovic R, Hulman I, Koren G. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol 2002;187:1623–30. Norgard B, Puho E, Czeizel AE, Skriver MV, Sorensen HT. Aspirin use during early pregnancy and the risk of congenital abnormalities: a population-based case–control study. Am J Obstet Gynecol 2005;192:922–23. Riuz-Irastorza G, Khamashta MA. Management of thrombosis in antiphospholipid syndrome and systemic lupus erythematosus in pregnancy. Ann N Y Acad Sci 2005;1051:606–12. Spitzer KA, Murphy D, Crowther M, Clark CA, Laskin CA. Postpartum management of women at increased risk of thrombosis – results of a Canadian pilot study. J Rheumatol 2006;33:2222–26. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database System Reviews 2005;18, CDD002859. Greer IA. Anticoagulants in pregnancy. J Thromb Thrombolysis 2006;21:57–65. Stephenson MD, Ballem PJ, Tsang P. Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot comparing low molecular weight heparin to unfractionated heparin. Can J Obstet Gynecol 2004;26:729–34. Noble LS, Kutteh WH, Lashey N, Frandklin RD, Herrad J. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low molecular weight heparin vs unfractionated heparin. Fertil Steril 2005;83:684–90. Ruiz-Irastorza G, Khamashta MA, Nelson-Piercy C, Hughes GR. Lupus pregnancy: is heparin a risk factor for osteoporosis?. Lupus 2001;10:597–600. Deruelle P, Coulon C. The use of low molecular weight heparins in pregnancy – how safe are they?. Curr Opin Obstet Gynecol 2007;19:573–77. Clowse ME, Magder L, Witter R, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006;54:3640–47. Khamashta MA, Buchanan NM, Hughes GR. The use of hydroxychloroquine in lupus pregnancy: the British experience. Lupus 1996;5(Suppl. 1):S65–6.

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s e c t i o n 9     Immunology l

168. Klinger G, Morad Y, Westall CA et al. Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases. Lancet 2001;358:813–14. 169. Motta M, Tincai A, Faden D et al. Follow-up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation. J Perinatol 2005;25:86–89. 170. Pradat P, Robert-Gnansia E, Di Tanna GLand contributors to the MADRE database et al. First trimester exposure to corticosteroids and oral clefts. Birth Defects Res A Clin Mol Teratol 2003;67:968–70. 171. Park-Wyllie L, Mazzotta P, Pastuszak A et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta analysis of epidemiological studies. Teratology 2000;62:385–92. 172. Day RO. Sulphasalazine. In: WN Kelley, ED Harris, S Ruddy, CB Sledge, eds. Textbook of Rheumatology, fifth ed.Vol. I. Philadelphia, PA: WB Saunders; 1997:741. 173. Janssen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medication on fertility, pregnancy, and lactation. Arch Intern Med 2000;160:610–19. 174. Ostensen M. Treatment with immunosuppressive and disease modifying drugs during pregnancy and lactation. Am J Reprod Immunol 1992;28:148–52. 175. Ferrero S, Ragni N. Inflammatory bowel disease: management issues during pregnancy. Arch Gynecol Obstet 2004;270:79–85. 176. Freeman JG, Reece VA, Venables CW. Sulphasalazine and spermatogenesis. Digestion 1982;23:68–71. 177. Jarnerot G, Into-Malmberg MB. Sulphasalazine treatment during breast feeding. Scand J Gastroenterol 1979;14:869–71. 178. Branski D, Kerem E, Gross-Kieselstein E, Hurvitz H, Litt R, Abrahamov A. Bloody diarrhea-a possible complication of sulfasalazine transferred through human breast milk. J Pediatr Gastroenterol Nutr 1986;5:316–17. 179. de Boer NK, Jarbandhan SV, de Graaf P, Mulder CJ, van Elburg RM, van Bodergraven AA. Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites. Am J Gastroenterol 2006;101:1390–92. 180. Goldstein LH, Dolinsky G, Greenberg R et al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol 2007;79:696–701. 181. Ramsey-Goldman R, Schilling E. Immunosuppressive drug use during pregnancy. Rheum Dis Clin North Am 1997;23:149–67. 182. French AE, Koren Gand the Motherisk Team. Effect of methotrexate on male fertility. Can Fam Physician 2003;49:577–78. 183. Temprano KK, Branlamudi R, Moore TL. Antirheumatic drugs in pregnancy and lactation. Semin Arthritis Rheum 2005;35:112–21. 184. Nandakumaran M, Eldeen AS. Transfer of cyclosporine in the perfused human placenta. Dev Pharmacol Ther 1990;15:101–5. 185. Venkataramanan R, Koneru B, Wang CC, Burckart GJ, Caritis SN, Starzl TE. Cyclosporine and its metabolites in mother and baby. Transplantation 1988;46:468–69.

186. Di Paolo S, Monno R, Stallone G et al. Placental imbalance of vasoactive factors does not affect pregnancy outcome in patients treated with Cyclosporine A after transplantation. Am J Kidney Dis 2002;39:776–83. 187. Ostensen M, Khamashta M, Lockshin M et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 2006;8:209. 188. Cockburn I, Krupp P, Monka C. Present experience of Sandimmun in pregnancy. Transplant Proc 1989;21:3730–32. 189. Armenti VT, Ahlswede KM, Ahlswede BA et al. National Transplantation Pregnancy Registry – outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1994;57:502–6. 190. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a metaanalysis. Transplantation 2001;71:1051–55. 191. Sifontis NM, Coscia LA, Constaninescu S, Lavelanet AF, Moritz MJ, Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006;82:1698–702. 192. Perez-Aytess A, Ledo A, Boso V et al. In utero exposure to mycophenolate mofetil: a characteristic phenotype?. Am J Med Genet 2008;146:1–7. 193. Downs SM. Induction of meiotic maturation in vivo in the mouse by IMP dehydrogenase inhibitors: effects on the developmental capacity of ova. Mol Reprod Develop 1994;38:293–302. 194. Vasiliauskas EA, Church JA, Silverman N, Barry M, Targan SR, Dubinsky MC. Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol 2006;4:1255–58. 195. Skomsvoll JF, Wallenius M, Koksvik HS et al. Drug insight: anti-tumor necrosis factor therapy for inflammatory arthropathies during reproduction, pregnancy and lactation. Nature Clin Pract Rheumatol 2007;3:156–64. 196. Carter JD, Vareriano J, Vasey FB. Tumor necrosis factoralpha inhibition and VATER association: a causal relationship. J Rheumatol 2006;33:1014–17. 197. Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Pregnancy in rheumatology patients exposed to anti-tumor necrosis factor (TNF)-alpha therapy. Rheumatology (Oxford) 2007;46:695–98. 198. Treacy G. Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal antibody. Hum Exp Toxicol 2000;19:226–28. 199. Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol 2004;99:2385–92. 200. Kimby E, Sverrisdotti A, Elinder G. Safety of rituximab therapy during the first trimester of pregnancy: a case history. Eur J Haematol 2004;72:292–95. 201. M. Herold, S. Scnohr, H. Bittrich, Efficacy and safety of a combined rituximab chemotherapy during pregnancy, J. Am. Acad. Dermatol. 52 (Suppl. 2) AB8:155–208.

Chapter

54

Oral Contraceptives and Autoimmune Diseases Taraneh Mehrani1, and Michelle Petri2 1

Union Memorial Hospital, Baltimore, MD, USA Professor, The Johns Hopkins University School of Medicine, Department of Medicine, and Director, Johns Hopkins Lupus Center, Baltimore, MD, USA 2

Introduction

As patients suffering from autoimmune rheumatic diseases are predominantly young females between the ages of 20 and 40 years, which is the period of highest childbearing potential, particular attention must be paid to the impact oral contraceptives have on these diseases. The relationship between oral contraceptives and autoimmune diseases is complex.10 This chapter will review the current status of oral contraceptives in autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, antiphospholipid syndrome, scleroderma, and systemic vasculitis.

The predominance of autoimmune disease in women may be attributable to the interaction between sex hormones and the immune system.1 Evidence implicates androgens, estrogens, and other hormones such as prolactin in the susceptibility to and progression of some autoimmune rheumatic diseases.2,3 Generally, estrogens and prolactin in physiologic concentrations seem to enhance immune responses, whereas androgens and progesterone seem to have a suppressive effect on cellular and humoral immunity.4,5 Sex hormones can exert local actions in the tissues in which they are formed or have additional actions because they enter the circulation. In autoimmune rheumatic diseases, local effects of sex hormones seem to be related to modulation of cell proliferation and cytokine production. Many conditions may change serum estrogen levels and their peripheral conversion rate, thereby inducing an altered androgen: estrogen ratio. These include changes that are physiologic (menstruation, pregnancy, postpartum period, menopause, aging), pathologic (chronic stress, increase of inflammatory cytokines), and therapeutic (use of corticosteroids, oral contraceptives, and steroid hormone replacement).6 An accelerated peripheral metabolic conversion of androgen precursors to more estrogenic metabolites such as 17-estradiol (E2) has been implicated in patients who have systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).6 Moreover, several studies and reviews strongly support the idea that there are decreased serum levels of dehydroepiandrosterone (DHEA), testosterone, and progesterone in male and female patients with SLE and related autoimmune diseases.7,8 These observations provide a basis for the continued exploration of the proper use of exogenous hormones for contraception, hormone replacement therapy, and even treatment of autoimmune diseases.9

Principles of Gender-Specific Medicine

Oral contraceptives Oral contraceptives (OCs) first became licensed for birth control in 1959. For almost five decades they have proven to be the most reliable form of reversible contraception and have been widely used in the general female population.11 In the United States, combined oral contraception is the most frequent nonsurgical method of birth control in women aged 15–44.12 Combined oral contraceptives contain both an estrogen and a progestin. The oral progestin-only contraceptives are used less frequently than the combined formulations, mainly because of related irregular endometrial bleeding. However, they are increasingly being offered to patients in whom estrogen is contraindicated, such as those with antiphospholipid syndrome.13

General Contraindications and Potential Risks to Use of Oral Contraceptives Adverse effects associated with oral contraceptive use, notably the increased risk of cardiovascular disease including

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ischemic and hemorrhagic stroke, myocardial infarction and thrombosis, were reported soon after their introduction to the market in the 1960s. Traditional risk factors such as hypertension, age, cigarette smoking, migraine headaches, morbid obesity, and diabetes mellitus are classically known to interact with OC use to increase the risk of stroke and myocardial infarction. Among women without major cardiovascular risk factors, the risk of myocardial infarction seems very low,14 and in some studies, no excess risk was observed at all.15 Overall, for women less than 35 years of age who are nonsmokers and normotensive, the risk of hemorrhagic stroke is not affected by oral contraceptive use.16 It has been noted in several studies that women, administered OCs containing less than 50 g of estrogen, who underwent regular blood pressure monitoring, did not have a significantly increased risk of ischemic stroke.17 It is known that exogenous estrogens increase the risk of venous thrombosis when used as oral contraceptives or as postmenopausal hormone replacement.18,19 In the general female population, the annual worldwide incidence of venous thrombosis in a young, healthy woman is 1 in 10 000.20 A cohort study of the risk of venous thromboembolism associated with various oral contraceptives estimated the absolute risk of venous thromboembolism (pulmonary embolus and deep venous thrombosis) among women exposed to any combined OC as 4.1 events per 10 000 woman-years, and noted that this finding accords with those of most previous studies.21 Recently, it has been shown that progestins in combination oral contraceptives also affect the risk of thrombosis,22 with users of the third-generation contraceptives containing the newest progestins carrying an increased risk of venous thrombosis compared with second-generation OCs.20 The discovery of the Factor V Leiden mutation has led to recognition that genetic causes of hypercoagulability affect OC risk. Vandenbrouke et al. showed the prevalence of this mutation to be 5%, with a risk of 5.7 venous thromboembolism events per 10 000 woman-years for reproductive-aged females not using OCs.23 In contrast, among OC users with this mutation, the rate increased to 28.5 per 10 000 womanyears. This study emphasizes that subsets of patients will have higher risk of thrombosis when using oral contraceptives than others, especially if they have a personal or family history of venous thrombosis and prothrombotic abnormalities such as factor V Leiden, prothrombin 20210A, and deficiencies of protein C, protein S, or antithrombin III.11 However, the absolute risk of arterial and venous thromboembolism remains low, indicating that several thousands of women would need to abstain from OCs to prevent 1 case of thrombosis per year.11 The introduction of OCs with decreased estrogen and progestin doses has significantly decreased the incidence of these cardiovascular complications16 Despite such changes in formulation, compliance and successful use is affected by problems related to side effects.24

Absolute contraindications to the use of combination OCs include a history of thrombosis, cerebrovascular or coronary artery disease, complicated valvular heart disease, vascular disease, uncontrolled hypertension, diabetes mellitus with vascular complications, cigarette smokers 35 years of age and older, pregnancy, and the presence of known thrombogenic mutations, breast cancer, liver malignancy or active liver disease, migraines with aura, and major surgery requiring prolonged immobilization.25

General Benefits of Oral Contraceptives Besides preventing unplanned or undesired pregnancies in a woman with autoimmune disease, there are also noncontraceptive benefits associated with OC use. They include decreased risk of ovarian cancer, endometrial cancer, salpingitis, and possibly colorectal cancer, protection against ectopic pregnancy, relief from menstrual disorders, reduction of acne, and improvement in bone density.16

Rheumatoid arthritis Rheumatoid arthritis (RA) is an articular and systemic inflammatory disorder characterized by chronic destructive synovitis, with a prevalence in developed countries estimated at 0.5–1% of the adult population.26 Women are more susceptible to RA than males, with an incidence of 1 per 2000 in women during their reproductive years.27 The possibility that oral contraception offers a protective role against the development of rheumatoid arthritis and reduces disease severity has been proposed by numerous investigators. However, there is lack of consensus in the literature regarding this hypothesis.28 Pregnancy, estrogen replacement therapy, and treatment with estrogen-containing oral contraceptives have been shown to improve symptoms in the majority of patients with rheumatoid arthritis.29 Flares are commonly seen in the postpartum period,30 with severe relapses in more than 70% of cases.31 It has been hypothesized that there is a possible protection against RA by exogenous female sex hormones, even though RA is more common in women than in men.32 Older studies were more optimistic about the benefits of OCs in patients with RA. In 1978, the Royal College of General Practitioners reported a 50% reduction in the risk of developing RA in current users of OCs.33 Over the years, this study population has undergone important secular trends as evidenced from the latest findings, which are based on data available in April 1987.34 In contrast with previous reports, the more recent analysis suggests OCs lead to a statistically non-significant 20% reduction in the risk of RA. The incidence of RA among former and never users has declined over the past two decades. Conversely, the authors have noted that current users have not experienced this temporal trend,

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and the ratio between current and never users has, therefore, approached unity. They conclude that ‘these secular changes may explain why some studies have found that oral contraceptives have a protective effect, while others have been unable to show such an effect’. Jorgensen and colleagues have also suggested a protective effect of oral contraceptives for severe or seropositive rheumatoid arthritis. In their case–control study of 176 women classified with either severe or mild RA who had at least one child, OC use had a protective role in terms of the course of RA (44% of RA patients with mild disease were OC users, compared with 21.7% of those with severe RA; p 0.001).35 Among those using OC for more than five years, the relative risk (RR) of developing severe disease was 0.1 (95% confidence interval 0.01–0.6), after adjustment for age, parity, and breast feeding. A review of 17 studies investigating the association of oral contraceptive use and rheumatoid arthritis by Brennan et al. found that 11 studies showed a protective effect, but six did not.36 Their own results based on 115 incident cases of inflammatory polyarthritis showed that current OC use did protect against the development of RA, with an adjusted odds ratio of 0.22 (95% confidence interval 0.06–0.85). Pladevall-Vila and colleagues attempted to partially explain the differences among study results regarding the relation between oral contraceptives and rheumatoid arthritis. They performed a meta-analysis of case–control and cohort studies based on data from 1968 to 1993, and found no conclusive evidence of a protective effect of oral contraceptives on the risk of developing rheumatoid arthritis.37 In general, the authors found that the source of controls was the most important characteristic in explaining the strong heterogeneity between studies (p  0.0006). After analyzing the source of heterogeneity, a meta-analysis by Spector and Hochberg concluded that no population-based studies had found a protective effect.38 On the other hand, hospital-based studies showed that oral contraceptives had an important negative association with rheumatoid arthritis. In a hypothesis paper discussing the association between rheumatoid arthritis, the contraceptive pill, and androgens, William James attempted to explain the disparities between the results mentioned above.39 He speculated that RA is not affected by the ingestion of oral contraceptives, but rather that low androgen concentrations are a cause of RA. He noted that among women using oral contraceptives, young women and those who have been taking oral contraceptives for only a short time have low estimated relative risks of RA. He felt that this is contrary to expectation if oral contraceptives have a true protective effect, and hypothesized that the oral contraceptive pill is a marker for some other factor, namely androgen concentrations. It has been well established that both male and female patients with RA have lower mean androgen concentrations than controls.40,41 He supports his hypothesis that low androgen concentrations are a risk factor for RA by suggesting that women who

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choose OCs initially have higher androgen concentrations than other women, and that a pharmacological effect of OCs is to lower androgen concentrations.

Oral Contraceptives and RA: Conclusion Despite the controversy surrounding the potential benefits of oral contraceptive pills on rheumatoid arthritis pathogenesis or activity, no evidence suggests that their use exacerbates the disease. Oral contraceptives are a safe, convenient, and effective birth-control option for women with RA. Future research is needed to determine whether there is a therapeutic role for OCs in patients with established RA, with well-designed prospective studies and better tools for meta-analysis that take heterogeneity and reliability of observational studies into consideration.37

Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is the most common connective tissue disease in woman of childbearing potential, with an incidence of approximately 1 per 1000 women.27 The effect of oral contraceptives on the incidence and disease activity of SLE has been a focus of research for many years.42,43 Traditionally in medical practice, women diagnosed with SLE have been advised to discontinue exogenous estrogens and oral contraceptives.44 This is reflected in the number of users before the diagnosis of SLE being much higher than after the diagnosis. For example, of the female patients enrolled in the Hopkins Lupus Cohort, 67% have taken oral contraceptives in the past, but only 4% are currently taking them.42 Similarly, in a questionnaire analysis from the United Kingdom by Lakasing et al., prior to the diagnosis of SLE, 64% of women had used the combined oral contraceptive pill, while only 8% were on it at the time of study.45 The large ratio of women to men presenting with SLE in the childbearing years,46 as well as the finding of altered estrone metabolism in lupus toward more potent 16hydroxylated compounds,47 is evidence suggesting that estrogen may be involved in the pathogenesis of SLE. Murine models have also demonstrated that the administration of exogenous estrogens can worsen disease activity in lupus-prone mice.48 Although these observations support the notion that SLE might be hormonally mediated, estrogens are not the only hormones that have been implicated in this disease.49 Several investigators have seen increases in the frequency of lupus ‘flares’ during pregnancy, even though lupus pregnancy has lower than normal estrogen levels,50,51 although some studies have shown no disease exacerbation by pregnancy.52,53 A retrospective analysis of 26 female patients with lupus nephropathy showed an overall incidence of lupus flare of

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43% in users of combined oral contraceptives as compared with none of the women receiving progestin-only pills. However, these patients had pre-existing renal disease, such that the findings may not be generalizable to all patients with SLE.44 Sanchez-Guerrero and colleagues previously noted that there was a slight increased incidence of SLE among women in the Nurses’ Health Study (NHS) who had ever used oral contraceptives (RR, 1.4; 95% CI 0.9–2.1) as compared to those who had never used oral contraceptives.43 More recently, Costenbader et al. reexamined the women in both the NHS and NSHII cohorts that have been followed prospectively for rheumatic disease. In a study of the reproductive and menopausal factors associated with the development of SLE, these investigators found a statistically significant association between age less than or equal to 10 years at menarche (pooled RR 2.1, 95% CI 1.4–3.2), use of postmenopausal hormones (RR 1.9, 95% CI 1.2–3.1), and oral contraceptive use (pooled RR 1.5, 95% CI 1.1–2.1) with an increased risk of SLE.54 Based on the above findings that suggested an exacerbation or increased risk of disease after starting oral contraceptives, there has been concern for many years about prescribing these medications to patients with systemic lupus erythematosus. However, as noted in an editorial by Bermas, the attitude toward prohibition of use of exogenous estrogen in women with lupus has changed in the past decade.55 Several studies have reflected a more positive light on the use of oral contraceptives and activity of systemic lupus erythematosus. In a retrospective analysis, Julkunen and colleagues demonstrated no difference in the rate of flares between users and non-users of oral contraceptives.56 Additionally, a study in the UK by Lakasing and Khamashta found no evidence of increased lupus exacerbation in women with SLE using the combined oral contraceptive pill.45 More recently, two large trials have prospectively evaluated the effect of lupus activity in women with stable disease and demonstrated that oral contraceptives do not significantly increase the risk of disease flare in this population. First, the Oral Contraceptives-Safety of Estrogens in Lupus Erythematosus National Assessment (OC-SELENA) was a double-blind, noninferiority trial that randomly assigned premenopausal women with inactive or stable active lupus to take either a low-estrogen oral contraceptive or placebo.57 Patients with a history of thrombosis, moderate to high titers of anticardiolipin antibodies, or a positive test for lupus anticoagulant were excluded. The rate of severe flares after 1 year was determined to be 0.084 in the oral contraceptive arm and 0.087 in the placebo arm. In fact, one severe renal flare was noted in the OC group and four in the placebo group. Additionally, OCs were not associated with an increase in mild-moderate or total flares over the course of one year. This supports the safety of estrogen-containing oral contraceptives as a birth-control option for patients with

inactive or stable, moderate SLE who are at low risk for thrombosis. In the second large clinical trial, Sanchez-Guerrero and colleagues performed a single-blind clinical trial involving 162 women with SLE who were randomly assigned to combined oral contraceptives, a progestin-only pill, or a copper intra-uterine device (IUD) for 1 year.58 No significant difference was seen between the groups. The probability of any flare was 0.91, 0.93, and 0.88, respectively (p  0.67). The probability of severe flare was 0.05, 0.10, and 0.04, respectively (p  0.62). Of note, lower-limb thromboses occurred in four patients, two in each group receiving hormones. All four of these patients had low titers of antiphospholipid antibodies. The incidence of flares (including severe flares), global disease activity, maximum SLEDAI score, time to first flare, and incidence of adverse events were similar among women with systemic lupus erythematosus, irrespective of the type of contraceptive.

Benefits of Oral Contraceptives in SLE Ideally, pregnancies in patients with SLE should be planned for a time when the disease is under good control. Planned pregnancies and conception during remission lead to better outcomes.59 Moreover, patients with very active disease or those receiving potentially teratogenic medications should use extremely reliable birth control.60 Non-contraceptive benefits of oral contraceptives, many specific to patients with SLE, have occasionally been the main reason for their use in this population. They include the following: Oral contraceptives might protect against premature ovarian failure and subsequent infertility due to cyclophosphamide, which occurs in 60% of women over age 30 with SLE on this therapy.61,62 OCs may positively affect bone mass, protect against osteoporotic fracture and avascular necrosis, and prevent glucocorticoid-induced osteoporosis in SLE.63,64 OCs are useful in decreasing the number of functional ovarian cysts, which occur more frequently in patients with SLE than in the general population.60,65 It has been shown that OCs may help to control cyclic SLE disease activity, predominantly in the cutaneous lupus rashes and musculoskeletal complaints that have been reported prior to the onset of menses.42,66 Oral contraceptives help in regulation of menstrual dysfunction, seen in 55% of SLE patients.67

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Oral Contraceptives and SLE: Conclusion There are clinical trial data to support the safety of oral contraceptives in lupus patients with inactive or moderately active stable disease. The safety of OCs in women with severe active disease has yet to be determined. Women with

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unstable lupus, hypercoagulability secondary to antiphospholipid antibodies or nephrotic syndrome, or past history of thrombosis should not be given OCs.60

Antiphospholipid syndrome Antiphospholipid syndrome (APS) is an autoimmune disease characterized by antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies and anti-beta2 glycoprotein I antibodies) and at least one clinical manifestation, including venous or arterial thrombosis, recurrent pregnancy losses, intra-uterine fetal demise, or severe pre-eclampsia. This disorder predominantly affects young women. It can be found in isolation (primary antiphospholipid syndrome) or associated with connective tissue diseases (secondary antiphospholipid syndrome), mainly systemic lupus erythematosus.68 Over the past few years there has been a great deal of interest in the association between oral contraceptives and thromboses in young women.69 The background incidence of thromboses in young, non-pregnant women with APS without previous thromboses and not using any hormonal contraception is approximately 5% per patient year.70,71 A few studies report no increased incidence of thromboembolic disease in women with increased titers of antiphospholipid antibodies (aPL) taking low dose combined oral contraceptives.72,73 However, the use of these medications in women with antiphospholipid syndrome has been generally discouraged in medical practice.74 Hormonal contraception, in particular the combined oral contraceptive pill, may promote venous thromboembolism in APS. This was demonstrated in an observational questionnaire-based study of 86 women with SLE and/or APS in which subjects were classified into three groups: (1) SLE only (n  39); (2) APS only (n  30); and (3) SLE and APS (n  17).45 Lakasing and colleagues found a doubling of the background incidence of thrombosis in non-pregnant women with APS (without any additional risk factors) that were using the combined oral contraceptive pill, with 7/32 (22%) users affected. None of the women in the APS-only arm, who developed thrombosis (4/7), had additional risk factors for venous thromboembolism, such as age over 35 years, obesity or smoking. Similar to patients in the Hopkins Lupus Cohort,42 Lakasing et al. observed that many patients were using oral contraceptives as their method of contraception prior to the diagnosis of SLE and/or APS, but very few were on them at the time of study. For instance, in the APS-only arm 22/30 (73%) of patients were using OCs prior to their diagnosis, whereas only 2/30 (7%) were on them at the time of study. This reflects the general practice of advising patients with APS not to use or to discontinue the use of the oral contraceptive pill. A retrospective cohort study conducted by Krnic-Barrie et al. examined factors that influence thrombotic recurrence

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in antiphospholipid syndrome for a median time of 77 months and found that 8/50 (16%) of the women experienced venous thrombosis while taking oral contraceptives.74 There are comparable studies with similar findings: Vianna et al. observed complications in 13 (13.5%) of 96,75 Silver et al. in 14 (10.9%) of 128 women,70 and Derksen et al. in 10 (29.4%) of 34 patients.76 It is thought that thrombosis is more likely to occur with the existence of two or more risk factors. For instance, up to 50% of patients with SLE may have antiphospholipid antibodies; the use of oral contraceptives in a hypercoagulable patient might be the ‘second hit’ leading to thrombosis.60 In the longitudinal Hopkins Lupus Cohort study, SLE patients with antiphospholipid antibodies (lupus anticoagulant by high level dilute Russel Viper Venom test measurements) were shown to have a 42% chance of a venous thrombotic event within 20 years of diagnosis.77 Other risk factors for arterial complications, such as migraines, atherosclerotic disease, or hyperlipidemia might be increased in SLE patients positive for antiphospholipid antibodies, and could further increase the risk for stroke or myocardial infarction.13 In patients with antiphospholipid antibodies, the risk of thrombosis is increased with the addition of prothrombotic heritable risk factors, including factor V Leiden and prothrombin mutation G20210A.78 Moreover, patients with a history of thrombosis or fetal loss secondary to APS are more likely to also have genetic risk factors than asymptomatic individuals with antiphospholipid antibodies.79

Catastrophic Antiphospholipid Syndrome In a review of 31 patients with antiphospholipid antibodies who developed multi-organ failure, Asherson and Piette determined that exogenous estrogen is one of the precipitants of catastrophic APS, also referred to as Asherson’s syndrome.80 Precipitating factors for catastrophic APS were found in more than one-third of the patients, including infections, surgical procedures, and the use of oral contraceptives.

Oral Contraceptives and APS: Conclusion Despite the lack of well-designed studies examining whether the risk of thrombosis is increased in patients with antiphospholipid antibodies who are taking oral contraceptives, there are multiple reports as the ones discussed above that describe a potential link between the two. Taken together, these findings suggest that women with antiphospholipid antibodies should be advised against using this form of contraception.45

Sjögren’s syndrome Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic and plasma cell infiltration

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of the salivary and lacrimal glands resulting in dry mouth, enlargement of the major salivary glands, and dry eyes.81 The prevalence of Sjögren’s syndrome in the population has been estimated to be 0.5–2.7%, with the most frequent age of onset between 30 and 50. The disease occurs at a femaleto-male ratio of 9:1.82 The higher incidence of this autoimmune disease in women suggests that, as in RA and SLE, sex hormones may be part of the etiology and/or disease progression. Animal models of SS suggest estrogens may aggravate disease activity, while androgens are protective.83 Steinberg et al. suggested a possible role for estrogens enhancing autoimmunity in SS by showing that oophorectomized NZBxNZW F1 mice had more pronounced antibody production with estrogens.84 Furthermore, testosterone administration to the same female mouse models of SS resulted in suppression of the inflammation and substantial increase in the functional activity of the lacrimal glands.83 In humans with SS, serum concentrations of testosterone are reportedly decreased, and it has been suggested that this reduction may predispose patients to the development of dry eye syndrome.85 As the levels of potent estrogens are known to be increased in SLE, it has been suggested that estrogens may also be involved in the female predominance of Sjögren’s syndrome. Schaumberg et al. recently performed an epidemiologic study that showed an increased risk of dry eye syndrome with hormone replacement therapy.86 In another study, Sullivan and colleagues examined whether women with SS have elevated serum concentrations of estrogens, while testing their main hypothesis that women with SS have a deficiency in total androgens.87 These investigators found low serum levels of some, but not all, androgens in women with SS compared with controls. In contrast, SS was not associated with significant alterations in serum concentrations of estrone or 17-estradiol. These findings could not be attributed to the influence of oral contraceptives or hormone replacement therapy (HRT). The authors concluded that as estrogens may enhance polyclonal B cell activation, autoantibody formation and tissue abnormalities in Sjögren’s syndrome,88 further studies of these hormones would be of particular interest. More recently, Brennan et al. hypothesized that patients with primary SS would have elevated estrogen levels that correlated with disease activity, and that androgens would be negatively correlated with disease activity.89 In their prospective analysis of 39 women with SS and 15 non-SS controls at the Sjögren’s Syndrome Clinic at the National Institutes of Health, they were surprised to find that all levels for sex steroid hormones were within the normal range for patients with SS. Specifically, no association between disease activity and estrogens was found. When comparing SS patients taking hormone replacement therapy (12/39) to those not taking hormone replacement therapy, no significant difference was noted for any measure of SS disease activity. Interestingly, higher levels of disease activity (erythrocyte sedimentation rate, serum protein, and salivary

gland focus score) were associated with higher concentrations of testosterone! They noted that this unexpected relationship might be attributable to the complexity of androgens in autoimmune disease or the result of the relatively small sample size.

Oral Contraceptives and Sjögren’s Syndrome: Conclusion Although there are no apparent contraindications to the use of oral contraceptive pills in patients with SS, there have been no controlled studies dedicated to this issue. As Sjögren’s syndrome predominantly affects postmenopausal women, giving appropriate contraceptive advice may be less of an issue in this population.

Scleroderma Systemic sclerosis or scleroderma (SSc) is a complex disease characterized by tissue fibrosis, vasculopathy, and a specific autoantibody response. The expression of this autoimmune disease has high variability and its pathogenesis is still unclear.90 The overall incidence rate of SSc in the adult population of the United States is approximately 20 per million per year,91 with a recent estimated prevalence of 27.6 cases per 100 000 US adults (95% CI 24.5–31.0). Women are affected 4.6 times more frequently than men.92 The average onset of SSc occurs between 40 and 50 years, but in women it is in the late childbearing years, between 30 and 39.93 There is a paucity of reliable and consistent epidemiological data regarding the use of exogenous sex hormones in women suffering from scleroderma. Moreover, there are conflicting viewpoints on whether oral contraceptives play a role in susceptibility to this disease. Nevertheless, there is an important role for counseling patients with diffuse scleroderma on contraceptive options. For instance, the incidence of ‘renal crisis’ is higher within the first two to four years of diagnosis.94 Significant cardiopulmonary disease is more likely in young women with diffuse scleroderma, and disability due to finger contractures makes child care and other work very difficult. Gastrointestinal disease may also limit pregnancy. Patients with limited scleroderma are more likely, in the absence of cardiopulmonary disease, to have successful pregnancies. The presence of microchimerism (small populations of cells from another individual) is thought to be involved in the pathogenesis of scleroderma.95 Hence, it has been suggested that hormones and pregnancy-related immuno­ biologic changes may explain why the incidence of SSc is higher in women and the peak onset is after childbearing age. Pisa et al. investigated the association between scleroderma and reproductive factors in a hospital-based Italian study of 46 women with SSc and 153 female controls.96

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Information on age at first pregnancy, number of children and abortions, and use of oral contraceptives was obtained. They found that parous women were at reduced risk of developing SSc (age-adjusted odds ratio 0.3, 95% CI 0.1–0.8) and the risk declined with an increasing number of children. Abortive pregnancies were also inversely related to SSc. Finally, use of oral contraceptives was not associated with an increased risk for scleroderma when compared with nonusers, with an age-adjusted odds ratio of 1.2 (95% CI 0.5–3.2). There was no difference when only premenopausal women younger than 50 years were considered (ageadjusted odds ratio 1.2, 95% CI 0.3–4.6). The investigators concluded that, although a lowered fertility due to subclinical disease could not be ruled out as an explanation for the inverse association of the risk of SSc with a history of pregnancy, their results did not support the hypothesis that immunobiologic modifications during pregnancy explained the excess of scleroderma among women. Similar results were achieved when Beebe and colleagues studied the association between reproductive history, oral contraceptive history, and estrogen replacement use in 472 female scleroderma patients and 2227 female controls.97 The investigators found that oral contraceptive use did not influence the risk of developing scleroderma (age- and year of birth-adjusted odds ratio  0.94; 95% CI, 0.74–1.22.) Earlier age of menarche (adjusted odds ratio  1.00; 95% CI, 0.79–1.22) or ever being pregnant (adjusted odds ratio  0.86; 95% CI, 0.64–1.15) were not associated with scleroderma. Of note, estrogen replacement therapy was associated with a modest but significant increased risk of disease development with an adjusted odds ratio of 1.40 (95% CI, 1.10–1.77).

Exogenous Estrogen Use in Scleroderma Patients with Raynaud’s Phenomenon Raynaud’s phenomenon is a reversible vasospastic condition that causes transient ischemia of the digits on cold exposure and sometimes also with emotional stress. It is seen more frequently in women than in men. The primary condition effects approximately 5% of the adult American population, while the secondary form is most frequently associated with scleroderma, in which Raynaud’s phenomenon affects 95%.91 Previous studies of Raynaud’s phenomenon in scleroderma have demonstrated that endothelial damage manifests throughout the disease course, and that estrogen can modify the function of the vascular endothelium directly.98 A case–control study of 12 female patients with scleroderma and Raynaud’s phenomenon found that short-term estrogen administration improved abnormal endothelial function.98 The effects of long-term estrogen administration in these patients deserves further study. More recently, Beretta and colleagues voiced concern over the use of oral contraceptives in patients with scleroderma or Raynaud’s phenomenon.99 The rationale behind

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their argument is that exogenous hormonal therapy may influence the natural history of scleroderma by interacting with the endothelium.100 A hypercoagulable state involving endothelial injury with associated increased prothrombotic activity and reduced fibrinolytic activity has been postulated to exist in patients with scleroderma and other secondary forms of Raynaud’s phenomenon.101 In their case report, Beretta et al. described the temporal relationship between the initiation of oral contraceptive therapy by a young woman and her progression from a clinically benign Raynaud’s phenomenon to definite scleroderma. The authors suggested that the combination oral contraceptive pill (containing ethinyl estradiol 30 g and drospirenone 30 mg) likely worsened her vasospasm and augmented the effects of thrombin, inducing endothelial damage and contributing to the development of scleroderma. They concluded that even if ‘newer’ progesterones such as drospirenone are deemed somewhat safe, their use is not totally without risk,102 and that caution should be exercised in prescribing both the ‘older’ and ‘newer’ formulations of progesterones to patients with preexisting microvascular disease such as scleroderma or Raynaud’s phenomenon. Although we cannot generalize the results of this single case report to all patients with scleroderma, the authors’ speculation and their discussion emphasizes the challenge in drawing conclusions on the association of a relatively rare disease as scleroderma with hormonal treatment. In fact, the limited number of well-designed epidemiologic studies investigating the risk and benefit of hormonal therapy in scleroderma prevents definitive conclusions.

Oral Contraceptives and Scleroderma: Conclusion There is no absolute contraindication to the use of oral contraceptives in patients with scleroderma. However, as with any medication, the use of OCs should be assessed on an individual basis depending on personal history (i.e. hypercoagulability, prior thrombosis, cardiovascular risk factors), manifestations of disease, risk and benefit profile, and preference of the patient. For example, the use of combined oral contraceptives in scleroderma patients that have moderate to high titers of antiphospholipid antibodies, evidence of venous occlusive disease or arterial occlusions such as digital gangrene is not warranted. The existence of large population cohorts as well as established patient cohorts of scleroderma patients should provide opportunities for future research in this area.91

Vasculitis The vasculitides are a heterogeneous group of rheumatic disorders which target the blood vessel.103 The 1994 Chapel Hill Consensus Conference categorized systemic vasculitis

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in terms of the size of the predominant vessel involved, namely small, medium or large.104 The incidence of the various inflammatory vascular diseases is age- and sex-specific. For example, giant cell arteritis (GCA) is a large vessel vasculitis predominantly seen in older adults with a minimum age at diagnosis of 50 years, whereas Kawasaki’s disease is primarily a vasculitis found in young children. In terms of gender differences in inflammatory vascular disorders, diseases such as Takayasu’s arteritis have a predilection for women, whereas Buerger’s disease is mainly seen in men.103 These age and gender differences are important in the discussion of the use of exogenous sex hormones in vasculitis as, unlike many forms of autoimmune rheumatic disease (such as RA, SLE, Sjögren’s syndrome, scleroderma), primary systemic vasculitis does not disproportionately affect females.105 Given that these diseases are rare, it has become a challenge to understand the association between oral contraceptives and vasculitis. Preconception planning is particularly important for patients with systemic vasculitis, as pregnancy should take place only after prolonged disease quiescence. Careful consideration must be given to the status of the patient’s underlying vasculitis and the immunosuppressive drugs frequently required to keep her disease under control.106 Some commonly used medications are teratogenic (such as methotrexate, mycophenolate mofetil, and cyclophosphamide). Therefore, contraception plays an important role in the timing of a successful pregnancy. There is a paucity of data in the literature on the association between oral contraceptives and vasculitis, with most information obtained from case reports. However, there is some evidence that pregnancy may be protective against giant cell arteritis and other forms of arterial disease, possibly secondary to the hyperestrogenic state associated with this period.107,108 Takayasu’s arteritis is particularly interesting, because, unlike most forms of systemic vasculitis, this disease mainly affects women of childbearing potential. These patients are at increased risk for cardiovascular complications of uncontrolled hypertension due to renovascular disease or arterial stenosis characteristic of this ‘pulseless disease’. Therefore the use of OCs would not be advisable. Behçet’s disease (BD) is a systemic inflammatory vasculitis that is characterized by chronic relapsing oral aphthous lesions, genial ulcers, uveitis, and vasculopathy of arteries and veins of all sizes.109. Venous and arterial thromboembolic disease is a known complication of BD.106 Uthman et al. presented the case of a female patient with Behçet’s disease on oral contraceptive pills who developed a deep venous thrombosis.109 She was found to have a mutation of the prothrombin (factor II) G20210A gene. The authors suggested that a thrombophilia evaluation may be warranted in BD patients, especially young women before they are prescribed oral contraceptives.

Oral Contraceptives and Vasculitis: Conclusion There are no absolute contraindications to the use of oral contraceptive pills in women with systemic vasculitis if hypercoagulability is not evident. However, there are no data regarding the safety of OCs in women with vasculitis. Unlike other forms of autoimmune disease, many forms of vasculitis are more common in men. This is further complicated by the heterogeneity of the diseases classified under the rubric vasculitis, each of which may be associated with a different underlying risk for thromboembolic disease. There is an important theoretical risk of venous thromboembolism among patients with vasculitis, such as Wegener’s granulomatosus, that may be heightened by the use of OCs.110 Caution should be used in prescribing estrogen-containing oral contraceptive pills during periods of active vasculitis and alternative contraceptive methods should likely be sought during disease flares.

Summary and conclusions There is clinical evidence supporting a role of sex hormones in the pathogenesis of some autoimmune diseases. Estrogens in physiologic concentrations are thought to augment immune responses, whereas androgens and progesterone seem to have a suppressive effect.4,5 Changes in levels of gonadal hormones have been described in patients with SLE, RA, and Sjögren’s syndrome. Reflected in the low numbers of women with autoimmune rheumatic diseases using oral contraception as compared to females in the general population, it is apparent that this form of birth control has generally been discouraged, on the most part because of the long-held belief of its association with exacerbation or susceptibility to autoimmune disease and thrombosis. However, as most autoimmune disease affects women of childbearing potential, the use of an effective and convenient form of contraception is of great importance. Oral contraceptives also carry benefits that may be particularly useful in patients with autoimmune disease, such as protection against infertility due to cyclophosphamide therapy,61,62 prevention of glucocorticoid-induced osteoporosis,63,64 treatment of ovarian cysts, and regulation of menstrual dysfunction, all of which occur more frequently in patients with SLE than in the general population.60,65 OCs also allow for a reversible method of contraception that is frequently needed in the postponement of a successful pregnancy until a time when disease is quiescent. There are different types of birth control pills, with the newer formulations containing lower doses of estrogens and carrying less risk of serious cardiovascular events when used in the proper patient with rheumatic disease. The type of progestin may also be important in determining the incidence of venous thromboembolism, with third generation

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progestin-containing preparations being considered the most thrombogenic.22 Oral contraceptives are generally safe in patients with rheumatoid arthritis. Women with RA might benefit from using OCs, as symptoms have been observed to improve during pregnancy, in contrast to the disease flares sometimes seen in pregnant patients with SLE. Although there are data showing that the use of OCs before onset of RA symptoms has a protective effect against disease and reduces its severity,111 there is still no clear answer to the question of whether the use of oral contraceptives is associated with a reduced risk of developing rheumatoid arthritis. Multiple observations have suggested that estrogen has an immunostimulatory effect and influences SLE disease activity. Based on older findings that suggested an exacerbation or increased risk of disease after starting oral contraceptives, there has been concern for many years about prescribing these medications to patients with systemic lupus erythematosus. However, over the past several years this attitude toward the prohibition of using OCs in women with SLE has changed. More recently, several studies have reflected a more positive light on the use of OCs and activity of SLE. Two large trials have prospectively evaluated the effect of lupus activity in women with stable disease and demonstrated that OCs do not significantly increase the risk of disease flare in this population. Therefore, both the investigators of the OC-SELENA trial and the prospective study by Sanchez-Guerrero and colleagues do not support concerns that use of exogenous estrogens by women with SLE will lead to disease exacerbation. On the basis of these studies, oral contraceptives seem to be a safe option for patients with inactive or stable active SLE, who do not have the presence of antiphospholipid antibodies or carry other risk factors for thrombosis. Multiple observational studies have demonstrated the association of venous thromboembolism in women with antiphospholipid syndrome on combined oral contraceptive pills. The addition of prothrombotic inherited risk factors to the presence of antiphospholipid antibodies further increases the risk of thrombosis. Furthermore, estrogen-containing OCS have been implicated as a precipitant of multi-organ failure in catastrophic antiphospholipid syndrome. Taken together, these findings suggest a high incidence of thromboses in women with APS using OCs, and that these women should be advised against using this form of contraception. While there is some evidence in humans suggesting that increasing estrogen levels may actually worsen symptoms associated with Sjögren’s syndrome,86,112 no clear relationships have been demonstrated between the use of exogenous hormone therapy and disease activity in these patients. Findings of significantly reduced levels of androgens in women with SS, and the potential role of estrogens in enhancing polyclonal B cell activation, autoantibody formation and tissue abnormalities in this disease88 offers future areas of exploration into the influence that these hormones have on the pathogenesis of Sjögren’s syndrome.

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There is a lack of reliable data on whether oral contraceptives play a role in susceptibility to scleroderma. How­ever, at least two case–control studies have been published that concluded that the risk of scleroderma is not increased by the use of oral contraceptives.96,97 A third case-control study of patients with scleroderma and Raynaud’s phenomenon found that administration of intravenous estrogen administration improved abnormal endothelial function;98 as the authors noted, future studies of the influence of longterm exogenous estrogen use would be interesting in these patients. In a review of epidemiologic studies of environmental agents and systemic autoimmune disease, it was suggested that evidence to date indicates that the addition of a progestin to estrogen may ameliorate the risk of developing lupus, scleroderma, and primary Raynaud’s phenomenon in postmenopausal women using estrogen replacement therapy.91 Yet in contrast to this, a case report by another investigator has suggested that caution should be exercised in prescribing progestin-containing OCs to patients with preexisting microvascular disease such as scleroderma or Raynaud’s phenomenon. Only with better epidemiologic studies in the future can we make definitive conclusions on whether there is more of a risk or benefit to exogenous hormonal therapy in patients with scleroderma. Finally, there are no studies in the literature regarding the use of exogenous estrogens or oral contraceptives in patients with systemic inflammatory vasculitis. From case reports it seems that, as in antiphospholipid syndrome, the use of oral contraceptives in vasculitis may be the second or third ‘hit’ that contributes to thrombosis in a patient with underlying hypercoagulability, such as the presence of an inherited prothrombotic mutation. Until we have a better understanding of the interactions of OCs in vasculitis, it seems reasonable to avoid these medications in patients with active disease. Generally, oral contraceptives are the preferred method of birth control in women of reproductive age because of their efficacy, convenience, and reversibility. They are a good option in patients with autoimmune rheumatic disease who do not have risk factors for thrombosis, active SLE, or antiphospholipid antibodies, and may provide non-contraceptive benefits in treating problems that disproportionately afflict patients with rheumatic disease. The influence of exogenous hormones, in particular combined oral contraceptives, brings another dimension to the complexity of the interactions between the immune system and endocrine system and, with it, brings future challenges for both basic and clinical research.

References 1. Cutolo M, Sulli A, Seriolo B, et al. Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol 1995;13:217. 2. Olsen NJ, Kovacs WJ. Gonadal steroids and autoimmunity. Endocr Rev 1996;17:369.

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3. Peeva E, Michael D, Cleary J, Rice J, Chen X, Diamond B. Prolactin modulates the naïve B cell repertoire. J Clin Invest 2003;111:275–83. 4. Cutolo M, Wilder R. Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheumatic Dis Clin North Am 2000;26:4. 5. Lahita RG. Sex steroids and the rheumatic diseases. Arthritis Rheum 1985;28:121–26. 6. Cutolo M, Lahita RG. Estrogens and arthritis. Rheum Dis Clin North Am 2005;31:19–27. 7. Cutolo M, Sulli A, Capellino S, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 2004;13:635–38. 8. Lahita RG, Bradlow HL, Ginzler E, et al. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 1987;30:241–48. 9. Merrill J, Dinu A, Lahita RG. Autoimmunity: the female connection. Medscape Womens Health 1996;1:5. 10. Grossman CJ. Regulation of the immune system by sex steroids. Endocr Rev 1984;5:435–55. 11. Rosendaal FR, Helmerhorst FM, Vandenbrouke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 2002;22:201–10. 12. National Center for Health Statistics Advance Data, NCHS, Washington, DC, 1990 182. 13. Sammaritano L. Therapy insight: guidelines for selection of contraception in women with rheumatic diseases. Nature Clin Pract Rheumatol 2007;3:273–81. 14. Farley TMM, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancing the risks. Hum Reprod Update 1999;5: 721–35. 15. Sidney S, Siscovick DS, Petitti DB, Schwartz SM, et al. Myo­cardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies. Circulation 1998;98: 1058–63. 16. Burkman R. Oral contraceptives: current status. Clin Obstet Gynecol 2001;44:62–72. 17. WHO Working Group. Cardiovascular Disease and Steroid Hormone Contraception. Geneva: World Health Organization; 1998. 18. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977–80. 19. Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983–87. 20. Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001;323:131–34. 21. Farmer RDT, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997;349:83–88. 22. World Health Organization. Effect of different progestins in low estrogen oral contraceptives on venous thromboembolic disease. World health organization collaborative study of cardiovascular disease and steroid hormone contraception. Lancet 1995; 346:1582–88.

23. Vandenbrouke JP, Koster T, Briet E, et al. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994;344: 1453–57. 24. Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynecol 1998;179:577–82. 25. World Health Organization, Medical Eligibility Criteria for Con­traceptive Use, third ed. 2004. www.who.int/reproductivehealth/publications/mec/3_cocs.pdf. (Accessed March 30, 2008.) 26. Helmick C, Felson D, Lawrence R, et al. For the national arthritis data workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheum 2008;58:15–25. 27. Mecacci F, Pieralli A, Bianchi B, Paidas M. The impact of autoimmune disorders and adverse pregnancy outcome. Semin Perinatol 2007;31:223–26. 28. Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum Dis North Am 2001;27:269–81. 29. Vollenhoven RF, McGuire JL. Estrogen, progesterone, and testosterone: can they be used to treat autoimmune diseases?. Cleve Clin J Med 1994;61:276–84. 30. Golding A, Haque U, Giles J. Rheumatoid arthritis and reproduction. Rheum Dis Clin North Am 2007;33:319–43. 31. Pope RM, Yoshinoya S, Rutstein J, et al. Effects of pregnancy on the prognosis and serology of rheumatoid arthritis. Am J Med 1983;74:973–79. 32. Hazes JMW, van Zeben D. Oral contraception and its possible protection against rheumatoid arthritis. Ann Rheum Dis 1991;50:72–74. 33. Royal College of General Practitioners’ Oral Contraception Study. Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Lancet 1978;1:569–71. 34. Hannaford P, Kay C, Hirsch S. Oral contraceptives and rheumatoid arthritis: new data from the royal college of general practitioners’ oral contraception study. Ann Rheum Dis 1990;49:744–46. 35. Jorgensen C, Picot MC, Bologna C, Sany J. Oral contraception, parity, breast feeding, and severity of rheumatoid arthritis. Ann Rheum Dis 1996;55:94–98. 36. Brennan P, Bankhead C, Silman A, et al. Oral contraceptives and rheumatoid arthritis: results from a primary carebased incident case-control study. Semin Arthritis Rheum 1997;26:817–23. 37. Pladevall-Vila M, Delclos G, Varas C, et al. Controversy of oral contraceptives and risk of rheumatoid arthritis: metaanalysis of conflicting studies and review of conflicting metaanalyses with special emphasis on analysis of heterogeneity. Am J Epidemiol 1996;144:1–14. 38. Spector TD, Hochberg MC. The protective effect of the oral contraceptive pill of rheumatoid arthritis: an overview of the analytic epidemiological studies using meta-analysis. J Clin Epidemiol 1990;43:1221–30. 39. James W. Rheumatoid arthritis, the contraceptive pill, and androgens. Ann Rheum Dis 1993;52:470–74. 40. Spector TD, Perry LA, Tubb G, Silman AJ, Huskisson EC. Low free testosterone levels in males with rheumatoid arthritis. Ann Rheum Dis 1988;47:65–68.

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41. Spector TD, Perry LA, Tubb G, Huskisson EC. Androgen status of females with rheumatoid arthritis. Br J Rheumatol 1987;26:316–18. 42. Petri M, Robinson C. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum 1997;40:797–803. 43. Sanchez-Guerrero J, Karlson EW, Liang MH, et al. Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum 1997;40:804–8. 44. Jungers P, Dougados M, Pelissier C, et al. Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum 1982;25:618–23. 45. Lakasing L, Khamashta M. Contraceptive practices in women with systemic lupus erythematosus and/or antiphospholipid syndrome: what advice should we be giving? J Fam Plann Reprod Health Care 2001;27:7–12. 46. Cevera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1000 patients. Medicine 1993;72: 113–38. 47. Lahita RG. Emerging concepts for sexual predilection in the disease systemic lupus erythematosus. Ann NY Acad Sci 1999;876:64–69. 48. Roubinian J, Talal N, Siiteri PK, Sadakian JA. Sex hormone modulation in autoimmunity in NZB/NZW mice. Arthritis Rheum 1979;22:1162–69. 49. Jara LJ, Lavalle C, Espinoza LR. Does prolactin have a role in the pathogenesis of systemic lupus erythematosus? J Rheumatol 1992;19:1333–36. 50. Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy: the hopkins lupus pregnancy center experience. Arthritis Rheum 1991;34:1538–45. 51. Ruiz-Irastorza G, Lima F, Alves J, et al. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol 1996;35:133–38. 52. Lockshin MD. Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis Rheum 1989;32:665–70. 53. Lockshin MD, Reinitz E, Murrman M, et al. Lupus pregnancy: case–control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. Am J Med 1984;77:893–98. 54. Costenbader K, Feskanich D, Stampfer M, Karlson E. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum 2007;56: 1251–62. 55. Bermas B. Oral contraceptives in systemic lupus erythematosus – a tough pill to swallow? N Engl J Med 2005;353: 2602–4. 56. Julkunen HA. Oral contraceptives in systemic lupus erythematosus: side-effects and influence on the activity of SLE. Scand J Rheumatol 1991;20:427–33. 57. Petri M, Kim M, Kalunian K, et al. Combined oral contraceptives in women with systemic lupus erythematosus in the OCSELENA trial. N Engl J Med 2005;353:2550–58. 58. Sanchez-Guerrero J, Uribe A, Jimenez-Santana L, et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med 2005;353:2539–49. 59. Clowse ME, Magder LS, Witter F, et al. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum 2005;52:514–21.

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60. Petri M. The hopkins lupus pregnancy center: ten key issues in management. Rheum Dis Clin North Am 2007;33:227–35. 61. Chapman RM, Sutcliffe SB. Protection of ovarian function by oral contraceptives in women receiving chemotherapy for Hodgkin’s disease. Blood 1981;58:849–51. 62. Slater CA, Liang MH, McCune JW, et al. Preserving ovarian function in patients receiving cyclophosphamide. Lupus 1999;8:3–10. 63. Petri M. Musculoskeletal conmplications of systemic lupus erythematosus in the Hopkins Lupus Cohort: an update. Arthritis Care Res 1995;8:137–45. 64. Lindsay R. The effect of sex steroids on the skeleton in premenopausal women. Am J Obstet Gynecol 1992;166:1993–96. 65. Agarwal S, Waltrous J, Petri M. Gynecological problems are more common in SLE than in the general female population [Abstract]. Arthritis Rheum 2006;54:S445. 66. Pando JA, Gourley MF, Wilder RL, Crofford LJ. Hormonal supplementation as treatment for cyclical rashes in patients with systemic lupus erythematosus. J Rheumatol 1995;22:2159–62. 67. Petri M, Lim GS, Goldman D. Menstruation and systemic lupus erythematosus [Abstract]. Arthritis Rheum 1992; 35:241. 68. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum 1999;42: 1309–11. 69. Faculty of Family Planning and Reproductive Health Care and Family Planning Association Joint Statement in response to the CSM letter of 18 October 1995. October 26, 1995. 70. Silver RM, Draper ML, Scott JR, et al. Clinical consequences of antiphospholipid antibodies: an historic cohort study. Obstet Gynecol 1994;83:372–77. 71. Shah N, Khamashta MA, Atsumi T, et al. Outcome of patients with anticardiolipin antibodies: a ten year follow-up of 52 patients. Lupus 1998;7:3–6. 72. Julkunen HA, Kaaja R, Friman C. Contraceptive practice in women with systemic lupus erythematosus. Br J Rheum 1993;32:227–30. 73. Bruneau C, Intrator L, Sobel A, et al. Antibodies to cardiolipin and vascular complications in women taking oral contraceptives. Arthritis Rheum 1986;29:1294. 74. Krnic-Barrie S, O’Conner C, Looney S, Pierangeli S, Harris N. A retrospective review of 61 patients with antiphospholipid syndrome: an analysis of factors influencing recurrent thrombosis. Arch Intern Med 1997;157:2101–8. 75. Vianna JL, Khamashta MA, Ordi-Ros J, et al. Comparison of the primary and secondary antiphospholipid syndrome: a European multicenter study of 114 patients. Am J Med 1994;96:3–9. 76. Derksen RHWM, deGroot PG, Kater L, et al. Patients with antiphospholipid antibodies and venous thrombosis should receive long term anticoagulation treatment. Ann Rheum Dis 1993;52:689–92. 77. Somers E, Magder LS, Petri M. Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with SLE. J Rheumatol 2002;29:2531–36. 78. Brouwer JL, Bijl M, Veeger NJ, et al. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial

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80.

81. 82. 83.

84.

85.

86.

87.

88.

89.

90. 91. 92.

93. 94. 95.

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thromboembolism in patients with systemic lupus erythematosus. Blood 2004;104:143–48. Forasterio R, Martinuzzo M, Adamczuk Y, et al. The combination of thrombophilic genotypes is associated with definite antiphospholipid syndrome. Haematologica 2001;86:735–41. Asherson RA, Piette JC. The catastrophic antiphospholipid syndrome 1996: acute multi-organ failure associated with antiphospholipid antibodies: a review of 31 patients. Lupus 1996;5:414–17. Weinstein A, Lahita RG. Educational review manual in family practice. Rheumatology 2004;1:32–36. Beeson PB. Age and sex association of 40 autoimmune diseases. Am J Med 1994;96:457–62. Sullivan DA, Edwards JA. Androgen stimulation of lacrimal gland function in mouse models of Sjögren’s syndrome. J Steroid Biochem Mol Biol 1997;60:237–45. Steinberg AD, Melez KA, Raveche ES, et al. Approach to the study of the role of sex hormones in autoimmunity. Arthritis Rheum 1979;22:1170–76. G. Xu, H. Shang, F. Zhu, Measurement of serum testosterone level in female patients with dry eye [Abstract], Proceedings of the International Congress of Ophthalmology Meeting Toronto, Canada. 1994. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA 2001;286:2114–19. Sullivan D, Belanger A, Cermak J. Are women with Sjögren’s syndrome androgen-deficient? J Rheumatol 2003;30: 2413–19. Ahmed SA, Aufdemorte TB, Chen JR, et al. Estrogen induces the development of autoantibodies and promotes salivary gland lymphoid infiltrates in normal mice. J Autoimmunity 1989;2:543–52. Brennan M, Sankar V, Leakan RA, et al. Sex steroid hormones in primary Sjöogren’s syndrome. J Rheumatol 2003;30:1267–71. Wigley FM. When is scleroderma really scleroderma?. J Rheumatol 2001;28:1471–73. Mayes M. Scleroderma epidemiology. Rheum Dis Clin North Am 2003;29:239–54. Helmick C, Felson D, Lawrence R, et al. For the national arthritis data workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States part I. Arthritis Rheumatism 2008;58:15–25. Medsger TA, Masi AT. The epidemiology of systemic sclerosis (scleroderma). Ann Intern Med 1971;74:714–21. Black CM, Stevens WM. Scleroderma. Rheum Dis Clin North Am 1989;15:193–212. Bianchi DW, Zickwolf GK, Weil GJ, et al. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci 1996;93:705–8. Pisa F, Bovenzi M, Romeo L. Reproductive factors and the risk of scleroderma: an Italian case-control study. Arthritis Rheum 2002;46:451–56.

  97. Beebe JL, Lacey JV Jr., Mayes MD, Gillespie BW, Cooper BC, Laing TJ, Schottenfield D. Reproductive history, oral contraceptive use, estrogen replacement therapy and the risk of developing scleroderma (Abstract). Arthritis Rheum 1997;40:S100.   98. Lekakis J, Mavrikakis M, Papamichael C, et al. Short-term estrogen administration improves abnormal endothelial function in women with systemic sclerosis and raynaud’s phenomenon. Am Heart J 1998;136:905–12.   99. Beretta L, Caronni M, Scorza R. Systemic sclerosis following oral contraception. Clin Rheumatol 2005;24:316–17. 100. Kahaleh MB, LeRoy EC. Autoimmunity and vascular involvement in systemic sclerosis. Autoimmunity 1999;31: 195–214. 101. Ames PR, Lupoli S, Alves J, et al. The coagulation/fibrinolysis balance is systemic sclerosis: evidence for a hematological stress syndrome. Br J Rheumatol 1997;36:1045–50. 102. Van Grootheest K, Vrieling T. Thromboembolism associated with the new contraceptive yasmin. BMJ 2003;326:257. 103. Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman M. Rheumatology, fourth ed.. St Louis, MO: Mosby; 2008, 1489–1497. 104. Jennette J, Falk R, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37:187–92. 105. Watts RA, Lane SE, Bentham G, et al. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum 2000;43:414–19. 106. Seo P. Pregnancy and vasculitis. Rheum Dis Clin North Am 2007;33:299–317. 107. Duhaut P, Abert MC, Le Page L, et al. Giant cell arteritis and polymyalgia rheumatica: influence of past pregnancies? The GRACG multicenter case control study. Rev Med Interne 2004;25:792–800. 108. Duhaut P, Pinede L, Demolombe-Rague S, et al. Giant cell arteritis and polymyalgia rheumatica: are pregnancies a protective factor? A prospective, multicenter case-control study, GRACG. Rheumatology 1999;38:118–23. 109. Uthman I, Otrock Z, Taher A. Deep venous thrombosis in a patient with behçet’s disease and homozygous prothrombin (factor II) G20210A mutation on oral contraceptive pills. Rheumatol Int 2006;26:758–59. 110. Merkel P, Lo G, Holbrook J, et al. Brief communication: high incidence of venous thrombotic events among patients with wegener granulomatosis: the wegener’s clinical occurrence of thrombosis (WeCLOT) Study. Ann Intern Med 2005;142:620–26. 111. Zeben D, Hazes JMW, Vandenbroucke JP, Dijksman BAC, Cats A. Diminished incidence of severe rheumatoid arthritis associated with oral contraceptive use. Arthritis Rheum 1990;33:1462–65. 112. Nagler RM, Pollack S. Sjögren’s syndrome induced by estrogen therapy. Semin Arthritis Rheum 2000;30: 209–14.

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Gender-Specific Issues in Organ Transplantation HILARY SANFEY Professor of Surgery and Vice-Chair for Education, Southern Illinois School of Medicine Department of Surgery, Springfield, IL, USA

The relationship between sex hormones and immunological processes is well documented. Women are known to have higher immunoglobulin levels than men, a higher incidence of immunologically based illnesses, and the ability to mount a more vigorous immune response to infections. Both cell-mediated immunity and natural killer cell activity are diminished during pregnancy and menopausal women have an increased release of interleukin-1 by monocytes, which is reversible by hormone replacement therapy.1 Depending on dose, estrogens may act as immunosuppressors or immunostimulants. Estrogen administered before bone marrow transplantation has been shown to result in increased graft failure. The mixed lymphocyte reaction is enhanced by estradiol and fluctuating lymphocyte responses are observed during normal menses,2 pregnancy, and the use of oral contraceptives.3 As might be expected, pregnancy and the menstrual cycle affect the severity of autoimmune disease.1 Androgens also affect immune function. Testosterone has been shown to suppress anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE),4 and graft rejection in rodents is delayed by injection of testosterone. Progesterone is an immunosuppressive agent,5,6 and may be the basis for the gender gap in the disease SLE.7 It is possible that genes related to autoimmunity may be hormonally regulated, although there is no direct evidence for this. Given these data it is hardly surprising to find that many gender related differences exist in the arena of organ transplantation. These differences will be discussed as they relate to organ failure, liver, kidney, and pancreas transplantation.

cirrhosis. Certain forms of liver disease such as primary biliary cirrhosis and autoimmune hepatitis are seen almost exclusively in women.8 However men with autoimmune hepatitis appear to have a higher relapse rate and younger age of disease onset, which may relate to increased prevalence of HLA A1 – B8-DR3. Despite this men have significantly better long-term survival and outcomes than women.9 Oral contraceptives have been associated with several hepatobiliary diseases,10 and there is some controversy regarding the risk of liver injury associated with estrogen replacement therapy. Androgen therapy has been implicated in the pathogenesis of focal nodular hyperplasia of the liver. Since women with liver disease may not have the hepatic capacity to metabolize endogenous or exogenous estrogens impaired liver function is a contraindication to HRT11 Nonoral estrogens may be safer in these patients, because they do not undergo a first-pass effect. Progestins are not mediated through a direct effect on hepatic clearance or excretion of metabolites12 and may be used safely in patients with chronic hepatobiliary disease.13 Selective estrogen receptor modulators such as tamoxifen are metabolized in the liver and have been associated with cholestatic jaundice and hepatotoxicity. Menstrual irregularities resulting in anovulation and infertility may be the first clinical indication of liver dysfunction in a woman and may improve following successful liver transplantation.14 Liver failure may occur as a result of pregnancy or be exacerbated by pregnancy occurring in a patient with known liver dysfunction.

LIVER FAILURE IN PREGNANCY A number of clinical syndromes, resulting in liver failure and arising in pregnancy in previously healthy women, have been described. Acute fatty liver of pregnancy (AFLP) is characterized by mitochondrial dysfunction15 and complicates between 1 in 700016 and 1 in 13 000 pregnancies.17 It is possible that hormonal changes augment the effects

ORGAN FAILURE Liver Failure Liver failure may be acute occurring de novo in a previously healthy patient or chronic in a patient with established Principles of Gender-Specific Medicine

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of an otherwise tolerable insult to the mitochondria.18 AFLP occurs more frequently in primiparous women, but can occur after several non-affected pregnancies.19,20 The only treatment is immediate delivery. After delivery, most patients improve slowly, but a full clinical and laboratory recovery may take from 1 to 4 weeks. Four cases of recurrent AFLP have been reported.21–23 Intrahepatic cholestasis is characterized by disturbed enterohepatic circulation with a decreased hepatocyte capacity to transport bile acids possibly due to an inherited hypersensitivity to estrogen at the gene level.24 Patients with increased estrogen levels or with a history of cholestatic hepatitis induced by oral contraceptive pills have an increased incidence. Treatment is directed at relieving the symptoms. The HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelets) complicates 0.1% of pregnancies and is observed in up to 10% of patients with pre-eclampsia.9,25 This syndrome usually peaks 24 hours after delivery, followed by clinical improvement, with laboratory levels gradually returning to normal within 3–11 days. The lower the gestational age at onset of symptoms the higher the risk of eclampsia.26 Women with nadir platelet counts ⬍50 000 cells/μl have an increased risk for adverse maternal outcomes. Once a clinical diagnosis has been made, aggressive intervention and expeditious delivery is indicated. The Budd–Chiari syndrome may present in either the pregnant or the postpartum patient.27 Inherited thrombophilic states, particularly in women who use birth control pills, predispose pregnant patients to thrombotic events.28 In addition, pregnancy is regarded as a hypercoagulable state.29 Among women previously treated for Budd–Chiari syndrome, successful pregnancy and delivery is possible.30,31

PREGNANCY IN LIVER FAILURE Pregnancy is associated with changes in maternal physiology that may adversely affect portal hypertension and increase the risks of variceal hemorrhage.25 However pregnancy is uncommon in patients with cirrhosis because of decreased fertility associated with advanced liver disease. The spontaneous abortion rate in patients with cirrhosis is about 15–20%.25 Postpartum hemorrhage occurs in women with portal hypertension who become pregnant in 7–10% of cases and is more common in those with cirrhosis.32 Pregnancy may induce a hypercoagulable state and cause portal hypertension in patients with or without cirrhosis leading to portal vein thrombosis.33 Hepatitis A infection is no more severe in pregnant women than in non-pregnant individuals.34 Chronic hepatitis B (HBV) carriers usually have normal pregnancies, unless there is also severe chronic hepatitis or secondary cirrhosis and associated complications.35 The significance of HBV infection derives from its potential to be transmitted vertically. Ten percent of infants born to women with acute HBV infection during the first trimester of pregnancy are HBs

Ag-positive at birth,36 and 80–90% become HBs Ag-positive without prophylactic therapy if acute maternal infection develops during the third trimester of pregnancy.37 Hepatitis B immunization has been shown to be feasible and effective in postpartum women.38 Transmission of HCV is horizontal through parenteral exposure to blood and blood products and, rarely, vertical unless maternal viral titers are unusually high. There is no evidence that pregnancy alters the natural history of hepatitis C (HCV) or that HCV interferes with normal pregnancy, unless the patient has cirrhosis.

Kidney Failure There are a number of gender-specific considerations unique to patients with end-stage renal disease. The rate of progression of many renal diseases is faster in men than women,39–42 and men show a standardized mortality rate twice that of women.43,44 Sex hormones may cause this gender difference by an effect on mesangial proliferation and extracellular matrix formation through the release of cytokines, vasoactive agents, and growth factors.45 Estrogens show potent antioxidant activity, unlike testosterone. Two prospective studies suggest that the protection afforded by female gender is only evident in premenopausal women.42,46 Other investigators have shown that manipulation of the hormonal environment influences the progression of experimental models of chronic renal disease.47 Gender plays a major role in the expression of some forms of renal disease, notably SLE: most patients are female, SLE is exacerbated by estrogens and oral contraceptives,48,49 and activity may worsen during the menstrual cycle50 and pregnancy. Male and female patients with SLE have normal levels of estrogen; however, the overall metabolism of such compounds is altered to favor more feminizing compounds.51 Studies of androgen metabolism in women with active SLE demonstrate decreased plasma levels of androgen.52,53 Early data suggest that there are significant health benefits from the use of hormone replacement therapy in postmenopausal patients but pre-menopausal use of estrogens in SLE should be avoided since hormone supplements induce a flare of disease in this group.54 A number of authors have noted that women and nonwhites demonstrated significantly higher odds for late initiation of dialysis compared with men and whites.55–58 In addition women are less likely to receive a renal transplant but more likely to donate a kidney.59,60 They postulated that this discrepancy may be due to a lack of physician awareness of possible gender and race effects on the presentation and management of illnesses, inaccurate assessment of renal function leading to overestimation of residual renal function, inadequate recognition of and efforts to overcome cultural barriers to medical care, and lack of financial resources to pay for medical care. Whites and women have an increased rate of hospitalization.61 Blacks and women have lower hematocrits than whites and men, and blacks and men have

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poorer blood pressure control than whites and women. Blacks and women are less likely to have fistulas compared with whites and men.62 A possible explanation for the gender difference in fistula placement is the technical difficulty in creating fistulas in women, who tend to be smaller than men and therefore have smaller blood vessels. This may be of significance since Sehgal noted that use of a catheter for vascular access is one of the more important barriers to adequate delivery of hemodialysis.62 Thus, interventions that expedite placement of fistulas may lead to improved adequacy of dialysis. In a national sample males were about 10% more likely than women to be non-compliant with therapy.62 As in the general population, male dialysis patients have a slightly higher mortality rate compared with female patients.63 This gender difference is attributable to a higher risk of death among men from cardiac causes and malignancy.64 Eliminating racial and gender differences requires that we become aware of such differences, determine barriers to optimal outcomes, and develop interventions to overcome these barriers.

PREGNANCY AND RENAL DISEASE Fertility is significantly reduced in women with renal failure. Only 10–42% of women dialysis patients of childbearing age menstruate.65,66 Prematurity is the greatest cause of morbidity and mortality in the infants of women with renal disease who manage to become pregnant. The National Register of Pregnancy in Dialysis recorded 222 pregnancies in women who were receiving dialysis at the time of conception.67 Only 55% of pregnancies that reached the second trimester resulted in surviving infants and 18% of the liveborn infants died in the neonatal period. Three maternal deaths have been reported.67 The timing of delivery is a matter of debate but most physicians are reluctant to prolong the pregnancy beyond 38 weeks gestation. Physicians should regard childbearing as one of the goals of treatment for renal disease in women of childbearing age, rather than as an accident to be dealt with when it occurs. The problems of hypertension, increased proteinuria, and infection can be anticipated and managed appropriately. Transplant recipients and women with renal insufficiency face the possibility that pregnancy may adversely affect renal function. For the transplant recipient, pregnancy is further complicated by immunosuppression and the risk for opportunistic infection. There have been reports suggesting that disease progresses less rapidly in women with similar degrees of renal dysfunction who do not become pregnant.67 In diabetic nephropathy, as in other renal diseases, the level of renal function at the time of conception is the most important determinant of the effect of pregnancy on the progression of the disease. There are a number of reasons to anticipate that pregnancy might have an adverse effect on the progression of renal disease. Normal pregnancy is accompanied by an increased glomerular filtration rate

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but the increase is brought about by increased renal blood flow, not by increased intraglomerular pressure.67 In addition, pregnancy is frequently accompanied by hypertension, proteinuria, and urinary tract infections.68 Women who start dialysis for progressive renal insufficiency usually require continued dialysis postpartum. SEXUAL FUNCTION Disturbances in sexual function are a common feature of chronic renal failure.69 Approximately 50% of uremic men complain of erectile dysfunction while an even greater percentage of both men and women complain of decreased libido and a marked decline in the frequency of intercourse.70,71 The causes are multifactorial and include uremia, peripheral neuropathy, autonomic insufficiency, and peripheral vascular disease. Psychological and physical stresses also contribute. In men with chronic renal failure, disturbances in the pituitary–gonadal axis can be detected as the renal failure progresses.69–72 These disorders rarely normalize with initiation of hemodialysis or peritoneal dialysis, but may improve in patients with a well-functioning kidney transplant.73 Chronic renal failure is associated with impaired spermatogenesis and testicular damage, often leading to infertility.74 Elevated plasma prolactin levels are commonly found in dialyzed men75 and may be related in part to the development of secondary hyperparathyroidism. Extreme hyperprolactinemia is associated with infertility, loss of libido, low circulating testosterone levels, and inappropriately low luteinizing hormone (LH) levels in men with normal renal function. Controlling the degree of secondary hyperparathyroidism may be of benefit in lowering prolactin levels and improving sexual function in some patients.69 Disturbances in menstruation and fertility are commonly encountered in women with chronic renal failure. The menstrual cycle typically remains irregular after the initiation of dialysis.76 Many uremic women are anovulatory, resulting in infertility.77 Women on chronic dialysis also tend to complain of decreased libido and reduced ability to reach orgasm,71,78 Women with chronic renal failure may have elevated circulating prolactin levels and, as is the case in men, these elevated prolactin levels may impair hypothalamic-pituitary function and contribute to sexual dysfunction. The age at which menopause begins in chronic renal failure tends to be decreased when compared to healthy women.69

Diabetes Mellitus Type 1 diabetes mellitus is a disease in which beta cells within the islets of Langerhans are destroyed by an autoimmune process resulting from genetic and unknown environmental factors. The annual incidence is approximately 55 new cases per million of the population. Diabetes is the leading cause of blindness and renal failure in the United

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States. Diabetics are four to seven times more likely to require an amputation and twice as likely to die of heart disease than the general population.79 As with other medical conditions, gender-based differences have been noted in diabetes. Olivarius80 found a relationship between body height and renal involvement in newly diagnosed type 2 diabetic patients and noted that urinary albumin concentration increased with decreasing height for women but not men. An association between diabetes mellitus and central obesity with short stature is more common in women.81,82 In experimental models, females are more prone to develop diabetes than males.83,84 There are several indications that the islet itself can respond to sex hormones since androgens lower insulin sensitivity, whereas estrogens increase it.85,86 Sex steroids also have recognized effects on leukocyte function, induce prediabetic islet abnormalities, and are known to modulate cytokine production by leukocytes, in particular by mononuclear phagocytes.87 Bilbao noted that autoantibodies against insulin occur more frequently in female diabetic patients and speculated that these differences could reflect the severity and specificity of the autoimmune attack against the endocrine pancreas and influence the rate of progression to type 1 diabetes.88 Davis et al. reasoned that a differential gender response to antecedent hypoglycemia might explain why type 1 diabetic women do not suffer a greater prevalence of hypoglycemia despite inherently reduced counter-regulatory responses.89 Gender inequity in diabetics was explored in one study from Sweden. In this study Jonsson demonstrated that diabetic women in Sweden report more frequent outpatient contacts, less patient satisfaction, and a lower health-related quality of life than diabetic men. No gender differences were found in glucose control.90

PREGNANCY AND DIABETES Diabetes occurs during 3% of all pregnancies. Risk factors include obesity, age older than 35 years, family history of type 2 diabetes, and prior delivery of a large (⬎9 lb) infant. White’s classification stratifies diabetes during pregnancy based on duration of diabetes, therapy, and the presence of retinopathy, nephropathy, or heart disease.91 Those women in class D with secondary complications of diabetes have the greatest potential for complications during pregnancy. Organogenesis occurs early in the first trimester therefore tight blood glucose control during this interval decreases congenital malformations and miscarriages. Oral hypoglycemic agents should be switched to insulin as soon as possible because these drugs cross the placenta, and can cause prolonged fetal hyperinsulinemia. Most women with uncomplicated type I diabetes do well during pregnancy, although maternal risks and perinatal mortality are increased slightly. Risk factors for maternal morbidity and relative contraindications to pregnancy include established renal disease (creatinine ⬎2.0 mg/dl or proteinuria ⬎2 g/day), uncontrolled hypertension, and atherosclerotic vascular disease. Diabetic

retinopathy progresses in 10–50% of cases; therefore an ophthalmologist should examine patients each trimester. Women with gestational diabetes usually normalize their blood glucose immediately post partum, about two-thirds will have gestational diabetes in subsequent pregnancies, and up to 50% will develop diabetes over the next 15 years.91

ORGAN DONATION Research has shown that men and women approach living donation in different ways.92–94 Simmons et al. found that women were more likely to make a spontaneous decision to pursue donation and to view the decision as consistent with the sex-role expectations of society or as an extension of their family obligations.93,94 Men, on the other hand, were more deliberative and ambivalent about donation. However, men expect to experience more negative health consequences after donation than women. Rodrique et al. postulated that in our society many women have an experience that is psychologically equivalent to a living organ donation, namely giving birth (i.e. life) to an infant.92 In the absence of such an experience, men may anticipate more negative health consequences related to living donation. In addition men are more likely than women to expect some form of ‘pay back’ after donation. Perhaps, this is because living donation for men, more so than for women, may represent more of a ‘sacrifice’ or an exceptional act.92,94 A number of recent studies have shown that with the advent of laparoscopic nephrectomy, there has been a decrease in the gender difference in kidney donation.56,95,96 Boulware97 performed a cross-sectional telephone survey of Maryland households to assess race and gender differences in willingness to donate blood and cadaveric organs and noted that before adjustment, black females were least willing to donate blood (41%), and black males were least willing to become cadaveric donors (19%). Adjustment for respondent concerns about mistrust of hospitals and discrimination in hospitals explained most differences in willingness to donate blood, whereas adjustment for respondents’ beliefs regarding the importance of spirituality and religion explained most differences in willingness to donate cadaveric organs. Clearly donor recruitment efforts should focus on race-gender groups with the lowest levels of willingness. In 1972, Simmons and Fulton93 compared individuals who had signed an organ donor card with neighbors who had not signed the card and identified being a young woman as one of the major determinants for willingness to be considered as a potential cadaveric donor. It is generally agreed that living donor transplantation represents the single best form of therapy for end-stage renal disease,98,99 Although the ethics of living donor transplantation have been debated, the gap between the supply of

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cadaveric donors and the demand for organs has encouraged an increasing use of living donors. Studies from the larger transplant registries and single-center experiences showed that in most subgroups, women predominated among living donors.100–104 Bloembergen et al. reviewed the US Renal Data System database from 1991 to 1993 and found women were 28% more likely to donate a kidney. Zimmerman et al. noted that 59% of the 198 living donor transplants in their institution were from women .The largest contributing factor to the overall excess of female donors is the overwhelming predominance of women among spousal donors.95,104 Among spousal donors, wives are 2.1–8.16 times more likely to donate than husbands.56,104–108 The United Network for Organ Sharing database reported that 73% of the 360 spousal donations were wife to husband.104 Although immunological issues are a real consideration in husband-to-wife allografts in cases in which a woman has borne her husband’s child, such concerns did not explain the under-representation of husbands. All spousal donations occurred as a result of the donor volunteering This observation would seem to contradict the hypothesis of some investigators109,110 that women’s greater tendency toward risk aversion accounts in part for their lower rate of access to such invasive procedures as angiography, cardiac bypass, and renal transplantation.105 What is unclear from this study is why husbands do not appear to come forward under similar circumstances. In an earlier study,94 it was found that, compared with men, women were more likely to perceive donation as an extension of their obligation to their family. Nearly equal proportions of male and female potential donors were excluded because of medical illness or ABO incompatibility. There are no data to suggest adverse long-term effects from kidney donation during subsequent pregnancies.111,112

TRANSPLANTATION Liver The first human liver transplant was performed in Colorado in 1963. Since then the concept of liver transplantation has changed from a procedure once regarded as experimental in patients with no hope of surviving to a widely accepted therapy for people with end-stage liver disease .The number of transplants performed annually has increased to a point where demand for donor organs outstrips supply. This has resulted in considerable discussion in the transplant community about expanding the donor pool to include marginal donors and more recently the use of right or left lobes from living donors. A number of studies have correlated donor– recipient factors in order to identify risk factors that might lead to optimum organ utilization. Marino et al.113 found that graft failure was significantly associated with donor age greater than 45, donor gender, previous liver transplantation,

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and UNOS status of the recipient. Livers from female donors yielded significantly poorer results, with 2-year graft survival of female to male 55%; female to female 64%; male to male72%; and male to female 78%. Candinas et al.114 noted transplantation of a liver from a male donor into a female recipient was associated with an increased probability of chronic rejection. Sensitization to antigens expressed by bile duct epithelium as in primary biliary cirrhosis or exposure to donor bile duct minor histocompatibility antigens, such as the male sex-related H-Y antigen, may provide an explanation.114 Francavilla115 noted that donor and recipient gender also affect graft and patient survival after pediatric liver transplantation. There is possibly an increased incidence of lymphoproliferative disease in the gender-mismatched group.116 It has been suggested that this difference in outcome may be hormone-related.117 Human liver displays gender-related differences, such as increased hepatic content of microsomal oxidative enzymes in males and different numbers of estrogen and androgen receptors on hepatocytes in males and females.118,119 In a rat model, following partial hepatectomy, serum estrogen levels and the number of estrogen hepatic receptors increase concomitantly with liver regeneration, and in a murine experiment Kahn et al.120 demonstrated a reduction in the number of estrogen receptors in the livers of gender-mismatched recipients (male to female and female to male) 10 days after transplantation. Thus, it is possible that the worse outcome of the female to male gender combination in humans is due to a reduced number of estrogen receptors in the male recipients of a female organ.117 These data will not have an immediate effect on organ allocation because of the relative shortage of suitable grafts.

Kidney Kidney transplantation remains the treatment of choice for most persons with end-stage renal disease. Studies suggest that patients who undergo transplantation enjoy a more prolonged life and an improved quality of life in comparison with individuals who choose dialysis.121–123 While living related and living unrelated kidney transplant rates have increased steadily over the past several years, cadaveric transplantation rates have declined sharply due to increased organ demand and decreased supply. A gender effect similar to that seen in liver transplantation has also been observed in kidney transplantation. Neugarten and Silberger44 showed a particularly poor prognostic trend for kidneys from older female donors. It was suggested that gender-related kidney size and nephron count discordance were responsible for the different outcome. Kouli124 retrospectively analyzed donor–recipient factors independent of rejection after kidney transplantation and noted that Cr clearance was 14.1 ml/min less in female recipients than in male recipients with female-to-female transplants having the lowest subsequent Cr clearance values.

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Pancreas The goals of pancreas transplantation are to provide physiological insulin replacement and prevent secondary complications of diabetes.125 Diabetic male patients are more likely to be afflicted by end-stage renal disease than diabetic female patients and this is reflected in the number of men who require kidney pancreas transplantation.125 However, this fact does not explain why female patients represent such a high proportion of pancreas transplant alone (PTA) recipients, because the incidence of type 1 diabetes is equal in male and female patients.126 It appears that non-uremic diabetic female patients are more likely to seek pancreas transplantation as an alternative to treatment with exogenous insulin. A successful pancreas transplant can reverse the lesions of diabetic nephropathy, although it takes at least 5 years of normoglycemia.125 Such reversal does not guarantee normal function because independent damage to the kidney may occur from the calcineurin inhibitors needed to prevent graft rejection. Other groups have also shown that a successful pancreas transplant can ameliorate microvascular complications, including retinopathy, nephropathy, and neuropathy.125,127 Recent successes with islet transplantation128 suggest that the dream of eliminating the major surgery of pancreas transplantation may soon be achieved.

OUTCOME POST-TRANSPLANTATION Graft Function DIFFERENCES IN METABOLISM The therapeutic effect and efficacy of many immunosuppressive drugs can be regulated by their rate of metabolism and elimination. Glucuronidation is an important metabolic process by which drugs are converted to a more readily excreted hydrophilic compound.129 Gender-dependant differences in rates of glucuronidation are known to exist.130 It is believed that mycophenolic acid (MPA) could compete for the same binding sites as estrogens and could explain the lower glucuronidation rate in females. Co-treatment with tacrolimus was also shown to affect MPA glucuronidation.130 Therefore gender differences and co-treatment with tacrolimus must be taken into consideration when the immunosuppressive drug mycophenolate mofetil (MMF) is being administered. Gasbarrini et al.131 demonstrated that isolated livers from female rats undergo greater oxidative injury during post-ischemia reperfusion than livers isolated from male animals. Other investigators have demonstrated that women are more sensitive to different kinds of liver injury, such as alcoholic liver disease, and that sex-specific liver diseases exist.132–134 It has been demonstrated that in the basal condition, modulation of several enzyme activities is related to the influence of estrogens.135 In particular, it has been

recently shown by Ikejima et al.135 that the increased susceptibility of females to alcohol is related to estrogen activity that increases expression of CD14 in Kupffer cells, leading to increased production of toxic mediators, thus exacerbating liver injury.135

IMPLICATIONS FOR REJECTION Donor and recipient gender influence many aspects of kidney transplantation. However, the precise nature of these interactions is still controversial. Female renal transplant recipients have an increased relative risk for acute rejection compared with male renal transplant recipients.43,136–141 In contrast, women have a decreased relative risk for the development of chronic allograft failure.136,138 This decreased risk for chronic allograft failure is age-dependent, with the younger patients demonstrating little difference between men and women. In contradistinction, patients over 45 years of age demonstrate a marked difference in the risk for chronic allograft failure between men and women. In a large-scale multivariate analysis, female recipients have been demonstrated to have an increased risk of acute rejection and a decreased risk for the development of chronic allograft failure.137,138 In contrast, a single-center multivariate analysis of graft survival showed that donor and recipient gender was not significant.137,141 Meier-Kreische et al.136 noted that the increased risk of acute rejection in female renal transplant recipients is equal to their overall decreased risk for chronic allograft failure (10% for each), and this may help explain why it has been difficult to document any difference in outcome between women and men.141–145 The relative protective status of female gender from chronic allograft failure may in large part explain the paradox of increased rejection yet equivalent long-term death censored graft survival seen in women. In men, increasing age linearly increases the risk of developing chronic allograft failure, whereas in women, only the oldest age group (age ⬎65) shows evidence of an increased risk of developing chronic allograft failure.136,137 It is possible that estrogen is in part responsible for the protective effect against chronic allograft failure that is seen in women while the increased risk of acute rejection seen in women may relate in some way to a general increase in immunoreactivity.146 It is also possible that the increased risk of sensitizing events in women (i.e., pregnancy) may also predispose to a higher risk of acute rejection. The protective effect against chronic allograft failure noted for women is likely related to differences in estradiol and testosterone levels between the sexes, and this is supported by experimental studies.147–149 It has been suggested that female kidneys contain fewer nephrons than male kidneys and, therefore, diminished long-term survival of kidneys donated from women may be explained by an inadequacy between the donor’s nephron supply and the recipient’s functional demand.137,150,151

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Or a smaller female kidney might be more susceptible to ischemic injury, immunologic reaction or nephrotoxicity.137,152 Other potential explanations include the direct influence of sex hormones on renal hemodynamics, mesangial cell proliferation and extracellular matrix metabolism.137 Also, sex hormones influence the synthesis and release of vasoactive substances, cytokines and other growth factors, which in turn are capable of altering the progression of renal disease.47,138 In addition, various humoral and cellular immune responses are regulated by sex hormones that can enhance or reverse the immunosuppressive activity of cyclosporine.137,153–155 Sex mismatch of donor and recipient after orthotopic liver transplantation (OLT) appear to be a risk factor for chronic irreversible rejection.114,115 One possible explanation is that the increased incidence of chronic rejection in women receiving a male liver is related to an immune attack against the Y chromosome antigen.114 However, the association between HLA matching and the incidence of chronic rejection suggest that mechanisms other than the H–Y minor histocompatibility antigen may be involved.113 It can be hypothesized that a greater sensitivity to ischemia–reperfusion injury may play an important role. It is still not clear why females are more sensitive than males to oxidative stress but since gender markedly affects the extent of postischemic reperfusion injury in isolated rat liver it is possible that this may account for the poor outcome of female organs after liver transplantation.131

IMPACT OF ORGAN SIZE ON OUTCOME Oh et al. compared the differences in early graft function based on donor gender, graft mass, and recipient metabolic demand.137 They determined that renal graft function early after transplantation from a female donor was not inferior to that from a male donor, as a few reports suggested.136,137,156 Even the graft weight from the female donors was not statistically lower than that from the male donors. On the contrary, they noted that recipient gender plays a role in the graft function after transplantation, and the serum creatinine was significantly higher in male recipients despite there being no gender difference in kidney graft weight or preoperative renal function of the donors. They could not find a statistically significant difference in the graft survival until 3 years post-transplantation by the gender groups of donors and recipients. Oh et al. concluded that the ‘recipient’ gender may be more important than the ‘donor’ gender for early graft function after adult living donor kidney transplantation. The effect of recipient gender on early graft function depends on the metabolic demands which, on average, are higher in male recipients.137 The MELD (Model for End Stage Liver Disease) score is widely used to assess the severity of liver cirrhosis.157 It is derived from a formula that takes into account the patient’s INR, total bilirubin, and serum creatinine. However it has

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some inherent limitations. Patients with coexisting cirrhosis-related complications, such as ascites or encephalopathy, may frequently have lower MELD scores that do not necessarily reflect disease severity and poor prognosis.158–161 A recent study raised a potential limitation of the MELD by showing that female patients may be treated unfairly in the prioritization of liver transplantation when they had the same GFR as the male patients.162 Huo et al.158 evaluated the actual survival rates at different points in time in association with the MELD scores in both males and females.158 Their results showed that adjusting the MELD scores in female candidates might not be a feasible strategy for the short-term outcome at 3 and 6 months because the mortality rates, for the most part, correlated with the baseline MELD scores between males and females. However, for the intermediate outcome at 9 and 12 months, female patients did have a higher mortality rate while associated with a lower baseline MELD score. In this regard, adjusting baseline MELD scores may fairly prioritize female transplant candidates. There were no gender differences in the other components of the MELD score, i.e. the INR or the bilirubin. However these authors stressed that the MELD was developed to look at the 3month survival rate in liver transplant candidates.157,158 If a corrected MELD score is to be given to all female patients, it could result in female patients having an ‘overshoot’ of MELD scores in prioritization of organ allocation, resulting in an increased short-term (3 and 6 month) mortality rate in males.158

Osteoporosis Patients with cirrhosis are predisposed to develop osteopenia because of poor nutrition, alcohol consumption, prolonged bed rest, reduced muscle mass, hormonal imbalances, and reduced levels of vitamin D, all of which contribute to metabolic bone disease.163 Chronic cholestasis results in decreased concentrations of bile acids in the intestine and subsequent malabsorption of vitamin D and calcium. After the initial post-transplant bone loss, bone density eventually stabilizes and subsequently improves to pre-transplant values. Immunosuppressive therapy is strongly implicated in the rapid postoperative loss of bone mass after liver transplantation. Even doses as low as 7.5 mg/day of prednisone may induce trabecular bone loss. Cyclosporine and tacrolimus can produce a high turnover osteopenia and accelerated bone resorption,163 and therefore, transplant recipients are at increased risk for the development of fractures.164,165 Estrogens are useful to prevent bone loss in normal postmenopausal patients but, as with calcium supplementation, no controlled trials have been performed in liver recipients. Most physicians are reluctant to prescribe estrogen because of concerns regarding hepatic toxicity. Most patients undergoing renal transplantation have some evidence of renal osteodystrophy prior to surgery.

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Silkensen166 demonstrated that female gender was associated with an elevated risk of fracture in a group of renal transplant recipients. Some investigators have demonstrated a decreased rate of vertebral fractures with calcitriol, although this drug should be used cautiously in patients with persistent hyperparathyroidism and a risk of hypercalcemia. In addition to the risk factors associated with renal transplantation those undergoing kidney pancreas transplantation appear to be at even greater risk of fracture. Fractures occur in approximately 50% of recipients within the first 5 years after transplantation.167 Factors that may be associated with increased osteopenia in diabetics include chronic hypocalcemia, insulin deficiency, relative hypoparathyroidism, decreased physical activity, impaired gonadal function, and metabolic acidosis. Sex steroid secretion is important in regard to outcome after transplantation. Shane168 and others164–167 have cited the contributing role of untreated hypogonadism to loss of bone density and increased fracture risk after solid organ transplantation. In one study 50% of patients had hypogonadism prior to pancreas transplant and 70% had hormone abnormalities post transplant. In this small series reproductive hormone abnormalities were common in women but uncommon in men before and after pancreas transplantation.169 The presence of long-standing untreated hypogonadism may have implications for bone loss and cardiovascular risk after pancreas transplantation, particularly in women. With correction of the metabolic abnormalities normalization of gonadal function should then be expected. Prednisone use after transplantation can aggravate insulin resistance and increase adrenal and ovarian androgen production with aromatization to estrogen as seen in the polycystic ovarian syndrome.

Reproductive Issues after Transplantation It has been almost 50 years since the first child was born to a female transplant recipient. Since that time pregnancy has become common after transplantation, but physicians have been left to rely on case reports, small series, and data from voluntary registries to guide the care of their patients. Many uncertainties exist, including the risks that pregnancy presents to the graft, the patient herself, and the long-term risks to the fetus. It is also unclear how to best modify immunosuppressive agents or treat rejection during pregnancy, especially in light of newer agents available where pregnancy safety has not been established. To begin to address these uncertainties and define clinical practice guidelines for the transplant physician and obstetrician, a consensus conference was held in Bethesda, MD in March 2003.170 The consensus recommendations are summarized in Table 55.1. FERTILITY AND CONTRACEPTION Patients with organ failure experience hypothalamicpituitary-gonadal dysfunction and decreased ovulation and

sperm maturation,72,171,172 which usually resolves by 6 months after successful renal transplantation.75,170 Fertility is clearly restored to such a degree that careful contraceptive counseling is required before transplantation. There are limited data on appropriate contraception following transplantation. Generally the transplant community has favored barrier methods, however, immunosuppressive agents decrease the effectiveness of intra-uterine devices, and immunocompromised subjects using such devices have increased risk for infection.170,173 While data are limited there is no information to suggest that estrogen/progestin is associated with adverse consequences in transplant patients when hypertension is well controlled.170 The optimal contraceptive agent to use after transplantation depends on balancing risks and benefits of each contraceptive method, and the patient’s desire to conceive. PREGNANCY Pregnancy will be discussed in terms of the risks to the graft, to the mother, and to the fetus. Risks to the Graft Despite years of experience and thousands of recorded gestation-specific risk factors, adverse graft outcomes have yet to be defined. Although registries have been of some assistance the voluntary nature of such data acquisition and lack of uniform protocols limits the potential of the data collected. While it has been suggested that pregnancy is an immunosuppressed state,170,174 a great deal of evidence shows pregnant women do not have diminished systemic immunity and that the uterus may in fact be an ‘immunoprivileged site.’170,175 While paternal cells have been found in maternal tissue, maternal regulatory T cells appear to specifically suppress responses to these antigens,170,176 and maternal responses to the allogeneic fetus are also suppressed locally, at the maternal–fetal interface.170,177 Therefore, inappropriate reduction in immunosuppression during pregnancy will lead to rejection of the transplanted organ.

Risks to the Mother Successful pregnancies have occurred after liver, kidney, and kidney–pancreas transplantation.170,178–182 Data on pregnancy outcomes are collected through a voluntary registry, the National Transplantation Pregnancy Registry (NTPR) in the United States, and through the UK Transplant Pregnancy Registry in the United Kingdom.170,183 Both registries point to several trends: spontaneous abortion rate about 14%, a high prevalence of hypertension, and an increased occurrence of preeclampsia.183,184 Over 50% of babies born to kidney transplant recipients are delivered at less than 37 weeks gestation.182,185 Over 14 000 pregnancies in renal allograft recipients have been documented since 1958.185 These pregnancies should all be considered high

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TABLE 55.1 Summary of Consensus Conference Guidelines Basis on which to determine timing of pregnancy

No rejection in the past year Adequate and stable graft function Minimal proteinuria No acute infections that might impact fetus Maintenance immunosuppression at stable dosing Maternal age Medical non-compliance Co-morbidity

Co-morbid factors that may influence pregnancy outcome

Etiology of original disease (risk of recurrent disease, etc.) Chronic allograft dysfunction Renal function and proteinuria Cardiovascular status and pulmonary status DM (or history of DM) HTN Inherited diseases in mother and/or father HBV, HCV, CMV Obesity

Preconception counseling

Should be introduced at least at the pre-transplant evaluation Should be followed up throughout the post-transplant process Should be offered to both the patient and her partner Ideally patients should be vaccinated pre-transplant, but if not should be vaccinated pre-pregnancy – influenza, pneumococcus, hepatitis B, tetanus Must discuss consequences of preterm birth and long-term consequences of preterm birth for both the mother and child with both prospective parents

Obstetrical management

Management of all pregnant transplant patients should be by high-risk obstetrician in conjunction with transplant physician Cesarean section indicated only for obstetric reasons Graft dysfunction during pregnancy warrants appropriate investigation (by biopsy if necessary) Immunosuppression must be maintained during pregnancy to avoid rejection Hyperemesis gravidum may lead to decreased absorption or inadequate immunosuppression

Source: McKay and Josephson, 2005172

risk and managed by an experienced team of healthcare providers. The risks to the mother are low if the mother is otherwise in good health with a Cr less than 1.5 mg/dl. Pregnancy has occurred less frequently in liver transplant recipients than renal transplant recipients. Scantlebury et al.178 reported 20 pregnancies in 17 liver transplant recipients in whom the rate of hepatic allograft dysfunction was 37% during pregnancy and 53% in the postpartum period. Findings in another group of 37 liver transplant recipients included drug-treated hypertension (46%), eclampsia/pre-eclampsia (21%), allograft rejection (17%), and graft loss (5.7%).179 More recent data from the University of Pittsburgh have suggested that when managed by an experienced team of physicians, pregnancy after transplantation has a good outcome.186 Renal dysfunction is the primary cause of adverse pregnancy outcomes in liver transplant recipients.187 A report from the European Dialysis and Transplant Association that included 53 women who became

pregnant found renal function unchanged in 67% and worse in 9%.188 Liver recipients are also at high risk for hypertension, preeclampsia, and preterm labor.170,186,189–191 Preeclampsia marked by HELLP syndrome is difficult to distinguish from rejection or progression of underlying liver disease, especially hepatitis associated with hepatitis C.192 Reports cite incidences of hypertension ranging from 14% to 44%, which is considerably higher than rates of 4% to 10% in the general population.190 In addition, the incidence of preeclampsia is also elevated (up to 33% in some series) among pregnant women after orthotopic liver transplantation.170 It is known that cyclosporine can cause endothelial cell dysfunction, decrease endogenous nitric oxide production,193 and be associated with renal dysfunction. In one series, renal dysfunction was more common in patients treated with cyclosporine than tacrolimus, and four of five pre-eclamptics had renal dysfunction.170,190 A series of 27

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pregnancies in 21 patients from the University of Pittsburgh also found that mothers using tacrolimus had a lower incidence of hypertension and pre-eclampsia than those using cyclosporine.186 Other pregnancy-related problems that have been reported in liver transplant recipients include anemia, hyperbilirubinemia,170 and infection,193 but not gestational diabetes. There have not been any ante- or peripartum deaths.190 However, five of the 29 women in one series died between 10 and 54 months after delivering, and all of them died before 1997.190 Only seven maternal deaths were reported in the 85 patients included in the National Transplantation Pregnancy Registry database (8%).180,190 These patients died 8–54 months after pregnancy, five of seven of recurrent liver disease. Although pregnancy does not increase maternal mortality in liver transplant patients, the overall long-term outcome needs to be taken into consideration as a couple contemplates parenthood.

Risks to the Fetus The risk of prematurity and intra-uterine growth restriction is very high – up to 50% of infants born to transplant recipients are premature and up to 20% have intra-uterine growth restriction.179,182,185 The consequences of decreased gestational age at delivery, particularly ⬍34 weeks gestation, include neonatal death and long-term morbidities such as cerebral palsy, blindness, deafness, and learning disabilities and low intelligence quotients.194,195 In addition, low birth weight may be associated with increased hypertension, diabetes and coronary artery disease in adulthood.170,196 The incidence of malformations in the general population is 2–3%. There is a slightly increased risk of malformations reported in previous studies of liver transplant recipients: 4% in patients taking corticosteroids, 6% in those taking tacrolimus,179,186,190,192,197 7% in those taking azathioprine182 and 3–5% in those taking cyclosporine.180,181,198,199 Learning disabilities may not be obvious until a child enters school and even then may be missed for several years. Therefore there is a need to follow the children exposed in utero to immunosuppressive agents and to report on outcomes. Breastfeeding perpetuates exposure of the newborn to drugs with nephrotoxic and immunosuppressive side effects.187 In addition, maternal immunosuppression may increase the risk of infections with cytomegalovirus. Calcineurin inhibitor levels should be closely monitored during pregnancy, particularly in the third trimester, when fetal metabolism of cyclosporine or tacrolimus may account for increased overall clearance. Adrenal insufficiency is unlikely in the infants of transplant recipients, if a woman’s daily prednisone dose has been decreased to 15 mg.200,201 Use of corticosteroids during pregnancy has been associated with fetal growth retardation.187 Azathioprine crosses the placenta readily, but to be active it must be converted to 6-mercaptopurine. The immature fetal liver lacks the enzyme inosinate pyrophosphorylase, needed for conversion. In high doses (6 mg/kg), azathioprine is teratogenic in animals,

but it has been used in thousands of pregnant women with the suggestion of teratogenicity in only one small study.67,187,202 Cyclosporine has not been associated with congenital anomalies but is associated with a higher risk for small-for-gestational-age babies and hypertension. Cyclosporine increases production of thromboxane and endothelin, both of which have been implicated in the pathogenesis of pre-eclampsia. Sifonits et al. evaluated 18 kidney recipients reporting 26 pregnancies with exposure to MMF.203 They noted 15 live births, and 11 spontaneous abortions. Structural malformations were reported in four of the 15 children (26.7%), including: hypoplastic nails and shortened fifth fingers (one), microtia with cleft lip and palate (one), microtia alone (one), and neonatal death with multiple malformations (one). One kidney/pancreas recipient reported one spontaneous abortion. Three liver recipients reported three pregnancies; two live births with no malformations, and one second trimester spontaneous abortion. They concluded that a higher incidence of structural malformations was seen with MMF exposures during pregnancy compared to the overall kidney transplant recipient offspring. Management The factors to be considered with regard to timing of pregnancy are outlined in Table 55.1. If the patient has adequate and stable graft function, is at low risk for opportunistic infections, and is not taking teratogenic medications, it may be that pregnancy can be attempted only one year after transplantation without concern of increased risks. Delivery of preterm babies is more frequent in transplant recipients than in the normal population but intervention for obstetric reasons is a contributing factor.197 Cesarean deliveries are not required despite the transplanted kidney in the pelvis, such surgical deliveries are reserved for obstetric indications. All pregnant renal transplant recipients have renal insufficiency, whether or not creatinine levels are in the ‘normal range,’ and one should apply the same management guidelines as those for pregnant subjects whose native kidneys have various degrees of kidney disease. The consensus opinion was that steroids are safe for anti-rejection therapy, but the safety of antilymphocyte globulins and rituximab in pregnancy are unknown.170 Immunosuppressants cross the placenta and appear in breast milk to varying degrees.204–206 Women of childbearing age awaiting renal transplantation should receive the rubella vaccine because live virus vaccines are contraindicated post transplantation.67 Women who are blood type Rhesus-negative and receive organs from Rhesus-positive donors should be made aware of this, because of the risk of sensitization. The data suggest that the frequency of prematurity, infection, and rejection are greater when pregnancy is undertaken earlier than 2 years post transplantation, although in select stable patients this may be unduly restrictive. Renal function should be stable, blood pressure should be normal or easily controlled with medication, and 24 hour urine protein levels should be less

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than 500 mg, prior to considering conception.67 The ethical issues surrounding pregnancy in transplant patients are considerable. While there are ample data showing good outcomes, there may be valid reasons to counsel against pregnancy, including the potential risks to the graft, to the mother and to the child. The potential parents need to be aware of the possibility of having a premature infant who survives with disability.170

Infections Women transplant recipients are at increased risk for bacterial infections, predominately urinary tract infections, during pregnancy.67 Maternal infection can cause infection in the fetus in 20–40% of the pregnant women who have primary CMV infections.207 The efficacy of treatment of the mother with either ganciclovir or CMV hyperimmune globulin in preventing disease in the fetus has not been established. Herpes simplex is usually spread from mother to child during birth, rather than through intra-uterine infection.208 Infection with toxoplasmosis during pregnancy results in neonatal infection in 25–65% of the infants.209 Pregnant women without a transplant who are HCV RNA-positive have a low rate of HCV maternal–fetal transmission (4–6%) but the rate of maternal–fetal hepatitis C transmission is unknown in liver transplant recipients and requires additional prospective analysis.170 The effect of gender on outcome of infection in hospitalized patients is unclear. Crabtree et al.210 evaluated a total of 892 patients in the surgical units of their hospital with 1470 consecutive infectious episodes. Among all infections, there was no significant difference in mortality based on gender: 11.1% for men compared with 14.2% for women. Mortality was higher in women for lung and soft tissue infection but for other infectious sites did not differ by gender. These authors also noted that despite similar severity of illness and length of treatment and a slightly younger age, infected men were hospitalized longer following initiation of treatment. They concluded that although gender may not be predictive of mortality among all infections, women appear to be at increased risk for death from hospital-acquired pneumonia, even after controlling for other co-morbidities.

Risk of Malignancy WOMEN The risk of developing cervical carcinoma has been estimated to be 3 to 16 times higher for renal transplant recipients than for the general population; however, 70% of these patients have in situ lesion.211,212 The incidence appears to be particularly increased among premenopausal patients with functioning grafts.213 Most cervical neoplasms in transplant recipients respond well to conventional therapy when treated at an early stage,214,215 therefore immunosuppressed women should undergo annual pelvic examinations. A

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recent report on ⬎23 000 female renal transplant recipients noted a breast cancer incidence of 0.3% during the first year after transplantation. This represented a relative risk of 0.49, compared with the general population.216 It has been suggested that immunosuppression during a premalignant phase in breast neoplasia may reduce the incidence of subsequent development of breast cancer,217 however it is possible that the lower incidence of breast cancer may be a direct consequence of increased examinations and screening before renal transplantation.216 Women with family histories of premenopausal breast cancer warrant aggressive screening, although there are few data to substantiate this. Several organizations have made detailed recommendations regarding screening for breast cancer.218–220 Applying these guidelines to the screening of women after renal transplantation seems to be prudent, although there have been no studies evaluating the effects of breast cancer screening in this population.221 MEN The incidences of prostate cancer among renal transplant recipients range from 0.3% to 1.9%.222–224 In renal transplant recipients radiation therapy could be associated with nephritis and damage to the renal allograft.223 The prostate-specific antigen test appears to be valid for the early detection of prostate cancer after renal transplantation;225 however there have been insufficient data to conclusively demonstrate decreases in the mortality rate for prostate cancer as a result of screening,226,227 but it seems prudent to screen immunosuppressed patients yearly starting at age 50 years for men whose life expectancy is ⱖ10 years. It is also reasonable to initiate screening at an earlier age (such as 40 years) for men with special risk factors, such as black race and family histories of prostate cancer.216

GENERAL CONSIDERATIONS Quality of Life Depending on the specific instrument used to assess quality of life (QoL), different conclusions can be reached about blacks and women compared with whites and men. One large study of 700 patients found no difference between blacks and whites with 10 instruments, higher QoL scores for blacks with two instruments, and lower scores for blacks with seven instruments. Women had the same score as men with 15 instruments, higher scores with two instruments, and lower scores with two instruments. Two more recent studies found higher QoL scores among blacks. A few studies with modest sample sizes have examined employment among dialysis patients. In the most recent national study 59% of men were employed compared with 41% of women.224–233 Because patients on dialysis can decide to discontinue

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treatment at any time, a willingness to continue such treatment may also be viewed as a measure of patient quality of life. Among females, 21% of deaths were associated with withdrawal compared with 18% among males. Greater life satisfaction was most strongly associated with being in control of one’s health and living a normally active life with satisfying emotional relationships.180 Previous work has highlighted the importance of normality, functional status, and social support networks in kidney transplant recipients and patients with end-stage renal disease (ESRD).234–238 Comorbidities are common, but their effect on life satisfaction differed. The relative importance placed on these co-morbid conditions by patients may be different from that assumed by the physician. For example, hypertension was of greater concern to physicians but blurred vision had a greater impact on patients’ perception of their quality of life. Significant sexual deficits are common and do not always improve after transplantation.99 The few studies examining female sexuality in the post-transplantation setting suggested that this issue is at least as prevalent as in men.239,240 In one study by Hricik et al.234 headaches had almost as strong an effect on quality of life as sexual dysfunction and a stronger effect than that of the more common adverse effects of altered body habitus, swelling of extremities, changes in hair growth, tremors, and easy bruising. Health-related worry such as fear of rejection and stress related to body image alteration are important factors in transplant recipients.234,241,242 The length of time spent on dialysis before transplantation may be relevant to a patient’s perception of change in quality of life. In a study looking at four types of solid organ transplant recipients from one center, Pinson et al.243 showed that patients receiving different types of transplants start at different levels of health-related quality of life. Lung and heart recipients start out the worst, liver recipients in the middle, and kidney recipients the best, perhaps because of dialysis support. Renal transplant recipients improve the least and retain their preoperative stratification during the first two postoperative years. The more limited improvement recorded in kidney recipients compared with the others may be explained by the much higher incidence of diabetes with secondary complications in this patient population.243

Access to Transplantation A number of studies have evaluated factors affecting access to renal transplantation and have identified such characteristics as female gender and black race as barriers to receipt of a renal allograft.121 Adult women with ESRD have historically been accepted for dialysis therapy less than males with ESRD.58,96,244–246 National data clearly show that substantial differences exist between age, race, and sex, with regard to wait listing,247–252 and time from wait listing to cadaveric renal transplantation.95,122,248,249,251,255–257 However, other authors have demonstrated that waiting list times are similar for females and males.252,258 Many of these differences in access

to transplantation are independent of PRA, and geographic region.123 Wolfe found a 16% lower rate of wait listing after the diagnosis of ESRD for females than for males.123 Women were about 10% less likely than men to be placed on a waiting list and 10% less likely to be transplanted following wait listing.255,256 A barrier to wait listing may exist for females because of patient preference, gender selection by healthcare personnel, concerns about steroid-induced osteoporosis, gender bias on the part of family and friends and economic or other reasons.110,258–260 Additional barriers to referral for transplantation among females on dialysis include age, comorbidity, less than a high school level of education, and unemployment or homemaker status.261 In addition females receive living donor kidneys less commonly than males,262–264 whether related263–265 or unrelated266 to the donor. The relative importance of patient vs. provider factors in explaining this gender difference is unclear. It is interesting to note that despite several poorer intermediate outcomes, blacks and women do better than whites and men in survival. An earlier study reported that women with new-onset ESRD were approximately 30% less likely than men to receive a kidney transplant, even after accounting for co-morbid medical conditions.267 Because men and women are referred to nephrologists at similar stages of renal failure,268 reduced wait-listing rates for women cannot be explained by delays in presentation that preclude early discussion. In fact, a recent study of renal transplant waiting list registrants demonstrated that although men outnumbered women by nearly 50%, the wait-listed women were slightly more likely than corresponding men to have been activated before initiating dialysis.269 Additionally, provider concerns about patient outcomes after transplantation are not likely to be explanatory, because studies have shown comparable patient and graft survival for men and women after transplantation.270 Lower rates of wait listing also may result if women are less aggressive about negotiating the multiple steps necessary for activation on the waiting list.271,272 Finally, the possibility of a gender bias by providers as shown in the use of cardiovascular procedures should be considered. Recent data suggest that Medicare ESRD patients who lack private supplementary insurance may face financial barriers that limit their access to the waiting list.273 Nevertheless, despite the inclusion of insurance information, women were less likely than men to be wait-listed in that study, as well. While equity in access to the transplant waiting list is desirable it will not reduce waiting times. The likelihood of transplantation is not principally affected by how quickly one progresses through the system but by the availability of donor organs and, to a lesser extent, the efficiency with which those organs are allocated

CONCLUSIONS As might be predicted given the relationship between sex hormones and immunological processes, many gender-related differences exist in the arena of organ failure and transplantation.

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Certain forms of liver and kidney disease are more common in either men or women and appear to be subject to hormonal fluctuation. The physiological changes associated with pregnancy present unique challenges to the transplant physician. Transplant recipients and women with renal insufficiency face the possibility that pregnancy may adversely affect renal function. For the transplant recipient, pregnancy is further complicated by immunosuppression and the risk for opportunistic infection. Donor and recipient gender affect graft and patient survival after transplantation and may contribute to an increased incidence of lymphoproliferative disease in the gender-mismatched group. In addition there is clearly some gender bias in organ donation and transplantation.

AREAS FOR FURTHER STUDY ●

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Why is liver graft survival inferior in males who receive female organs? Clarify the effects of transplantation and immunosuppression on fertility in male and female solid organ recipients. Define the long-term effects on the offspring. Establish whether the mother is immunosuppressed by the pregnancy.

References 1. Legato MJ. Immunology. In: Gender Specific Aspects of Human Biology for the Practicing Physician. Armonk, NY: Futura Publishing Company; 1997. 2. Lahita RG. Sex hormones and systemic lupus erythematosus. Rheum Dis Clin North Am 2000;26(4):951–68. 3. Sthoeger ZM, Chiorazzi N, Lahita RG. Regulation of the immune response by sex hormones. I. In vivo effects of estradiol and testosterone on pokeweed mitogen-induced B-cell differentiation. J Immunol 1988;141:91–98. 4. Kanda N, Tsuchida T, Tamaki K. Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum 1997;40:1703–11. 5. Jo T, Terada N, Saji F, et al. Inhibitory effects of estrogen, progesterone, androgen and glucocorticoid on death of neonatal mouse uterine epithelial cells induced to proliferate by estrogen. J Steroid Biochem Mol Biol 1993;46:25–32. 6. Van VR, McGuire JL. Estrogen, progesterone, and testosterone: can they be used to treat autoimmune diseases? Cleve Clin J Med 1994;61:276–84. 7. Whiteacre C, Reingold SC, O’Looney PA, et al. A gender gap in autoimmunity. Science 1999;283:1277–78. 8. George ED, Schluger LK. Special women’s health issues in hepatobiliary diseases. Clin Fam Prac 2000;2(1):155–69. 9. Al-Chalabi T, Underhill JA, Portmann BC, et al. Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis. J Hepatol 2008;48:140–47. 10. Dourakis SP, Tolis G. Sex hormonal preparations and the liver. Eur J Contracept Reprod Health Care 1998;3:7–16.

●

Gender-Specific Issues in Organ Transplantation

669

11. American College of Obstetricians and Gynecologists: Technical Bulletin. Hormone Replacement Therapy 1992; 166:1–8. 12. Tierney S, et al. Progesterone alters biliary flow dynamics. Ann Surg 1999;229:205–9. 13. Connolly TJ, Zuckerman AL. Contraception in the patient with liver disease. Semin Perinatol 1998;22:178–82. 14. Brenner PF. Differential diagnosis of abnormal uterine bleeding. Am J Obstet Gynecol 1996;175:766–69. 15. Bacq Y, et al. Liver function tests in normal pregnancy: a prospective study of 103 pregnant women and 103 matched controls. Hepatology 1996;23:1030–34. 16. Castro MA, Fassett MJ, Reynolds TB, Shaw KJ, Goodwin TM. Reversible peripartum liver failure: a new prospective on the diagnosis, treatment and cause of acute liver failure of pregnancy based on 28 consecutive cases. Am J Obstet Gynecol 1999;181:389–95. 17. Reyes H. Acute fatty liver of pregnancy: a cryptic disease threatening mother and child. Clin Liver Dis 1999;3(1):69–81. 18. Fromenty B, Pessayre D. Inhibition of mitochondrial betaoxidation as a mechanism of hepatoxicity. Pharmacol Ther 1995;67(1):101–54. 19. Burroughs AK, Seong NGH, Dojcinov DM, et al. Idiopathic acute fatty liver of pregnancy in 12 patients. Q J Med 1982;204:481–97. 20. Reyes H, Sandoval L, Wainstein A, et al. Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients. Gut 1994;35:101. 21. Barton CH, Mirahmadi MK, Vaziri ND. Effects of long-term testosterone administration on pituitary-testicular axis in endstage renal failure. Nephron 1982;31:61–64. 22. MacLean MA, Cameron AD, Cumming GP, Murphy K, Mills P, et al. Recurrence of acute fatty liver of pregnancy. Br J Obstet Gynaecol 1994;101:453–54. 23. Visconti M, Manes G, Giannattasio F, et al. Recurrence of acute fatty liver of pregnancy. J Clin Gastroenterol 1995;21:243–45. 24. Davidson KM. Intrahepatic cholestasis of pregnancy. Semin Perinatol 1998;22:104–11. 25. Misra S, Sanyal AJ. Pregnancy in a patient with portal hypertension. Clin Liver Dis 1999;3(1):147–62. 26. Haddad B, Barton JR, Livingston JC, et al. Risk factors for adverse maternal outcomes among women with HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am J Obstet Gynecol 2000;183(2):444–48. 27. Gordon Stuart C. Pregnancy and liver disease. Budd–Chiari and infarct in pregnancy. Clin Liver Dis 1999;3:97–113. 28. De Stefano V, Leone G, Mastrangelo S. Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C and protein S. Thromb Haemost 1994;71:799. 29. De Boer K. Haemostasis in normal and complicated pregnancy [thesis]. Rodopi, Amsterdam: University of Amsterdam; 1991, 31-42. 30. Vons C, Smadja C, Franco D, et al. Successful pregnancy after Budd–Chiari syndrome. Lancet 1984;2:975. 31. Walcott WO, Derick DE, Jolley JJ, et al. Successful pregnancy in a liver transplant patient. Am J Obstet Gynecol 1978;132:340. 32. Cheng YS. Pregnancy in liver cirrhosis and/or portal hypertension. Am J Obstet Gynecol 1977;128:812–22.

670

SECTION 9

●

Immunology

33. Goodrich MA, James EM, Baldus WP, et al. Portal vein thrombosis associated with pregnancy. J Reprod Med 1993;38:969–72. 34. Reinus JF, Leikin EL. Pregnancy and liver disease. Viral hepatitis in pregnancy. Clin in Liver Dis 1999;3(1):115–30. 35. Schweitzer IL, Peters RL. Pregnancy in hepatitis B antigen positive cirrhosis. Obstet Gynecol 1976;48:535. 36. Sweet RL. Hepatitis B infection in pregnancy. Obstet Gynecol Rep 1990;2:128. 37. Arevalo JA. Hepatitis B in pregnancy. West J Med 1989;150:668. 38. Jurema MW, Polaneczky M, Ledger WJ. Hepatitis B immunization in postpartum women. Am J Obstet Gynecol 2001;185(2):355–58. 39. Ishikawa I, Maeda K, Nakai S, et al. Gender differences in the mean age at the induction of hemodialysis in patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis 2000;35(6):1072–75. 40. Hannedouche T, Chauveau P, Kalou E, et al. Factors affecting progression in advanced chronic renal failure. Clin Nephrol 1993;39:312–20. 41. Tierney WM, McDonald CJ, Luft FC. Renal disease in hypertensive adults: effect of race and type II diabetes mellitus. Am J Kidney Dis 1989;13:485–93. 42. Coggins CH, Lewis JB, Caggiula AW, et al. Differences between women and men with chronic renal disease. Nephrol Dial Transplant 1998;13:1430–37. 43. Schrander VD, Meer AM, van Saase JLCM, et al. Mortality in patients receiving renal replacement therapy, a singlecenter study. Clin Nephrol 1995;43:174–79. 44. Neugarten J, Silbiger SR. The impact of gender on renal transplantation. Transplantation 1994;58:1145. 45. Kochakian CD. Regulation of kidney growth by androgens. Adv Steroid Biochem Pharmacol 1977;6:1–34. 46. Simon P, Ramee MP, Autuly V, et al. Epidemiology of primary glomerular diseases in a French region: variations according to period and age. Kidney Int 1994;46:1192–98. 47. Silbiger SR, Neugarten J. The impact of gender on the progression of chronic renal disease. Am J Kidney Dis 1995;25:515–33. 48. Chapel TA, Burns RE. Oral contraceptives and exacerbations of SLE. Am J Obstet Gynecol 1971;110:366–9369. 49. Petri M, Robinson C. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum 40:797–803. 50. Rose E, Pillsbury DM. Lupus erythematosus (erythematodes) and ovarian function: observations on a possible relationship with a report of six cases. Ann Intern Med 1944;21:1022–32. 51. Lahita RG. Sex steroids and SLE: metabolism of androgens to estrogens [editorial]. Lupus 1992;1:125–27. 52. Jungers P, Nahoul K, Pelissier C. Low plasma androgens in women with active or quiescent SLE. Arthritis Rheum 1982;25:454–57. 53. Jungers P, Pelissier C, Bach JF, et al. Les androgenes plasmatiques chez les femmes atteintes de lupus erythemateux disseminé (LED). Pathol Biol (Paris) 1980;28:391–92. 54. Buyon JP. Hormone replacement therapy in postmenopausal women with systemic lupus erythematosus. J Am Women Med Assoc 1998;53:13–17. 55. Kjellstrand CM, Logan GM. Racial, sexual and age inequalities in chronic dialysis. Nephron 1987;45:257.

56. Tuohy KA, Johnson S, Khwaja K, et al. Gender disparities in the live kidney donor evaluation process. Transplantation 2006;82(11):1402–7. 57. US Renal Data System: USRDS 1996 Annual Data Report, National Institutes of Health, Bethesda, MD, National Institute of Diabetes and Kidney Diseases, Am. J. Kidney Dis. 28 (1996) S1–165. 58. Van Woerden HC, Wilkinson J, Heaven M, et al. The effect of gender, age, and geographical location on the incidence and prevalence of renal replacement therapy in Wales. BMC Nephrology 2007;8:1. 59. Delano B, Macey L, Friedman E. Gender and racial disparity in peritoneal dialysis patients undergoing kidney transplantation. ASAIO J 1997;43:M861–64. 60. Bloembergen WE, Young EW, Woods JD, et al. Factors associated with late referral among new dialysis patients in the US. J Am Soc Nephrol 1997;8:186A, Abstr. 61. Kausz AT, Obrador GT, Arora P, et al. Late initiation of dialysis among women and ethnic minorities in the United States. J Am Soc Nephrol 2000;11(12):2351–57. 62. Sehgal AR. Outcomes of renal replacement therapy among blacks and women. Am J Kidney Dis 2000;35(4 Suppl 1): S148–52. 63. US Renal Data System: USRDS 2000 Annual Data Report, The National Institutes of Health, Bethesda, MD, National Institutes of Diabetes and Digestive and Kidney Diseases, Available at ⬍www.usrds.org/adr_2000.htm/⬎, (Accessed 11.08.09) 64. Bloembergen WE, Port FK, Mauger EA, et al. Causes of death in dialysis patients: racial and gender differences. J Am Soc Nephrol 1994;5:1231–42. 65. Holley JL, Schmidt RJ, Bender FH, et al. Gynecologic and reproductive issues in women on dialysis. Am J Kidney Dis 1997;29:685–90. 66. Perez RJ, Lipner H, Abdulla N, et al. Menstrual dysfunction of patients undergoing hemodialysis. Obstet Gynecol 1978;51:552–55. 67. Hou S. Pregnancy in chronic renal insufficiency and end stage renal disease. Am J Kidney Dis 1999;33(2):235–52. 68. Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or severe renal insufficiency. N Engl J Med 1996;335(4):226–32. 69. Palmer BF. Sexual dysfunction in uremia. J Am Soc Nephrol 1999;10(6):1381–88. 70. Procci WR, Goldstein DA, Adelstein J, et al. Sexual dysfunction in the male patient with uremia: a reappraisal. Kidney Int 1981;19:317–23. 71. Toorians AW, Janssen E, Laan E, et al. Chronic renal failure and sexual functioning: clinical status vs. objectively assessed sexual response. Nephrol Dial Transplant 12:2654–2663. 72. Handelsman DJ. Hypothalamic-pituitary gonadal dysfunction in renal failure, dialysis and renal transplantation. Endocrinol Rev 1985;6:151–82. 73. Saha MT, Saha HH, Niskanen LK, et al. Time course of serum prolactin and sex hormones following successful renal transplantation. Nephron 2002;92:735–37. 74. Prem AR, Punekar SV, Kalpana M, et al. Male reproductive function in uremia: efficacy of haemodialysis and renal transplantation. Br J Urol 1996;78:635–38.

CHAPTER 55 75. Gomez F, de la Cueva R, Wauters J-P, et al. Endocrine abnormalities in patients undergoing long-term hemodialysis: the role of prolactin. Am J Med 1980;68:522–30. 76. Holley JL, Schmidt RJ, Bender FH, et al. Gynecologic and reproductive issues in women on dialysis. Am J Kidney Dis 1987;29:685–90. 77. Ginsburg ES, Owen WF Jr. Reproductive endocrinology and pregnancy in women on hemodialysis. Semin Dial 1993;6:105–16. 78. Steele TE, Wuerth D, Finkelstein S, et al. Sexual experience of the chronic peritoneal dialysis patient. J Am Soc Nephrol 1996;7:1165–68. 79. Peters C, Sutherland DE, Simmons RL, et al. Patient and graft survival in amputated versus nonamputated diabetic primary renal allograft recipients. Transplantation 1981;32(6):498–503. 80. Olivarius ND. Renal involvement is related to body height in newly diagnosed diabetic women aged 40 years or over. Diabetes Metab 2001;27(1):14–18. 81. Pan WH. Undiagnosed diabetes mellitus in Taiwanese subjects with impaired fasting glycemia: impact of female sex, central obesity and short stature. Chin J Physiol 2001;44(1):44–51. 82. Wong GW. Sex differences in the growth of diabetic children. Diabetes Res Clin Pract 2000;50(2):187–93. 83. Rosmalen JG. Sex steroids influence pancreatic islet hypertrophy and subsequent autoimmune infiltration in nonobese diabetic (NOD) and NOD SCID mice. Lab Invest 2001;81(2):231–39. 84. Fitzpatrick F, Lepault F, Homo-Delarche F, et al. Influence of castration, alone or combined with thymectomy, on the development of diabetes in the nonobese diabetic mouse. Endocrinology 1991;129:1382–90. 85. Kava RA, West DB, Lukasik VA, et al. Sexual dimorphism of hyperglycemia and glucose tolerance in Wistar fatty rats. Diabetes 1989;38:159–63. 86. Leiter EH. The genetics of diabetes susceptibility in mice. FASEB J 1989;3:2231–41. 87. Homo-Delarche F, Durant S. Hormones, neurotransmitters and neuropeptides as modulators of lymphocyte functions. In: M Rola-Pleszczynski, ed. Handbook of Immunopharmacology. London: Elsevier; 1994. 88. Bilbao JR, Rica I, Vazquez JA, et al. Influence of sex and age of onset on auto antibodies against insulin, GAD 65, and IA2 in recent onset type 1 diabetics. Horm Res 2000;54(4):181–85. 89. Davis SN, Shavers C, Costa F. Gender related differences in counterregulatory responses to antecedent hypoglycemia in normal humans. J Clin Endocrinol Metab 2000;85(6):2148–57. 90. Jonsson PM. Gender equity in health care: the case of Swedish diabetes care. Health Care Women Int 2000;21(5):413–31. 91. Elliot D. Pregnancy: hypertension and other common medical problems. In: L Goldman, JC Bennett, eds. Cecil Textbook of Medicine, twenty first ed.. Pennsylvania, PA: WB Saunders; 2000:1355–57. 92. Rodrigue JR, Widows MR, Guenther R, et al. The expectancies of living kidney donors: do they differ as a function of relational status and gender? Nephrol Dial Transplant 2006;21:1682–88. 93. Simmons RG, Fulton R. The prospective organ transplant donor: problems and perspectives of medical innovations. Omega 1972;3:319–39.

●

Gender-Specific Issues in Organ Transplantation

671

94. Simmons RG, Klein Marine RS, Simmons RL. Gift of Life: The Effect of Organ Transplantation on Individual, Family and Societal Dynamics. New Brunswick, NJ: Transaction Books; 1977. 95. Bal MM, Saikia B. Gender bias in renal transplantation: are women alone donating kidneys in India? Transplant Proc 2007;39:2961–63. 96. Oien CM, Reisaeter AV, Leivestad T. Living donor kidney transplantation: the effects of donor age and gender on shortand long-term outcomes. Transplantation 2007;83(5):600–6. 97. Boulware LE. Understanding disparities in donor behavior: race and gender differences in willingness to donate blood and cadaveric organs. Med Care 2002;40(2):85–95. 98. Russell JD, Barcroft ML, Ludwin D, et al. The quality of life in renal transplantation – a prospective study. Transplantation 1985;54:656. 99. Laupacis A, Keown P, Pus N, et al. A study of the quality of life and cost-utility of renal transplantation. Kidney Int 1996;50(1):235–37. 100. Binet I, Bock AH, Vogelbach P, et al. Outcome in emotionally related living kidney donor transplantation. Nephrol Dial Transplant 1997;12:1940–48. 101. Bloembergen WE, Port FK, Mauger EA, et al. Gender discrepancies in living related renal transplant donors and recipients. J Am Soc Nephrol 1996;7:1139–44. 102. Pirsh JD, D’Alessandro AM, Sollinger HW, et al. Livingunrelated renal transplantation at the University of Wisconsin. Clin Transpl 1990:241–45. 103. Sesso R, Klag MJ, Ancao MS, et al. Kidney transplantation from living unrelated donors. Ann Intern Med 1992; 117:983–89. 104. Terasaki PI, Cecka JM, Gjertson DW, et al. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995;333:333–36. 105. Zimmerman D, Donnelly S, Miller J, Stewart D, Albert SE. Gender disparity in living renal transplant donation. Am J Kidney Dis 2000;36(3):534–40. 106. Kayler LK, Armenti V, Dafoe D, et al. Patterns of volunteerism, testing, and exclusion among potential living kidney donors. Health Care Women 2005;26(4):285. 107. Kayler LK, Meier-Kreische HU, Punch JD, et al. Gender imbalance in living donor kidney transplantation. Transplantation 2002;73:248. 108. Kayler LK, Rasmussen CS, Dykstra DM, et al. Gender imbalance and outcomes in living donor renal transplantation in the United States. Am J Transplant 2003;3:452. 109. Karlson EW, Daltroy LH, Liang MK, et al. Gender differences in patient preferences may underlie differential utilization of elective surgery. Am J Med 1997;102:524–30. 110. Aaronson KD, Schwartz JS, Goin JE, et al. Sex differences in patient acceptance of cardiac transplant candidacy. Circulation 1995;91:2753–61. 111. Hostetter TH, Olson JL, Rennke HG, et al. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J Am Soc Nephrol 2001;2(6):1315–25. 112. Wrenshall LE, McHugh L, Felton P, et al. Pregnancy after donor nephrectomy. Transplantation 1996;62:1934–36. 113. Marino IR, Doyle HR, Aldrighetti L, et al. Effect of donor age and sex on the outcome of liver transplantation. Hepatology 1995;22:1754–62.

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114. Candinas D, Gunson BK, Nightingale P, et al. Sex mismatch as a risk factor for chronic rejection of liver allografts. Lancet 1985;346:1117. 115. Francavilla R, Hadzic N, Heaton N, et al. Gender matching and outcome after pediatric liver transplantation. Transplantation 1998;66(5):602–5. 116. Brooks BK, Levy MF, Jennings LW, et al. Influence of donor and recipient gender on the outcome of liver transplantation. Transplantation 1996;62:1784. 117. Kahn D, Gavaler JS, Makowka L, et al. Gender of donor influences outcome after orthotopic liver transplantation in adults. Dig Dis Sci 1993;38:1485–88. 118. Gustafsson JA, Mode A, Norstedt G, et al. Sex steroid induced changes in hepatic enzymes. Ann Rev Physiol 1983;45:51. 119. Roy AK, Chateterjee B. Sexual dimorphism in the liver. Ann Rev Physiol 1983;45:37. 120. Kahn D, Zeng Q, Makowka L, et al. Orthotopic liver transplantation and the cytosolic estrogen-androgen receptor status of the liver: the influence of the sex of the donor. Hepatology 1989;10:861. 121. Chertow GM, Zenios SA. Gridlock on the road to kidney transplantation. Am J Kidney Dis 2001;37(2):435–37. 122. Eggers PW. Effect of transplantation on the Medicare endstage renal disease program. N Engl J Med 1988;318:223–29. 123. Wolfe RA, Ashby VB, Milford EL, et al. Differences in access to cadaveric renal transplantation in the United States. Am J Kidney Dis 2000;36(5):1025–33. 124. Kouli F. Impact of donor/recipient traits independent of rejection on long-term renal function. Am J Kidney Dis 2001;37(2):356–65. 125. Sutherland DE. Lessons learned from more than 1000 pancreas transplants in a single institution. Ann Surg 233 (4) 463–501. 126. Laporte RE, Matsushima M, Chang YF. Prevalence and incidence of insulin-dependent diabetes. In: MI Harris, ed. Diabetes in America. Washington, DC: NIH; 1995:37–46. 127. Navarro X, Sutherland DER, Kennedy WR. Long term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 1997;42:727–36. 128. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus I using a glucocorticoid free immunosuppressive regimen. N Engl J Med 2000;343:230–38. 129. Morissette P, Albert C, Busque S, et al. In vivo higher glucoronidation of mycophenolic acid in male than in female recipients of a cadaveric kidney allograft and under immunosuppressive therapy with mycophenolate mofetil. Ther Drug Monit 2001;23(5):520–25. 130. Mulder GJ. Sex differences in drug conjugations and their consequences for drug toxicity. Sulfation, glucuronidation and glutathione conjugation. Chem Biol Interact 1986;57:1–15. 131. Gasbarrini A, Adolorato G, Campli C, et al. Gender affects reperfusion injury in rat liver. Dig Dis Sci 2001;46(6):1305–12. 132. Norton R, Batey R, Dwyer T, et al. Alcohol consumption and the risk of alcohol related cirrhosis in women. Br Med J 1987;295:80–82. 133. Guattery JM, Faloon WW. Effect of estradiol upon serum enzymes in primary liver cirrhosis. Hepatology 1987;7:737–42.

134. Becker U. The influence of ethanol and liver disease on sex hormones and hepatic estrogen receptors in women. Dan Med Bull 1993;40:447–59. 135. Ikejima K, Enomoto N, Iimuro Y, et al. Estrogen increase sensitivity of Kupffer cells to endotoxin. Am J Physiol 1998; 274:G669–76. 136. Meier-Kriesche H, Ojo A, Leavey S, et al. Gender differences in the risk for chronic renal allograft failure. Transplantation 2001;71(3):429–32. 137. Oh CK, Lee BM, Jeon KO, et al. Gender-related differences of renal mass supply and metabolic demand after living donor kidney transplantation. Clin Transpl 2006;20(2):163–70. 138. Vereerstraeten P, Wissing M, De Pauw L, et al. Male recipients of kidneys from female donors are at increased risk of graft loss from both rejection and technical failure. Clin Transpl 1999;13:181. 139. Zeier M, Dohler B, Opelz G, et al. The effect of donor gender on graft survival. J Am Soc Nephrol 2002;13:2570–76. 140. Zhou YC, Cecka JM. Effect of sex on kidney transplants. Clin Transpl 1989:361–67. 141. Cecka JM. The roles of sex, race, and ABO groups. Clin Transpl 1986:199–221. 142. Matas AJ, Gillingham AJ, Humar A, et al. Immunologic and non-immunologic factors: different risks for cadaver and living donor transplantation. Transplantation 2000;69:54. 143. Koka P, Cecka JM. Sex and age effects in renal transplantation. Clin Transpl 1990:437–46. 144. Shibue T, Kondo K, Iwaki Y, Terasaki PI. Effect of sex on kidney transplants. Clin Transpl 1987:351–60. 145. Yuge J, Cecka JM. Sex and age effects in renal transplantation. Clin Transpl 1991:257–67. 146. Michet CJJ, McKenna CH, Elveback LR, et al. Epidemiology of systemic lupus erythematosus and other connective tissue diseases in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 1985;60:105. 147. Kwan G, Neugarten J, Sherman M, et al. Effects of sex hormones on mesangial cell proliferation and collagen synthesis. Kidney Int 1996;50:1173. 148. Muller V, Szabo A, Viklicky O, et al. Sex hormones and gender-related differences: their influence on chronic renal allograft rejection. Kidney Int 55:2011. 149. Zeier M, Schonherr R, Amann K, et al. Effects of testosterone on glomerular growth after uninephrectomy. Nephrol Dial Transplant 1998;13:2234–40. 150. Kasiske BL, Umen JA. The influence of age, race, sex and body hiatus on kidney weight in humans. Arch Pathol Lab 1986;110:55. 151. Kim YS, Moon JL, Kim DK, et al. Ratio of donor kidney weight to recipient body weight as an index of graft function. Lancet 2001;357:1180. 152. Iguro T, Okazaki H, Sato T, et al. The effect of donor age, and sex on cyclosporine associated nephrotoxicity. Transplant Proc 1989;21:1554. 153. Enosawa S, Hirasawa K. Sex-associated differences in the survival of skin grafts in rats. Transplantation 1989;47:933. 154. Hirasawa K, Enosawa S. Effects of sex steroid hormones on sex-associated differences in the survival time of allogeneic skin grafts in rats: evidence that testosterone enhances and estradiol reverses the immunosuppressive activity of cyclosporine. Transplantation 1990;50:637.

CHAPTER 55 155. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:863. 156. Valdes F, Pita S, Alonso A, et al. The effect of donor gender on renal allograft survival and influence of donor age on posttransplant graft outcome and patient survival. Transplant Proc 1997;29(8):3371–72. 157. Wiesner R, Edwards E, Freeman R, et al. United Network for Organ Sharing Liver Disease Severity Score Committee. Model for end stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91. 158. Huo SC, Huo TI, Lin HC, et al. Is the corrected-creatinine model for end-stage liver disease a feasible strategy to adjust gender difference in organ allocation for liver transplantation? Transplantation 2007;84(11):1406–12. 159. Huo TI, Lin HC, Wu JC, et al. Limitation of the model for end-stage liver disease for outcome prediction in patients with cirrhosis-related complications. Clin Transpl 2006;20:188. 160. Yoo HY, Edwin D, Thuluvath PJ. Relationship of the model for end-stage liver disease (MELD) scale to hepatic encephalopathy, as defined by electroencephalography and neuropsychometric testing, and ascites. Am J Gastroenterol 2003;98:1395. 161. Huo TI, Wu JC, Lee SD. MELD in liver transplantation: the da Vinci code for the Holy Grail? J Hepatol 2005;42:477. 162. Cholongitas E, Marelli L, Kerry A, et al. Female liver transplant recipients with the same GFR as male recipients have lower MELD scores – a systematic bias. Am J Transplant 2007;7:685. 163. Munoz SJ, Rothstein KD, Reich D, et al. Long term care of the liver transplant recipient. Clin Liver Dis 2000;4(3):691–710. 164. Epstein S, Shanem E, Bilezikian JP. Organ transplantation and osteoporosis. Curr Opin Rheumatol 1995;7:255. 165. Ramsey-Goldman R, Dunn JE, Dunlop DD, et al. Increased risk of fracture in patients receiving solid organ transplants. J Bone Miner Res 1999;14:456. 166. Silkensen JR. Long-term complications in renal transplantation. J Am Soc Nephrol 2000;11(3):582–88. 167. Chiu MY, Sprague SM, Bruce DS, et al. Analysis of fracture prevalence in kidney-pancreas allograft recipients. J Am Soc Nephrol 1998;9:677. 168. Shane E, Silverberg S, Donovan D. Osteoporosis in lung transplantation candidates with end-stage pulmonary disease. Am J Med 1996;101:262. 169. Mack-Shipman LR, Ratanasuwan T, Leone JP, et al. Reproductive hormones after pancreas transplantation. Transplantation 2000;70(8):1180–83. 170. McKay DB, Josephson MA. Reproduction and Transplantation: Report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant 2005;5(7): 1592–99. 171. Madersbacher S, Brunberger T, Maier U. Andrological status before and after liver transplantation. J Urol 1994;151:1251–54. 172. Tappler B, Katz M. Pituitary–gonadal dysfunction in lowoutput cardiac failure. Clin Endocrinol 1979;10:219–26. 173. Zerner J, Doil KL, Drewry J, et al. Intrauterine contraceptive device failures in renal transplant patients. J Reprod Med 1981;26(2):99–102.

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174. Szekeres-Bartho J, Csernus V, Hadnagy J, et al. Immunosuppressive effect of serum progesterone during pregnancy depends on the progesterone binding capacity of the lymphocytes. J Reprod Immunol 1983;5(2):81–88. 175. Streilein JW. Peripheral tolerance induction: lessons from immune privileged sites and tissues. Transplant Proc 1996;28:2066–70. 176. Aluvihare VR, Kallikourdis M, Betz AG. Tolerance, suppression and the fetal allograft. J Mol Med epub ahead of print December 17, 2004. 177. Koch CA, Platt JL. Natural mechanisms for evading graft rejection: the fetus as an allograft. Springer Semin Immunopathol 2003;25(2):95–117. 178. Scantlebury V, Gordon R, Tzakis A, et al. Childbearing after liver transplantation. Transplantation 1990;49(2):317–21. 179. Radomski JS, Moritz MJ, Munoz SJ, et al. National transplantation registry: analysis of pregnancy outcome in female liver transplant recipients. Liver Transpl Surg 1995;1:281–84. 180. Armenti VT, Moritz MJ, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Safety 1998;19:219. 181. Armenti VT, Coscia LA, McGrory CH, et al. National Transplantation Pregnancy Registry. Update on pregnancy and renal transplantation. Nephrology News Issues 1998;12(8): 19–23. 182. Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 2003:131–41. 183. EBPG Expert group in renal transplantation. European best practice guidelines for renal transplantation. Section IV. Long-term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients. Nephrol Dial Transplant 2002;17(Suppl 4):50–55. 184. Podymow T, August P, Umans JG. Antihypertensive therapy in pregnancy. Semin Nephrol 2004;24:616–25. 185. Davison JM, Bailey DJ. Pregnancy following renal transplantation. J Obstet Gynaecol Res 2003;29(4):227–33. 186. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997;64:559–65. 187. Molmenti EP, Jain AB, Marino N, et al. Pregnancy and liver disease: liver transplantation and pregnancy. Clin Liver Dis 1999;3(1):163–74. 188. Rizzoni G, Ehrich JHH, Broyer M, et al. Successful pregnancies in women on renal replacement therapy: Report from the EDTA Registry. Nephrol Dial Transplant 1992;7:279–87. 189. Jain AB, Reyes J, Marcos A, et al. Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center’s experience update at 13 years. Transplantation 2003;76:827–32. 190. Nagy S, Bush MC, Berkowitz R, et al. Pregnancy outcome in liver transplant recipients. Obstet Gynecol 2003;102(1):121–28. 191. Riely CA. Contraception and pregnancy after liver transplantation. Liver Transpl 2001;7(11 Suppl 1):S74–6. 192. Ville Y, Fernandez H, Samuel D, et al. Pregnancy in liver transplant recipients: course and outcome in 19 cases. Am J Obstet Gynecol 1993;168:896–902. 193. Laifer SA, Guido RS. Reproductive function and outcome after liver transplantation. Mayo Clin Proc 1995;70:388–94.

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194. Stratta P, Canavese C, Giacchino F, et al. Pregnancy in kidney transplantation: satisfactory outcomes and harsh realities. J Nephrol 2003;16:792–806. 195. Sgro MD, Barozzino T, Mirghani HM, et al. Pregnancy outcome post renal transplanation. Teratology 2002;65:5–9. 196. Robinson R. The fetal origins of adult disease. BMJ 2001;322(7283):375–76. 197. Kainz A. Analysis of 100 pregnancy outcomes in women treated systemically with Tacroloimus. Transpl Int 2000;13:S299–300. 198. Lamarque V, Leleu MF, Monka C, et al. Analysis of 629 pregnancy outcomes in transplant recipients treated with Sandimmun. Transplant Proc 1997;29:2480. 199. Product Information Neoral 55, In: Physicians’ Desk Reference 55, fifty third ed. Medical Economics Company Inc., Montvale, NJ, 1999, 2067. 200. Cohen D, Galbraith C. General health management and long term care of the renal transplant recipient. Am J Kidney Dis 2001;38(6):S10–24. 201. Penn I, Makowski EL, Harris P. Parenthood following renal transplantation. Kidney Int 1980;18(2):221–33. 202. Saarikoski S, Seppala M. Immunosuppression during pregnancy. Transmission of azathioprine and its metabolites from mother to fetus. Am J Obstet Gynecol 1973;115:1100–6. 203. Sifontis NM, Coscia LA, Constantinescu S, et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006;82(12):1698–702. 204. Moretti ME, Sgro M, Johnson DW, et al. Cyclosporine excretion into breast milk. Transplantation 2003;75(12):2144–46. 205. Flechner SM, Katz AR, Rogers AJ, et al. The presence of cyclosporine in body tissues and fluids during pregnancy. Am J Kidney Dis 1985;5:60–63. 206. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93(1):137–50. 207. Stagno S, Whitley RJ. Herpesvirus infections of pregnancy. Part I: cytomegalovirus and Epstein–Barr virus infection. N Engl J Med 1985;313:1270–74. 208. Hutto C, Arvin A, Jacobs R, et al. Intrauterine herpes simplex virus infections. J Pediatr 1987;110:97–101. 209. MacLeod CL, Lee RV. Parasitic infections. In: GN Burrow, TF Ferris, eds. Medical Complications During Pregnancy. Philadelphia, PA: WB Saunders; 1988:425–27. 210. Crabtree TD, Pelletier SJ, Gleason TG, Pruett TL, Sawyer RG. Gender-dependent differences in outcome after the treatment of infection in hospitalized patients. JAMA 1999;282(22):2143–48. 211. Fairley CK, Sheil AGR, McNeil JJ, et al. The risk of anogenital malignancies in dialysis and transplant patients. Clin Nephrol 1994;41:101–5. 212. Halpert R, Fruchter RG, Sedlis A, et al. Human papillomavirus and lower genital neoplasia in renal transplant patients. Obstet Gynecol 1986;68:251–58. 213. Brunner FP, Landais P, Selwood NH. Malignancies after renal transplantation: the EDTA-ERA Registry experience. Nephrol Dial Transplant 1985;10(Suppl. 1):74–80. 214. Haar-van Eck SA, Rischen-Vos J, Chadha-Ajwani S, et al. The incidence of cervical intraepithelial neoplasia among women with renal transplant in relation to cyclosporine. Br J Obstet Gynaecol 1995;102:58–61.

215. Porreco R, Penn I, Droegemueller W, et al. Gynecologic malignancies in immunosuppressed organ homograft recipients. Obstet Gynecol 1975;45:359–64. 216. Weiss NS. Risk of breast cancer after renal or cardiac transplantation. Lancet 1995;346:1422. 217. Stewart T, Tsai S-CJ, Grayson H, et al. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 1995;346:796–98. 218. National Cancer Institute. Screening for Breast Cancer [Pamphlet]. Bethesda, MD: National Institutes of Health; 1998. 219. United States Preventive Services Task Force. Screening for breast cancer. In: C Di Guiseppi, D Atkins, S Woolf, eds. Guide to Clinical Preventive Services, second ed.. Baltimore, MD: Williams & Wilkins; 1996:73–87. 220. Leitch AM, Dodd GD, Costanza M, et al. American Cancer Society guidelines for the early detection of breast cancer. CA Cancer J Clin 1997;47:150–53. 221. Kasiske BL, Vazquez MA, Harmon WE, et al. Recommendations for the outpatient surveillance of renal transplant recipients. J Am Soc Nephrol 2000;11(Suppl. 15):S1–S86. 222. Birkeland SA, Storm HH, Lamm LU, et al. Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer 1995;60:183–89. 223. Konety BR, Tewari A, Howard RJ, et al. Prostate cancer in the post-transplant population. Urology 1998;52:428–32. 224. Reppeto L, Granetto C, Hall RR. Prostate cancer. Crit Rev Oncol Hematol 1998;27:145–46. 225. Morton JJ, Howe SF, Lowell JA, et al. Influence of end-stage renal disease and renal transplantation on serum prostatespecific antigen. Br J Urol 1995;75:498–501. 226. United States Preventive Services Task Force. Screening for prostate cancer. In: C Di Guiseppi, D Atkins, S Woolf, eds. Guide to Clinical Preventive Services, second ed.. Baltimore, MD: Williams & Wilkins; 1996:119–34. 227. National Cancer Institute. Screening for Prostate Cancer [Pamphlet]. Bethesda, MD: National Institutes of Health; 1998. 228. Gross CR, Savik K, Bohman RM, et al. Long-term health status and quality of life outcomes of lung transplant recipients. Chest 1995;108:1587–93. 229. Jofre R, Lopez-Gomez JM, Moreno F, et al. Changes in quality of life after renal transplantation. Am J Kidney Dis 1998;32:93–100. 230. Painter PL, Luetkemeier MJ, Moore GE, et al. Health-related fitness and quality of life in organ transplant recipients. Transplantation 1997;64:1795–800. 231. Littlefield C, Abbey S, Fiducia D, et al. Quality of life following transplantation of the heart, liver, and lungs. Gen Hosp Psych 1996;18:S36–47. 232. Grieco A, Long C. Investigation of the Karnofsky Performance Status is a measure of quality of life. Health Psychol 1984;53:129–42. 233. Testa MA, Simonson DC. Assessment of quality-of-life outcomes. N Engl J Med 1996;334:835–40. 234. Hricik DE, Halbert RJ, Barr ML, et al. Life satisfaction in renal transplant recipients: preliminary results from the transplant Learning Center. Am J Kidney Dis 2001;38(3):580–87. 235. Fisher R, Gould D, Wainwright S, et al. Quality of life after renal transplantation. J Clin Nurs 1998;7:553–63.

CHAPTER 55 236. King K. Patients’ perspective of factors affecting modality selection: a National Kidney Foundation patient survey. Adv Ren Replace Ther 2000;7:261–68. 237. Manninen DL, Evans RW, Dugan MK. Work disability, functional limitations, and the health status of kidney transplantation recipients post transplant. In: P Terasaki, ed. Clinical Transplants. Los Angeles, CA: UCLA Tissue Typing Laboratory; 1991:193–203. 238. Shidler NR, Peterson RA, Kimmel PL. Quality of life and psychosocial relationships in patients with chronic renal insufficiency. Am J Kidney Dis 1998;32:557–66. 239. Schover LR, Novick AC, Steinmuller DR, et al. Sexuality, fertility, and renal transplantation: a survey of survivors. J Sex Marital Ther 1990;16:3–13. 240. Alleyne S, Dillard P, McGregor C, et al. Sexual function and mental distress status of patients with end-stage renal disease on hemodialysis. Transplant Proc 1989;21:3895–98. 241. Sutton TD, Murphy SP. Stressors and patterns of coping in renal transplant patients. Nurs Res 1989;38:46–49. 242. Fallon M, Gould D, Wainwright SP. Stress and quality of life in the renal transplant patient: a preliminary investigation. J Adv Nurs 1997;25:562–70. 243. Pinson CW, Feurer ID, Payne JL, et al. Health related quality of life after different types of solid organ transplantation 2000;232(4):597–607. 244. Øien CM, Varberg Reisæter A, Leivestad T, et al. Gender imbalance among donors in living kidney transplantation: the Norwegian experience. Nephrol Dial Transplant 2005;20:783. 245. Westlie L, Leivestad T, Holdaas H, et al. Report from the Norwegian national hospitals living donor registry: one-year data, January 1, 2002. Transplant Proc 2003;35:777. 246. Fauchald P, Sødal G, Albrechtsen D, et al. The use of elderly living donors in renal transplantation. Transpl Int 1991;4:51. 247. Rothman KJ. Measuring interactions. In: KJ Rothman, ed. Epidemiology: An Introduction. New York, NY: Oxford University Press; 2002:168. 248. Hosmer DW, Lemeshow S. Confidence interval estimation of interaction. Epidemiology 1992;3:452. 249. De Fijter JW, Mallat MJK, Doxiadis II., et al. Increased immunogenicity and cause of graft loss of old donor kidneys. J Am Soc Nephrol 2001;12:1538. 250. Matas AJ, William PD, Sutherland DE, et al. 2,500 living donor kidney transplants: a single-center experience. Ann Surg 2001;234:149. 251. Pessione F, Choen S, Durand D, et al. Multivariate analysis of donor risk factors for graft survival in kidney transplantation. Transplantation 2003;75:361. 252. Kassiske BL, Snyder J, Matas AT, et al. The impact of transplantation on survival with kidney failure. In: PI Terasaki, JM Cecka, eds. Clinical Transplant 2000. Los Angeles: UCLA Tissue Typing Laboratory; 2001:135–43. 253. Holdaas H, Fellström B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial. Lancet 2003;361:2024.

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254. De La Vega LS, Torres A, Bohorquez HE, et al. Patient and graft outcomes from older living kidney donors are similar to those from younger donors despite lower GFR. Kidney Int 2004;66:1654. 255. Kjellstrand KM. Age, sex and race inequality in renal transplantation. Arch Intern Med 1988;148:1305–9. 256. Bloembergen WE, Mauger EA, Wolfe RA, Port FK. Association of gender and access to cadaveric renal transplantation. Am J Kidney Dis 1997;30:733–38. 257. Garg PP, Furth SL, Fivush BA, et al. Impact of gender on access to the renal transplant waiting list for pediatric and adult patients. J Am Soc Nephrol 2000;11:958–64. 258. Bloembergen WE, Young EW, Woods JD, et al. Factors associated with late referral among new dialysis patients in the US. J Am Soc Nephrol 1997;8:A186. 259. Soucie JM, Neylan JF, McClellan W. Race and sex differences in the identification of candidates for renal transplantation. Am J Kidney Dis 1992;19:414–19. 260. Healy B. The Yentl syndrome. N Engl J Med 1991;325:274–76. 261. Sijpkens YWJ, Doxiadis IIN, Mallat MJK, et al. Early versus late acute rejection episodes in renal transplantation. Transplantation 2003;75:204. 262. Halloran PF, Melk A, Barth C. Rethinking chronic allograft nephropathy: the concept of accelerated senescence. J Am Soc Nephrol 1999;10:167. 263. Neugarten J, Kasiske B, Silbiger SR, et al. Effects of sex on renal structure. Nephron 2002;90:139. 264. Neugarten J. Gender and progression of renal disease. J Am Soc Nephrol 2002;13:2807. 265. Kasiske BL, Snyder J. Matching older kidneys with older patients does not improve allograft survival. J Am Soc Nephrol 2002;13:1067. 266. Martins PN, Pratschke J, Pascher A, et al. Age and immune response in organ transplantation. Transplantation 2005;79:127. 267. Gaylin DS, Held PJ, Port FK, et al. The impact of co morbid and sociodemographic factors on access to renal transplantation. JAMA 1993;269(5):603–8. 268. Arora P, Obrador GT, Ruthazer R, et al. Prevalence, predictors, and consequences of late nephrology referral at a tertiary care center. J Am Soc Nephrol 1999;10:1281–86. 269. Kasiske BL, London W, Ellison MD. Race and socioeconomic factors influencing early placement on the kidney transplant waiting list. J Am Soc Nephrol 1998;9:2142–47. 270. Port F, Wolfe R, Mauger E, et al. Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients. JAMA 1993;270:1339–43. 271. Alexander GC, Sehgal AR. Why hemodialysis patients fail to complete the transplantation process. Am J Kidney Dis 2001; 37:321–28. 272. Alexander GC, Sehgal AR. Barriers to cadaveric renal transplantation among blacks, women, and the poor. JAMA 1998;280:1148–52. 273. Garg P, Powe NR. The impact of Medicare supplementary insurance on access to the kidney transplant waiting list. J Gen Int Med 1999;14(Suppl 2):32.

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INTRODUCTION ADRIAN DOBS The field of endocrinology and metabolism has always emphasized sex differences since the hypothalamic–pituitary– gonadal systems of males and females vary greatly by the synthesis of sex hormones and their concentration in the serum. We are now appreciating that other hormonal axes also vary across the sexes. The mechanisms to explain these differences in the prevalence of disease and its manifestations are not all clear. Although circulating serum hormone levels are an obvious first choice, it certainly does not explain all of the variability of endocrine disorders between men and women. They seem to have differences in prevalence of endocrine disorders, such as thyroid disease being more common in women, as well as its manifestation, e.g. abdominal obesity of metabolic syndrome is more common in men. This section reviews some key endocrine abnormalities in which there are distinct differences between men and women. The chapter on sexual function/dysfunction in men and women, written by Drs Boyle and Burnett, suggest that the concentration of serum testosterone is just one of many factors that influence libido and normal sexual activity. The response to testosterone treatment has a similar effect on both men and women, but the side effect profiles are of great concern. Metabolic bone disease, specifically osteoporosis, is observed in both sexes, but has a predominance in women. We need a greater understanding of the reasons for this

and what are the risk factors unique to men vs. women. The chapter on osteoporosis emphasizes the importance of more research into in the area of osteoporosis in males. Historically most attention has been focused on bone metabolism in women, particularly postmenopausal women. Yet, both testosterone and its metabolite estradiol mediate osteoblastic function. Similarly, treatment for individuals with osteoporosis may vary, based on their baseline hormonal status and tolerance to medications. Dr Golden’s chapter on diabetes highlights that men and women suffer from diabetes to an equal extent, but the early stages of insulin resistance show a dimorphic response to sex hormones. Endogenous androgens may be a cardiovascular risk factor in women; while male hypogonadism and reduced circulating serum testosterone and reduced sex hormone-binding globulin may be risk factors for cardiovascular disease. Finally, the whole area of changes in sex hormones in men as they age is now being recognized as an important medical problem, one in which we require greater information on its prevalence, incidence, and eventual consequences. As reviewed by Dr El-Maouche and myself, there is accumulating evidence that hypogonadism may indeed be a risk factor for increased mortality in the aging population. In summary, both the prevalence and presentation of endocrine disorders vary between men and women. This section attempts to discern the contributors to these effects, such as circulating hormones, aging, immune function and/ or genetic differences between the sexes.

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Endogenous Sex Hormones and Risk of Type 2 Diabetes Mellitus in Men and Women SHERITA HILL GOLDEN Associate Professor of Medicine and Epidemiology, The Johns Hopkins University School of Medicine, Division of Endocrinology and Metabolism, Welch Center for Prevention, Epidemiology, and Clinical Research; The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

globulin) with adiposity, insulin resistance, and type 2 diabetes in men and women; (2) to highlight gender differences and similarities in these associations; and (3) to discuss the pathophysiological mechanisms by which sex hormones may influence insulin sensitivity. To provide a conceptual framework for understanding the gender dimorphism of the association between testosterone and diabetes, we will review the literature examining the association between diabetes and PCOS in women and hypogonadism in men. However, the majority of the studies reviewed will be population-based studies of individuals without clinical gonadal disorders who were not receiving hormone therapy to reduce potential confounding in interpreting the associations.

INTRODUCTION Obesity and diabetes are growing health problems in the United States that pose a significant public health burden. A review conducted by the American Diabetes Association on the economic costs of diabetes estimates that currently approximately 17.5 million people in the United States have diagnosed diabetes, which has risen from an estimated 12.1 million which was estimated in 2002.1 There are several reasons for the rise in the number of individuals diagnosed with diabetes, including, but not limited to (1) an aging population, (2) increased prevalence of obesity and overweight, (3) improved diabetes detection, (4) decreasing mortality from diabetes, and (5) growth of minority populations with high rates of diabetes.1 While traditional risk factors, such as obesity, family history of diabetes, ethnic minority status, and physical inactivity, are known to increase diabetes risk, they do not explain all of the variance in diabetes prevalence in the population. Therefore, it is important to identify novel risk factors that can lead to development of new preventive measures to complement existing prevention strategies. It is well established that polycystic ovary syndrome (PCOS), an endocrinopathy of reproductive age women characterized by hyperandrogenism, is associated with an increased risk of subsequent type 2 diabetes. Recent literature in men with clinical hypogonadism of various etiologies shows that they are at increased risk of developing insulin resistance and type 2 diabetes. This suggests that sex hormones in men and women may play a role in regulating glucose metabolism, either through their effects on adiposity or through independent mechanisms. The objectives of this chapter are (1) to review the associations of endogenous sex hormones (testosterone, estradiol, and sex hormone-binding Principles of Gender-Specific Medicine

GENDER DIFFERENCES IN THE ASSOCIATION BETWEEN ENDOGENOUS TESTOSTERONE AND RISK FACTORS FOR TYPE 2 DIABETES Endogenous Testosterone and Diabetes Risk in Women Hyperandrogenism is Associated with Insulin Resistance and Type 2 Diabetes in Women with PCOS The polycystic ovary syndrome (PCOS) is the most common endocrinopathy of women of reproductive age and is associated with hyperandrogenism and chronic anovulation.2,3 While not present in all women with PCOS, many women with PCOS also have insulin resistance and impaired beta cell function and are at increased risk of developing type 2 diabetes.2 Among women with PCOS, the combined prevalence of impaired glucose tolerance 679

Copyright 2010 , Elsevier Inc. All rights reserved.

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and type 2 diabetes is estimated to be 35–40%.3 In addition, several studies have found that the risk of developing type 2 diabetes is 3–7 times higher in women with PCOS compared to those without PCOS.2,4–7 Obesity is also more prevalent among women with PCOS, leading to decreased sex hormone-binding globulin (SHBG) and increased free testosterone.2 Although it is unclear whether hyperandrogenism contributes causally to insulin resistance and type 2 diabetes in women with PCOS, their association is well established. However, it is becoming increasingly clear that higher endogenous testosterone levels, even within the normal range, may also be associated with disordered glucose metabolism in women not taking hormone therapy.

Endogenous Testosterone is Associated with Insulin Resistance and Type 2 Diabetes in Women Without Hyperandrogenism Association of testosterone with measures of adiposity: As summarized in Table 56.1, several population-based studies have found that measures of testosterone are positively associated with measures of adiposity in pre-, peri-, and postmenopausal women. Two analyses of older postmenopausal women in the Rancho Bernardo Heart and Chronic Disease Study found that free testosterone was positively correlated with body mass index (BMI)8,9 and waist girth.8 Similarly, Kalish et al. found that in middle-aged postmenopausal women, bioavailable testosterone showed significant positive associations with several measures of adiposity, including BMI, waist girth, and waist-to-hip ratio.10 Two studies have examined these associations in a multi-ethnic cohort of pre- and perimenopausal women in the Study of Women Across the Nation (SWAN) and have also confirmed that free androgen index was positively correlated with BMI.11,12 Association of testosterone with measures of insulin resistance: Higher endogenous testosterone levels are associated with insulin resistance among women not taking hormone replacement therapy (Table 56.2). With the exception of three more recent studies,10,12,13 the majority of the studies have examined this association in smaller populations.8,14–18 In a small sample of postmenopausal women with type 2 diabetes recruited from an outpatient clinic, women with type 2 diabetes had higher free testosterone compared to control subjects with similar BMI and plasma insulin was positively correlated with free testosterone.14 Other studies in postmenopausal women have confirmed similar cross-sectional associations. Oh et al. found that free testosterone was positively correlated with baseline postchallenge insulin in the Rancho Bernardo Study.8 In a subgroup of postmenopausal women in the Atherosclerosis Risk in Communities (ARIC) Study, we found that higher free androgen index was associated with the hyperinsulinemia

and hyperglycemia components of the metabolic syndrome.17 In two large studies of postmenopausal women, increasing quartiles of bioavailable testosterone were associated with increasing insulin resistance; however, these associations did not persist following adjustment for adiposity.10,13 In both pre- and perimenopausal women, free androgen index and free testosterone were positively associated with plasma insulin,12,15 insulin:glucose ratio,16 and homeostasis model assessment of insulin resistance (HOMA-IR).12 Although small, only one study has examined the association between testosterone and insulin sensitivity measured by the gold standard euglycemic-hyperinsulinemic clamp. Just like other studies that used simpler estimates of insulin sensitivity, they found a positive correlation between free androgen index and insulin resistance.18 Finally, only one study has examined testosterone as a predictor of insulin resistance.8 In the Rancho Bernardo Study, Oh et al. showed that higher levels of baseline free testosterone predicted higher levels of HOMA-IR and fasting insulin over 8 years of follow-up in older adult women.8 Association of testosterone with type 2 diabetes: The association between endogenous testosterone and type 2 diabetes in women was recently summarized in a metaanalysis.19 Given that testosterone is associated with major risk factors for type 2 diabetes, including adiposity and insulin resistance, it is not surprising that testosterone is associated with type 2 diabetes both cross-sectionally and prospectively. In the meta-analysis of 16 cross-sectional studies in pre- (n ⫽ 9) and postmenopausal (n ⫽ 7) women, those with type 2 diabetes had significantly higher levels of testosterone compared to those without diabetes (mean difference ⫽ 6.1 ng/dl; 95% CI 2.3 to 10.1), independent of study level differences in age, race, diabetes diagnostic criteria, and internal control of adiposity.19 Following publication of this meta-analysis, we found that increasing quartiles of bioavailable testosterone were associated with a significantly increased odds of impaired fasting glucose and type 2 diabetes in 1973 postmenopausal women not taking hormone therapy in the Multi-Ethnic Study of Atherosclerosis (MESA).13 Compared to women in the lowest quartile, those in the highest quartile had a two-fold higher odds of impaired fasting glucose (OR ⫽ 2.32; 95% CI 1.75 to 3.07) and type 2 diabetes (OR ⫽ 2.05; 95% CI 1.45 to 2.89).13 While the association with impaired fasting glucose persisted following multivariable adjustment (including waist circumference) the association with type 2 diabetes became non-significant. Only two studies have examined endogenous testosterone as a predictor of type 2 diabetes in postmenopausal women. In the Rancho Bernardo Study, Oh et al. found that among 233 older adult women, those in the highest quartile of total testosterone were nearly three times as likely to

TABLE 56.1 Association of endogenous sex hormones with measures of adiposity in women without clinical hyperandrogenism and not taking hormone therapy Study information

Study design

N

Population characteristics

Associations T

Associations E2

Oh, 20028

Cross-sectional (baseline associations)

233

Postmenopausal women aged 55–89 not taking estrogen replacement Rancho Bernardo Heart and Chronic Disease Study

Free T positively correlated with baseline BMI and waist girth

Total and bioavailable E2 were associated with measures of adiposity (BMI and waist)

Goodman-Gruen, 20009

Cross-sectional

633

Post-menopausal women not taking estrogen replacement Rancho Bernardo Heart and Chronic Disease Study

Free T positively correlated with BMI

Randolph, 200311

Cross-sectional

2930

Premenopausal and early perimenopausal women aged 42–52 years Study of Women Across the Nation (SWAN) (black, white, Chinese, Hispanic, Japanese)

Free T index was positively correlated with BMI

Kalish, 200310

Cross-sectional

845

Postmenopausal women aged 45–65 years within 10 years of menopause not taking hormone replacement therapy

Bioavailable T showed significant positive associations with measures of adiposity (BMI, waist girth, WHR)

Associations with SHBG

SHBG showed a strong inverse association with BMI

Total and bioavailable E2 significant positive associations with measures of adiposity (BMI, waist girth, WHR)

SHBG showed significant negative associations with several measures of adiposity (BMI, waist girth, WHR) SHBG was negatively correlated with BMI in univariate and multivariable analyses

Sutton-Tyrrell, 200512

Cross-sectional

3297

Premenopausal and early perimenopausal women aged 42–52 years Study of Women Across the Nation (SWAN) (black, white, Chinese, Hispanic, Japanese)

Andersson, 199414

Cross-sectional

39

Postmenopausal women with type 2 diabetes not on hormone replacement therapy and not diagnosed with PCOS Recruited from outpatient clinic

Free androgen index was positively correlated with BMI

Abbreviations: BMI ⫽ body mass index; E2 ⫽ estradiol; SHBG ⫽ sex hormone binding globulin; T ⫽ testosterone; WHR ⫽ waist-to-hip ratio.

SHBG was negatively correlated with measures of adiposity (BMI and waist-to-hip ratio)

TABLE 56.2 Association of endogenous sex hormones with measures of insulin resistance in women without clinical hyperandrogenism and not taking hormone therapy Study information

Study design

N

Population characteristics

Associations with testosterone

Andersson, 199414

Crosssectional

39

Postmenopausal women with type 2 diabetes not on hormone replacement therapy and not diagnosed with PCOS Recruited from outpatient clinic

Women with type 2 diabetes had higher free T and insulin compared to control subjects with similar BMI Plasma insulin was positively correlated with free T

Larsson, 199618

Crosssectional

88

22 with impaired glucose tolerance 46 with normal glucose tolerance Aged 57–59

Freed androgen index was higher in impaired glucose tolerance compared to normal glucose tolerance Insulin sensitivity assessed via euglycemic-hyperinsulinemic clamp was negatively correlated with free androgen index in both groups

Falkner, 199915

Crosssectional

116

Premenopausal black women without diabetes Mean age 31 years

Free T positively correlated with plasma insulin

Oh, 20028

Cross-sectional (baseline associations) Longitudinal (follow-up associations)

233

Postmenopausal women aged 55–89 not taking estrogen replacement Rancho Bernardo Heart and Chronic Disease Study

Free T positively correlated with baseline post-challenge insulin Free T positively correlated with follow-up fasting insulin and HOMA-IR Higher levels of free T predicted higher levels of follow-up HOMA-IR and fasting insulin

Maturana, 200216

Crosssectional

104

Peri- and postmenopausal women referred from general practitioners and gynecologists in Brazil

Free androgen index positively correlated with insulin glucose ratio independent of BMI

Associations with estradiol

Associations with SHBG Plasma insulin was negatively correlated with SHBG in univariate analyses

SHBG negatively correlated with plasma insulin in univariate analyses Bioavailable E2 was associated with greater HOMA-IR and fasting insulin during 8 years of follow-up (among those who did not develop incident diabetes)

SHBG had a significant negative association with insulin:glucose ratio Hyperinsulinemic patients had lower SHBG

Odds for insulin resistance (assessed by HOMA-IR) were significant and increased in a dose-response fashion across each quartile of total and bioavailable E2—persisted following adjustment for measures of adiposity for bioavailable E2

Lower SHBG was associated with a higher odds of insulin resistance, independent of adiposity

Free androgen index was positively correlated with insulin and HOMA-IR

E2 was not correlated with measures of glucose metabolism

SHBG was negatively correlated with insulin and HOMA-IR in univariate analyses

Bioavailable T was positively associated with HOMA-IR after multivariable adjustment

E2 was positively associated with HOMA-IR after multivariable adjustment

SHBG was inversely associated with HOMAIR after multivariable adjustment

Crosssectional

845

Postmenopausal women aged 45–65 years within 10 years of menopause not taking hormone replacement therapy

Odds for insulin resistance were significant and increased in a doseresponse fashion across each quartile of bioavailable T; however, this association did not remain after adjusting for BMI

Golden, 200417

Cross-sectional

362

Postmenopausal women aged 45–64 not taking hormone replacement therapy with and without significant carotid atherosclerosis white and black Atherosclerosis Risk in Communities Study

Higher free androgen index was associated with the hyperinsulinemia and hyperglycemia components of the metabolic syndrome

Sutton-Tyrell, 200512

Cross-sectional

3, 297

Premenopausal and early perimenopausal women aged 42–52 years Study of Women Across the Nation (SWAN) (black, white, Chinese, Hispanic, Japanese)

Golden, 200713

Cross-sectional

1100

Postmenopausal women aged 45–84 not taking hormone replacement therapy with normal glucose tolerance Multi-Ethnic Study of Atherosclerosis (white, black, Hispanic, and Chinese)

Kalish, 200310

Abbreviations: BMI ⫽ body mass index; E2 ⫽ estradiol; HOMA-IR ⫽ homeostasis model assessment of insulin resistance; SHBG ⫽ sex hormone binding globulin; T ⫽ testosterone; WHR ⫽ waist-to-hip ratio.

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develop type 2 diabetes as those in the lowest quartile, after adjusting for baseline age, BMI, and systolic blood pressure (OR ⫽ 2.9; 95% CI 1.1 to 8.4).8 Most recently, Ding et al. conducted a case–control study in the Women’s Health Study in which endogenous sex hormones were measured at baseline in 359 women who developed type 2 diabetes over 10 years and 359 controls. In this population, testosterone was found to be a strong predictor of diabetes. Following adjustment for BMI, family history of diabetes, lifestyle and reproductive factors, women in the highest quintile of total and bioavailable testosterone had a four-fold (RR ⫽ 4.18; 95% CI 1.21 to 14.2) and 15–fold (RR ⫽ 14.9; 95% CI 4.44 to 49.2) greater risk of developing type 2 diabetes compared to those in the lowest quintile.20 The results of all of these studies suggest that testosterone levels within the normal range play a role is associated with glucose metabolism in women and may contribute to diabetes risk.

Endogenous Testosterone and Diabetes Risk in Men Hypogonadism is Associated with Insulin Resistance and Type 2 Diabetes in Men Hypogonadism is associated with insulin resistance and type 2 diabetes in men. This association has been shown in several studies in men with prostate cancer treated with androgen deprivation therapy (ADT) or orchiectomy. Both therapies induce a clinical state of hypogonadism and these men have a significantly increased likelihood of developing insulin resistance and type 2 diabetes. In men treated with ADT for prostate cancer, total and free testosterone were negatively correlated with fasting insulin and glucose and an estimate of insulin resistance.21 In addition, among men treated with ADT, low total and free testosterone were associated with higher body mass index (BMI) and a higher prevalence of metabolic syndrome.22 Hypogonadism is also prospectively associated with increased risk of developing the metabolic syndrome and type 2 diabetes. A prior study found that for each one standard deviation decrease in free testosterone, there was a 1.58–fold increased risk of developing type 2 diabetes.23 In a large study of 73 196 Medicare enrollees ⱖ66 years of age, those receiving ADT with a gonadotropin-releasing hormone agonist for locoregional prostate cancer had a 44% increased risk of diabetes during follow-up (HR ⫽ 1.44; p⬍0.001).24 In that same population, men treated with orchiectomy had a 34% increased risk of developing diabetes (HR ⫽ 1.34; p ⬍0.001).24 In the Massachusetts Male Ageing Study, clinical androgen deficiency was associated with a two-fold increased risk of developing metabolic syndrome in middle-aged men with BMI ⬍25 kg/m2 (RR ⫽ 2.51; 95% CI 1.12 to 5.56).25 As summarized below, even in the absence of clinical androgen deficiency, lower

endogenous testosterone is associated with increased diabetes and diabetes risk factors in men. Endogenous Testosterone is Associated with Insulin Resistance and Type 2 Diabetes in Men without Clinical Hypogonadism Association of testosterone with measures of adiposity: As summarized in Table 56.3, several studies have examined the association between testosterone and measures of adiposity in men. Testosterone has been inversely correlated with body fat by CT and DEXA scan 26 as well as with BMI 27–29 and waist circumference.27,28 Osuna et al. also found that total testosterone was lower in men with obesity compared to those who were overweight or normal weight.28 In a prospective analysis of the Massachusetts Male Ageing Study, baseline obesity and central adiposity were associated with decreased levels of total and free testosterone during 6–8 years of follow-up.30 Association of testosterone with measures of insulin resistance: Testosterone has also been shown to be inversely related to measures of insulin resistance (Table 56.4). Tsai et al. found that bioavailable testosterone was inversely associated with insulin and HOMA-IR; however, this association was not independent of total body or abdominal fat.26 Another study similarly found that total testosterone was negatively correlated with insulin and HOMA-IR.28 Association of testosterone with type 2 diabetes: The cross-sectional and longitudinal association between endogenous testosterone and type 2 diabetes in men was recently summarized in a meta-analysis by Ding et al.19 In a metaanalysis of 20 cross-sectional studies, men with type 2 diabetes had significantly lower plasma total testosterone than men without type 2 diabetes (mean difference ⫽ ⫺76.6 ng/dl; 95% CI ⫺99.4 to ⫺53.6 ng/dl).19 In a recent cross-sectional analysis of adult, non-institutionalized males ⬎20 years of age in the National Health and Nutrition Examination Survey III, Selvin et al. found that men in the lowest tertile of bioavailable testosterone were four times as likely to have diabetes compared to those in the highest tertile (OR ⫽ 4.12; 95% CI 1.25 to 13.55).31 This association was independent of age, race/ethnicity, and adiposity. Four prospective studies have examined testosterone as a predictor of type 2 diabetes in men. In a metaanalysis of these studies, men in the upper versus lower dichotomy of total testosterone had a 42% lower risk of diabetes (RR ⫽ 0.58; 95% CI 0.39 to 0.87).19 In addition, testosterone was significantly lower among cases of incident diabetes compared to individuals who did not develop diabetes (mean difference ⫽ ⫺71. ng/dl; 95% CI ⫺116.4 to ⫺26.8).19 The results of all of these studies suggest that lower endogenous testosterone in men without clinical hypogonadism is associated with increased adiposity, insulin resistance, and diabetes risk.

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685

TABLE 56.3 Association of endogenous sex hormones with measures of adiposity in men without clinical hypogonadism Study information

Study design

N

Population characteristics

Associations with testosterone

Associations with estradiol

Vermeulen, 199329

Crosssectional

Oh, 20028

Associations with SHBG

35

Obese men (BMI ⬎30) aged 17–61 years (compared to a non-obese control group)

Negative correlation between free T and BMI

Significant positive correlation between E2 levels and BMI

Crosssectional and longitudinal

294

Older adults aged 55–89 years Rancho Bernardo Study

Tsai, 200426

Crosssectional

221

Non-diabetic men ages 45–65 years

Bioavailable and total T were inversely correlated with body fat assessed by CT scan and DEXA

SHBG was inversely correlated with body fat assessed by CT scan and DEXA

Osuna, 200628

Crosssectional

77

Ages 20–60 years in Venezuela Divided into 3 categories of BMI: ⬍24.9 (normal), 25–29.9 (overweight), and ⬎30 kg/m2 (obese)

Total T was lower in the obese group compared to the overweight and normal groups T was negatively correlated with BMI and waist circumference

SHBG was lower in the obese group compared to the overweight and normal groups SHBG was negatively correlated with BMI and waist circumference

Derby, 200630

Longitudinal

942

Ages 40–70 years at baseline Obesity defined as BMI ⬎30 kg/m2. Central adiposity defined as waist circumference ⬎100 cm. Massachusetts Male Ageing Study

Obesity and central adiposity was associated with decreased levels of total and free T over follow-up

Obesity and central adiposity was associated with decreased levels of SHBG over follow-up

Kapoor, 200727

Crosssectional

355

Men with type 2 diabetes ⬎30 years of age United Kingdom

T was negatively correlated with BMI and waist circumference, with the association being stronger for waist circumference

Neither total nor bioavailable E2 were associated with measures of adiposity

Abbreviations: BMI ⫽ body mass index; E2 ⫽ estradiol; SHBG ⫽ sex hormone binding globulin; T ⫽ testosterone; WHR ⫽ waist-to-hip ratio.

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TABLE 56.4 Association of endogenous sex hormones with measures of insulin resistance in men without clinical hypogonadism Study information

Study design

N

Population characteristics

Associations with testosterone

Associations with estradiol

Associations with SHBG

Birkeland, 199333

Crosssectional

23

Well-characterized diabetic men Insulin sensitivity estimated using hyperinsulinemic euglycemic clamp

Strong positive correlation between SHBG and insulin sensitivity independent of obesity and abdominal fat

Falkner, 199915

Crosssectional

105

Black men without diabetes Mean age 31 years

Inverse correlation of insulin with SHBG

Oh, 20028

Crosssectional and longitudinal

294

Older adults aged 55–89 years Rancho Bernardo Study

Tsai, 200426

Crosssectional

221

Non-diabetic men ages 45 to 65 years

Bioavailable T was inversely associated with insulin and HOMA-IR but not independent of total body or abdominal fat

SHBG was inversely correlated with insulin and HOMA-IR independent of body fat

Osuna, 200628

Crosssectional

77

Ages 20–60 years in Venezuela Divided into 3 categories of BMI: ⬍24.9 (normal) , 25–29.9 (overweight), and ⬎30 kg/m2 (obese)

Total T was negatively correlated with insulin and HOMA-IR

SHBG was negatively correlated with insulin and HOMA-IR

Neither total nor bioavailable E2 were associated with measures of insulin resistance

Abbreviations: BMI ⫽ body mass index; E2 ⫽ estradiol; HOMA-IR ⫽ homeostasis model assessment of insulin resistance; SHBG ⫽ sex hormone binding globulin; T ⫽ testosterone; WHR ⫽ waist-to-hip ratio.

Endogenous Estradiol and Diabetes Risk in Women and Men In contrast to testosterone, where there appears to be gender dimorphism in the association between testosterone and diabetes risk, in both men and women, estradiol appears to be positively associated with type 2 diabetes and its risk factors, although this association has not been studied as extensively as the association with testosterone. Association of estradiol with measures of adiposity: Two population-based studies in postmenopausal women have shown that total and bioavailable estradiol were positively associated with BMI,8,10 waist girth,8,10 and waist-to-hip ratio10 (Table 56.1). The results in men are not consistent. While one small study (n ⫽ 35) found a significant positive

correlation between estradiol and BMI in obese men aged 17–61 years, a larger population-based study of elderly men in the Rancho Bernardo Study found that neither total nor bioavailable estradiol were associated with measures of adiposity8 (Table 56.3). Association of estradiol with measures of insulin resistance: Four population-based studies have examined the association between estradiol and insulin resistance in postmenopausal women (Table 56.2). In the Rancho Bernardo Study, Oh et al. demonstrated that bioavailable estradiol was prospectively associated with greater HOMA-IR and fasting insulin during 8 years of follow-up among elderly women who did not develop incident type 2 diabetes.8 Kalish et al. found that the odds of insulin resistance,

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assessed by HOMA-IR, were increased in a dose–response fashion across quartiles of total and bioavailable estradiol.10 The association with bioavailable estradiol persisted following adjustment for adiposity.10 In our study in the MESA cohort, we found that total estradiol was positively associated with HOMA-IR following multivariable adjustment, including adiposity, in cross-sectional analysis.13 In contrast, among pre- and perimenopausal women in the SWAN Study, estradiol was not correlated with measures of glucose metabolism.12 We could find very few studies that have examined the association between estradiol and measures of insulin resistance in men (Table 56.4). In the Rancho Bernardo Study, neither total nor bioavailable estradiol were associated with measures of insulin resistance in men.8 Association of estradiol with type 2 diabetes: The association between endogenous estradiol and type 2 diabetes in women and men was recently summarized in a metaanalysis, which showed positive associations between estradiol and type 2 diabetes in both genders.19 In the metaanalysis of four studies in women and five studies in men, those with type 2 diabetes had higher estradiol levels than individuals without diabetes (mean difference ⫽ 3.5 pg/ ml; 95% CI 0.94 to 6.0).19 We recently found that among postmenopausal women in the Multi-Ethnic Study of Atherosclerosis, women in the highest quartile of total estradiol had a three-fold higher odds of impaired fasting glucose (OR ⫽ 3.24; 95% CI 2.40 to 4.37) and a two-fold higher odds of type 2 diabetes (OR ⫽ 2.29; 95% CI 1.56 to 3.35), which persisted following multivariable adjustment.13 Two studies have prospectively examined estradiol as a predictor of type 2 diabetes in men and women and have yielded conflicting results. In the Rancho Bernardo Study, neither total nor bioavailable estradiol were predictors of incident type 2 diabetes in men or women; however, in this study, the number of incident diabetes cases was small.8 In contrast, Ding et al. recently showed that estradiol was a significant predictor of type 2 diabetes in postmenopausal women in the Women’s Health Study.20 In that study, following multivariable adjustment for risk factors including BMI, women in the highest quintile of total and free estradiol were 12 times (RR ⫽ 12.6; 95% CI 2.83 to 56.3) and 13 times (RR ⫽ 13.1; 95% CI 4.18 to 40.8) more likely to develop type 2 diabetes, respectively, compared to those in the lowest quartiles.20 Larger studies examining the prospective association between estradiol and risk of type 2 diabetes in men are needed.

Sex Hormone-Binding Globulin (SHBG) and Diabetes Risk in Men and Women Similar to estradiol, the direction of association between SHBG and diabetes risk in men and women is the same – namely, higher SHBG levels are associated with less adiposity, less insulin resistance, and a lower risk of diabetes.

687

Association of SHBG with measures of adiposity: Studies in premenopausal women have consistently shown an inverse correlation between several measures of adiposity, including BMI11,12,32 and waist-to-hip ratio32 (Table 56.1). Similarly, in postmenopausal women, SHBG has been inversely associated with BMI,10,14,32 waist-to-hip ratio,10,14,32 and waist circumference.10 SHBG is also inversely related to adiposity in men (Table 56.3). In a review written by Haffner, three studies in men showed inverse correlation between SHBG and BMI and waist-tohip ratio.32 Similarly, Tsai et al. found an inverse correlation between SHBG and body fat assessed by CT and DEXA scan in non-diabetic middle-aged men.26 Osuna et al. showed that SHBG levels were lower in obese compared to overweight and normal weight men and that SHBG was negatively correlated with BMI and waist circumference.28 In the Massachusetts Male Ageing Study, obesity and central adiposity at baseline predicated decreased levels of SHBG over a period of longitudinal follow-up.30 Association of SHBG with measures of insulin resistance: SHBG has been shown to be inversely associated with fasting insulin in both premenopausal15,32 and postmenopausal114,32 women (Table 56.2). In a small study (n ⫽ 104) of peri- and postmenopausal women, SHBG was inversely associated with insulin:glucose ratio and hyperinsulinemic patients had lower SHBG.16 Three large population-based studies, two of which were multi-ethnic, estimated insulin resistance by calculating HOMA-IR.10,12,13 In one study in pre- and perimenopausal women, SHBG was negatively correlated with insulin resistance.12 In two studies in postmenopausal women, SHBG was also inversely associated with insulin resistance, following multivariable adjustment for measures of adiposity.10,13 Similarly, SHBG is inversely related to measures of insulin resistance in men, including fasting insulin15,32 and HOMA-IR26,28 (Table 56.4). One small study (n ⫽ 23) in diabetic men estimated insulin sensitivity directly using the hyperinsulinemic euglycemic clamp. The authors found a strong positive correlation between SHBG and insulin sensitivity independent of obesity and abdominal fat.33 Association of SHBG with type 2 diabetes: The association between SHBG and type 2 diabetes in men and women was recently summarized in a meta-analysis by Ding et al.19 In the meta-analysis of 13 cross-sectional studies in pre(n ⫽ 6) and postmenopausal (n ⫽ 7) women, those with type 2 diabetes had significantly lower mean SHBG levels than those without diabetes (mean difference ⫽ ⫺16.23 nmol/l; 95% CI ⫺20.24 to ⫺12.22).19 Although the association was not as strong as that seen among the women and was not statistically significant, men with type 2 diabetes tended to have lower SHBG levels than men without diabetes (mean difference ⫽ ⫺5.07 nmol/l; 95% CI ⫺11.92 to 1.77).19 In both men and women, these associations remained consistent following adjustment for age, race, diabetes diagnosis criteria, and internal control for BMI.19 Among postmenopausal

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women in the MESA Study, increasing quartiles of SHBG were associated with a lower odds of impaired fasting glucose and type 2 diabetes.13 Compared to women in the lowest quartile, those in the highest quartile had a 65% lower odds of impaired fasting glucose (OR ⫽ 0.35; 95% CI 0.22 to 0.53) and 70% lower odds of type 2 diabetes (OR ⫽ 0.30; 95% CI 0.16 to 0.54), following multivariable adjustment that included adiposity.13 Only a few studies have examined SHBG as a predictor of type 2 diabetes in population-based studies in women and men. In the two studies in women, higher SHBG was associated with an 80% lower risk of developing type 2 diabetes (RR ⫽ 0.20; 95% CI 0.12 to 0.32). Although not as strong, higher SHBG in men was also associated with a 52% lower risk of developing type 2 diabetes (RR ⫽ 0.48; 95% CI 0.34 to 0.69).19 These studies all suggest a protective effect of SHBG on diabetes risk in men and women.

PATHOPHYSIOLOGY OF ENDOGENOUS SEX HORMONES AS RISK FACTORS FOR TYPE 2 DIABETES A summary of the available observational data demonstrates sexual dimorphism in the association between testosterone and type 2 diabetes, with higher testosterone being associated with greater adiposity, insulin resistance, and diabetes in women and lower testosterone being associated with the same outcomes in men. In contrast, the direction of association between estradiol and SHBG and type 2 diabetes is the same for women and men, although the association of SHBG with diabetes is somewhat stronger for women. There are several plausible biological mechanisms that may link endogenous sex hormones and diabetes risk in women and men, which are summarized below. TESTOSTERONE Effect of Testosterone on Glucose Metabolism in Women As was recently summarized, there are several mechanisms by which androgens and insulin resistance may be related17 (see Figure 56.1). First, research in premenopausal women with PCOS suggests that hyperinsulinemia leads to increased bioavailable testosterone through stimulation of P450c 17α activity in ovarian thecal cells following stimulation of ovarian insulin receptors, suppression of SHBG, and stimulation of luteinzing hormone release from the pituitary gland.38 In obese women with PCOS, suppression of insulin levels with diazoxide leads to a reduction in serum testosterone34 Second, abdominal obesity itself might directly lead to hyperandrogenism via conversion of adrenal androstenedione to testosterone via 17β-hydroxysteroid oxidoreductase in abdominal adipose tissue.35 Alternatively,

MECHANISM 1 VISCERAL OBESITY

MECHANISM 2 ↑ BIOAVAILABLE TESTOSTERONE

HYPERINSULINEMIA HYPERINSULINEMIA INSULIN RESISTANCE Stimulation of ovarian insulin receptors

Stimulation of luteinizing hormone release from pituitary

Stimulation of P450c17α activity in ovarian thecal cells

Stimulation of ovaries

↓ Sex hormone binding globulin ↑ BIOAVAILABLE TESTOSTERONE

MECHANISM 3 ↑ BIOAVAILABLE TESTOSTERONE

Skeletal muscle glycogen synthase activity

IMPAIRED GLUCOSE UTILIZATION

FIGURE 56.1 Proposed mechanism relating androgens to glucose homeostasis. From Golden et al., 2004.17 Reproduced with permission of Oxford University Press.

hyperandrogenism might result in increased insulin resistance. Androgen administration to healthy women has been shown to reduce insulin sensitivity and impair peripheral glucose utilization, as assessed by the hyperinsulinemic– euglycemic clamp.36–38 In addition, anti-androgen treatment given to women with hyperandrogenism has resulted in partial improvement in insulin sensitivity.39,40 A study of female oopherectomized rats suggested another mechanism at the level of the skeletal muscle by which testosterone might impair glucose utilization. In this study, rats treated with testosterone replacement therapy showed reduced glycogen synthase protein expression in skeletal muscle.41 Finally, in women, testosterone increases lipogenesis in visceral fat depots, which can lead to an increased risk for type 2 diabetes.19 In short-term clinical trials, androgen administration to healthy women has been shown to reduce insulin sensitivity and impair glucose utilization.36–38 Anti-androgen therapy given to women with PCOS and hyperandrogenism has resulted in partial improvement in insulin sensitivity39,40 and a decrease in visceral abdominal fat.42 In postmenopausal women, androgen therapy resulted in a gain in visceral abdominal fat but there was no change in fasting glucose or insulin sensitivity.43 Effect of Testosterone on Glucose Metabolism in Men As summarized above, low testosterone is associated with adiposity, insulin resistance, and diabetes in men and there are several proposed mechanisms (see Figure 56.2).23

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689

Hypothalamus

↓ Kisspeptins ↓ Response to GnRH

Pituitary

↓ LH secretion ↓ LH pulse frequency

Leydig cells ↑ Cytokines ↑ Insulin ↑ Sensitivity to negative androgen feedback

↓ SHBG

↑ Leptin ↓ Testosterone

↑ Glucose transport ↓ Anti-oxidant effect

↑ Insulin resistance

↑ Aromatase ↓ SHBG ↑ Lipoprotein lipase

↑ Adipocytes

Androgen receptor polymorphisms

FIGURE 56.2 Mechanism of hypogonadism-related glucose intolerance. GnRH, gonadotropin releasing hormone; LH, luteinizing hormone; SHBG, sex hormone-binding globulin. Reproduced by permission of Wolters Kluwer Health from Kalyani, 2007.23 Copyright © (2007) Lippincott Williams & Wilkins: http://www.lww.com.

SHBG levels are reduced in men with greater adiposity, which can lead to low total testosterone levels. Both animal and human studies suggest that central hypogonadotropism may be present in men with diabetes. In a rat model of diabetes, there was decreased basal and pulsatile luteinizing hormone secretion that was improved with insulin administration, increased sensitivity of leutinizing hormone to negative feedback from androgens, a reduced gonadotropin-releasing hormone response, and a reduced leutinizing hormone response following gonadectomy.23 Other animal studies have examined the role of the kisspeptins

in hypogonadism associated with diabetes.44 Kisspeptins are strong stimulants of the gonadotropin-releasing hormone–gonadotropin axis.23 In this model, there was a reduction in hypothalamic kisspeptin-1 mRNA with a blunted rise following orchiectomy; however, administration of kisspeptins increased leutinizing hormone and testosterone bursts, resulting in partial restoration of prostate and testicular weight.44 In a human study, the gonadotropin response to gonadotropin-releasing hormone was reduced in diabetic males;45 however, another study failed to demonstrate an association between insulin sensitivity, assessed

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via the hyperinsulinemic euglycemic clamp, and leutinizing hormone secretion.46 In the second study, however, administration of human chorionic gonadotropin with a gonadotropin-releasing hormone antagonist led to increased testosterone production, suggesting deficient Leydig cell testosterone secretion.46 In addition to being associated with central hypogonadism, there are additional proposed mechanisms linking low testosterone to insulin resistance and diabetes. Obesity and diabetes are associated with increased inflammatory cytokines, including interleukin-1β, interleukin-6, and tumor necrosis factor-alpha, which likely inhibit steroidogenesis at the testicular level.23 In addition, obesity is associated with increased aromatase activity, and enzyme in fat that converts testosterone to estradiol in men and women. Thus, increased adiposity would lead to enhanced peripheral conversion of testosterone to estradiol, causing feedback pituitary inhibition of gonadotropins in males.23 The fact that baseline levels of testosterone have been predictive of incident type 2 diabetes in men suggests that it may have direct effects on glucose metabolism and insulin resistance. Testosterone in men inhibits lipoprotein lipase activity, leading to decreased triglyceride uptake by adipocytes and decreased visceral adiposity.23 Thus, the opposite effect would be observed in men with low testosterone levels, leading to increased visceral adiposity, which is a known risk factor for type 2 diabetes. Androgens have also been shown to enhance insulin sensitivity in human erythrocytes by inhibiting glucose exit from these cells, a process which is blocked by administration of the anti-androgen flutamide.47,48 Therefore, hypogonadism may contribute to insulin resistance at the cellular level by allowing glucose efflux from these cells.23 Finally, androgens have antioxidant effects and hyperglycemia is known to produce oxidative stress. In humans, total antioxidant capacity is reduced in young males with hypogonadism.49 Animal studies have demonstrated that oxidative stress-induced beta-cell apoptosis in hypogonadal streptozocin-induced diabetic rats can be diminished with administration of testosterone.23 Finally, studies in hypogonadal men with type 2 diabetes have shown that treatment with testosterone leads to improved glycemic control50,51 and insulin sensitivity50 and reduced adiposity.50 In addition, weight loss in a small group of abdominally obese men resulted in increased SHBG and free testosterone.52

ESTRADIOL In women, higher endogenous estradiol was cross-sectionally associated with greater adiposity and insulin resistance, and in both genders higher estradiol was cross-sectionally associated with type 2 diabetes. In one recent study estradiol was a significant predictor of incident type 2 diabetes in women,20 although this has not been shown in men. While there are only a small number of studies examining the

association between estradiol and diabetes risk in men and women, there are several proposed mechanisms by which estradiol might impact glucose tolerance. As noted above, testosterone is converted to estradiol by aromatase in adipose tissue and hence, the observed effects of estradiol on insulin sensitivity and adiposity may really reflect the underlying effect of testosterone. In women, particularly those who are postmenopausal, higher estradiol may reflect higher levels of testosterone and the observed association may be confounded; however, in the MESA Study, we found that the association of estradiol with measures of glucose tolerance persisted when adjusting for testosterone.13 In men with greater adiposity who have increased aromatase activity, there would be enhanced conversion of testosterone to estradiol, resulting in feedback inhibition of pituitary gonadotropins by estradiol, further decreasing testosterone levels. Some of the observed effects of estradiol on glucose metabolism have been independent of adiposity.19 The literature regarding the effects of estrogen on glucose metabolism is mixed. Rodent models of estradiol deficiency have insulin resistance and rodent models of type 2 diabetes demonstrate that ovariectomy makes female rats susceptible to beta-cell destruction.53 These defects are reversed with estradiol administration. Several studies have shown that treating healthy women with unopposed estradiol or continuous equine estrogen improves insulin sensitivity and decreases blood glucose54–57 and among women with diabetes, unopposed estradiol58–60 or combination hormone replacement therapy61 improves insulin sensitivity and glycemic control. However, although exogenous estrogen administered via hormone replacement therapy was associated with a reduced risk of developing diabetes in postmenopausal women with coronary artery disease,62 pregnancy, a state of high endogenous estrogen, is associated with insulin resistance.38 Further studies are needed to further understand potential mechanisms of estradiol’s effect on glucose metabolism in both men and women.

SHGB Like estradiol, the direction of association between SHBG and glucose tolerance is similar in men and women; however, the association is stronger for women.19 SHBG consistently shows an inverse association with adiposity, measures of insulin resistance, and type 2 diabetes in multiple populations of men and women. In vitro, insulin is a potent inhibitor of SHBG production by hepatoma cells, suggesting that decreased SHBG levels may be indicative of underlying insulin resistance.63 As previously discussed,64 there are additional mechanisms by which SHBG may effect insulin resistance, adiposity, and type 2 diabetes: (1) by regulating levels of bioavailable androgen and estrogen levels or (2) by its direct effects at the cellular level. SHBG binds testosterone, dihydrotestosterone, and estradiol with high affinity, regulating their free concentrations.65 Because

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SHBG is stable and estradiol is bound with less affinity than testosterone, total estradiol is proportional to free estradiol; however, a smaller fraction of testosterone is free and biologically active.66 In women, lower SHBG likely reflects greater free testosterone and hence greater androgenicity. However, in men, lower SHBG is associated with lower total testosterone and the proportion of free testosterone is therefore lower than that of men with higher SHBG levels. Finally, in vitro studies have demonstrated SHBG receptors in certain human tissue, which, when bound by SHBG and dihydrotestosterone or estradiol, causes a rise in intracellular cyclic adenosine monophosphate.65 Thus, in addition to transporting steroid hormones in plasma, SHBG may also help mediate glucose metabolic effects of estradiol and testosterone at the cellular level by regulating intracellular physiology. Whether there is an independent effect of SHBG remains controversial and this is an important area of future investigation.

FUTURE DIRECTIONS AND CONCLUSIONS Diabetes and obesity continue to be rising epidemics, with an estimated net growth rate in diabetes from 2002 to 2007 of approximately 1 million people per year.1 It is therefore important to identify novel risk factors that may be targets for future diabetes prevention interventions. Review of the literature suggests that sex hormones appear to be associated with type 2 diabetes and its risk factors, even in men and women without gonadal disorders. The fact that certain sex hormones, particularly testosterone and SHBG, predict incident type 2 diabetes suggests that these hormones may have a causal role in altering insulin sensitivity prior to the onset of diabetes. Further research in larger studies of humans is needed to confirm this as well as to understand more fully the molecular mechanisms by which sex hormones influence insulin signaling, glucose transport, and lipid metabolism in relation to adiposity. Finally, studies aimed at altering the hormonal milieu in men and women may have implications for altering glucose metabolism and diabetes risk.

References 1. American Diabetes Association. Economic costs of diabetes in the US. Diabetes Care 2008;31:1–20. 2. Kousta E, Tolis G, Franks S. Polycystic ovary syndrome. Revised diagnostic criteria and long-term health consequences. Hormones (Athens) 2005;4:133–47. 3. Yildiz BO, Gedik O. Assessment of glucose intolerance and insulin sensitivity in polycystic ovary syndrome. Reprod Biomed Online 2004;8:649–56. 4. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65:499–507.

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5. Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992;57:505–13. 6. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165–69. 7. Wild S, Pierpoint T, Jacobs H, McKeigue P. Long-term consequences of polycystic ovary syndrome: results of a 31 year follow-up study. Hum Fertil (Camb) 2000;3:101–5. 8. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care 2002;25:55–60. 9. Goodman-Gruen D, Barrett-Connor E. Sex differences in the association of endogenous sex hormone levels and glucose tolerance status in older men and women. Diabetes Care 2000;23:912–18. 10. Kalish GM, Barrett-Connor E, Laughlin GA, Gulanski BI. Association of endogenous sex hormones and insulin resistance among postmenopausal women: results from the Postmenopausal Estrogen/Progestin Intervention Trial. J Clin Endocrinol Metab 2003;88:1646–52. 11. Randolph JF Jr., Sowers M, Gold EB, et al. Reproductive hormones in the early menopausal transition: relationship to ethnicity, body size, and menopausal status. J Clin Endocrinol Metab 2003;88:1516–22. 12. Sutton-Tyrrell K, Wildman RP, Matthews KA, et al. Sex hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN). Circulation 2005;111:1242–49. 13. Golden SH, Dobs AS, Vaidya D, et al. Endogenous sex hormones and glucose tolerance status in postmenopausal women. J Clin Endocrinol Metab 2007;92:1289–95. 14. Andersson B, Marin P, Lissner L, Vermeulen A, Bjorntorp P. Testosterone concentrations in women and men with NIDDM. Diabetes Care 1994;17:405–11. 15. Falkner B, Sherif K, Sumner A, Kushner H. Hyperinsulinism and sex hormones in young adult African Americans. Metabolism 1999;48:107–12. 16. Maturana MA, Spritzer PM. Association between hyperinsulinemia and endogenous androgen levels in. Metabolism 2002;51:238–43. 17. Golden SH, Ding J, Szklo M, Schmidt MI, Duncan BB, Dobs A. Glucose and insulin components of the metabolic syndrome are associated with hyperandrogenism in postmenopausal women: the atherosclerosis risk in communities study. Am J Epidemiol 2004;160:540–48. 18. Larsson H, Ahren B. Androgen activity as a risk factor for impaired glucose tolerance in postmenopausal women. Diabetes Care 1996;19:1399–403. 19. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006;295:1288–99. 20. Ding EL, Song Y, Manson JE, Rifai N, Buring JE, Liu S. Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia 2007;50:2076–84.

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21. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 2006;106:581–88. 22. Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006;24:3979–83. 23. Kalyani RR, Dobs AS. Androgen deficiency, diabetes, and the metabolic syndrome in men. Curr Opin Endocrinol Diabetes Obes 2007;14:226–34. 24. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448–56. 25. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab 2006;91:843–50. 26. Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care 2004;27:861–68. 27. Kapoor D, Aldred H, Clark S, Channer KS, Jones TH. Clinical, and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 2007;30:911–17. 28. Osuna JA, Gomez-Perez R, Arata-Bellabarba G, Villaroel V. Relationship between BMI, total testosterone, sex hormonebinding-globulin, leptin, insulin and insulin resistance in obese men. Arch Androl 2006;52:355–61. 29. Vermeulen A, Kaufman JM, Deslypere JP, Thomas G. Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men. J Clin Endocrinol Metab 1993;76:1140–46. 30. Derby CA, Zilber S, Brambilla D, Morales KH, McKinlay JB. Body mass index, waist circumference and waist to hip ratio and change in sex steroid hormones: the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf) 2006;65:125–31. 31. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 2007;30:234–38. 32. Haffner SM. Sex hormones, obesity, fat distribution, type 2 diabetes and insulin resistance: epidemiological and clinical correlation. Int J Obes Relat Metab Disord 2000;24(Suppl. 2):S56–8. 33. Birkeland KI, Hanssen KF, Torjesen PA, Vaaler S. Level of sex hormone-binding globulin is positively correlated with insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 1993;76:275–78. 34. Nestler JE. Insulin resistance effects on sex hormones and ovulation in the polycystic ovary syndrome. In: GM Reaven, A Laws, eds. Insulin Resistance. Totowa, NJ: Humana Press; 1999:347–65. 35. Mohamed-Ali V, Pinkney JH, Coppack SW. Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 1998;22:1145–58. 36. Polderman KH, Gooren LJ, Asscheman H, Bakker A, Heine RJ. Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 1994;79:265–71.

37. Diamond MP, Grainger D, Diamond MC, Sherwin RS, Defronzo RA. Effects of methyltestosterone on insulin secretion and sensitivity in women. J Clin Endocrinol Metab 1998;83:4420–50. 38. Livingstone C, Collison M. Sex steroids and insulin resistance. Clin Sci (Lond) 2002;102:151–66. 39. Moghetti P, Tosi F, Castello R, Magnani CM, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 1996;81:952–60. 40. Buffington CK, Kitabchi AE. Evidence for a defect in insulin metabolism in hyperandrogenic women with polycystic ovarian syndrome. Metabolism 1994;43:1367–72. 41. Rincon J, Holmang A, Wahlstrom EO, et al. Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment. Diabetes 1996;45:615–21. 42. Gambineri A, Pagotto U, Tschop M, et al. Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome. J Endocrinol Invest 2003;26:629–34. 43. Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli R, Rood JC, Greeson C, Partington C. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women–a clinical research center study. J Clin Endocrinol Metab 1996;81:2198–203. 44. Castellano JM, Navarro VM, Fernandez-Fernandez R, et al. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes 2006;55:2602–10. 45. Baccetti B, La Marca A, Piomboni P, et al. Insulin-dependent diabetes in men is associated with hypothalamo-pituitary derangement and with impairment in semen quality. Hum Reprod 2002;17:2673–77. 46. Pitteloud N, Hardin M, Dwyer AA, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab 2005;90:2636–41. 47. Lacko L, Wittke B, Geck P. Interaction of steroids with the transport system of glucose in human erythrocytes. J Cell Physiol 1975;86(Suppl. 2):673–80. 48. Naftalin RJ, Afzal I, Cunningham P, et al. Interactions of androgens, green tea catechins and the antiandrogen flutamide with the external glucose-binding site of the human erythrocyte glucose transporter GLUT1. Br J Pharmacol 2003;140:487–99. 49. Demirbag R, Yilmaz R, Erel O. The association of total antioxidant capacity with sex hormones. Scand Cardiovasc J 2005;39:172–76. 50. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154:899–906. 51. Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003;6:1–7. 52. Niskanen L, Laaksonen DE, Punnonen K, Mustajoki P, Kaukua J, Rissanen A. Changes in sex hormone-binding

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53.

54.

55.

56.

57.

58.

59.

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globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome. Diabetes Obes Metab 2004;6:208–15. Louet JF, LeMay C, Mauvais-Jarvis F. Antidiabetic actions of estrogen: insight from human and genetic mouse models. Curr Atheroscler Rep 2004;6:180–85. Espeland MA, Hogan PE, Fineberg SE, et al. Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators. Postmenopausal Estrogen/ Progestin Interventions. Diabetes Care 1998;21:1589–95. Crespo CJ, Smit E, Snelling A, Sempos CT, Andersen RE. Hormone replacement therapy and its relationship to lipid and glucose metabolism in diabetic and nondiabetic postmenopausal women: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 2002;25:1675–80. Saglam K, Polat Z, Yilmaz MI, Gulec M, Akinci SB. Effects of postmenopausal hormone replacement therapy on insulin resistance. Endocrine 2002;18:211–14. Li C, Samsioe G, Borgfeldt C, Bendahl PO, Wilawan K, Aberg A. Low-dose hormone therapy and carbohydrate metabolism. Fertil Steril 2003;79:550–55. Andersson B, Mattsson LA, Hahn L, et al. Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997;82:638–43. Brussaard HE, Gevers Leuven JA, Frolich M, Kluft C, Krans HM. Short-term oestrogen replacement therapy improves

60.

61.

62.

63.

64.

65. 66.

693

insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia 1997;40:843–49. Friday KE, Dong C, Fontenot RU. Conjugated equine estrogen improves glycemic control and blood lipoproteins in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 2001;86:48–52. Perera M, Sattar N, Petrie JR, et al. The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2001;86:1140–43. Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/Progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:1–9. Pugeat M, Crave JC, Elmidani M, et al. Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. J Steroid Biochem Mol Biol 1991;40:841–49. Golden SH, Maguire A, Ding J, et al. Endogenous postmenopausal hormones and carotid atherosclerosis: a case-control study of the atherosclerosis risk in communities cohort. Am J Epidemiol 2002;155:437–45. Rosner W. Plasma steroid-binding proteins. Endocrinol Metab Clin North Am 1991;20:697–720. Spratt D, Loughlin J, Kellett R. Hypothalamic–pituitary–ovarian axis. In: WT Moore, RC Eastman, eds. Diagnostic Endocrinology, second ed. St Louis, MO: Mosby; 1996:311–37.

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Thyroid Disorders and Pregnancy MATTHEW KIM Assistant Professor of Medicine, The Johns Hopkins Hospital, Division of Endocrinology, Baltimore, MD, USA

increased production of thyroxine-binding globulin driven by increasing estrogen levels, and (b) a parallel increase in plasma volume that occurs throughout the course of pregnancy. Free thyroid hormone levels may increase during the first trimester as a result of direct stimulation of thyroid tissue by human chorionic gonadotropin (hCG).8 The embryo and placenta produce and secrete hCG as a heterodimer comprised of a distinct beta subunit bound to an alpha subunit that is identical to that present in thyroid-stimulating hormone (TSH). The homology conferred by this shared alpha subunit is sufficient enough to allow circulating hCG to bind to TSH receptors to stimulate the synthesis and secretion of thyroxine (T4) and triiodothyronine (T3) in functional thyroid tissue. In some instances free thyroid hormone levels may increase to the point where they attenuate secretion of TSH from the pituitary. This may be reflected in TSH levels that transiently drop below the limits of normal reference ranges. While embryologic development of the fetal thyroid is largely complete by the end of the first trimester, intrinsic production of fetal thyroid hormone usually does not reach stable levels until well into the second trimester.9 Neurologic development during the second trimester is almost entirely supported by maternal thyroid hormone delivered to the fetus via the placenta. High levels of type 3 deiodinase present in placental tissue may regulate the amount of T4, T3, and iodide transferred to the fetal circulation. Fetal thyroid hormone production during the third trimester depends on access to adequate levels of iodide derived from maternal stores.

INTRODUCTION Gender-based differences in the evaluation and management of thyroid disorders principally stem from considerations that arise in the setting of pregnancy. Interactions may be viewed from different perspectives. On one hand, it must be recognized that thyroid autoimmunity and functional disorders that persist as untreated conditions may have a significant impact on fertility, fetal development, and maternal outcomes. At the same time due consideration must be given to the extent to which approaches to the evaluation and management of functional disorders and neoplastic changes identified during pregnancy must be guided by an understanding of (a) physiologic adaptations in thyroid function that occur during the course of gestation, and (b) limitations imposed by the potential teratogenicity of agents commonly used to diagnose and treat thyroid disorders. An informed appreciation of these interactions is particularly important in light of the estimated prevalence of readily diagnosed thyroid disorders in women of reproductive age.1,2,3 During the course of gestation, increased renal blood flow and glomerular filtration act to increase clearance and excretion of iodide.4 The net effect is to increase dietary iodine requirements. Current recommendations specify that pregnant women maintain an average iodine intake of 250 μg daily.5 Women who live in iodine-sufficient regions are usually able to achieve this goal through a combination of dietary supplementation and daily ingestion of specifically formulated prenatal vitamins. In cases where adequate iodine intake may be in question due to dietary restrictions or limited access to prenatal care, urine iodine concentrations can be measured to assess stores.6 Concentrations less than 100 μg/l have been correlated with mild to moderate iodine deficiency in population-based studies.7 Thyroid hormone production increases significantly during gestation to maintain relatively stable total thyroid hormone levels in response to the combined effects of (a)

Principles of Gender-Specific Medicine

AUTOIMMUNE THYROIDITIS Screening evaluations have determined that autoimmune thyroiditis may be present in up to 20% of women in iodinesufficient regions at the time of conception.10 While this

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disorder is defined by the lymphocytic infiltration of thyroid tissue, diagnosis in practice usually rests on demonstration of elevated antithyroid antibody levels. Elevated antithyroid peroxidase antibodies may be a more sensitive indicator of underlying autoimmune thyroiditis than antithyroglobulin antibodies when measured in clinical settings.11 Studies that have evaluated the impact of thyroid disorders on fertility have demonstrated a significantly increased risk of miscarriage in women with autoimmune thyroiditis, irrespective of its impact on intrinsic thyroid function.10,12,13 Speculation regarding the basis for this association has focused on the disparate notions that autoimmune thyroiditis may either (a) predispose to subtle but significant hypothyroidism that may compromise gestation, or (b) signal the presence of a more general state of autoimmunity that limits the viability of fetal development. In a randomized controlled

CASE 1 A 26-year-old G2P0 female presents for evaluation of thyroid function test abnormalities identified during an evaluation of fertility. She has a history of two miscarriages that each occurred before 10 weeks gestation. Lab tests checked 2 months after the second episode revealed a TSH level of 5.8 mIU/l (normal range 0.5–4.5 mIU/l) and a free T4 level of 1.2 ng/dl (normal range 0.6–1.8 ng/dl). Repeat lab tests checked 4 months later revealed a TSH level of 2.3 mIU/l. The patient reports a history of premature graying, but does not identify any symptoms consistent with hypothyroidism. Physical examination reveals slight enlargement of the thyroid with a firm lobular texture and no discrete nodularity. Deep tendon reflexes are normal. Lab tests reveal a TSH level of 3.2 mIU/L and an anti-thyroid peroxidase antibody level of 249 IU/ml (normal range 0–34 IU/ml), confirming a suspected diagnosis of autoimmune thyroiditis.

It may be difficult to predict the risk of development of subclinical or overt hypothyroidism during pregnancy in women with antecedent or newly diagnosed autoimmune thyroiditis with normal intrinsic thyroid function. The state of pregnancy itself is known to be associated with a general amelioration of autoimmunity that is presumably mediated by marked increases in circulating progesterone levels.15 It might be anticipated that this effect would reduce the risk of progressive autoimmune destruction of thyroid tissue predisposing to the development of hypothyroidism. A study that tracked the status of women with autoimmune thyroiditis known to be euthyroid at the outset of pregnancy determined that despite a substantial reduction in antithyroid antibody titers during the course of gestation, a significant number demonstrated changes in thyroid function profiles

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trial that sought to address this question, investigators treated pregnant women with autoimmune thyroiditis and normal intrinsic thyroid function with levothyroxine administered at doses of 0.5–1.0 μg/kg daily throughout the course of gestation.14 Analysis revealed that women who received levothyroxine demonstrated lower rates of miscarriage and premature delivery than those followed without treatment. While further studies would likely need to confirm these results before treatment along these lines could be recommended, this intriguing finding lends some increased weight to arguments in favor of widespread measurement of antithyroid antibodies in women of reproductive age to screen for underlying autoimmune thyroiditis. Current recommendations for screening are limited to targeted case findings based on measurement of TSH levels in women considered to be at high risk for functional disorders.5

The patient is offered the option of starting treatment with a low dose of thyroid hormone and elects to pursue this course. She is started on levothyroxine at an initial dose of 50 μg daily. Lab tests checked after 2 months of good adherence with this treatment reveal a TSH level of 2.1 mIU/l. After 5 months of attempting to conceive, the patient notes a positive result on a home pregnancy test. Pregnancy is confirmed with a positive qualitative serum hCG level. A fetal ultrasound checked at 12 weeks estimated gestation reveals a normal intra-uterine pregnancy. The patient continues on levothyroxine throughout her pregnancy with serial monitoring of TSH levels. Her dose is adjusted to maintain a TSH level between 2.0 and 4.5 mIU/l. By the end of the third trimester her dose has increased to 88 μg daily. She delivers a healthy full-term infant without complications. Levothyroxine is held after delivery and lab tests checked 2 months later reveal a TSH level of 4.8 mIU/l. The patient elects to resume treatment with levothyroxine at a dose of 50 μg daily.

marked by increases in TSH levels and decrements in free T4 levels compared to those noted in controls.16 While current guidelines recommend monitoring of TSH levels in women with autoimmune thyroiditis during pregnancy, specific criteria regarding thresholds for the diagnosis and treatment of subclinical hypothyroidism in this setting have not been identified.5 Postpartum thyroiditis is defined as autoimmune thyroiditis identified during the first year after delivery. Estimates of the prevalence of this disorder have varied widely depending on the populations studied and criteria utilized to established disorders. Reliable estimates of the prevalence in the general population range between 4 to 6%.17 In some cases it may represent a new development, while in others it likely reflects a resurgence of preexisting autoimmune thyroiditis

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that may have been suppressed during the course of gestation.18 Up to 50% of women with positive antithyroid peroxidase antibodies measured before or during pregnancy eventually progress to develop postpartum thyroiditis.19 In 20–30% of cases, the onset and progression of autoimmune inflammation may precipitate the release of stored thyroid hormone.20 If the quantity of thyroid hormone released is excessive, it can lead to the development of transient thyrotoxicosis marked by a suppressed TSH level, elevated T4 and T3 levels, and characteristic symptoms including palpitations, tremulousness, anxiety, and irritability.21 In most cases transient thyrotoxicosis lasts from 2 to 8 weeks and is followed by the development of hypothyroidism characterized by an elevated TSH level, decreased T4 and T3 levels, and mild hypothyroid symptoms. This phase may resolve over the course of weeks to months, or may persist as permanent hypothyroidism in up to 30% of cases.22,23 The diagnosis of postpartum thyroiditis presenting with thyrotoxicosis may be complicated by the fact that (a) the specificity of elevated antithyroid antibodies may be limited in this setting, (b) other endogenous disorders associated with thyrotoxicosis may also first become apparent

CASE 2 A 33-year-old G2P2 female presents for evaluation of thyrotoxicosis identified after the delivery of her second child. At the time of her 6–week postpartum checkup she was noted to be tachycardic with a resting heart rate of 124 beats per minute. An electrocardiogram revealed sinus tachycardia. Lab tests checked at that time revealed a hemoglobin of 12.7 g/dl and a TSH level ⬍ 0.02 mIU/l. Repeat lab tests confirmed a suppressed TSH level with a concomitant free T4 level of 2.8 ng/dl. The patient reports a 2 week history of intermittent symptomatic palpitations that have been forceful enough to wake her from sleep. She has been experiencing persistent fatigue, and has been noting recent heat intolerance and hyperdefecation. She has been breastfeeding without difficulty. Physical examination reveals mild bilateral lid lag without proptosis or scleral injection. The thyroid is normal in size and texture without any nodularity or tenderness. There is no audible bruit or

Hypothyroidism Untreated hypothyroidism is known to be associated with an increased risk of infertility and may be associated with increased rates of miscarriage after conception.13,24 Current guidelines recommend that women who fall into specific

after delivery, and (c) radionuclide tracers used to measure thyroid uptake to distinguish between hyperthyroidism and thyroiditis cannot be administered to women who are breastfeeding. In cases where the underlying cause of thyrotoxicosis is not clearly evident, it may be prudent to monitor thyroid function test profiles over time to see if there is a progressive decline in T4 and T3 levels consistent with resolving postpartum thyroiditis. Treatment with beta blockers may help to relieve thyrotoxic symptoms. Agents commonly used in this setting include atenolol at doses of 25–100 mg daily and long-acting propranolol at doses of 60–120 mg daily. Hypothyroidism that is noted to develop after delivery may progress to become severe enough to warrant treatment with supplemental thyroid hormone. Doses of levothyroxine targeted to provide adequate replacement can be prescribed as a temporizing measure. Once treatment has been started, it may need to be halted at a later date to definitively determine whether there has been recovery of normal thyroid function. Milder cases can be tracked over time without any intervention to determine whether they resolve or progress to states of permanent hypothyroidism.

palpable thrill. Deep tendon reflexes are noted to be hyperdynamic. Lab tests reveal a TSH level ⬍ 0.02 mIU/l, a free T4 level of 2.5 ng/dl, and a T3 level of 265 ng/dl (normal range 80–200 ng/dl). An antithyroid peroxidase antibody level is elevated at 1251 IU/ml. The patient is provisionally diagnosed with postpartum thyroiditis and is started on treatment with atenolol at a dose of 50 mg daily. Her palpitations subside over the course of several days. Serial thyroid function tests checked over the course of the next six months demonstrate gradual resolution of thyrotoxicosis with subsequent progression from a euthyroid state marked by a TSH level of 3.7 mIU/l to a hypothyroid state marked by a TSH level of 17.4 mIU/l and a free T4 level of 0.3 ng/dl. Atenolol is stopped and the patient is started on levothyroxine at a dose of 75 μg daily. This is continued for another 3 months until lab tests demonstrate a normalized TSH level. Levothyroxine is held, and lab tests checked at 2 and 6 month intervals reveal normal TSH and free T4 levels.

categories associated with an increased risk of hypothyroidism be screened by measurement of TSH levels prior to planned conception.5 Factors identified as associated with an increased risk of hypothyroidism include a personal or family history of a confirmed thyroid disorder, a history of infertility or miscarriage, a history of generalized

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or specific autoimmunity, and the presence of any symptoms or signs consistent with thyroid autoimmunity or functional thyroid disorders. Women who have been diagnosed with subclinical or overt hypothyroidism prior to conception should be started on treatment with levothyroxine at doses targeted to provide adequate replacement. Levothyroxine is available in a number of different brand and generic preparations formulated as color-coded tablets that provide a range of graded doses between 25 and 300 μg. While there has been some debate regarding the methods used to assess the bioequivalence of generic preparations, to date there have not been any studies documenting adverse outcomes associated with the use of different types.25,26 Overt hypothyroidism usually requires treatment with full replacement doses of levothyroxine that can be estimated to provide 0.8 μg/kg daily. Subclinical hypothyroidism can usually be treated with lower starting doses in the range of 25–50 μg daily. Doses should be adjusted at 4–6 weeks intervals based on measurement of serial thyroid function tests. Some experts have recommended that doses be adjusted to maintain TSH levels between 0.5 and 2.5 mIU/l based on the distribution of values in normal subjects. To date there have not been any rigorous studies that have evaluated the relative benefits of different target ranges of thyroid hormone replacement prior to conception. Studies have estimated that up to 2.5% of pregnant women may present with undiagnosed hypothyroidism at the time of conception.16 Confirmation of a suspected diagnosis is based on documentation of a TSH level greater than the upper limit of the reference range. It has been suggested that a TSH level lower than the usual designated upper limit of the reference range should be used to identify women who may benefit from treatment with levothyroxine during pregnancy, though data supporting this assertion are limited.27 Subsequent measurement of free T4 levels can help to distinguish between subclinical hypothyroidism (associated with normal range free T4 levels) and overt hypothyroidism (associated with low free T4 levels). Total T4 and T3 levels may be difficult to interpret in this setting due to changes in thyroxinebinding globulin levels that occur during early gestation. Inadequate treatment of overt and subclinical hypothyroidism during pregnancy has been associated with an increased risk of miscarriage and preterm delivery.28 The risk of preterm delivery appears to be higher in the setting of inadequately treated overt hypothyroidism. Other complications linked to overt hypothyroidism during pregnancy include increased rates of maternal anemia, preeclampsia, fetal distress, placental abruption, low birth weight and postpartum hemorrhage.29,30,31 Undiagnosed or inadequately treated hypothyroidism during pregnancy may have a significant impact on fetal neurologic development. A landmark study that retrospectively identified women who

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had been hypothyroid during pregnancy reported significant decrements in the IQ scores of their children compared to normal controls.32 A key observation noted in this study was that none of these children had been diagnosed with hypothyroidism during neonatal screening, lending credit to the notion that adequate maternal thyroid hormone stores are needed to support normal growth and development of the cerebral cortex during early stages of gestation.33 While these results were compelling in their own right, they did not appear to have a substantial impact on the debate regarding recommendations for universal screening of pregnant women for thyroid dysfunction. Thyroid hormone replacement requirements may increase to varying degrees throughout the course of pregnancy.34 Standing doses of levothyroxine may have to be augmented by up to 50% to provide enough thyroid hormone to occupy the greater number of binding sites generated through production of increased quantities of thyroxine-binding globulin distributed in an expanding plasma volume. Some experts recommend that doses of levothyroxine be reflexively augmented and administered in double or triple doses for a brief period as soon as pregnancy is confirmed to avoid precipitation of hypothyroidism that may impact fetal neurologic development. Others recommend a more conservative approach to adjustment based on serial measurement of thyroid function tests.26 Current guidelines recommend that doses of levothyroxine be adjusted to maintain TSH levels between 0.5 and 2.5 mIU/l during the first trimester and 0.5 and 3.0 mIU/l during the second and third trimesters.5 Repeat thyroid function tests should be measured at least 4 weeks after an adjustment is made to allow for equilibration to a steady state. Women who are taking iron supplements to treat anemia during pregnancy should be cautioned to separate them from doses of levothyroxine by at least 4 hours to avoid problems with impaired absorption of thyroid hormone.35 In most cases the quantity of iron incorporated in prenatal vitamins is not high enough to significantly affect absorption of thyroid hormone.26 Treatment with desiccated thyroid hormone and preparations or combinations that incorporate triiodothyronine should be avoided during pregnancy. The rapid action and short half-life of exogenous T3 may lead to artifactual suppression of TSH levels that may make it difficult to assess true thyroid hormone requirements. After delivery, thyroid hormone replacement requirements may rapidly decline to pre-pregnancy levels. In most cases women can safely be shifted back to prior standing doses of levothyroxine without difficulty. In situations where women have gained a substantial amount of weight during pregnancy, it may be prudent to gradually reduce doses based on measurement of thyroid function tests. The same precautions for separation of doses apply to women who need to take iron supplements after delivery to correct postpartum anemia.

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CASE 3 A 29-year-old G1P0 female with a history of treated hypothyroidism presents for evaluation after recent confirmation of pregnancy. She is estimated to be at 9 weeks gestation per dating based on her last menstrual period. She was originally diagnosed with hypothyroidism at age 19 when lab tests checked to evaluate persistent fatigue revealed an elevated TSH level and low total T4 level. She has been treated with levothyroxine with varying dose requirements. For several years she was stably maintained on a dose of 175 μg daily while taking an estrogen-containing oral contraceptive. Shortly after ceasing this oral contraceptive she developed thyrotoxic symptoms. Her dose was reduced to 137 μg daily after lab tests revealed a suppressed TSH level. She has continued to take this dose since with some intermittent episodes of non-adherence. Physical examination reveals a resting heart rate of 92 beats per minute. Examination of the thyroid reveals a minimal amount of atrophic tissue. Deep tendon reflexes show normal terminal phase relaxation. Lab tests reveal a TSH level of 7 mIU/l with

Hyperthyroidism The diagnosis and management of thyrotoxicosis identified during pregnancy may be complicated by the fact that (a) physiologic changes that occur during the first trimester may produce manifestations that are indistinguishable from autoimmune-mediated hyperthyroidism, (b) radionuclide agents commonly used to assess and treat hyperthyroidism are contraindicated during pregnancy, and (c) inadequate treatment of hyperthyroidism may have a negative impact on maternal and fetal outcomes.36 A majority of women who present with thyrotoxicosis ascribed to hyperthyroidism that is confirmed prior to conception or after delivery eventually prove to have underlying Graves’ disease. Measures taken to evaluate thyrotoxicosis in women of reproductive age may vary depending on expressed wishes regarding the timing of desired fertility. In cases where women are not planning to conceive in the near future and are actively practicing contraception, radionuclide agents can safely be used to (a) perform thyroid uptake studies to distinguish between hyperthyroidism and non-hyperthyroid thyrotoxicosis, and (b) obtain scan images to delineate specific underlying causes of hyperthyroidism. In cases where women are actively attempting to conceive within a specific time frame, the risks of potential fetal exposure to radionuclide agents may preclude use of these studies. Evaluation in this setting may rely on clinical assessment to distinguish between potential underlying causes of hyperthyroidism. Physical examination findings regarded as more specific for underlying Graves’ disease include goitrous enlargement of the thyroid with a palpable thrill or audible bruit indicative

a free T4 level of 0.6 ng/dl. The patient’s dose of levothyroxine is increased to 150 μg daily, and the importance of regular adherence with treatment is emphasized. Repeat lab tests checked 4 weeks later reveal a TSH level of 8.3 mIU/l. The patient’s dose of levothyroxine is increased to 175 μg daily. Repeat lab tests checked 5 weeks later reveal a TSH level of 7.6 mIU/l. When the patient is contacted to confirm adherence with treatment, she reports that she was diagnosed with anemia and has been started on treatment with ferrous sulfate tablets that she has been ingesting at the same time as her daily dose of levothyroxine. She is instructed to separate her doses of levothyroxine and ferrous sulfate by taking one in the morning and the other at bedtime. Lab tests checked after 4 weeks on this regimen reveal a TSH level of 2.1 mIU/l. The patient continues on the same doses throughout the course of her pregnancy with serial lab tests demonstrating adequate thyroid hormone replacement. After delivery, her dose of levothyroxine is immediately reduced to 150 μg daily. Lab tests checked 4 months after delivery reveal a TSH level of 1.4 mIU/l and a hemoglobin of 13.4 g/dl.

of increased blood flow, periorbital or infraorbital inflammatory changes consistent with thyroid eye disease, and dermopathic changes consistent with pretibial myxedema. In the absence of any of these findings, focal enlargement of the thyroid confirmed to represent a solitary nodule on ultrasound may be consistent with an emerging toxic adenoma. Strategies for the treatment of hyperthyroidism prior to conception vary depending on the putative underlying cause and the degree to which thyroid hormone levels are noted to increase. Suspected toxic adenomas associated with any degree of overt hyperthyroidism can be definitively treated by surgical means via targeted nodulectomy or hemithyroidectomy. Suspected Graves’ disease associated with moderate to severe overt hyperthyroidism can be treated with the same regimens of antithyroid drugs recommended for use during pregnancy. When hyperthyroidism is identified during pregnancy, the principal questions that must be addressed are (a) whether it is more likely to reflect persistent or emerging Graves’ disease or the sequela of exaggerated physiologic changes that occur during the first trimester, and (b) whether the potential risks of treatment outweigh the benefits in either case. The emergence of autoimmune hyperthyroidism ascribed to Graves’ disease during pregnancy is thought to be a relatively rare event, complicating less than 0.01% of pregnancies in developed countries.3 By way of contrast, exaggerated physiologic changes that lead to transient hyperthyroidism during the first trimester may be detectable in up to 3% of all pregnancies.37 There appears to be significant geographic variation in the presentation of these changes that is not

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explained by differences in iodine sufficiency or underlying rates of pre-existing thyroid disorders. This form of hyperthyroidism, formally identified as gestational thyrotoxicosis or gestational transient thyrotoxicosis, appears to be precipitated by excessive stimulation of normal functioning thyroid tissue mediated by hCG produced and secreted by the embryo and placenta during gestation.38,39 It has yet to be determined whether this excessive stimulation is predominantly caused by the secretion of abnormally high levels of normal hCG or the production of variant forms that demonstrate greater affinities for thyroid tissue.27 Comparisons between singleton and twin pregnancies have demonstrated that higher extended peak hCG levels measured in twin pregnancies appear to be associated with higher transient increases in free T4 levels and reflexive suppression of TSH levels. Gestational thyrotoxicosis has frequently been noted to develop in tandem with hyperemesis gravidarum, a condition characterized by excessive nausea and vomiting during pregnancy that leads to weight loss of greater than 5%.39 Up to 50% of pregnant women presenting with hyperemesis gravidarum may have evidence of gestational thyrotoxicosis based on measurement of TSH and thyroid hormone levels.40 In cases tracked over time, it appears that the relative severity of each of these conditions may vary in proportion to quantitative changes in hCG levels.41 Hydatidaform moles, gestational trophoblastic tumors, and choriocarcinomas that secrete markedly elevated levels of hCG in an unregulated fashion may also present with physical and biochemical manifestations of gestational thyrotoxicosis.42 Thyrotoxicosis during pregnancy may first be suspected when a woman presenting for prenatal evaluation reports problems with symptomatic palpitations, tremulousness, or excessive fatigue in the absence of sleep disturbances or significant anemia. Suspicion of underlying thyroid dysfunction may also be raised by documentation of weight loss tracked during the course of gestation or by identification of an enlarged thyroid on physical examination. Laboratory testing that reveals a TSH level below the normal limit of the reference range will confirm exposure to excessive levels of thyroid hormone consistent with thyrotoxicosis. Documentation of concomitant free thyroid hormone levels will help to distinguish between subclinical and overt thyrotoxicosis, and may provide some clues to suggest an underlying etiology. Measurement of total thyroid hormone levels is often less informative in this setting, as hyperthyroxinemia may be anticipated to develop as a normal occurrence during early gestation. Normal or mildly elevated free thyroid hormone levels are more consistent with gestational thyrotoxicosis or mild Graves’ disease, while markedly elevated free thyroid hormone levels in the absence of hyperemesis gravidarum are more consistent with moderate to severe Graves’ disease. While inflammation of the thyroid rarely occurs during pregnancy, the possibility that autoimmune or subacute thyroiditis could be precipitating non-hyperthyroid thyrotoxicosis should be considered, especially when there

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is identification of focal pain or tenderness localized to the thyroid itself. Measurement of antithyroid antibody levels can help to ascertain the likelihood of underlying autoimmune thyroiditis. Care must be taken in interpreting the significance of elevated antithyroid peroxidase or antithyroglobulin antibody levels, as both may be found in cases of Graves’ disease. While it might be expected that measurement of thyroid-stimulating immunoglobulin levels would be a direct means of identifying Graves’ disease, in practice this test has not proven to be sensitive enough to confirm a suspected diagnosis.43 While markedly elevated levels may provide supporting evidence to establish a suspected diagnosis, normal range levels are often seen in cases presenting with florid hyperthyroidism. The true value of this test may lie in establishing a baseline during early pregnancy that can be compared to later values to assess the risk of development of neonatal Graves’ disease. Elevated quantitative hCG levels may be associated with an increased likelihood of gestational thyrotoxicosis, particularly in the setting of hyperemesis gravidarum. Markedly elevated hCG levels identified in tandem with a pelvic ultrasound that fails to locate a normal intra-uterine pregnancy should prompt evaluation for gestational neoplastic disease. Nuclear studies are contraindicated during pregnancy due to the potential risk of damage to the developing fetal thyroid. Ultrasonography may help to define the extent of any palpable or suspected nodularity, but it is limited in its ability to delineate the functional status of any abnormalities identified on imaging. A thyroid ultrasound that reveals a markedly enlarged dominant nodule may suggest the presence of a possible toxic adenoma, but could also be representative of a non-functioning nodule in the setting of gestational thyrotoxicosis or Graves’ disease. Determination of whether a suppressed TSH level detected during pregnancy represents the effects of gestational thyrotoxicosis or Graves’ disease is almost entirely based on clinical assessment, and as such should be relegated to specialists who are experienced at discerning subtle findings associated with Graves’ disease and its attendant complications. Examination of the thyroid itself can be misleading, as a certain degree of mild enlargement may occur as part of the normal adaptation to pregnancy.44 Marked goitrous enlargement of the thyroid with a definable pyramidal lobe, palpable thrill, or audible bruit is more likely to be consistent with Graves’ disease. Findings consistent with thyroid eye disease associated with Graves’ disease may include scleral injection, conjunctival chemosis, periorbital swelling, measurable proptosis, and disconjugate extraocular motion.45 Orbital ultrasound can be used to measure the diameter and density of extraocular muscles without exposure to ionizing radiation. Dermopathic changes consistent with pretibial myxedema may present as pruritic, orange peel-like thickening of the skin along the anterior aspects of the shins. The dorsal aspects of the feet and fingers, the extensor surface of the elbows, and the face can also be affected.

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CASE 4 A 22-year-old G2P0 female presents for evaluation of possible hyperthyroidism. She is estimated to be at 11 weeks gestation based on a recent fetal ultrasound. Her pregnancy has been complicated by morning sickness that has progressed to become severe enough to compromise nutritional intake. She has lost 7 lb over the course of the past 2 weeks, and was noted to be tachycardic and mildly orthostatic at the time of her last prenatal visit. Lab tests revealed a TSH of 0.15 mIU/l, a total T4 level of 11.9 μg/dl (normal 4.5–11.5 μg/dl), a free T4 level of 0.9 ng/dl, and a potassium level of 3.2 meq/l. She does not report any antecedent history of significant weight loss, symptomatic palpitations, or ocular irritation. Physical examination reveals a resting heart rate of 88 beats per minute with an orthostatic drop in systolic blood pressure If a case of thyrotoxicosis during pregnancy is thought to represent hyperthyroidism ascribed to Graves’ disease, the ultimate decision regarding whether and how to initiate treatment should be based on a considered assessment of the severity of the condition and the potential risks associated with unchecked progression. Untreated hyperthyroidism during pregnancy has been correlated with a higher risk of a range of adverse outcomes including preeclampsia, premature delivery, and low birthweight.36 The prohibition against the use of radioactive iodine during pregnancy effectively limits the range of treatment options to (a) medical therapy with antithyroid drugs, or (b) surgical resection of thyroid tissue. Methimazole and propylthiouracil (PTU) are thionamide agents that act to inhibit thyroid hormone biosynthesis by competitively blocking the organification and coupling of iodotyrosine in thyroid tissue. While methimazole is generally recognized as the preferred agent for the treatment of hyperthyroidism in most situations due to its once-daily dosing schedule and titratability, there have been documented cases of gastrointestinal embryopathy and a fetal scalp defect known as aplasia cutis associated with its use during pregnancy.46,47 Current guidelines recommend that PTU be used as a first line agent to treat hyperthyroidism during pregnancy, as it demonstrates lower rates of transplacental passage and is not known to be associated with any congenital defects.5 Prescribed doses of PTU usually range from 25 mg twice daily to 100 mg three times daily. The most common

CASE 5 A 25-year-old G0P0 female with a history of Graves’ disease presents for preconception planning. She was originally diagnosed at age 21 after presenting with weight loss, anxiety, and goitrous enlargement of her

of 8 mmHg. There is no proptosis or scleral injection. Examination of the thyroid reveals mild bilateral enlargement with a lobular texture. There are no areas of discrete nodularity or tenderness, There is no palpable pyramidal lobe or audible bruit. There are no skin changes suggestive of pretibial myxedema. A clinical diagnosis of gestational thyrotoxicosis appears to be likely, and a decision is made to monitor the patient’s status while she starts on treatment with supplemental enteral nutrition and antiemetic agents. Lab tests checked after 2 weeks of treatment with ondansetron and enteral nutrition administered via a nasoduodenal tube reveal a TSH level of 0.5 mIU/l and a free T4 level of 1.1 ng/dl. Her nausea subsides over the course of the next 4 weeks to the point where she is able to resume unsupported intake. Lab tests checked at subsequent 1, 4, and 6 month intervals reveal persistently normal TSH and free T4 levels. side effect associated with use that may occur in up to 5% of treated patients is development of a diffuse pruritic rash that necessitates discontinuation. Other common side effects include fevers and arthralgias. In cases where side effects prove to be limiting, methimazole may be tried as an alternative. Agranulocytosis and hepatitis are rare but potentially fatal adverse reactions that may occur with treatment with either agent. While there is no evidence that routine monitoring of white blood cell counts and transaminase levels prevents these complications, they should be checked if a patient develops a fever, pharyngitis, abdominal pain, or jaundice, particularly while on treatment with doses of PTU that exceed 300 mg daily or doses of methimazole that exceed 20 mg daily. Doses should be adjusted at 2–4 week intervals to maintain free T4 levels close to the upper limit of the reference range to avoid treatment-induced hypothyroxinemia that could impair fetal neurologic development.48 Block-and-replace regimens that combine suppressive doses of antithyroid drugs with doses of levothyroxine adjusted to provide replacement should be avoided during pregnancy. The progressive amelioration of autoimmunity that occurs during the second and third trimesters of pregnancy may attenuate hyperthyroidism precipitated by antibody-mediated stimulation of thyroid tissue. When this phenomenon is noted to occur, doses of antithyroid drugs may need to be tapered downward or discontinued to avoid treatmentinduced hypothyroxinemia.

thyroid. Lab tests revealed indices consistent with thyrotoxicosis. A thyroid uptake and scan study performed at that time revealed elevated 24 hour uptake with diffuse distribution of tracer consistent with Graves’ disease. The patient elected to pursue treatment with antithyroid drugs, and has been maintained on methimazole (Continued)

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CASE 5

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continued

at doses ranging from 5 mg daily to 20 mg daily. She is currently taking 10 mg daily with good adherence. Physical examination reveals mild bilateral proptosis with conjugate extraocular motion. The thyroid is noted to be slightly enlarged with a palpable pyramidal lobe and a firm grainy texture. Lab tests reveal a TSH level of 1.1 mIU/l, a free T4 level of 1.0 ng/dl, and a T3 level of 136 ng/dl. A decision is made to transition the patient to PTU at a dose of 25 mg twice daily. This dose is increased to 50 mg twice daily after 4 weeks when repeat lab tests reveal a TSH level of 0.07 mIU/ l. Subsequent lab tests while on this dose reveal TSH levels ranging between 0.7 and 2.8 mIU/L. The patient successfully conceives after 7 months of treatment. Serial thyroid function tests are checked at monthly While surgical resection of thyroid tissue is usually considered to be an option of limited resort, it may be considered as a means of treating Graves’ disease during pregnancy when patients manifest severe adverse reactions that preclude ongoing treatment with antithyroid drugs. Surgery may also be considered as an immediate measure to definitively control severe hyperthyroidism that may jeopardize the viability of the fetus or health of the mother if left unchecked. When possible, surgery should be delayed until the second trimester to limit the risk of spontaneous abortion associated with general anesthesia.49 Subtotal thyroidectomy targeted to resect enough functioning thyroid tissue to control hyperthyroidism is considered to be the procedure of choice in this setting. Controversy exists regarding the optimal amount of tissue that should be removed during subtotal thyroidectomy. Proponents of near-total resection point to the risk of recurrence associated with leaving enough tissue in place to promote euthyroid function.50 Pre-treatment with iodine administered as five drops of a saturated solution of potassium iodide twice daily for may help to lower the risk of intraoperative complications by reducing the vascularity of the thyroid prior to resection. Thyroid function tests must be tracked closely at regular intervals following surgery to determine when there is progression to a euthyroid or hypothyroid state. Transplacental passage of maternal thyroid-stimulating immunoglobulins can lead to stimulation of developing thyroid tissue that promotes goitrous enlargement of the fetal

CASE 6 A 24-year-old female is hospitalized after presenting with delirium and dehydration. She is noted to have a resting heart rate of 140 beats per minute that persists after administration of isotonic intravenous fluids. She reports a four month history of secondary amenorrhea and a three week

intervals during pregnancy. PTU is withheld and then discontinued in the fifth month of gestation after successive lab tests demonstrate TSH levels greater than 4.0 mIU/l. A thyroid-stimulating immunoglobulin activity level checked during the second trimester is noted to be mildly elevated at 164% (normal ⬍125%). Fetal ultrasounds performed during the third trimester reveal normal range heart rates and growth parameters without any evidence of goitrous enlargement of the thyroid. The patient delivers via cesarean section 5 days after her estimated due date without any intrapartum or postpartum complications. Lab tests checked 3 months after delivery reveal a TSH level of 0.03 mIU/l and a free T4 level of 2.2 ng/dl. The patient elects to resume treatment with methimazole at her previous standing dose. thyroid while inducing a state of hyperthyroidism. This complication may occur in up to 10% of pregnancies impacted by Graves’ disease.51 Relative changes in maternal thyroidstimulating immunoglobulin levels may provide a rough index of the risk of developing fetal and neonatal hyperthyroidism. Current guidelines recommend that levels be checked either prior to conception or by the end of the second trimester in cases of known or suspected Graves’ disease.5 A finding of elevated levels should prompt obstetric evaluation with high resolution fetal ultrasound focused on searching for evidence of increased motility, persistent tachycardia, growth retardation, or goitrous enlargement of the fetal thyroid. In very rare instances where confirmation of a diagnosis of fetal hyperthyroidism might significantly impact the management of a pregnancy, fetal thyroid hormone levels can be measured via cord blood sampling. Findings at birth that suggest the presence of neonatal Graves’ disease include goitrous enlargement of the thyroid, persistent tachycardia, and hyperirritability. Cord blood samples that demonstrate suppressed TSH levels in combination with elevated free T4 levels will confirm a suspected diagnosis. Management in most cases is expectant, as the hyperthyroidism usually resolves over time as a result of gradual degradation of maternal thyroidstimulating immunoglobulins. Severe cases complicated by congestive heart failure or weight loss may require brief courses of treatment with antithyroid drugs, iodine, and glucocorticoids to curtail the effects of thyrotoxicosis.

history of progressive weight loss, symptomatic palpitations, anxiety, insomnia, and nausea with recurrent emesis. A urine hCG test is noted to be positive, and pelvic ultrasound confirms an intra-uterine pregnancy of uncertain gestational age. Physical examination reveals a marked stare with bilateral lid lag. Examination of the thyroid reveals visible and palpable goitrous enlargement with an audible (Continued)

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bruit and palpable thrill. Auscultation of the chest reveals tachycardia with a distinct S4. Deep tendon reflexes are noted to be hyperdynamic. A pronounced resting tremor is evident. Lab tests reveal a TSH level ⬍0.02 mIU/l, a free T4 level of 6.3, a total T4 level of 22.7 μg/dl, and a T3 level of 536 ng/dl. Thyroid ultrasound reveals significant enlargement of both lobes with diffuse hypervascularity consistent with Graves’ disease. No discrete nodules are evident. The patient is started on treatment with propranolol at a dose of 20 mg three times daily and PTU at a dose of 100 mg three times daily. She develops a diffuse pruritic urticarial rash on her chest and upper extremities after the second day of treatment. This resolves over the course of 48 hours after PTU is withheld. Methimazole is then started at an initial dose of 40 mg daily, but must be withheld after the patient develops recurrence of the

In cases of mild thyrotoxicosis during pregnancy where there are not obvious finding consistent with the stigmata of Graves’ disease, it may be difficult if not impossible to determine whether the changes noted are caused by mild Graves’ disease or gestational thyrotoxicosis. Tracking serial thyroid function test profiles over time may not prove to be informative, as both conditions may gradually remit with the progression of gestation. Expectant approaches to management usually focus on holding off on initiation of treatment with antithyroid drugs unless there is definitive evidence of increasing or persistently elevated thyroid hormone levels, markedly elevated thyroid-stimulating immunoglobulin levels, or radiographic findings consistent with fetal hyperthyroidism. In cases where mild thyrotoxicosis remits during pregnancy, it may be necessary to wait until after delivery to determine if underlying Graves’ disease is present. The potentiation of autoimmunity that occurs in tandem with declines in progesterone levels after delivery may lead to a significant exacerbation of underlying Graves’ disease. Care must be taken to distinguish hyperthyroidism associated with an exacerbation of Graves’ disease from thyrotoxicosis associated with the onset of postpartum thyroiditis, as the presenting manifestations of both conditions may be strikingly similar. The potential for concentration of radionuclide tracers in breast milk limits the utility of functional studies in this setting. When a mother is not breastfeeding, a thyroid uptake study may help to distinguish between these two conditions. Otherwise, diagnosis and planning for monitoring and treatment may rest on clinical grounds.

Thyroid nodules and thyroid cancer Palpable thyroid nodules may become more apparent during pregnancy. In part this may be due to the growth of existing

rash associated with abdominal discomfort and migratory arthralgias. A decision is made to proceed with subtotal thyroidectomy. Propranolol is continued and the patient is treated with saturated solution of potassium for three days prior to surgery. She undergoes a subtotal thyroidectomy that is complicated by blood loss significant enough to require postoperative transfusion. Her thyroid hormone levels steadily decline after surgery, and she is started on levothyroxine at a dose of 75 μg daily when her free T4 level falls to 0.6 ng/dl. A thyroid-stimulating immunoglobulin activity level measured after surgery is elevated at 206%. Fetal ultrasound performed during the third trimester reveals visible enlargement of the thyroid. The patient delivers 2 weeks before her estimated due date. Her infant is of low birthweight, but does not manifest any findings consistent with hyperthyroidism.

thyroid nodules stimulated by increased iodide clearance and generalized enlargement of thyroid tissue that occurs during gestation.52 The increased frequency of clinical encounters associated with adequate prenatal care may also have some bearing on the rate at which existing or new thyroid nodules are detected on physical examination. Any focal enlargement in the lower anterior region of the neck suspected to represent a thyroid-based mass in a pregnant woman should be evaluated with a dedicated thyroid ultrasound.53 Specific attention should be paid to delineation of the dimensions and characteristics of any discrete thyroid nodules or abnormal appearing cervical lymph nodes. Decisions regarding the need to consider sampling via fine needle aspiration biopsy should be based on estimates of the risk of potential malignancy. Historical factors linked to an increased risk of malignancy include a history of mantle irradiation for treatment of childhood lymphoma or a family history of disorders associated with multiple endocrine neoplasia type 2 or familial medullary thyroid cancer. Symptoms that may suggest invasion of structures in the lower anterior region of the neck include dysphagia, dysphonia, dyspnea, odynophagia, and hemoptysis. Findings on physical examination that may be particularly concerning include detection of a firm nodule that is fixed in place with associated ipsilateral cervical lymphadenopathy or vocal cord paresis. Radiographic features of thyroid nodules and cervical lymph nodes discernible on ultrasound that may be associated with an increased risk of malignancy include punctuate microcalcifications and irregular margins. In most cases the size of an identified nodule will prove to be the principal factor that guides decisions regarding sampling. Aggregate guidelines recommend that sampling be considered to evaluate (a) nodules that are clearly visible or palpable, (b) non-palpable nodules that are greater

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than 1–1.5 cm in maximal diameter, and (c) non-palpable nodules or cervical lymph nodes that demonstrate radiographic features associated with an increased risk of malignancy.54,55 Fine needle aspiration biopsy of a thyroid nodule is a low-risk procedure that has proven to be a sensitive means of identifying lesions suspicious for malignancy. In most cases it can be performed on an outpatient basis with little or no local anesthesia. The use of ultrasound to guide sampling helps to increase the yield of fine needle aspiration, and is often a necessary measure when attempting to biopsy non-palpable nodules.56 Samples that return an adequate amount of cytologic material can be distinctly categorized as benign, malignant, indeterminate, or inadequate.57 An inadequate cytopathologic designation should prompt a second attempt at sampling with ultrasound guidance to see if a diagnostic yield of material can be obtained. Nodules that are clearly benign and have not enlarged to the point of causing any compressive symptoms can be safely observed and monitored. A repeat thyroid ultrasound checked at an interval after delivery can help to determine whether there has been regression of a benign nodule. In the rare instance where an enlarging benign nodule is noted to cause significant dysphagia or dyspnea during pregnancy, surgical resection might be considered, though the prospective benefits of intervention would have to be weighed carefully against the potential risks of anesthesia.

CASE 7 A 33-year-old G3P2 female presents for evaluation of a thyroid nodule. She is currently at 18 weeks gestation. A visible and palpable left-sided thyroid nodule was noted during her last prenatal visit. Lab tests revealed a TSH level of 34 mIU/l. A thyroid ultrasound revealed a discrete 3.5 cm clearly marginated hypoechoic nodule in the left lobe with focal calcifications and increased central blood flow. There was no evidence of any suspicious lymphadenopathy. The patient does not report any history of head or neck radiation exposure. She has been experiencing some reflux symptoms during her pregnancy, but has not experienced any oropharyngeal dysphagia, dysphonia, or compressive symptoms in her neck while lying recumbent. Physical examination reveals a firm rounded nodule in the left lobe of the thyroid without any tracheal deviation or stridor. Ultrasound-guided fine

When a sampled thyroid nodule is determined to represent a focus of malignancy, plans for management may vary depending on (a) the point in the course of gestation at which it has been identified, (b) the specific type of malignancy, and (c) the estimated stage of disease at the time

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Although the criteria used to classify indeterminate samples are subject to debate, this cytopathologic designation usually indicates that there is a 15–20% chance that an indetermina nodule represents a malignancy.58 Accurate diagnosis requires excision to allow for pathologic evaluation of the perimeter of the lesion to determine whether there is evidence of invasion consistent with malignancy. Strategies targeted to stratify risk based on the extent to which levothyroxine suppression therapy impedes growth have proven to be of limited utility. A radionuclide scan that helps to determine whether a nodule is autonomously functioning (and therefore more likely to be benign) could help to stratify risk, but this option is not available for use during pregnancy. While the usual course of action would be to consider a hemithyroidectomy for diagnostic purposes or a total thyroidectomy to excise a potential malignancy, most experts recommend a more conservative approach when an indeterminate nodule is identified in the setting of pregnancy.5 The limited proportionate risk of malignancy coupled with the knowledge that most malignancies that are identified tend to be of early stage favors a more judicious course of observation. Serial thyroid and neck ultrasounds can be checked during the course of pregnancy to monitor the size and appearance of an indeterminate nodule. In the absence of significant enlargement, changes concerning for invasive growth, or evidence of possible metastatic involvement of cervical lymph nodes, definitive evaluation via surgical resection can be safely deferred until after delivery.

needle aspiration biopsy of the nodule returns an adequate specimen comprised of clusters of follicular cells and sparse dense colloid identified as consistent with an indeterminate follicular neoplasm. A decision is made to continue to monitor the status of this nodule without direct intervention. Serial ultrasounds checked throughout the course of pregnancy reveal progressive enlargement of the nodule to a maximum diameter of 5.2 cm. The patient develops some intermittent dysphagia to solids that requires modification of her diet. The enlargement is noted to persist after delivery. A thyroid scan performed 5 months later when the patient has stopped breastfeeding reveals a cold deficit in the region of the left thyroid nodule. The patient undergoes an uncomplicated left hemithyroidectomy. The pathology of the resected specimen is consistent with a benign follicular adenoma. Subsequent thyroid function tests do not reveal any evidence of postsurgical hypothyroidism.

of presentation. The vast majority of malignancies identified in palpable thyroid nodules in women of reproductive age represent early stage papillary thyroid carcinomas that carry a favorable prognosis after complete surgical excision. The slow growth rate of this form of differentiated thyroid

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carcinoma has led most experts to conclude that it is may be prudent to wait until after delivery before proceeding with surgical resection.5 Studies that have tracked the course of differentiated thyroid carcinomas identified during pregnancy have shown that while there may be growth of these tumors during gestation, there is no evidence of progression to a later stage when they are left in place until after delivery.59 The resultant offset in the timing of radioactive iodine treatment that may occur does not appear to have any impact on rates of persistence or recurrence of disease. Current guidelines recommend that women diagnosed with thyroid cancer during pregnancy who choose this course of action be treated with thyroid hormone administered in doses targeted to suppress TSH levels to subnormal ranges.54 Surgery to resect an identified thyroid malignancy during pregnancy may be considered in particular circumstances. When medullary thyroid cancer is diagnosed during pregnancy, a total thyroidectomy and central neck dissection (along with lateral neck dissection as needed) may be considered as soon as surgery is deemed to be feasible, particularly if there is evidence of extensive cervical lymph node metastases. In such a case plasma and urine catecholamine

CASE 8 A 27-year-old G1P0 female presents for evaluation of a self-identified neck mass. She is currently at 12 weeks gestation, and first palpated a mass on the right side of her neck two weeks ago when putting on a necklace. She has a history of stage II Hodgkin’s disease that was diagnosed at age 11 and treated with mantle radiation. She has never undergone any anatomic imaging of her thyroid. She has not experienced any oropharyngeal dysphagia or dysphonia. Physical examination reveals a firm fixed nodule in the right lobe of the thyroid without any stridor. Lab test reveal a TSH level of 4.2 mIU/l. Fine needle aspiration biopsy of the nodule performed under direct palpation returns a sample comprised of abnormal enlarged follicular cells with nuclear grooves and inclusions consistent with papillary thyroid carcinoma. A thyroid ultrasound reveals a solitary right upper pole nodule and an enlarged right level IV lymph node. Ultrasound guided fine needle aspiration biopsy of this node reveals benign lymphoid tissue. The patient elects to defer surgery until

metabolites should be measured to screen for a pheochromocytoma that may signal the presence of unrecognized multiple endocrine neoplasia. Calcitonin and carcinoembryonic antigen levels should also be checked as baseline tumor markers prior to surgery. Expedient total thyroidectomy and neck dissection may also be considered during pregnancy in cases of papillary thyroid carcinoma that present with clinical features consistent with direct invasion, radiographic findings suggesting local spread, or confirmed evidence of cervical lymph node metastases. When surgery proves to be necessary, procedures should be timed to occur during the second trimester if feasible. Calcium levels should be monitored carefully after surgery to check for evidence of postsurgical hypoparathyroidism that may require treatment with calcium supplements and vitamin D analogs. Radioactive iodine treatment utilizing I131 to ablate any residual thyroid carcinoma or thyroid tissue must be delayed until after delivery. In situations where mothers elect to breastfeed after delivery, treatment must be delayed until an even later interval due to concerns that radioactive iodine may be taken up and concentrated in engorged breast tissue, limiting delivery to sites that require active treatment.

after delivery. She is started on levothyroxine at an initial dose of 112 μg daily. This is titrated to maintain a TSH level ⬍ 1.5 mIU/l throughout the remainder of her pregnancy. Serial thyroid ultrasounds reveal stable dimension of the focus of papillary thyroid carcinoma. The patient undergoes a total thyroidectomy 6 weeks after delivery. The pathology of the resected specimen reveals multifocal papillary thyroid carcinoma with marginal extension. There is no evidence of extrathyroidal spread or metastases to cervical lymph nodes. The patient elects to breastfeed for a span of 6 months. At the end of that time, she completes a thyroid hormone withdrawal protocol and undergoes whole body radioactive iodine scanning. Survey images reveal foci of tracer uptake in the central neck with a significant amount of diffuse uptake in both breasts. The patient resumes treatment with levothyroxine for another three months, and then completes a second thyroid hormone withdrawal protocol. She is treated with a therapeutic dose of radioactive iodine after survey images show no sign of uptake in either breast.

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References 1. Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000;7:127–30. 2. Becks GP, Burrow GN. Thyroid disease and pregnancy. Med Clin North Am 1991;75:121–50. 3. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am 1997;26:189–218. 4. Glinoer D. The regulation of thyroid function during normal pregnancy: importance of the iodine nutrition status. Best Pract Res Clin Endocrinol Metab 2004;18:133–52. 5. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:S1–S47. 6. Dunn JT, Delange F. Damaged reproduction: the most important consequence of iodine deficiency. J Clin Endocrinol Metab 2001;86:2360–63. 7. Delange F, Burgi H, Chen ZP, Dunn JT. World status of monitoring iodine deficiency disorders control programs. Thyroid 2002;12:915–24. 8. Hershman JM. Role of human chorionic gonadotropin as a thyroid stimulator. J Clin Endocrinol Metab 1992;74:258–59. 9. Thorpe-Beeston JG, Nicolaides KH, Felton CV, Butler J, McGregor AM. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med 1991;324:532–36. 10. Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Alvarez-Marfany M, Davies TF. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990;264:1422–25. 11. Mariotti S, Caturegli P, Piccolo P, Barbesino G, Pinchera A. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990;71:661–69. 12. Glinoer D, Soto MF, Bourdoux P, et al. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions. J Clin Endocrinol Metab 1991;73:421–27. 13. Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 2003;9:149–61. 14. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006;91:2587–91. 15. Geenen V, Perrier de Hauterive S, Puit M, et al. Autoimmunity and pregnancy: theory and practice. Acta Clin Belg 2002; 57:317–24. 16. Glinoer D, Riahi M, Grun JP, Kinthaert J. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 1994;79: 197–204. 17. Gerstein HC. How common is postpartum thyroiditis? A methodologic overview of the literature. Arch Intern Med 1990;150:1397–400. 18. Amino N, Tada H, Hidaka Y. Postpartum autoimmune thyroid syndrome: a model of aggravation of autoimmune disease. Thyroid 1999;9:705–13.

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19. Premawardhana LD, Parkes AB, John R, Harris B, Lazarus JH. Thyroid peroxidase antibodies in early pregnancy: utility for prediction of postpartum thyroid dysfunction and implications for screening. Thyroid 2004;14:610–15. 20. Lucas A, Pizarro E, Granada ML, Salinas I, Foz M, Sanmarti A. Postpartum thyroiditis: epidemiology and clinical evolution in a nonselected population. Thyroid 2000;10:71–77. 21. Lazarus JH, Hall R, Othman S, et al. The clinical spectrum of postpartum thyroid disease. QJM 1996;89:429–35. 22. Othman S, Phillips DI, Parkes AB, et al. A long-term follow-up of postpartum thyroiditis. Clin Endocrinol (Oxf) 1990;32:559–64. 23. Lucas A, Pizarro E, Granada ML, Salinas I, Roca J, Sanmarti A. Postpartum thyroiditis: long-term follow-up. Thyroid 2005;15: 1177–81. 24. Thomas R, Reid RL. Thyroid disease and reproductive dysfunction: a review. Obstet Gynecol 1987;70:789–98. 25. Joint Statement on the US Food and Drug Administration’s decision regarding bioequivalence of levothyroxine sodium. Thyroid 14 (2004) 486. 26. Chopra IJ, Baber K. Treatment of primary hypothyroidism during pregnancy: is there an increase in thyroxine dose requirement in pregnancy? Metabolism 2003;52:122–28. 27. Werner SC, Ingbar SH, Braverman LE, Utiger RD. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text, 9th ed. Lippincott Williams & Wilkins, Philadelphia, PA. 28. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt, and subclinical hypothyroidism complicating pregnancy. Thyroid 2002;12:63–68. 29. Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol 1988;72:108–12. 30. Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol 1993;81:349–53. 31. Wasserstrum N, Anania CA. Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement. Clin Endocrinol (Oxf) 1995;42:353–58. 32. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549–55. 33. Kester MH, Martinez de Mena R, Obregon MJ, et al. Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. J Clin Endocrinol Metab 2004;89:3117–28. 34. Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990;323:91–96. 35. Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med 1992;117:1010–13. 36. Davis LE, Lucas MJ, Hankins GD, Roark ML, Cunningham FG. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989;160:63–70. 37. Glinoer D, De Nayer P, Robyn C, Lejeune B, Kinthaert J, Meuris S. Serum levels of intact human chorionic gonadotropin (HCG) and its free alpha and beta subunits, in relation to maternal thyroid stimulation during normal pregnancy. J Endocrinol Invest 1993;16:881–88.

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38. Goodwin TM, Montoro M, Mestman JH. Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 1992;167:648–52. 39. Tan JY, Loh KC, Yeo GS, Chee YC. Transient hyperthyroidism of hyperemesis gravidarum. BJOG 2002;109:683–88. 40. Hershman JM. Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors. Thyroid 1999;9:653–57. 41. Leylek OA, Cetin A, Toyaksi M, Erselcan T. Hyperthyroidism in hyperemesis gravidarum. Int J Gynaecol Obstet 1996;55: 33–37. 42. Amir SM, Osathanondh R, Berkowitz RS, Goldstein DP. Human chorionic gonadotropin and thyroid function in patients with hydatidiform mole. Am J Obstet Gynecol 1984;150: 723–28. 43. Ilicki A, Gamstedt A, Karlsson FA. Hyperthyroid Graves’ disease without detectable thyrotropin receptor antibodies. J Clin Endocrinol Metab 1992;74:1090–94. 44. Nelson M, Wickus GG, Caplan RH, Beguin EA. Thyroid gland size in pregnancy. An ultrasound and clinical study. J Reprod Med 1987;32:888–90. 45. Mizen TR. Thyroid eye disease. Semin Ophthalmol 2003;18:243–47. 46. Clementi M, Di Gianantonio E, Pelo E, et al. Methimazole embryopathy: delineation of the phenotype. Am J Med Genet 1999;83:43–46. 47. Johnsson E, Larsson G, Ljunggren M. Severe malformations in infant born to hyperthyroid woman on methimazole. Lancet 1997;350:520. 48. Momotani N, Noh JY, Ishikawa N, Ito K. Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves’ hyperthyroidism. J Clin Endocrinol Metab 1997;82:3633–36. 49. Ghaneim A, Atkins P. Management of thyrotoxicosis in pregnancy. Int J Clin Pract 1998;52:36–38.

50. Jortso E, Lennquist S, Lundstrom B, Norrby K, Smeds S. The influence of remnant size, antithyroid antibodies, thyroid morphology, and lymphocyte infiltration on thyroid function after subtotal resection for hyperthyroidism. World J Surg 1987;11:365–71. 51. Laurberg P, Nygaard B, Glinoer D, Grussendorf M, Orgiazzi J. Guidelines for TSH-receptor antibody measurements in pregnancy: results of an evidence-based symposium organized by the European Thyroid Association. Eur J Endocrinol 1998;139:584–86. 52. Kung AW, Chau MT, Lao TT, Tam SC, Low LC. The effect of pregnancy on thyroid nodule formation. J Clin Endocrinol Metab 2002;87:1010–14. 53. Khati N, Adamson T, Johnson KS, Hill MC. Ultrasound of the thyroid and parathyroid glands. Ultrasound Q 2003;19:162–76. 54. Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16:109–42. 55. Frates MC, Benson CB, Charboneau JW, et al. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Ultrasound Q 2006;22:231–38, discussion 239-40. 56. Titton RL, Gervais DA, Boland GW, Maher MM, Mueller PR. Sonography, and sonographically guided fine-needle aspiration biopsy of the thyroid gland: indications and techniques, pearls and pitfalls. AJR Am J Roentgenol 2003;181:267–71. 57. Castro MR, Gharib H. Continuing controversies in the management of thyroid nodules. Ann Intern Med 2005;142: 926–31. 58. Carling T, Udelsman R. Follicular neoplasms of the thyroid: what to recommend. Thyroid 2005;15:583–87. 59. Nam KH, Yoon JH, Chang HS, Park CS. Optimal timing of surgery in well-differentiated thyroid carcinoma detected during pregnancy. J Surg Oncol 2005;91:199–203.

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Sexual Function and Dysfunction in Men and Women KAREN ELIZABETH BOYLE1, AND, ARTHUR L. BURNETT2 1

Director, Reproductive Medicine and Surgery, Sexuality & Aesthetics Chesapeake Urology Associates, Baltimore, MD, USA Professor of Urology, The Johns Hopkins Hospital, James Buchanan Brady Urological Institute, Baltimore, MD, USA

2

too often, only one partner’s sexual function is addressed and treated, which clearly does not treat the whole disease. With FSD gaining more attention from both a research and clinical perspective, and physicians understanding the importance of addressing, if indicated, the complete couple, there will be improved success in the treatment of sexual dysfunction.

INTRODUCTION Sexual dysfunction is a highly prevalent, but often underdiagnosed condition affecting both men and women. It is recognized that risk factors for erectile dysfunction (ED) include diabetes mellitus, increasing age, cardiovascular disease, tobacco use, and decreased physical activity. Therefore, sexual dysfunction can be a sign and symptom of possible underlying disease and pathology – penile health reflects overall health. Beyond the obvious impact sexual dysfunction can have on an individual personally, emotionally, and socially, this dysfunction can be viewed as an opportunity to address even greater co-morbid disease. Sexual dysfunction in men includes: ED, problems with ejaculation including premature ejaculation (PE) and anejaculation, anorgasmia, decreased libido, hypogonadism, and sexual pain disorders. With the discovery of the nitric oxide signaling pathway, and the development of phosphodiesterase-5 inhibitors, the treatment of ED was revolutionized, and as a result, men became more comfortable discussing their sexual dysfunction with their physicians, partners, and friends. We are awaiting FDA approval of a medication developed for the specific treatment of PE. Female sexual dysfunction (FSD) includes: disorders of sexual desire, disorders of sexual arousal, and sexual pain. In comparison, the female sexual response is still not completely understood or agreed upon. Since female arousal and orgasm is multifactorial in nature, the therapies developed for men have not been shown to have the same efficacy in women. At the time this chapter was written, no FDA approved medication has been released, and the therapeutic prospects are still in Stage III clinical trials. Sexual dysfunction should be viewed not only as an individual disease state, but also as a couple’s problem. All Principles of Gender-Specific Medicine

MALE SEXUAL HEALTH Erectile Dysfunction DEFINITION AND EPIDEMIOLOGY Erectile dysfunction (ED) is defined as ‘the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance.’ Over 30 million men in the United States are affected by ED, and this number continues to increase with improved longevity and public awareness. Still, the majority of men suffering from ED do so silently, and the disease continues to be underdiagnosed and undertreated. It has been reported that more than 10 million men in the United States have been treated for ED, which represents close to 1 in 5 men older than 40 years of age.1 The Massachusetts Male Aging Study (MMAS) is the most frequently cited survey to report prevalence data in the United States. MMAS included 1709 men between the ages of 40 and 70 years living in the greater Boston area. The study estimated the prevalence of all degrees of ED at 52% (minimal at 17.2%, moderate at 25.5%, and complete at 9.6%). Subject age was most strongly associated with ED. Between the ages of 40 and 70 years the probability of complete ED increased from 5 to 15% and the probability of moderate ED from 17 to 34%.2 707

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Utilizing the United Nations projected male population distributions by age groups for 2025, the prevalence rates for ED were applied from the Massachusetts Male Aging Study to calculate the estimated prevalence of ED. It was estimated from the MMAS that the global prevalence would increase from 152 million worldwide in 1995 to 322 million men in 2025.3 PHYSIOLOGY OF ERECTION Animal studies have demonstrated that the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus and hippocampus are integration centers for sexual function and penile erection. Norepinephrinemediated inhibitory signals and dopamine-mediated proerectile stimuli originate in the amygdala and travel to the mPOA. Also, the paraventricular nucleus (PVN) of the hypothalamus receives neural input from the MPOA, and may have a proerectile action through oxytocin-mediated descending pathways. The periaqueductal gray matter, which provides neural connections between the mPOA and the brainstem, may also have proerectile qualities. The penis receives its innervations from both the autonomic and somatic nervous system. Somatic afferent fibers carry sensory signal from the penile skin through the dorsal nerve of the penis. The dorsal nerve of the penis used to be regarded as a purely somatic; however, Burnett demonstrated the presence of nitric oxide synthase (NOS), which is autonomic in origin.4 Somatic efferent fibers are responsible for the bulbocavernosal and ischiocavernosal muscle contractions, which occur during erection. Autonomic nerves include both the sympathetic and parasympathetic fibers. Sympathetic input originates at spinal cord level T10–T12 and travels through the superior hypogastric plexus to the pelvic plexus. Parasympathetic input originates at spinal cord level S2–S4, and travels through the pelvic nerve to the pelvic plexus. It is at the pelvic plexus where sympathetic and parasympathetic fibers integrate and form one single source of autonomic input to the penis as the neurovascular bundles of Walsh. These bundles lie posterolateral to the prostate, and are susceptible to injury during prostatectomy. Identification of these neurovascular bundles by Walsh and Donker, and the nerve-sparing radical prostatectomy procedure described by Walsh revolutionized the surgical treatment of prostate cancer and allowed men to maintain potency following surgery.5 An erection is a hemodynamic event. Sympathetic neural activity is responsible for detumescence and a flaccid penis; blood flow into the corpora cavernosa is minimal. With sexual stimulation, parasympathetic activity leads to increased blood flow into the corpora cavernosa and smooth muscle relaxation. The main neurotransmitter responsible for penile erection is nitric oxide (NO). NO is released from the corpora cavernosa endothelium during nonadrenergic, noncholinergic stimulation. NO then activates guanylyl cyclase, which in turn increased intracellular concentration of cyclic

guanosine monophosphate (GMP). Cyclic GMP then activates a specific protein kinase, which phosphorylates specific protein and ion channels, which results in potassium channel opening and hyperpolarization of the muscle cell membrane. Intracellular calcium is sequestered by the endoplasmic reticulum, and influx of calcium is blocked. Calcium concentration thereby drops and smooth muscle relaxes, resulting in arterial dilation and increased blood flow into the sinuses of the corpora cavernosa.6–8 NO may also influence subcellular contractile protein functions of cavernosal smooth muscle resulting in tissue relaxation. PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION The risk factors for ED include advancing age, heart disease, hypertension, diabetes mellitus, depression, tobacco use, stress, alcohol and/or drug abuse, and sedentary lifestyle. Therefore, the main etiologies of ED are vascular, neurogenic, hormonal, anatomic and drug-induced (organic), psychogenic (inorganic), or mixed. The prevalence of ED is highly related to age, and is also markedly high among men who also have one or more cardiovascular risk factors, such as hypertension or cardiovascular disease. In addition, among men with diabetes mellitus, the prevalence of ED is 51.3%. For this reason, screening for ED in patients with known risk factors such as diabetes and hypertension is advised.9 EVALUATION Evaluation for ED begins with a comprehensive sexual, medical, surgical, and psychosocial history to elicit risk factors and possible etiologies. A detailed physical examination, including cardiovascular, neurologic and genital assessment, is recommended. Laboratory evaluation should include fasting blood glucose, a lipid profile, total and free testosterone, and thyroid function test. Specialized testing may include more detailed psychological evaluation, nocturnal penile tumescence assessment, vascular diagnostics with intracavernosal injection, and penile Doppler ultrasound. Advanced testing may include CT or MRI imaging, neurologic testing, and vascular imaging. TREATMENT OF ERECTILE DYSFUNCTION The treatment of ED is typically staged, from least invasive therapies to most invasive therapies. Patients typically progress through the various stages of therapy until they have achieved a level of comfort with the treatment selected as well as success. First-Line Therapy: Phospodiesterase-5 Inhibitors (PDE5 Inhibitors) There are three PDE5 inhibitors available for use: sildenafil (Pfizer US Pharmaceutical Group, New York, NY), tadalafil (Lilly-ICOS, Indianapolis, IN), and vardenafil (Bayer Pharmaceuticals, New Haven, CT). Sildenafil

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was the first of its class available for use, and is an FDAapproved, orally active, highly potent selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5). Sildenafil enhances the effect of NO on smooth muscle relaxation and thereby strengthens and prolongs erection. Sildenafil is contraindicated in patients who are using organic nitrates, as it potentiates the hypotensive effect of the nitrate. Since it has been available for use the longest, sildenafil is also the most widely studied of the PDE5 inhibitors. Numerous studies support its efficacy, and more than 95% of men have had improved erectile function with its use.10 Tadalafil and vardenafil have also been shown to be highly effective therapies for ED and act in a similar mechanism of action, but pharmacologic differences exist. The pharmacokinetics of tadalafil are not adversely affected by food or alcohol use.11 The half-life of tadalafil is 17.5 hours, as compared to sildenafil’s median half-life, which is 3–5 hours, and vardenafil’s, which is 4 hours. The prolonged half-life of tadalafil supports the clinical trials results, which indicate efficacy for up to 36 hours following drug administration. Patients should be advised that sexual stimulation is necessary for any of the PDE5 inhibitors to work, and that it is necessary to try the medication at a few different episodes, as there are reports of first time failures not indicative of overall treatment failure. Patients not responding to an initial treatment with a PDE5 inhibitor should be counseled on proper use, and may benefit from increasing the dose. Sildenafil needs to be taken on an empty stomach. Patients should be counseled about the possible side effects of PDE5 inhibitors. Use of nitrites is a complete contraindication to the use of PDE5 inhibitors because the combination of these two medications can dangerously lower blood pressure. Other infrequent side effects of PDE5 inhibitors include headache (16%), flushing (10%), gastrointestinal upset (7%), and optical changes (3%).12 A penile vacuum device can also be used as a firstline therapy. Vacuum devices work by drawing blood into the penis, and then applying a constriction ring at the base. The device works well in all forms of ED, but not all patients like the quality of the erection or the side effects, which include decreased sensation and penile pain. Despite this, there is a population of patients who use the vacuum as their form of treatment, and some satisfaction rates have been noted to be over 80%.13 Other studies have noted discontinuation of use as high as 30% because of inadequate rigidity, penile pain, inability to ejaculate and generalized dissatisfaction.14

Second-Line Therapy: Intraurethral Alprostadil When oral medications fail, second line pharmacologic therapies are delivered directly to the penis. The least invasive of these is intraurethral alprostadil (synthetic prostaglandin E1), MUSE (Vivus, Menlo Park, CA). When placed inside the urethra via a small applicator, alprostadil is absorbed through the urethral mucosa, into the corpora

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spongiosum and then into the corpora cavernosa. Treatment success ranges from 49% to 66%, although this rate is considered high for clinical practice, as the select group that formed the clinical trial does not reflect the typical patient.10 The benefit of MUSE is that no needles are necessary, but the high rate of local penile pain (33%) and the often less firm erection than desired result in its not being a highly popular form of treatment. Still, systemic side effects (1–3%) are minimal, although it can cause hypotension, which is why all first-time doses are administered in the physician’s office. Second-Line Therapy: Intracavernosal Injection Treatment Intracavernosal injection therapy is more efficacious better tolerated and often preferred over the transurethral application of medication.15 Intracavernosal injections are typically used in men who fail oral medications and have no history of Peyronie’s disease. Prostaglandin E1 is the most common medication first prescribed, and its mechanism of action is that it modulates adenyl cyclase to increase cAMP concentrations, which leads to a decrease in intracellular free calcium, which then causes smooth muscle relaxation of the arterioles of the corpora, thereby resulting in an erection. Combination therapies are also available, and often involve different concentrations of prostaglandin E1, papaverine, and phentolamine. The first injection of any medication or combination therapy is performed in the office to monitor success, ensure priapism does not occur, and to perform teaching of technique. Side effects include priapism (1.3%), penile pain (16.8%), hematoma (1.5%), and fibrosis. Third-Line Therapy: Penile Prosthesis When all other therapies fail, or patients are unable to effectively use the other therapies available, the final choice in the treatment algorithm is placement of a penile prosthesis. This treatment option is typically used for patients with severe, pharmacotherapy-refractory end organ failure, or for those who do not tolerate, fail to respond to, or are unwilling to consider more conservative treatments. When Peyronie’s disease and concomitant ED are present, placement of a penile prosthesis, with or without modeling (manipulating the penile tissue to break the plaque and straighten the penis over the implant) is the preferred treatment over penile plication.16 Satisfaction rates with placement of a penile prosthesis are extremely high, well over 85%. The procedure is performed in the operating room under general or regional anesthesia, and the patient either stays overnight or depending, upon surgeon’s preference, is discharged the same day. Complications include perforation of the corpora cavernosa, urethral injury, crossover with dilation, difficult closure of the corporotomy, SST deformity, erosion of the device, bleeding, rate of reoperation (15% at 10 year postop time-point) and infection (2–3%). Despite these risks, complication rates are low, and

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placement of a penile prosthesis is a very safe and effective treatment of ED.

Ejaculatory Dysfunction EVALUATION AND MANAGEMENT Ejaculatory dysfunction is one of the most common sexual dysfunctions, with premature ejaculation affecting nearly 30% of all men. It is considered a dysfunction of the orgasmic phase and has specific diagnostic criteria: the persistent or recurrent onset of orgasms and ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it; marked distress or interpersonal difficulty; and symptoms not due exclusively to the direct effects of a substance use or withdrawal. A complete discussion of PE would extend far beyond the scope of this chapter. PE can be divided into physiologic constitution PE, which would include neurologic causes, psychosexual skills deficit PE, and psychogenic PE. Neurologic constitution PE is characterized by a lifelong onset and typically occurs during all sexual encounters. Men with PE have been found to have faster bulbocavernosal reflexes (BCR) as compared with men who do not have PE. Men presenting with PE should have a complete neurologic examination, focusing on the sacral reflex arc. Fortunately, pharmacologic interventions with medications that act to delay ejaculation are available. Selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine or sertraline hydrochloride and the tricyclic antidepressants amitryptyline, clomipramine, and desimpramine have been used. When paroxetine and sildenafil are used together in combination, success has been optimized.17 A short-acting SSRI, dapoxetine, has been formulated specifically for the indication of PE. It has been under review by the FDA, and at the time of writing of this chapter is still in Phase III clinical trials.

Decreased Libido and Hypogonadism in Men and Women The testes in men, the ovaries in women, and the adrenal glands in both men and women secrete testosterone. It is well known that testosterone levels decrease with aging, but the significance of this phenomenon is not agreed upon. Low testosterone may clinically present with ED, decreased libido, fatigue, and depression.18 All men presenting with these symptoms should be screened for hypogonadism with a free and total testosterone level drawn in the early morning. Androgen deficiency has been reported to be present in up to 47% of men presenting with ED and correlates significantly with age, uncontrolled diabetes, and hypercholesterolemia.19 Testosterone can be replaced in symptomatic men who have a normal PSA and digital rectal examination when testosterone levels are low or low normal. Patients need to be counseled about the possible adverse effects of replacement

therapy, which include increased hematocrit, weight gain, blood pressure elevation, acceleration of pre-existing prostate cancer, and suppression of spermatogenesis and infertility. Normalization of testosterone levels can improve libido, erection quality, mood, energy, and osteoporosis. Testosterone can be administered as an injection, patch, buccal mucoadhesive, cutaneous gel formulation or implantable pellet. Today most physicians initiate therapy with the cutaneous gels and then proceed to injectables when clinically necessary. In women, however, androgen therapy is debated. It is very common for women, like men, to complain of decreased sexual desire with age, and androgen therapy in women has received much attention and media coverage. In 2004, the Food and Drug Administration voted not to approve the transdermal testosterone patch (Intrinsa) until long-term safety data are available. Industry-sponsored studies demonstrated that transdermal testosterone therapy resulted in statistically significant improvement in libido in surgically menopausal women who were already on estrogen treatment. The follow-up was extremely short (24 weeks), and we await the FDA approval of a testosterone therapy for women.20 Until that time, use of dehydroepiandrosterone (DHEA) has been suggested, although the efficacy has been disputed. DHEA is a natural steroid hormone precursor and is delivered in an oral form.

FEMALE SEXUAL HEALTH Female sexual dysfunction (FSD) is a complex and multidimensional problem affecting between 30 and 50% of all women in America.21 The most commonly quoted study was conducted by the National Health and Social Life Survey of 1749 women, which concluded that 43% of women have complaints of sexual dysfunction.21 This study faced criticism for labeling what was defined as sexual ‘problems’ in the interviews as sexual ‘dysfunctions’ in the results.22 Much of the history of FSD originates from the field of psychology, and although it is true that emotional, personal and relationship issues clearly influence female sexual response and function, it is only in the last decade that it has been widely accepted that FSD is more than purely psychological. FSD can be both organic and inorganic, just as with ED, and the medical problems, which are cited as risk factors for ED, are the same for women.23 Aging, diabetes mellitus, hypertension, tobacco use, hypercholesterolemia, and endocrinopathy should be recognized as co-morbid disease.24

Female Sexual Response Cycle In 1966 Masters and Johnson first described the female sexual response as four successive phases: excitement, plateau, orgasm, and resolution. Then, in 1979, Kaplan proposed that desire, arousal and orgasm were components, with desire being the inciting factor to initiate the overall sexual

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response cycle. It is upon Kaplan’s work that the DSM IV definitions of FSD were grounded, as well as the reclassification system in 1998 by the American Foundation of Urologic Disease (AFUD) Consensus Panel.25 Further revisions were made at the 2nd International Consultation on Sexual Medicine: Men and Women’s Sexual Dysfunction in Paris July 2003 (see Table 58.1).26 Many of these revisions were based upon new considerations to the female sexual response cycle, and it is clear that the accurate diagnosis and treatment of these disorders is a challenge.27

Physiology of Female Sexual Response Centrally, the same areas of the brain that are cited in male sexual stimulation are proposed for female sexual stimulation. The medial preoptic (MPOA) is an important area, that when stimulated resulted in increased vaginal blood flow and vaginal wall tension.28 The paraventricular hypothalamus, the periaqueductal gray, the hippocampus, the amygdala, and the cerebellum are all activated during orgasm.29 The paragigantocellularis nucleus has been cited to be inhibitory to female sexual response. The female genital sexual response is still not completely understood. Anatomically, the vagina, the uterus, the muscles of the pelvis and perineum, the mons pubis, the labia minora and majora, the clitoris, the vestibule, the vaginal introitus and the urethral meatus all play a role in sexual arousal. Arousal to the genitals is described as genital vasocongestion that is under the influence of the autonomic nervous

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system. Blood flow to the pelvis and perineum leads to vascular engorgement of the labia, the vaginal wall that causes lubrication, and the clitoris, the erectile tissue in the female.30 As in the male, the female sexual response is innervated by both somatic and autonomic neural input. The pelvic nerves arising from S2 to S4, the parasympathetic nucleus, the hypogastric and lumbosacral sympathetic chain arising from T12 to L3, the pudendal nerve and the vagus nerve account for the neural input for female sexual response. The main sensory input for eliciting orgasm is from clitoral stimulation.31 The idea of vaginal or coital orgasm is hypothesized to be a result of stimulation of the female internal genital orgasm – the vagina, cervix, and uterus. The concept of the Grafenberg spot has been highly debated since its first description in 1950.32 The G-spot, as it was nicknamed by Addiego in 1981,33 is an area located on the anterior vaginal wall that with stimulation causes increased arousal and orgasm. Much less is known about the neurotransmitters and mediators of genital sexual response in women. Vasoactive intestinal polypeptide (VIP) has been considered to be one of the most important neurotransmitters in vaginal blood flow in female arousal, but more investigation is necessary.34 The role of NO and the cyclic guanosine monophosphate system on clitoral engorgement, as in male corpora cavernosum, has been proposed.35,36 Sildenafil has been demonstrated to inhibit PDE5 within the human clitoris, and studies have shown NO synthase within the glans and clitoris. Despite these findings, further research is necessary to better understand the details of the female sexual response cycle.

TABLE 58.1 Revised Classification and Definitions of Female Sexual Dysfunctions According to the Second International Consultation on Sexual Medicine in Paris, July 2003 I. Sexual desire disorders (a) Hypoactive sexual desire disorder – Absent or diminished feelings of sexual interest or desire, absent sexual thoughts or fantasies and a lack of responsive desire. Motivations (here defined as reasons/incentives) for attempting to become sexually aroused are scarce or absent. The lack of interest is considered to be beyond a normative lessening with life cycle and relationship duration (b) Sexual aversion disorder – Extreme anxiety and/or disgust at the anticipation of/or attempt to have any sexual activity II. Sexual arousal disorders (a) Sexual subjective arousal disorder – Absence of or markedly diminished feelings of sexual arousal (sexual excitement and sexual pleasure) from any type of sexual stimulation. Vaginal lubrication or other signs of physical response still occur (b) Genital sexual arousal disorder – Absent or impaired genital sexual arousal. Self-report may include minimal vulval swelling or vaginal lubrication from any type of sexual stimulation and reduces sensations from caressing genitalia. Subjective sexual excitement still occurs from nongenital sexual stimuli (c) Combined genital and subjective arousal disorder – Absence of or markedly diminished feelings of sexual arousal (sexual excitement and sexual pleasure) from any type of sexual stimulation as well as complaints of absent or impaired genital sexual arousal (vulval, swelling, lubrication) (d) Persistent sexual arousal disorder (provisional) – Spontaneous, intrusive and unwanted genital arousal (e.g. tingling, throbbing, pulsating) in the absence of sexual interest and desire. Any awareness of subjective arousal is typically but not invariably unpleasant. The arousal is unrelieved by one or more orgasms, and the feelings of arousal persist for hours or days III. Women’s orgasmic disorder – Despite the self-report of high sexual arousal/excitement, there is either lack of orgasm, markedly diminished intensity of orgasmic sensations, or marked delay of orgasm from any kind of stimulation. IV. Sexual pain disorders (a) Dyspareunia – persistent or recurrent pain with attempted or complete vaginal – persistent difficulties to allow vaginal entry of a penis, a finger, and/or any object, despite the woman’s expressed wish to do so. There is variable involuntary pelvic muscle contraction, (phobic) avoidance, and anticipation/fear/experience of pain. Structural or other physical abnormalities must be ruled out/addressed Source: Basson et al., 200426

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Pathophysiology of FSD FSD shares the same risk factor with ED and can be broken down into vasculogenic, neurogenic, hormonal, anatomic, and psychogenic causes. Cardiovascular disease, hypertension, diabetes mellitus, hypercholesterolemia, and tobacco use all contribute to possible vasculogenic causes.37 Underlying atherosclerosis can cause disease to the aorta and iliac vessels, which can adversely affect pelvic blood flow. Trauma to the iliohypogastric and pudendal arterial bed from either iatrogenic causes or pelvic fractures can also result in poor clitoral and vulvar blood flow. Patients with spinal cord injury (SCI), diabetic neuropathy, and nervous system disorders may experience difficulty achieving orgasm. Hormonally speaking, women face unique challenges throughout their lives. Early in life, a woman may not desire pregnancy, and may choose birth control medications that adversely affect libido. During her fertile years, testosterone may begin to decrease, and this, combined with pregnancy and postpartum states, may contribute to sexual dysfunction. Then, with menopause – either natural or surgical – a woman may suffer from loss of desire, lack of sexual arousal, and vaginal dryness, all which then may contribute to orgasmic dysfunction.38 With estrogen levels decreasing both systemically and locally in the vagina, dryness may worsen. Androgen deficiency may explain the loss of interest in intercourse, decreased energy and depression, similar to men with hypogonadism. As previously stated, however, the benefit of testosterone replacement in women is not clearly proven, and long-term safety data are not yet available. Diseases of the vulva may contribute to the pain disorders previously presented. Vulvovaginitis, vulvovestibulitis, chronic yeast infections, vaginal atrophy, genital herpes, urethritis, episiotomy, sexual trauma, and local irritants may contribute to dyspareunia. Pelvic inflammatory diseases, pelvic adhesions, fibroids, endometriosis, urinary tract infections, and fibromyalgias may cause pelvic dyspareunia. Involuntary muscle spasms, which result in vaginismus, may be a condition that is a combination of spastic muscle and psychological aversion and anxiety. Psychogenic causes, including emotional and relationship issues, are still prominent causes of sexual dysfunction. The female sexual response is multifactorial, and issues of self-esteem, body image, relationship, and intimacy significantly contribute to a woman’s sexual well-being. Medications such as birth control pills and antidepressants can adversely affect sexual desire, arousal, and orgasm.

Classification and Diagnosis of Female Sexual Dysfunction SEXUAL DESIRE DISORDERS Hypoactive Sexual Desire Hypoactive sexual desire disorder is defined as absent or diminished feelings of sexual interest or desire, absent

sexual thoughts or fantasies, and a lack of responsive desire. Motivations (here defined as reasons/incentives) for attempting to become sexually aroused are scarce or absent. The lack of interest is considered to be beyond a normative lessening with life cycle and relationship duration. Decreased sexual desire is very common among women, with close to 35% of women experiencing diminished sexual desire. Sexual Aversion Disorder Sexual aversion disorder is defined as extreme anxiety and/ or disgust at the anticipation of/or attempt to have any sexual activity. During evaluation of sexual aversion disorder, it would be essential to elicit a possible history of sexual abuse or trauma. SEXUAL AROUSAL DISORDERS Sexual Subjective Arousal Disorder Sexual subjective arousal disorder is defined as the absence of or markedly diminished feelings of sexual arousal (sexual excitement and sexual pleasure) from any type of sexual stimulation. Vaginal lubrication or other signs of physical response still occur. Genital Sexual Arousal Disorder Genital sexual arousal disorder is defined as absent or impaired genital sexual arousal. Self-report may include minimal vulvar swelling or vaginal lubrication from any type of sexual stimulation and reduced sensations from caressing genitalia. Subjective sexual excitement still occurs from non-genital sexual stimuli. Combined Genital and Subjective Arousal Disorder Combined genital and subjective arousal disorder is defined as absence of or markedly diminished feelings of sexual arousal (sexual excitement and sexual pleasure) from any type of sexual stimulation as well as complaints of absent or impaired genital sexual arousal (vulval, swelling, lubrication). Persistent Sexual Arousal Disorder (Provisional) Persistent sexual arousal disorder is defined as spontaneous, intrusive, and unwanted genital arousal (e.g. tingling, throbbing, pulsating) in the absence of sexual interest and desire. Any awareness of subjective arousal is typically but not invariably unpleasant. The arousal is unrelieved by one or more orgasms, and the feelings of arousal persist for hours or days. Sexual arousal disorders are highly prevalent, with 20% of women aged 18–59 reporting difficulty with lubrication. With age, vaginal lubrication diminishes and vaginal atrophy occurs, which would explain the increased incidence of problems in postmenopausal women that approaches 45%.

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WOMEN’S ORGASMIC DISORDER Women’s orgasmic disorder is defined as, despite the selfreport of high sexual arousal/excitement, either lack of orgasm, markedly diminished intensity of orgasmic sensations, or marked delay of orgasm from any kind of stimulation. Orgasmic disorder is highly prevalent, although difficult to measure. The NHSLS reported 15.4% of premenopausal women and 34.7% of postmenopausal women have difficulty in achieving an orgasm during sexual stimulation.39 SEXUAL PAIN DISORDERS Dyspareunia is defined as persistent or recurrent pain with attempted or complete vaginal entry and/or vaginal intercourse. Vaginismus is defined as persistent difficulties to allow vaginal entry of a penis, a finger, and/or any object, despite the woman’s expressed wish to do so. There is variable involuntary pelvic muscle contraction, (phobic) avoidance, and anticipation/fear/experience of pain. Structural or other physical abnormalities must be ruled out/addressed.40

Evaluation of Female Sexual Dysfunction A detailed medical, surgical, sexual, obstetric/gynecologic, and psychological history must be taken. Physical examination, with specific attention to the vulva, should be performed. Hormonal evaluation with a total and free testosterone, sex hormone-binding globulin, DHEA-S, and thyroid function tests should be obtained.

Treatment of Female Sexual Dysfunction First-Line Therapy As with men, treatment for FSD follows a stepwise treatment algorithm, which begins with modification of reversal causes. Sex therapy, physical therapy, cognitive behavior therapy, lifestyle changes including exercise and diet, alteration of prescription medications and discontinuation of recreational medications are all things recommended at the initiation of therapy. Identification and management of partner sexual dysfunction is also initiated at this time. First-line therapies include hormone therapies with androgens, local and or systemic estrogens, progestins, dopamine agonists, oral phosphodiesterase 5 inhibitors, mechanical vibrators, and a clitoral vacuum device. Secondline therapies include surgery and reconstruction. PDE5 inhibitors have not been nearly as efficacious in women as in men. In most of the larger, placebo-controlled studies of women with sexual dysfunction, specifically female sexual arousal disorder, sildenafil has not proved beneficial. However, smaller studies have reported improvement in SSRI-induced sexual dysfunction following the use of sildenafil.41–43

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Vaginal estrogen treatment is highly beneficial in the treatment of atrophic vaginitis and can improve genital response in women.44 Delivered in the form of a ring or cream, the estrogen is not systemically absorbed, and therefore the concerns of formal hormone replacement do not exist. Replacement of vaginal estrogen has also been noted to decrease the incidence of recurrent urinary tract infections in postmenopausal women. Concern has risen about systemic estrogen replacement plus progesterone as therapy for menopausal symptoms. The Women’s Health Initiative (WHI) study found increased risk of breast cancer, heart attack, blood clots, stroke, and pulmonary embolism, which are the primary reasons many physicians and patients now are reluctant to pursue replacement therapy. The American College of Obstetrics and Gynecology recently issued a statement supporting evidence that women in early menopause, who are in good cardiovascular health, are at low risk of adverse cardiovascular outcomes and should be considered as candidates for replacement therapy to relieve menopausal vasomotor symptoms.45 A more detailed discussion on hormone replacement is found elsewhere in this textbook. Studies have suggested an improvement in general health and sexual well-being in surgically postmenopausal women on testosterone therapy as compared to estrogen alone.46 As presented earlier in this chapter, however, there is difficulty in developing a testosterone replacement for women. Testosterone assays are designed and developed to detect hormone levels in men, not the much lower levels found in normally functioning women. Measurement of SHBG and calculation of free-androgen index is necessary to assess female hypogonadism, and clinicians should not rely on total and free testosterone values alone. Perhaps until the outcomes of Phase III clinical studies on the long-term safety and efficacy of testosterone become available, the use of DHEA can be recommended. Women who are symptomatic and have abnormally low freeandrogen index values can proceed with a trial of testosterone gel, typically at 1/10 the dose of men. The side effects of acne and hirsutism are usually very low. Mechanical vibrators can be used to improve primary and secondary anorgasmia in women. The clitoral vacuum device (EROS Therapy Device, UroMetrics Inc., St Paul, MN) has been approved by the FDA for the treatment of female sexual dysfunction. In a small, uncontrolled study 90% of women reported improved sensation, 80% reported improved lubrication, 55% noted improved orgasm, and 80% improved sexual satisfaction.47

Second-Line Therapies Treatment of vulvar vestibulitis is most commonly medical, involving the treatment of the inflammation of the vestibular glands. However, rarely, a vestibulectomy is necessary, which involves the surgical removal of the vestibular glands and vaginal advancement to cover the ostia of the Bartholin glands.

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Phimosis of the prepuce of the clitoris may lead to balanitis of the clitoral glans. Conservative treatment includes topical antifungal treatment, but a dorsal slit procedure may be required. Treatment of vaginismus has traditionally been biofeedback and relaxation techniques, combined with psychological counseling. It has been suggested in a small series of patients that injectable Botox be used to treat refractory vaginismus. Twenty-three patients (95.8%) had vaginal examinations 1 week postoperatively that showed little or no vaginismus; 18 (75%) achieved satisfactory intercourse after the first injection, and 4 (16.7%) had mild pain.48

CONCLUSIONS Although similarities exist in the physiology and pathophysiology of male and female sexual function, the differences help explain why finding effective treatments for women pose such a challenge. Female sexuality is much less well understood, in part because of the emotional and psychological influences on the female sexual response. We await with much anticipation further clinical and basic science research into the female sexual response cycle so that additional, highly efficacious treatments can be developed. Biological research will continue to increase our advanced understanding of both the science of sexual responses in men and women. Pharmacotherapy, growth factor therapy, gene therapy, and regenerative medicine exist as the exciting therapeutic advances in development.49 It is with these novel new approaches to the treatment of sexual dysfunction under investigation that we are hopeful for improved future success and cure.

References 1. McVary KT. Erectile dysfunction. N Engl J Med 2007; 357:2472–81. 2. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151(1):54–61. 3. Aytaç M, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50–56. 4. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science 1992;257(5068):401–3. 5. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128(3):492–97. 6. Burnett AL, Tillman SL, Chang TS, et al. Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J Urol 1993;150:73. 7. Lue TF. Erectile dysfunction. N Engl J Med 2000;342: 1802–13.

8. Rajfer J, Aronson WJ, Bush PA. Nitric oxide as a mediator of relaxation of the corpus cavernosum in reposonse to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 1992;326:90–94. 9. Burnett AL. Erectile dysfunction. J Urol 2006;175(3 pt 2): S25–31. 10. Padma-Nathan H, Hellstrom WJ, Kaiser FE. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997;336:1–7. 11. Portst H. IC351 (tadalafil, Cialis): update on clinical experience. Int J Impot Res 2002;14(Suppl. 1):57–64. 12. Prescribing information. Sildenafil. Pfizer, New York, NY. 13. Bosshardt BJ. Objective measurement of the effectiveness, therapeutic success and dynamic mechanisms of the vacuum erection device. Br J Urol 1995;75:786. 14. Sidi AA. Patient acceptance of and satisfaction with an external negative pressure device for impotence. J Urol 1990;144:1154. 15. Shabsigh R, Padma-Nathan H, Gittleman M. Intracavernous alprostadil alfadex is more efficacious, better tolerated, and preferred over intraurethral alprostadil plus optional actis: a comparative, randomized, crossover, multicenter study. Urology 2000;55:109–13. 16. Carson CC. Penile prosthesis implantation in the treatment of Peyronie’s disease. Int J Impot Res 1998;10(1):125–1128. 17. Chen J, Mabjeesh NJ, Matzkin H, Greentein A. Efficacy of sildenafil as adjuvant therapy to selective serotonin reuptake inhibitor in alleviating premature ejaculation. Urology 2003;61(1):197–200. 18. Hwang TI, Lin YC. The relationship between hypogonadism and erectile dysfunction. Int J Impot Res 2008;20(3):231–35. 19. Kohler TS, Kim J, Feia K, et al. Prevalence of androgen deficiency in men with erectile dysfunction. Urology 2008;71(4):693–97. 20. Basaria S, Dobs AS. Clinical review: controversies regarding transdermal androgen therapy in postmenopausal women. J Clin Endocrinol Metab 2006;91(12):4743–52. 21. Berman J, Berman L, Goldstein I. Female sexual dysfunction: incidence, pathophysiology, evaluation, and treatment options. Urology 1999;54:385–91. 22. Meston CM, Bradford A. Sexual dysfunctions in women. Annu Rev Clin Psychol 2007;3:233–56. 23. Burnett AL, Truss MC. Mediators of the female sexual response: pharmacotherapeutic implications. World J Urol 2002;20(2):101–5. 24. Park K, Goldstein I, Andry C, Siroky M, Krane R, Azadzoi K. Vasculogenic female sexual dysfunction: the hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency. Int J Impot Res 1997;9:27–37. 25. Basson R, Berman J, Burnett A, Derogatis L, Ferguson D, Fourcroy J. Report of the international consensus development conference on female sexual dysfunction: definitions and classifications. Urology 2000;163:888–93. 26. Basson R, Leiblum S, Brotto L, et al. Revised definitions of women’s sexual dysfunction. J Sex Med 2004;1(1):40–48. 27. Basson R, Althof S, Davis S, et al. Summary of the recommendations on sexual dysfunctions in women. J Sex Med 2004;1(1):24–34. 28. Giuliano F, Allard J, Compagnie S, et al. Vaginal physiological changes in a model of sexual arousal in anesthetized rats. Am J Physiol Reg Integr Comp Physiol 2001;281:R140–49.

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29. Whipple B, Komisaruk BR. Brain (PET) responses to vaginalcervical self-stimulation in women with complete spinal cord injury: preliminary findings. J Sex Marital Ther 2002;28:79–86. 30. Dickinson RL. Human Sex Anatomy, 2nd ed. London: Bailliere, Tindal & Co.; 1949. 31. Levin RJ. The mechanisms of human female sexual arousal. Annu Rev Sex Res 1992;3:1–48. 32. Grafener E. The role of urethra in female orgasm. Int J Sexology 1950;3(3):145–48. 33. Addiego F, Belzer EG, Cornolli J, Moger W, Perry JD, Whipple B. Female ejaculation: a case study. J Sex Res 1981;17(1):13–21. 34. Levin RJ. VIP, vagina, clitoral, and periurethral glans – an update on human female genital arousal. Esp Clin Endocrino 1991;98:61–69. 35. Cellek S, Moncada S. Nitrergic neurotransmission mediates the non-adrenergic non-cholinergic responses in the clitoral corpus cavernosum of the rabbit. Br J Pharmacol 1998;125:1627–29. 36. Park JK, Kim JU, Lee SO. Nitric oxide-cyclic GMP signaling pathway in the regulation of rabbit clitoral cavernosum tone. Exp Biol Med 2002;227:1022–30. 37. Berman JR, Jassuk J. Physiology and pathophysiology of female sexual function and dysfunction. World J Urol 2002;20:111–18. 38. Goldstein I, Alexander JL. Practical aspects in the management of vaginal atrophy and sexual dysfunction in perimenopausal and postmenopausal women. J Sex Med 2005;S3:154–65. 39. Meston CM, Hull E, Levin R, Sipski M. Disorders of orgasm in women. J Sex Med 2004;1(1):66–68. 40. Farmer MA, Meston CM. Predictors of genital pain in young women. Arch Sex Behav 2007;36:831–43.

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41. Shen WW, Urosevich A, Clayton DO. Sildenafil in the treatment of female sexual dysfunction induced by selective serotonin reuptake inhibitors. J Reprod Med 1999;44: 535–42. 42. Berman J, Berman L, Lin H, Flaherty E, Lahey N, Goldstein I. Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J Sex Marital Ther 2001;27:411–20. 43. J. Berman, L. Berman, S. Toler, J. Gill, S. Haughie, Efficacy and tolerability of sildenafil citrate in women with sexual arousal disorder: a double-blind, placebo-controlled study [abstract], Annual Meeting of the International Society for the Study of Women’s Sexual Health, October 10-13 (2002) 49. 44. Basson R. The complexities of female sexual arousal disorder: potential role of pharmacotherapy. World J Urol 2002;20: 119–26. 45. ACOG Committee Opinion No. 420, November 2008: hormone therapy and heart disease. Committee on Gynecologic Practice, Obstet. Gynecol., 112 (5) (2008) 1189–1192 46. Shifren JL, Braunstein GD, Simon JA. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682–88. 47. Billups KL. The role of mechanical devices in treating female sexual dysfunction and enhancing the female sexual response. World J Urol 2002;20:137–41. 48. Ghazizadeh S, Nikzad M. Botulinum toxin in the treatment of refractory vaginismus. Obstet Gynecol 2004;104(5 pt 1): 922–25. 49. Burnett AL. Erectile dysfunction. Management for the future. J Androl 2009;30(4):391–96.

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Osteoporosis in Men and Women KENDALL F. MOSELEY1, AND SUZANNE M. JAN DE BEUR2 1

Clinical Fellow, Division of Endocrinology, The Johns Hopkins Hospital, Baltimore, MD, USA Associate Professor of Medicine, The Johns Hopkins University School of Medicine, Director, Division of Endocrinology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA 2

We are on the cusp of a ‘Silver Tsunami’ as our population ages, bringing with it waves of co-morbid conditions in both genders. Osteoporosis is at the forefront of these disease states. \When it comes to the skeleton, men and women differ; bone formation is different; bone loss with aging is different; and underlying reasons for osteoporosis are different. Public health awareness initiatives have targeted women, improving detection and treatment of osteoporosis in a gender usually underrepresented in clinical research. In this case, men and their physicians have been left uniquely unaware of the significant risk of osteoporosis, higher mortality related to fracture, and the differences in underlying causes of osteoporosis in men. In this chapter, we will explore gender differences in skeletal physiology, epidemiology of osteoporosis, causes of osteoporosis, evaluation of osteoporosis, and treatment of osteoporosis. Osteoporosis is defined as a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture.1 The clinical definition of osteoporosis is based on bone densitometry with dual x-ray absorptiometry (DXA). Compared to a 30-year-old matched for ethnicity and gender, a score between 1.0 and ⫺1.0 standard deviations is considered normal bone density, a score between ⫺1.0 to ⫺2.5 standard deviations is osteopenia and a score that is below ⫺2.5 standard deviations is osteoporosis (Table 59.1). Bone densitometry, however, is only a qualitative tool. Thus, with improved understanding of those qualitative factors that influence the formation and destruction of bone in men and women, prevention and treatment will be that much more feasible.

TABLE 59.1 Normal

Osteopenia

Osteoporosis

Severe (or established) osteoporosis

A value for BMD that is not more than one SD below the young adult mean value (T score above ⫺1.0) A value for BMD that lies between 1 and 2.5 SDs below the young adult mean value (T score between ⫺1.0 and ⫺2.5) A value for BMD that is more than 2.5 SDs below the young adult mean value (T score at or less than ⫺2.5) A value for more than 2.5 SDs below the young adult mean value in the presence of one or more fragility fractures

million are women and 2 million are men.2 This number is likely an underestimate, given the fact that osteoporosis is often not diagnosed until a fracture occurs that brings the patient to medical attention. Clinically, these fractures are identified in the proximal femur (hip), vertebrae (spine), distal forearm, proximal humerus, pelvis, and other skeletal sites.3 Thus, to really explore the epidemiology of osteoporosis, it may be wise to consider the disease in the context of fracture, as osteoporosis begets fracture and fracture leads to morbidity and mortality.

Osteoporosis and Fracture in Women Osteoporosis is more common amongst women than men. Women have lower peak bone mass, smaller bone size, go through menopause (a period of accelerated bone loss), and have greater longevity when compared to men.4 The lifetime risk of osteoporotic fracture at any site in women is as high as 40–50%.5 Of these fractures, 35% will be vertebral, 18% hip, and 17% are likely to be in other sites such as the

EPIDEMIOLOGY OF OSTEOPOROSIS The National Osteoporosis Foundation estimates that over 10 million people in the US have osteoporosis; of these, 8 Principles of Gender-Specific Medicine

WHO diagnostic categories of BMD (men and women)

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wrist.6 As an added complication, 14% of women will have repeat hip fractures, while 25% have multiple vertebral fractures.7 Without question, osteoporosis is a public health issue that is especially critical for women.3 Osteoporotic fractures are often turning points in women’s lives. For those who suffer clinical vertebral fractures, quality of life drops substantially, as measured by physical function, social function, and well-being.8,9 Perhaps more physically debilitating, hip fractures have been reported to decrease a woman’s functionality by as much as 50% as compared to prefracture lifestyle.10 Data on mortality are even more dismal, with both vertebral and hip fractures carrying substantial mortality risk. There is still some debate as to whether fractures, namely hip, exacerbate co-morbidities that hasten death, or whether the fracture carries its own risk.11 Up to 25% of hip fracture patients die during the first year after their hip fracture, with the highest mortality occurring in the first six months.12 International studies indicate that after 5 years, survival following vertebral and hip fractures in women older than 65 is only 56.5 and 41.7%, respectively.13

Osteoporosis and Fracture in Men Although the older members of both sexes eventually experience bone loss at the same rate,14 women get an earlier start, as they experience a period of rapid decline in bone mineral density (BMD) with menopause; the decline in men is more gradual, but just as detrimental. Some studies even speculate that men will experience up to two-thirds the bone loss of their female counterparts by the end of life.15,16 As a result, the lifetime risk of osteoporotic fracture in men is 13–22% with 4% of these fractures in the hip and 11% in the spine.17 The morbidity and mortality sustained from fractures and osteoporosis in men does not completely parallel that of women. Men, too, report a distinct decline in quality of life following a vertebral or hip fracture, with 50% failing to regain their independence and mobility.18 Men also suffer a 25% mortality rate within the year following hip fracture. Unlike women, who are two times more likely to have a hip fracture following a vertebral fracture, men are at four times the risk.19 The mean age of first hip fracture in men is up to 6 years younger than women.20,21 Where men and women differ significantly is in the mortality following initial fracture. Cooper et al. demonstrated that 5 years following vertebral fracture, relative survival rates for men and women were 72% and 84%, respectively.22 Additional international studies further supported that men were at increased mortality risk following vertebral fracture, a trend also appreciated at the hip.23–25 Further, Nguyen et al. showed the mortality ratio 5 years after hip fracture was 3.17 in men as compared to 2.18 in women.17

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FINANCIAL BURDEN OF OSTEOPOROSIS The morbidity and mortality of osteoporosis is not without its reciprocal costs to the healthcare system. No matter which model one uses, fractures are expensive. Direct costs to the individual are high; for example, in the US, hospitalization for a hip fracture can cost up to $7000, rising to $21 000 in the first year.26 Compounding this cost is our aging population, which will spark an increase in hip fractures worldwide from 1.7 million in 1990 to a projected 6.3 million in 2050, resulting in a staggering cost of $131.5 billion. While many acknowledge the financial burden of hip fractures, non-hip fractures also account for much of the expense of osteoporotic fractures. In 1995, the National Osteoporosis Foundation reported on medical expenditures for fractures in all persons older than 45 in the US.27 At the time of report release, health care costs stemming directly from osteoporotic fractures were estimated at $13.8 billion. Of these dollars, $10.3 billion (75.1%) was for the treatment of white women, $2.5 billion (18.4%) for white men, $0.7 billion (5.3%) for nonwhite women, and $0.2 billion (1.3%) for non-white men. Since that publication, and with the rising awareness of the prevalence of osteoporosis in men, new estimates have returned, suggesting that men play an even larger role in osteoporosis health care costs.28

SKELETAL DEVELOPMENT One cannot understand osteoporosis and subsequent sex differences without first appreciating the building blocks of the skeleton and how hormones affect its construction. Bone is a remarkable architectural undertaking. On the outside of bone is the periosteal surface, with the endocortical, trabecular, and intracortical bone components making up the endosteal surface. The basic multicellular unit (BMU) consists of those cells responsible for bone formation (osteoblasts) and resorption (osteoclasts). The BMUs reside on the endosteal and periosteal surfaces and are thus ultimately responsible for changes in bone over time. Bone can grow, thin, thicken, bend, and shift depending on the complex interactions of bone remodeling units. Endosteal resorption without concomitant periosteal bone formation thins the cortex; similarly, incomplete mineralization of trabecular struts leaves compromised bone integrity.29 Skeletal growth occurs in several phases. From the moment of birth, the skeleton undergoes a period of rapid growth in total body length. Although this is followed by a period of slowing, at 12 months of age the appendicular skeleton again grows longitudinally, and at a faster rate than the axial skeleton.30,31 It is not until puberty that axial growth overtakes appendicular long bone growth and the epiphyses fuse. When longitudinal growth has reached its

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completion and a person has reached his or her peak bone mass (usually by the third decade of life), there is likely a steady state of bone resorption and formation. During this remodeling period, there is no net gain or loss of bone as osteoclasts on the endosteal surface resorb bone, followed by replacement of that volume by osteoblasts. Primary and secondary mineralization then takes place within the new bone to optimize bone integrity. With this understanding of the development of bone and those factors that affect its remodeling, one can then appreciate the pathophysiology of osteoporosis. The onset of bone loss begins when remodeling ceases to be in steady state. For reasons not completely understood, as men and women age, the balance of osteoblast activity becomes overshadowed by osteoclast resorption, resulting in pockets of incompletely restored bony volume, unfinished mineralization, and ultimately an unstable framework.

Gender Differences in Skeletal Development The male and female skeletons are quite distinct from one another. Although growth begins in the same manner, puberty marks a shift in male and female skeletons that will set the groundwork for bone health and integrity in later life.32 Boys enter puberty later than girls, allowing for greater appendicular growth. As a result, men are traditionally taller and have longer legs than women. Although axial growth and torso length are similar in men and women, men predominantly acquire growth via periosteal bone formation while women’s axial skeleton grows predominantly via endosteal apposition. The result is a slightly thicker cortex (distance between peri- and endosteal surfaces) in men when compared with women. Bone mass is achieved in parallel with enlarging bone in men and women, leaving volumetric BMD unchanged. Thus, it is the size and length that make men’s bones stronger, not higher bone density.33 After peak bone mass has been reached and steady state breached, the bones of both men and women begin to thin as resorption occurs on endocortical and trabecular surfaces.34 The rate of this bone loss is similar for both sexes, with compensation occurring on the periosteal surface with new bone formation.35 Interestingly, periosteal growth is more successful in men, enlarging their bones with age, and resulting in a smaller net decrease in bone mass over time when compared with women.36 Both sexes also experience a loss in trabecular connectivity over time, although the rate of trabecular thinning without adequate remodeling is thought to be faster in women than in men.37

Hormonal Control of Bone Bone growth and remodeling is regulated by a number of different hormones. These include androgens, estrogens, vitamin D, growth hormone, insulin-like growth factor 1 (IGF-1), and parathyroid hormone (PTH). These circulating

hormones independently and additively act via local growth factors to dictate osteoblast and osteoclast activity.38 In the early stages of development and throughout life, these hormones work in harmony with one another. Any imbalance, whether it be hyperparathyroidism, vitamin D deficiency, or excessive growth hormone will be reflected in bone pathology. For the purposes of this chapter, the sex hormones estrogen and testosterone best define the gender differences in bone and osteoporosis and will be described below.

Gender Differences in Hormonal Control of Bone Bone metabolism was once thought to be hormonally sexspecific. That is, testosterone seemed primarily responsible for bone growth and maintenance in men, while estrogen modulated a woman’s skeleton. The thought is not completely unreasonable; true, puberty does mark the point in which men and women’s skeletons begin to differ as sex hormones surge. True, the plummeting estrogen associated with menopause brings with it a substantial decline in a woman’s BMD, an event not paralleled in men.39 To challenge these assumptions, however, evidence has emerged to offer a different story. In men and women, estrogen acts via a number of different mechanisms in bone growth and remodeling. On the larger scale, estrogen acts to conserve bone mass, suppressing bone turnover and regulating the balance of bone resorption and remodeling.40 This is best appreciated at the cellular level where estrogen has effects on both osteoblasts and osteoclasts. Some data suggest that to promote bone growth, estrogen increases osteoblast formation, differentiation, and proliferation.41–43 Estrogen concurrently increases apoptosis in osteoclasts while limiting apoptosis in osteoblasts.44,45 The importance of estrogen in the skeleton becomes abundantly clear in menopause when serum levels plummet and the bone resorption is accelerated. One might imagine how disregulation of osteoblast and osteoclast proliferation and apoptosis resulting from estrogen deficiency might affect the skeleton – osteoclasts resorb bone without estrogen’s inhibition, and bone is further compromised without suppression of osteoblast apoptosis.46 Estrogen’s usually suppressive role in the formation of new BMUs remits, leading to more areas of resorption and remodeling that the osteoblasts have no time to fill. The cortex and the trabeculae thin with time, and BMD declines.47 Testosterone has many of the same effects on osteoblasts and osteoclasts as estrogen. Like estrogen, testosterone acts to reduce bone resorption, as is illustrated by hypogonadal men who develop osteoporosis.48 This is achieved through testosterone-mediated osteoblast proliferation and osteoclast apoptosis.49 To some extent, testosterone’s effects on BMUs may be through peripheral aromatization to estrogen.50 The importance of estrogen in the male skeleton was

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revealed in studies of men deficient in aromatase and alphaestrogen receptors, key steps in the aromatization of testosterone to estrogen.51–53 These men were unable to convert free testosterone into estrogen, and as a result, had incomplete epiphyseal fusion and reduced BMD. These men required estrogen to stop growing and optimize the acquisition of new bone.54 The degree of aromatization needed to maintain the male skeleton is unknown, but estrogen is undoubtedly an important component of skeletal formation in men.55 Although both estrogen and testosterone regulate osteoblast and osteoclast function, they likely work at different stages of osteoclast and osteoblast differentiation. The two hormones may also act at different skeletal sites. For example, in the growing skeleton, bone size in women increases via endocortical apposition, thought to be mediated by estrogen. Men, on the other hand, achieve cortical widening via periosteal growth, mediated by testosterone.56,57 As would be expected, when women experience a decline in estrogen, endocortical bone loss ensues. Men compensate for endocortical loss in aging with testosterone-driven periosteal thickening.58 The specific roles of estrogen and testosterone in the male and female skeleton are not completely known, but evolving understanding will clearly impact future therapeutic interventions for osteoporosis.

RISK FACTORS FOR OSTEOPOROSIS The major underlying etiologies of osteoporosis in men and women are different. While most women have postmenopausal osteoporosis, up to half of men will have a secondary form of osteoporosis. Therefore, a helpful approach to risk factor assessment in osteoporosis is its categorization into primary and secondary causes. Primary osteoporosis is the bone loss associated with natural aging and the decline of gonadal function in both men and women. When there is an identifiable drug, disease process, or nutritional deficiency which is thought to precipitate accelerated bone loss, a patient is thought to have secondary osteoporosis. Overlap of primary and secondary osteoporosis occurs frequently in the same patient.59

Primary Osteoporosis and Fracture Risk Factors in Women As will be described further below, many of the osteoporosis screening guidelines for women seek to identify those characteristics that put a woman at risk for osteoporosis in the absence of other medical co-morbidities (Table 59.2).60 Practically, the physician can think of these as modifiable versus non-modifiable risk factors, especially when educating the patient about osteoporosis prevention strategies.61 One does not choose their family history, for example, but a first-degree relative in the patient’s family with a history of osteoporosis or pathologic fractures will still put that

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patient at risk. Modifiable risk factors, such as smoking, weight loss, and dietary intake, may all be areas of potential intervention.

Primary Osteoporosis and Fracture Risk Factors in Men Because men have only recently been recognized to be at risk of having osteoporosis and falling victim to fragility fractures, less is known about the characteristics of those men that develop osteoporosis. In a recent meta-analysis, Liu et al. evaluated 167 studies which examined risk factors for low-BMD-related fracture in men and women.62 Although many of the studies addressed risk factors for men and women heterogeneously, authors were able to identify those major factors that put men at risk for osteoporosis and fracture (Table 59.3).63

Secondary Osteoporosis and Fracture Risk Factors in Women Rare is the patient who walks into the physician’s office without a host of co-morbidities, some of which may or may not influence his or her bone density. In the perimenopausal woman, more than 50% of cases of osteoporosis are associated with secondary causes.61 The contribution of secondary causes to postmenopausal osteoporosis is thought to be lower, although the proportion is unknown. Table 59.4 is by no means exhaustive, but it does emphasize the many medical conditions that have secondary effects on the bone. Of these conditions, hypoestrogenemia, chronic inflammatory disease, glucocorticoid use of greater than 3 months, thyroid hormone excess, and anticonvulsant therapy are the worst TABLE 59.2 Major risk factors for primary osteoporosis in women Personal history of fracture after the age of 50 Family history of osteoporosis or history of fracture in a first-degree relative Current smoking Low body weight (⬍127 lbs) or low BMI Estrogen deficiency at an early age (⬍45 years old) Low lifetime calcium intake

TABLE 59.3

Major risk factors for primary osteoporosis in men

Age (⬎70 years) Low body weight (BMI ⬍20–25 kg/m2) Weight loss (⬎10%) Physical inactivity Previous osteoporotic fracture Current smoking* Low lifetime calcium intake* *

Moderate risk

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offenders. Similarly, any condition for which a patient has required long-term steroids (rheumatologic, inflammatory, dermatologic, etc.) have deleterious effect on bone health. Those diseases that result in malnutrition, calcium or vitamin D deficiency can also result in bone loss and osteoporosis. In secondary osteoporosis, treatment of the underlying condition is critical and is often done in tandem with specific treatments for osteoporosis.

Secondary Osteoporosis and Fracture Risk Factors in Men Secondary causes are thought to be responsible for 30–60% of cases of male osteoporosis. Without question, men are susceptible to many of the same conditions listed in Table 59.4 TABLE 59.4 Secondary medical conditions associated with increased risk of osteoporosis Endocrine disorders

Hyperthyroidism, hypogonadism (primary or secondary), hyperprolactinemia, Cushing syndrome or disease, type 1 diabetes mellitus Rheumatologic disorders Rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, juvenile polyarticular arthritis Gastrointestinal disorders Malabsorption syndromes, inflammatory bowel disease, liver disease or failure (primary biliary cirrhosis and primary sclerosing cholangitis), gastrectomy or dumping syndrome Bone marrow disorders Multiple myeloma, lymphoma, leukemia, mastocytosis, hemochromatosis, hemophilia Genetic syndromes Hypophosphatemic rickets, osteogenesis imperfecta Medications Glucocorticoids, anticonvulsants, heparin, lithium, cytotoxic drugs, premenopausal tamoxifen, L-thyroxine overreplacement, drugs causing hypogonadism (aromatase inhibitors, methotrexate, antimetabolite chemotherapy, gonadotropins-releasing hormone agonists, etc.), cytotoxic drugs, immunosuppressants Other Multiple sclerosis, chronic obstructive pulmonary disease, organ transplantation, chronic renal failure, anorexia nervosa, movement disorders, amyloidosis, HIV/AIDS, cerebrovascular accident, cigarette smoking, heavy alcohol use, sedentary lifestyle or immobilization Source: Institute for Clinical Systems Improvement (ICSI). Diagnosis and Treatment of Osteoporosism, 4th edn. Bloomington, MN: Institute for Clinical Systems Improvement; 2995.

as women, but there are some notable secondary conditions that are particularly prevalent in men.64 Historically, chronic alcoholism has been thought to contribute to low BMD in men. Certainly, it puts one more at risk for fall and fracture, but does it lower BMD? In Liu et al.’s metaanalysis, greater than 20 studies were identified correlating alcohol intake with BMD. Unexpectedly, these studies failed to demonstrate an association between the two.65–68 Nevertheless, alcoholism is still considered a risk factor for low bone mass, perhaps because it precipitates a malnourished state. Androgen deprivation therapy, on the other hand, has definite links to osteoporosis in men.69 In multiple studies of those men treated for prostate cancer either with castration or gonadotropin-releasing hormone agonists, patients were at a statistically significant increased risk for low BMD.70 Those studies that took the analysis a step further to see if these therapies and resultant hypogonadism affected bone density found that lower serum values of testosterone or luteinizing hormone correlated with increased osteoporosis risk.71–73

DIAGNOSIS, SCREENING, AND RISK FACTOR ASSESSMENT Screening for Osteoporosis in Women As is the case with most disease states, the physician should seek early diagnosis, followed by the appropriate therapy, if warranted. For osteoporosis, screening recommendations depend on the publishing organization, and each physician must make his or her own choice as to which set of guidelines to use. In women, the parameters are not so disparate, with most organizations in agreement that, universally, women over the age of 65 should have a bone mineral density evaluation. Most guidelines also recommend that women who are at risk for osteoporosis or have had a fragility fracture be screened earlier. Thus, when dealing with women younger than the age of 65, the physician must obtain an appropriate past medical history and family history to best characterize a patient’s risk for early disease. Table 59.5 summarizes some of the most common recommendations for BMD testing in women.

Screening for Osteoporosis in Men Like other realms of osteoporosis research in men, there is not a great deal of data to support definite screening guidelines based on cost-effectiveness and outcome.74 In publications by both the American College of Physicians and the International Society for Clinical Densitometry, screening recommendations in men have been primarily based on the variable that puts men most at risk: age.63,75 Men older than 70 years or younger men with clinical risk factors for osteoporosis, as described above, should receive a DXA scan

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TABLE 59.5 Bone density testing guidelines for women a

NOF

AACEb

USPSTFc

BMD testing for: BMD testing for: all women 65 years or older ● all women 65 years or older ● younger postmenopausal women with one ● pre- and postmenopausal women who or more risk factors (other than being white, have risk factors for fracture postmenopausal, and female) ● all women over 40-years old who have sustained a fracture ● postmenopausal women who present with fractures (to confirm the diagnosis and ● women beginning or receiving long-term determine disease severity) glucocorticoid therapy ● in women who have x-ray findings that suggest osteoporosis ● in all adult women with symptomatic hyperparathyroidism or other associated diseases or nutritional conditions ●

BMD testing for: all women 65 years or older ● for women at increased risk for fracture, begin screening at age 60 ●

Sources: aNational Osteoporosis Foundation (NOF). Osteoporosis Bone Mass. Available at: www.nof.org/osteoporosis/bonemass.htm (Accessed June 12, 2008) b American Association of Clinical Endocrinologists (AACE) Medical Guidelines for Clinical Practice for the Prevention and Treatment of Postmenopausal Osteoporosis: 2001 Edition, with selected updates for 2003. Endocr Pract 2003;9:544-63. c US Preventive Services Task Force (USPSTF) Recommendations and Rationale: Screening for Osteoporosis in Postmenopausal Women. Available at: http://www.ahrq.gov/clinic/3rduspstf/osteoporosis/osteorr.htm (Accessed June 16, 2008)

as a part of their healthcare maintenance.62 The Institute for Clinical Systems Improvement (ICSI) osteoporosis screening guidelines incorporate the National Osteoporosis Foundation guidelines with added recommendations for men, premenopausal, and postmenopausal women (Table 59.6).76

WHO Fracture Risk Assessment In 2008, the World Health Organization (WHO) released an algorithm to help with the calculation of a patient’s risk of hip or major osteoporotic fracture in a 10-year period of time. Available at www.shef.ac.uk/FRAX, the tool is a multivariate model, incorporating not only measured femoral neck BMD, but also those factors that put a person at risk for osteoporosis.77 As described in previous sections, there are a number of conditions that may put one at higher risk for fracture. This tool includes age, sex, previous fracture, femoral neck BMD, body mass index, past use of prolonged systemic glucocorticoids, history of rheumatoid arthritis, parental history of hip fracture, current cigarette smoking, and current alcohol intake.78 These specific factors were incorporated into the model after evaluation of nine large, prospective, population-based cohorts involving approximately 31 000 women and 15 000 men.79 The FRAX calculator is helpful when determining how measured BMD and known risk factors contribute to fracture risk, and it may help with patient education and therapeutic decision making. In some analyses, a 3% or greater 10-year risk of hip fracture was needed for osteoporosis treatment to be costeffective, but the true implications of the algorithm will, no doubt, take time to surface.80,81 In this, the tool cannot replace clinician-based decision making for the individual.

TABLE 59.6 ICSI Guidelines for BMD testing in high risk individuals Men or women with previous fragility fracture (spontaneous fracture or fracture after a fall from standing height or less) Men or women currently or previously treated with ⬎3 months of glucocorticoid therapy ⬎5 mg/d of prednisone Men or women with radiographic osteopenia or vertebral fracture documented radiographically All women ⬎65 years old Postmenopausal women ⬍65 years with at least one of the following additional risk factors: BMI ⬍20, family history of fracture (first-degree relative older than 45 years), current smoker (⬎1ppd), menopause before 40 years) Men or women with a chronic disease known to be associated with bone loss Premenopausal women with amenorrhea ⬎1 year Men with hypogonadism ⬎5 year Men or women with prolonged immobilization ⬎1 year Men or women who have received solid organ or allogenic bone marrow transplants

Imaging When measuring bone mineral density, dual x-ray absorptiometry (DXA) is considered the gold standard within clinical practice. Its precision depends on the calibration of the machine and the skill of the technologist. If BMD is followed over time, ideally the same machine and technologist should be employed for the most informative trend. DXA is not, however, the only modality for imaging BMD. In the office setting, calcaneal ultrasound can be a quick, though less sensitive and specific, method of gauging bone density. More sophisticated, quantitative computed tomography for

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TABLE 59.7 Condition

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History and physical exam findings in more common conditions causing secondary osteoporosis Pertinent information on history

Hyperthyroidism

Physical exam findings

Weight loss, anxiety, insomnia, heat intolerance, hyperdefecation, tremulousness, menstrual irregularities Primary hyperparathyroidism Nephrolithiasis, abdominal pain, depression, bone pain, constipation, polyuria, polydipsia, myalgias Cushing syndrome Weight gain, rounding of facies, low back pain, nephrolithiasis, polyuria and polydipsia, acne, hirsutism, menstrual irregularities, weakness, new onset diabetes or worsening of control, new diagnosis of hypertension Hypogonadism, male Fatigue, diminished muscle strength, low libido, erectile dysfunction, decreased shaving frequency or thinning of beard; history of mumps, testicular trauma or radiation Hypogonadism, female Premature menopause, primary amenorrhea (no menses in lifetime), cardiac or renal congenital abnormalities (Turner syndrome)

measurement of both central and peripheral sites, quantitative ultrasonometry, radiographic absorptiometry, and singleenergy x-ray absorptiometry have all been used to some extent to help physicians in patient risk assessment for osteoporosis. Quantitative CT has the added benefit of diagnosing osteoporosis via volumetric density measurement rather than areal density, the product of DXA.82

Workup for Causes of Secondary Osteoporosis Because treating a disease process must include addressing and treating underlying conditions, identification of secondary causes of osteoporosis is important. The physician can often employ the usual arsenal of history, physical examination, and laboratory studies to accomplish this investigation. HISTORY AND PHYSICAL EXAM A thorough history and physical examination is invaluable in the workup for secondary osteoporosis. The history should include a record of all lifetime fractures of the patient and family members, growth and development history, dietary practices, and exercise habits. It should include medication records – steroids, anticonvulsants, and other medications should be documented along with their duration of use. Past medical history of concurrent medical conditions which might include rheumatoid arthritis or bowel disease should be investigated in a secondary search. If these conditions are not immediately apparent, the physician should seek to identify undiagnosed secondary causes of osteoporosis. For example, a patient recently given a diagnosis of hypertension or diabetes should be questioned for other symptoms and signs of possible Cushing’s syndrome. Patients with a history of recurrent nephrolithiasis should be probed for other symptoms of hyperparathyroidism.

Goiter, hyperreflexia, resting tremor, documented weight loss, proptosis, exopthalmos, lid lag, smooth, velvety skin Few physical exam findings Moon facies, terminal hair growth, violaceous striae, supraclavicular fullness or retrocervical fat pad, proximal muscle wasting with central obesity, hypertension Small testicular size, eunichoid body habitus, gynecomastia, diminished muscle mass

Evidence of androgenization, short stature, webbed neck (Turner syndrome)

The physical examination, too, can be invaluable in working up secondary causes of osteoporosis in men and women. Resting tachycardia could herald underlying thyroid hormone excess, whereas dermatographia may prompt screening for mastocytosis. Eunuchoid-appearing men with small testes may have underlying hypogonadism. Although not exhaustive, Table 59.7 highlights some of the more common history and physical exam findings that the internist may encounter in a secondary osteoporosis workup. GENERAL LABORATORY INVESTIGATION Currently, there is no consensus as to the most cost-effective, sensitive testing panel for secondary causes of osteoporosis. Testing should be based on the individual, with an eye to postmenopausal women with risk factors for secondary osteoporosis, and any man or premenopausal woman with history of fragility fracture or unexplained bone loss.83 Laboratory Investigation in Women The American Association of Clinical Endocrinologists (AACE) recommends that all women with osteoporosis have a workup consisting of a complete blood cell count, serum chemistry studies (calcium, phosphorus, total protein, albumin, liver enzymes, alkaline phosphatase, creatinine, electrolytes), and urinary calcium excretion.82 Depending on history, physical examination, and clinical suspicion, one might also order a serum thyrotropin level, serum protein electrophoresis and tests for urinary Bence Jones protein (to check for monoclonal gammopathy), anti-tissue transglutaminase antibodies (celiac sprue), 24-hour urinary cortisol, and human immunodeficiency virus antibodies. As is also becoming more routine clinical practice, serum levels of intact PTH and 25-hydroxyvitamin D should also be measured, with supplementation if needed.

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Laboratory Investigation in Men Because secondary causes of osteoporosis in men may be responsible for up to 60% of cases, men with Z scores below ⫺2.0 (2 SD below the age-specific mean) on bone densitometry are candidates for further workup. In addition to those basic tests listed above for women and in Table 59.8, hypogonadism should be considered and evaluated with total serum testosterone and sex hormone-binding globulin levels.82 Primary hypercalciuria is also a common secondary cause of osteoporosis in men; and thus a 24 hour urine calcium excretion should be measured in men.

TREATMENT Lifestyle Like any treatment goal in disease, the physician should keep an eye towards prevention. Osteoporosis is no different – one should seek to prevent a patient’s first fracture and reduce the risk in those who have already sustained a fracture. In this, there are a number of lifestyle modifications to be made that will improve outcomes in osteoporosis.

TABLE 59.8 Recommendations for secondary osteoporosis workup Initial (AACE Recommendations): ● complete blood cell count ● serum chemistry studies (includes calcium, phosphorus, total protein, albumin, liver enzymes, alkaline phosphatase, creatinine, electrolytes) ● 24-hour urinary calcium excretion If clinically indicated: Serum thyrotropin levels ● Intact PTH ● Serum 25-hydroxyvitamin D ● Erythrocyte sedimentation rate ● Serum parathyroid hormone concentration (for possible primary or secondary hyperparathyroidism) ● Urinary free cortisol and other tests for suspected adrenal hypersecretion ● Acid-base studies ● Biochemical markers of bone turnover (for example, bonespecific alkaline phosphatase and urine or serum collagen cross-links) ● Serum tryptase, urine N-methylhistamine, or other tests for mastocytosis ● Serum or urine protein electrophoresis (or both) ● 24 hour urine calcium ● Bone marrow aspiration and biopsy to look for marrow-based diseases ● Undecalcified iliac bone biopsy with double tetracycline labeling (consider only when osteoporosis is diagnosed and the patient has no apparent cause for the condition, no response to therapy, or suspected osteomalacia or mastocytosis) ●

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First and foremost, the patient should be counseled to discontinue those behaviors that are modifiable risk factors. Smoking cessation and only moderate alcohol intake should be stressed at each clinic visit. For persons who have more sedentary lifestyles (or even days filled with everything but exercise), weight-bearing activities have been shown to maintain and even increase bone density.84 Walking, aerobics, and weight lifting should be tailored to a patient’s fitness level. Weight-bearing exercise will also increase overall muscle mass, contributing to improved gait stability for those prone to falls.85 Fall prevention is an important intervention when considering fracture risk.86 Older patients should be evaluated for visual impairment, musculoskeletal disabilities, poor balance, diminished cognition, and postural hypotension. Gait aids, physical therapy, and even environmental modifications such as transitioning the bedroom to the first floor of the home may be important additions to patient safety.87

Nutrition Both calcium and vitamin D supplementation can help to prevent bone loss and perhaps increase BMD. In a recent meta-analysis including 29 randomized trials, Tang et al. demonstrated the benefits of calcium and vitamin D in men and women over the age of 50. In these 64 000 patients, supplementation of 1200 mg calcium and 800 IU vitamin D not only reduced the rate of bone loss in the hip (0.54%) and spine (1.19%), but it also reduced fracture risk (24%). Those patients who were more compliant with the therapy had more diminished rates of new fracture.88 Currently, the NOF recommends that adults under age 50 get 1000 mg of calcium, whereas adults 50 and over need 1200 mg daily.89 Some experts recommend calcium intake of up to 1500 mg per day. Ideally, calcium should come from the diet in the form of dairy products, fortified juices or cereals. For those who do not meet daily recommendations, calcium supplements are available in a variety of compounds, of which calcium carbonate or calcium citrate are the most popular. Cheaper, calcium carbonate should be taken with meals and at doses no higher than 500–600 mg at once. Calcium citrate does not require stomach acid for absorption (and need not be taken with meals), but should be taken in preparations no higher than 500–600 mg at once.90 Vitamin D appears to be as important in the maintenance of bone health as calcium. Reduced sun exposure coupled with aging skin’s diminished ability to produce vitamin D has led to epidemic proportions of vitamin D insufficiency and deficiency. As a result, the NOF recommends that adults under 50 get 400–800 International Units (IU) of vitamin D3 daily, and that adults 50 and over get 800–1000 IU of vitamin D3.91 Some experts suggest doses of up to 2000 units daily. If serum levels of 25-hydroxyvitamin D are lower than 30 ng/ml, vitamin D repletion is indicated. The goal is to maintain serum levels of 25 hydroxy vitamin D at 40 ng/ml

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or greater which is associated with reduced fracture in osteoporotic populations.92

in men. Where applicable, the data will be discussed with gender-specificity. ALENDRONATE IN WOMEN Alendronate, perhaps one of the best known bisphosphonates, was the first drug approved by the FDA for use in the prevention and treatment of osteoporosis in women and men. It is currently available as a daily or weekly formulation, with or without added vitamin D. Since its arrival on the market, four randomized controlled studies have investigated alendronate’s effects on BMD and fracture reduction. Of the earliest studies, Liberman et al. showed that amongst 994 postmenopausal women, alendronate effectively reduced the incidence of morphometrically identified vertebral fractures by 48% over 3 years.96 The studies that followed sought to more clearly define alendronate’s effects on the prevention of new fractures in the vertebrae versus hip versus nonvertebral bone in women with and without prior fractures. BMD data in women taking alendronate was also collected. Much of the alendronate fracture data referenced today stem from the Fracture Intervention Trial (FIT) and FIT-II. This two-arm study was comprised of over 5000 postmenopausal women (ages 55–80), with the women in each arm assigned to either placebo or alendronate 10 mg/d (changed from 5 mg daily in lieu of preliminary evidence suggesting improved BMD efficacy at a higher dose). Participants were then followed up to 4 years for fracture event, BMD changes, and adverse effects. In FIT-I, 2027 women (mean age 71) with prior clinical or radiographically defined vertebral fractures were assigned either alendronate 5 mg daily for 2 years, then 10 mg orally daily for 9 months or placebo. All participants received calcium and vitamin D supplementation. In those patients receiving alendronate, the risk of new morphometrically identified vertebral fractures was reduced by 47%, while the risk of clinically determined fractures decreased by 55%. Multiple new fractures were further reduced by 90%. The risk for hip fractures we reduced by 51%, but alendronate’s effect on other nonvertebral fractures was not significant.97

Medical Therapy: Bisphosphonates/Antiresorptives GENERAL An ideal agent for the treatment for osteoporosis should increase BMD and clinically reduce the likelihood of fracture.93 While diet and lifestyle modifications should be stressed in all patients, medical therapy is often required to halt and hopefully reverse bone loss. Table 59.9 summarizes those medical interventions currently in employed to improve BMD and fracture rate in both men and women, where applicable. Within the therapeutic arsenal, bisphosphonates remain the first-line therapy for men and women with osteoporosis. Targeting the underlying pathophysiology of osteoporosis, bisphosphonates are stable analogs of inorganic pyrophosphate that prevent osteoclastic bone resorption. They selectively bind to the hydroxyapatite crystals in bone, inhibiting demineralization and osteoclast function by blocking steps in cholesterol synthesis.94 Bisphosphonates ultimately act to decrease not only osteoclast activity, but their lifespan and perhaps number.95 The drug class may also have positive effects on osteoblasts by inhibiting osteocyte and osteoblast apoptosis. The end point is a strengthened trabecular framework as osteoblasts continue to build bone. Originally a once-daily preparation, these medications have evolved into more user-friendly preparations – weekly, monthly, and even yearly administration. When treating disease, the physician should seek to prescribe medicines that are efficacious, safe, and tolerated by the patient. Of the oral bisphosphonates that fit these criteria, three will be discussed below: alendronate, risedronate, and ibandronate. Available by IV infusion only, zolendronic acid has also been evaluated in osteoporosis trials. Data for each of these drugs indicate their success in treating postmenopausal osteoporosis, but only alendronate, risedronate, and zoledronic acid trials have highlighted the drugs’ effects

TABLE 59.9 Osteoporosis therapy in women and men Drug

Alendronate Risedronate Ibandronate Zoledronic acid Raloxifene Calcitonin Teriparatide

Decreased vertebral fracture?

Decreased non-vertebral fracture?

Increased vertebral BMD?

Increased nonvertebral BMD?

F

M

F

M

F

M

F

M

Yes Yes Yes Yes Yes Yes Yes

Yes Yes N/D Yes N/D N/D Yes

Yes Yes No Yes No No Yes

No N/D N/D Yes N/D N/D N/D

Yes Yes Yes Yes Yes Yes Yes

Yes Yes N/D Yes N/D Yes Yes

Yes Yes Yes Yes Yes No Yes

Yes Yes N/D Yes N/D No Yes

F ⫽ women; M ⫽ men; N/D ⫽ not done

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In FIT-II, 4432 women without fractures (mean age 68) were also assigned alendronate (5 mg, then 10 mg) versus placebo for an average of 4.2 years. Similar to FIT-I, alendronate reduced the risk of morphometrically identified new vertebral fractures by 44%. Unlike FIT-I, this arm demonstrated no drug effect on clinical vertebral, nonvertebral, hip, or multiple fractures. Only in a FIT-II post hoc analysis was it revealed that those women who entered the study with osteoporosis of the femoral neck (T-score ⫺2.5) had a 36% and 56% risk reduction in any clinical fracture and hip fracture, respectively.98 When FIT-I and II were evaluated as a whole, those women with previous vertebral fracture and/or a diagnosis of osteoporosis via BMD measurements at the femoral neck appeared to benefit the most in reduction of both nonvertebral and hip fractures.99 The multinational study (FOSIT) further reinforced alendronate’s efficacy in risk reduction of new clinical nonvertebral fractures by 47%.100 Each of the trials summarized above not only proved alendronate therapy translated to clinical reduction in fractures, but also showed morphometric improvement in patient BMD. ALENDRONATE IN MEN It was not until 2000 that increasing awareness of the morbidity and mortality of osteoporosis in men took form in two randomized trials designed to examine alendronate’s efficacy in this population.101 In the first of the two studies, Orwoll et al. randomized 241 men (ages 31–87) to receive either alendronate 10 mg orally daily or placebo. It is worth noting that greater than one-third of participants had low serum free testosterone at the outset, whereas men with other secondary causes of osteoporosis (steroid use, vitamin D deficiency, etc.) were excluded from the trial. Inclusion criteria were different from the BMD requirements of the women’s trials – men with a femoral neck BMD of ⬍⫺2 and a lumbar spine BMD of ⬍⫺1 (or a BMD at the femoral neck of ⬍⫺1 in men with vertebral deformities and/or prior osteoporotic fracture) comprised the study population. Also unlike comparable studies in women, those men with digestive difficulties or on NSAIDs were included. Ultimately, after 2 years alendronate significantly both increased BMD at the hip, spine, and total body sites, but also reduced fracture incidence when compared to placebo. A year later, a second, non-blinded study was conducted in a slightly different population of males with osteoporosis which compared alendronate and alfacalcidol.102 These 134 men were randomized to either alendronate 10 mg or 1-alfacalcidol 1 μg daily. Hypogonadal men were excluded, and BMD inclusion criteria (BMD T-score ⬍⫺2.5) were notably more stringent than the Orwoll study. With a mean BMD of the L-spine ⫺3.4 and ⫺.5 at the femoral neck, these patients were more osteoporotic. Interestingly, and perhaps as a result, following 2 years of alendronate participants experienced greater overall BMD increases at all sites measured.

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Although neither of the studies of alendronate in men was large enough to definitively show reduced fracture incidence in sites other than the lumbar spine, pooled results have shown improved BMD in the spine and hip following 2 years of alendronate administration. These results, though derivatives of a more sparse patient population and study number, are comparable to similar trials in postmenopausal women.103 BMD of the lumbar spine increased to a similar degree in both male and female trials. Further, changes in stature and levels of bone turnover markers in both sexes were comparable, suggesting that alendronate’s efficacy is gender-independent.

RISEDRONATE IN WOMEN Another member of the bisphosphonate class, risedronate is available in both weekly and monthly oral preparations. Data on risedronate indicate that it, too, reduces hip and vertebral fractures with concurrent increases in BMD. In the two arms of the Vertebral Efficacy with Risedronate Therapy (VERT) trials, women from North America (VERT-NA) and in Europe and Australia (VERT-MN), were randomized to either placebo or risedronate 5 mg (from 2.5 mg) and followed for 3 years. All participants received calcium and vitamin D supplementation. The study participants had either established osteoporosis and/or at least two radiographically confirmed vertebral fractures (9% in VERT-NA, 35% in VERT-MN). Pooled data after 3 years of the study drug indicated that new, morphometrically identified vertebral fractures were reduced by 61–65% after one year of therapy. By the third year, this risk reduction was 41–49%. In the North American study only, nonvertebral fractures were significantly reduced by 39% after 3 years, whereas the findings in the multinational trial were not significant. Although VERT-MN was not powered to demonstrate a reduction in hip fracture/non-vertebral fracture risk, pooled data indicate risedronate reduces the incidence of new vertebral and hip fractures, sustains fracture reduction, and increases the BMD in women with osteoporosis and prior vertebral fractures.104,105 Triggered by the significant morbidity and mortality associated with hip fractures as compared to other fracture types , the Hip Intervention Program Study Group (HIP) specifically investigated the effects of risedronate on the risk of hip fracture in elderly women aged 70–79 (HIP I) and over 80 years old (HIP II).106 Whereas in HIP I the 5445 women had osteoporosis, as defined by a femoral neck BMD (⬍⫺4 or ⬍⫺3 if one nonskeletal risk factor for fracture), in HIP II, the 3886 women only required one clinical risk factor for a hip fracture to be eligible for enrolment. These risk factors included low femoral neck BMD (⬍⫺4), difficulty standing, poor gait, smoking, previous hip fracture, maternal hip fracture, long hip axis length, and previous fall-related injury. Interestingly, in HIP I, the determinant for risedronate’s effects on hip fracture was prevalence of vertebral fracture

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prior to entering the study. Of the 39% of women in HIP I with vertebral fracture on entry, there was a 60% risk reduction in hip fracture over 3 years. In the remaining 61% of women without vertebral fracture, there was no hip fracture risk reduction. Of those women in HIP II with osteoporotic risk factors alone, risedronate had no significant effect on incidence of hip fractures. Neither arm was without its confounders. In HIP I, there was a low incidence of hip fractures amongst the small group of women. In HIP II, the majority of the participants did not have BMD measurements on entry – of those that did, only 24% (941 women) had osteoporosis, leaving a question as to whether the remainder even had low BMD at the outset despite their advanced age. RISEDRONATE IN MEN To date, there has been only one prospective, randomized control trial investigating risedronate’s effects on the male skeleton.107 For one year, 315 men with primary and secondary osteoporosis were given either risedronate 5 mg or placebo. Both groups were given calcium supplementation. Very much like alendronate, those males taking the bisphosphonate had increases in lumbar spine BMD (4.7% compared to 1.0% increase in placebo). At the level of the total hip and femoral neck, BMD increased 2.7% and 1.8%, respectively. Risedronate also had a significant effect on the incidence of new vertebral fractures, with a reduction of 60% as compared to control. Although this was not a blinded study, it has been one of the few to include men with both secondary and primary osteoporosis. IBANDRONATE Ibandronate is one of the newest oral bisphosphonates on the market. As a result, relevant data on the drug are substantially sparser than for alendronate and risedronate. To this end, there have been no clinical trials to date investigating ibandronate’s effects in the male skeleton; nor has there been enough data in either sex to show statistically significant reductions in hip fracture risk with the use of ibandronate. Vertebral fracture data have been described. The Ibandronate Osteoporosis Vertebral Fracture trial in North America and Europe (BONE) showed that daily ibandronate effectively improved vertebral BMD by 5% and reduced the risk of new vertebral fractures by 62% in postmenopausal women with one or more pre-existing vertebral fractures.108,109 BONE was followed in 2005 with the Monthly Oral Ibandronate In Ladies (MOBILE) study, a 2-year, randomized, double-blind, multinational trial designed to prove the non-inferiority of monthly ibandronate administration as compared to daily. MOBILE enrolled 1609 women with postmenopausal osteoporosis and randomized them to one of three monthly oral regimens (50/50 mg, 100 mg, or 150 mg) versus ibandronate 2.5 mg orally daily. After one year (and sustained through 2 years), once-monthly ibandronate dosing

of 100 mg or 150 mg proved to be non-inferior to daily formulations. Further, with results indicating a ⬎6% lumbar spine BMD increase and ⬎3% total hip BMD increase relative to daily dosing, monthly ibandronate exceeded BMD improvements in total spine and hip, thus making it the preferred dosing of prescribing physicians today.110–113 ZOLEDRONIC ACID Zoledronic acid is an intravenous formulation of bisphosphonate approved for use in postmenopausal osteoporosis. Originally used only for malignant hypercalcemia, in those with osteolytic metastases from breast and lung cancer, and in multiple myleoma, zoledronic acid now plays an important role in osteoporosis therapy.114,115 Its once-yearly administration schedule is appealing as data continue to emerge on poor patient compliance with daily and weekly oral bisphosphonate regimens.116 Daily, and to a somewhat lesser extent, weekly preparations of oral bisphosphonates are met with poor compliance.117 Although no specific qualities seem associated with those women more likely to discontinue therapy or use it sporadically, the inconvenience of taking a drug on an empty stomach, drinking a full glass of water, waiting for 30 minutes, etc. was thought to be a likely trigger.118 Zoledronic acid is also a solution for those patients who cannot tolerate oral bisphosphonates for their gastrointestinal side effects, or for those patients with malabsorption. From the social and economic standpoint, noncompliance is not to be taken lightly; increased or new fractures inevitably translated to hospitalization and health care costs.119,120 ZOLEDRONIC ACID IN WOMEN This bisphosphonate was initially investigated in 2002 when Reid et al. treated 351 postmenopausal women with low bone mineral density in a one-year, randomized, doubleblind, placebo-controlled trial.121 Zoledronic acid was given at 3-month, 6-month, and 12-month intervals for a maximum infusion dose of 4 mg. After one year, those women receiving zoledronic acid – no matter the divided dose – had substantial increases of total spine and femoral neck BMD as compared to placebo, with no real increase in adverse effect. Zoledronic acid seemed to be a solution to compliance issues, but longitudinal data were needed to show that Reid et al.’s results were reproducible and sustained. The HORIZON Pivotal Fracture Trial did just this, paving the way to FDA approval. In this randomized, double-blind, placebo-controlled, multinational study, 7736 postmenopausal women were randomized to zoledronic acid 5 mg infusion or placebo and evaluated at one-year intervals for a median duration of 3 years.122 Primary endpoints included incidence of morphometric vertebral fractures and the incidence of hip fractures. After 3 years, zoledronic acid had significant effects in all areas studied. BMD was increased at the lumbar spine, total

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hip, and femoral neck by 6.7%, 6.0%, and 5.1%, respectively, over 3 years. Furthermore, zoledronic acid significantly reduced the incidence of new vertebral fractures by 70% and hip fractures by 41%. When given as a once-yearly infusion, the medication is well tolerated, and compliance has been increased.123 Additionally, those patients previously on alendronate and other oral regimens may be safely transitioned, with sustained maintenance of bone density.124 ZOLEDRONIC ACID IN MEN Unlike data for many of the other bisphosphonates, men have not been entirely absent from zoledronic acid trials. In part, this is because the context of zoledronic acid use is historically different in men. Rather than therapy for primary osteoporosis, the drug has been evaluated for use in a secondary cause – bone density loss following androgen suppression in prostate cancer treatment.125,126 Results from several randomized trials have indicated that intravenous infusion of zoledronic acid during the course of androgen deprivation both preserves bone density and may suppress bone turnover in those patients with and without bone metastases.127,128 The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial has been the only trial thus far to address the utility of zoledronic acid in men with osteoporosis, as defined by a recent hip fracture.129,130 As a subset of an international, multicenter, randomized, double-blind, placebo-controlled trial involving 2127 patients with recent hip fracture, men represented 24.5% and 23.3% of persons receiving placebo and zoledronic acid 5 mg infusion, respectively. The drug was given within 90 days of hip fracture, and patients were evaluated for new clinical fracture. At the end of up to 5 years, zoledronic acid reduced the rate of new clinical fractures by 35% and improved survival after low-trauma hip fracture. This result was not gender-dependent. More investigation into the efficacy of zoledronic acid is needed for those men with osteoporosis who have not sustained fracture, as well as those who have fractures at non-hip sites. RALOXIFENE Estrogen has known anabolic effects on the bone, as previously discussed, so it makes sense to use these effects as a target for osteoporosis therapy.131 Raloxifene, a selective estrogen modulator (SERM), takes advantage of estrogen’s action on bone formation by selectively stimulating estrogen receptors in the bone with concomitant antagonism of receptors in the endometrium and breast.132 Raloxifene is the only drug of its class approved for the prevention and treatment of osteoporosis.133 Raloxifene in Women To date, raloxifene remains a second line antiresorptive agent in women due to its undemonstrated efficacy in

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preventing hip fractures. The medication has been shown to reduce new vertebral fractures. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, over the course of 36 months, raloxifene effectively increased BMD in the spine as well as nonvertebral sites by 2.7% and 2.4%, respectively.134 Further, at a dose of 120 mg/d, raloxifene was shown to decrease the occurrence of new vertebral fractures by as much as 50% in women without previous fracture, and by 30% in those with previous vertebral fracture. The study was not sufficiently powered to show benefit in drug administration on hip fracture occurrence. A continuation of this study, called CORE, was undertaken to evaluate longer-term effects of raloxifene on the skeleton in addition to incidence of invasive breast cancer.135 After an additional 4 years of therapy, the increases of BMD were maintained, if not improved at all skeletal sites. BMD increases of 2.2% and 3.0% were noted in the lumbar spine and femoral neck, respectively, when compared with placebo. BMD was significantly increased from MORE baseline at all time-points and at both sites with raloxifene. The drug continued to have no effect on nonvertebral fracture risk after 8 years, although study design was not optimal for fracture assessment. It should be noted that raloxifene underwent much scrutiny for its potential risks and benefits in heart disease and breast cancer, and to describe that research would be beyond the scope of this chapter.136,137 Like hormonal replacement, raloxifene is not recommended for women at high risk for deep venous thrombosis or those with vasomotor symptomatology associated with menopause.138 Raloxifene in Men The role of estrogen in the male skeleton may be as important, if not more important than testosterone.139 As discussed, estrogen helps regulate osteoblast proliferation and osteoclast apoptosis, following the aromatization of testosterone. Thus, it makes sense that some research has focused on the effects of raloxifene in osteoporotic men. To date, there are limited data to suggest that raloxifene has a role in treating osteoporotic men with low serum estradiol levels. In those hypogonadal men with non-metastatic prostate cancer undergoing treatment with GnRH agonists, the SERM significantly increased hip and vertebral BMD by 1% at each location.140 The study did not address fracture outcome. Doran et al. published such a study showing that in 50 elderly men with estradiol levels ⬍22 pg/ml demonstrated a decrease in urinary cross-linked N-telopeptide (measure of bone turnover) in a 6-month period.141 In contrast, Ubelhart et al. followed with raloxifene administration in 43 healthy, non-osteoporotic, eugonadal men. In these men, markers of bone formation were diminished (serum osteocalcin and total alkaline phosphatase) while markers of resorption remained unchanged.142 One might argue that raloxifene in those with normal serum estradiol levels could have negative metabolic effects.143

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CALCITONIN Calcitonin acts at the level of the osteoclasts, inhibiting bone resorption via binding to osteoclast surface receptors.144 It comes in intravenous, subcutaneous or, more common, intranasal preparations at doses of 200 IU daily (alternating nostrils).145 Oral preparations are under investigation. Calcitonin in Women Often thought of as a drug to administer in times of hypercalcemic crisis, calcitonin has also been approved for use in postmenopausal women with osteoporosis.146 Data from the Prevent Recurrence of Osteoporotic Fractures (PROOF) study indicates that the benefit of this drug is limited to prevention of vertebral fractures.147 In this study, 1255 postmenopausal women with either osteoporosis of the lumbar spine and one to five previous vertebral fractures were given nasal salmon calcitonin at doses of 100, 200, or 400 IU daily. After 5 years, those women receiving 200 IU calcitonin had an overall reduction of new vertebral fractures by 33%, although the drug had no effect on the incidence of multiple vertebral fractures. For nonvertebral and hip fractures, calcitonin 100 IU showed some benefit in PROOF, and another retrospective analysis indicated minor reduction in hip fractures using calcitonin.148 Unlike other antiresorptive medications, BMD remained unchanged at the levels of the lumbar spine, femoral neck, and trochanter at the end of 5 years when compared with placebo. Data for BMD improvement or fracture reduction has been less than robust with calcitonin, although its biochemical effects on bone microarchitecture may yet suggest a role the medication in osteoporosis treatment. In PROOF, nasal calcitonin at 200 IU daily significantly decreased the serum marker of bone turnover, C-telopeptide, over 5 years of the study when compared to baseline. QUEST was designed to help take this data further.149 In this doubleblind, placebo-controlled trial, 91 postmenopausal women were given calcitonin nasal spray 200 IU daily or placebo and followed for 2 years. Although BMD was collected for the duration, women also underwent testing with high resolution MRI in several regions of the distal radius to evaluate bone microarchitecture. Interestingly, calcitonin preserved trabecular microarchitecture regardless of BMD changes, lending more insight into whether BMD truly parallels fracture risk.150 Calcitonin in Men Although calcitonin has not been approved for use in men with osteoporosis, there have been randomized trials demonstrating it may have benefit in this population. One of the earliest studies was in 12 castrated men who demonstrated rapid bone loss in the lumbar spine.151 Calcitonin was found to significantly decrease, but not normalize urinary hydroxyproline excretion, a measure of bone turnover, after 3

months of treatment. In another small study, Erlacher et al. treated nine male patients vertebral osteoporosis with subcutaneous calcitonin 100 IU three times weekly.152 Patients were treated for 3 months, given a 3-month holiday, and then treated for an additional 3 months. All patients received calcium supplementation. After one year, patients had BMD increases of 2–3% at the lumbar spine and hip, although there was no control group, leaving some debate as to whether the improvement was a result of calcitonin, calcium, or both agents. Over the past few years, there have been two randomized trials to further qualify and quantify calcitonin’s role in the male skeleton. Of the most recent, Toth et al. demonstrated that 200 IU nasal spray administered every other month for 18 months increased the BMD at the spine and femoral neck by ⫹3.5% and ⫹3.2%, respectively.153 This was in contrast to Trovas et al., who demonstrated that calcitonin 200 IU intranasal only increased BMD at the spine after one year.154 The general conclusion amongst studies appears to be improvement in spinal BMD with intermittent calcitonin dosing in males with idiopathic and secondary osteoporosis. Further study will be needed to appropriately address fracture rates and risk reduction with the administration of calcitonin in men.

Anabolic Therapy As noted, bone integrity is multifactorial – a composite of mineralization, microarchitecture, and the balance of osteoclast and osteoblast activity which mediates bone turnover. Up until this point, the antiresorptive therapeutics discussed have targeted the osteoclast, inhibiting destruction of bone to allow for the laying down of new osteoid by osteoblasts and time for mineralization. Anabolic therapy approaches the pathophysiology of osteoporosis from a different angle. These agents directly stimulate bone formation and allow for greater degrees of reconstruction and mineralization than that proposed by antiresorptives.155 PTH/TERIPARATIDE In 2002, rh-PTH(1-34), or teriparatide, was the first anabolic agent approved by the FDA for use in treating both men and women with osteoporosis. Teriparatide is a recombinant human parathyroid hormone analogue and is thought to act via a number of mechanisms to strengthen bone.156 It may enhance mineralization, strengthen microarchitecture, and fortify the periosteal and cortical bone.157,158 Given at intermittent doses, PTH stimulates bone turnover, favoring bone formation over resorption.159 Teriparatide in Women Investigation into this anabolic therapy began far earlier than when teriparatide received formal FDA approval for osteoporosis therapy.160 In 1997, Hodsman et al. conducted

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a small, randomized controlled trial on 30 women with postmenopausal osteoporosis which ultimately showed that cyclical PTH successfully increased spinal BMD by approximately 8–10% over 2 years, without significant effects on femoral BMD.161 Buoyed by such promising results, the Fracture Prevention Trial was a much larger study involving 1637 women with osteoporosis and prior vertebral fracture.159 Assigned either 20 μg or 40 μg PTH(1-34) daily versus placebo, these women were followed for changes in BMD and incidence of new fractures for a mean of 21 months. Compared with placebo, 20 μg and 40 μg teriparatide increased BMD by 9% and 13% in the lumbar spine and 3% and 6% in the femoral neck, respectively. Further, the drug decreased fracture risk. In the lumbar spine, the two doses decreased the risk of new fractures by 65% and 69%, while nonvertebral fractures decreased by 35% and 40%, respectively. More side effects (cramping, nausea) were seen with the higher dose, with little BMD benefit, leading to FDA approval of the 20 μg dose. The use of teriparatide in postmenopausal women has since been explored as a precursor to bisphosphonate therapy or in combination with other antiresorptive therapies. PTH administered with hormone replacement therapy in women with postmenopausal osteoporosis showed vertebral, hip, and total body BMD gains by 13%, 4.4%, 3.7%, respectively, as demonstrated by Cosman et al.162 Conversely, concomitant therapy with PTH and alendronate did not improve patient BMD when compared with PTH alone. In fact, combination therapy seemingly diminished the anabolic effects of teriparatide, as measured by volumetric density.163 Bisphosphonates do, however, seem to play a role in the maintenance of the BMD gained by teriparatide administration. Black et al. addressed this theory with the Parathyroid Hormone and Alendronate (PaTH) study.164 In this investigation, postmenopausal women received one year of parathyroid hormone (1-84), with predicted gains in bone density at the level of the spine and hip. The women then went on to receive either an additional year of alendronate or placebo. BMD gains in the PTH–alendronate group as compared to the losses in the PTH–placebo group were significant in the spine and hip (13.3% and 10.1%, respectively). Alendronate helped to maintain if not increase BMD gains in those treated with one year of PTH (1-84), while those who did not receive bisphosphonate following PTH lost densitometric benefit.

Teriparatide in Men The male skeleton, too, has been studied as an anabolic target for teriparatide. Orwoll et al. took 437 men with idiopathic or hypogonadal osteoporosis (spine or hip BMD ⬍⫺2) and assigned them to teriparatide 20 μg or 40 μg or placebo.165 After 11 months, spinal BMD had increased by

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5.9% (20 μg) and 9% (40 μg) compared to placebo. Femoral neck BMD also increased by 1.5% (20 μg) and 2.9% (40 μg). It should be noted that this study was stopped prematurely when similar studies in rats suggested that PTH therapy may increase one’s risk for osteosarcoma.166 When an oncology panel deemed that these findings were not likely to transfer to humans, Orwoll et al.’s study was continued for an additional 12 months with 355 of the original participants.167 The importance of the study continuation was twofold: On one hand, fracture data could be ascertained at 18 months after therapy was initiated (7 months from drug discontinuation). In those men who received teriparatide, the risk of vertebral fracture was reduced by 51% , with the incidence of moderate or severe fractures reduced by 83%. On the other hand, after PTH therapy, some men went on to receive antiresorptive therapy (bisphosphonate, testosterone). As shown in studies with women, bone mineral density decreased following discontinuation of teriparatide unless patients went on to take antiresorptives. Kurland et al. went on to reinforce the importance of PTH therapy followed by bisphosphonates in their 2004 publication.168 To date, much of the data supports improved BMD and reduced vertebral fractures in those men who take teriparatide, but unlike PTH studies in women, nonvertebral fracture efficacy has yet to emerge.

Hormone Replacement ESTROGEN Physiologically, there is a clear association in the decline of estrogen levels with age and the onset of osteoporosis. It would only make sense that estrogen be used routinely in the prevention and management of postmenopausal osteoporosis. Such was the case until publication of the Women’s Health Initiative (WHI) in 2002. While findings did reflect that estrogen alone or in combination with progesterone decreased bone turnover, bone loss, and fractures, other outcomes make this therapy controversial today.169 In brief, the WHI showed that combination estrogen and progesterone in women was associated with a mildly increased risk of coronary artery disease, stroke, venous thromboembolism, and breast cancer. The WHI also demonstrated that estrogen reduces hip fractures. Estrogen therapy alone came with the same absolute risk increase with the exception of coronary disease.170 Currently, the FDA guidelines recommend estrogen replacement for the prevention of osteoporosis only in those individuals with severe vasomotor symptoms. It remains up to the physician to assess individual patient risk, taking into consideration co-morbid conditions that could be either improved or worsened by hormone replacement. For example, the surgically postmenopausal woman with severe hot flashes may benefit from a short trial of estrogen, whereas this treatment would be contraindicated in the woman with hypertension and diabetes.171

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TESTOSTERONE Hypogonadism is prevalent not only in the aging male with osteoporosis but is also found in younger males with seemingly idiopathic osteoporosis until a testosterone level is checked. As a result, there has been investigation into testosterone replacement in the treatment of osteoporosis. To date, there has been no study using fracture as a primary endpoint.172 In hypogonadal men, testosterone does improve BMD. Amory et al. demonstrated in a 3-year study of hypogonadal men (65 years and over) that testosterone increased spinal BMD by 8.9% when compared to placebo.173 Benito et al. followed 10 hypogonadal men for 2 years, measuring spine and hip BMD via DXA, in addition to microMRI of the distal tibia. Here, too, BMD improved – in the spine by BMD 7.4%, and of the total hip by 3.8%. MRI showed shifts in architectural parameters, suggestive of improved microarchitecture in those men treated with testosterone.174 Despite the benefits that testosterone has in those men with hypogonadism and resultant osteoporosis, there is no real consensus on its use in eugonadal patients. Observational studies have shown that intramuscular testosterone may improve spinal BMD in eugonadal men with idiopathic osteoporosis.175,176 In another series, however, men 65 years and older were treated with transdermal testosterone without significant effect in BMD.177 Because testosterone use is not without side effects including benign prostatic hyperplasia, unearthed prostate cancer, polycythemia, reduced HDL, and sleep apnea, testosterone is not approved therapy for osteoporotic men with normal serum testosterone. Ultimately, the decision must be at the discretion of the physician.178

Emerging Therapies Improved understanding of the pathophysiology of osteoporosis will continue to pave the way for the development of therapeutic interventions.179 Antiresorptive and anabolic drugs are in varied phases of development – each one illustrating different targets in osteoporosis prevention and treatment. SARMS One of the newest undertakings in osteoporosis research is that of the selective androgen receptor modulator (SARM). As discussed above, androgens are responsible for many facets of skeletal growth and remodeling. Administration of testosterone has been problematic due to cardiovascular, prostate, and lipid effects in men, and virilization in women.180 Androgen preparations selective to muscle and bone are in development to counter these side effects.181 To date, animal studies in both ovariectomized (female) and orchiectomized (male) rats have yielded positive results. In both populations, parameters including body composition, muscle mass, and bone density were compared before and after administration of SARMs.182,183 The preparations

improved muscle mass and bone density while decreasing body fat – all welcome components in new therapeutics targeting osteoporosis. STRONTIUM RANELATE Available for the treatment of postmenopausal osteoporosis in Europe, strontium ranelate has yet to be approved in the United States. Further, the drug has not been extensively studied in male osteoporosis. Strontium consists of two atoms of stable strontium and ranelic acid. In humans its mechanism of action is not well understood, although in animals it appears to be anabolic by decreasing bone resorption and increasing formation.184 In a series of trials in postmenopausal women, strontium 2 g/day has been shown to increase bone mineral density at the lumbar spine and reduce the risk of new vertebral fractures.185,186 In larger trials, too, strontium not only reduces the risk of vertebral fracture, but has efficacy in improving BMD at the hip and reduces the risk of fracture at non-vertebral sites.187 These data have been confirmed in a meta analysis.188 DENOSUMAB AND OTHER POTENTIAL THERAPIES Among some of the upcoming antiresorptive agents, denosumab shows much promise as a human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand (RANKL). In binding to RANKL, the antibody inhibits downstream osteoclast differentiation, action, and survival. In this way, denosumab acts much like osteoprotegerin which, in vivo, fulfills the same role. Trials amongst postmenopausal women have thus far shown that denosumab does improve bone mineral density at the lumbar spine and total hip.189 Further, it reduces the markers of bone turnover. The data from larger, upcoming trials should further address fracture prevention data and safety, and denosumab’s efficacy in male osteoporosis has yet to be investigated.190 In addition to those agents listed above, other therapies – both antiresorptive and anabolic – will be emerging soon. Cathepsin K inhibitors are in development to target the protease’s catabolic effects on bone, while upcoming antisclerostin antibodies, activators of the Wnt signaling pathway, should further inhibit bone resorption and target increasing bone formation, respectively.191,192 Oral calcium-sensing receptor antagonists are in development, and are thought to lead to a transient rise in endogenous PTH – much like the exogenous teriparitide.193 Finally, integrin antagonists may interfere with integrins, proteins essential in the adhesion of osteoclasts to bone.194 These emerging therapies highlight the varied steps in bone metabolism that may offer sites for potential osteoporosis drug targets.

CONCLUSION Osteoporosis is common in men and women and will only grow as a major public health problem. While both genders

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are more susceptible to osteoporosis and fractures with age, women have more fractures while fractures in men lead to greater mortality. Current osteoporosis therapies have been well tested in women but variably tested in men, forcing the generalization that most therapies appear to be effective in both genders. Without question, understanding the distinct, gender-specific physiology of bone formation in men and women will lead to therapies that are tailored to address these skeletal differences and improve outcomes.

References 1. Anonymous. Consensus development conference: diagnosis, prophylaxis and treatment of osteoporosis. Am J Med 1993; 94:646–50. 2. National Osteoporosis Foundation. Osteoporosis Disease Statistics: ‘Fast Facts.’ Available at: www.nof.org/osteoporosis/ diseasefacts.htm. (Accessed May 1, 2008.) 3. Melton LJ III, Chriscilles EA, Cooper C, et al. Perspective: how many women have osteoporosis? J Bone Miner Res 1992; 7:1005–10. 4. Scane AC, Sutcliffe AM, Francis RM. Osteoporosis in men. Clin Rheumatol 1993;7:589–601. 5. Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int 2005;16(Suppl. 2):S3–S7. 6. Chrischilles EA, Butler CD, Dais CS, et al. A model of lifetime osteoporosis impact. Arch Intern Med 1991;151:1005–1010. 7. Jordan KM, Cooper C. Epidemiology of osteoporosis. Best Pract Res Clin Rheumatol 2002;16:795–806. 8. Lips P, van Schoor NM. Quality of life in patients with osteoporosis. Osteoporos Int 2005;16:447–455. 9. Greendale GA, Barrett-Connor E, Ingles S, et al. Late physical and functional effects of osteoporotic fracture in women. The Rancho Bernardo Study. J Am Geriatr Soc 1995;43:955–961. 10. Sernbo I, Johnell O. Consequences of a hip fracture: a prospective study over 1 year. Osteoporos Int 1993;3:148–153. 11. Browner WS, Pressman AR, Nevitt MC, et al. Mortality following fractures in older women. The study of osteoporotic fractures. Arch Intern Med 1996;156:1521–1525. 12. Kanis JA, Oden A, Johnell O, et al. The components of excess mortality after hip fracture. Bone 2003;32:468–473. 13. van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone 2001;29:517–522. 14. Hannan MT, Felson DR, Anderson JJ. Bone mineral density in elderly men and women: Results from the Framingham Osteoporosis Study. J Bone Miner Res 1992;7:547–553. 15. Jones G, Nguyen T, Sambrook P, et al. Progressive loss of bone in the femoral neck in elderly people: longitudinal findings from the Dubbo Osteoporosis Epidemiology Study, BMJ 309 691–695 16. Orwoll ES, Klein RF. Osteoporosis in men. Endocr Rev 1995;16:87–116. 17. Nguyen ND, Ahlborg HG, Center JR, et al. Residual lifetime risk of fractures in women and men. J Bone Miner Res 2007;22:781–788. 18. Gruntmanis U. Male osteoporosis: deadly, but ignored. Am J Med Sci 2007;333:85–92. 19. Melton LJ III, Atkinson EJ, Cooper C, et al. Vertebral fractures predict subsequent fractures. Osteoporos Int 1999;10:214–221.

●

Osteoporosis in Men and Women

731

20. Holmberg S, Thorngren KG. Statistical analysis of femoral neck fractures based on 3053 cases. Clin Orthop 1987;218:32–41. 21. Nydegger V, Rizzoli R, Rapin CH, et al. Epidemiology of fractures of the proximal femur in Geneva: incidence, clinical and social aspects. Osteoporos Int 1991;2:42–47. 22. Cooper C, Atkinson EJ, Jacobsen SJ, et al. Population based study of survival after osteoporotic fractures. Am J Epidemiol 1993;137:1001–1005. 23. Center JR, Nguyen TV, Schneider D, et al. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 1999;353:878–882. 24. Hasserius R, Karlsson MK, Jonsson B, et al. Long-term morbidity and mortality after a clinically diagnosed vertebral fracture in the elderly: a 12- and 22-year follow-up of 257 patients. Calcif Tissue Int 2005;76:235–242. 25. Trombetti A, Herrmann F, Hoffmeyer P, et al. Survival and potential years lost after hip fracture in men and age-matched women. Osteoporos Int 2002;13:731–737. 26. Johnell O. The socio-economic burden of fractures: today and in the 21st century. Am J Med 1997;103:20S–26S. 27. Ray NF, Chan JK, Thamer M, et al. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995; report from the National Osteoporosis Foundation. J Bone Miner Res 1997;12:24–35. 28. Gehlbach SH, Burge RT, Puleo E, et al. Hospital care of osteoporosis-related vertebral fractures. Osteoporos Int 2003; 14:53–60. 29. Seeman E. Estrogen, androgen, and the pathogenesis of bone fragility in women and men. Curr Osteoporos Rep 2004;2:90–96. 30. Tupman GS. A study of bone growth in normal children and its relationship to skeletal maturation. J Bone Joint Surg 1962;44B:42–67. 31. Bass S, Delmas PD, Pearce G, et al. The differing tempo of growth in bone size, mass and density in girls is regionspecific. J Clin Invest 1999;104:795–804. 32. Seeman E. Clinical review 137: sexual dimorphism in skeletal size, density and strength. J Clin Endocrinol Metab 2001;86:4576–4584. 33. Seeman E. Pathogenesis of bone fragility in women and men. Lancet 2002;359:1841–1850. 34. Parfitt AM. Quantum concept of bone remodeling and turnover: implications for the pathogenesis of osteoporosis. Calcif Tissue Int 1979;28:1–5. 35. Meier DE, Orwoll ES, Jones JM. Marked disparity between trabecular and cortical bone loss with age in healthy men. Measurement by vertebral computed tomography and radial photon absorptiometry. Ann Intern Med 1984;101:605–612. 36. Ruff CB, Hayes WC. Sex differences in age-related remodeling of the femur and tibia. J Orthop Res 1998;6:886–896. 37. Seeman E. During aging, men lose less bone than women because they gain more periosteal bone, not because they resorb less endosteal bone. Calcif Tissue Int 2001;69:205–208. 38. Lindsay R, Cosman F. Osteoporosis. In: L Jameson, ed. Harrison’s Endocrinology. New York, NY: McGraw–Hill; 2006:467–468. 39. Riggs BL, Khosla S, Melton LJ III. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998;13:763–773.

732

SECTION 10

●

Endocrinology

40. Riggs BL, Khosla S, Melton LJ III. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002;23:279–302. 41. Qu Q, Perala-Heape M, Kapanen A, et al. Estrogen enhances differentiation of osteoblasts in mouse bone marrow culture. Bone 1998;22:201–209. 42. Majeska RJ, Ryaby JT, Einhorn TA. Direct modulation of osteoblastic activity with estrogen. J Bone Joint Surg Am 1994;76A:713–721. 43. Chow J, Tobias JH, Colston KW, Chambers TJ. Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation. J Clin Invest 1992;89:74–78. 44. Hughes DE, Dai A, Tiffee JC, et al. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF beta. Nat Med 1996;2:1132–1136. 45. Gohel A, McCarthy MB, Gronowicz G. Estrogen prevents glucocorticoid-induced apoptosis in osteoblasts in vivo and in vitro. Endocrinology 1999;140:5339–5347. 46. Parfitt AM. Skeletal heterogeneity and the purposes of bone remodeling: implications for the understanding of osteoporosis. In: R Marcus, D Feldman, J Kelsey, eds. Osteoporosis, 2nd ed. San Diego, CA: Academic Press; 2000: 433–447. 47. Frost HM. Bone dynamics in metabolic bone disease. J Bone Joint Surg 1966;48:1192–1203. 48. Bellido T, Jilka R, Boyce B, Girasole G, et al. Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. J Clin Invest 1995;95:2886–2895. 49. Kasperk CH, Wergedal JE, Farley JR, et al. Androgens directly stimulate proliferation of bone cells in vitro. Endocrinology 1989;124:1576–1578. 50. Falahati-Nini A, Riggs BL, Atkinson EJ, et al. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 2000;106:1553–1560. 51. Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331:1056–1061. 52. Morishima A, Grumbach MM, Simpson ER, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689–3698. 53. Carani C, Qin K, Simoni M, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997;337:91–95. 54. Herrmann BL, Saller B, Janssen OE, et al. Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J Clin Endocrinol Metab 2002;87:5476–5484. 55. Bilezikian JP, Morishima A, Bell J, Grumbach MM. Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 1998;339(9):599–603. 56. Wakley GK, Schutte HD Jr, Hannon KS, Turner RT. Androgen treatment prevents loss of cancellous bone in the orchidectomized rat. J Bone Miner Res 1991;6:325–330. 57. Bradney M, Karlsson MK, Duan Y, et al. Heterogeneity in the growth of the axial and appendicular skeleton in boys: implications for the pathogenesis of bone fragility in men. J Bone Miner Res 2000;15:1871–1878.

58. Duan Y, Turner CH, Kim BT, Seeman E. Sexual dimorphism in vertebral fragility is more the result of gender differences in age-related bone gain than bone loss. J Bone Miner Res 2001;16:2267–2275. 59. Mauck K, Clarke B. Diagnosis, screening, prevention, and treatment of osteoporosis. Mayo Clin Proc 2006;81:662–672. 60. Nelson HD, Helfand M, Woolf SH, Allan JD. Screening for postmenopausal osteoporosis: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;137:529–541. 61. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785–795. 62. Liu H, Paige NM, Goldzweig CL, et al. Screening for osteoporosis in men: a systematic review for an American College of Physicians guideline. Ann Intern Med 2008;148:685–701. 63. Qaseem A, Snow V, Shekelle P, et al. Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening for osteoporosis in men: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2008;148:680–684. 64. Glynn NW, Meilahn EN, Charron M, et al. Determinants of bone mineral density in older men. J Bone Miner Res 1995;10:1769–1777. 65. Orwoll ES, Bevan L, Phipps KR. Determinants of bone mineral density in older men. Osteoporos Int 2000;11:815–821. 66. Deutschmann HA, Weger M, Weger W, et al. Search for occult secondary osteoporosis: impact of identified possible risk factors on bone mineral density. J Intern Med 2002;252:389–397. 67. Cauley JA, Fullman RL, Stone KL, et al. Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int 2005;16:1525–1537. 68. Kim MJ, Shim MS, Kim MK, et al. Effect of chronic alcohol ingestion on bone mineral density in males without liver cirrhosis. Korean J Intern Med 2003;18:174–180. 69. Melton LJ III, Alothman KI, Khosla S, et al. Fracture risk following bilateral orchiectomy. J Urol 2003;169:1747–1750. 70. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154–164. 71. Moyad MA. Osteoporosis – Part I: Risk factors and screening. Urol Nurs 2002;22:276–279. 72. Yeh SS, Phanumas D, Hafner A, Schuster MW. Risk factors for osteoporosis in a subgroup of elderly men in a Veterans Administration nursing home. J Invest Med 2002;50:452–457. 73. Stanley HL, Schmitt BP, Poses RM, Deiss WP. Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men? J Am Geriatr Soc 1991;39:766–771. 74. Ebeling PR. Clinical practice. Osteoporosis in men. N Engl J Med 2008;358:1474–1482. 75. Leib ES, Lewiecki EM, Binkley N, Hamdy RS. International Society for Clinical Densitometry. Official positions of the International Society for Clinical Densitometry. J Clin Densitom 2004;7:1–6. 76. Institute for Clinical Systems Improvement (ICSI). Diagnosis and Treatment of Osteoporosis, 4th ed. Bloomington, MN: Institute for Clinical Systems Improvement (ICSI); 2005. 77. Kanis JA, Black D, Cooper C, et al. A new approach to the development of assessment guidelines for osteoporosis. Osteoporos Int 2002;13:527–536.

CHAPTER 59 78. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007;18:1033–1046. 79. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int 2005;16:581–589. 80. Tosteson AN, Melton LJ III, Dawson-Hughes B, et al. National Osteoporosis Foundation Guide Committee. Costeffective osteoporosis treatment thresholds: the United States perspective. Osteoporos Int 2008;19:437–447. 81. Dawson-Hughes B, Tosteson AN, Melton LJ III, et al. National Osteoporosis Foundation Guide Committee. Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the USA. Osteoporos Int 2008;19:449–458. 82. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Prevention and Treatment of Postmenopausal Osteoporosis: 2001 Edition, with selected updates for 2003, Endocr. Pract. 9 (2003) 544–563 83. Kelman A, Lane NE. The management of secondary osteoporosis. Best Pract Res Clin Rheumatol 2005;19:1021–1037. 84. Bonaiuti D, Shea B, Iovine R, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev 2002;40(3):199–209. 85. Taaffe DR, Duret C, Wheeler S, Marcus R. Once-weekly resistance exercise improves muscle strength and neuromuscular performance in older adults. J Am Geriatr Soc 1999;47:1208–1214. 86. Mauck KF, Clarke BL. Diagnosis, screening, prevention, and treatment of osteoporosis. Mayo Clin Proc 2006;81:662–672. 87. Rubenstein LZ, Robbins AS, Josephson KR, et al. The value of assessing falls in an elderly population. A randomized clinical trial. Ann Intern Med 1990;113:308–316. 88. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta analysis. Lancet 2007;370:657–666. 89. National Osteoporosis Foundation, Osteoporosis Prevention, Available at: www.nof.org/prevention/calcium2.htm. (Accessed June 14, 2008.) 90. Mauck KF, Clarke BL. Diagnosis, screening, prevention, and treatment of osteoporosis. Mayo Clin Proc 2006;81:662–672. 91. National Osteoporosis Foundation, Osteoporosis Prevention, Available at: www.nof.org/prevention/vitaminD.htm. (Accessed June 14, 2008.) 92. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357: 266–281. 93. MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197–213. 94. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008, E pub Jan 24. 95. Fleish H. Bisphosphonates: Mechanism of action. Endocr Rev 1998;19:80–100. 96. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

●

Osteoporosis in Men and Women

733

fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437–1443. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535–1541. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077–2082. D.M. Black, D.E. Thompson, D. Bauer, et al. Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial, J. Clin. Endocrinol. Metab. 85 4118–4124. Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: Results of the FOSIT Study. Osteoporos Int 1999;9:461–468. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000;343:604–610. Ringe JD, Faber H, Dorst A. Alendronate treatment of established primary osteoporosis in men: results of a 2-year prospective study. J Clin Endocrinol Metab 2001;86:5252–5255. Ringe JD, Orwoll E, Daifotis A, et al. Treatment of male osteoporosis: recent advances with alendronate. Osteoporos Int 2002;13:195–199. Harris ST, Watts NB, Genant H, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized contolled trial. Vertebral efficacy with risedronate therapy (VERT) Study Group. JAMA 1999;282:1344–1352. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established post-menopausal osteoporosis. Osteoporos Int 2000;11:83–91. McClung M, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:333–340. Ringe JD, Faber H, Farahmand P, et al. Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study. Rheumatol Int 2006;26:427–431. Delmas PD, Recker RR, Chesnut CH, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int 2004;15:792–798. Chesnut CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004;19:1241–1249. Reginster JY, Felsenberg D, Cooper C, et al. A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate. Osteoporos Int 2006;17:159–166. Miller PD, McClung MR, Macovei L, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res 2005;20:1315–1322. Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal

734

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

SECTION 10

●

Endocrinology

osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis 2006;65:654–661. Pyon EY. Once-monthly ibandronate for postmenopausal osteoporosis: review of a new dosing regimen. Clin Ther 2006;28:475–490. Body JJ, Lortholary A, Romieu G, et al. A dose-finding study of zoledronate in hypercalcemic cancer patients. J Bone Miner Res 1999;14:1557–1561. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558–567. Rackoff PJ, Sebba A. Optimizing administration of bisphosphonates in women with postmenopausal osteoporosis. Treat Endocrinol 2005;4:245–251. Cramer JA, Amonkar MM, Hebborn A, Altman R. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin 2005;21:1453–1460. Lo JC, Pressman AR, Omar MA, Ettinger B. Persistence with weekly alendronate therapy among postmenopausal women. Osteoporos Int 2006;17:922–928. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc 2006;81:1013–1022. Huybrechts KF, Ishak KJ, Caro JJ. Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Bone 2006;38:922–928. Reid I, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653–661. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809–1822. Devogelaer JP, Brown JP, Burckhardt P, et al. Zoledronic acid efficacy and safety over five years in postmenopausal osteoporosis. Osteoporosis International 2007;8:1211–1218. McClung M, Recker R, Miller P, et al. Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate. Bone 2007;41:122–128. Israeli RS, Rosenberg SJ, Saltzstein DR, et al. The effect of zoledronic acid on bone mineral density in patients undergoing androgen deprivation therapy. Clin Genitourin Cancer 2007;5:271–277. Rodrigues P, Hering FO, Bruna P, et al. Comparative study of the protective effect of different intravenous bisphosphonates on the decrease in bone mineral density in patients submitted to radical prostatectomy undergoing androgen deprivation therapy. A prospective open-label controlled study. Int J Urol 2007;14:317–320. Smith MR, Eastham J, Gleason DM, et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003;169:2008–2012. Michaelson MD, Kaufman DS, Lee H, et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 2007;25:1038–1042.

129. Colón-Emeric CS, Caminis J, Suh TT, et al. The HORIZON Recurrent Fracture Trial: design of a clinical trial in the prevention of subsequent fractures after low trauma hip fracture repair. Curr Med Res Opin 2004;20:903–910. 130. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799–1809. 131. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641–1647. 132. Fuchs-Young R, Glasebrook AL, Short LL, et al. Raloxifene is a tissue-selective agonist/antagonist that functions through the estrogen receptor. Ann NY Acad Sci 1995;761:355–360. 133. Goldstein SR. Selective estrogen receptor modulators: a new category of compounds to extend postmenopausal women’s health. Int J Fertil Womens Med 1999;44:221–226. 134. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287:847–857. 135. Siris ES, Harris ST, Eastell R, et al. Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res 2005;20:1514–1524. 136. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125–137. 137. Ensrud KE, Stock JL, Barrett-Connor E, et al. Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial. J Bone Miner Res 2008;23:112–120. 138. Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445–1451. 139. Khosla S, Melton LJ III, Riggs BL. Clinical review 144: estrogen and the male skeleton. J Clin Endocrinol Metab 2002;87:1443–1450. 140. Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab 2004;89:3841–3846. 141. Doran PM, Riggs BL, Atkinson EJ, et al. Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men. J Bone Miner Res 2001;16:2118–2125. 142. Uebelhart B, Herrmann F, Pavo I, et al. Raloxifene treatment is associated with increased serum estradiol and decreased bone remodeling in healthy middle-aged men with low sex hormone levels. J Bone Miner Res 2004;19:1518–1524. 143. Plouffe L Jr., Siddhanti S. The effect of selective estrogen receptor modulators on parameters of the hypothalamic– pituitary–gonadal axis. Ann NY Acad Sci 2001;949:251–258. 144. Nicholson G, Moseley J, Sexton P, et al. Abundant calcitonin receptors in isolate rat osteoclasts, biochemical, and autoradiographic characterization. J Clin Invest 1986;78:355–360. 145. Chesnut CH III, Azria M, Silverman S, et al. Salmon calcitonin: a review of current and future therapeutic indications. Osteoporos Int 2008;19:479–491.

CHAPTER 59 146. Pecherstorfer M, Brenner K, Zojer N. Current management strategies for hypercalcemia. Treat Endocrinol 2003;2: 273–292. 147. Chesnut CH III, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med 2000;109:267–276. 148. Kanis JA, Johnell O, Gullberg B, et al. Evidence for efficacy of drugs affecting bone metabolism in preventing hip fracture. BMJ 1992;305:1124–1128. 149. Chesnut CH III, Majumdar S, Newitt DC, et al. Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study. J Bone Miner Res 2005;20:1548–1561. 150. Marcus R, Wong M, Heath H III, et al. Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint. Endocr Rev 2002;23:16–37. 151. Stepan JJ, Lachman M, Zverina J, et al. Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J Clin Endocrinol Metab 1989;69:523–527. 152. Erlacher L, Kettenbach J, Kiener H, et al. Salmon calcitonin and calcium in the treatment of male osteoporosis: the effect on bone mineral density. Wien Klin Wochenschr 1997;109:270–274. 153. Toth E, Csupor E, Meszaros S, et al. The effect of intranasal salmon calcitonin therapy on bone mineral density in idiopathic male osteoporosis without vertebral fractures-an open label study. Bone 2005;36:47–51. 154. Trovas GP, Lyritis GP, Galanos A, et al. A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers. J Bone Miner Res 2002;17:521–527. 155. Rosen CJ, Bilezikian JP. Anabolic therapy for osteoporosis. J Clin Endocrinol Metab 2001;86:957–964. 156. Paschalis EP, Glass EV, Donley DW, et al. Bone mineral and collagen quality in iliac crest biopsies of patients given teriparatide: new results from the fracture prevention trial. J Clin Endocrinol Metab 2005;90:4644–4649. 157. Dempster DW, Cosman F, Kurland ES, et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res 2001;16:1846–1853. 158. Parfitt AM. Parathyroid hormone and periosteal bone expansion. J Bone Miner Res 2002;17:1741–1743. 159. Cosman F, Nieves J, Woelfert L, et al. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001;16:925–931. 160. Cosman F, Lindsay R. Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence. Calcif Tissue Int 1998;62:475–480. 161. Hodsman AB, Fraher LJ, Watson PH, et al. A randomized controlled trial to compare the efficacy of cyclical parathyroid hormone versus cyclical parathyroid hormone and sequential calcitonin to improve bone mass in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 1997;82:620–628. 162. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density

163.

164.

165.

166.

167.

168.

169.

170.

171. 172. 173.

174.

175.

176.

177.

178.

179.

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in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434–1441. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207–1215. Black DM, Bilezikian JP, Ensrud KE, et al. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 2005;353:555–565. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 2003;18:9–17. Vahle JL, Sato M, Long GG, et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol 2002;30:312–321. Kaufman J-M, Orwoll E, Goemaere S, et al. Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy. Osteoporos Int 2005;16:510–516. Kurland ES, Heller SL, Diamond B. The importance of bisphosphonate therapy in maintaining bone mass in men after therapy with teriparatide [human parathyroid hormone (1-34)]. Osteoporos Int 2004;15:992–997. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:701–712. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. Mauck K, Clarke B. Diagnosis, screening, prevention, and treatment of osteoporosis. Mayo Clin Proc 2006;81:662–672. Ebeling PR. Clinical practice. Osteoporosis in men. N Engl J Med 2008;358:1474–1482. Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004;89:503–510. Benito M, Vasilic B, Wehrli FW, et al. Effects of testosterone replacement on trabecular architecture in hypogonadal men. J Bone Miner Res 2005;20:1785–1791. Anderson FH, Francis RM, Faulkner K. Androgen supplementation in eugonadal men with osteoporosis – effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. Bone 1996;18:171–177. Finklestein JS, Klibanski A, Neer RM, et al. Increases in bone density during treatment of men with idiopathic hypogonadotrophic hypogonadism. J Clin Endocrinol Metab 1989;69:776–783. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999;84:1966–1972. Anderson F, Francis RM, Peaston RT, et al. Androgen supplementation in eugonadal men with osteoporosis: effects of six months’ treatment on markers of bone formation and resorption. J Bone Miner Res 1997;12:472–478. Becker C. Antiresorptive therapies for osteoporosis in women and men. In: ML Legato, ed. Principles of Gender-Specific

736

180.

181.

182.

183.

184.

185.

186.

187.

SECTION 10

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Medicine. New York, NY: Academic Press; 2004:1010–1020, Section 11 Bone, ch. 93. Bhasin S, Bremner WJ. Clinical Review 85: Emerging issues in androgen replacement therapy. J Clin Endocrinol Metab 1997;82:3–8. Rosen J, Negro-Vilar A. Novel, non-steroidal, selective androgen receptor modulators (SARMs) with anabolic activity in bone and muscle and improved safety profile. J Musculoskelet Neuronal Interact 2002;2:222–224. Kearbey JD, Gao W, Narayanan R, et al. Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. Pharm Res 2007; 24:328–335. Hanada K, Furuya K, Yamamoto N, et al. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol Pharm Bull 2003;26:1563–1569. Bonnelye E, Chabadel A, Saltel F, et al. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone 2008;42:129–138. Meunier PJ, Slosman DO, Delmas PD, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis – a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab 2002;87:2060–2066. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–468. Reginster JY, Felsenberg D, Boonen S, et al. Effects of longterm strontium ranelate treatment on the risk of nonvertebral

188.

189.

190.

191. 192.

193.

194.

and vertebral fractures in postmenopausal osteoporosis: results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum 2008;58:1687–1695. O’Donnell S, Cranney A, Wells GA, et al. Strontium ranelate for preventing and treating postmenopausal osteoporosis. Cochrane Database Syst Rev 2006;18, CD005326. McClung MR, Lewiecki EM, Cohen SB, et al. AMG 162 Bone Loss Study Group. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;54:821–831. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 2008;93:2149–2157. Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 2008;83:172–176. Li X, Ominsky MS, Warmington KS, et al. Sclerostin antibody treatment increases bone formation, bone mass and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 2008, Epub Dec 2. Arey BJ, Seethala R, Ma Z, et al. A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo. Endocrinology 2005;146:2015–2022. Murphy MG, Cerchio K, Stoch SA, et al. L-000845704 Study Group. Effect of L-000845704, an alphaVbeta3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J Clin Endocrinol Metab 2005;90:2022–2028.

C HA PTER

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Testosterone Replacement Therapy in Men and Women DIALA EL-MAOUCHE1, AND ADRIAN DOBS2 1

Post-doctoral Fellow, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Professor of Medicine and Oncology, The Johns Hopkins University School of Medicine, Department of Medicine and Oncology, Baltimore, MD, USA

In the nineteenth century, the French neuroscientist Charles Brown-Séquard rejuvenated himself by injecting extracts of guinea pig testes, and claimed that this ‘elixir of life’ had restored his potency and virility. Years later, many physicians were injecting this solution into their patients, and many were intrigued by its mysterious role as a ‘fountain of youth.’ Testosterone was the first hormone to be discovered and to be chemically synthesized but, many years later, we are still learning about the role of testosterone in aging. Testosterone has received a lot of praise and also skepticism for claiming its role in ‘restoring youth’ but a great deal is unknown about its efficacy, safety, and mechanism of action. Only recently testosterone is proving to be more than a drug for restoring sexuality; it is an important regulator of many physiologic effects. As testosterone is associated with masculinity, it has had no role in women until recently, when evidence started to show that testosterone may play a role beyond masculinity in both men and women.

and peripheral tissues, as well as in the ovaries. The conversion of testosterone to its more powerful metabolite DHT takes place in the testis and in the peripheral tissues via 5α-reductases. Testosterone circulates in the blood in two forms: it can either be free (unbound) T, which constitutes around 2% of total T, or it can be bound to plasma proteins, which constitutes around 98% of the total T. The two plasma proteins that bind T are sex-hormone-binding globulin (SHBG) and albumin. In men, SHBG binds around 40% of T and albumin binds the remaining 60%; whereas in women, SHBG binds most of the T and albumin binds around 25%. Because the affinity of testosterone to SHBG is much higher than that to albumin, T that is bound to albumin can rapidly dissociate and is therefore considered, along with free testosterone, bioavailable testosterone. Testosterone is metabolized mainly in the liver, where it is oxidized to DHT, etiocholanone, androsterone, and 3αandrostenediol. Testosterone and its metabolites can be glucourinated or sulfated into water-soluble forms which are excreted in the urine and bile. It can also be metabolized in the peripheral tissues, mainly prostate and skin, where it is converted to the more potent androgen DHT, by the enzyme 5α-reductase. Testosterone can also be aromatized to estradiol by the enzyme CYP-19 aromatase, mostly in the adipose tissues. The effect of androgens on target tissues is mediated by the androgen receptor (AR), located in the cytoplasm and the nucleus. After the lipophilic androgen crosses the cell membrane, it binds to the AR and is translocated to the nucleus, where it directly binds DNA and induces gene expression. Both T and DHT are direct-acting androgens which bind to the same AR, but DHT binds to AR with almost double the affinity of T, which explains its more potent nature.1

ANDROGEN PHYSIOLOGY The term androgen comprises the steroids testosterone (T), androstenedione, dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS), and dihydrotestosterone (DHT). Testosterone and DHT are the only direct-acting androgens, whereas the other androgens are precursors of testosterone and need to be converted to testosterone before they exert their effects. Androgens are 19-C steroids synthesized from the precursor cholesterol in a series of enzymatic reactions that convert 21-C steroids to 19-C steroids, which include DHEA and androstenedione. This common pathway is shared by the adrenals, testes, and ovaries. The conversion of androstenedione to testosterone takes place in the testis Principles of Gender-Specific Medicine

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ANDROGEN PRODUCTION IN MEN Androgen synthesis and secretion in men is regulated by the complex interaction between the hypothalamus–pituitary– testicular axis. The hypothalamus secretes gonadotropinreleasing hormone (GnRH) which stimulates the pituitary gland into secreting luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates testicular Leydig cell secretion of T whereas FSH stimulates spermatogenesis in Sertoli cells of the seminiferous tubules. The hypothalamus and pituitary are in return controlled by negative feedback by testosterone, inhibin, and estrogen. GnRH secretion by the hypothalamus occurs in a pulsatile manner, peaking every 60–90 minutes, with corresponding pulsatile secretion of LH and FSH. GnRH is also influenced by a circadian rhythm, where in young men, testosterone shows a diurnal variation with peak levels in the early morning. It is unknown if this diurnal variation is maintained in older men, as the literature reports different findings. Testosterone secretion in men is derived predominantly from the Leydig cells, which secrete 3–10 mg of T per day, constituting around 95% of total testosterone. The remaining testosterone is secreted by the adrenal glands, directly in the form of testosterone, but mostly by peripheral conversion of androstenedione to testosterone. DHT on the other hand is mostly derived from peripheral conversion of testosterone, whereas very little is secreted by the testis. Along with testosterone, DHT, and DHEA, the testes also secrete a small amount of estradiol, estrone, and pregnenolone.

Androgen Levels in Aging Men After the age of 50, testosterone levels in men decline about 1% per year, independent of other factors.2 At the level of the hypothalamus, the activity of the GnRH pulse generator is thought to be reduced with old age, with possible loss of circadian rhythm. At the level of the testicles, Leydig cell response to GnRH is also reduced with aging. Levels of SHBG are known to increase with age, thereby causing the free level of testosterone to decrease. Co-morbid agerelated health status, chronic diseases, medications, smoking, alcohol, and lifestyle are all factors that contribute to reduced testosterone levels in older men. Hypogonadism in men is defined as the inadequate production of testosterone or sperm, associated with clinical symptoms of androgen deficiency. Andropause, the decline of androgens with aging in men, is related to the symptoms of hypogonadism as a result of the reduced testosterone levels, and not merely reduced testosterone levels. Symptoms of hypogonadism include fatigue, impaired libido, erectile dysfunction, and reduced muscle mass along with other symptoms (Table 60.1). Unlike menopause, hormone levels tend to decline modestly rather than dramatically, and the associated symptoms may or may not be present. Levels of DHEA, DHEAS, and androstenedione are also thought to

TABLE 60.1 Symptoms and signs of male hypogonadism Symptoms

Signs

Loss of body (axillary and pubic) hair, reduced shaving Very small or shrinking testes (⬍5 ml) Height loss, low-trauma fracture Reduced muscle bulk and strength, increased body fat or BMI Inability to father children, oligo- or azo-spermia

Diminished libido, erectile dysfunction Hot flushes, sweats Decreased energy or motivation, depressed mood Poor concentration and memory, sleep disturbance Mild anemia

Adapted from Endocrine Society Clinical Practice Guidelines 2006

decline with age; the extent to which those declines contribute to symptoms of hypogonadism is unknown.3

ETIOLOGY AND PREVALENCE OF HYPOGONADISM IN MEN Primary hypogonadism results from failure of the testes to produce testosterone, and is associated with increased gonadotropins (FSH, LH) due to loss of negative feedback. Secondary hypogonadism, or hypogonadotropic hypogonadism is due to pituitary or hypothalamic disorders and is characterized by reduced or inappropriately normal levels of LH and FSH in the presence of low testosterone levels. Causes of hypogonadism are outlined in Table 60.2. Conditions that increase SHBG such as obesity, glucocorticoids, and thyroxine, also reduce the level of testosterone (Table 60.3). The prevalence of hypogonadism in aging men, defined by the Baltimore Longitudinal Study as levels below the 2.5th percentile for young men, increases from 35% for men in their 60s to 90% for men in their 80s using the free T index.4 The prevalence of hypogonadism in systemic illness and other conditions has been assessed by several studies, and has been found to be significantly higher in obesity, chronic opiate use, diabetes, hypertension, and HIV-infection (Figure 60.1). Severe illness, stress, malnutrition and chronic disease states such as cancer, end-stage renal disease, and intense exercise can also cause hypogonadism. Although the mechanism of hypogonadism in these states in not entirely clear, but it is believed to be mostly through a central mechanism; except for HIV where the mechanism is more complex and primary gonadal failure might also contribute to hypogonadism.5 The prevalence of hypogonadism in systemic illness and its impact on morbidity and mortality is a new concept that might change the approach to T deficiency as more knowledge is gained in this area.

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TABLE 60.2 Causes of hypogonadism in men Mechanism

Cause

Primary (testicular) Congenital

Klinefelter syndrome, anorchia due to bilateral torsion or vanishing testes syndrome, sex chromosomal disorders Mumps orchitis, chemotherapy, radiotherapy, trauma Ketoconazole, cyclophosphamide (inhibit gonadal steroid production) Kallmann syndrome (isolated hypogonadotropic hypogonadism), Prader–Willi (CNS syndrome) Compressing tumor, trauma, radiation, infiltrative disease (sarcoidosis, histiocytosis, hemochromosytosis), prolactinoma, eating disorders, excessive exercise, marijuana Opiates (inhibit GnRH relsease), glucocorticoids and anabolic steroids (inhibit gonadotropin release), phenothiazines and H2-blockers (increase prolactin) Aging, alcoholism, hemochromatosis, sickle cell disease Androgen insensitivity at androgen-receptor (AR) or LH-receptor level, type II 5-α-reductase deficiency

Acquired Medication-related Secondary (central) Congenital Acquired

Medication-related

Mixed (Primary and Secondary) Other

Adapted from Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology, 11th edn. Philadelphia, PA: Saunders; 2007

TABLE 60.3 Conditions associated with SHBG alterations Increased SHBG

Decreased SHBG

Aging Hyperthyroidism or use of thyroid hormone supplement

Moderate obesity

Hepatic cirrhosis Use of estrogens Use of anti-convulsants HIV-infection

Use of progestins, glucocorticoids, androgenic steroids Nephrotic syndrome Hypothyrodism

Adapted from Endocrine Society Clinical Practice Guidelines 2006

FIGURE 60.1 Prevalence of hypogonadism in systemic illness and other conditions. Adapted from Daniell HW. J Pain 2002;3:377–84; Dobs AS. Baillière’s Clin Endocrinol Metab 1998;12:379–90; Grinspoon S, et al. Ann Intern Med 1998;129:18–26; Mulligan T, et al. Int J Clin Pract 2006;60:762–9

Evaluation and Diagnosis of Hypogonadism in Men In ‘classic hypogonadism,’ or established causes of primary or secondary hypogonadism, diagnosis is usually straightforward and testosterone replacement is a clear indication.

There is great controversy, however, over diagnosing hypogonadism that is associated with age, or more importantly, controversy over indication of testosterone replacement in this population. There is growing awareness of the ageassociated decline in testosterone levels, as this syndrome has been given several names like ‘late-onset hypogonadism’ or ‘partial androgen decline in aging males’. Several problems exist in dealing with this definition. First, none of the available means for measuring T is reliable or accurate. Immune-assay with extraction and chromatography is an assay that offers increased sensitivity by removing proteins that interfere with measurement, but is still not validated for T measurement. Mass spectrometry offers some improvement over immune-assays but is expensive and not widely available. Total T is the most commonly used screening test for hypogonadism, and as it is affected by SHBG, it is important to consider all conditions that might alter these levels (Table 60.3). In such cases, bioavailable or free T levels are better indicators of androgen status. Free Androgen Index (FAI), a measure of T/SHBG, is another alternative and is commonly used in women. Testosterone levels are usually measured in the morning to account for the circadian rhythm of production, although this is not commonly preserved in elderly men. The second problem with defining hypogonadism is the cut-off levels for testosterone. Studies define hypogonadism by T levels below the 2.5th percentile of T level curve in young men. The Massachusetts Male Aging Study found those numbers to be 251, 216, 196, 156 ng/dl for men in their 40s, 50s, 60s, and 70s respectively.6 Most sources use a lower limit – between 250 and 350 ng/dl – for total T to define hypogonadism. The diagnosis of hypogonadism, however, relies primarily on physical exam and history, with symptoms and signs consistent with hypogonadism

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Male 50 years old and over

Testosterone: (T) tT: total T fT: free T bT: bioavailable T

Screen for relevant symptoms (orally or via questionnaire) in stable, non-hospitalized man

Symptoms present

totT < 200 ng/dl* Androgen deficiency

Measure early morning serum totT:

totT 200-400 ng/dl Repeat, if still within range:

totT > 400 ng/dl No T deficiency

Calculate fT and/or bT from tT and SHBG OR Measure early morning fT by dialysis method OR Measure bT by ammonium sulfate method

T normal Defer treatment, Repeat test in 6 months

Low T confirmed Measure early morning LH serum and prolactin level

If totT < 150ng/dl + elevated prolactin or subnormal/ inappropriately normal LH MRI of sella turcica/ refer to endocrinologist

If LH, prolactin normal R/O absolute contraindications, consider relative contraindications

Contraindications present Defer TRT

No contraindications Obtain baseline Hct, PSA, DRE, if normal Consider TRT

* If low SHBG suspected (e.g. nephrotic), follow guidelines of totT 200-400

FIGURE 60.2 Algorithm for initiation of Testosterone Replacement Therapy (TRT) in men. Adapted from Cunningham G, Swerdloff RS. Summary from the Second Annual Andropause Consensus Meeting. Bethesda, MD: The Endocrine Society; 2001

(Table 60.1). Several questionnaires have been developed to help assess the symptoms of hypogonadism in men, including the St Louis University ADAM questionnaire, which serves as a tool for forming a clinical diagnosis.7 An algorithm has also been designed to aid with the diagnosis and decision for initiating testosterone replacement therapy (TRT) (Figure 60.2). Aging is associated with symptoms and signs that are very similar to those of hypogonadism, but it is unknown if these symptoms are actually due to declining T. As the symptoms of hypogonadism are largely non-specific, and biochemical diagnosis is not reliable, diagnosis of hypogonadism remains subjective when T levels are borderline and some symptoms are present. Lastly, it is unknown how much TRT in this population would actually restore good health or functioning comparable to that in young men. Evidence on TRT has shown

clear benefits on sexual functioning, with early evidence on benefits with bone, muscle, and quality of life. Recent studies provide evidence that relates mortality to T levels in men. The Rancho Bernardo study, which followed men over 20 years, found that men with T levels in the lowest quartile were 40% more likely to die than those with higher levels, independent of other variables.8 The same study also found that low T also predicted cardiovascular mortality, a new and interesting finding which challenges the common concerns of T and cardiovascular risk. Two previous studies have shown an inverse relation between T levels and mortality,9,10 although results of the Massachusetts Male Aging Study did not show similar findings.11 As many areas are still uncertain, the ultimate benefits of TRT are still under study and a lot remains to be known. TRT is associated with cardiovascular and prostate-related

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safety concerns, and decision to treat older men should always be guided by evaluating the risk-benefit ratio using the available data. The role of TRT in systemic illness is even more controversial, as information on the role of testosterone in such conditions is now emerging.

Testosterone Therapy Modalities for Men The earliest form of testosterone replacement began in the 1940s with the development of subdermal testosterone implants, followed by the development of testosterone esters in the 1950s. Esterification of testosterone renders the molecule lipid soluble and suitable for intramuscular injection. Intramuscular testosterone was the most widely used form of testosterone for years, and remains a common and inexpensive modality in spite of its associated unfavorable pharmacokinetic profile of fluctuating T levels. Oral testosterone was later developed, and required alkylation of testosterone in order to avoid first-pass hepatic metabolism. Oral formulations, however, were associated with concerns over liver safety from hepatic adenomas to hepatic cancers

TABLE 60.4

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and other pathologies; and are currently not recommended. Transdermal delivery of testosterone became available in the early 1990s with the development of the scrotal patch followed by non-scrotal transdermal patch and later gel. The scrotal patch was developed on the basis of enhanced absorption of the thin and vascular scrotal skin. Poor adherence to the skin and other limitations led to its discontinuation in the US. Transdermal patches by daily administration offer the advantage of mimicking the circadian rhythm, but are associated with local skin irritation due to permeation enhancers, a side effect that occurs in one-third of users. Transdermal gel is now the most commonly used formulation of TRT despite its expensive cost, and seems to offer convenient tolerability and safety. The buccal form of testosterone was then developed, consisting of a tablet-like system which adheres to the buccal mucosa and is absorbed by the buccal venous system thereby avoiding first-pass hepatic degradation. This formulation is associated with adverse events like gum or mouth irritation and bitter taste. Testosterone modalities available in the United States, with the recommended dose, advantages, and disadvantages, are presented in Table 60.4.

Testosterone modalities available in the US

Formulation

Recommended dose

Monitoring of T levels

Advantages

Disadvantages

Injectable esters Testosterone enanthate/cypionate

100 mg every week or 200 mg every 2 weeks

Midway between injections

Inexpensive; administered every 2 weeks

‘Roller coaster’ pharmacokinetics commonly associated with mood swings; painful injections

2–6 pellets of 75 mg, every 3–6 months

No standard interval for monitoring

Convenient 6 month biological duration

Expensive; requires small incision; high rate of extrusion; available only through manufacturer

Buccal testosterone Striant®

30 mg b.i.d.

Immediately before or after application of new system

Testosterone levels within physiological range

Expensive; twice-daily dosing; possible oral irritation

Testosterone patch Androderm

5 mg/day

3–12 hours after application of patch

Mimics circadian rhythm

Expensive, daily administration; skin irritation in 30% of patients

Testosterone gel Androgel/TestogelTestim

5 g/day

Any time after 1 week of treatment

Testosterone levels within physiological range

Expensive; daily administration; possible transference to intimate contacts within 6 hours of application

Testosterone pellets Testopel®

Adapted from Edelstein D, Dobs A, Basaria S. Emerging drugs for hypogonadism. Expert Opin Emerg Drugs 2006;1(4):685–707

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The Role of Endogenous and Exogenous Testosterone in Men SEXUAL FUNCTION Sexual dysfunction is the most common presentation of androgen deficiency in hypogonadal men. The incidence of sexual function in hypogonadal men is unknown, but decline in sexual function with age is common. Up to35% of men with ED are hypogonadal,12 but since many factors are involved in erectile physiology, investigation of secondary causes should always be considered. The relation between testosterone levels and sexual function has not been established, but TRT has been reported to improve sexual function in elderly hypogonadal men in a good number of studies. Animal studies have shown that T acts on the dopaminergic receptors in the hypothalamus to increase rewardseeking and motivational behavior in male mammals.13 Castration in animals causes smooth muscle apoptosis and increased collagen deposition in the corpora cavernosa affecting penile tumescence.14 Animal studies have also shown that nitric oxide synthase, which synthesizes nitric acid in cavernous nerves, is controlled by DHT.15 Studies in men show that T is necessary in maintaining spontaneous nocturnal erections but not visual-induced erections.16 Effect on libido might be mediated by the effects of testosterone on mood. It is postulated that estrogen, via aromatization, is also a key player, but the mechanism is not yet clear.17,18 Studies show that TRT is proven to increase sexual functioning in the domains of sexual desire, spontaneous sexual thoughts, attentiveness to erotic auditory stimuli, frequency or erections, duration and magnitude of nocturnal erections, volume of ejaculate, and overall sexual activity scores.19 Testosterone replacement has been successful mainly in restoring libido or sexual desire with a smaller effect on erectile dysfunction (ED) or potency. A study of young eugonadal men showed that TRT improved libido in those with normal potency and low libido, but did not improve potency in those with ED and normal libido.20 Adding testosterone therapy in men with ED who are not responding to phosphodiesterase (PDE-5) inhibitors however has been successful in men with low or low-normal testosterone levels.21,22 The mechanism is thought to be by increasing arterial inflow to the penis during sexual stimulation.21 Overall sexual performance is seen to improve within 1–3 months after initiating therapy, and is associated with improvement in mood.23 There does not seem to be a dosedependent relationship in testosterone levels and sexual function in young men with levels above or near normal, as some partially hypogonadal men continue to have normal sexual functioning despite borderline T levels.24 However, a dose–response relation may exist when T levels are below normal, which would exist in older males. Erectile function response seems to increase with lower baseline T levels,

but effects tend to decline over time.25 Sexual impairment therefore seems to occur below a certain threshold of T level, and TRT might be beneficial in some patients with low or low–normal T levels. Recent studies show that T in the low–normal range seems to be adequate in maintaining sexual function, and if treatment benefits are obtained without having to achieve high levels, treatment might be more favorable. Considering the benefits of TRT experienced by many hypogonadal men with sexual dysfunction, current guidelines for TRT in sexual dysfunction recommend a trial of TRT in men with low T levels and low libido, and in men with ED and low T levels after ED has been evaluated. Older men should always be treated more cautiously, as long-term safety has not been established.

BONE The rate of vertebral fractures among elderly men and women is nearly the same. Although the rate for the hip fractures remains higher in women, the mortality associated with hip fractures in men is higher.26,27 Hypogonadism is an important risk factor and cause of osteoporosis in men, and can sometimes be present with no other features of hypogonadism. Data looking at elderly men found the prevalence of hypogonadism between 58 and 71% in men with hip fractures,28–30 and up to 20% in men with vertebral fractures.31 Hypogonadism is associated with low bone mineral density (BMD), as is seen in younger men with hypogonadotropic hypogonadism, older men with age-related hypogonadism, but most strikingly in men with prostate-cancer after androgen deprivation therapy. Free T was found to be one of the determinants of BMD in a study evaluating the role of sex steroids on BMD,32 whereas another study found bioavailable estrogen to be a BMD predictor in men.33 The mechanism of androgen action on bone is complex. Androgen receptor (AR) is present on osteoblasts, which express 5α-reducatase activity. Testosterone action through AR is responsible for mineralization and increased periosteal apposition of bone, accounting for the larger size and thicker cortices of bone in men. Testosterone also acts on osteoclasts via estrogen receptors after aromatization, and by inhibiting IL-6, the osteoclast-activating factor.34 Estrogen is thought to play a role mainly in preventing bone resorption, whereas both T and estrogen play a role in bone formation.35 Osteopenia, osteoporosis, and other bone deformities found in men with estrogen receptor mutation or aromatase deficiency provide evidence for the important role of estrogens in men in achieving peak bone mass and maintaining BMD.36,37 Testosterone replacement has shown positive effects on bone quantitatively by increasing BMD and qualitatively by improving trabecular architecture.26 Studies of hypogonadal men on TRT reported improvements in BMD of the hip and spine which were sustained, although levels achieved did not compare to those in young men. Generally, BMD

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increase seen in the lumbar spine was greater than in the hip, with an average increase of 5% as shown in many studies.31,38,39 One observational study which followed hypogonadal men on TRT for up to 16 years found an increase of 25% in spinal BMD. The biggest changes in BMD were usually in those with lower pre-treatment T levels, with the response being greatest during the first year.38,40 This finding is not different from estrogen replacement in women, where those with lower pre-treatment BMD respond more, mainly during the first year of therapy. Interestingly, the increase in spine BMD in response to estrogen replacement in postmenopausal women is also greater than that of hip BMD.38 The testosterone levels achieved with TRT seem to be related to the increase in BMD, with high–normal levels producing greater response than low–normal levels. These factors, along with duration of treatment, might account for the different response rates seen in studies. Older men with normal T levels, however, do not experience an increase in BMD when placed on TRT,38 but young eugonadal men with osteoporosis might benefit from TRT according to early evidence, probably due to the estrogenic effects of testosterone.41 It is unclear whether the benefits of TRT on bone are due to testosterone itself or secondary to aromatization to estradiol. Serum bone markers have been measured to assess the mechanism of action in TRT, where some studies found reduction of resorption markers alone, and others found markers indicating reduced resorption and increased formation.41, 42 Recent evidence shows that estrogen has a greater role in maintaining BMD in men,33 but estrogen supplementation in men would be unfavorable because of feminizing effects. Estrogen deficiency is also not a common part of aging in men, and levels of estrogen do not correlate with testosterone as they may be increased in men with obesity. Achieving normal testosterone levels is therefore the best physiological option to ensure that adequate estrogen levels are achieved through aromatization. It is also important to choose aromatizable androgens for replacement when targeting BMD. DHT is thought to have a less important role in bone, as administration of T and finasteride, a type II 5α-reductase inhibitor that inhibits DHT formation, did not produce results different from T administration alone.43 Testosterone replacement is associated with clear physiologic benefits on the bone, but benefits beyond this have not been studied. Studies evaluating the relation between testosterone levels and non-traumatic hip fractures in men are scarce and inconsistent; with the question mostly arising in the temporal association between hip fractures and testosterone levels. While some report no relation between the two,44,45 evidence of hypogonadism as a risk factor of hip fractures is growing,29,46 but further studies are needed to establish causality. There is no data on the role of TRT in preventing fractures in hypogonadal men. While TRT has shown to increase BMD in hypogonadal men, there is need

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for prospective studies to assess the efficacy of TRT in preventing osteoporosis with fractures as clinical endpoints.

MUSCLE Aging is associated with loss of muscle and strength, known as sarcopenia, which contributes to frailty and increased morbidity in this population. The attempt to reverse these changes in hypogonadal men with TRT has been explored, although the association between testosterone levels and age-related functional deterioration is not well elucidated. Androgenic steroids have long been used by athletes for their anabolic effects on muscle. Although studies have shown that testosterone increases muscle size, less is known on how it affects muscle strength and physical performance. Testosterone causes skeletal muscle hypertrophy mainly by increasing muscle synthesis, and possibly by increasing muscle fiber diameter.47,48 An indirect mechanism might be present by stimulating the expression of IGF-1 and downregulation of IGF-binding-protien-4 in the muscle, thereby amplifying the anabolic signal.49 Weight gain seen with TRT is associated with positive nitrogen balance48 as well as increase in body potassium,50 indicating that this gain is due to increase in lean body mass rather than water retention. DHT is not thought to play an important role in mediating these effects.51 There is also evidence that free testosterone is a predictor of skeletal muscle mass in elderly men.52 TRT in hypogonadal elderly men has shown to increase lean muscle mass53,54 and muscle strength,49,55 although the magnitude of these changes is varied. When physiological doses were given to hypogonadal men, increase in muscle mass was seen, with or without increase in strength, mainly in the lower limbs.53,54,56 This effect was also seen when eugonadal men were placed on TRT,57 although no gain in strength was reported. A major problem however exists in the lack of a reliable measure of muscle function, and the different means employed by those studies might account for the variability of results. When supraphysiological doses of testosterone were given to young eugonadal men, significant increases in muscle mass and strength were seen, especially when combined with exercise.58 As response to TRT is heterogeneous among men of different ages, one trial assessed the skeletal muscle response to testosterone among different age groups in men, and found elderly men to be as responsive as younger men in muscle mass and strength gain.59 However, the incidence of associated adverse events like polycythemia was higher in older men because of lower testosterone clearance rates, indicating that older men should be treated more cautiously, possibly using lower doses. Present evidence on TRT suggests that there is dose-dependent response in outcomes, like muscle mass and strength, and adverse events like hemoglobin level in association with testosterone levels achieved.60 Another limitation of such studies is that strength outcomes, such as

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grip strength have unknown significance on physical functioning, although improvement in rehabilitation outcomes have been reported with TRT.61 Because the clinical significance of these changes in improving physical function or preventing fractures is not well-documented yet, risk– benefit assessment is an issue when considering testosterone replacement for frailty, as it is unknown whether doses that would restore functional capacity would be safe to use. Modification of lifestyle and exercise are encouraged when endpoints like muscle gain and strength are desired. BODY COMPOSITION Aging is related to increasing adiposity, similar to that seen in men with frank hypogonadism, suggesting that the decline in testosterone levels might be responsible for these changes in older men. TRT is associated with changes in body composition and fat distribution, and there seems to be a relation between testosterone levels and adiposity independent of changes in muscle mass.62 Lean muscle mass change indicates change in skeletal muscle mass as well as fat content,63 and decline in fat mass was seen in most studies along with increase in lean mass.54,57 Testosterone has shown to enhance lipolysis in animal models,64 but it is unknown if a similar mechanism exists in man. Some studies show TRT to be associated with decreased lipid uptake into, and increased lipid release from the abdominal fat depot,65 as well as decreased visceral fat.66,67 Other studies found fat reduction to be in the extremities rather than in the abdomen.53 A study examining the effect of TRT on regional adipose tissue distribution found fat loss to be evenly distributed between the trunk and extremities, with greater loss in the extremities using supraphysiological doses of testosterone.68 Testosterone has been efficient in restoring lean body mass and fat-redistribution associated with HIVinfection and AIDS-related wasting.69,70 The Endocrine Society recommends that short-term testosterone therapy be offered in HIV-infected men with low testosterone or men treated with glucocorticoids with low testosterone levels. Future uses of testosterone might include treatment of cancer-associated cachexia. METABOLISM Testosterone is thought to have an effect on metabolism, independent of its effect on age and BMI.71 Testosterone deficiency has been linked to the development of insulin resistance and the metabolic syndrome,72 and replacement has shown to improve insulin sensitivity and reduce blood sugars in middle-aged obese men.73 Recent data from the third National Health and Nutrition Examination Survey (NHANES III) shows a strong association between free or bioavailable testosterone and type 2 diabetes mellitus.74 One mechanism of mediating glucose metabolism is thought to be at the level of the muscle; as castration in rats

inhibits glycogen synthesis, and testosterone replacement in men causes skeletal muscle hyperplasia that increases glucose uptake.75 Reduction in visceral adiposity could also contribute to this mechanism, as visceral adiposity is associated with diabetes and the metabolic syndrome. Reduction of central and peripheral fat in TRT is associated with reduction in lipoprotein lipase activity with a more rapid turnover of triglycerides.65 Other possible mechanisms include increase in leptin, a key regulator of metabolism and appetite, which is seen in some men treated with testosterone.55,71 However, the role of testosterone in insulin resistance is debatable, as androgen excess in women and men is associated with insulin resistance.76 Testosterone administration in rats was associated with increased islet insulin content and secretion.77 Adiponectin, a cardioprotective marker associated with insulin resistance, has been reported to decline with TRT.51 Further, some studies report no or neutral effect on metabolism. A 2-year study of TRT in elderly hypogonadal men found no improvement in carbohydrates or insulin action,78 The largest randomized trial to date has shown mixed metabolic results due to increased insulin sensitivity and decreased HDL levels.79 As evidence is mixed, it is too early to consider TRT for the goal of improving insulin resistance or the metabolic syndrome at this stage, but these findings could help in understanding the role of testosterone in modifying cardiovascular risk, which has been a main safety issue in TRT. As recent evidence is starting to show a positive role for TRT in cardiovascular risk, understanding the effect of TRT on various cardiac risk factors is important.

COGNITIVE FUNCTION The brain is an androgen-sensitive organ, and declining brain levels of testosterone are common in all aging men. The possibility that there is a causal relationship between testosterone decline and cognitive decline is of great interest. Hypogonadal men score lower on memory and visuospatial performance, and have a faster decline in visual memory than eugonadal men.80 Cross-sectional studies show that men with Alzheimer’s disease have lower testosterone levels than normal age-matched controls,81 and longitudinal studies show that testosterone levels in men who develop Alzheimer’s disease are lower than in those who do not.82 Autopsy results also showed that men with Alzheimer’s disease had significantly lower brain testosterone levels than normal men.83 In animal studies, androgen depletion increases β-amyloid protein, the causal factor in pathogenesis of Alzheimer’s disease,84 and testosterone replacement might reverse this memory impairment,85 possibly by aromatization to estrogen.86 There is evidence that higher levels of testosterone are associated with better cognitive scores,80,87 but the benefits of TRT in restoring or preventing cognitive decline in men have been mixed. It seems that testosterone substitution

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effects on the brain are domain-specific. Men and women differ on tasks of spatial cognition, which include visual perception, spatial attention, and visual memory processing.88 Some studies with TRT in men have shown improvement in spatial cognition and to a lesser extent verbal memory,88,89 whereas others have found no, or minimal and insignificant, changes.55,90,91 Supraphysiological levels of testosterone on the other hand were found to have detrimental effects on verbal memory.92 There is a lot of speculation on the role of aromatization in these studies. Estrogen was long thought to have a protective role on cognition, although more recent evidence in the Women’s Health Initiative has challenged this concept.93 In a study of TRT in men, estradiol was found to have an inverse relation with spatial cognition, with benefits of testosterone postulated to be due to inhibition of estradiol.94 Studies that found beneficial effect of TRT on cognition conclude that improvement in verbal memory is due to aromatization of T to estradiol, whereas spatial memory improvement is due to direct T effect.95 It is clear that testosterone and estrogen have different effects on cognitive function, and potential benefits of testosterone could be both due to its direct as well as indirect effect through aromatization. Evidence of testosterone’s effect on cognition is promising, but results have been inconsistent, which may be partly due to the limitations of studies including small numbers of patients, different patient characteristics, and different cognition tests. Studies offer some evidence that there may be a relationship between testosterone levels and cognitive decline, but it is unknown if TRT can delay cognitive decline or prevent the onset of Alzheimer’s disease, as further research is needed.

MOOD There is belief that testosterone is related to mood, with low levels common in depression and high levels historically reported in relation to aggressiveness and hostility in criminals. Cross-sectional studies show that bioavailable testosterone is significantly and inversely related to depression scores, independent of other confounders.96,97 It is unknown, however, whether depression precedes declining testosterone levels in such cases. Early studies in old, depressed males showed immediate and dramatic response to TRT with relapse upon discontinuation.98 Recent randomized trials in hypogonadal depressed men have shown mixed results, where some showed significant improvement,99 and others showed results similar to placebo.100 TRT has been successful in treatment of depression as a co-morbid illness in chronic hypogonadal men, in HIVpositive hypogonadal men,101 and in some men who failed to respond to SSRIs.102 Mood improvement is also commonly reported with improvement in sexual interest, but such studies were not designed to measure the antidepressant effect of testosterone, and baseline psychiatric

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status was usually not assessed. It is unclear whether testosterone benefits on mood can be expanded to include all cases of depression among the elderly. When physiologic doses of testosterone were given to eugonadal men, no changes in mood were seen, and even when supraphysiologic levels were given, changes such as agitation, irritability, or aggressiveness were also not seen.103 There might be a relation between mood and T/DHT ratio, as mood improvement was seen to stabilize when a certain ratio was achieved.104 The literature has also reported aggression in relation to certain levels of T/DHT,105,106 but this may be more valid in men with certain predispositions. As evidence is limited on the benefits of TRT on mood, testosterone is not used for this goal, as more research is needed to confirm any potential benefits. QUALITY OF LIFE Quality of life (QOL) is a concept that includes physical, psychological, social, and other domains of functioning.107 Late-onset hypogonadism in aging is associated with declining QOL. The relation between declining testosterone and decline in QOL has been demonstrated in men with androgen deprivation following prostate cancer, where these men scored lowest on the SF-36 questionnaire, a common tool for measuring health-related QOL.108,109 Testosterone impact on QOL can be mediated by benefits on mood or sexual functioning, but studies showed that most improvements occurred in physical functioning, where changes were seen most with in men with lowest pretreatment testosterone levels.53,110 Other studies however have found no change in QOL in men taking testosterone.111 The lack of sensitivity of current methods in assessing QOL is a major limitation in assessing the potential role of TRT on QOL. Before any conclusions can be made on such relation, there is need for better scales for evaluation of QOL. IMMUNE SYSTEM Androgens may be involved in immunosuppressive activity. Autoimmune diseases are more common in women as well as in men with Klinefelter syndrome.112 Most autoimmune rheumatological diseases are also associated with low testosterone, and remission upon TRT has been reported in men with Klinefelter, mainly through an effect on CD4/CD8 suppressor cells.113 There might be a potential role for testosterone in modulating the mechanisms in some of these diseases, but the data have been too scarce in that field, and no studies have further assessed such effects.

Safety Issues in Men PROSTATE The primary concern in TRT is adverse effects on the prostate gland. Prostate cancer (PCa) is the most common cancer in men, and its incidence tends to increase at the same

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time that testosterone levels decline. Prostate adenocarcinoma is androgen-responsive, and androgen-deprivation therapy is a mainstay therapy in regression of benign and malignant prostate neoplasia. The literature reports different findings on the relation between testosterone levels and incidence of PCa. Aggressive PCa has also been associated with low testosterone levels,114 but it is unknown if there is real association in those cases, as the development of PCa in the absence of androgens remains almost null. Evidence has shown that TRT in hypogonadal men increases prostate size to that comparable to age-matched eugonadal men.115 TRT is also associated with elevation of PSA levels, which tend to rise during the first 6–9 months of treatment, then stabilize thereafter. The longest trial of men treated with testosterone for 3 years showed no significant changes in PSA levels beyond 6 months of TRT.38 Studies that assessed this goal have found minimal or insignificant rise in PSA levels when TRT was given for shorter periods of time.116 TRT has been associated with a low number of new PCa cases, but placebo-controlled trials show that the incidence was not different from that in untreated men.117 Most of the studies on TRT however have included only healthy men without underlying prostate abnormalities, and concerns still arise in older men more representative of the population. A study that assessed one year of TRT in men with highgrade prostatic intraepithelial neoplasia did not find the risk of PCa to be higher than that in normal men, although sample size and treatment duration constituted some limitations.118 TRT is contraindicated in men with PCa, as metastatic prostate cancers can grow when stimulated by exogenous T.119 Recent trials have challenged this concept by showing that selected patients with history of PCa but now deemed cured could benefit from TRT without significant rise in PSA levels or recurrence of disease.120,121 It would be too early, however, to draw conclusions based on these studies. Benign prostatic hyperplasia (BPH) on the other hand is not absolutely contraindicated in TRT if the symptoms are mild to moderate, as assessed by the International Prostate Symptom Score (IPSS). TRT is not recommended, however, in severe obstructive BPH, as the mildest increase in prostate volume could exacerbate symptoms, where finasteride, a type II 5α-reductase inhibitor, is commonly used for symptomatic treatment of BPH. Although DHT has a major role in stimulating growth of prostate size, estrogens are also thought to play an important role in prostate disease pathogenesis, as seen in animal studies with nonaromatizable androgens.122,123 The prevalence of men with subclinical foci of PCa is estimated to be more than 50% in men over 70, the majority of whom will not be diagnosed clinically.124 It is unknown if TRT will unmask those foci or make them grow. Men on TRT undergo intense monitoring and screening, and are more likely to undergo biopsies, uncovering subclinical cancers that would otherwise not be detected. The Institute of Medicine has delayed the initiation of a large trial to answer

questions on safety of TRT because of concerns over prostate and cardiovascular risks, suggesting smaller trials be undertaken instead to evaluate the risk–benefit ratio. The development of selective-androgen-receptor-modulators (SARMs) is under investigation to target muscle and bone tissue while avoiding the prostate gland. Although evidence that TRT increases risk of PCa is weak, close monitoring of PSA levels, lower urinary tract symptoms, DRE, urologic consults and biopsy when needed are an essential part of TRT until further research confirms its long-term safety.

CARDIOVASCULAR Men die earlier than women because of heart disease, and testosterone was commonly thought to have a possible role in this mechanism. Plasma lipoproteins in prepubertal children show no gender difference until puberty, when HDL levels decline in boys along with slight elevation of LDL and triglycerides. There is some concern that testosterone replacement is related to unfavorable effects on lipid profile, mainly by decreasing HDL levels. Most studies in older men have found a slight reduction in total cholesterol, LDL, and HDL, most of which were insignificant. A decline of 10–15% in HDL levels is seen in younger men treated with TRT.125,126 Decline in HDL levels seems to be dosedependent,127 and is greater with non-aromatizable androgens. Some studies, however, did not detect significant difference in HDL levels regardless of the mode of administration,128 and others report that the effect of testosterone replacement on serum lipids appears to be consistent with physiological effects of testosterone.129 Testosterone might have positive effects on the coronary vasculature by inducing coronary vasodilation,130 and low-dose TRT in men with chronic stable angina improves angina threshold as shown in recent studies of TRT.131,132 Studies also suggest that induced hypogonadism after androgen-deprivation therapy might be related to arterial stiffness in those men.133 Testosterone was historically used to treat anemia in end-stage renal failure before synthetic erythropoietin was developed, as testosterone stimulates erythropoietin secretion by the kidneys and stimulates production of red blood cell precursors by the bone marrow.134 This might also explain why hematocrit (Hct) increases in boys after puberty, where the difference between genders is maintained throughout life. Mild anemia in elderly men is postulated to be due to declining testosterone levels,135 and is sometimes corrected by TRT. Increase in Hct is the most common adverse event associated with TRT, and studies have reported an increase in Hct in 5–40% of patients,136 but very few cases have required discontinuation or phlebotomy. Concerns arise mainly in men with pre-existing conditions like heart failure, COPD, and sleep apnea, which could be aggravated by increased blood viscosity. A dose–response relation seems to exist between testosterone replacement and Hct levels, and is more likely to occur

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with parenteral testosterone.128 Fluid retention with TRT is rare, but is another concern why TRT should be used more cautiously in men with heart failure or renal insufficiency. To conclude, no increase in angina, stroke, or myocardial infarction is seen in patients receiving TRT. Although there are some reports of coronary and cerebrovascular deaths in athletes using supraphysiological doses of anabolic steroids, no causal relation was established.137,138 As testosterone levels are lower in men with cardiovascular disease,139 and recent evidence even shows that low testosterone is associated with cardiovascular mortality,8,9 there seems to be an optimum level of testosterone below and above which cardiovascular or prostate-related risk factors would be elevated. OTHER POTENTIAL ADVERSE EVENTS Gynecomastia with or without breast tenderness is a common side effect of aromatizable androgens, and results from an imbalance between estrogen and testosterone. It is usually transient and resolves with continuation of the treatment. It is more common in elderly men, probably because of increased SHBG levels. Gynecomastia is also more common with parenteral testosterone. Sleep apnea is another concern in TRT, although data has mainly come from studies using supraphysiologic doses. Development or exacerbation of sleep apnea is more common in obese men or men with COPD or smoking history. Suggested mechanisms of TRT include central blunting of CO2 or increased collapsibility of upper airway during sleep, but the exact cause is unknown.140 Should symptoms occur while on TRT, they could be evaluated by sleep study depending on severity. Dose adjustment, discontinuation or treatment with CPAP is warranted depending on the individual case, risk factors, and severity. Liver toxicity, including cholestasis, hepatomas, and peliosis hepatis, is associated mostly with oral forms of testosterone, which are alkylated to avoid first-pass hepatic metabolism. As a result, oral T is no longer commonly used.

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Adverse events of the skin, such as acne, oiliness, increased body hair, and flushing, are due to the action of DHT on the skin, however are usually tolerable. Another issue with TRT is fertility, which is greatly compromised during TRT because of pituitary–gonadal axis suppression. TRT is not recommended in men who wish to conceive. Gonadotropin suppression in TRT is also associated with reduction in testicular size. Reduced fertility and testicular size changes, however, are reversible with cessation of treatment.

Monitoring in Men The different modalities of testosterone available provide different benefits and are associated with formulationspecific adverse events, which is why choice of therapy must be individualized in each case. The presence of prostate cancer, male breast cancer, hematocrit greater than 55%, or severe obstructive BPH is an absolute contraindication in TRT. Relative contraindications include mild BPH, obstructive sleep apnea, hematocrit greater than 52%, and advanced congestive heart failure. Baseline characteristics and follow-up with monitoring are important in each patient to be started on TRT, and are summarized in Table 60.5. To conclude, the role of testosterone in hypogonadal and aging men is growing, and many of the endogenous actions of testosterone are now coming to benefit with testosterone replacement. The potential safety concerns with TRT have slowed down and limited the efforts to effectively study the risk–benefit ratio of TRT, as many small trials have to be conducted before a large trial can be undertaken. However, the available evidence generally points towards an overall beneficial effect of treating hypogonadal men to bring their testosterone to mid-normal ranges. As more small studies will evaluate the use of testosterone, likely the time will come when a large trial will either validate or abolish the role of testosterone in men.

TABLE 60.5 Monitoring of men on TRT Test

Base-line

3 months

Annually

Goal/Comments

Symptom assessment

X

X

X

T-level

X

X

X

PSA/DRE

X

X

X

DEXA

X

Hematocrit

X

X

X

Evaluate whether symptoms have responded to treatment or if there are adverse effects Therapy should aim to raise serum testosterone levels into the midnormal range Obtain urological consultation if: PSA ⬎4 ng/ml or increased ⬎1.4 ng/ml within any 12 months period Detection of a prostatic abnormality on DRE If patient has osteoporosis/osteopenia at baseline, measurement BMD of lumbar spine and/or femoral neck every other year of TRT is indicated If hematocrit is ⬎54%, stop therapy until hematocrit decreases to a safe level

Adapted from Endocrine Society Clinical Practice Guidelines 2006

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ANDROGEN PRODUCTION IN WOMEN In women, androgen synthesis takes place in the ovarian cells as well as in the adrenal glands. Ovarian steroidogenesis, similar to testicular steroidogenesis, is under the control of the hypothalamus–pituitary axis. Preovulatory follicular growth and estradiol production in the granulosa cell is stimulated by FSH and is predominant in the first half of the menstrual cycle. LH induces ovulation and maintains the corpus luteum in the second half of the menstrual cycle, where progesterone and 17-(OH)-progesterone are the main hormones secreted during this time. LH has a major role in ovarian androgen production of DHEA, androstenedione, and testosterone, which happens mainly in the thecal cells and to a lesser extent in the ovarian stroma. Androstenedione, the major androgen secreted by the ovaries, can be converted to estrogen or testosterone in the ovaries and extraglandular tissues. Levels of testosterone in reproductive-age women fluctuate according to the time of the menstrual cycle, with peak levels occurring at mid-cycle and nadir levels early in the follicular phase. As in men, androgen production in premenopausal women also shows diurnal variability according to some studies,141 whereas less has been reported on this circadian rhythm in postmenopausal women. Testosterone can be converted to the more potent DHT in peripheral tissues like skin, hair follicles, and external genitalia; and in excessive rates is related to hirsutism. The source of androgens as well as the relative concentration of different androgens in women are largely dependent on age, and can be divided into two categories, premenopausal vs. postmenopausal (Figure 60.3). In women of reproductive age, the ovaries contribute by 25% to the total testosterone, with the remainder produced by the adrenal glands, mostly indirectly by peripheral conversion of androstenedione, and some directly in the form of testosterone.141 The major androgen produced by the adrenal gland is DHEAS (⬎80%), whereas the predominant androgen produced by the ovary, as mentioned above, is androstenedione. Daily production rates of testosterone are in the range of 0.1–0.4 mg/day.141 In postmenopausal women, adrenal secretion of androgens decreases, peripheral conversion of androstenedione to testosterone continues, whereas ovarian secretion of testosterone continues or is slightly increased.142,143 The relative decline of estrogen production by the ovary is greater than the decline of androgen production, which makes the ovary a predominantly androgen-producing gland. Increased levels of gonadotropins in postmenopausal women might stimulate steroidogenesis and the corresponding relative increase in androgen production.144

Androgen Levels in Aging Women Androgen levels decline with age, starting in the early reproductive years, where one cross-sectional study showed

Androstenedione production in women Premenopausal

Postmenopausal Ovarian: 0.3 mg/24 hr (20%)

Adrenal: 1.5 mg/24hr (50%)

Ovarian: 1.5 mg/24hr (50%)

Adrenal: 1.2 mg/24hr (80%)

Testosterone production in women Postmenopausal

Premenopausal Ovarian: 60 µg/24hr (25%)

Adrenal: 190 µg/24hr (75%)

Adrenal: 90 µg/24hr (50%)

Ovarian: 90 µg/24hr (50%)

FIGURE 60.3 Androgen production in women. Adapted from Adashi EY. The climacteric ovary as a functional gonadotropin-driven androgen-producing gland. Fertil Steril 1994;62:20–7

that women in their 40s had nearly half the testosterone levels of women in their 20s.145 Declining androgens are thought to be due to age, and not menopause, as mean testosterone levels do not vary in the years around menopause.146 Whereas reduced adrenal production of DHEAS after menopause is clear, the decline of total testosterone is still somewhat controversial. Free testosterone levels might even show slight increase in the years after menopause possibly because SHBG levels decline with the cessation of ovarian estrogen production.147 Changes in SHBG levels with aging in women may not follow the same trend as in men, which might account for the different findings in postmenopausal testosterone levels.

Etiology of Androgen Deficiency in Women Androgen deficiency in women can be primary (caused by adrenal or ovarian disorders), secondary (pituitary or hypothalamic disorders), or associated with chronic disease or medication (Table 60.6). The degree of deficiency is more severe in central disorders like hypopituitarism than in primary disorders like adrenal insufficiency or surgical menopause, as central disorders affect the two major sources of androgen in women. Natural menopause on the other hand might be associated with relative androgen insufficiency, since the ovary continues to secrete T but adrenal T drops.

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TABLE 60.6 Causes of androgen deficiency in women

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TABLE 60.7 Female androgen insufficiency syndrome

Cause

Type of damage

Symptoms

Signs

Hypothalamus–pituitary

Hypopituitarism (any cause), suppression of gonadatropins by: glucocorticoids, anorexia nervosa, opioids Oopherectomy (unilateral or bilateral), premature ovarian failure (autoimmune), chemotherpay, radiotherapy, infiltrative diseases, Turner syndrome Adrenalectomy, adrenal insufficiency, glucocorticoids (by suppression of ACTH) Cancer, HIV, systemic lupus erythematosus, rheumatoid arthritis (through various mechanisms) Alteration of SHBG levels by: oral estrogen therapy, thyroid medication, hyperthyroidism

Low libido with global decrease in sexual desire or fantasy Persistent, unexplained fatigue Decreased sense of wellbeing Blunted motivation Flattened or dysphoric mood

Genital atrophy unresponsive to estrogen

Ovarian

Adrenal

Chronic illness

Other

Adapted from Basaria S, Dobs AS. Clinical Review: Controversies regarding transdermal androgen therapy in postmenopausal women. J Clin Endocrinol Metab 2006;91(12):4743–52; and The North American Menopause Society (NAMS) 2005

The real problem lies in diagnosing adrenal sufficiency in women without clear causes of androgen sufficiency like oopherectomy or hypopituitarism, but who may have more subtle forms of androgen deficiency causing distress.

Androgen Deficiency in Women: Diagnosis and Indications for Treatment There is no consensus on defining androgen deficiency in women. A major problem in establishing such a definition is the lack of an accurate testosterone immune assay for low levels of testosterone. As women have testosterone levels that are one-tenth to one-twentieth of those in men, current available assays are not optimized for testosterone measurement in women. Another problem in assessing androgen deficiency in women is related to the concept of intracrinology, which refers to the fact that hormones produced in cells peripherally can exert their effect without release into the systemic circulation.18,148 This individual variation might explain why some women with hirsutism have low or normal testosterone, or why some women with low testosterone have normal libido.149 The age-related decline in DHEA, DHEAS, testosterone, and the remaining androgens in women may not therefore reflect androgenic activity. The Princeton Consensus Conference first defined female androgen insufficiency based on symptoms of androgen deficiency in women (Table 60.7), accompanied by a testosterone

Decreased lean body mass Osteopenia/osteoporosis Thinning or loss of pubic hair

Adapted from Bachman G, Bancroft J, Braunstein G, et al. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril 2002;77(4):660–5

TABLE 60.8

Contraindications for androgen replacement in women

Absolute

Relative

Endometrial hyperplasia/cancer Breast cancer Pregnancy Lactation Polycythemia Severe acne

Metabolic syndrome Hyperlipidemia Psychiatric disorders Moderate hirsutism Androgenic alopecia Moderate acne

Adapted from Basaria S, Dobs AS. Clinical Review: Controversies regarding transdermal androgen therapy in postmenopausal women. J Clin Endocrinol Metab 2006;91(12):4743–52

level which falls in lowest quartile for reproductive-age women, and a normal estrogen level. The Endocrine Society, however, recommends against the diagnosis of androgen deficiency in women as no normative data exist on testosterone levels in women across their lifespan and the associated clinical picture is not well defined. Most of the evidence of androgen replacement in women includes adding testosterone therapy to estrogen therapy in women with established causes of androgen deficiency and symptoms of sexual dysfunction. Data in reproductive-age women are scarce, and testosterone replacement in this population imposes a risk of masculinizing effects on the fetus. While testosterone replacement is not currently approved in women, addition of testosterone to estrogen therapy in postmenopausal women with sexual dysfunction has shown positive effects and could be considered if certain criteria are met, and no contraindications exist (Table 60.8). A decisionmaking algorithm for initiating androgen therapy in women is suggested in Figure 60.4. Although the algorithm states that the use of oral estrogens or oral contraceptives is a cause of androgen deficiency in women, it is unclear if testosterone replacement can be given without estrogen. Further studies will probably evaluate the use of low-dose estrogen before the trial of testosterone alone without estrogen.

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Endocrinology Female Androgen Insufficiency Symptoms Is there an alternative explanation or cause of these symptoms (major depression, chronic fatigue syndrome)? No (If yes, manage as appropriate) Is the woman in optimum estrogen state? Yes (If no, initiate estrogen replacement)

Are lab values consistent with a diagnosis of androgen insufficiency? This includes: at least 2 of 3 measures of total T, free T, or SHBG; with androgen levels in lowest quartile of normal range for reproductive age women Yes (If no, consider alternative treatments) Is there specific treatable cause for androgen insufficiency, such as oral estrogen/contraceptive use? No (If yes, treat the specific cause) Consider trial of androgen replacement therapy

FIGURE 60.4 Algorithm for initiation of testosterone replacement in women. Adapted from Bachman G, Bancroft J, Braunstein G, et al. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril 2002;77(4):660–5

Testosterone Therapy Modalities for Women There is no FDA-approved testosterone form for treatment of sexual dysfunction in women; such use of testosterone is currently off-label. Methyltestosterone (MT) in combination with esterified estrogens (Estratest® and Estratest-HS®) is available for the treatment of vasomotor menopausal symptoms unresponsive to estrogen. MT is the most commonly used testosterone in trials with women, but given its possible association with declines in HDL levels, transdermal formulations would probably be more favorable.

The Role of Exogenous Testosterone in Women Androgen replacement in women is a relatively new concept, and several limitations exist when dealing with testosterone replacement in women. First, the formulations used by most studies were created for men, and therefore provided high or supraphysiologic levels of testosterone. Second, almost all trials compared testosterone and estrogen vs. estrogen alone, with or without progestin depending on whether the woman had a uterus. The benefits of testosterone per se are therefore unclear in the absence of estrogen, or at times, progestins. Finally, most of the studies did not exceed one year, which means the long-term benefits or side effects are not really known. Existing data, however, shows that positive effects were seen in most of the

trials without serious adverse events, which implies further studies should be done to assess the potential risk–benefit ratio.

SEXUAL FUNCTION Sexual dysfunction in women can arise from disorders in one or more of four categories: desire, arousal, orgasm, or pain. Hypoactive sexual desire disorder (HSDD), defined as low or absent sexual desire, accounts for most of the female sexual dysfunction disorders. Estrogen therapy improves sexual function in women with dyspareunia due to atrophic vaginitis, but has no effect on other aspects like sexual drive or arousal. Although no relation has been established between endogenous testosterone levels and sexual dysfunction, administration of testosterone in many studies has shown beneficial effects in postmenopausal women with HSDD. Androgen replacement in the treatment of HSDD constitutes the most available evidence for testosterone replacement in women. There are differences in serum levels of testosterone achieved and in baseline deficiency status, but benefits were seen in most of the studies. In women with bilateral oopherectomy, positive results were seen with doses of 300 μg/day using transdermal testosterone, where lower doses did not result in statistically significant results.150–153 Such doses were associated with some androgenic side effects on the skin and were associated with

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supraphysiological serum concentrations of testosterone and DHEA in most of the women. Studies in women with hypopituitarism found that physiological levels of testosterone were successful in achieving improved sexual function with few side effects.154 Improvement in sexual parameters was also seen in studies of women with natural menopause with relative androgen insufficiency, who reported increased scores of sexual desire and frequency when testosterone was added to estrogen.155–157 In a study of premenopausal women with low libido testosterone replacement resulted in significant improvements in sexual self-reported scores and wellbeing, where mean testosterone levels achieved were on the high end of normal, with no adverse events reported.158 However, data on testosterone administration without estrogen to eugonadal premenopausal women with sexual dysfunction are scarce. Young women with primary ovarian failure or with bilateral oopherectomy and sexual dysfunction are likely to benefit most from TRT. Benefits of adding T to hormone replacement therapy (HRT) seem to work mainly by increasing libido, sexual fantasies, and arousal, and to a lesser extent, sexual functioning, whereby scores in desire correlate with serum testosterone levels.159–161 A dose–response effect might exist in improving sexual symptoms, with higher doses proving more efficient in sympton reversal. Generally, most studies reported no or minimal adverse events, consisting mainly of hirsutism. There are several mechanisms by which testosterone is postulated to improve sexual dysfunction in women. Studies showed that women receiving testosterone and estrogen replacement had greater increase in limbic activation in brain MRI in response to visual erotic stimuli as compared to the response of women receiving estrogen alone.18,162 There is also some evidence that testosterone might increase vaginal congestion,18,163 suggesting a role for testosterone at the genital level, although most of the evidence points towards a central role. DHEA, the primary measure of adrenal androgen, is available as a synthetic over-the-counter product. It has shown some efficiency in improving sexual functioning in women with adrenal insufficiency. DHEA, however, is not a true androgen as it does not bind to androgen receptor, and it can be converted either to estradiol or to testosterone. It has been studied as an alternative to testosterone for HSDD, but not enough is yet known about its benefits. It is important to note that sexual dysfunction in women can result from many medical or social conditions, and elimination of such causes along with biochemical evidence of testosterone levels in the lowest quartile is necessary before considering androgen replacement for HSDD.

BONE Osteopenia and osteoporosis are common in women after menopause, and HRT has been one of the options for treatment. There is some evidence on the correlation between

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BMD and androgens in postmenopausal women.164,165 Studies have noted increase in bone mass when T was added to estrogen in postmenopausal women. Several randomized controlled trials showed that postmenopausal women receiving T and estrogen had increased BMD compared to the group receiving estrogen alone, with or without progestin.156,166,167 Increases in BMD were seen in whole body,156,167 lumbar,168 or hip166 areas with no consistent findings on region-specific benefits. Significant results were seen generally with higher doses, sometimes associated with supraphysiological levels of testosterone. One study of young women with hypopituitarism however detected improvement in hip BMD with physiological doses of testosterone.154 Another study measuring biochemical bone markers found that postmenopausal women on MT and estrogen had increased bone formation markers as compared to decreased levels in the group receiving estrogen alone, suggesting a possible role for T in reversing the inhibitory effects of estrogen on bone.169 It should be noted, however, that these studies included a small number of women, and are inconclusive in warranting androgen therapy for treating osteoporosis or osteopenia. Larger randomized trials are needed to examine the efficiency and safety at levels required for improving BMD and reaching clinical endpoints such as preventing osteoporosis or reducing fractures.

BODY COMPOSITION AND MUSCLE Menopause is associated with increase in body fat and decrease in lean mass due to declining hormones, similar to the aging process in men. Although most trials of testosterone replacement in women showed a tendency toward weight gain, data on changing body composition are inconsistent. One study in postmenopausal women showed that the addition of parenteral T to estrogen therapy may attenuate the reduction in centralized body fat achieved by estrogen.170 Administration of nandrolone, an anabolic steroid with weak androgenic activity, resulted in significant lean mass gain while independently modulating abdominal fat in obese postmenopausal women, awhere visceral fat gain and subcutaneous fat loss were seen in the abdominal area.171 In a pilot study of women with AIDS wasting syndrome, low-dose T was associated with positive trends in weight gain and quality of life.172 Two studies done using transdermal patches in HIV-infected women had different results, however. One concluded that T was well tolerated and successful in increasing muscle strength,173 whereas the other concluded that while physiological doses were safe to use, they did not result in significant increases of fat-free mass, body weight, or muscle performance.174 It is therefore unclear if any anabolic effects of T for treating sarcopenia in women can be obtained using physiological levels. This bears some resemblance to the dose–response effect of T on muscle seen in men. Further investigation is needed to assess

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a possible role of T in reducing abdominal obesity, improving muscle strength, or affecting cardiovascular risk factors and functional measures.

testosterone and physiologic levels of free testosterone.186 These studies however were small, and the effects of testosterone on QOL cannot be concluded.

Safety Issues in Women COGNITION AND MOOD There seems to be a positive relation between T levels and abilities of spatial cognition, as discussed previously in TRT benefits on cognition in men. Women with higher T levels perform better on spatial tasks than those with lower levels,175 and women perform better on spatial tasks when their T levels are high than when these levels drop.176 Female-to-male transsexuals show improved spatial ability following highdose-testosterone treatment for masculinization.177,178 Several studies have also shown improvement in specific aspects of cognitive function with TRT in women, using supraphysiological doses.179 Other studies however showed cognitive improvement in women on estrogen, with or without androgen replacement.180 One challenge in evaluating the effect of testosterone in such studies is that few cognitive measurements are valid in assessing cognition. One study was able to quantify the improvement in spatial cognition by detecting changes on PET scan of the brain in a subset of women with anorexia nervosa who were given T.181 Another challenge in evaluating these benefits is that, as T is aromatized to estrogen in the brain, it is unknown how much of the benefits seen are due to testosterone. It is therefore early to conclude the benefits of TRT in this area in women, as more evidence would be needed to see if any clinically significant results are possible and at what risk. Improvement in mood as a secondary endpoint was seen in many of the trials that showed improvement in sexual functioning. A covariation between circulating levels of estrogen and testosterone with affect was seen in a trial of oopherectomized women, where depression scores improved on taking combined estrogen-testosterone and regressed when therapy was stopped.182 Testosterone might be beneficial in improving mood and treating depression, but studies that measure these effects as primary outcomes are needed to validate any benefits.

VASOMOTOR AND QUALITY OF LIFE Androgen therapy in women was first used in the 1930s for the treatment of menopausal symptoms,183 and later for improving overall wellbeing and quality of life. Further studies however did not confirm findings on improving menopausal symptoms,184 suggesting that testosterone might increase the efficiency of estrogen by suppressing SHBG, thereby increasing the free estradiol.185 A review of two trials assessing the effects of hormonal therapy on quality of life found that adding testosterone therapy improved wellbeing at supraphysiologic levels of total

CARDIOVASCULAR Androgen deficiency has been suggested as a cardiovascular risk factor in postmenopausal women,187 but there is a lot of controversy over the role of sex steroids in modulating cardiovascular risk in women. The effect of testosterone on cardiovascular risk can be assessed at different levels. In women, elevated free androgen index was found to be associated with an atherogenic lipid profile,188 and androgenecity found to be independently associated with central fat distribution.189 Significant reductions in HDL along with triglycerides are seen with oral androgens like MT. Other formulations of aromatizable testosterone do not seem to cause reductions in HDL. Non-aromatizable androgens on the other hand, like nandrolone, seem to have the most unfavorable effect on lipids by increasing LDL and reducing HDL. Testosterone was associated with significant reduction in plasma viscosity in one trial despite causing significant increases in fibrinogen, and this was explained by significant reduction in triglycerides which contributed to the decreased viscosity.190 The other potential risk with TRT is polycythemia which is common in men on TRT, but no similar effect is seen in women so far. Significant elevation in hematocrit was seen in one trial of TRT in women, but levels remained within normal range.191 Polycythemia was seen in female-to-male transsexuals,192 but none was seen using physiologic doses of T. Testosterone does not seem to increase coagulation or clotting factors,193 but more data is needed as existing evidence is scarce. There is also some evidence that adding T to estrogen therapy in postmenopausal women improves arterial vasodilation.194 Androgens were recently associated with improved insulin resistance in men. It is unknown if the same effect occurs in women. Polycystic ovary syndrome (PCOS) is associated with insulin resistance and possibly a higher risk of developing type 2 diabetes and cardiovascular disease. Low SHBG levels, which might increase free testosterone, are also associated with insulin resistance.195 Studies show, however, little evidence of association between hyperandrogenism per se and cardiovascular risk in polycystic ovary syndrome.196 Furthermore, studies on T replacement in women did not show changes in fasting glucose or insulin levels, or insulin sensitivity. The available data are preliminary and the relation between androgens and insulin resistance in women is still unclear. The effect of testosterone on cardiovascular markers in relation to mortality or morbidity is unknown at this time.

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No increase in cardiovascular morbidity or mortality was seen in a 20-year survey of female-to-male transsexuals treated with supraphysiological levels of testosterone.197 There is no current evidence that physiological T has an adverse effect on cardiovascular risk factors in women, but TRT data on cardiovascular endpoints including MI, stroke, thromboembolic events, and mortality should be obtained from prospective large-scale studies. Estrogen replacement in women has been known to affect SHBG, lipid profile, fibrinogen, and other cardiovascular factors. After the Women’s Health Initiative (WHI),198 and the Heart Estrogen Replacement Study (HERS)199 have challenged the previous belief in the cardioprotective role of estrogens in postmenopausal women, the benefits of adding T to estrogen are even more difficult to asses. As current evidence recommends against the use of T without estrogen, trials to assess the true risks of long-term T without estrogen are therefore controversial. BREAST AND ENDOMETRIUM Data on T in relation to breast and breast cancer is varied. Androgens acting though the AR on the breast are antiproliferative and are associated with breast atrophy in women with high endogenous circulating androgens.200 Advanced premalignant lesions of the breast, however, have enhanced local aromatase activity,201 and TRT in such cases can promote tumor growth. This could explain why elevated T has been associated with metastases in breast cancer.202 Data on the relation of T levels and risk of breast cancer in women is inconclusive, and no association can be made at this time. Similarly for the endometrium, androgen is believed to have antiproliferative effects by acting through the AR.198 Testosterone, however, might be involved in the mechanism of cell proliferation in invasive endometrial cancers.203 Few reports of endometrial hyperplasia exist with supraphysiologic or physiologic testosterone levels.204 No reports of endometrial cancer or breast cancer with physiological levels of testosterone exist to date, but endometrial cancer, unexplained vaginal bleeding, or breast cancer remain absolute contraindications to testosterone replacement in women. VIRILIZING EFFECTS Acne and hirsutism are common in women with high circulating endogenous androgens, such as in PCOS and congenital adrenal hyperplasia (CAH). Most of the trials assessing testosterone replacement however have not reported an increase in the rates of acne and hirsutism.198 Some trials reported mild acne and hirsutism with MT,191,204 while others have not,205 a finding that might be explained by the variable degree of sensitivity of androgen receptors.204 Not all studies of TRT in women have addressed these side effects, and existing reports are limited by lack of objective

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measures. One study found no increase on hirsutism as measured by the Lorenzo scale, but detected increase in depilatory rate as compared to baseline.150 Frank virilization, including deepening of the voice, clitoromegaly, and temporal balding, is rare but can occur with high doses of T such as those used to treat female-to-male transsexuals. In general, the occurrence of such masculinizing effects is low when physiological levels are used, and is usually mild and reversible on discontinuation of the treatment. OTHER ADVERSE EVENTS Hepatotoxicity can result from high doses of oral androgens due to alkylation of testosterone. None of the TRT in women trials has reported elevations of liver enzymes or other hepatic disturbance, suggesting that the doses used are not likely to be hepatotoxic. Aggressive behavior with TRT is a rare and unlikely event. One study did show increase in hostility scores in postmenopausal women on high doses of parenteral T.182 Other trials have not reported or have not measured such outcomes, but it is unlikely that physiological doses would result in hostility or anger.

Monitoring in Women It is important to counsel women about the possible benefits and risks associated with the off-label use of androgens for HSDD. Although no major effects have been reported in any of these areas, studies are limited by sample size, and information on safety of T beyond 24 weeks does not exist. Monitoring of androgen therapy in women is based on clinical improvement in symptoms rather than biochemical testing of T levels. Efficacy measures like sexual desire, fantasy and arousal, receptivity to sexual advances, frequency of sexual activity, as well as overall sense of wellbeing are usually assessed at each visit. Side effects like hirsutism can be monitored using the Ferriman– Gallwey or Lorenzo scales; and acne can be assessed through use of Palatsi scale.206 Lipid profile should be monitored in case MT is to be used, or other formulationspecific side effects screened when using other formulations (Table 60.4). Breast exams, mammograms, and endometrial ultrasounds are also recommended as the safety of TRT in women is unknown at this time. Testosterone replacement in women is a new and challenging concept. Benefits of TRT for sexual dysfunction in women with surgical menopause are now known, but more studies need to show whether the same would apply to other areas and clinical endpoints. It would be important to know if low dose testosterone can be given alone without estrogen, especially after the recent controversy regarding estrogen replacement in women. Finally, little is known about the importance and prevalence of androgen deficiency in younger females, and the potential role of testosterone

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replacement in this population. As knowledge is growing on the role of testosterone in men, this will affect and warrant more research on its role in women.

CONCLUSION Androgen deficiency in women and in men is a condition that has been underdiagnosed, because little was known about the role of testosterone in both genders. In men with an established diagnosis of hypogonadism, testosterone treatment is a clear indication. For men and women with partial androgen deficiency or with unclear etiology of hypogonadism, however, the decision to initiate TRT is subjective, and depends on severity and nature of symptoms. Assessment of symptoms, signs, and potential adverse events with the current data should guide the decision for a short-term trial of testosterone. As more studies are showing the potential benefits of short-term testosterone replacement, further research would have to address improved methods for diagnosing androgen deficiency, as well as the long-term safety of testosterone replacement.

References 1. Bhasin S. Testicular disorders. In: HM Kronenberg, S Melmed, KS Polonsky, PR Larsen, eds. Williams Textbook of Endocrinology, eleventh ed. Philadelphia, PA: Saunders; 2007:645. 2. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002;87:589–98. 3. Lamberts S. Endocrinology and aging. In: HM Kronenberg, S Melmed, KS Polonsky, PR Larsen, eds. Williams Textbook of Endocrinology, eleventh ed. Philadelphia, PA: Saunders; 2007:1185. 4. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore longitudinal study of aging. J Clin Endocrinol Metab 2001;86:724–31. 5. Salehian B, Jacobson D, Swerdloff RS, Grafe MR, SinhaHikim I, McCutchan JA. Testicular pathologic changes and the pituitary-testicular axis during human immunodeficiency virus infection. Endocr Pract 1999;5:1–9. 6. Mohr BA, Guay AT, O’Donnell AB, McKinlay JB. Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts male ageing study. Clin Endocrinol (Oxf) 2005;62:64–73. 7. Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000;49:1239–42. 8. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93:68–75.

9. Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation 2007;116:2694–701. 10. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006;166:1660–65. 11. Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB. Sex steroids and all-cause and causespecific mortality in men. Arch Intern Med 2007;167:1252–60. 12. Morelli A, Corona G, Filippi S, et al. Which patients with sexual dysfunction are suitable for testosterone replacement therapy? J Endocrinol Invest 2007;30:880–88. 13. King BE, Packard MG, Alexander GM. Affective properties of intra-medial preoptic area injections of testosterone in male rats. Neurosci Lett 1999;269:149–52. 14. Traish AM, Park K, Dhir V, Kim NN, Moreland RB, Goldstein I. Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology 1999;140:1861–68. 15. Lugg JA, Rajfer J, Gonzalez-Cadavid NF. Dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat. Endocrinology 1995;136:1495–501. 16. Carani C, Granata AR, Bancroft J, Marrama P. The effects of testosterone replacement on nocturnal penile tumescence and rigidity and erectile response to visual erotic stimuli in hypogonadal men. Psychoneuroendocrino 1995;20:743–53. 17. Bagatell CJ, Heiman JR, Rivier JE, Bremner WJ. Effects of endogenous testosterone and estradiol on sexual behavior in normal young men. J Clin Endocrinol Metab 1994;78:711–16. 18. Bhasin S, Enzlin P, Coviello A, Basson R. Sexual dysfunction in men and women with endocrine disorders. Lancet 2007;369:597–611. 19. Bhasin S, Basson R. Sexual dysfunction in men and women. In: HM Kronenberg, S Melmed, KS Polonsky, PR Larsen, eds. Williams Textbook of Endocrinology, eleventh ed. Philadelphia, PA: Saunders; 2007:701. 20. O’Carroll R, Bancroft J. Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry 1984;145:146–51. 21. Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf) 2003;58:632–38. 22. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol 2004;172:658–63. 23. Basaria S, Dobs AS. New modalities of transdermal testosterone replacement. Treat Endocrinol 2003;2:1–9. 24. Buena F, Swerdloff RS, Steiner BS, et al. Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range. Fertil Steril 1993;59:1118–23. 25. Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf) 2005;63:381–94.

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26. Benito M, Vasilic B, Wehrli FW, et al. Effect of testosterone replacement on trabecular architecture in hypogonadal men. J Bone Miner Res 2005;20:1785–91. 27. Trombetti A, Herrmann F, Hoffmeyer P, Schurch MA, Bonjour JP, Rizzoli R. Survival and potential years of life lost after hip fracture in men and age-matched women. Osteoporos Int 2002;13:731–37. 28. Abbasi AA, Rudman D, Wilson CR, et al. Observations on nursing home residents with a history of hip fracture. Am J Med Sci 1995;310:229–34. 29. Jackson JA, Riggs MW, Spiekerman AM. Testosterone deficiency as a risk factor for hip fractures in men: a case-control study. Am J Med Sci 1992;304:4–8. 30. Stanley HL, Schmitt BP, Poses RM, Deiss WP. Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men? J Am Geriatr Soc 1991;39: 766–71. 31. Francis RM. Androgen replacement in aging men. Calcif Tissue Int 2001;69:235–38. 32. Keles I, Aydin G, Basar MM, et al. Endogenous sex steroids and bone mineral density in healthy men. Joint Bone Spine 2006;73:80–85. 33. Khosla S, Melton LJ III, Robb RA, et al. Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men. J Bone Miner Res 2005;20:730–40. 34. Bellido T, Jilka RL, Boyce BF, et al. Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. J Clin Invest 1995;95: 2886–95. 35. Falahati-Nini A, Riggs BL, Atkinson EJ, et al. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 2000;106:1553–60. 36. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689–98. 37. Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331:1056–61. 38. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999;84:1966–72. 39. Francis RM. The effects of testosterone on osteoporosis in men. Clin Endocrinol (Oxf) 1999;50:411–14. 40. Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 1997;82:2386–90. 41. Anderson FH, Francis RM, Peaston RT, Wastell HJ. Androgen supplementation in eugonadal men with osteoporosis: effects of six months’ treatment on markers of bone formation and resorption. J Bone Miner Res 1997; 12:472–78. 42. Wang C, Eyre DR, Clark R, et al. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men – a clinical research center study. J Clin Endocrinol Metab 1996;81:3654–62.

755

43. Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004;89:503–10. 44. Center JR, Nguyen TV, Sambrook PN, Eisman JA. Hormonal and biochemical parameters and osteoporotic fractures in elderly men. J Bone Miner Res 2000;15:1405–11. 45. Nyquist F, Gardsell P, Sernbo I, Jeppsson JO, Johnell O. Assessment of sex hormones and bone mineral density in relation to occurrence of fracture in men: a prospective population-based study. Bone 1998;22:147–51. 46. Leifke E, Wichers C, Gorenoi V, Lucke P, von zur Muhlen A, Brabant G. Low serum levels of testosterone in men with minimal traumatic hip fractures. Exp Clin Endocrinol Diabetes 2005;113:208–13. 47. Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men – a clinical research center study. J Clin Endocrinol Metab 1996;81:3469–75. 48. Griggs RC, Kingston W, Jozefowicz RF, Herr BE, Forbes G, Halliday D. Effect of testosterone on muscle mass and muscle protein synthesis. J Appl Physiol 1989;66:498–503. 49. Urban RJ, Bodenburg YH, Gilkison C, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol 1995;269:E820–26. 50. Forbes GB. The effect of anabolic steroids on lean body mass: the dose response curve. Metabolism 1985;34: 571–73. 51. Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005; 90:1502–10. 52. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999;107:123–36. 53. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999;84:2647–53. 54. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2001;56:M266–72. 55. Sih R, Morley JE, Kaiser FE, Perry HM III, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12month randomized controlled trial. J Clin Endocrinol Metab 1997;82:1661–67. 56. Bhasin S, Storer TW, Berman N, et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 1997;82:407–13. 57. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003;58:618–25. 58. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996;335:1–7.

756

SECTION 10

●

Endocrinology

59. Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005;90:678–88. 60. Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose–response relationships in healthy young men. Am J Physiol Endocrinol Metab 2001;281:E1172–81. 61. Bakhshi V, Elliott M, Gentili A, Godschalk M, Mulligan T. Testosterone improves rehabilitation outcomes in ill older men. J Am Geriatr Soc 2000;48:550–53. 62. Denti L. The PADAM syndrome and its clinical manifestations: the muscle mass. J Endocrinol Invest 2005;28:43–45. 63. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996;81:4358–65. 64. Xu X, De Pergola G, Bjorntorp P. The effects of androgens on the regulation of lipolysis in adipose precursor cells. Endocrinology 1990;126:1229–34. 65. Marin P, Oden B, Bjorntorp P. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab 1995;80:239–43. 66. Marin P. Testosterone, and regional fat distribution. Obes Res 1995;3(Suppl. 4):609S–612S. 67. Allan CA, Strauss BJ, Burger HG, Forbes EA, McLachlan RI. Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. J Clin Endocrinol Metab 2008;93:139–46. 68. Woodhouse LJ, Gupta N, Bhasin M, et al. Dose-dependent effects of testosterone on regional adipose tissue distribution in healthy young men. J Clin Endocrinol Metab 2004;89:718–26. 69. Bhasin S, Storer TW, Asbel-Sethi N, et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998;83:3155–62. 70. Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;129:18–26. 71. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 2006;106:581–88. 72. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27:1036–41. 73. Marin P, Krotkiewski M, Bjorntorp P. Androgen treatment of middle-aged, obese men: effects on metabolism, muscle and adipose tissues. Eur J Med 1992;1:329–36. 74. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men: results from the third national health and nutrition examination survey (NHANES III). Diabetes Care 2007;30:234–38. 75. Holmang A, Bjorntorp P. The effects of testosterone on insulin sensitivity in male rats. Acta Physiol Scand 1992;146:505–10.

76. Cohen JC, Hickman R. Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab 1987;64:960–63. 77. Morimoto S, Fernandez-Mejia C, Romero-Navarro G, Morales-Peza N, Diaz-Sanchez V. Testosterone effect on insulin content, messenger ribonucleic acid levels, promoter activity, and secretion in the rat. Endocrinology 2001;142:1442–47. 78. Basu R, Dalla Man C, Campioni M, et al. Effect of 2 years of testosterone replacement on insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, and postprandial glucose turnover in elderly men. Diabetes Care 2007;30:1972–78. 79. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008;299:39–52. 80. Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 2002;87:5001–7. 81. Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer’s disease. Neuro Endocrinol Lett 2001;22:163–68. 82. Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, et al. Free testosterone and risk for Alzheimer disease in older men. Neurology 2004;62:188–93. 83. Rosario ER, Chang L, Stanczyk FZ, Pike CJ. Age-related, testosterone depletion and the development of Alzheimer disease. JAMA 2004;292:1431–32. 84. Ramsden M, Nyborg AC, Murphy MP, et al. Androgens modulate beta-amyloid levels in male rat brain. J Neurochem 2003;87:1052–55. 85. Morley JE, Kumar VB, Bernardo AE, et al. Beta-amyloid precursor polypeptide in SAMP8 mice affects learning and memory. Peptides 2000;21:1761–67. 86. Goodenough S, Engert S, Behl C. Testosterone stimulates rapid secretory amyloid precursor protein release from rat hypothalamic cells via the activation of the mitogen-activated protein kinase pathway. Neurosci Lett 2000;296:49–52. 87. Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002;50:707–12. 88. Janowsky JS, Oviatt SK, Orwoll ES. Testosterone influences spatial cognition in older men. Behav Neurosci 1994;108:325–32. 89. Cherrier MM, Asthana S, Plymate S, et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 2001;57:80–88. 90. Kenny AM, Bellantonio S, Gruman CA, Acosta RD, Prestwood KM. Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2002;57:M321–25. 91. Kenny AM, Fabregas G, Song C, Biskup B, Bellantonio S. Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci 2004;59:75–78. 92. Maki PM, Ernst M, London ED, et al. Intramuscular testosterone treatment in elderly men: evidence of memory decline and altered brain function. J Clin Endocrinol Metab 2007;92:4107–14.

CHAPTER 60

●

Testosterone Replacement Therapy in Men and Women

93. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the women’s health initiative memory study: a randomized controlled trial. JAMA 2003;289:2651–62. 94. Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 1999;84:3681–85. 95. Cherrier MM, Matsumoto AM, Amory JK, et al. The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology 2005;64:290–96. 96. Zitzmann M, Nieschlag E. Testosterone levels in healthy men and the relation to behavioural and physical characteristics: facts and constructs. Eur J Endocrinol 2001;144:183–97. 97. Barrett-Connor E, von Mühlen DG, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: the rancho bernardo study. J Clin Endocrinol Metab 1999;84:573–77. 98. Seidman SN, Walsh BT. Testosterone, and depression in aging men. Am J Geriatr Psychiatry 1999;7:18–33. 99. Pope HG Jr., Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:105–11. 100. Seidman SN, Spatz E, Rizzo C, Roose SP. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. J Clin Psychiatry 2001;62:406–12. 101. Rabkin JG, Wagner GJ, Rabkin R. A double-blind, placebo-controlled trial of testosterone therapy for HIVpositive men with hypogonadal symptoms. Arch Gen Psychiatry 2000;57:141–47, discussion 155-6. 102. Seidman SN, Rabkin JG. Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. J Affect Disord 1998;48:157–61. 103. Tricker R, Casaburi R, Storer TW, et al. The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men – a clinical research center study. J Clin Endocrinol Metab 1996;81:3754–58. 104. Wang C, Alexander G, Berman N, et al. Testosterone replacement therapy improves mood in hypogonadal men – a clinical research center study. J Clin Endocrinol Metab 1996;81:3578–83. 105. Scaramella TJ, Brown WA. Serum testosterone and aggressiveness in hockey players. Psychosom Med 1978;40:262–65. 106. Christiansen K, Knussmann R. Androgen levels and components of aggressive behavior in men. Horm Behav 1987;21:170–80. 107. Haren MT, Kim MJ, Tariq SH, Wittert GA, Morley JE. Andropause: a quality-of-life issue in older males. Med Clin North Am 2006;90:1005–23. 108. Basaria S, Lieb J II, Tang AM, et al. Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol (Oxf) 2002;56:779–86. 109. Dacal K, Sereika SM, Greenspan SL. Quality of life in prostate cancer patients taking androgen deprivation therapy. J Am Geriatr Soc 2006;54:85–90. 110. Park NC, Yan BQ, Chung JM, Lee KM. Oral testosterone undecanoate (Andriol) supplement therapy improves the

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125. 126.

127.

757

quality of life for men with testosterone deficiency. Aging Male 2003;6:86–93. Reddy P, White CM, Dunn AB, Moyna NM, Thompson PD. The effect of testosterone on health-related quality of life in elderly males – a pilot study. J Clin Pharm Ther 2000;25:421–26. Bizzarro A, Valentini G, Di Martino G, DaPonte A, De Bellis A, Iacono G. Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter’s syndrome. J Clin Endocrinol Metab 1987;64:32–36. Kocar IH, Yesilova Z, Ozata M, Turan M, Sengul A, Ozdemir I. The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin Exp Immunol 2000;121:448–52. Schatzl G, Madersbacher S, Thurridl T, et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 2001;47:52–58. Meikle AW, Arver S, Dobs AS, et al. Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology 1997;49:191–96. Rhoden EL, Morgentaler A. Influence of demographic factors and biochemical characteristics on the prostate-specific antigen (PSA) response to testosterone replacement therapy. Int J Impot Res 2006;18:201–5. Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA 2006;296:2351–61. Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol 2003;170:2348–51. Fowler JE Jr., Whitmore WF Jr.. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 1981;126:372–75. Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 2005;173:533–36. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 2004;172:920–22. Walsh PC, Wilson JD. The induction of prostatic hypertrophy in the dog with androstanediol. J Clin Invest 1976;57:1093–97. Pollard M, Snyder DL, Luckert PH. Dihydrotestosterone does not induce prostate adenocarcinoma in L-W rats. Prostate 1987;10:325–31. Ruijter E, van de Kaa C, Miller G, Ruiter D, Debruyne F, Schalken J. Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev 1999;20:22–45. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;75:1092–98. Bagatell CJ, Heiman JR, Matsumoto AM, Rivier JE, Bremner WJ. Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men. J Clin Endocrinol Metab 1994;79:561–67. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older

758

128.

129.

130.

131.

132.

133.

134. 135. 136.

137.

138. 139.

140. 141. 142.

143.

144.

SECTION 10

●

Endocrinology

men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005;60:1451–57. Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab 1999;84:3469–78. Dobs AS, Bachorik PS, Arver S, et al. Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system. J Clin Endocrinol Metab 2001;86:1026–33. Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 1999;100:1690–96. Malkin CJ, Pugh PJ, Morris PD, et al. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart 2004;90:871–76. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 2000;102:1906–11. Smith JC, Bennett S, Evans LM, et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab 2001;86:4261–67. Shahidi NT. Androgens and erythropoiesis. N Engl J Med 1973;289:72–80. Basaria S, Dobs AS. Risks versus benefits of testosterone therapy in elderly men. Drugs Aging 1999;15:131–42. Rhoden EL, Morgentaler A. Risks of testosteronereplacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482–92. Melchert RB, Welder AA. Cardiovascular effects of androgenic-anabolic steroids. Med Sci Sports Exerc 1995;27:1252–62. Wight JN Jr., Salem D. Sudden cardiac death and the ‘athlete’s heart’. Arch Intern Med 1995;155:1473–80. English KM, Mandour O, Steeds RP, Diver MJ, Jones TH, Channer KS. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur Heart J 2000;21:890–94. Basaria S, Dobs AS. Hypogonadism, and androgen replacement therapy in elderly men. Am J Med 2001;110:563–72. Burger HG. Androgen production in women. Fertil Steril 2002;77(Suppl. 4):S3–S5. Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the rancho bernardo study. J Clin Endocrinol Metab 2000;85:645–651. Jiroutek MR, Chen MH, Johnston CC, Longcope C. Changes in reproductive hormones and sex hormonebinding globulin in a group of postmenopausal women measured over 10 years. Menopause 1998;5:90–94. Judd HL, Fournet N. Changes of ovarian hormonal function with aging. Exp Gerontol 1994;29:285–298.

145. Zumoff B, Strain GW, Miller LK, Rosner W. Twentyfour-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab 1995;80:1429–1430. 146. Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 2000;85:2832–2838. 147. North American Menopause Society. The role of testosterone therapy in postmenopausal women: position statement of the north american menopause society. Menopause 2005;12:496–511, quiz 649. 148. Labrie F, Belanger A, Belanger P, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol 2006;99:182–188. 149. Davis SR, Burger HG. Clinical review 82: Androgens and the postmenopausal woman. J Clin Endocrinol Metab 1996;81:2759–2763. 150. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682–688. 151. Braunstein GD, Sundwall DA, Katz M, et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Arch Intern Med 2005;165:1582–1589. 152. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005;105:944–952. 153. Simon J, Braunstein G, Nachtigall L, et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005;90:5226–5233. 154. Miller KK, Biller BM, Beauregard C, et al. Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebocontrolled study. J Clin Endocrinol Metab 2006;91:1683–1690. 155. Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 2003;79:1341–1352. 156. Davis SR, McCloud P, Strauss BJ, Burger H. Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 1995;21:227–236. 157. Burger HG, Hailes J, Menelaus M, Nelson J, Hudson B, Balazs N. The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas 1984;6:351–358. 158. Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause 2003;10:390–398. 159. Sherwin BB. Changes in sexual behavior as a function of plasma sex steroid levels in post-menopausal women. Maturitas 1985;7:225–233. 160. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study

CHAPTER 60

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

●

Testosterone Replacement Therapy in Men and Women

of sex steroid administration in the surgical menopause. Psychosom Med 1985;47:339–351. Sherwin BB, Gelfand MM. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol 1985;151: 153–160. Archer JS, Love-Geffen TE, Herbst-Damm KL, Swinney DA, Chang JR. Effect of estradiol versus estradiol and testosterone on brain-activation patterns in postmenopausal women. Menopause 2006;13:528–537. Tuiten A, Van Honk J, Koppeschaar H, Bernaards C, Thijssen J, Verbaten R. Time course of effects of testosterone administration on sexual arousal in women. Arch Gen Psychiatry 2000;57:149–153, discussion 155-6. Jassal SK, Barrett-Connor E, Edelstein SL. Low bioavailable testosterone levels predict future height loss in postmenopausal women. J Bone Miner Res 1995;10:650–654. Slemenda C, Longcope C, Peacock M, Hui S, Johnston CC. Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women. J Clin Invest 1996;97:14–21. Miller BE, De Souza MJ, Slade K, Luciano AA. Sublingual administration of micronized estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density. Menopause 2000;7:318–326. Barrett-Connor E, Young R, Notelovitz M, et al. A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles. J Reprod Med 1999;44:1012–1020. Watts NB, Notelovitz M, Timmons MC, Addison WA, Wiita B, Downey LJ. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 1995;85:529–537. Raisz LG, Wiita B, Artis A, et al. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab 1996;81:37–43. Davis SR, Walker KZ, Strauss BJ. Effects of estradiol with and without testosterone on body composition and relationships with lipids in postmenopausal women. Menopause 2000;7:395–401. Lovejoy JC, Bray GA, Bourgeois MO, et al. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women – a clinical research center study. J Clin Endocrinol Metab 1996;81:2198–2203. Miller K, Corcoran C, Armstrong C, et al. Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. J Clin Endocrinol Metab 1998;83:2717–2725. Dolan S, Wilkie S, Aliabadi N, et al. Effects of testosterone administration in human immunodeficiency virus-infected women with low weight: a randomized placebo-controlled study. Arch Intern Med 2004;164:897–904. Choi HH, Gray PB, Storer TW, et al. Effects of testosterone replacement in human immunodeficiency virusinfected women with weight loss. J Clin Endocrinol Metab 2005;90:1531–1541.

759

175. Gouchie C, Kimura D. The relationship between testosterone levels and cognitive ability patterns. Psychoneuroendocrinology 1991;16:323–334. 176. Moffat SD, Hampson E. A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference. Psychoneuroendocrinology 1996;21:323–337. 177. Slabbekoorn D, van Goozen SH, Megens J, Gooren LJ, Cohen-Kettenis PT. Activating effects of cross-sex hormones on cognitive functioning: a study of shortterm and long-term hormone effects in transsexuals. Psychoneuroendocrinology 1999;24:423–447. 178. Van Goozen SH, Cohen-Kettenis PT, Gooren LJ, Frijda NH, Van de Poll NE. Activating effects of androgens on cognitive performance: causal evidence in a group of female-to-male transsexuals. Neuropsychologia 1994;32:1153–1157. 179. Aleman A, Bronk E, Kessels RP, Koppeschaar HP, van Honk J. A single administration of testosterone improves visuospatial ability in young women. Psychoneuroendocrino 2004;29:612–617. 180. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrino 1988;13:345–357. 181. Miller KK, Grieco KA, Klibanski A. Testosterone administration in women with anorexia nervosa. J Clin Endocrinol Metab 2005;90:1428–1433. 182. Sherwin BB, Gelfand MM. Sex steroids and affect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology 1985;10:325–335. 183. Bachmann GA. Androgen cotherapy in menopause: evolving benefits and challenges. Am J Obstet Gynecol 1999;180:S308–S311. 184. Dow MG, Hart DM, Forrest CA. Hormonal treatments of sexual unresponsiveness in postmenopausal women: a comparative study. Br J Obstet Gynaecol 1983;90: 361–366. 185. Simon J, Klaiber E, Wiita B, Bowen A, Yang HM. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999;6:138–146. 186. Kotz K, Alexander JL, Dennerstein L. Estrogen and androgen hormone therapy and well-being in surgically postmenopausal women. J Womens Health (Larchmt) 2006;15:898–908. 187. Rako S. Testosterone deficiency: a key factor in the increased cardiovascular risk to women following hysterectomy or with natural aging? J Womens Health 1998;7:825–829. 188. Shelley JM, Green A, Smith AM, et al. Relationship of endogenous sex hormones to lipids and blood pressure in mid-aged women. Ann Epidemiol 1998;8:39–45. 189. Svendsen OL, Hassager C, Christiansen C. Relationships and independence of body composition, sex hormones, fat distribution and other cardiovascular risk factors in overweight postmenopausal women. Int J Obes Relat Metab Disord 1993;17:459–463. 190. Basaria S, Nguyen T, Rosenson RS, Dobs AS. Effect of methyl testosterone administration on plasma viscosity in postmenopausal women. Clin Endocrinol (Oxf) 2002;57:209–214.

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Endocrinology

191. Hickok LR, Toomey C, Speroff L. A comparison of esterified estrogens with and without methyltestosterone: effects on endometrial histology and serum lipoproteins in postmenopausal women. Obstet Gynecol 1993;82:919–924. 192. Moore E, Wisniewski A, Dobs A. Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects. J Clin Endocrinol Metab 2003;88:3467–3473. 193. Buckler HM, McElhone K, Durrington PN, Mackness MI, Ludlam CA, Wu FC. The effects of low-dose testosterone treatment on lipid metabolism, clotting factors and ultrasonographic ovarian morphology in women. Clin Endocrinol (Oxf) 1998;49:173–178. 194. Worboys S, Kotsopoulos D, Teede H, McGrath B, Davis SR. Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen. J Clin Endocrinol Metab 2001;86:158–161. 195. Sowers M, Derby C, Jannausch ML, Torrens JI, Pasternak R. Insulin resistance, hemostatic factors, and hormone interactions in pre- and perimenopausal women: SWAN. J Clin Endocrinol Metab 2003;88:4904–4910. 196. Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev 2003;24:302–312. 197. van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997;47:337–342. 198. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal

199.

200.

201.

202.

203.

204.

205.

206.

women: principal results from the women’s health initiative randomized controlled trial. JAMA 2002;288:321–333. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin replacement study (HERS) research group. JAMA 1998;280:605–613. Wierman ME, Basson R, Davis SR, et al. Androgen therapy in women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91:3697–3710. Agarwal VR, Bulun SE, Leitch M, Rohrich R, Simpson ER. Use of alternative promoters to express the aromatase cytochrome P450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients. J Clin Endocrinol Metab 1996;81:3843–3849. Ballerini P, Oriana S, Duca P, et al. Urinary testosterone as a marker of risk of recurrence in operable breast cancer. Breast Cancer Res Treat 1993;26:1–6. Maia H Jr., Maltez A, Fahel P, Athayde C, Coutinho E. Detection of testosterone and estrogen receptors in the postmenopausal endometrium. Maturitas 2001;38:179–188. Basaria S, Dobs AS. Safety, and adverse effects of androgens: how to counsel patients. Mayo Clin Proc 2004;79:S25–S32. Barrett-Connor E, Young R, Notelovitz M, et al. A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles. J Reprod Med 1999;44:1012–1020. Braunstein GD. Androgen insufficiency in women. Growth Horm IGF Res 2006;16(A):S109–S117.

Index

A Ablatio penis, sexual orientation and gender identity outcomes following prenatal endocrine abnormalities, 107–108 Action potential duration (APD), testosterone effects in heart, 157–158 Acupuncture, in vitro fertilization use, 396 Acute fatty liver of pregnancy (AFLP), features, 333 Acute lymphoblastic leukemia (ALL), sex differences, 54–56 AD, see Alzheimer’s disease Adalimumab, inflammatory bowel disease management and pregnancy safety, 310–311 ADHD, see Attention deficit hyperactivity disorder Adjudin, male sterilization, 363 Adult respiratory distress syndrome (ARDS), genetic susceptibility, 297 AFLP, see Acute fatty liver of pregnancy Age adjustment, gender-specific frequency studies, 115 Aggression male athletes, 71 sex differences, 96–97 Aging, see also Menopause cardiac effects, 153–154 lower urinary tract symptoms bladder, 434 overview, 432 pelvic floor, 435–436 prospects for study, 444–445 prostate, 436 urethra, 434–435 urinary incontinence behavioral therapy, 440–442 epidemiology, 437 etiology, 437, 439–440 evaluation, 438, 440 lifestyle modification, 440 pharmacological therapy, 442 supportive care, 443 surgery, 443 types, 437–438 vagina, 433–434 vulva, 433–434

oral contraceptives and venous thromboembolism risks, 229 ovarian reserve, 383 testosterone levels men, 742 women, 752 urinary tract infection, 436–437 AIH, see Autoimmune hepatitis AIS, see Androgen insensitivity syndrome Alcohol coronary heart disease prevention and sex differences, 168 liver disease in women, 340 Alendronate, osteoporosis management men, 728 women, 727–728 ALL, see Acute lymphoblastic leukemia Alloimmunization, fetal effects in later life, 8 Aloprostadil, erectile dysfunction management, 411, 711 Alosetron, irritable bowel syndrome management, 351–352 Alpha-blockers, benign prostate hypertrophy management, 429, 443–444 ALS, see Amyotrophic lateral sclerosis Alzheimer’s disease (AD), gender-specific frequency studies, 121 Amenorrhea, female athletes, 68–69 γ-Aminobutyric acid (GABA), arcuate nucleus sex differences, 93 Amyotrophic lateral sclerosis (ALS), genderspecific frequency studies, 122 Anabolic steroids, athlete use, 70–71 Androgen deficiency, see Hypogonadism; Testosterone Androgen insensitivity syndrome (AIS) features, 20 sexual orientation and gender identity outcomes following prenatal endocrine abnormalities complete, 109 partial, 108 Androphilic, definition, 103 Anger, cardiovascular disease risks, 189 Angiotensin II, cardiac effects, 157 Ankylosing spondylitis, pregnancy, 634–635

761

Anteroventroperiventricular nucleus (AVPV), sex differences, 90–92 Antibiotics, inflammatory bowel disease management and pregnancy safety, 309 Antiphospholipid antibodies pregnancy, 631 venous thromboembolism, 226 Antiphospholipid syndrome (APS), oral contraceptive studies, 649 Anti-sperm antibodies (ASA), male infertility, 374 Anxiety cardiovascular disease risks, 169 sex differences, 97, 137–138 Aortic stenosis, gender ratio, 9 APD, see Action potential duration Apgar score, gender differences in preterm infant outcomes, 10 Apolipoprotein B-100, cardiovascular risks, 179 Apomorphine, female sexual dysfunction management, 406 APS, see Antiphospholipid syndrome Arcuate nucleus, sex differences, 93 ARDS, see Adult respiratory distress syndrome Aromatase, placental deficiency, 20 Artificial bowel sphincter, fecal incontinence management, 323–324 ASA, see Anti-sperm antibodies ASD, see Atrial septal defect; Autism spectrum disorder Aspirin coronary heart disease prevention and sex differences, 167 stroke prevention and sex differences, 129–130 Asthma atopy, 39–40 epidemiology, 38–39 fetal exposure to smoking, 39 gender differences animal models of hormone effects dehydroepiandrosterone, 221 estrogen, 218–220 progesterone, 220–221 developmental differences, 217–218 hormone replacement therapy risks, 217 perimenstrual asthma, 217

762

Index

Asthma (continued) prospects for study, 221–222 puberty, 215–217 ratio, 9, 215 hormonal influences, 40 inflammation, 215 smoking effects in children and teens, 39 Ataxia telangiectasia, features, 485 Atherosclerosis, see Coronary heart disease; Stroke Athletes, see Sports ATM, ataxia telangiectasia mutations, 485 Atopy, asthma, 39–40 Atrial fibrillation, sex differences in stroke, 130–131 Atrial septal defect (ASD), gender ratio, 9 Attention deficit hyperactivity disorder (ADHD), sex differences in children, 63, 136 Autism spectrum disorder (ASD), sex differences in children, 136–137 Autoimmune disease, see also specific diseases autoimmune thyroiditis in pregnancy, 695–696 dendritic cells, 587 estrogen receptor modulation, 586 hormone modulation, 278, 585, 587 incidence in women, 277 innate immunity, 587 mediators and signals, 585–586 oral contraceptive use, see specific diseases pathogenesis, 277–278 prolactin role bromocriptine therapy clinical studies, 606–608 immunosuppressive properties, 606 prophylaxis, 606 rationale, 605–606 hyperprolactinemia preceding disease, 600 rheumatoid arthritis, 600–602 systemic lupus erythematosus, 602–605 immune stimulation, 599–601 sex hormones cytokine modulation, 593 peripheral metabolism, 593–594 T-helper cells, 587 Autoimmune hepatitis (AIH), features in women, 338 AVPV, see Anteroventroperiventricular nucleus Azathioprine inflammatory bowel disease management and pregnancy safety, 309–310 rheumatic disease management in pregnancy, 638

B Bacterial vaginosis (BV), pregnancy, 550 Bartonellosis clinical features, 505–506 gender differences, 506 laboratory findings, 506 overview, 505 treatment, 506 Bed nucleus of the stria terminalis (BNST), sex differences, 90–92, 106 Bell palsy, gender-specific frequency studies, 120, 122

Benign metastasizing leiomyoma (BML) computed tomography, 286–287 differential diagnosis, 287 epidemiology, 286 pathogenesis, 286 treatment, 287 Benign prostate hypertrophy (BPH) features, 425 treatment, 429–430, 443–444 Bevacizumab, breast cancer management, 468 Bisexual, definition, 103 Bisphosphonates, osteoporosis management, 727–730 Bladder, aging effects, 434 Bladder outlet obstruction (BOO), features in women, 425 BML, see Benign metastasizing leiomyoma BNST, see Bed nucleus of the stria terminalis Bone marrow transplantation, pediatric cancer treatment effects, 57–58 BOO, see Bladder outlet obstruction Bovine spongiform encephalopathy, see Prion disease BPH, see Benign prostate hypertrophy Brain sex differences cellular mechanism apoptosis, 91–92 cell genesis/differentiation, 92 cell-to-cell communication, 92–94 cerebral blood flow, 81–82 cerebral metabolic rate, 82 cognitive processing, 75–77, 106 emotion processing, 77–78 implications in functional brain organization, 82–83 neuroanatomy regional volumes, 80–81, 89–90, 105–106 whole brain, 79–80 neurotransmitter systems, 82 prospects for study, 83 stress response, 78 synaptic patterning, 90–91 sexual differentiation history of study, 88–89 overview, 87–88 prenatal hormonal hypothesis gender identity and sexual orientation following disruptions, 107–109 overview, 103 presumed correlates, 104–107 testing, 104–106 prospects for study, 97–98, 109–111 rodent studies, 103–104 sexual behavior as readout, 95–96 timing, 104 tumors, gender-specific frequency studies, 120, 122 BRCA1 breast cancer mutations, 462, 482–483 prostate cancer mutations, 488–489 BRCA2 breast cancer mutations, 462, 482–483 prostate cancer mutations, 488–489 Breast, anatomy and development, 459 Breast cancer

clinical presentation, 462 diagnosis, 462–464 epidemiology, 459–460 evaluation in menopause, 453 hereditary syndromes ataxia telangiectasia, 485 Cowden syndrome, 484 gene mutations, 482–483 genetic testing, 490 Li–Fraumeni syndrome, 484–485 low penetrance genes, 485 overview, 492 Peutz–Jeghers syndrome, 485 screening, 483 pathology, 464 prognostic factors, 464–465, 468–469 risk factors diet, 461 environmental, 461–462 genetics, 462 hormonal, 460–461 survival, 468–469 treatment chemotherapy, 466–467 endocrine therapy, 466–467 molecular targets, 466–468 radiation therapy, 467 surgery, 465–466 Breastfeeding, see Lactation Bromocriptine, autoimmune disease management clinical studies, 606–608 immunosuppressive properties, 606 prophylaxis, 606 rationale, 605–606 Budd–Chiari syndrome, oral contraceptive studies, 337 Buproprion, female sexual dysfunction management, 406 BV, see Bacterial vaginosis

C CAH, see Congenital adrenal hyperplasia Calcitonin, osteoporosis management, 731 Cancer, see specific cancers Cancer, pediatric germ cell tumors, 474 incidence, 53–54 risk factors, 54–55 survival and sex differences, 55–56 treatment effects, 56–58 prospects for study, 58 Cardiothoracic surgery coronary artery bypass grafting, 200 gender differences biology, 200–202 coronary artery bypass graft recovery, 207–208 off-pump surgery, 208–209 risk factors, 202–205 surgical outcomes, 205–207 valve surgery, 208 Carotid stenosis, stroke prevention and sex differences, 131 CASA, see Computer-assisted semen analysis CBF, see Cerebral blood flow CBT, see Cognitive behavioral therapy

Index CC, see Clomiphene citrate Cerebral blood flow (CBF) gender differences in preterm infant outcomes, 10–11 sex differences, 81–82 Cerebral metabolic rate, sex differences, 82 CF, see Cystic fibrosis CFTR, see Cystic fibrosis transmembrane regulator CGD, see Chronic granulomatous disease Chancroid, sexually transmitted infection, 524 CHD, see Coronary heart disease Chemotherapy, pediatric cancer treatment effects, 56–58 CHF, see Congestive heart failure Chikungunya fever clinical features, 500 gender differences, 500–501 laboratory findings, 500 overview, 500 treatment, 500 Chlamydia pregnancy, 549 sexually transmitted infection, 521–522 Cholelithiasis oral contraceptive studies, 336 pregnancy, 335 Cholestasis, oral contraceptive studies, 336 Cholesterol, see Dyslipidemia Chrohn’s disease, see Inflammatory bowel disease Chronic granulomatous disease (CGD), sex differences, 53 Chronic obstructive pulmonary disease (COPD) clinical manifestations, 255 diagnosis, 253–255 epidemiology, 252–253 management, 255–257 CJD, see Creutzfeldt–Jacob disease Clinical impression, limitations in gender-specific frequency studies, 113–114 Clitoris, anatomy and physiology, 400–401 Cloacal exstrophy, sexual orientation and gender identity outcomes following prenatal endocrine abnormalities, 108 Clomiphene citrate (CC), female infertility management, 384 Clostridium difficile, pregnancy, 555–556 Clotting factor deficiencies, sex differences, 53 CMV, see Cytomegalovirus Coarctation of the aorta, gender ratio, 9 Cognitive behavioral therapy (CBT), irritable bowel syndrome management, 352 Cognitive function hormone replacement therapy in women, see Hormone replacement therapy menopause, 143 selective estrogen modulator effects, 146 sex differences, 75–77, 106 testosterone role men, 748–749 women, 756 Colonic transit time, constipation evaluation, 319 Colorectal cancer familial adenomatous polyposis, 486 hereditary nonpolyposis colon cancer, 486–487

screening, 483 Computed tomography (CT) benign metastasizing leiomyoma, 286–287 inflammatory bowel disease imaging, 313 osteoporosis evaluation, 725 Computer-assisted semen analysis (CASA), male infertility evaluation, 375 Condom male, 360–361 female, 361 Congenital adrenal hyperplasia (CAH), gene mutations, 20 Congestive heart failure (CHF), pathophysiology and sex differences, 154–155 Constipation diagnosis, 318 etiology, 318–319 evaluation colonic transit time, 319 defecography, 319 electromyography, 319–320 prevalence, 318 treatment descending perineum or rectocele, 320–321 non-relaxing puborectalis, 320 sacral nerve stimulation, 321 slow transit constipation, 321 Contraception, see also Oral contraceptives condom female, 361 male, 360–361 depot medroxyprogesterone acetate, 358 diaphragm, 361 emergency contraception, 362 intrauterine devices, 358 lactational amenorrhea, 362 NuvaRing, 360 Ortho Evra patch, 360 periodic abstinence, 361–362 spermicide, 361 sponge, 361 subdermal progestin implants Implanon, 358–359 Norplant, 359 systemic lupus erythematosus, 632 transplant recipients, 664 COPD, see Chronic obstructive pulmonary disease Coronary artery bypass graft, see Cardiothoracic surgery Coronary heart disease (CHD) atherosclerosis animal models and stress effects, 187–188 coronary artery physiology, 151–152 hormone replacement therapy effects, 167–168, 179–180 physical activity in prevention, 166 psychosocial risk factors anger, 189 anxiety, 169 chronic stress, 169, 192 depression, 168–169, 189–190 job strain, 191–192 positive affect benefits, 190–191 social support benefits, 192 socioeconomic status, 191

763

sex differences alcohol in prevention, 168 aspirin prevention, 167 diabetes, 166–167, 176 dyslipidemia, 163–164 electrophysiology, 157–158 hypertension, 163, 176 left ventricular mass, 152–154 obesity, 164–165, 175 smoking rates, 162–163, 176 vascular function, 152 Corticosteroids chronic obstructive pulmonary disease management, 256 inflammatory bowel disease management and pregnancy safety, 309 rheumatic disease management in pregnancy, 637–638 Cortisol, excess and growth effects, 24 Cowden syndrome, 484 C-reactive protein (CRP), inflammation and sex differences in stroke, 131 Creatine, athlete use, 71 Creutzfeldt–Jacob disease (CJD) clinical features, 511–512 gender differences, 512 overview, 510–512 treatment, 512 CRP, see C-reactive protein CT, see Computed tomography Cyclophosphamide, rheumatic disease management in pregnancy, 638 Cyclosporine A inflammatory bowel disease management and pregnancy, 310 rheumatic disease management in pregnancy, 638 CYP1A1, sex differences in expression, 263 Cystic fibrosis (CF) clinical features, 40–41 sex differences age at diagnosis, 41 bacterial colonization, 42 diabetes association, 43 nutritional status and fitness, 42–43 pulmonary function, 41–42 sex hormone influences, 43 survival, 41 Cystic fibrosis transmembrane regulator (CTFR), male infertility mutations, 372–373 Cystourethroscopy, lower urinary tract symptom evaluation, 427 Cytomegalovirus (CMV), fetal and neonatal transmission, 545–546

D Danazol, systemic lupus erythematosus management, 621 Deep venous thrombosis, see Venous thromboembolism Defecation, see Constipation; Fecal incontinence Defecography, constipation evaluation, 319 Defeminization, sexual differentiation of brain, 95 Dehydroepiandrosterone (DHEA) asthma animal models of effects, 221 cognition effects, 145–146

764

Index

Dehydroepiandrosterone (DHEA) (continued) peripheral metabolism in autoimmune disease, 593 systemic lupus erythematosus management, 621 Dementia, see also specific diseases menopause, 143–144 sex differences, 139 Dengue, pregnancy, 554 Denosumab, osteoporosis management, 733 Depot medroxyprogesterone acetate (DMPA), injectable contraception, 358 Depression cardiovascular disease risks, 168–169, 189–190 sex differences, 137–138 DHEA, see Dehydroepiandrosterone DHT, see Dihydrotestosterone Diabetes coronary heart disease risks and sex differences, 166–167, 176 cystic fibrosis association, 43 fetal exposure effects in later life, 8 pregnancy, 535, 660 stroke prevention and sex differences, 130 type I, 659–660 type II endogenous estradiol and risks, 686–687 endogenous testosterone and risk in men adiposity measures, 684–685 hypogonadism and insulin resistance, 684 insulin resistance, 684, 686 endogenous testosterone and risk in women adiposity measures, 680–681 insulin resistance, 680, 682–683 meta-analysis, 680, 684 polycystic ovary syndrome, 679–680 glucose metabolism effects estradiol, 690 testosterone, 688–690 sex hormone-binding globulin and risks, 687–688, 690–691 Diaphragm, contraception, 361 Diet, see Nutrition Dihydrotestosterone (DHT) immmune response to stress, 293, 295 synthesis in men, 742 DIO, see Indoleamine 2,3-dioxygenase Diptheria, see Tetanus/diptheria/pertussis Disorders of sexual development, see Sexual development DMD, see Duchenne muscular dystrophy DMPA, see Depot medroxyprogesterone acetate Double-outlet right ventricle, gender ratio, 9 Drug abuse, fetal exposure effects in later life, 8–9 Dual X-ray absorptiometry (DXA), osteoporosis evaluation, 724–725 Duchenne muscular dystrophy (DMD), sex differences in children, 64 DXA, see Dual X-ray absorptiometry Dysgerminoma, see Germ cell tumors Dyslipidemia apolipoprotein B-100, 179 coronary heart disease risks and sex differences, 163–164, 176

high-density lipoprotein cholesterol, 178 hormone replacement therapy effects, 179–180 lipid physiology, 176–177 lipoprotein(a), 179 low-density lipoprotein cholesterol, 177–178 management ezetimibe, 182–183 fibrates, 182 nicotinic acid, 182 nutrition, 180 physical activity, 180 statins, 180–182 non-high-density lipoprotein cholesterol, 178–179 prospects for study, 183 triglycerides, 178 Dyspareunia, female sexual dysfunction, 404

E ED, see Erectile dysfunction Ejaculatory dysfunction, evaluation and management, 712 Electromyography (EMG), constipation evaluation, 319–320 EMG, see Electromyography Emotion processing, sex differences, 77–78 Endometriosis, in vitro fertilization, 385–386 Endometritis, puerperal infection, 539–540 Endothelin-1 (ET-1), estrogen effects on expression, 296 Enterohemorrhagic Escherichia coli, see Escherichia coli 0157 Epididymitis, sexually transmitted infection, 527 Epilepsy gender-specific frequency studies, 117, 121 sex differences in children, 63–64 Erectile dysfunction (ED) definition, 408, 709 epidemiology, 409, 709–710 evaluation goal-directed approach, 410 history, 409 laboratory tests, 410 nocturnal penile tumescence, 410 overview, 710 physical examination, 410 questionnaires, 409–410 vascular testing, 410 management aloprostadil, 411, 711 intracavernosal injection, 411, 711 penile prosthesis, 411, 711–712 phosphodiesterase inhibitors, 410–411, 710–711 vacuum erection device, 411 vascular surgery, 411 pathophysiology, 408–409, 710 physiology of erection, 408, 710 risk factors, 409 Escherichia coli, 0157 clinical features, 507 gender differences, 508 laboratory findings, 507 overview, 506–507

prevention, 507–508 treatment, 507 Esophageal varices, pregnancy, 335 Estrogen asthma animal models of effects, 218–220 autoantibodies and hyperestrogenism, 621 autoimmune disease cytokine modulation, 593 modulation, 278 peripheral metabolism, 593–594 benign metastasizing leiomyoma treatment with antagonists, 287 diabetes type II studies endogenous estradiol and risks, 686–687 glucose metabolism effects, 690 genomic versus non-genomic effects, 294 heart effects, 156–157 immune modulation, 616–617 lung cancer modulation, 264 metabolism, 617–618 neuroprotection in stroke, 132–133 oral contraceptive dose, delivery, and venous thromboembolism, 229 osteoporosis management, 732 prolactin interactions, 598–599 Estrogen receptor antagonist therapy in systemic lupus erythematosus, 588 autoimmune disease modulation, 586 knockout mice and cognition effects, 142–143 status in breast cancer, 464 Estrogen replacement therapy, see Hormone replacement therapy ET-1, see Endothelin-1 Exercise, see Physical activity Ezetimibe, dyslipidemia management, 182–183

F Factor V Leiden (FVL) oral contraceptive users, 230 pregnancy, 234 venous thromboembolism, 225 Familial adenomatous polyposis (FAP), features, 486 FAP, see Familial adenomatous polyposis Fecal incontinence etiology, 322 evaluation anorectal anatomy, 322 anorectal physiology, 322–323 imaging, 322 prevalence, 321–322 treatment artificial bowel sphincter, 323–324 dynamic graciloplasty, 323 fecal diversion, 324 overlapping sphincteroplasty, 323 sacral nerve stimulation, 324 submucosal injections, 323 Female infertility, see also In vitro fertilization aging and ovarian reserve, 383 cervical factors, 383 etiology, 366–367, 381–383 luteal phase defect, 383

Index overview, 381 ovulatory disorders, 382–383 treatment, 383–384 tuboperitoneal defects, 382 uterine defects, 382 Female orgasmic disorder (FOD), features, 404 Female sexual arousal disorder (FSAD), features, 404 Female sexual dysfunction (FSD) anatomy and physiology clitoris, 400–401 orgasm, 402 peripheral neurophysiology, 401 uterus, 401 vagina, 401 vulva, 401 diagnostic criteria and classification, 713–715 dyspareunia, 404 epidemiology evaluation, 402–403 female orgasmic disorder, 404 female sexual arousal disorder, 404 health-related factors, 402 hypoactive sexual desire disorder, 403 National Health and Social Life Survey, 400 pathophysiology, 714 psychological factors, 402 sexual response cycle, 712–713 physiology, 713 treatment apomorphine, 406 buproprion, 406 flibanserin, 406 Kegel exercises, 405 masturbation training, 404 melanocortin receptor agonists, 405–406 neural endopeptidase inhibitors, 405 nitric oxide modulators, 405 overview, 715–716 oxytocin, 406 phosphodiesterase inhibitors, 405 prostaglandin E1 agonists, 405 sensate focus, 405 testosterone, 406 tibolone, 406 vaginal dilators, 405 vaginismus, 404 Feminization, sexual differentiation of brain, 95 Fertility, see Female infertility; Male infertility; Sterilization Fibrates, dyslipidemia management, 182 Fibromyalgia etiology, 622 hormone therapy, 622 Finger length ratio, sex and gender differences, 107 Flibanserin, female sexual dysfunction management, 406 Flu, see Influenza Focal nodular hyperplasia, oral contraceptive studies, 337 FOD, see Female orgasmic disorder Follicle-stimulating hormone (FSH), male infertility evaluation, 370

Fracture, see Osteoporosis Fragile X syndrome, sex differences in children, 64 FSAD, see Female sexual arousal disorder FSD, see Female sexual dysfunction FSH, see Follicle-stimulating hormone FVL, see Factor V Leiden

G GABA, see γ-Aminobutyric acid Gardasil, see Human papillomavirus Gastric emptying gastroparesis clinical presentation, 328 etiology, 328 evaluation, 328–329 gastric motility abnormalities, 327–328 idiopathic gastroparesis, 328 treatment, 329 normal physiology, 326 scintigraphy, 329 sex differences, 326–327, 350 Gastrin-releasing peptide receptor (GRPR), lung cancer role, 263 Gastroparesis, see Gastric emptying GBS, see Group B streptococcus; Gullain–Barré syndrome GCTs, see Germ cell tumors Gender assessment as risk factor, 115 dysphoria, 102 identity, 101 role behaviors, 101 Gender identity disorder (GID), definition, 102 Genetic counseling, familial cancers, 489 Genetic testing familial cancers, 490 informed consent, 490 psychological impact, 490–491 Germ cell tumors (GCTs) diagnosis, 477 extragonadal tumors clinical features, 477 origins, 476 gender differences biology female, 475–476 male, 475 clinical presentation, 476 epidemiology children, 474 adults, 474–475 germ cell development and maturation men, 473–474 women, 474 histology, 476 prospects for study, 479 treatment dysgerminoma, 477–478 non-dysgerminoma, 479 non-seminoma, 478 seminoma, 477–478 Gestation, see Pregnancy GH, see Growth hormone GID, see Gender identity disorder

765

Gingivitis, pregnancy, 535 Glioblastoma, gender-specific frequency studies, 120 Glucose-6-phosphate dehydrogenase deficiency, sex differences, 52 Glutathione S-transferase (GST), deletion and cancer risk, 263 GnRH, see Gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH), agonists/antagonists for in vitro fertilization, 388–389 Gonorrhea, pregnancy, 549 Graves’ disease, pregnancy, 702–703 Group B streptococcus (GBS), pregnancy, 553–554 Growth normal patterns, 22–23 puberty, 22 sex differences fetus, 5 neonate, 5–6 short stature chromosomal abnormalities, 23 environmental factors, 25 genetics, 23 hormonal etiologies, 24–25 skeletal disorders, 25 Growth hormone (GH) deficiency, 24 insensitivity, 24–25 GRPR, see Gastrin-releasing peptide receptor GST, see Glutathione S-transferase Gullain–Barré syndrome (GBS), gender-specific frequency studies, 122 Gynectomastia, boys in puberty, 28 Gynephilic, definition, 103

H Hantavirus clinical features, 501 gender differences, 502 laboratory findings, 501–502 overview, 501 Headache, gender-specific frequency studies, 122 Health care, gender differences in access and delivery, 297 Heart, see also pecific diseases aging effects, 153–154 cardiomyocyte renewal, 155 contractile properties, 153 hormone effects, 156–157 myofibers, 152–153 surgery, see Cardiothoracic surgery Heart rate variability (HRV), stress effects, 187 Height, see Growth HELLP syndrome, features, 333–334 Hematopoiesis, pediatric features, 51–52 Hemolytic uremic syndrome, see Escherichia coli 0157 Hemophilia, sex differences, 53 Hendra virus (HeV) clinical features, 499 gender differences, 499–500 laboratory findings, 499 overview, 498–499

766

Index

Hendra virus (HeV) (continued) pathology, 499 prevention, 499 treatment, 499 Heparin rheumatic disease management in pregnancy, 637 venous thromboembolism management in pregnancy, 236 Hepatitis A epidemiology, 569–570 pregnancy, 552 vaccination contraindications, 570 efficacy, 570 historical perspective, 570 pregnancy, 574 recommendations for adults, 570 Hepatitis B epidemiology, 568 pregnancy, 552–553 vaccination efficacy, 569 pregnancy, 574–575 recommendations for adults, 569 types, 569 Hepatitis C, pregnancy, 553 Hepatitis E, pregnancy, 334, 541 Hereditary nonpolyposis colon cancer (HNPCC) features, 486–487 genetic testing, 490 Herpes simplex virus (HSV) fetal and neonatal transmission, 546–547 sexually transmitted infection, 525–526 HeV, see Hendra virus HG, see Hyperemesis gravidarum HGA, see Human granulocytic anaplasmosis HH, see Hypogonadotropic hypogonadism High-density lipoprotein, see Dyslipidemia HIV, see Human immunodeficiency virus HMG-CoA reductase inhibitors, see Statins HNPCC, see Hereditary nonpolyposis colon cancer Hormone replacement therapy (HRT) asthma risks, 217 cognitive benefits Alzheimer’s disease, 144–145 early post-menopause effects, 145 estrogenic agents, 145 prospects for study, 146 rodent studies, 142–143 Women’s Health Initiative Memory Study, 144 coronary heart disease effects, 167–168, 179–180 definition, 142 dyslipidemia effects, 179–180 indications, 142, 453 lung cancer modulation, 264 systemic lupus erythematosus effects, 620–621 testosterone, see Testosterone replacement therapy venous thromboembolism effects biological plausibility, 232–233 evidence, 230–232 selective estrogen receptor modulators, 233 Women’s Health Initiative findings, 454

HPV, see Human papillomavirus HRT, see Hormone replacement therapy HRV, see Heart rate variability HSDD, see Hypoactive sexual desire disorder HSV, see Herpes simplex virus Human granulocytic anaplasmosis (HGA), pregnancy, 555 Human immunodeficiency virus (HIV), pregnancy, 550–552 Human papillomavirus (HPV) epidemiology, 563–564 pregnancy, 550 sexually transmitted infection, 524–525 vaccination contraindications and precautions, 565 efficacy, 564–565 historical perspective, 564 pregnancy, 575 recommendations for adults, 565 Hydroxychloroquine, rheumatic disease management in pregnancy, 637 17α-Hydroxylase, deficiency, 20 3β-Hydroxysteroid dehydrogenase, deficiency, 20 17β-Hydroxysteroid dehydrogenase, deficiency and sexual orientation/gender identity outcomes following prenatal endocrine abnormalities, 108–109 Hyperemesis gravidarum (HG), liver disease, 332 Hyperlipidemia, stroke prevention and sex differences, 130 Hypertension coronary heart disease risks and sex differences, 163, 176 stress response in women, 188 stroke prevention and sex differences, 130 Hypoactive sexual desire disorder (HSDD), features, 403 Hypogonadism, see also Hypogonadotropic hypogonadism insulin resistance, 684 male diagnosis, 743–745 etiology, 742–743 prevalence, 742 systemic lupus erythematosus risks in men, 620 testosterone replacement therapy for men formulations, 745 initiation algorithm, 744 Hypogonadotropic hypogonadism (HH) boys, 30 girls, 31 male infertility evaluation, 370–371 ovarian failure, 31 testicular failure, 30–31 Hypoplastic left heart syndrome, gender ratio, 9 Hypothyroidism growth effects, 24 pregnancy, 697–698

I Ibandronate, osteoporosis management, 729 IBD, see Inflammatory bowel disease IBS, see Irritable bowel syndrome ICI, see Intracavernous injection ICP, see Intrahepatic cholestasis of pregnancy

ICSI, see Intracytoplasmic sperm injection Idiopathic pulmonary arterial hypertension, see Pulmonary hypertension Immunization, see Vaccination Implanon, contraception, 358–359 INAH3, see Interstitial nucleus of the anterior hypothalamus Incidence advantages in gender-specific frequency studies, 113–114 study design, 114–115, 123 Incontinence, see Fecal incontinence; Lower urinary tract symptoms Indoleamine 2,3-dioxygenase (DIO), production in pregnancy, 535 Infant mortality birthweight dependence, 6 growth interactions, 7 male preponderance, 6–7 preterm infant outcomes, 9–10 race differences, 6–7 Infertility, see Female infertility; Male infertility; Sterilization Inflammatory bowel disease (IBD) diagnosis endoscopy, 312 imaging, 312–313 fertility impact, 306–307 gynecological complications menstrual abnormalities, 305 rectovaginal fistula, 305–306 heredity, 306 lactation and management, 312 osteoporosis, 306 pregnancy effects on disease course, 307–308 medication safety, 308–311 mode of delivery, 308 outcomes, 307 supplements in management, 311 symptomatic therapy, 311 self image aspects, 313–314 Infliximab, inflammatory bowel disease management and pregnancy safety, 310 Influenza epidemiology, 566–567 vaccination contraindications, 568 efficacy, 567–568 historical perspective, 567 pregnancy, 575 recommendations for adults, 568 Informed consent, genetic testing, 490 Insomnia, gender differences, 247–248 Intersex, definition, 102 Interstitial nucleus of the anterior hypothalamus (INAH3), gender differences, 105–106 Intra-vas device (IVD), male sterilization, 363 Intracavernosal injection, ejaculatory dysfunction management, 711 Intracavernous injection (ICI), erectile dysfunction management, 411 Intracytoplasmic sperm injection (ICSI) in vitro fertilization, 386, 392 male infertility management, 366, 376

Index Intrahepatic cholestasis of pregnancy (ICP), features, 332–333 Intrauterine device (IUD), contraception, 358 Intrauterine position (IUP) effect, 96 In vitro fertilization (IVF) assisted hatching, 392 blastocyst transfer, 391 cryopreservation of embryos, 392–393 embryo co-culture systems, 391–392 embryo transfer, 390–391 evaluations before procedure, 388 historical perspective, 384–385 indications age, 387–388 endometriosis, 385–386 fertility preservation, 387 genetic disorders, 387 ovulatory disorders, 387 tubal disease, 385 insemination and fertilization, 390 intracytoplasmic sperm injection, 386, 392 luteal phase support, 391 oocyte donation, 394 oocyte retrieval, 389–390 outcomes, 394–396 ovarian stimulation protocols gonadotropin-releasing hormone agonists/ antagonists, 388–389 high responders, 389 low responders, 389 preimplantation genetic diagnosis, 393–394 Iron deficiency anemia, sex differences, 52 Irritable bowel syndrome (IBS) diagnosis, 351 diagnostic criteria, 347 epidemiology, 347–348 gastrointestinal motility and sex differences, 350 pathophysiology central pain processing, 349 intestinal permeability, 349 sex differences in anatomy, 349–350 small intestinal bacterial overgrowth, 349 visceral hypersensitivity, 348–349 risk factors atopy, 351 obesity, 351 psychiatric comorbidity, 350–351 psychosocial risk factors, 350 treatment, 351–352 IUD, see Intrauterine device IUP effect, see Intrauterine position effect IVD, see Intra-vas device IVF, see In vitro fertilization Ixabepilone, breast cancer management, 468

J Job strain, cardiovascular disease risks, 191–192

K Kegel exercises, female sexual dysfunction management, 405 Kidney failure etiology, 658–659

pregnancy, 659 sexual function, 659 transplantation, 661 Klinefelter syndrome, male infertility, 373

L Lactation amenorrhea and birth control, 362 inflammatory bowel disease management, 312 systemic lupus erythematosus management, 632 LAM, see Lymphangioleiomyomatosis Lapatinib, breast cancer management, 467–468 LCMV, see Lymphocytic choriomeningitis virus Leflunomide, rheumatic disease management in pregnancy, 639 Left ventricular hypertrophy (LVH), pathophysiology and sex differences, 155–156 Leukocytospermia, male infertility, 373 Levator anti spasm, see Pelvic pain LHRH, see Luteinizing hormone-releasing hormone Libido, decrease and management, 712 Lichen planus (LP), features and management, 418–419 Lichen sclerosis (LS), features and management, 418 Lichen simplex chronicus (LSC), features and management, 418 Lipopolysaccharide (LPS), sex differences in inflammatory response, 297 Lipoprotein(a), cardiovascular risks, 179 Listeriosis, pregnancy, 554 Liver failure etiology, 657 pregnancy, 657–658 transplantation, 661 Liver disease, see also specific diseases alcoholic liver disease in women, 340 autoimmune hepatitis in women, 338 oral contraceptive studies Budd–Chiari syndrome, 337 cholelithiasis, 336 cholestasis, 336 focal nodular hyperplasia, 337 hepatic adenoma, 336–337 pregnancy coincident diseases cholelithiasis, 335 chronic liver disease, 335 hepatitis E, 334 transplantation of liver, 335–336 unique diseases acute fatty liver of pregnancy, 333 HELLP syndrome, 333–334 hepatic hemorrhage or rupture, 334 hyperemesis gravidarum, 332 intrahepatic cholestasis of pregnancy, 332–333 ovarian hyperstimulation syndrome, 331–332 overview, 331 primary biliary cirrhosis in women, 338–339 transplantation outcomes in women, 339–340

767

Li–Fraumeni syndrome, features, 484–485 LKB1, Peutz–Jeghers syndrome mutations, 485 Loperamide, inflammatory bowel disease management and pregnancy safety, 311 Low-density lipoprotein, see Dyslipidemia Low-molecular-weight heparin, venous thromboembolism management in pregnancy, 236 Lower urinary tract symptoms (LUTS) aging bladder, 434 overview, 432 pelvic floor, 435–436 prospects for study, 444–445 prostate, 436 urethra, 434–435 urinary incontinence behavioral therapy, 440–442 epidemiology, 437 etiology, 437, 439–440 evaluation, 438, 440 lifestyle modification, 440 pharmacological therapy, 442 supportive care, 443 surgery, 443 types, 437–438 vagina, 433–434 vulva, 433–434 anatomy, 421–422 assessment cystourethroscopy, 427 history, 425–426 imaging of upper tract, 427 pad test, 427 physical examination, 426 post-void residual urine, 427 urinalysis, 426 urodynamic testing, 427 uroflowmetry, 426–427 voiding cystourethrogram, 427 voiding diary, 426 benign prostate hypertrophy, 425 bladder outlet obstruction in women, 425 classification, 421–423 etiology men and women, 423–424 men only, 424 women only, 424 overactive bladder syndrome, 424–425 treatment benign prostate hypertrophy, 429–430 storage problems, 427–428 voiding problems, 429–430 urinary incontinence, 424–425 LP, see Lichen planus LPS, see Lipopolysaccharide LS, see Lichen sclerosis LSC, see Lichen simplex chronicus Lubiprostone, irritable bowel syndrome management, 352 Lung specific diseases fetal development fetal breathing, 36 respiratory physiology, 35–36 surfactant production, sex differences, 36–37 postnatal development

768

Index

Lung specific diseases (continued) alveolar and airway sex differences, 37–38 pulmonary function in infants and children, 38 sex hormones in lung physiology and respiratory distress syndrome development, 37 Lung cancer epidemiology, 260 scleroderma association, 279–280 sex differences cancer types, 261 female susceptibility, 261–262 mechanisms environmental exposures, 262 hormones, 264 molecular epidemiology, 262–264 prognosis, 264–265 smokers versus non-smokers, 260–261 Luteinizing hormone-releasing hormone (LHRH) benign metastasizing leiomyoma treatment with antagonists, 287 LUTS, see Lower urinary tract symptoms LVH, see Left ventricular hypertrophy Lymphangioleiomyomatosis (LAM) diagnosis, 288–289 epidemiology, 287–288 pathogenesis, 288 treatment, 289 Lymphocytic choriomeningitis virus (LCMV), pregnancy, 555

M Magnetic resonance imaging (MRI) brain sex differences regional volumes, 80–81 whole brain, 79–80 breast cancer, 463–464 inflammatory bowel disease imaging, 313 Malaria antimalarials for rheumatic disease management in pregnancy, 637 pregnancy, 541–543 Male infertility acupuncture treatment, 396 etiology, 366–367 evaluation genetic analysis, 372–373 hormone evaluation, 370–372 medical history, 368 physical examination, 368 post-ejaculatory urinalysis, 372 reproductive history, 366–368 semen analysis ejaculate volume, 368–369 morphology, 370 motility and forward progression, 369–470 overview, 368–369 sperm concentration and count, 369 sperm function analysis anti-sperm antibodies, 374 computer-assisted semen analysis, 375 DNA fragmentation, 374 leukocytospermia, 373 post-coital test, 374–375 viability, 374

ultrasonography, 372 management hormone therapy, 376 non-obstructive azoospermia, 376 obstructive azoospermia, 375–376 varicocele, 376 ovarian hyperstimulation syndrome risks, 395 Mammogram, see Breast cancer Masculinization, sexual differentiation of brain, 95 Mastitis, puerperal infection, 541 Masturbation training, female sexual dysfunction management, 404 Measles/mumps/rubella (MMR), vaccination in pregnancy, 575 Melanocortin receptor, agonists for female sexual dysfunction management, 405–406 MEN2, see Multiple endocrine neoplasia type 2 Meningococcal disease, see Neisseria meningitides Menopause, see also Hormone replacement therapy cognitive decline, 143 definition, 449 dementia, 143–144 evaluation breast cancer, 453 mood and cognition, 452 osteoporosis, 453 urogenital atrophy, 451–452 uterine bleeding, 452 vasomotor instability, 451 physiology, 450 sexually transmitted infection susceptibility, 520 sleep effects, 246 Menstruation perimenstrual asthma, 217 sleep effects, 245 6-Mercaptopurine, inflammatory bowel disease management and pregnancy safety, 309–310 Metabolic programming, fetus, 7–8 Methicillin-resistant Staphylococcus aureus (MRSA) clinical features, 509 gender differences, 510 overview, 508–509 treatment, 509–510 Methotrexate inflammatory bowel disease management and pregnancy safety, 310 rheumatic disease management in pregnancy, 638 MG, see Myasthenia gravis Migraine, gender-specific frequency studies, 122 MMF, see Mycophenolate mofetil MMR, see Measles/mumps/rubella Monkeypox clinical features, 502–503 diagnosis, 503 gender differences, 503 overview, 502 treatment, 503 Mood, testosterone role men, 749 women, 756

MRI, see Magnetic resonance imaging MRSA, see Methicillin-resistant Staphylococcus aureus MS, see Multiple sclerosis Multiple endocrine neoplasia type 2 (MEN2), features, 488 Multiple sclerosis (MS) gender-specific frequency studies, 118–119, 121–122 sex differences in experimental autoimmune encephalitis, 589 Mumps, see Measles/mumps/rubella Muscular dystrophy, see Duchenne muscular dystrophy Myasthenia gravis (MG), gender differences, 120, 122, 589 Mycophenolate mofetil (MMF), rheumatic disease management in pregnancy, 638

N Neisseria gonorrhoeae, sexually transmitted infection, 520–521 Neisseria meningitides epidemiology, 573 vaccination contraindications, 574 Menactra, 574 Menoimmune, 573–574 pregnancy, 575 recommendations for adults, 574 NEP, see Neural endopeptidase Neural endopeptidase (NEP), inhibitors for female sexual dysfunction management, 405 Nicotinic acid, dyslipidemia management, 182 Nipah virus (NiV) clinical features, 499 gender differences, 499–500 laboratory findings, 499 overview, 498–499 pathology, 499 prevention, 499 treatment, 499 NiV, see Nipah virus Nocturnal penile tumescence (NPT), erectile dysfunction evaluation, 410 Nonsteroidal anti-inflammatory drugs (NSAIDs), rheumatic disease management in pregnancy, 636–637 Norplant, contraception, 359 NPT, see Nocturnal penile tumescence NSAIDs, see Nonsteroidal anti-inflammatory drugs Nutrition breast cancer risks, 461 dyslipidemia management, 180 osteoporosis management, 726–727 NuvaRing, contraception, 360

O Obesity coronary heart disease risks and sex differences, 164–165, 175 irritable bowel syndrome risks, 351 obstructive sleep apnea hypoventilation syndrome, 44–45

Index Obstructive sleep apnea (OSA), gender differences, 246–247 Obstructive sleep apnea hypoventilation syndrome (OSAHS) children, 45–46 clinical features, 44 epidemiology, 44 pathogenesis, 44–45 risk factors, 45–46 OHSS, see Ovarian hyperstimulation syndrome Oral contraceptives antiphospholipid syndrome studies, 649 benefits, 646 breast cancer risks, 460–461 combined oral contraceptives versus progestinonly pills, 359–360 contraindications, 645–646 liver disease studies Budd–Chiari syndrome, 337 cholelithiasis, 336 cholestasis, 336 focal nodular hyperplasia, 337 hepatic adenoma, 336–337 rheumatoid arthritis studies, 646–647 scleroderma studies, 650–651 sexually transmitted infection susceptibility, 518–519 Sjögren’s syndrome studies, 649–650 systemic lupus erythematosus effects, 588, 620–621, 647–649 vasculitis studies, 651–652 venous thromboembolism effects age as risk factor, 229 biological plausibility, 228–229 estrogen dose and delivery method, 229 evidence, 227–228 hereditary thrombophilias and risks, 230 progestins, 229–230 Organ transplantation, see also specific organs access, 668 cancer risks men, 667 women, 667 donors, 660–661 failure etiologies, 657–659 fertility and contraception, 664 graft function and gender differences metabolism, 662 organ size and outcomes, 663 rejection implications, 662–663 infection and gender differences, 667 osteoporosis, 663–664 pregnancy diabetes, 660 fetal risks, 666 graft risks, 664 kidney, 659 liver, 657–658 management, 666–667 maternal risks, 664–666 quality of life considerations, 667–668 Orgasm female anatomy and physiology, 402 male, see Ejaculatory dysfunction; Erectile dysfunction Ortho Evra, contraception, 360 OSA, see Obstructive sleep apnea

OSAHS, see Obstructive sleep apnea hypoventilation syndrome Osteoporosis diagnostic criteria, 719 epidemiology men, 720 women, 719–720 evaluation history, 725 laboratory investigations, 725–726 menopause, 453 physical examination, 725 female athletes, 68–69 financial burden, 720 fracture risk assessment, 724 imaging studies, 724–725 management bisphosphonates, 727–730 calcitonin, 731 denosumab, 733 estrogen, 732 lifestyle modification, 726 nutrition, 726–727 ralifoxene, 730 selective androgen receptor modulators, 733 strontium ranelate, 733 teriparatide, 731–732 testosterone, 733 risk factors and sex differences primary osteoporosis, 722 secondary osteoporosis, 722–723 screening men, 723–724 women, 723 skeletal development hormonal control, 721–722 overview, 720–721 sex differences, 721 transplant recipients, 663–664 Ovarian cancer, hereditary syndromes ataxia telangiectasia, 485 Cowden syndrome, 484 gene mutations, 482–483 genetic testing, 490 Li–Fraumeni syndrome, 484–485 low penetrance genes, 485 Peutz–Jeghers syndrome, 485 screening, 483 Ovarian failure, hypergonadotropic hypogonadism, 31 Ovarian hyperstimulation syndrome (OHSS) in vitro fertilization, 395 liver disease and pregnancy, 331–332 Overactive bladder syndrome, features, 424–425 Oxytocin, female sexual dysfunction management, 406

P Pain irritable bowel syndrome and central pain processing, 349 perception, gender differences in neonates, 11–12 sex differences in pediatric cancer treatment, 58 Pancreas, transplantation, 662

769

Parasomnias, types and sex differences in childhood, 43–44 Parathyroid hormone, see Teriparatide Parkinson’s disease (PD), gender-specific frequency studies, 119, 122 Parvovirus, fetal and neonatal transmission, 547–548 Patent ductus arteriosus (PDA), gender ratio, 9 PBC, see Primary biliary cirrhosis PCOS, see Polycystic ovarian syndrome PD, see Parkinson’s disease PDA, see Patent ductus arteriosus Pelizaeus–Merzbacher disease (PMD), sex differences in children, 64–65 Pelvic floor, aging effects, 435–436 Pelvic inflammatory disease (PID), sexually transmitted infection, 526–527 Pelvic pain dermatoses contact dermatitis, 417–418 evaluation, 417 lichen planus, 418–419 lichen sclerosis, 418 lichen simplex chronicus, 418 levator anti spasm, 414–415 treatment intralesional injections, 417 oral drugs, 416–417 surgery, 417 topical therapy, 416 vulvar hygiene, 416 vulvodynia, 415–416 Penile prosthesis, erectile dysfunction management, 411, 711–712 Perfenidone, benign metastasizing leiomyoma treatment, 287 Pertussis, see Tetanus/diptheria/pertussis Peutz–Jeghers syndrome, features, 485 PGD, see Preimplantation genetic diagnosis Pharmacokinetics, sex differences and pediatric cancer treatment effects, 58 Phosphodiesterase inhibitors erectile dysfunction management, 410–411 female sexual dysfunction management, 405 Physical activity coronary heart disease prevention, 166 dyslipidemia management, 180 PID, see Pelvic inflammatory disease Placenta, immune modulation in pregnancy, 533–534 PMD, see Pelizaeus–Merzbacher disease Pneumonia, pregnancy, 536, 538–539 POA, see Preoptic area Polycystic ovarian syndrome (PCOS) diabetes risks, 679–680 infertility, 382–383 Precocious puberty, see Puberty Pre-eclampsia, systemic lupus erythematosus, 630 Pregnancy fertility effects in women, 629 gestation length effects on sex ratio, 5 immune function in connective tissue diseases, 627–628 immunology, 628 infection antibiotics, 556–557

770

Index

Pregnancy (continued) biliary ascariasis, 541 Clostridium difficile, 555–556 dengue, 554 epidemiology, 531 fetal and neonatal transmission cytomegalovirus, 545–546 herpes simplex virus, 546–547 parvovirus, 547–548 rubella, 544–545 toxoplasmosis, 544 varicella zoster virus, 548–549 group B streptococcus, 553–554 hepatitis A, 552 hepatitis B, 552–553 hepatitis C, 553 hepatitis E, 541 human granulocytic anaplasmosis, 555 intestinal parasites, 541 listeriosis, 554 lymphocytic choriomeningitis virus, 555 malaria, 541–543 puerperal infection endometritis, 539–540 fever, 539 mastitis, 541 prevention, 541 wound infection, 540 pneumonia, 536, 538–539 schistosomiasis, 543–544 sexually transmitted infections bacterial vaginosis, 550 chlamydia, 549 gonorrhea, 549 human immunodeficiency virus, 550–552 human papillomavirus, 550 syphilis, 549–550 Trichomonas vaginalis, 550 smallpox, 556 susceptibility mechanisms anatomic changes, 535–536 diabetes, 535 endocrine changes, 534 physiological changes, 535 placenta immune modulation, 533–534 T-helper cell balance, 532–533 tuberculosis, 539 urinary tract infection, 536–537 vaccination, 557 viral hemorrhagic fevers, 555 West Nile virus, 554 inflammatory bowel disease effects on disease course, 307–308 medication safety, 308–311 mode of delivery, 308 outcomes, 307 supplements in management, 311 symptomatic therapy, 311 liver disease coincident diseases cholelithiasis, 335 chronic liver disease, 335 hepatitis E, 334 transplantation of liver, 335–336 unique diseases acute fatty liver of pregnancy, 333

HELLP syndrome, 333–334 hepatic hemorrhage or rupture, 334 hyperemesis gravidarum, 332 intrahepatic cholestasis of pregnancy, 332–333 ovarian hyperstimulation syndrome, 331–332 overview, 331 lung development, see Lung metabolic programming of fetus, 7–8 postnatal effects of fetal exposure alloimmunization, 8 distress, 8 drug abuse, 8–9 maternal diabetes, 8 smoking, 8 rheumatoid arthritis effects on pregnancy, 633 family planning, 634 management, 633–634, 636–639 pregnancy effects on disease, 632–633 remission mechanisms, 633 scleroderma clinical features, 635 effects on pregnancy, 635 management, 635–636 pregnancy effects on disease, 635 sexually transmitted infections, 519–520 sleep effects, 245–246 spondyloarthropathies, 634–635 systemic lupus erythematosus antiphospholipid antibodies, 631 effects on pregnancy and outcomes, 630–631 management, 631–632 monitoring, 631 neonatal outcomes, 631 pre-eclampsia in active disease, 630 pre-pregnancy evaluation, 629 pregnancy effects on disease, 629–630 prolactin bromocriptine therapy, 608 hyperprolactinemia, 604 thyroid disease autoimmune thyroiditis, 695–696 case studies Graves’ disease, 702–703 hyperthyroidism, 699–702 hypothyroidism, 697–698 postpartum thyroiditis, 696–697 thyroid cancer, 704–706 transplant recipients diabetes, 660 fetal risks, 666 graft risks, 664 kidney, 659 liver, 657–658 management, 666–667 maternal risks, 664–666 vaccination hepatitis A, 574 hepatitis B, 574–575 human papillomavirus, 575 influenza, 575 measles/mumps rubella, 575 Neisseria meningitides, 575

overview, 574 Streptococcus pneumoniae, 575 tenanus/diptheria, 576 varicella zoster virus, 576 venous thromboembolism clinical presentation and diagnosis, 234–236 prevention of recurrence, 236–237 thrombophilia mechanisms, 233–234 treatment, 236 Preimplantation genetic diagnosis (PGD) cancer, 482 overview, 393–394 Preoptic area (POA), sex differences, 93–94 Preterm infants, gender differences in outcomes Apgar score, 10 cerebral blood flow, 10–11 mortality, 9–10 pain perception, 11–12 prognosis, 12 respiratory distress syndrome, 11 septicemia, 11 Prevalence, limitations in gender-specific frequency studies, 113–114 Primary biliary cirrhosis (PBC), features in women, 338–339 Prion disease clinical features, 511–512 gender differences, 512 overview, 510–512 treatment, 512 Progesterone asthma animal models of effects, 220–221 benign metastasizing leiomyoma treatment with antagonists, 287 immune modulation, 617 lung cancer modulation, 264 metabolism, 618–619 Progressive systemic sclerosis, see Scleroderma Prolactin autoimmune disease role bromocriptine therapy clinical studies, 606–608 immunosuppressive properties, 606 prophylaxis, 606 rationale, 605–606 hyperprolactinemia preceding disease, 600 rheumatoid arthritis, 600–602 systemic lupus erythematosus, 602–605 immune stimulation, 599–601 immune modulation animal models, 597–598, 606 estrogen interactions, 598–599 overview, 597 Prostaglandins preoptic area sex differences, 93–94 prostaglandin E1 agonists for female sexual dysfunction management, 405 Prostate, aging effects, 436 Prostate cancer features, 488–489 screening, 483 testosterone replacement therapy risks, 749–750 Pseudotumor cerebri, gender-specific frequency studies, 122

Index Psoriatic arthritis, pregnancy, 634–635 PTEN, Cowden syndrome mutations, 484 Puberty, see also GrowthSexual development asthma, 215–217 constitutional delay, 28 gynecomastia in boys, 28 normal features, 26–27 precocious puberty boys complete, 28–29 incomplete, 29 girls complete, 29–30 incomplete, 30 premature adrenarche, 28 pubarche, 27–28 thelarche, 28 Pulmonary atresia, gender ratio, 9 Pulmonary embolism, see Venous thromboembolism Pulmonary fibrosis, scleroderma association, 281 Pulmonary hypertension classification, 270–271 idiopathic pulmonary arterial hypertension clinical features, 270–271 diagnosis, 273 epidemiology, 271–272 pathogenesis, 272–273 treatment, 273 scleroderma pathogenesis, 274 pulmonary hypertension association, 273–274, 281 treatment, 274

R RA, see Rheumatoid arthritis Race/ethnicity infant mortality differences, 6–7 venous thromboembolism differences, 226 Ralifoxene osteoporosis management, 730 venous thromboembolism risks, 233 Raynaud’s phenomenon, see Scleroderma RDS, see Respiratory distress syndrome Reactive arthritis, pregnancy, 634–635 5α-Reductase deficiency overview, 20 sexual orientation/gender identity outcomes following prenatal endocrine abnormalities, 108 inhibitors in benign prostate hypertrophy management, 429, 444 Respiratory distress syndrome (RDS) gender differences in preterm infant outcomes, 11 sex hormones in lung physiology and development, 37 Restless leg syndrome (RLS), gender differences, 248 Reversible inhibition of sperm under guidance (RISUG), male sterilization, 362–363 Rheumatoid arthritis (RA) gender differences, 588

oral contraceptive studies, 646–647 pregnancy effects on pregnancy, 633 family planning, 634 management, 633–634, 636–639 pregnancy effects on disease, 632–633 remission mechanisms, 633 prolactin role, 600–602 sex differences, 278–279 sex hormone peripheral metabolism, 593–594 Risedronate, osteoporosis management men, 729 women, 728–729 RLS, see Restless leg syndrome Rubella, see also Measles/mumps/rubella fetal and neonatal transmission, 544–545

S Sacral nerve stimulation (SNS) constipation management, 321 fecal incontinence management, 324 Salmeterol, chronic obstructive pulmonary disease management, 256 SARMs, see Selective androgen receptor modulators Schistosomiasis, pregnancy, 543–544 Schizophrenia, sex differences, 138–139 Scintigraphy, gastric emptying, 329 Scleroderma diagnosis, 279 environmental factors in sex differences, 280–281 epidemiology, 279 estrogen therapy for Raynaud’s phenomenon, 651 hormone modulation in women, 281 lung cancer association, 279–280 oral contraceptive studies, 650–651 pregnancy clinical features, 635 effects on pregnancy, 635 management, 635–636 pregnancy effects on disease, 635 prognosis, 279 pulmonary fibrosis association, 281 pulmonary hypertension association, 273–274, 281 pathogenesis, 274 treatment, 274 Raynaud’s phenomenon, 280 SDN-POA, see Sexually dimorphic nucleus of the preoptic area Selective androgen receptor modulators (SARMs), osteoporosis management, 733 Selective estrogen receptor modulators (SERMs) cognition effects, 146 venous thromboembolism risks, 233 Selective serotonin reuptake inhibitors (SSRIs) irritable bowel syndrome management, 352 menopause management, 454 pelvic pain management, 417 Semen analysis, see Male infertility Seminoma, see Germ cell tumors Sensate focus, female sexual dysfunction management, 405

771

Sepsis epidemiology, 291–293 gender differences genetics, 296–297 health care access and delivery, 297 hemodynamic response to stress, 295–296 sex hormones and immmune response to stress, 293–295 pathogenesis, 291 Septicemia, gender differences in preterm infant outcomes, 11 SERMs, see Selective estrogen receptor modulators Serotonin, irritable bowel syndrome modulation, 348–349 SES, see Socioeconomic status Sex, definition, 101 Sex assignment, disorders of sexual development, 21–22 Sex hormone-binding globulin (SHBG) diabetes type II studies of risks, 687–688, 690–691 overview, 741 Sex ratio conception and male losses, 3–4 fetal loss, 4 gestation length effects, 5 infant mortality, see Infant mortality manipulation, 4–5 periconceptional influences, 4 Sexual development brain, see Brain cancer treatment effects, 56 disorders of sexual development anatomic etiologies, 20 chromosomal etiologies, 19 environmental etiologies, 21 hormonal etiologies, 19–20 overview, 102 sex assignment, 21–22 sexual orientation and gender identity outcomes following prenatal endocrine abnormalities ablatio penis, 107–108 cloacal exstrophy, 108 complete androgen insensitivity syndrome, 109 17β-hydroxysteroid dehydrogenase deficiency, 108–109 5α-reductase deficiency, 108 partial androgen insensitivity syndrome, 108 prospects for study, 109–111 fetal sex differentiation, 18–19, 87 Sexual function, see Ejaculatory dysfunction; Erectile dysfunction; Female sexual dysfunction; Libido Sexual identity, definition, 102 Sexual orientation, definition, 102 Sexually dimorphic nucleus of the preoptic area (SDN-POA), 89–90, 92, 95–96, 105–106 Sexually transmitted infection (STI) chancroid, 524 Chlamydia trachomatis, 521–522 epididymitis, 527

772

Index

Sexually transmitted infection (STI) (continued) gender differences behavioral susceptibility, 516–517 biological factors men, 517 women, 517–520 herpes simplex virus, 525–526 human papillomavirus, 524–525 Neisseria gonorrhoeae, 520–521 pelvic inflammatory disease, 526–527 pregnancy bacterial vaginosis, 550 chlamydia, 549 gonorrhea, 549 human papillomavirus, 550 syphilis, 549–550 Trichomonas vaginalis, 550 syphilis latent, 523 primary, 522–523 secondary, 523 tertiary, 523–524 Trichomonas vaginalis, 526 SHBG, see Sex hormone-binding globulin SIBO, see Small intestinal bacterial overgrowth Sickle cell disease, sex differences, 52–53 SIRS, see Systemic inflammatory response syndrome Sitzmarks study, constipation evaluation, 319 Sjögren syndrome (SS) gender differences, 588–599 oral contraceptive studies, 649–650 Skeletal development hormonal control, 721–722 overview, 720–721 sex differences, 721 SLE, see Systemic lupus erythematosus Sleep female characteristics menopause, 246 menstruation, 245 pregnancy, 245–246 sex differences insomnia, 247–248 obstructive sleep apnea, 246–247 overview, 244–245 prospects for study, 248 restless leg syndrome, 248 stages, 244 Small intestinal bacterial overgrowth (SIBO), irritable bowel syndrome risks, 349 Smallpox, pregnancy, 556 Smoking, see also Chronic obstructive pulmonary diseaseLung cancer asthma effects in children and teens, 39 fetal exposure effects in later life, 8, 39 sex differences in rates and coronary heart disease, 162–163, 176 SNS, see Sacral nerve stimulation Socioeconomic status (SES), cardiovascular disease risks, 191 Sperm, sex ratio manipulation, 4–5 Spermicide, contraception, 361 Sponge, contraception, 361 Sports demographic trends, 67

female athletes ligamentous injury, 69 nutrition, 69–70 triad of disorders, 68–69 male athletes aggression, 71 ergogenic aids, 70–71 physiology and sex differences biomechanics, 68 body composition, 68 body proportions, 68 cardiorespiratory system, 68 size, 67–68 SS, see Sjögren syndrome SSRIs, see Selective serotonin reuptake inhibitors Statins, dyslipidemia management, 180–182 Stature, see Growth Sterilization female, 362 male Adjudin, 363 intra-vas device, 363 reversible inhibition of sperm under guidance, 362–363 spermatogenesis suppression, 363 vasectomy, 362 STI, see Sexually transmitted infection Streptococcus pneumoniae epidemiology, 570–571 vaccination efficacy, 571 historical perspective, 571 pregnancy, 575 recommendations for adults, 571–572 Stress cardiovascular effects activity at rest, 186 anger, 189 anxiety, 169 atherosclerosis animal models, 187–188 breathing inhibition and hypertension in women, 188 chronic stress, 169, 192 job strain, 191–192 positive affect benefits, 190–191 reactivity, 187 social support benefits, 192 socioeconomic status, 191 hemodynamic response, 295–296 irritable bowel syndrome and psychosocial risk factors, 350 sex differences in response, 78, 97 sex hormones and immmune response, 293–295 Stroke, sex differences epidemiology, 129 gender-specific frequency studies, 115–117, 120–121 inflammation, 131 mechanisms estrogen neuroprotection, 132–133 heritability, 133 prevention aspirin, 129–130 atrial fibrillation, 130–131 carotid stenosis management, 131

diabetes management, 130 hyperlipidemia management, 130 hypertension management, 130 prospects for study, 133 symptoms and recovery, 132 tissue plasminogen activator therapy, 131–132 Strontium ranelate, osteoporosis management, 733 Sulfasalazine, inflammatory bowel disease management and pregnancy safety, 308–309 Sulfasalazine, rheumatic disease management in pregnancy, 638 Surfactant, sex differences in production, 36–37 Syphilis latent, 523 pregnancy, 549–550 primary, 522–523 secondary, 523 tertiary, 523–524 Systemic inflammatory response syndrome (SIRS) clinical features, 291 epidemiology, 291–293 gender differences genetics, 296–297 health care access and delivery, 297 hemodynamic response to stress, 295–296 sex hormones and immmune response to stress, 293–295 pathogenesis, 291 Systemic lupus erythematosus (SLE) androgen therapy, 621 behavioral effects, 621–622 estrogen receptor blocker therapy, 588 hormone replacement therapy effects, 620–621 males hypogonadic patients, 620 normal patients, 619–620 oral contraceptive effects, 588, 620–621, 647–649 prolactin bromocriptine therapy, 607–608 role, 602–605 sex hormones cytokine modulation, 593 modulation, 585, 588 peripheral metabolism, 593–594 T-regulatory cell role, 586–587

T Tamoxifen, venous thromboembolism risks, 233 Tegaserod, irritable bowel syndrome management, 352 Tension-type headache, gender-specific frequency studies, 122 Teriparatide, osteoporosis management men, 732 women, 731–732 Testicular cancer, features, 487–488 Testicular failure, hypergonadotropic hypogonadism, 30–31 Testosterone action potential duration effects in heart, 157–158 androgen deficiency, see also Hypogonadism; Testosterone replacement therapy

Index aging effects on levels, 742 women diagnosis, 753 etiology, 752–753 indications for treatment, 753–754 diabetes type II studies endogenous testosterone and risk in men adiposity measures, 684–685 hypogonadism and insulin resistance, 684 insulin resistance, 684, 686 endogenous testosterone and risk in women adiposity measures, 680–681 insulin resistance, 680, 682–683 meta-analysis, 680, 684 polycystic ovary syndrome, 679–680 glucose metabolism effects, 688–690 female sexual dysfunction management, 406 functions men body composition, 748 bone, 746–747 cognitive function, 748–749 immunity, 749 metabolism, 748 mood, 749 muscle, 747 quality of life, 749 sexual function, 746 women body composition, 755–756 bone, 755 cognition, 756 mood, 756 muscle, 755–756 quality of life, 756 sexual function, 754–755 immune modulation, 616 male infertility evaluation, 372 metabolism, 741 osteoporosis management, 733 sepsis response, 295 synthesis defects, 20 men, 742 women, 752 Testosterone replacement therapy (TRT) androgen deficiency management, 712 formulations men, 745 women, 754 initiation algorithms female androgen deficiency, 754 male hypogonadism, 744 monitoring men, 751 women, 757–758 safety in men cardiovascular risks, 750–751 gynecomastia, 751 prostate, 749–750 sleep apnea, 751 safety in women breast and endometrium, 757 cardiovascular risks, 756–757 virilization, 757 Tetanus/diptheria/pertussis

epidemiology, 572 pregnancy and tetanus/diptheria vaccine, 576 vaccination contraindications, 573 efficacy, 572 historical perspective, 572 recommendations for adults, 572–573 Tetralogy of Fallot, gender ratio, 9 Thalidomide, inflammatory bowel disease management and pregnancy safety, 310 Thelarche, premature, 28 T-helper cell balance in pregnancy, 532–533 Th-1 in autoimmune disease, 587 Thrombotic thrombocytopenic purpura, see Escherichia coli 0157 Thyroid cancer pregnancy, 704–706 sex differences, 55 Thyroid-stimulating hormone (TSH), female infertility evaluation, 383 Thyroiditis, postpartum, 696–697 Tibolone, female sexual dysfunction management, 406 Tiotropium, chronic obstructive pulmonary disease management, 256 Tissue plasminogen activator (t-PA), sex differences in stroke management, 131–132 TLRs, see Toll-like receptors TNF-α, see Tumor necrosis factor-α Toll-like receptors (TLRs) autoimmune disease and innate immunity, 587 sepsis response, 294 signaling, 296–297 Tourrette’s syndrome (TS), sex differences in children, 63 Toxoplasmosis, fetal and neonatal transmission, 544 TP53, Li–Fraumeni syndrome mutations, 484–485 t-PA, see Tissue plasminogen activator Transgenderism, definition, 102 Transposition of the great arteries, gender ratio, 9 Transsexual, definition, 102 Transurethral resection of the ejaculatory ducts (TURED), male infertility management, 375 Transurethral resection of the prostate (TURP), indications, 444 Trichomonas vaginalis pregnancy infection, 550 sexually transmitted infection, 526 Tricuspid atresia, gender ratio, 9 Triglycerides, see Dyslipidemia TRT, see Testosterone replacement therapy TS, see Tourrette’s syndrome TSH, see Thyroid-stimulating hormone Tuberculosis, pregnancy, 539 Tumor necrosis factor-α (TNF-α), antagonists for rheumatic disease management in pregnancy, 63 TURED, see Transurethral resection of the ejaculatory ducts TURP, see Transurethral resection of the prostate

773

U Ulcerative colitis, see Inflammatory bowel disease Urethra, aging effects, 434–435 Urinary incontinence, see Lower urinary tract symptoms Urinary tract infection (UTI) elderly, 436–437 pregnancy, 536–537 Uterus, anatomy and physiology, 401 UTI, see Urinary tract infection

V Vaccination hepatitis A contraindications, 570 efficacy, 570 historical perspective, 570 recommendations for adults, 570 hepatitis B efficacy, 569 recommendations for adults, 569 types, 569 human papillomavirus contraindications and precautions, 565 efficacy, 564–565 historical perspective, 564 recommendations for adults, 565 influenza contraindications, 568 efficacy, 567–568 historical perspective, 567 recommendations for adults, 568 Neisseria meningitides contraindications, 574 Menactra, 574 Menoimmune, 573–574 recommendations for adults, 574 pregnancy hepatitis A, 574 hepatitis B, 574–575 human papillomavirus, 575 influenza, 575 measles/mumps rubella, 575 Neisseria meningitides, 575 overview, 557, 574 Streptococcus pneumoniae, 575 tenanus/diptheria, 576 varicella zoster virus, 576 sex differences in response, 615 Streptococcus pneumoniae efficacy, 571 historical perspective, 571 recommendations for adults, 571–572 tetanus/diptheria/pertussis contraindications, 573 efficacy, 572 historical perspective, 572 recommendations for adults, 572–573 varicella-zoster virus contraindications, 566 efficacy, 566 historical perspective, 566 recommendations for adults, 566 Vacuum erection device (VED), erectile dysfunction management, 411

774

Index

Vagina aging effects, 433–434 anatomy and physiology, 401 dilators for female sexual dysfunction management, 405 Vaginismus, female sexual dysfunction, 404 Varicella zoster virus (VZV), fetal and neonatal transmission, 548–549 epidemiology, 565–566 vaccination contraindications, 566 efficacy, 566 historical perspective, 566 pregnancy, 576 recommendations for adults, 566 Varicocele, male infertility management, 387 Vascular dementia, gender-specific frequency studies, 118, 121 Vasculitis, oral contraceptive studies, 651–652 Vasectomy, male sterilization, 362 VCUG, see Voiding cystourethrogram VED, see Vacuum erection device Venous thromboembolism (VTE) deep venous thrombosis versus pulmonary embolism, 225 gender differences, 226–227 hormone replacement therapy effects biological plausibility, 232–233

evidence, 230–232 selective estrogen receptor modulators, 233 oral contraceptive effects age as risk factor, 229 biological plausibility, 228–229 estrogen dose and delivery method, 229 evidence, 227–228 hereditary thrombophilias and risks, 230 progestins, 229–230 pregnancy clinical presentation and diagnosis, 234–236 prevention of recurrence, 236–237 thrombophilia mechanisms, 233–234 treatment, 236 risk factors, 225–226 Ventricular septal defect (VSD), gender ratio, 9 Ventromedial nucleus (VMN), sex differences, 94 VMN, see Ventromedial nucleus Voiding cystourethrogram (VCUG), lower urinary tract symptom evaluation, 427 Von Willebrand disease (VWD), sex differences, 53 VSD, see Ventricular septal defect VTE, see Venous thromboembolism Vulva aging effects, 433–434 anatomy and physiology, 401 pain, see Pelvic pain

Vulvodynia, see Pelvic pain VWD, see Von Willebrand disease VZV, see Varicella zoster virus

W West Nile virus (WNV) clinical features, 503–504 gender differences, 504 laboratory findings, 504 overview, 503 pregnancy, 554 prevention, 504 treatment, 504 Wilms tumor, sex differences, 55 WNV, see West Nile virus

Y Y chromosome, microdeletions in male infertility, 373

Z Zolendronic acid, osteoporosis management men, 730 women, 729–730