Clinical Reproductive Medicine and Surgery

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1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 CLINICAL REPRODUCTIVE MEDICINE AND SURGERY Copyright © 2007 by Mosby, Inc., an affiliate of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions.”

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on his or her own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors/Authors assume any liability for any injury and/or damage to persons or property arising out or related to any use of the material contained in this book.

Library of Congress Cataloging-in-Publication Data Clinical and reproductive medicine and surgery/[edited by] Tommaso Falcone, William W. Hurd p.; cm. ISBN-10: 0-323-03309-1 ISBN-13: 978-0-323-03309-1 1. Generative organs—Diseases. 2. Generative organs, Female—Diseases. 3. Infertility. 4. Human reproduction. I. Falcone, Tommaso. II. Hurd, William W. [DNLM: 1. Genital Diseases, Female. 2. Genital Diseases, Female–surgery. 3. Gynecologic Surgical Procedures–methods. 4. Reproductive Medicine–methods. WP 140 C6403 2007] RC875.C555 2007 616.65—dc22 2006048168

Acquisitions Editor: Rebecca Schmidt Gaertner Developmental Editors: Jennifer Ehlers and Christine Oberle Project Manager: Mary B. Stermel Design Direction: Louis Forgione Marketing Manager: Matt Latuchie Printed in Hong Kong Last digit is the print number: 9

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ISBN-13: ISBN-10:

978-0-323-03309-1 0-323-03309-1

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Contributors Cynthia Abacan, MD Fellow Department of Endocrinology, Diabetes, and Metabolism Cleveland Clinic Cleveland, Ohio Ashok Agarwal, PhD, HCLD Director Andrology Laboratory and Reproductive Tissue Bank; Director Reproductive Research Center; Professor Cleveland Clinic Lerner College of Medicine Case Western Reserve University; Glickman Urological Institute and Departments of Obstetrics and Gynecology, Anatomic Pathology, and Immunology Cleveland Clinic Cleveland, Ohio Raedah Al-Fadhli, MD Fellow Reproductive Endocrinology and Infertility McGill University Montreal, Quebec, Canada Shyam S.R. Allamaneni, MD Resident Department of General Surgery Saint Vincent Catholic Medical Center Jamaica, New York

Marjan Attaran, MD Head Section of Pediatric Gynecology Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio Cynthia Austin, MD Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio Jaswant S. Bal, MD, FRCOG, FACOG Assistant Clinical Professor Department of Obstetrics and Gynecology SUNY Health Science Center Syracuse, New York Sheela Barhan, MD Department of Obstetrics and Gynecology Wright State University School of Medicine Dayton, Ohio Kurt Barnhart, MD, MSCE Associate Professor of Obstetrics and Gynecology and Epidemiology Penn Fertility Care University of Pennsylvania Philadelphia, Pennsylvania

Lawrence S. Amesse, MD, PhD Department of Obstetrics and Gynecology Wright State University School of Medicine Dayton, Ohio

Kshonija Batchu, MD Research Assistant Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Stanford University School of Medicine Stanford, California

Aydin Arici, MD Professor Department of Obstetrics and Gynecology Yale University School of Medicine New Haven, Connecticut

Mohamed A Bedaiwy, MD Fellow Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio

Francisco Arredondo, MD, MPH Department of Obstetrics and Gynecology University Hospitals of Cleveland Cleveland, Ohio

Sarah L. Berga, MD Professor and Chair Department of Obstetrics and Gynecology Emory University School of Medicine Atlanta, Georgia

Khalid Ataya, MD Professor Department of Obstetrics and Gynecology MetroHealth Medical Center Cleveland, Ohio

Charles V. Biscotti, MD Department of Anatomic Pathology Cleveland Clinic Cleveland, Ohio

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Contributors

Linda D. Bradley, MD Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio

Miriam Delaney, MD Department of Rheumatic and Immunologic Disease Cleveland Clinic Cleveland, Ohio

Ronald T. Burkman, MD Chairman Department of Obstetrics and Gynecology Baystate Medical Center Springfield, Massachusetts; Deputy Chair and Professor Department of Obstetrics and Gynecology Tufts University School of Medicine Boston, Massachusetts

Nina Desai, PhD Assistant Professor Director In Vitro Fertilization Laboratories Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio

John Carey, MD Department of Rheumatic and Immunologic Disease Cleveland Clinic Cleveland, Ohio Allison M. Case, MD Department of Obstetrics and Gynecology Royal University Hospital Saskatoon, Saskatchewan, Canada Robert F. Casper, MD Professor Toronto Center for A.R.T. Toronto, Ontario, Canada SuYnn Chia, MD Department of Endocrinology Cleveland Clinic Cleveland, Ohio Gregory M. Christman, MD Associate Professor of Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility University of Michigan Medical School; Associate Professor Reproductive Sciences Program Department of Obstetrics and Gynecology University of Michigan Health System Ann Arbor, Michigan Brian Clark, MD, PhD Professor Department of Obstetrics and Gynecology Magee-Womens Hospital Center for Medical Genetics Pittsburgh, Pennsylvania Damon Davis, MD Resident Department of Urology University of Michigan Medical School Ann Arbor, Michigan

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Anne S. Devi Wold, MD Reproductive Research Center Lexington, Massachusetts Michael P. Diamond, MD Associate Chair and Kamran S. Moghissi Professor of Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Wayne State University Detroit, Michigan Richard L. Drake, PhD Professor Department of Education Cleveland Clinic Cleveland, Ohio Janice Duke, MD Department of Obstetrics and Gynecology Wright State University School of Medicine Dayton, Ohio Kristin A. Englund, MD Department of Infectious Disease Cleveland Clinic Cleveland, Ohio Navid Esfandiari, DVM, PhD, ELD, HCLD Director IVF, Andrology and Research Laboratories Toronto Center for A.R.T. Toronto, Ontario, Canada Charles Faiman, MD Department of Endocrinology Cleveland Clinic Cleveland, Ohio Tommaso Falcone, MD Professor and Chairman Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio

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Contributors

Stephanie Fisher MD, FRCS(C) Assistant Professor Department of Obstetrics and Gynecology University of British Columbia Vancouver, British Columbia, Canada

Gary M. Horowitz, MD Associate Professor Department of Obstetrics and Gynecology Southern Illinois School of Medicine Springfield, Illinois

Maria Fleseriu, MD Assistant Professor Division of Endocrinology, Diabetes, and Clinical Nutrition Oregon Health and Sciences University Portland, Oregon

Elizabeth M. Hurd, RN, BSN Lactation Consultant Miami Valley Hospital Dayton, Ohio

Margo Fluker MD, FRCS(C) Co-Director Genesis Fertility Center; Clinical Professor Department of Obstetrics and Gynecology University of British Columbia Vancouver, British Columbia, Canada Gita Gidwani, MD Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio Jeffrey M. Goldberg, MD Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio James Goldfarb, MD, MBA Clinical Professor Beachwood Family Health Center Cleveland Clinic Beachwood, Ohio Dorothy Greenfeld, MSW, LCSW Associate Professor Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University Fertility Center Yale University School of Medicine New Haven, Connecticut

William W. Hurd, MD, MS Professor of Obstetrics and Gynecology and Community Health Department of Obstetrics and Gynecology Wright State University School of Medicine Dayton, Ohio Shahryar K. Kavoussi, MD, MPH Fellow Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology University of Michigan Health System Ann Arbor, Michigan Elizabeth Ann Kennard, MD Ohio Reproductive Medicine Columbus, Ohio Harry J. Khamis, PhD Director and Professor Statistical Consulting Center Wright State University Dayton, Ohio Peter N. Kolettis, MD Division of Urology University of Alabama at Birmingham Birmingham, Alabama Layne Kumetz, MD House Officer Department of Obstetrics and Gynecology Cedars-Sinai Medical Center Los Angeles, California

Manjula K. Gupta, PhD Department of Clinical Pathology Cleveland Clinic Cleveland, Ohio

William H. Kutteh, MD, PhD, HCLD Division of Reproductive Endocrinology University of Tennessee Memphis, Tennessee

Robert Hemmings, MD OVO Clinic Montreal, Quebec, Canada

Steven R. Lindheim, MD Department of Obstetrics and Gynecology University of Wisconsin Madison, Wisconsin

Melissa Hiner, BS Embryologist Department of Obstetrics and Gynecology University of Michigan Medical School Ann Arbor, Michigan

Hanna Lisbona, MD Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio

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Contributors

James H. Liu, MD Arthur H. Bill Professor and Chair Department of Obstetrics and Gynecology University Hospitals/MacDonald Women’s Hospital; Department of Reproductive Biology Case School of Medicine Cleveland, Ohio J. Ricardo Loret de Mola, MD Department of Obstetrics and Gynecology University Hospitals of Cleveland Cleveland, Ohio Tammy L. Loucks, MPH Director of Clinical Research Department of Obstetrics and Gynecology Emory University School of Medicine Atlanta, Georgia Andrea Magen, MD Department of Radiology Cleveland Clinic Cleveland, Ohio

Pasquale Patrizio, MD, MBe Yale Fertility Center Yale University New Haven, Connecticut Teresa Pfaff-Amesse, MD Assistant Professor, Departments of Pathology and Neuroscience, Cell Biology, and Physiology Wright State University School of Medicine Dayton, Ohio Barry Peskin, MD Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio

Neal Gregory Mahutte, MD Assistant Professor Reproductive Endocrinology and Infertility Dartmouth Medical School Lebanon, New Hampshire

Susanne A. Quallich, NP Nurse Practitioner Division of Andrology and Microsurgery Department of Urology University of Michigan Ann Arbor, Michigan

Beth A. Malizia, MD Fellow Reproductive Endocrinology and Fertility Beth Israel Deaconess Medical Center Boston, Massachusetts

S. Sethu K. Reddy, MD Department of Endocrinology, Diabetes, and Metabolism Cleveland Clinic Cleveland, Ohio

Mohamed F. Mitwally, MD Clinical Assistant Professor Department of Obstetrics and Gynecology Wayne State University Detroit, Michigan

Robert L. Reid, MD Department of Obstetrics and Gynecology Queen’s University Kingston General Hospital Kingston, Ontario, Canada

Dana A. Ohl, MD Professor of Urology Department of Urology Head Division of Andrology and Microsurgery University of Michigan Ann Arbor, Michigan

Ellen S. Rome, MD Department of Pediatric and Adolescent Medicine Cleveland Clinic Cleveland, Ohio

Sophia Ouhilal, MD Assistant Professor Reproductive Endocrinology and Infertility Dartmouth Medical School Lebanon, New Hampshire

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John K. Park, MD Division of Reproductive Endocrinology and Fertility Department of Obstetrics and Gynecology Emory University School of Medicine Atlanta, Georgia

Kelly Pagidas, MD Department of Reproductive Medicine Women and Infants Hospital Providence, Rhode Island

Jonathan Ross, MD Glickman Urological Institute Cleveland Clinic Cleveland, Ohio Joseph S. Sanfilippo, MD, MBA Professor, Obstetrics-Gynecology and Reproductive Sciences University of Pittsburgh School of Medicine; Vice Chairman, Reproductive Sciences Division Director, Reproductive Endocrinology Residency Program Director Magee-Womens Hospital Pittsburgh, Pennsylvania

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Contributors

Erin J. Saunders, MD Clinical Professor Department of Obstetrics and Gynecology Vanderbilt University Nashville, Tennessee Timothy G. Schuster, MD Assistant Professor Department of Urology Division of Andrology and Microsurgery University of Michigan Ann Arbor, Michigan Beata Seeber, MD Department of Obstetrics and Gynecology University of Pennsylvania Philadelphia, Pennsylvania; Department of Gynecologic Endocrinology and Reproductive Medicine Medical University of Innsbruck Innsbruck, Austria Rakesh K. Sharma, PhD Center for Advanced Research in Human Reproduction, Infertility, and Sexual Function Glickman Urological Institute Department of Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio Howard T. Sharp, MD Department of Obstetrics and Gynecology University of Utah Medical Center Salt Lake City, Utah Cristine Silva, BS Embryologist Department of Obstetrics and Gynecology University of Michigan Medical School Ann Arbor, Michigan Gary D. Smith, MD Department of Obstetrics and Gynecology University of Michigan Medical School Ann Arbor, Michigan Jonathon M. Solnik, MD Director Minimally Invasive Gynecologic Surgery Department of Obstetrics and Gynecology Cedars-Sinai Medical Center; Assistant Professor Department of Obstetrics and Gynecology The David Geffen School of Medicine at UCLA Los Angeles, California Michael P. Steinkampf, MD Director Alabama Fertility Specialists Birmingham, Alabama

Thomas G. Stovall, MD Women’s Health Specialists Germantown, Tennessee Holly L. Thacker, MD, FACP Director Women’s Health Center Departments of Internal Medicine and Obstetrics and Gynecology Cleveland Clinic Cleveland, Ohio Geoffrey D. Towers, MD Assistant Professor Department of Obstetrics and Gynecology Wright State University Dayton, Ohio Togas Tulandi, MD, MHCM Professor and Chief of Obstetrics and Gynecology, JGH Department of Obstetrics and Gynecology Milton Leong Chair in Reproductive Medicine McGill University Montreal, Quebec, Canada Meike L. Uhler, MD Clinical Associate Professor Department of Obstetrics and Gynecology Loyola University School of Medicine Maywood, Illinois; Fertility Centers of Illinois Chicago, Illinois Joseph C. Veniero, MD Department of Radiology Cleveland Clinic Cleveland, Ohio Gary Ventolini, MD Associate Professor Department of Obstetrics and Gynecology Wright State University Dayton, Ohio James L. Whiteside, MD Department of Obstetrics and Gynecology Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Mylene W. M. Yao, MD Assistant Professor Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Stanford University School of Medicine Stanford, California

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Preface Reproductive medicine and surgery have together evolved into a distinctive field of modern gynecology. The focus of this field is on the identification and restoration of medical and anatomic abnormalities affecting the human reproductive system. Replacement therapy and more extensive surgery are now used only when required, since natural reproductive function is often more effective and safer than the best artificial replacement techniques. The knowledge gained in reproductive sciences over the last half of the 20th century is truly remarkable, and encyclopedic volumes have been written as a result. These distinguished works, however, deal primarily with the medical aspects of reproduction, and little has been written about the surgical aspects. This book is unique in that it includes both medical and surgical treatments, an approach we believe to be more reflective of the clinical practice of reproductive medicine. When compiling this text, we focused on two goals. The first was to provide a comprehensive review of all facets of clinical reproductive medicine and surgery. This review encompasses basic science and pathophysiology, clinical diagnosis and imaging, and medical and surgical treatment approaches. The second, and perhaps more challenging goal, was to create a book designed to be read rather than a reference work to be reserved for consultation. To this end, we diligently organized information provided

by many experts into 53 understandable and consistent chapters. We hope this book serves as a concise knowledge base for those in training and in the early years of practice, especially those planning to take comprehensive examinations on this information. With these goals in mind, we divided the book into seven parts. The first deals with basic science, covering the classic topics of neurophysiology, gametogenesis, fertilization and genetics, as well as anatomy, histology, statistics, and bioethics. The clinical medicine section has three parts that cover pediatric, adolescent and adult clinical reproductive medicine and infertility for both men and women. There are separate sections that cover the broad areas of female contraception and imaging. The final section deals with reproductive surgery performed to maintain fertility. Since visualization is an important part of learning surgery, a number of instructive video presentations on compact disk are included to reinforce the text. We hope that this book weaves together the elements of basic, clinical, and surgical science in such a way that the reader emerges with both a broad understanding of the basic science of reproductive medicine and a comprehensive approach to the reproductive patient. TOMMASO FALCONE BILL HURD

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Section 1 Basic Science Chapter

1

The Hypothalamic-Pituitary-Ovarian Axis and Control of the Menstrual Cycle Neal Gregory Mahutte and Sophia Ouhilal

INTRODUCTION The hypothalamus and pituitary gland form a unit that exerts control over a wide range of endocrine organs, including the gonads. This chapter describes the hypothalamic-pituitary-ovarian axis and control of the menstrual cycle, which is modulated by the central nervous system, other endocrine systems, and the environment. Key hormones in the hypothalamic-pituitary-ovarian axis include gonadotropin-releasing hormone (GnRH), folliclestimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone (Table 1-1). Supporting roles are also played by inhibin, activin, follistatin, and endorphins.

THE HYPOTHALAMUS The hypothalamus forms the lower part of the lateral wall and the floor of the third ventricle, and weighs approximately 10 grams. The hypothalamus is typically divided into eight specific nuclei (consistently clustered groups of neurons) and three areas (less clustered, less distinctly demarcated neurons), as illustrated in Figure 1-1. From a reproductive standpoint, the most important of these are the arcuate nucleus and the preoptic area, the principal sites of GnRH-producing neurons.1 The arcuate nucleus is located in the medial basal hypothalamus and is the most proximal of all the hypothalamic nuclei to the optic chiasm and the pituitary stalk. The arcuate nucleus is also the site of dopamine-secreting neurons that function to inhibit pituitary prolactin secretion and neurons that secrete growth hormone-releasing hormone.

Neurosecretory cell products from the hypothalamus, including GnRH, are released into the portal system from the median eminence, a prominence in the pituitary stalk at the floor of the third ventricle. The portal system serves as the major route of communication between the hypothalamus and the anterior pituitary. In contrast, the pituitary stalk (infundibulum) directly connects neuronal cell bodies in the hypothalamus to the posterior pituitary. The pituitary stalk lies immediately posterior to the optic chiasm.

GnRH GnRH is the primary hypothalamic regulator of pituitary reproductive function. Two human forms of GnRH (GnRH-I and GnRH-II) have been identified.2,3 Both are decapeptides and are the products of different genes. At least 20 other types of GnRH have been identified in fish, amphibians and protochordates, but none of these are believed to be present in humans.4,5 GnRH-I was first characterized and synthesized in 1971 by Andrew Schally and Roger Guillemin, an accomplishment for which both men ultimately received the Nobel prize.6–9 The structure of GnRH-I is common to all mammals, and its action is similar in males and females (Fig. 1-2). GnRH-I is synthesized from a much larger, 92-amino acid precursor peptide that contains GnRH-associated peptide.10 GnRH-I then travels along an axonal pathway called the tuberoinfundibular tract to the median eminence of the hypothalamus, where it is released into

Table 1-1 Major Hormones of the Hypothalamic-pituitary-ovarian Axis Hormone

Structure

Gene Location

Major Site(s) of Production

Half-Life

Serum Concentration

GnRH

Decapeptide

8p21-8p11.2

Arcuate nucleus of hypothalamus

2–4 min

N/A

FSH

Glycoprotein with α and β subunits

α: 6q12.2 β: 11p13

Gonadotrophs of anterior pituitary

1.5–4 hr

5–25 mIU/mL

LH

Glycoprotein with α and β subunits

α: 6q12.21 β: 19q12.32

Gonadotrophs of anterior pituitary

20–30 min

5–25 mIU/mL

Estradiol

18-carbon steroid

N/A

Granulosa cells

2–3 hr

20–400 pg/mL

Progesterone

21-carbon steroid

N/A

Theca-lutein cells

5 min

0.1–30 ng/mL

Inhibin

Peptide with α and β subunits Inhibin A= α + βA Inhibin B= α + βB

α: 2q33 βA: 2q13 βB: 7p15

Granulosa cells

30–60 min

A: 10–60 pg/mL B: 10–150 pg/mL

GnRH = gonadotropin-releasing hormone; FSH = follicle-stimulating hormone; LH = luteinizing hormone; N/A = not available

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Section 1 Basic Science

DH

PV

DM

PA

AH

VM

Hypothalamus PH

PM LM

MM

SO SC

Arcuate nucleus

Superior hypophyseal artery Optic chiasm Median eminence Middle hypophyseal artery Portal circulation

Inferior hypophyseal artery

Internal carotid artery Anterior pituitary

Sphenoid sinus

Posterior pituitary

Sella turcica

Figure 1-1 Illustration of the hypothalamus, pituitary, sella turcica, and portal system. The arcuate nucleus is the primary site of neurons that produce gonadotropin-releasing hormone (GnRH). GnRH is released from the median eminence into the portal system. The blood supply of the pituitary gland derives from the internal carotid arteries. In addition to the arcuate nucleus, the other hypothalamic nuclei are SO, supraoptic nucleus; SC, suprachiasmatic nucleus; PV, paraventricular nucleus; DM, dorsal medial nucleus; VM, ventromedial nucleus; PH, posterior hypothalamic nucleus; PM, premammillary nucleus; LM, lateral mammillary nucleus; MM, medial mammillary nucleus. The three hypothalamic areas are PA, preoptic area; AH, anterior hypothalamic area; DH, dorsal hypothalamic area.

pyro

Glu 1

Hi

s2 p Tr

3

7

Ser 4

Figure 1-2

2

6

Tyr5

Gly

Leu

Arg8

Pro9

Gly10

NH2

Structure of GnRH-I.

the portal circulation in a pulsatile fashion. The half-life of GnRH-I is very short (2 to 4 minutes) because it is rapidly cleaved between amino acids 5 and 6, 6 and 7, and 9 and 10. Because of its short half-life and rapid dilution in the peripheral

circulation, serum GnRH-I levels are difficult to measure and do not correlate with pituitary action. GnRH-I has three principal actions on anterior pituitary gonadotrophs: (1) synthesis and storage of gonadotropins, (2) movement of gonadotropins from the reserve pool to a point where they can be readily released, and (3) direct secretion of gonadotropins. GnRH-I pulses occur in response to intrinsic rhythmic activity within GnRH neurons in the arcuate nucleus. Pulsatile release of GnRH-I from the median eminence within a critical frequency and amplitude results in normal gonadotropin secretion.11,12 Continuous, rather than pulsatile, exposure to GnRH-I results in suppression of FSH and LH secretion and suppression of gonadotropin gene transcription.13,14

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Chapter 1 The Hypothalamic-Pituitary-Ovarian Axis and Control of the Menstrual Cycle Table 1-2 Menstrual Cycle Variation in LH Pulse Frequency and Amplitude Cycle Phase

Mean Frequency (minutes)

Early follicular

90

Mean Amplitude (mIU/mL) 6.5

Mid-follicular

50

5

Late follicular

60–70

7

Early luteal

100

15

Mid-luteal

150

12

Late luteal

200

8

Table 1-3 Neurotransmitter Effects on GnRH Release Neurotransmitter

Effect

Dopamine

Inhibits GnRH release

Endorphin

Inhibits GnRH release

Serotonin

Inhibits GnRH release

Norepinephrine, epinephrine

Stimulates GnRH release

In the absence of gonadal feedback, the GnRH pulse frequency is approximately once per hour.15 During the menstrual cycle the frequency and amplitude of GnRH pulses vary in response to hypothalamic feedback (Table 1-2).16 In general, the follicular phase is characterized by high-frequency, low-amplitude pulses, and the luteal phase is characterized by lower-frequency, higheramplitude pulses.17,18 However, considerable variability exists both between and within individuals.19 In humans, GnRH-I pulse frequency and amplitude are best approximated by measuring LH pulse frequency and amplitude. GnRH-II is most highly expressed outside of the brain, in tissues that include kidneys, bone marrow, and prostate. This is in contrast to GnRH-I, which is not expressed in high levels outside the brain. Although GnRH-II can induce release of both FSH and LH, it appears to have a wide array of physiologic functions outside the brain including regulation of cellular proliferation and mediation of ovarian and placental hormone secretion.20 Initial attempts in the mid-1990s to identify estrogen receptors in GnRH neurons were unsuccessful.21,22 However, subsequent use of more sophisticated techniques identified estrogen receptors α and β in the arcuate nucleus.23–26 Both receptors mediate estrogen action on GnRH neurons in vivo.27,28 The GnRH gene contains a hormone response element for the estrogen–estrogen receptor complex.29 Transcription of GnRH-I and GnRH-II is differentially regulated by estrogen.30 The regulatory role of estradiol on GnRH is complex. Estrogen inhibits GnRH gene expression/biosynthesis, but secretion of GnRH may be increased, decreased, or unaffected.31,32 The activity of the hypothalamus is further modulated by nervous stimuli from higher brain centers. GnRH neurons exhibit many connections to each other and to other neurons. Some of the neurotransmitters that modulate GnRH secretion are outlined in Table 1-3. The effects of these neurotransmitters help explain the mechanism by which certain physical or clinical conditions may affect the menstrual cycle (Table 1-4).

Table 1-4 Mechanisms for Oligo/amenorrhea in Various Clinical Conditions Hyperprolactinemia

Elevated dopamine suppresses GnRH

Hypothyroidism

Elevated TRH increases prolactin, which in turn increases dopamine which, then suppresses GnRH

Stress

Increased corticotropin (ACTH) results in increased endorphins (both are derived from the same peptide precursor); endorphins suppress GnRH

Exercise

Increased endorphins suppress GnRH

TRH = thyrotropin-releasing hormone; GnRH = gonadotropin-releasing hormone.

Cells that produce GnRH originate embryologically from the olfactory area.33 GnRH neurons, like olfactory epithelial cells of the nasal cavity, have cilia.34 During embryogenesis GnRH neurons migrate from the medial olfactory placode to the arcuate nucleus of the hypothalamus.35 The common origin of GnRH and olfactory neurons is demonstrated by Kallmann’s syndrome, where GnRH deficiency is associated with anosmia. Kallmann’s syndrome is believed to be caused by a variety of gene defects that affect neuronal cell migration.36 The common origin of GnRH and olfactory neurons is also suggestive of the relationship between pheromones and menstrual cyclicity. Pheromones are small airborne chemicals that when secreted externally by one individual may be perceived by other individuals of the same species, producing a change in sexual or social behavior. It is well recognized that women who work or live together often develop synchrony of their menstrual cycles.37 Moreover, it has been shown that odorless compounds from the axillae of cycling women can alter the cycle characteristics of recipient women.38 Presumably, these alterations occur through olfactory GnRH-mediated mechanisms.

The GnRH Receptor The GnRH-I receptor is a G-protein receptor that utilizes inositol triphosphate and diacylglycerol as second messengers to stimulate protein kinase, release of calcium ions, and cyclic adenosine monophosphate (cAMP) activity. The GnRH-I receptor is encoded by a gene on chromosome 14q21.1 and is expressed in many parts of the body outside of the brain, including ovarian follicles and the placenta. In humans it appears that GnRH-II signaling occurs through the GnRH-I receptor.5 Although a GnRH-II receptor is present in many mammalian species, its functional capacity is limited due to a frame shift and a stop codon. GnRH receptors are regulated by many substances, including GnRH itself, inhibin, activin, estrogen, and progesterone. Changes to the amino acid sequence of GnRH can extend its half-life to hours or days and can change its biologic activity from an agonist to an antagonist. All of the GnRH agonists currently available extend their half-life by substitutions at amino acid 6 and sometimes amino acid 10 of native GnRH (Table 1-5). Continuous activation of the GnRH receptor results in desensitization due to phosphorylation and conformational change of the receptor, uncoupling from G proteins, internalization of the receptor via endocytosis, and decreased receptor synthesis.39,40 On administration all GnRH agonists increase gonadotropin secretion (the flare effect). However, after 7 to 14 days GnRH receptor desensitization occurs and pituitary suppression is achieved.

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Section 1 Basic Science Table 1-5 Properties of Commercially Available GnRH Agonists

Agonist

Structure and Substitutions at Position 6 and 10

Half-Life

Relative Potency

Route of Administration

GnRH

Native decapeptide

2–4 min

1

IV, SC

Naferelin

Decapeptide 6: Nal for Gly

3–4 hr

200

Intranasal

Triptorelin

Decapeptide 6: Trp for Gly

3–4 hr

36–144

SC, IM depot

Leuprolide

Nonapeptide 6: Leu for Gly 10: NHEt for Gly

1.5 hr

50–80

SC, IM depot

Buserelin

Nonapeptide 6: Ser(OtBu) for Gly 10: NHEt for Gly

1.5 hr

20–40

SC, intranasal

Goserelin

Decapeptide 6: Ser(OtBu) for Gly 10: AzaGly for Gly

4.5 hr

50–100

SC implant

Histrelin

Decapeptide 6: DHis for Gly 10: AzaGly for Gly

50 min

100

SC

that recombines in long portal veins draining down the pituitary stalk to the anterior pituitary, where they break up into another capillary network. The blood supply of the posterior pituitary (neurohypophysis) comes from the middle and inferior hypophyseal arteries. Veins from these arteries drain into the cavernous sinuses, from which they ultimately reach the petrosal sinuses and then the jugular veins. The posterior pituitary is best understood as a continuation of the hypothalamus. The posterior pituitary is a direct downgrowth of nervous tissue from the hypothalamus through the pituitary stalk. The posterior pituitary is composed of glial tissue and axonal termini that secrete oxytocin and arginine vasopressin (AVP, also known as antidiuretic hormone). Oxytocin is synthesized in the paraventricular nucleus of the hypothalamus, whereas AVP is synthesized in the supraoptic nucleus, just above the arcuate nucleus. Oxytocin and AVP pass down the length of the pituitary stalk and are stored in terminal parts of axons in the posterior pituitary. Both oxytocin and AVP consist of nine amino acid residues (nonapeptides). Release of oxytocin and AVP is controlled directly by nervous impulses passing down the axons from the hypothalamus.

The Anterior Pituitary In contrast, GnRH antagonists directly inhibit gonadotropin secretion. Structurally, GnRH antagonists are characterized by multiple amino acid substitutions to the natural GnRH decapeptide. The commercially available GnRH antagonists cetrorelix and ganirelix have large amino acid additions to position 1 of native GnRH. GnRH antagonists compete for and occupy pituitary GnRH receptors, thus competitively blocking endogenous GnRH–GnRH receptor binding. In contrast to GnRH agonists, there is no flare effect with GnRH antagonists. Because receptor loss does not occur, a constant supply of antagonist is necessary to ensure that all GnRH receptors are continuously occupied. Thus, the therapeutic dosage range for antagonists is typically higher than that for agonists (mg versus μg).

THE PITUITARY

4

The pituitary gland measures approximately 15 × 10 × 6 mm and weighs approximately 500 to 900 mg. The pituitary gland lies immediately beneath the third ventricle and just above the sphenoidal sinus in a bony cavity called the sella turcica (Turkish saddle). It consists of anterior and posterior lobes, each having different embryologic origins, functions, and control mechanisms (Fig. 1-3). The secretion of pituitary hormones is controlled primarily by the hypothalamus. However, the activity of the hypothalamus and pituitary are modulated by nervous stimuli from higher brain centers and feedback from circulating hormones. There is no direct nervous connection between the hypothalamus and the anterior pituitary gland. Instead, communication occurs via the hypothalamic-pituitary portal system. The arterial blood supply of the pituitary is derived from branches of the internal carotid artery. The anterior pituitary gland is the most richly vascularized of all mammalian tissues. The blood supply of the anterior pituitary comes from the superior hypophyseal artery. The superior hypophyseal artery forms a capillary network in the median eminence of the hypothalamus

The anterior pituitary arises from an epithelial upgrowth from the roof of the primitive oral cavity (Rathke’s pouch). The anterior pituitary wraps around the posterior pituitary and constitutes two thirds of the volume of the pituitary gland. The portion of Rathke’s pouch in direct contact with the posterior pituitary develops less extensively than the rest of the anterior pituitary and is termed the pars intermedia. The major cell types of the anterior pituitary are outlined in Table 1-6. The anterior pituitary is a classic endocrine gland in that it is composed of secretory cells of epithelial origin supported by connective tissue rich in blood and lymphatic capillaries. In accordance with their active synthetic function the endocrine cells are characterized by prominent nuclei and prolific mitochondria, endoplasmic reticulum, Golgi bodies, and secretory vesicles. Synthesis of gonadotropins takes place in the rough endoplasmic reticulum, after which the hormones are packaged within the Golgi apparatus and stored as secretory granules. In response to GnRH the secretory granules are extruded from the cell membrane. The endothelial lining of capillary sinusoids is fenestrated, facilitating the passage of pituitary hormones into the sinusoids.

Gonadotropins The anterior pituitary secretes two hormones that stimulate the growth and activity of the gonads, FSH and LH. These glycoprotein hormones, termed gonadotropins, work in conjunction to stimulate secretion of steroid hormones from the ovary. FSH

FSH is a glycoprotein with a molecular weight of approximately 29,000 daltons. It consists of both an α and β subunit. The α subunit consists of 92 amino acids stabilized by 5 disulfide bonds and is identical to the α subunit of LH, thyroid-stimulating hormone (TSH) and human chorionic gonadotropin (hCG). The β subunit contains 118 amino acids and 5 sialic acid residues. Neither subunit has any intrinsic biologic activity by itself.

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A D

B

E Figure 1-3 X-ray and T1-weighted magnetic resonance images (MRI) of the pituitary gland. A, Lateral skull film with the sphenoidal sinus and sella turcica. B, Sagittal section demonstrating the relationship between the sphenoidal sinus and the pituitary gland. The normal posterior pituitary is brighter on MRI compared to the anterior pituitary. The sella turcica is not well seen on MRI. C, Sagittal section after administration of gadolinium contrast. Because the pituitary lies outside the blood-brain barrier, both the anterior and posterior pituitary are illuminated with the contrast. D, Coronal section demonstrating the relationship of the pituitary to the optic chiasm and the pituitary stalk. E, Coronal section after gadolinium contrast demonstrating the close proximity of the pituitary to the internal carotid arteries.

C

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Section 1 Basic Science Table 1-6 Major Cell Types of the Anterior Pituitary Gland

Cell Type

Appearance on Light Microscopy

Cellular Frequency

Hormone Products

Somatotrophs

Acidophilic

50%

Growth hormone

Lactotrophs

Acidophilic

20%

Prolactin

Corticotrophs

Basophilic

20%

Corticotropin

Thyrotrophs

Basophilic

5%

Thyroid-stimulating hormone (TSH) and free α subunit

Gonadotrophs

Basophilic

5%

Follicle-stimulating hormone (FSH), luteinizing hormone (LH) and free α subunit

The sialic acid content of FSH, LH, TSH, and hCG varies, and these differences are largely responsible for variations in half-life of the glycoprotein hormones. The liver is the major site of clearance for gonadotropins. Sialic acid prevents hepatic clearance; thus, the greater the sialic acid content, the longer the half-life.41 hCG, with 20 sialic acid residues, has the longest half-life (about 24 hours), whereas LH (1 to 2 sialic acid residues) has the shortest half-life (20 to 30 minutes). Addition of sialic acid residues in urinary-derived commercially available gonadotropins (e.g., hMG) is responsible for their longer half-life (30 hours). In gonadotrophs of the anterior pituitary, GnRH signaling leads to transcription of the α and β subunits for both FSH and LH. The GnRH-dependent availability of the β subunits is the rate-limiting step in gonadotropin synthesis. Although both FSH and LH require GnRH stimulation, synthesis of the FSH β subunit also requires the presence of activin.42,43 Follicle-stimulating hormone plays a crucial role in follicle recruitment and selection of the dominant follicle. FSH has a trophic effect on granulosa cells in antral follicles, including the induction of aromatase activity, inhibin synthesis, and expression of LH receptors. A certain amount of FSH (the FSH threshold) is required to induce these changes in a given follicle. FSH must then remain above that threshold for folliculogenesis to continue. In the normal menstrual cycle serum concentrations of FSH begin to rise a few days before the onset of menstruation. FSH levels plateau in the midfollicular phase and decline in the late follicular phase in response to the rise in estrogen and inhibin B. This decline contributes to the dominance of selected follicles over others. FSH levels then peak briefly during the ovulatory gonadotropin surge, after which they decline to their nadir in the luteal phase. LH

6

LH is a glycoprotein with a molecular weight of 29,000 daltons. Like FSH, TSH, and hCG, it consists of both an α and β subunit. The α subunit is identical to the α subunit of FSH, TSH, and hCG. The β subunit of LH has 121 amino acids and 1 to 2 sialic acid residues. Luteinizing hormone is synthesized in gonadotrophs of the anterior pituitary gland. Because it contains fewer sialic acid residues than FSH, LH is rapidly cleared from the circulation by the liver and kidney. For this reason LH is rapidly biosynthesized,

and LH pulses occur at higher amplitude than those of FSH. It is believed that the pituitary content of LH is turned over 1 to 2 times per day. Serum LH levels begin to rise a few days before the onset of menstruation. They increase very gradually during the follicular phase. Unlike FSH, serum LH values rise in the late follicular phase, surpassing FSH values around cycle day 9 or 10. The LH surge at midcycle is followed by a steady decline to their nadir in the midluteal phase.

FSH and LH Receptors The actions of both LH and FSH are mediated by G protein receptors on the cell membrane. LH receptors are found exclusively on theca cells in the ovary. Stimulation of these receptors by increased cytochrome P450c17 enzyme activity (17-hydroxylase and 17,20-lyase) in theca cells, resulting in activation of both adenylate cyclase and cAMP-dependent protein kinases and leading to increased production of androstenedione and testosterone. In contrast, FSH receptors are found exclusively on granulosa cells in the ovary. FSH binds to receptors on the cell surface of granulosa cells in antral follicles. Like LH, FSH acts via the cAMP-dependent protein kinase pathway.44 In response to FSH the androgens produced as a result of LH stimulation are then aromatized to estrogens in granulosa cells.

Opioid Modulation of Pituitary Hormones Opioids (i.e., endogenous opiates) are natural occurring sedative narcotics produced in the brain whose structure and function are similar to opium. Opioids include enkephalins, endorphins, and dynorphins; they modulate every pituitary hormone by acting on the hypothalamus. An important action of opioids is to inhibit gonadotropin secretion by suppressing GnRH release.45 Opioid tone is an important regulator of menstrual cyclicity.46-49 Endorphins are at a nadir in the early follicular phase (menstruation) and gradually rise to peak levels in the luteal phase in response to the rise in estrogen and progesterone. It is believed that opioids mediate the negative feedback of ovarian steroids on gonadotropin release, particularly in the luteal phase.50 Endogenous opioids appear to play a central role in hypothalamic amenorrhea. Treatment of women suffering from this condition with an opioid receptor antagonist (e.g., naltrexone) results in the return to ovulatory menstrual patterns and even conception in some cases.51,52 Women with stress-related amenorrhea demonstrate increased hypothalamic corticotropinreleasing hormone and pituitary corticotropin, which manifests as hypercortisolism.53 The corticotropin precursor peptide, proopiomelanocortin, is also the precursor for endorphin synthesis. It is hypothesized that stress-related amenorrhea is the result of GnRH inhibition secondary to increased production of endogenous opioids. Opioids also rise during exercise (“runners’ high”), and this may contribute to hypothalamic amenorrhea in athletes.54,55

Ovarian Peptide Hormone Feedback on Gonadotropin Secretion The ovary secrets two polypeptide hormones that inhibit or stimulate FSH secretion by the anterior pituitary. Inhibin and activin act as opposing nonsteroidal gonadal hormones that

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Inhibin and activin are members of the transforming growth factor-β (TGF-β) superfamily of ligands, which includes müllerian inhibiting substance (MIS; see Chapter 2). Like the gonadotropins, inhibin and activin are comprised of two subunits. Inhibin is comprised of an α and β subunit and has been isolated in two forms containing different β subunits, Inhibin-A and Inhibin-B. Activin is comprised of two beta subunits identical to those found in inhibin. Inhibin is secreted by granulosa cells in response to FSH.56 However, mRNA for inhibin has also been found in pituitary gonadotrophs. Inhibin selectively inhibits FSH but not LH secretion.57 Thus, a negative feedback loop is created where FSH stimulates inhibin and in turn inhibin suppresses FSH. Inhibin B is predominantly secreted in the follicular phase of the menstrual cycle, whereas inhibin A is predominantly secreted in the luteal phase.58 Peak levels of inhibin B in the follicular phase are in the range of 50 to 100 pg/mL. Peak levels of inhibin A in the luteal phase are between 40 and 60 pg/mL. Activin is also secreted by granulosa cells. Activin augments the secretion of FSH by the pituitary by enhancing GnRH receptor formation. Activin is also required for synthesis of the FSH β subunit. In the ovary, activin augments FSH action and stimulates production of follistatin by a paracrine effect. These effects of activin are blocked by both inhibin and follistatin. With increased GnRH stimulation, activin is increasingly antagonized by inhibin and bound by follistatin.

Cell Type

Major Steroid Hormone Products

Theca cells

Androgens (androstenedione, DHEA, testosterone)*

Granulosa cells

Estrogens (estradiol, estrone)

Theca-lutein cells

Progestogens (progesterone, 17-hydroxyprogesterone)**

Granulosa-lutein cells

Estrogens (estradiol, estrone)

*Mostly via Δ5 pathway **Via Δ4 pathway

Cholesterol C27 P450scc 3βHSD Pregnenolone C21

Progesterone C21 P450c17

Δ4 pathway

Inhibin and Activin

Table 1-7 Site of Synthesis of Major Steroidogenic Products of the Ovary

17 hydroxypregnenolone C21

Δ5 pathway

regulate FSH synthesis and secretion by the pituitary. They also have paracrine effects within the ovary, where they modulate follicle growth and steroidogenesis. Follistatin is a binding protein that modulates the effects of activin but not inhibin.

17 hydroxyprogesterone C21 P450c17 3βHSD DHEA C19

Androstenedione C19 17βHSD

Aromatase

Follistatin

Follistatin is an activin-binding protein that sequesters activin. Follistatin is produced in the same tissues as activin, including the pituitary, and regulates activin’s local paracrine and autocrine actions. In the circulation, follistatin binds the majority of activin, thereby inhibiting FSH secretion. This suggests that activin’s primary actions are paracrine in nature. Follistatin does not bind inhibin, thus allowing it to act as a conventional endocrine hormone between the ovary and the pituitary in addition to its local ovarian effects.

OVARIAN STEROIDOGENESIS DURING THE MENSTRUAL CYCLE Ovarian steroidogenesis during the menstrual cycle occurs in granulosa and theca cells (Table 1-7 and Fig. 1-4). Before ovulation, theca cells are separated from granulosa cells in the same follicle by a basal membrane. Thus, granulosa cells of preovulatory follicles do not have a blood supply. However, at the time of the LH surge the preovulatory follicle undergoes luteinization with disappearance of the basal membrane and capillary invasion of the granulosa cells. Theca cells become theca-lutein cells, and granulosa cells become granulosa-lutein cells. If pregnancy does not occur, the lifespan of the corpus luteum is fixed at approximately 14 days. After 12to 14 days luteolysis and apoptosis are initiated. The corpus luteum involutes, and

Estrone C18 17βHSD

Testosterone C19

Aromatase

Estradiol C18 Figure 1-4 The Δ5 and Δ4 pathways. The rate-limiting step in steroidogenesis is the conversion of cholesterol to pregnenolone via side chain cleavage (P450scc). In the follicular phase pregnenolone is preferentially converted to androstenedione via the Δ5 pathway involving 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA). In contrast, the corpus luteum preferentially converts pregnenolone to progesterone (Δ4 pathway) via 3β-hydroxysteroid dehydrogenase (3βHSD).

menstruation occurs. Ovarian steroidogenesis then shifts to a new cohort of follicles with their granulosa and theca cells.

Two-Cell Theory The two-cell, two-gonadotropin theory of ovarian steroidogenesis holds that follicular estrogen/androgen production is compartmentalized.59 Ovarian theca cells produce androgens in response to LH. These androgens may then be aromatized to estrogens in

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Section 1 Basic Science Table 1-8 Location Specificity of P450c17 and Aromatase Enzyme

Location

Function

P450c17

Theca cells only

Converts 21-carbon steroids (progesterone/pregnenolone) to 19-carbon steroids (androstenedione, DHEA)

Aromatase

Granulosa cells only

FSH

LH Cholesterol

Theca cell

Cholesterol

+

Converts 19-carbon steroids (androstenedione/testosterone) to 18-carbon steroids (estrone, estradiol)

Estrogens Estrogens are 18-carbon steroids that include estradiol (i.e., 17β-estradiol), estrone, and estriol. The most potent estrogen, estradiol, is predominantly secreted by the ovary. Estrone, which is one twelfth as potent as estradiol, is also secreted by the ovary. However, the principal source of estrone is from peripheral conversion from androstenedione. Estriol, which is one eightieth as potent as estradiol, is the principal estrogen formed by the placenta during pregnancy. Estriol is also formed by metabolism of estradiol and estrone by the liver and is the most abundant estrogen found in urine. Estrogen is largely bound to carrier proteins in serum. Approximately 60% of estradiol is bound to albumin, 38% is bound to sex hormone-binding globulin (SHBG), and 2% to 3% is free. It had previously been thought that only the free hormone was active and could enter cells, but recent evidence suggests that hormone transport and hormone availability may be more complex.62 Estrogen Receptors

8

There are two known estrogen receptors, ERα and ERβ. Both contain a steroid-binding domain, a DNA-binding domain, a hinge region, and a transcription-activation functional domain. The negative feedback of estradiol on FSH secretion is a direct effect of estradiol coupled to its receptor repressing transcription of the FSH β subunit.63 Negative feedback of estradiol on FSH may also be modulated by the estrogen-associated decline in pituitary expression of activin.64 Estrogens can enter any cell, but only cells with estrogen receptors will respond to its presence. When estrogens enter susceptible cells, estrogen associates with its receptor in the cell nucleus. This binding then activates the receptor. The DNAbinding domain of the estrogen–ER complex then associates with

P450scc Pregnenolone

LH-R

granulosa cells appropriately stimulated by FSH. FSH receptors are present only on granulosa cells, and early in the follicular phase LH receptors are present only on theca cells.60 The enzyme P450c17 (17-hydroxylase and 17,20-lyase) is only present in theca cells. Thus, only theca cells have the ability to convert 21-carbon steroids to 19-carbon steroids. In contrast, aromatase is only present in granulosa cells. Thus, in the ovary only granulosa cells have the ability to aromatize androgens to estrogens (Table 1-8 and Fig. 1-5). Supporting evidence for the two-cell theory includes the fact that women with hypogonadotropic hypogonadism may develop follicles in response to treatment with recombinant FSH, but do not significantly elevate androgen or estrogen levels unless LH is added to the stimulation regimen.61

StAR

+

P450c17

cAMP

17 hydroxypregnenolone

+

P450c17 DHEA 3βHSD

+

Androstenedione Basement membrane Granulosa cell cAMP

Androstenedione

+

Aromatase Estrone

FSH-R 17βHSD

Estradiol Figure 1-5 The two-cell theory and follicular phase steroidogenesis. Binding of luteinizing hormone (LH) to LH receptors on ovarian theca cells stimulates conversion of cholesterol to androstenedione. Binding of folliclestimulating hormone (FSH) to FSH receptors on granulosa cells then stimulates the aromatization of androgens to estrogens. StAR, steroidogenic acute regulatory protein; scc, side chain cleavage; HSD, hydroxysteroid dehydrogenase.

specific promoter sequences (DNA response elements) and activates gene transcription. Estrogen Metabolism

Serum concentrations of estradiol are less than 50 pg/mL in the early follicular phase. In response to follicle development estradiol levels rise, typically peaking at 200 to 300 pg/mL just before ovulation. Estradiol levels drop at the time of ovulation, then rise again, with a second peak in the midluteal phase reflecting estrogen secretion from the corpus luteum. The liver conjugates estrogens to form glucuronides and sulfates, about 80% of which are then excreted into the urine and 20% of which are excreted in the bile. In the liver, circulating estradiol is rapidly converted to estrone by 17β-hydroxysteroid dehydrogenase. Estrone may then be further metabolized in the

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Chapter 1 The Hypothalamic-Pituitary-Ovarian Axis and Control of the Menstrual Cycle liver to 16α-hydroxyestrone and then estriol. Estriol is then converted to estriol 3-sulfate-16-glucuronide before excretion by the kidney. Some 16α-hydroxyestrone may also be converted to catechol estrogens (i.e., 2-hydroxy or 4-hydroxyestrone). Biologically active catechol estrogens may then be converted to 2-methoxy and 4-methoxy compounds. Catechol estrogens are important because they have been implicated in carcinogenesis. Metabolism of catechol estrogens may generate oxygen free radicals.

Progesterone Progesterone, a 21-carbon steroid, is the principle secretory steroid of the corpus luteum. Progesterone is responsible for the induction of secretory changes that prepare estrogen-primed endometrium for implantation. If implantation occurs, continued progesterone production is necessary for maintenance of the pregnancy. The release of FSH and LH require the continuous pulsatile release of GnRH. The coordinated secretion of FSH and LH control follicle growth, ovulation, and maintenance of the corpus luteum. The release of FSH and LH is both positively and negatively influenced by estrogen and progesterone. Whether estrogen and progesterone stimulate or inhibit gonadotropin release depends on the quantity and duration of exposure to the steroid. At high concentrations progesterone inhibits both FSH and LH secretion by negative feedback on both the hypothalamus and pituitary.65 Progesterone also slows the GnRH pulse generator; hence the decline in GnRH pulse frequency in the luteal phase. However, at low concentrations, and only after previous exposure to estrogen, progesterone stimulates LH release.66 Progesterone Receptors

Progesterone receptors are similar to estrogen receptors in that they contain a steroid-binding domain, a DNA-binding domain, a hinge region, and a transcription-activation functional domain. There are two progesterone receptors, A and B. Receptor B is the positive regulator of progesterone-responsive genes. Binding of progesterone to progesterone receptor A inhibits activity of receptor B. Progesterone causes a depletion of estrogen receptors. This is the mechanism by which progestins protect against endometrial hyperplasia.

Progesterone is rapidly cleared from the circulation by the liver. The liver converts progesterone to pregnanediol. Pregnanediol is then conjugated to glucuronic acid, and pregnanediol glucuronide is excreted in the urine. Measurement of urinary pregnanediol glucuronide can be used as an index of progesterone production.

Androgens Ovarian theca cells secrete a variety of androgens (i.e., 19-carbon steroids), including androstenedione, testosterone, and dehydroepiandrosterone (DHEA). Androstenedione is the principal androgen secreted by ovarian theca cells. Theca cells also possess the enzyme 17β-hydroxysteroid dehydrogenase, which may convert androstenedione to testosterone. In premenopausal women, at least 60% of circulating testosterone is derived from the ovary, by either this conversion or direct secretion. Androstenedione and testosterone can then be aromatized to estrogens in granulosa cells under the influence of FSH. Androstenedione can also be converted to estrone or testosterone in peripheral tissues. Unlike testosterone and dihydrotestosterone, androstenedione does not have high affinity for the androgen receptor. Side chain cleavage of cholesterol to pregnenolone is the starting point and rate-limiting step in steroidogenesis. In the ovary cholesterol side chain cleavage is regulated by LH. Lowdensity lipoprotein (LDL) cholesterol is the principal source of cholesterol for steroidogenesis in the human ovary.67 Increased cAMP production due to LH stimulation of adenylate cyclase increases transcription of LDL receptor mRNA and LDL uptake. cAMP-activated steroidogenic acute regulatory protein then increases the intracellular transport of cholesterol to the inner mitochondrial membrane, where side chain cleavage occurs.68 In the preovulatory follicle the preferred pathway for androgen/ estrogen synthesis involves conversion of pregnenolone to 17-hydroxypregnenolone, the so-called Δ5 pathway (see Fig. 1-4). Ovarian theca cells have the enzymatic capability to convert pregnenolone to androgens, but lack the ability to aromatize androstenedione or testosterone into estrogens. Only granulosa cells, under the influence of FSH, can aromatize androgens to estrogens. In contrast to the preovulatory follicle, the corpus luteum prefers the Δ4 pathway, the initial conversion of pregnenolone to progesterone. Androgen Receptors

Progesterone Metabolism

Throughout the follicular phase serum progesterone concentrations are less than 1 ng/mL. Much of this progesterone is believed to result from adrenal production of pregnenolone and progesterone as a by-product of cortisol and aldosterone synthesis. In the late follicular phase progesterone levels begin to rise as the ovary starts to contribute to progesterone production. The rise in progesterone accelerates markedly after ovulation, and progesterone levels reach 10 to 20 ng/mL in the midluteal phase. If pregnancy does not occur, progesterone levels fall in the late luteal phase and return to levels below 1 ng/mL just before the onset of menstruation. In the circulation, approximately 80% of progesterone is bound to albumin. Another 18% is bound to corticosteroidbinding globulin. About 2.5% is freely circulating, and only about 0.5% is bound to SHBG.

The androgen receptor is similar to the estrogen receptor. It activates target gene expression via a similar sequence of ligand binding, nuclear translocation, DNA binding, and complex formation with coregulators and general transcription factors. Although the androgen receptor is known to play a central role in the development of male sex organs and secondary sexual characteristics, its physiologic roles in female reproduction remain unclear. Recent studies in androgen-deficient animals suggest that androgen receptors play an important role in granulosa cell development.69 These animals also exhibit reduced fertility with defective folliculogenesis, reduced corpus luteum formation, and reduced uterine response to gonadotropins. Androgen Metabolism

Androstenedione is produced in equal amounts by the ovaries and adrenal glands. The serum concentrations mirror estradiol

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Section 1 Basic Science levels and range from 0.5 to 3 ng/mL. Androstenedione levels increase in the mid- to late follicular phase and are maximal just before the LH surge. They decline at the time of ovulation, reach a second peak in the midluteal phase, and are lowest around the time of menstruation. Serum testosterone concentrations, in contrast, vary to a much lesser extent during the menstrual cycle and exhibit only a transient periovulatory increase. Testosterone concentrations range from 1.5 to 60 ng/dL.

CONTROL OF THE MENSTRUAL CYCLE Normal menstrual cycles, termed eumenorrhea, normally range in length between 24 to 35 days, with menstrual bleeding lasting 3 to 7 days. The average amount of blood loss is approximately 30 mL.70 Heavy, prolonged, or irregular menses are referred to as abnormal uterine bleeding and are considered in length in Chapter 21. Normal menstrual cycles result from a relatively precise interaction of the hypothalamus, pituitary, and ovaries. Under the influence of pituitary gonadotropins, the ovary undergoes cyclic changes providing for the development and release of a mature oocyte and production of ovarian hormones that prepare the endometrial lining for implantation. LH stimulates androgen production in theca cells; FSH promotes follicle development and aromatization of androgens to estrogens in granulosa cells (see Fig. 1-5). In turn, estrogens lead to proliferation of the endometrial lining and the induction of endometrial receptors for both estrogen and progesterone.71 To understand the menstrual cycle it is helpful to divide it into four phases: the follicular phase, the ovulatory phase, the luteal phase, and the luteal–follicular transition. We concentrate on changes in pituitary and ovarian hormones and the effects that these hormones have on the hypothalamus, pituitary, and ovary.

Follicular Phase The purpose of the follicular phase is to develop a single mature follicle to release a mature oocyte at ovulation. The presence of sufficient FSH also leads to expression of LH receptors on mature granulosa cells of preovulatory follicles. Thus, in the late follicular phase LH can sustain follicular endocrine activity, even in the absence of FSH.72 The follicular phase is variable in duration, but the other three phases are relatively constant, averaging 14 ± 2 days.

granulosa cells can cause upregulation or downregulation of granulosa cell FSH receptors.75 Without functional FSH follicle growth and ovarian estrogen production cannot occur.76 The steady decline in FSH beginning in the midfollicular phase serves to inhibit development of all but the dominant follicle. The dominant follicle remains dependent on FSH and must complete its development in spite of declining FSH levels. Because it has the largest cohort of granulosa cells, it has the largest cohort of FSH receptors and thus is able to grow in the face of insufficient FSH for smaller follicles. Luteinizing hormone levels are stable in the first half of the follicular phase. However, in the second half LH levels rise in response to positive feedback from increasing estrogen. Ovarian Hormones

Estradiol levels rise as the dominant follicle emerges. FSH and estrogen synergistically exert a mitogenic effect on granulosa cells, stimulating their proliferation. This in turn increases the FSH receptor content of the follicle, enhancing the ability of the follicle to respond to FSH and produce estrogen. Curiously, not every granulosa cell must express FSH receptors to respond to the gonadotropin signal. Gap junctions between cells allow cells with receptors to transmit protein kinase activation to their neighbors.77

LH FSH

A Estradiol Inhibin B Inhibin A

B

GnRH

Progesterone

Throughout most of the follicular phase GnRH pulses occur every 60 to 90 minutes. Just before the onset of the LH surge both GnRH pulse frequency and amplitude increase. Gonadotropins

10

FSH levels rise in the early follicular phase due to the lack of negative inhibition from estradiol and inhibin (Fig. 1-6). FSH stimulates follicle growth and estrogen production.73 Through binding of FSH to its receptor, granulosa cells in developing follicles attain the ability to aromatize androstenedione to estrone and testosterone to estradiol. Importantly, receptors for FSH are not detected on granulosa cells until the preantral stage.74 Moreover, both in vitro and in vivo administration of FSH to

2

C

4

6

8

10

12

14 16 18 Cycle day

20

22

24

26

28

30

Figure 1-6 Hormone fluctuations during the menstrual cycle. A, Mean values of follicle-stimulating hormone and luteinizing hormone throughout the cycle. B, Mean values of estradiol and inhibin. C, Mean values of progesterone during the menstrual cycle.

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Chapter 1 The Hypothalamic-Pituitary-Ovarian Axis and Control of the Menstrual Cycle Within the follicular fluid of follicles greater than 8 mm in diameter, the concentration of FSH, estradiol, and progesterone are all extremely high. Within smaller antral follicles, androgens predominate in the follicular fluid. The role of androgens in the follicle is dose-dependent. At low levels androgens provide a substrate for aromatization. However, at higher levels androgens are converted in granulosa cells by 5α-reductase to more active forms such as dihydrotestosterone (DHT) that cannot be aromatized to estrogens.78,79 Granulosa cells have androgen receptors.80 Activation of granulosa cell androgen receptors inhibits aromatase activity and also inhibits FSH induction of granulosa LH receptors.81 Follicles exposed to excessive androgens eventually become atretic.82,83 In contrast, follicles with the highest estrogen-to-androgen ratios and the highest estrogen concentrations are most likely to contain a competent oocyte.84 Rising estradiol levels have a dual role for the follicle. Within the follicle, estradiol promotes granulosa cell growth, aromatization of androgens to estrogens, and, in combination with FSH, induction of development of LH receptors on granulosa cells. However, outside the follicle rising serum estradiol levels have an inhibitory effect on FSH secretion. The resulting decline in FSH levels in the mid- to late follicular phase limits aromatase activity in smaller follicles, leading to higher androgen levels and follicular atresia. Indeed, a reduction in granulosa cell expression of FSH receptors is one of the first signs of follicular atresia. Inhibin B levels begin to rise almost immediately after the rise in FSH levels. By the midfollicular phase the rise in estradiol and inhibin B levels causes FSH levels to decline. Inhibin B levels peak approximately 4 days after the FSH peak.47 In the late follicular phase inhibin B levels fall, mirroring the decline in FSH levels. Progesterone and inhibin A levels are low throughout most of the follicular phase, but both begin to rise in the days immediately preceding ovulation. The rise in progesterone in the late follicular phase mirrors the rise in LH.

Ovulatory Phase The ovulatory phase begins with the midcycle LH surge, which disrupts contacts between granulosa cells and the cumulus oophorus (specialized granulosa cells surrounding the oocyte), causing the oocyte to detach from the follicle wall. The LH surge also induces the resumption of meiosis within the oocyte and release of the oocyte–cumulus complex from the follicle (ovulation). GnRH

GnRH plays a supporting role for the midcycle gonadotropin surge, but it does not trigger the surge.85 There is no change in GnRH pulse frequency during the midcycle gonadotropin surge.86 Rather, ovarian steroid feedback to the primed anterior pituitary triggers the LH surge.87 Whereas estrogen inhibits the secretion of pituitary gonadotropins, it facilitates their synthesis and storage. Estrogen also increases the expression of GnRH receptors.88,89 Thus, in the mid- to late follicular phase each pulse of GnRH is met with a greater gonadotropin response.90,91 When the estradiol level in the circulation meets a critical level for a sufficiently long period of time, the inhibitory action of estradiol on LH secretion changes to a stimulatory one. The LH surge is accompanied by a surge of GnRH in both portal and peripheral blood.92 However, as demonstrated by women with hypo-

gonadotropic hypogonadism treated with a pulsatile GnRH pump, ovulation and pregnancy may occur in the absence of any change in GnRH pulse frequency or amplitude.93 Moreover, the LH surge ends before there is a decline in the GnRH signal.94 Gonadotropins

Both FSH and LH levels peak just before ovulation. The initiation of the gonadotropin surge is dependent on attaining serum estradiol levels of at least 200 pg/mL for at least 2 days.95 In natural cycles this level of estradiol is typically not attained until the dominant follicle reaches a mean diameter of 15 mm.96 During the gonadotropin surge serum LH levels increase tenfold over a period of 2 to 3 days, while FSH levels increase fourfold. Within the dominant follicle the LH surge induces detachment of the oocyte–cumulus complex from the follicle wall. The release of the oocyte–cumulus complex from its follicular wall attachments is accompanied by the resumption of meiosis and release of the first polar body. The LH surge also induces luteinization of the periovulatory follicle. Luteinization refers to functional and morphologic changes within the theca–granulosa cell complex associated with accumulation of a yellow pigment called lutein. The function of the FSH surge is less clearly known, but it is believed to ensure an adequate number of LH receptors on the granulosa layer and to increase production of plasminogen activator, thus increasing the concentration of the proteolytic enzyme plasmin. Ovulation typically occurs from mature follicles 34 to 36 hours after the onset of the LH surge.97 The peak of LH and FSH occurs 10 to 12 hours before ovulation.98 The LH surge usually lasts 48 to 50 hours and must be maintained for at least 14 hours for full maturation of the oocyte to occur.99 The mechanism that turns off the LH surge is unknown. It may simply reflect the depletion in pituitary LH content. Ovarian Hormones

Just prior to ovulation the follicle becomes vascularized.100 Angiogenesis is mediated by LH and a variety of other factors, including vascular endothelial growth factor.101-103 Prostaglandins reach peak levels in the follicular fluid.104 Proteolytic enzymes digest collagen in the follicular wall, resulting in distensibility and thinning just before ovulation.105 Progesterone rises in the follicular fluid. FSH, LH, and progesterone all serve to increase the activity of proteolytic enzymes. There is a rapid increase in follicular fluid volume, but due to increased elasticity there is little to no change in intrafollicular pressure. Finally, a protrusion (stigma) appears on the follicular wall, and it is at this site that ovulation ultimately occurs. Interestingly, spontaneous lueteinization occurs in the absence of LH when granulosa cells are removed from follicles and cultured in vitro. Similarly, cumulus-enclosed oocytes removed from developing follicles before the LH surge will spontaneously resume meiosis.106,107 These findings have led to speculation that substances functioning as oocyte maturation inhibitors or luteinization inhibitors must exist within each follicle. Further support for this hypothesis lies in the fact that cumulus cells lack LH receptors. Estradiol levels fall beginning with the onset of the LH surge. Progesterone and inhibin A levels continue to rise at the time of ovulation. Inhibin B levels surge at the time of ovulation. Luteinization of the follicle begins.

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Section 1 Basic Science Luteal Phase The luteal phase is the time when the ovary secrets progesterone, resulting in endometrial receptivity for embryo implantation. LH receptors on granulosa cells result in luteinization, driving the postovulatory follicle to become a corpus luteum. Granulosa cells become granulosa-lutein cells with their own blood supply and begin secretion of both estrogen and progesterone. Release of large amounts of progesterone from the corpus luteum results in secretory endometrial changes and the final development of endometrial receptivity. GnRH and Gonadotropins

GnRH pulse frequency declines but pulse amplitude increases in the luteal phase. Changes in GnRH pulse frequency correlate with the duration of exposure to progesterone; changes in pulse amplitude correlate with progesterone levels.17 Luteinizing hormone and FSH levels reach a nadir during the luteal phase in response to the elevation in estrogen, progesterone, and inhibin A. Nevertheless, function of the corpus luteum is dependent on continued low-level pituitary gonadotropin secretion throughout the luteal phase.108 LH pulses stimulate pulses of progesterone secretion from the corpus luteum.17,109 Moreover, reducing LH pulse frequency and amplitude with a GnRH agonist in the luteal phase shortens the luteal phase itself.110 Ovarian Hormones

After ovulation granulosa and theca cells of the dominant follicle are luteinized. Luteinization involves both chemical and morphologic changes. Granulosa and theca cells hypertrophy and increase steroidogenesis. Moreover, breakdown of the basal membrane that previously separated granulosa and theca cells leads to capillary invasion around granulosa-lutein cells. Granulosa-lutein cells can now make progesterone directly from LDL via side chain cleavage and 3β-hydroxysteroid dehydrogenase. Levels of mRNA for side chain cleavage and 3βhydroxysteroid dehydrogenase are maximal at the time of ovulation and in the early luteal phase.111 The induction of LDL receptor expression in granulosa cells occurs in response to the LH surge and is an early feature of luteinization.112 Progesterone secretion correlates with the number of LH receptors and adenylate cyclase activity.113 Progesterone levels peak during the midluteal phase. Granulosa-lutein cells cannot make estrogens directly from cholesterol because they lack the enzyme P450c17. However, granulosa-lutein cells continue to be able to aromatize thecalutein produced androgens to estrogens, and estrogen levels remain high throughout most of the luteal phase. In granulosa-lutein cells inhibin production switches from inhibin B to inhibin A. Thus inhibin B levels decline to their nadir during the luteal phase, whereas inhibin A levels reach their peak. Secretion of inhibin A by granulosa-lutein cells is controlled by LH.114 Inhibin A, like inhibin B, suppresses FSH levels.115

Luteal–Follicular Transition

12

As the luteal phase continues, progesterone inhibits LH release via a negative feedback loop on the anterior pituitary. During the luteal–follicular transition, subsequent decline in LH causes the

corpus luteum to involute unless the corpus luteum is rescued by production of hCG from an implanting embryo. Involution of the corpus luteum leads to a fall in both estrogen and progesterone production. The endometrium can no longer be maintained and menstruation occurs. The fall of estrogen production then reactivates FSH secretion, initiating a new cycle of follicular development with estrogen secretion and renewed proliferation of the endometrial lining. GnRH

A progressive and rapid increase in GnRH pulse frequency occurs during the luteal–follicular transition. GnRH pulse frequency, as estimated by LH pulse frequency, increases from 3 pulses per 24 hours (midluteal phase) to 14 pulses per 24 hours.18 Gonadotropins

FSH and LH levels rise from their nadir due to the decline in negative feedback from estradiol and inhibin and the rise in activin.116 The rise in FSH initiates recruitment of gonadotropinresponsive follicles for the next menstrual cycle. This recruitment of antral follicles actually begins at least 2 days before the onset of menstrual bleeding. In fact, an increase in FSH bioactivity can be measured back to the midluteal phase.117 During the luteal–follicular transition both inhibin A and B levels are at a nadir.118 In contrast, activin levels begin to increase in the late luteal phase and peak at the time of menstruation.119 Activin plays an important role as gonadotropin responses to GnRH require the presence of activin.43 Ovarian Hormones

In the absence of pregnancy corpus luteum function declines approximately 10 days after ovulation. The exact mechanisms for luteolysis are unclear. Luteolysis involves apoptosis and expression of matrix metalloproteinases.120,121 Luteolysis may also be mediated by nitric oxide.122 Nitric oxide induces apoptosis in the human corpus luteum.123 One of the final signs of luteolysis is ovarian production of prostaglandin F2α, which inhibits luteal steroidogenesis. Thus, unless the corpus luteum is rescued by the hCG of pregnancy, estrogen, progesterone, and inhibin levels fall as the luteal–follicular transition occurs.

PEARLS ●

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●

●

GnRH-secreting neurons are found predominantly in the arcuate nucleus of the hypothalamus. GnRH is released into the portal circulation at the median eminence in a pulsatile fashion and binds to cell membrane receptors in the anterior pituitary. GnRH pulse frequency and amplitude vary during the menstrual cycle. The follicular phase is characterized by highfrequency (q60–90 minutes), low-amplitude pulses; the luteal phase is characterized by lower-frequency (q2–4 hours), higher-amplitude pulses. The activity of GnRH-releasing neurons is modified by a variety of factors, including neurotransmitters, glycoprotein hormones, and steroid hormones. GnRH has an extremely short half-life (2 to 4 minutes). GnRH agonists and antagonists are characterized by modifications to the native GnRH decapeptide structure that extend its half-life.

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The pituitary gland lies in the sella turcica and is connected to the hypothalamus via the pituitary stalk. The blood supply to the pituitary gland comes from the internal carotid artery. Specialized cells within the anterior pituitary (gonadotrophs) secrete FSH and LH in response to GnRH. Gonadotrophs comprise only 5% of all the cells in the anterior pituitary gland. FSH and LH are glycoproteins that share the same α subunit. The half-life of LH (20 to 30 minutes) is much shorter than that of FSH (1 to 4 hours), and LH pulse frequency/amplitude correlates closely with GnRH pulse frequency and amplitude. FSH and LH bind to cell membrane receptors that activate adenylate cyclase, thus raising intracellular cyclic AMP. FSH plays a crucial role in folliculogenesis, as well as inducing aromatization of androgens to estrogens. LH plays a crucial role in ovulation and steroidogenesis. Certain steroidogenic enzymes are specific to certain ovarian cell types. Only theca cells express P450c17, the enzyme

●

●

●

●

that allows conversion of progestins (21-carbon steroids) to androgens (19-carbon steroids). In turn, only granulosa cells, stimulated by FSH, have the ability to aromatize androgens to estrogens (18-carbon steroids). Granulosa cells of preovulatory follicles do not have a direct blood supply; they are separated from theca cells by a basal membrane. In contrast, almost immediately after ovulation capillaries invade the granulosa layer. In theca cells of the preovulatory follicle pregnenolone is preferentially converted to 17-hydroxypregnenolone (Δ5 pathway) on the way to synthesis of androstenedione. In the corpus luteum pregnenolone is preferentially converted to progesterone (Δ4 pathway). Progesterone, 17-hydroxyprogesterone, and inhibin A levels all peak in the luteal phase. The lifespan of the corpus luteum is fixed at approximately 14 days. If the corpus luteum is not rescued by hCG, luteolysis and apoptosis are initiated.

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3′,5′-monophosphate: One molecule, two messages. Clin Endocrinol (Oxf) 37:51–58, 1992. Oktay K, Briggs D, Gosden RG: Ontogeny of follicle-stimulating hormone receptor gene expression in isolated human ovarian follicles. J Clin Endocrinol Metab 82:3748–3751, 1997. LaPolt PS, Tilly JL, Aihara T, et al: Gonadotropin-induced up- and down-regulation of ovarian follicle-stimulating hormone (FSH) receptor gene expression in immature rats: Effects of pregnant mare’s serum gonadotropin, human chorionic gonadotropin, and recombinant FSH. Endocrinology 130:1289–1295, 1992. Matthews CH, Borgato S, Beck-Peccoz P, et al: Primary amenorrhoea and infertility due to a mutation in the beta-subunit of folliclestimulating hormone. Nat Genet 5:83–86, 1993. Fletcher WH, Greenan JR: Receptor mediated action without receptor occupancy. Endocrinology 116:1660–1662, 1985. McNatty KP, Makris A, Reinhold VN, et al: Metabolism of androstenedione by human ovarian tissues in vitro with particular reference to reductase and aromatase activity. Steroids 34:429–443, 1979. Hillier SG, van den Boogaard AM, Reichert LE Jr, van Hall EV: Intraovarian sex steroid hormone interactions and the regulation of follicular maturation: Aromatization of androgens by human granulosa cells in vitro. J Clin Endocrinol Metab 50:640–647, 1980. Hild-Petito S, West NB, Brenner RM, Stouffer RL: Localization of androgen receptor in the follicle and corpus luteum of the primate ovary during the menstrual cycle. Biol Reprod 44:561–568, 1991. Jia XC, Kessel B, Welsh TH Jr, Hsueh AJ: Androgen inhibition of follicle-stimulating hormone-stimulated luteinizing hormone receptor formation in cultured rat granulosa cells. Endocrinology 117:13–22, 1985. Erickson GF, Magoffin DA, Dyer CA, Hofeditz C: The ovarian androgen producing cells: A review of structure/function relationships. Endocr Rev 6:371–399, 1985. Chabab A, Hedon B, Arnal F, et al: Follicular steroids in relation to oocyte development and human ovarian stimulation protocols. Hum Reprod 1:449–454, 1986. Andersen CY: Characteristics of human follicular fluid associated with successful conception after in vitro fertilization. J Clin Endocrinol Metab 77:1227–1234, 1993. Knobil E, Plant TM, Wildt L, et al: Control of the rhesus monkey menstrual cycle: Permissive role of hypothalamic gonadotropinreleasing hormone. Science 207:1371–1373, 1980. Adams JM, Taylor AE, Schoenfeld DA, et al: The midcycle gonadotropin surge in normal women occurs in the face of an unchanging gonadotropin-releasing hormone pulse frequency. J Clin Endocrinol Metab 79:858–864, 1994. Nakai Y, Plant TM, Hess DL, et al: On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey. Endocrinology 102:1008–1014, 1978. Gregg DW, Nett TM: Direct effects of estradiol-17 β on the number of gonadotropin-releasing hormone receptors in the ovine pituitary. Biol Reprod 40:288–293, 1989. Bauer-Dantoin AC, Weiss J, Jameson JL: Roles of estrogen, progesterone, and gonadotropin-releasing hormone (GnRH) in the control of pituitary GnRH receptor gene expression at the time of the preovulatory gonadotropin surges. Endocrinology 136:1014–1019, 1995. Adams TE, Norman RL, Spies HG: Gonadotropin-releasing hormone receptor binding and pituitary responsiveness in estradiol-primed monkeys. Science 213:1388–1390, 1981. Menon M, Peegel H, Katta V: Estradiol potentiation of gonadotropinreleasing hormone responsiveness in the anterior pituitary is mediated by an increase in gonadotropin-releasing hormone receptors. Am J Obstet Gynecol 151:534–540, 1985. Xia L, Van Vugt D, Alston EJ, et al: A surge of gonadotropin-releasing hormone accompanies the estradiol-induced gonadotropin surge in the rhesus monkey. Endocrinology 131:2812–2820, 1992. Leyendecker G, Wildt L, Hansmann M: Pregnancies following chronic intermittent (pulsatile) administration of Gn-RH by means of a portable pump (“Zyklomat”)—a new approach to the treatment of infertility in hypothalamic amenorrhea. J Clin Endocrinol Metab 51:1214–1216, 1980.

94. Caraty A, Antoine C, Delaleu B, et al: Nature and bioactivity of gonadotropin-releasing hormone (GnRH) secreted during the GnRH surge. Endocrinology 136:3452–3460, 1995. 95. Young JR, Jaffe RB: Strength–duration characteristics of estrogen effects on gonadotropin response to gonadotropin-releasing hormone in women. II. Effects of varying concentrations of estradiol. J Clin Endocrinol Metab 42:432–442, 1976. 96. Cahill DJ, Wardle PG, Harlow CR, Hull MG: Onset of the preovulatory luteinizing hormone surge: Diurnal timing and critical follicular prerequisites. Fertil Steril 70:56–59, 1998. 97. Hoff JD, Quigley ME, Yen SS: Hormonal dynamics at midcycle: A reevaluation. J Clin Endocrinol Metab 57:792–796, 1983. 98. Pauerstein CJ, Eddy CA, Croxatto HD, et al: Temporal relationships of estrogen, progesterone, and luteinizing hormone levels to ovulation in women and infrahuman primates. Am J Obstet Gynecol 130:876–886, 1978. 99. Zelinski-Wooten MB, Hutchison JS, Chandrasekher YA, et al: Administration of human luteinizing hormone (hLH) to macaques after follicular development: Further titration of LH surge requirements for ovulatory changes in primate follicles. J Clin Endocrinol Metab 75:502–507, 1992. 100. McClure N, Macpherson AM, Healy DL, et al: An immunohistochemical study of the vascularization of the human graafian follicle. Hum Reprod 9:1401–1405, 1994. 101. Wulff C, Wilson H, Wiegand SJ, et al: Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinology 143:2797–2807, 2002. 102. Wulff C, Wilson H, Largue P, et al: Angiogenesis in the human corpus luteum: Localization and changes in angiopoietins, tie-2, and vascular endothelial growth factor messenger ribonucleic acid. J Clin Endocrinol Metab 85:4302–4309, 2000. 103. Dickson SE, Fraser HM: Inhibition of early luteal angiogenesis by gonadotropin-releasing hormone antagonist treatment in the primate. J Clin Endocrinol Metab 85:2339–2344, 2000. 104. Lumsden MA, Kelly RW, Templeton AA, et al: Changes in the concentration of prostaglandins in preovulatory human follicles after administration of hCG. J Reprod Fertil 77:119–124, 1986. 105. Yoshimura Y, Santulli R, Atlas SJ, et al: The effects of proteolytic enzymes on in vitro ovulation in the rabbit. Am J Obstet Gynecol 157:468–475, 1987. 106. Edwards RG: Maturation in vitro of human ovarian oocytes. Lancet 2(7419):926–929, 1965. 107. Edwards RG: Maturation in vitro of mouse, sheep, cow, pig, rhesus monkey and human ovarian oocytes. Nature 208:349–351, 1965. 108. Hutchison JS, Zeleznik AJ: The rhesus monkey corpus luteum is dependent on pituitary gonadotropin secretion throughout the luteal phase of the menstrual cycle. Endocrinology 115:1780–1786, 1984. 109. Filicori M, Butler JP, Crowley WF Jr: Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest 73:1638–1647, 1984. 110. Sheehan KL, Casper RF, Yen SS: Luteal phase defects induced by an agonist of luteinizing hormone-releasing factor: A model for fertility control. Science 215:170–172, 1982. 111. Bassett SG, Little-Ihrig LL, Mason JI, Zeleznik AJ: Expression of messenger ribonucleic acids that encode for 3 β-hydroxysteroid dehydrogenase and cholesterol side-chain cleavage enzyme throughout the luteal phase of the macaque menstrual cycle. J Clin Endocrinol Metab 72:362–326, 1991. 112. Brannian JD, Shiigi SM, Stouffer RL: Gonadotropin surge increases fluorescent-tagged low-density lipoprotein uptake by macaque granulosa cells from preovulatory follicles. Biol Reprod 47:355–360, 1992. 113. Rojas FJ, Moretti-Rojas I, Balmaceda JP, Asch RH: Regulation of gonadotropin-stimulable adenylyl cyclase of the primate corpus luteum. J Steroid Biochem 32:175–182, 1989. 114. McLachlan RI, Cohen NL, Vale WW, et al: The importance of luteinizing hormone in the control of inhibin and progesterone secretion by the human corpus luteum. J Clin Endocrinol Metab 68:1078–1085, 1989.

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Section 1 Basic Science 115. Molskness TA, Woodruff TK, Hess DL, et al: Recombinant human inhibin-A administered early in the menstrual cycle alters concurrent pituitary and follicular, plus subsequent luteal, function in rhesus monkeys. J Clin Endocrinol Metab 81:4002–4006, 1996. 116. le Nestour E, Marraoui J, Lahlou N, et al: Role of estradiol in the rise in follicle-stimulating hormone levels during the luteal-follicular transition. J Clin Endocrinol Metab 77:439–442, 1993. 117. Christin-Maitre S, Taylor AE, Khoury RH, et al: Homologous in vitro bioassay for follicle-stimulating hormone (FSH) reveals increased FSH biological signal during the mid- to late luteal phase of the human menstrual cycle. J Clin Endocrinol Metab 81:2080–2088, 1996. 118. Roseff SJ, Bangah ML, Kettel LM, et al: Dynamic changes in circulating inhibin levels during the luteal-follicular transition of the human menstrual cycle. J Clin Endocrinol Metab 69:1033–1039, 1989.

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119. Muttukrishna S, Fowler PA, George L, et al: Changes in peripheral serum levels of total activin A during the human menstrual cycle and pregnancy. J Clin Endocrinol Metab 81:3328–3334, 1996. 120. Shikone T, Yamoto M, Kokawa K, et al: Apoptosis of human corpora lutea during cyclic luteal regression and early pregnancy. J Clin Endocrinol Metab 81:2376–2380, 1996. 121. Young KA, Hennebold JD, Stouffer RL: Dynamic expression of mRNAs and proteins for matrix metalloproteinases and their tissue inhibitors in the primate corpus luteum during the menstrual cycle. Mol Hum Reprod 8:833–840, 2002. 122. Friden BE, Runesson E, Hahlin M, Brannstrom M: Evidence for nitric oxide acting as a luteolytic factor in the human corpus luteum. Mol Hum Reprod 6:397–403, 2000. 123. Vega M, Urrutia L, Iniguez G, et al: Nitric oxide induces apoptosis in the human corpus luteum in vitro. Mol Hum Reprod 6:681–687, 2000.

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2

Ovarian Hormones: Structure, Biosynthesis, Function, Mechanism of Action, and Laboratory Diagnosis Manjula K. Gupta and SuYnn Chia

INTRODUCTION The main function of the ovaries, maturation and release of oocytes, is accomplished via the production of several steroidal and nonsteroidal hormones that locally modulate a series of complex events. Peripherally, these hormones act on various target organs, including the uterus, vagina, fallopian tubes, mammary glands, adipose tissue, bones, kidneys, and liver, leading to the female phenotype. The secretion of the ovarian hormones in turn is precisely regulated by the hypothalamic-pituitary axis. The complex interactions and regulations of the hypothalamic, pituitary, and ovarian hormones are collectively responsible for the regular and predictable ovulatory menstrual cycle and fertility in females.

STEROIDOGENESIS AND STEROID HORMONES OF THE OVARY The ovary contains multiple distinctive steroid-producing cells, including stromal cells, theca cells, granulosa cells, and luteinized granulosa cells. Each cell type contains all the enzymes necessary for synthesis of androgens, estrogens, and progesterone. However, the types of hormones produced vary according to the cell type and the expression of steroidogenic enzymes. Other factors that influence which steroid hormone is synthesized in a given cell include the level and expression of gonadotropin and the availability of low-density lipoprotein (LDL) cholesterol. (As discussed below, steroid hormone synthesis occurs via one of two pathways: the Δ5[3β-hydroxysteroid] pathway or the Δ4[3 ketone] pathway.)

Steroidogenesis

The Ovary as an Endocrine Organ A single ovarian follicle is regarded as the basic endocrine/ reproductive unit of the ovary. It is composed of one germ cell that is surrounded by a cluster of endocrine cells, which are organized in two layers separated by a basal membrane. The inner layer surrounding the oocyte is composed of granulosa cells, and the outer layer is composed of thecal cells. These two cell types provide the basic machinery that is responsible for producing ovarian hormones. These cells are also differentially regulated by the gonadotropins (i.e., luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and produce distinctly different steroid hormones. The two-cell theory describes the sequence of events that occurs during ovarian follicular growth and steroidogenesis. According to this theory, LH primarily stimulates thecal cells to produce androstenedione and testosterone, both 19-carbon steroids. In contrast, FSH primarily stimulates granulosa cells to aromatize these 19-carbon steroids into estrogens.1,2 The ovarian production of steroid hormones is regulated both within the ovary, by paracrine (intercellular) and autocrine (intracellular) mechanisms, and by endocrine regulation of FSH secretion by the pituitary. Central to this regulation are several nonsteroidal hormones and factors produced by the ovary.3 This chapter focuses on these aspects of the ovary and discusses the biochemistry, biosynthesis, regulation, and actions of both steroidal and peptide ovarian hormones.

The ovary, like the adrenal gland, produces all three classes of steroid hormones from cholesterol—estrogens, progesterone, and androgens. In contrast to the adrenal gland, the ovary cannot produce glucocorticoids or mineralocorticoids because it lacks the enzymes 21-hydroxylase and 11β-hydroxylase. Steroid hormone formation in the steroid-producing endocrine glands follows the same fundamental pathway and mainly relies on exogenous (or plasma) cholesterol, with the exception of the liver and intestinal mucosa, which are capable of synthesizing cholesterol endogenously from acetyl-coA. The primary source of cholesterol for steroidogenesis in the ovary is derived from the uptake of plasma LDL.4 The rate-limiting step in steroidogenesis is transfer of cholesterol from the cytosol to the inner membrane of the mitochondria.5 This is mediated by an LH-induced mitochondrial enzyme called steroidogenic acute regulatory (StAR) protein.6 The StAR gene is located on chromosome 8p11.2 and codes for a 285-amino acid precursor protein, of which 25 amino acids are cleaved off after transport to the mitochondria.7,8 Nonsense mutations of the StAR gene that result in premature stop codons have been identified as a cause of congenital lipoid adrenal hyperplasia, which is characterized by the presence of intracellular lipid deposits that destroy steroidogenesis.7 Ovary steroid hormones are synthesized in both interstitial and follicular cells. The basic structure of cholesterol is three hexagonal carbon rings and a pentagonal carbon ring to which a side chain is attached (Fig. 2-1). Two important methyl groups are also attached at positions 18 and 19. Progestins and corticosteroids

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20 18 11

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HO

1

19 10

9

5

3 4

12

8

13

C

22

21

17

14

24 16

C

26 25 27

15

7 6

Cholesterol C27

Pregnane C21

Androstane C19

Estrane C18

Progestins

Androgens

Estrogens

CH C

O

HO

O

O

O

O

Progesterone

Androstendione

Estrone

OH

O

OH

O

Testosterone

Estradiol

Figure 2-1 Structures of cholesterol (27 carbons) and of the three major classes of ovarian steroids: the progestins (21 carbons), androgens (19 carbons), and estrogens (18 carbons).

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(pregnane series 21-carbon steroids) are produced by partial cleavage of the side chain (i.e., the desmolase reaction). Androgens (androstane series 19-carbon steroids) are produced by the total removal of the side chain. Estrogens (estrane series 18-carbon steroids) are produced by aromatization of one of the three hexagonal carbon rings to a phenolic structure with loss of the 19-methyl group. The first step in steroidogenesis is the conversion of cholesterol to pregnenolone via hydroxylation at the carbon 20 and 22 positions, which is followed by cleavage of the side chain (Fig. 2-2). From pregnenolone, steroid hormones are produced by one of two general pathways.5 The pregnenolone (Δ5) pathway produces androgens and estrogens (pregnenolone → 17OH-pregnenolone → dehydroepiandrosterone [DHEA] → testosterone → estrogen). The progesterone (Δ4) pathway produces androgens and estrogens (pregnenolone → progesterone → 17OH-progesterone → androgen → estrogen). In the adrenal gland, the Δ4 pathway produces mineralocorticoids and glucocorticoids. The enzymes involved in the intracellular synthesis of steroid hormones include five hydroxylases, two dehydrogenases, a reductase, and an aromatase. The hydroxylases and aromatase belong to the cytochrome P450 (CYP) supergene family (Table 2-1). These enzymes exist on both the mitochondria and endoplasmic reticulum.

Table 2-1 Enzyme Reaction and Cellular Location of Steroidogenic Enzymes Cellular Location/ Tissue Location

Enzyme Reaction

Gene (Enzyme)

Cholesterol side chain cleavage

CYP11A (P450scc)

Mitochondria (theca; granulosa)

17α-hydroxylase

CYP17 (P450c17)

ER (theca)

17,20-hydroxylase (lyase)

CYP17 (P450c17)

ER (theca)

Aromatase

CYP19 (P450arom)

ER (granulosa)

3β-hydroxysteroid dehydrogenase

3βHSD

ER (theca; granulosa)

17β-hydroxysteroid dehydrogenase

17βHSD

ER (granulosa)

21-hydroxylase

CYP21 (P450c21)

ER (adrenal)

11β-hydroxylase

CYP11B1 (P450c11)

Mitochondria (adrenal)

ER, endoplasmic reticulum

Of these nine enzymes, four key enzymes regulate the main steps of steroidogenesis (see Fig. 2-2): CYP11A (P450scc), a side chain cleavage enzyme that catalyzes the conversion of cholesterol to pregnenolone; 3βHSD, or 3 βa-hydroxysteroid

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Chapter 2 Ovarian Hormones Theca cells Cholesterol LH Corpus luteum

Δ4 pathway

CYP11A (P450scc)

Pregnenolone

Δ5 pathway

3βHSD

CYP17 (P450c17)

Progesterone

17OH Pregnenolone

CYP17

17,20 lyase

CYP17 17OH Progesterone

DHEA 3βHSD

CYP17 CYP21

CYP21 17βHSB

11-Deoxycorticosterone CYP11

11 Deoxycortisol

Androstenedione

Testosterone

CYP19 (P450arom)

CYP11B1

FSH

CYP19

17βHSB Corticosterone

Cortisol

Estrone

Estradiol Granulosa cells

18-OH Corticosterone

Aldosterone Adrenal gland Figure 2-2 Steroid hormone biosynthesis pathways in the ovary. The Δ4 pathway converts pregnenolone to progesterone and is the main pathway in the corpus luteum. The Δ5 pathway converts pregnenolone to androgens and subsequently estrogens and is the preferred pathway in the thecal cells. Also shown are the conversion of 17OH-progesterone to aldosterone and cortisol as a result of CYP21 and CYP11, which occurs exclusively in the adrenal gland. Irreversible reactions are denoted by a single arrow, and reversible reactions are denoted by double arrows.

dehydrogenase, which converts pregnenolone to progesterone; CYP17 (P450c17), an hydroxylase that converts pregnenolone to androgens; and CYP19 (P450arom), an aromatase that converts androgens to estrogens. Most reactions are irreversible (denoted by a single arrow in Fig. 2-2). The few reversible reactions (denoted by double arrows) are dependent on cofactor availability (e.g., NADP/NADPH ratio). The kind of hormone produced depends on the nature of the cell and the presence or absence of the inherent steroidogenic enzymes in the tissue. The adrenal cortex lacks 17βHSD; hence, adrenal androgen production is limited to DHEA and androstenedione. In the testes, LH controls 17βHSD activity and testosterone production. The steroid-producing cells of the ovary (granulosa, theca, corpus luteum) contain the full enzymatic complement for steroid hormone synthesis. In the thecal cells, LH also controls 17βHSD activity and androstenedione production, whereas CYP19 (P450arom) activity in the granulosa cells is controlled by FSH and hence estradiol production.

These relationships are the basis for the two-cell, twogonadotropin system (Fig. 2-3). Aromatization occurs in the endoplasmic reticulum. In each of the two cell types, the amount of the various enzymes differs depending on the stage of follicle development. CYP11A (P450scc) and 3βHSD are expressed in both thecal and granulosa cells of antral and preovulatory follicles and in the luteinized granulosa and thecal cells of the corpus luteum. In contrast, CYP17 (P450c17) is expressed only in the thecal cells of antral and preovulatory follicles and of the corpus luteum (see Fig. 2-3).

Steroid Hormones of the Ovary On the basis of chemical structure and biologic function, the major steroid hormones synthesized and secreted by the ovaries can be classified into three major types: estrogens, progesterone, and androgens.

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Section 1 Basic Science Pituitary gland LH

FSH

LH receptor

LH receptor

FSH receptor

Cholesterol

GTP

Gs

Cholesterol

CYP11A1

GTP

Gs

CYP11A1

GDP

GDP

Pregnenolone

Pregnenolone

CYP17 Gs

GTP

cAMP

CYP17 ATP

17α-OH pregnenolone Protein kinase A

cAMP

CYP17

Adenylate cyclase

Gs

Progesterone

3βHSD

17βHSD

CYP19

Testosterone

Androstenedione 17βHSD

Adenylate cyclase

Androstenedione

DHEA

CYP19

Testosterone

17βHSD Estradiol

Protein kinase A Estrone

Blood

Blood Thecal cell Granulosa cell Figure 2-3 Differential regulation by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) of ovarian estrogen, progesterone, and androgen production, the basis of the two-cell, two-gonadotropin system. LH acts on both thecal and granulosa cells; FSH acts only on granulosa cells. FSH and LH stimulate adenylate cyclase via G protein-coupled receptors. Cyclic adenosine monophosphate (cAMP) generated from adenosine triphosphate (ATP) activates protein kinase A, which in turn stimulates steroidogenic enzymes. Gs, G protein; GDP, guanosine diphosphate; GTP, guanosine triphosphate.

Estrogens Physiologic Role

20

Estrogens are essential in the development and maintenance ofthe female phenotype, germ cell maturation, and pregnancy. In addition to their reproductive effects, estrogens also have many other nonreproductive systemic effects, such as bone metabolism/remodeling, nervous system maturation, and endothelial responsiveness.9 At puberty, estrogen stimulates breast development and enlargement and maturation of the uterus, ovaries, and vagina.10,11 Estrogen also works in concert with growth hormone and insulinlike growth factor I (IGF-I) to produce a growth spurt and stimulates the maturation of chondrocytes and osteoblasts, which ultimately leads to epiphyseal fusion.12,13 After midpuberty, estrogen begins to exert a positive feedback on gonadotropin-releasing hormone (GnRH) secretion, leading to the progressive increase of LH and FSH production, culminating in the LH surge, ovulation, and the initiation of the menstrual cycle. In the adult female, estrogen plays a critical role in maintaining the menstrual cycle.14 The cyclical changes in estradiol, progesterone, and pituitary hormones are illustrated in Figure 2-4. In the early follicular phase of the menstrual cycle, FSH stimulates granulosa cell aromatase activity, resulting in increased follicular concentrations of estrogen. The rising estrogen level further increases the sensitivity of the follicle to FSH and estrogen by increasing the number of estradiol receptors on the granulosa cells. Follicular growth and antral formation is also

promoted by estrogen. This sets up a positive feedback cycle, which culminates in one dominant follicle producing an exponential rise in estrogen levels. This exerts a negative feedback on FSH so that falling FSH levels contribute to atresia of other nondominant follicles. The dominant follicle secretes large quantities of estrogen; estradiol levels must be greater than 200 pg/mL for approximately 50 hours before a positive feedback on LH release is achieved.13,15 Once the LH surge is initiated, luteinization of the granulosa cells and progesterone production occurs. In pregnancy, estrogen augments uterine blood flow, although it is not required in itself for the maintenance of pregnancy.16 In the central nervous system, estrogen withdrawal at menopause has been associated with reduced libido, altered mood, and cognitive disturbances. These effects have been attributed to estrogen’s ability to modulate the synthesis, release, and metabolism of many neuropeptides and neurotransmitters.17 Estrogen acts as a serotoninergic agonist by increasing serotonin synthesis in the brain, which may positively influence mood.18 Although prospective observational studies in postmenopausal women have suggested that estrogen replacement therapy might protect against cognitive decline19 and the development of dementia,20 randomized trials of estrogen in the treatment of Alzheimer’s disease have shown no evidence of benefit.21–24 In the skeletal system, estrogen antagonizes the effect of parathyroid hormone by directly inhibiting the function of osteoclasts, which decreases the rate of bone resorption and diminishes bone loss. The Postmenopausal Estrogen/Progestin

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80

200

60

150

40

100

20

50

0

0

Inhibin B (pg/mL)

Inhibin A (pg/mL)

Ovarian Hormones

Biosynthesis and Metabolism

A 1500

Progesterone (nmol/L)

40 1000 30 20

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Estradiol (pmol/L)

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LH (U/L)

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30

0 –7 0 7 Days relative to midcycle LH peak

disease.31 These studies led to the conviction that estrogen replacement therapy would consequently prevent the progression of atherosclerosis and coronary heart disease. However, the WHI study and the Heart and Estrogen/progestin Replacement Study (HERS), both large randomized, prospective trials designed to specifically address this issue, have not shown any benefit of estrogen for either the primary or secondary prevention of coronary artery disease, respectively.26,32

14

Figure 2-4 Plasma hormone concentrations (mean ± standard error) during the female menstrual cycle. Graph A, inhibins; Graph B, progesterone and estradiol; Graph C, LH and FSH. (Data from Groome NP, et al: Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab 81:1401-1405, 1996.)

Interventions (PEPI) trial was a prospective, placebo-controlled trial designed to study the effects of hormone replacement on bone density in postmenopausal women. After 12 months of treatment with estrogen, bone mineral density increased by 1.8% at the hip and by 3% to 5% at the spine.25 The Women’s Health Initiative (WHI) showed that estrogen reduced the risk of both hip and vertebral fractures by 30% to 39%.26 In the cardiovascular system, there is strong evidence that estrogen has a natural vasoprotective role. At a cellular level, estrogen receptors are found on the smooth muscle cells of coronary arteries27 and the endothelial cells of various sites.28 Estrogen causes short-term vasodilation by increasing nitric oxide and prostacyclin release in endothelial cells.29 Several large observational studies, including the Framingham study and the Nurses Health Study, have shown that cardiovascular incidence rates are lower in premenopausal than postmenopausal women.30 There was also a significant association between a younger age at menopause and a higher risk of coronary artery

Estrogens are 18-carbon steroids derived from cholesterol (see Fig. 2-1). The three forms of naturally occurring estrogen include estrone, 17β-estradiol, and estriol. In nonpregnant females, estrone and estradiol are the main biologically active estrogens secreted by the ovary. Estradiol is almost 2 to 5 times more potent than estrone.33 The circulating levels of estradiol are 2 to 4 times higher than those of estrone in premenopausal women. Estradiol concentrations in postmenopausal women are one tenth of those in premenopausal women. Estrone concentrations do not differ with menopausal status; thus, over time, the premenopausal estradiol-to-estrone ratio is reversed.34 In contrast, estriol is not the secretory product of the ovary but is the peripheral metabolite of estrone and estradiol. The main estrogen in premenopausal women is estradiol, which is produced primarily by the granulosa cells of the ovary. Androstenedione is converted to testosterone via 17βHSD, which is rapidly demethylated at the C-19 position and aromatized to estradiol. Estradiol is also generated to some degree from androstenedione via estrone. Estrone is also a secreted product of the ovary. It constitutes the remaining circulating estrogen (40%) and is mainly derived from the extragonadal peripheral aromatization of adrenal androstenedione.35 Peripheral conversion of androgens to estrogens occurs in skin, muscle, and adipose tissue and in the endometrium.36 In the normal adult female, the production of estradiol varies according to the phase of the menstrual cycle. During the mid luteal phase, for example, the production rate is about 100 to 270 μg/day. In comparison, the production rate for androstenedione is about 3 mg/day, and with its peripheral conversion rate to estrone of about 1.5%, it accounts roughly for about 10% to 30% of estrone production per day. Secondary increases in estrone formation occur in patients with polycystic ovaries or with ovarian cancer characterized by increased androgen production. In such patients, the increased estrogen can disturb the menstrual cycle. In postmenopausal women, the ovarian contribution shrinks, leaving estrone, derived from adrenal androstenedione, as the main source of circulating estrogen.37 In the pregnant woman, the placenta becomes the main source of estrogen in the form of estriol. The placenta is unable to synthesize steroids de novo and depends on circulating precursors from both fetal and maternal steroids. Most of the placental estrogens are derived from fetal androgens (e.g., DHEA sulfate), produced by the fetal adrenal gland.38 Fetal DHEA sulfate is converted to free DHEA by placental sulfatase and then to androstenedione and testosterone before being aromatized to estrone and estradiol. Finally, it is hydroxylated to form estriol. Estradiol is rapidly converted in the liver to estrone by 17βHSD. Estrone can be further metabolized via three pathways. First, it can be hydroxylated to 16α-hydroxyestrone,

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Section 1 Basic Science which is then converted to estriol. Estriol is further metabolized by sulfation and glucuronidation, and the conjugates are excreted into the bile or urine. Secondly, estrone can be conjugated to form estrone sulfate, which occurs primarily in the liver. Estrone sulfate is biologically inactive and is present in concentrations that are 10-fold to 20-fold higher than concentrations of estrone or estradiol.39 Estrone sulfate can be hydrolyzed by sulfatases present in various tissues to estrone and may serve as a reserve of estrogen in an inactive form. Estrone sulfate may be of some importance in assessing estrogenicity in women and can be detected in serum as well as in urine.40 Thirdly, estrone can also be metabolized by hydroxylation to form 2-hydroxyestrone and 4-hydroxyestrone, which are known as catechol estrogens. These are then converted to the 2-methoxy and 4-methoxy compounds by catechol-O-methyltransferase. Progesterone Physiologic Role

Progesterone plays a critical role in reproduction. It inhibits further endometrial proliferation mediated by estrogen and converts the endometrium into a secretory type, preparing it not only to receive the blastocyst for implantation, but also to maintain the pregnancy. It inhibits uterine contractions and increases the viscosity of cervical mucus. Progesterone also inhibits the action of prolactin so that lactation occurs only after delivery. It raises the basal body temperature by about 0.5°C (0.9°F) and increases the sensitivity of the respiratory center to carbon dioxide (CO2), leading to hyperventilation. During pregnancy, progesterone increases insulin resistance in concert with the production of the other placental counterregulatory hormones, including placental growth hormone, placental lactogens, placental corticotropin-releasing hormone, and cortisol.41 Biosynthesis and Metabolism

Progesterone is part of the group of 21-carbon steroids, which also includes pregnenolone and 17OH-progesterone. Progesterone is responsible for all the progestational effects, whereas pregnenolone is the precursor for all steroid hormones. 17OHprogesterone has little biologic activity. Progesterone and 17OH-progesterone are mainly produced by the corpus luteum in the luteal phase of the menstrual cycle and by the placenta if pregnancy occurs. Circulating levels of progesterone at concentrations greater than 4 to 5 ng/mL (12.7 to 15.9 nmol/L) are indicative of ovulation.42 Progesterone is rapidly metabolized by the liver and has a half-life of approximately 5 minutes. It is converted to pregnanediol and conjugated to glucuronic acid in the liver. Pregnanediol glucuronide is excreted in the urine. Pregnanetriol is the main urinary metabolite of 17OH-progesterone. Androgens Physiologic Role

22

In women, androgens originate as 19-carbon steroids from the adrenals and ovaries. The major androgens produced in the ovary, primarily by the thecal cells and to a lesser degree by the ovarian stroma, include DHEA, androstenedione, and a small amount of testosterone. Both DHEA and androstenedione serve as precursors to estrogen synthesis and have little, if any, androgenic activity. However, these biologically inactive androgens are

converted by extraglandular metabolism to biologically active androgens such as testosterone and dihydrotestosterone (DHT). Normally, the levels of these potent androgens are low in females and have no significant physiologic function. Excessive production of androgens by the ovary or adrenals has been implicated as the cause of hirsutism and virilization in women.43 In contrast, in the male the androgens, of which testosterone and DHT are the most crucial, are of primary importance. Biosynthesis and Metabolism

Androgens are 19-carbon steroids derived from cholesterol. The rate-limiting step in androgen synthesis is the conversion of cholesterol to pregnenolone, which is mediated by the action of LH on the ovary and testes. In a normal ovulatory woman, the ovaries secrete approximately 1 to 2 mg of androstenedione, 1 mg of DHEA, and approximately 0.1 mg of testosterone. The majority (≈0.2 mg) of circulating testosterone is derived from peripheral metabolism of DHEA and androstenedione. Overall, testosterone production in women is about 0.3 mg/day; roughly 50% of this is derived from peripheral conversion whereas the remaining 50% is secreted equally by the ovary and the adrenals.44 In the male, more than 95% of circulating testosterone is secreted by the testicular Leydig cells. The testes also secrete small amounts of DHT and the weak androgen DHEA and androstenedione. In most androgen target cells, testosterone is converted to the biologically more potent DHT by the enzyme 5α-reductase. In the female, androgens are derived either from the adrenal cortex in the form of DHEA and androstenedione or from the peripheral conversion of these androgen precursors to testosterone and DHT. Most of the circulating testosterone is metabolized in the liver into androsterone and etiocholanolone, which are conjugated with glucuronic acid or sulfuric acid and excreted in the urine as 17-ketosteroids. Of note, only 20% to 30% of urinary 17-ketosteroids are derived from testosterone metabolism; the rest originate from the metabolism of adrenal steroids.

Transport of Ovarian Steroid Hormones in Plasma Steroid hormones are not water-soluble and require transport proteins to be carried to their target tissues. The two types of transport proteins are general carrier proteins such as albumin and transthyretin and specific carrier proteins such as thyroxinebinding globulin, sex hormone-binding globulin (SHBG), and transcortin. Both types of proteins are produced in the liver. Less than 2% of ovarian steroid hormones are free in the circulation; the remainder are mostly bound to SHBG and albumin.45,46 Sex hormone-binding globulin, a β-globulin of 95 kDa, is synthesized in the liver. Its gene is localized on the short arm of chromosome 17 (p12-13).47 It is a homodimer composed of two polypeptide chains and has a single binding site for androgens and estrogens. Dimerization is a necessary step in the binding process.48 The bound and free fractions appear to exist in a steady state of equilibrium. The amount of free fraction depends on the concentration of steroid hormone and on the levels and binding affinities of the binding proteins. Of all the steroid hormones, DHT has the highest affinity for SHBG. Approximately 98% of testosterone circulates bound to SHBG (≈65%) and albumin (≈33%). Estradiol is primarily bound to albumin (≈60%) but also to SHBG (38%); about 2%

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Chapter 2 Ovarian Hormones circulates as the free fraction.49 Progesterone, on the other hand, is mainly bound to albumin (≈80%) but also to transcortin (≈18%). Only approximately 0.6% of progesterone is bound to SHBG and about 2% exists in the free state. The metabolic clearance of these steroids is inversely related to their binding affinity to SHBG. Thus, conditions that affect levels of SHBG (e.g., pregnancy, oral contraceptives) directly affect the levels of free hormone. Because estrogens increase SHBG synthesis and androgens decrease its synthesis, SHBG levels are twice as high in women compared to men. Several other hormones and other factors are known to influence SHBG levels. Thyroid hormones increase its synthesis and release by the liver.46 Insulin, IGF-I, and prolactin have been shown to inhibit SHBG production in cultured cells.50,51 Furthermore, serum concentrations of SHBG are increased in many disease states, including hyperthyroidism and liver cirrhosis. Certain drugs, including estrogen, tamoxifen, and phenytoin, can also increase serum SHBG concentrations. Carrier protein levels are decreased by hypothyroidism, obesity, and acromegaly and by administration of exogenous androgens, glucocorticoids, and growth hormones. For many years, only the free fraction of testosterone was regarded as the biologically active component. However, researchers noted that steroid hormones bind with greater affinity to their specific carrier proteins and with much less affinity to albumin. In addition, studies of tissue delivery in vivo showed that the dissociation of albumin-bound testosterone can occur rapidly in a capillary bed so that the active fraction can be larger than the free fraction measured under equilibrium conditions in vitro.52 Thus, unconjugated steroids that are bound to albumin may be treated as free and biologically available.53,54 As mentioned above, SHBG levels can be influenced by numerous disease states. As such, changes in SHBG concentrations can result in large shifts in the free and SHBG-bound fractions. Hence, measurement of SHBG is of great clinical interest because it allows more accurate assessment of free hormones. SHBG is measured by a technique called saturation analysis, in which specific binding capacity of 3H-labeled testosterone is detected.55,56 With modifications, this method can also measure the non-SHBG bound fraction (bioavailable).57 Recently, specific nonisotopic two-site immunoassays for SHBG have become available and are used in most clinical laboratories.

Measurement of Steroid Hormones in Circulation The technique responsible for the accurate measurement of low concentrations of various steroid hormones and metabolites is competitive inhibition immunoassay or radioimmunoassay (RIA), which was originally described in 1960 by Yalow and Berson.58 However, the development of steroid immunoassays presented several problems. First, they are not immunogenic and have a similar structure—they all have a same cyclopentahaptene nucleus with only minor structural variations—which makes it difficult to generate specific antibodies. Steroids can be made immunogenic via chemical coupling to a carrier protein known as hapten, and antibodies can be raised by immunization with haptens.59 However, the site of the steroid where the protein is conjugated has a significant impact on the specificity of the resulting antibody.59 Antibodies raised to conjugates of BSA coupled at the 19th position show higher specificity than

those coupled at the 3rd or 17th positions.60 For accurate clinical interpretation, it is important to know the cross-reactivity data on each antibody that is selected for a given assay. Most commercial assay reagent manufacturers provide cross-reactivity data, but it may not always be reliable and must be evaluated in the clinical laboratories performing the assay.61 Second, the high-affinity binding proteins such as SHBG in the serum compete with the antibody and thus interfere with the measurement of steroid molecules by RIA. This makes direct measurement difficult and necessitates a preassay extraction procedure with organic solvents and often a chromatographic separation of the steroid. Alternatively, the use of certain chemicals, such as 8-anilinonaphthalene sulfonic acid can inhibit the binding of steroids to proteins, which allows the direct measurement of steroid hormones without the extraction step. Direct assays are fast and can be automated. Several automated platforms for measuring estradiol, progesterone, and testosterone are commercially available and are used in most clinical laboratories. These assays, however, have a low sensitivity and, when used to measure very low concentrations, have poor reliability.62 Therefore, they may not be the best choice for clinical applications that require the ability to measure very low hormone concentrations such as estradiol measurement in children and in men ( 20 ulU/mL Sens = 68.7 Spec = 93.2 AUC 0.874 ± 0.087

60 40 20 0

60 HOMA > 3.8 Sens = 81.0 Spec = 77.3 AUC 0.867 ± 0.056

40 20 0 0

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with a sensitivity of 95% and specificity of 84% compared to the frequently sampled intravenous glucose tolerance test.94 Ducluzeau and coworkers later confirmed that the G0/I0 ratio is a predictor of insulin resiatnce in nonobese women as well.95 This study sought to identify the best markers of insulin resistance compared to the hyperinsulinemic euglycemic clamp. They measured serum SHBG, leptin, adiponectin, OGTT, and HOMA in addition to the G0/I0 ratio. The G0/I0 ratio emerged as the strongest independent parameter to appraise insulin resistance. The 2-hour OGTT can also be used to detect insulin resistance, with a 2-hour G0/I0 ratio of less than 1.0 suggestive of the diagnosis in the PCOS population.94 Correlation of insulin levels to glucose levels from the OGTT reveals how impaired glucose tolerance appears to be the result of decreased insulin sensitivity while impaired fasting glucose is a result of defective insulin secretion.96 One must be cognizant that there is considerable ethnic variability when screening for diabetes and insulin resistance. No normative values have been developed that are ethnicityspecific. Kauffman and colleagues studied white and Mexican American women with PCOS and found differing values for G0/I0 ratios to detect insulin resistance in the two populations.97 A fasting insulin greater than 20 μU/mL and G0/I0 ratio less than 7.2 detected insulin resistance in white women; a fasting insulin greater than 23 μU/mL and G0/I0 ratio less than 4.0 detected insulin resistance in Mexican American women (Fig. 15-4). In the clinical setting, the 2-hour OGTT that measures both fasting and postprandial glucose and insulin levels will yield the most information about glucose intolerance and

60 40

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20 0 0

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Figure 15-4 Receiver operating characteristic (ROC) curves for fasting insulin, glucose-to-insulin (G/I) ratio, and homeostasis model assessment (HOMA) values in white and Mexican American populations. If different cutoff values are implemented in each ethnic group, good sensitivity and specificity for each screening test is found. There is no statistical difference among each test of insulin resistance when applied to nonglucose-intolerant populations. (Data from Kauffman RP, Baker VM, DiMarino P, et al: Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: A comparison of two distinct populations. Am J Obstet Gynecol 187:1362–1369, 2002.)

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Chapter 15 Polycystic Ovary Syndrome hyperinsulinemia. It is recommended that the 2-hour OGTT be used to screen for the metabolic syndrome in obese women with PCOS, as well as any nonobese women with PCOS who have risk factors for insulin resistance.98 It is also reasonable to obtain a fasting lipid profile in women suspected of having risk factors for cardiovascular disease.

TREATMENT There are many considerations when deciding on therapy for PCOS (Fig. 15-5). Identification of patient concerns is necessary when prioritizing goals and formulating a treatment plan. A combination of therapies may be warranted, and the practitioner should appropriately counsel the patient on treatment expectations. Amelioration of long-term health risks should be emphasized regardless of the primary complaints of the patient.

Weight Loss Weight reduction should be a major component of any treatment plan for the overweight patient (BMI 26 or greater). Any sustained improvement in weight should involve diet and exercise, and consultation with a nutritionist may be helpful for those with difficulty achieving weight reduction. Obese PCOS patients who achieve weight loss will have an increase in SHBG, decrease in free testosterone, and improvement in fasting insulin levels.99

Oral Contraceptives Combination oral contraceptives have been the mainstay of PCOS management for the patient not interested in conception. Contraceptives suppress pituitary LH and consequently reduce ovarian androgen secretion, increase SHBG, and reduce free testosterone, while regulating menses and reducing the risk of endometrial hyperplasia or malignancy. However, there may be mild attenuation of insulin sensitivity. Korytkowski and coworkers have shown that short-term use of combination oral contraceptives in PCOS women results in a small decrease in insulin sensitivity and no change in the baseline elevation in triglyceride levels.100 However, in normal women, combination oral contraceptives were shown to produce an even more pronounced decline in insulin sensitivity, along with a significant elevation in triglyceride levels. The longer-term effects of combination oral contraceptives on insulin sensitivity and lipoprotein profiles have not been well documented. PCOS women are at greater risk for the development of diabetes and cardiovascular disease, and further investigation into the safety of long-term hormonal therapy is needed.

Antiandrogens Antiandrogens are commonly used as an adjunct to oral contraceptive therapy for treatment of hirsutism, but they have also been found to improve ovulation and restore regular

Desires conception?

Yes

No

Diabetes or glucose intolerance?

No

Yes Anovulatory?

Anovulatory? Yes

• Anti-androgens • Oral contraceptives

Hirsutism or acne?

Yes No

Expectant management Oral contraceptives

No

Yes

Ovulation induction: • Clomiphene • Gonadotropins • Exercise • Weight loss • ? Insulin sensitizers

Ovarian hyperstimulation

Expectant management No

• Exercise • Weight loss • Insulin sensitizers

Yes

No

• Ovarian drilling • Aromatase inhibitors

Persistent hirsutism? Yes

• Further evaluation • Anti-androgens • Glucocorticoids • GnRH-agonist+ addback HRT

Dyslipidemia or glucose intolerance? Yes

• Nutritional counseling • Weight loss • Medication • Insulin sensitizers

Figure 15-5 Polycystic ovary syndrome treatment algorithm. (Data from Berga S: The obstetrician-gynecologist’s role in the practical management of polycystic ovary syndrome. Am J Obstet Gynecol 179:109S–113S, 1998.)

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Section 3 Adult Reproductive Endocrinology

Insulin-Sensitizing Agents

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Insulin-sensitizing agents have been shown to improve endocrine and reproductive abnormalities in PCOS. Metformin is the most thoroughly investigated insulin-lowering agent used in PCOS. It is a biguanide that primarily works by suppressing hepatic gluconeogenesis and, to a lesser degree, increasing peripheral insulin sensitivity (Fig. 15-6).103 Thiazolidinediones are peroxisome proliferator activating receptor agonists that improve peripheral insulin sensitivity but do not appear to have an effect on hepatic glucose production (see Fig. 15-6).103 This class of medications includes troglitazone, pioglitazone, and rosiglitazone. Troglitazone is the oldest but was removed from the market in 2000 due to hepatotoxicity. Rosiglitazone and pioglitazone are still available and appear to be safer. The role of insulinsensitizing agents is still an area of active investigation. Many studies have demonstrated the positive effects of metformin on the reproductive axis of PCOS patients, with one of the most comprehensive studies recently demonstrating a dramatic improvement after 6 months of treatment. Metformin administration to nonobese hyperandrogenic PCOS patients resulted in a reduction of (1) LH pulse amplitude; (2) androstenedione levels; (3) testosterone levels; (4) ovarian volume; and (5) Ferriman-Gallway scores. Menstrual cyclicity was also improved in most patients.104 The investigators did not determine if metformin increased the likelihood of ovulation or if FSH levels rose. Similarly, troglitazone-treated PCOS patients demonstrated improved ovulation, decreased hirsutism, decreased free testosterone level, and increased SHBG.105 Insulin-sensitizing agents have a favorable effect on hyperandrogenism by reducing LH secretion, thereby removing the main stimulus for pathologic ovarian and adrenal androgen production. The reduction in insulin levels elevates hepatic SHBG production, decreasing free androgen levels. The concurrent improvement in hyperinsulinemia and hyperandrogenemia conferred by the use of insulin-sensitizing agents may ameliorate hirsutism.

e

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menses. It is important to remember that all antiandrogens are teratogenic and pose a risk of feminizing a male fetus, and thus should be used along with an effective form of contraception. Spironolactone is an aldosterone antagonist and is the most commonly used adjunctive agent in the treatment of hirsutism. It competes for testosterone binding sites on the pilosebaceous unit, inhibits 5α-reductase, and inhibits androgen production by interfering with cytochrome P450.102 The potassium-sparing effect warrants judicious use in the patient on potassium supplementation or with preexisting hypertension. Flutamide is a nonsteroidal antiandrogen that competes for the androgen receptor. Anovulatory PCOS patients treated with flutamide experienced resumption of ovulation with restoration of normal ovarian appearance with one dominant follicle.103 This study also reported a reduction in plasma levels of LH, androstenedione, and testosterone. Liver toxicity is a rare but potentially serious side effect of flutamide. Finasteride is a potent inhibitor of 5α-reductase used for treatment of prostatic hyperplasia with promising results as a treatment for hirsutism. All antiandrogens should be used along with a form of contraception because they are teratogenic and pose a risk of feminizing a male fetus.

75

50 P=0.03

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Figure 15-6 Mean (±SE) percent changes within subjects in endogenous glucose production and the glucose disposal rate under hyperinsulinemic clamp conditions after 3 months of therapy with metformin or troglitazone. NS, not significant. (From Inzucchi S, Maggs D, Spollett G, et al: Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 338:867–872, 1998. Copyright 1998 Massachusetts Medical Society. All rights reserved.)

The improvement in ovulation and menstrual cyclicity in patients treated with insulin-sensitizing agents suggests improved fertility. Indeed, spontaneous and clomipheneinduced ovulation rates in metformin-treated PCOS women are increased.106 Spontaneous ovulation occurred in 34% of those treated with 500 mg of metformin three times daily compared to only 4% in the placebo group. Clomiphene-induced ovulation occurred in 90% of women who received metformin compared to 8% who received placebo. For those who are clomipheneresistant, significant improvements in ovulation and pregnancy rates were reported in a randomized, double-blind, placebocontrolled trial for women pretreated with metformin.107 Troglitazone alone and the combination of troglitazone plus clomiphene is also associated with increased rates of ovulation and pregnancy in insulin-resistant women with PCOS.108 Though metformin is a category B medication, its use throughout pregnancy is becoming more attractive. In one retrospective study, Jakubowicz and colleagues found a significant reduction in the rate of early pregnancy loss for PCOS women who conceived while taking metformin and continued the agent throughout pregnancy. The rate of early pregnancy loss in the metformin group was 8.8% compared to 41.9% in controls. In the women with a prior history of miscarriage, the early loss rate was 11.1% for the metformin group compared with 58.3% in the control group.109 The efficacy of metformin for pregnancy loss is not yet clear, and safety data for this indication are lacking. Another possible beneficial effect of metformin administration during pregnancy is the significant reduction in gestational diabetes, as seen in one prospective cohort study.110

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Chapter 15 Polycystic Ovary Syndrome Randomized trials are needed before use of metformin is supported to prevent gestational diabetes in PCOS women with insulin resistance. Metformin should not be given to those with conditions associated with elevated lactate levels, such as renal or hepatic disease, because there is a risk of lactic acidosis with an associated mortality of 50%.111 Although most studies of metformin in PCOS used a dose of 500 mg three times daily, no studies have been performed to determine the optimal dosing regimen for improvement in insulin sensitivity, reduction of androgens, and resumption of ovulation. A dose–response study of type 2 diabetic patients demonstrated that the 2000 mg daily dose was optimal for improvement of glucose homeostasis,112 but the relevance of this dose to the PCOS population remains to be investigated. Metformin should be initiated in a stepwise approach, titrating the dose slowly over several weeks to minimize side effects. Most patients will experience gastrointestinal symptoms such as nausea, diarrhea, indigestion, and abdominal discomfort. Side effects will resolve in several days for most patients, which allow incremental dosing increases on a weekly basis up to a maximum dose of 1000 mg twice a day. Baseline serum creatinine should be obtained with yearly monitoring to avoid lactic acidosis. If metformin is being used to improve reproductive status rather than to correct hyperglycemia, reproductive parameters can be monitored. One would want to employ the lowest dose that results in ovulation for those strictly interested in conceiving. The optimal dose for amelioration of hyperandrogenic phenotype has not been established, and the outcome variables to monitor will be cosmetic sequelae or circulating androgen levels. There are no guidelines currently on the long-term use of metformin to prevent or improve health outcomes in patients with PCOS. One of the serious reactions to the thiazolidinediones is hepatotoxicity. Initiation of treatment requires baseline liver function studies along with periodic monitoring.

Ovarian Surgery Ovarian Wedge Resection

Ovarian wedge resection is a surgical procedure that has been found to restore both regular menses and ovulation in the majority of cases when used in PCOS patients. This procedure, originally performed by laparotomy, consists of removing a wedge of ovarian tissue and reconstructing the ovary. In the past, it was recommended for women who remained anovulatory despite therapy with clomiphene citrate, and many of the patients who became ovulatory also achieved pregnancy. Laparoscopic techniques for ovarian wedge resection have been described. The primary disadvantage of this approach is the formation of significant pelvic adhesions, which occurs in at least one third of the patients. The concern is that these adhesions might actually decrease fertility and increase the risk of pelvic pain. Another concern is that the restoration of ovulation is unlikely to be permanent, because the ovaries are not the causal agents in this complex systemic disorder. However, the actual long-term effectiveness of wedge resection has never been reported. Ovarian Drilling

A laparoscopic variant with similar results to ovarian wedge resection is called ovarian drilling (see Chapter 37). This

procedure involves making multiple punctures in the ovarian cortex and destroying ovarian tissue using unipolar electrosurgery or laser. The results and complications for this approach appear to be similar or slightly less than those for ovarian wedge resection, although a prospective, randomized study has never been done. There are additional concerns about long-term effects of ovarian drilling on ovarian function.

Hair Removal In women with significant hirsutism, removal of unwanted hair, especially on the face, chest, and abdomen, is often an important concern. Shaving, plucking, waxing and depilatories are the most common approaches used for temporary removal. These approaches do not induce coarser or faster hair growth, but must be repeated at frequent intervals. Electrolysis

Electrolysis, wherein a fine needle is inserted into each hair follicle and an electrical current is applied, is probably the most commonly used technique for permanent hair removal. Hair follicles must be treated individually, and several treatments may be needed to destroy the follicle. Usually, repeated treatments are required over a 12- to 18-month period. Possible side effects include pain, infection, hyperpigmentation or hypopigmentation, and keloid formation in susceptible women. Laser Hair Removal

Lasers and related intense pulsed light devices are other options for hair removal. These techniques work by emitting light at various wavelengths, energy output, and pulse widths that are selectively absorbed by darker structures. For this reason, laser hair removal works best for light-skinned people with dark hair. As with electrolysis, laser treatments for hair removal must be repeated. There remains some controversy over whether these techniques actually result in permanent destruction of hair follicles or simply retard the regrowth of new hair. Possible side effects, though uncommon, are related to damage to the surrounding healthy tissue in the form of scars, burns, redness, and swelling. These techniques are relatively expensive. Topical Eflornithine Hydrochloride

Eflornithine hydrochloride (Vaniqa) is a prescription-only topical cream approved by the U.S. Food and Drug Administration (FDA) for reducing and inhibiting the growth of unwanted facial hair. It was initially developed as an oral drug for the treatment of malignancies (for which it is ineffective) and is currently being used overseas to treat African trypanosomiasis (sleeping sickness). This drug works by irreversibly inhibiting ornithine decarboxylase, an enzyme that facilitates cell division in hair follicles. The cream is applied twice a day to areas of unwanted facial hair, and less than 1% is absorbed systemically. It is designated by the FDA as a pregnancy category C drug. Noticeable results are usually observed after 4 to 8 weeks of therapy. Application must be continued for as long as inhibition of hair growth is desired, although facial hair growth is reduced for up to 8 weeks after discontinuation.

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Section 3 Adult Reproductive Endocrinology SUMMARY

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PCOS is a complex disorder affecting multiple aspects of the endocrine system. Reproductive endocrinologists can no longer claim sole jurisdiction over this disease; patients may be presenting to internists, medical endocrinologists, and cardiologists for problems seemingly unrelated to the hypothalamicpituitary-ovarian axis. The underlying cause remains to be identified; there are several competing schools of thought. Some believe that abnormal hypothalamic drive is responsible; others hypothesize that hyperandrogenemia resulting from altered steroidogenesis is to blame. Another theory claims that insulin resistance is the key component, although others feel that insulin resistance better describes a subset of patients with PCOS. Indeed, multiple pathogenic mechanisms result in a PCOS picture. Treatment of PCOS is usually multifaceted, directed toward salient patient treatment goals while also aiming to diminish long-term risks of morbidity. When conception is desired, some forms of treatment are incongruous with others. For example, antiandrogens may be teratogenic, and HMG-CoA reductase inhibitors are contraindicated in those seeking conception. An idealized treatment algorithm is presented in Figure 15-5, which is likely to require revision as our understanding of the pathogenesis of PCOS improves.

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The diagnostic criteria for PCOS from the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group require two out of the following three criteria be present: (1) oligo-ovulation or anovulation, (2) hyperandrogenism and/or hyperandrogenemia, and (3) polycystic ovaries. A polycystic ovary is defined as having 12 or more follicles in one ovary measuring 2 to 9 mm in diameter and/or ovarian volume greater than 10 mL. PCOS patients have an increase in LH pulse frequency and amplitude and a decrease in FSH.

●

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●

GnRH neurons constitute the GnRH pulse generator. The GnRH pulse generator in PCOS patients is intrinsically faster, leading to increased LH secretion. This may also be the explanation for the relative reduction in FSH. Aberrant folliculogenesis and anovulation is due to the relative reduction in FSH. Ovarian sensitivity to FSH is preserved. GnRH secretion into portal blood may be regulated by glial and endothelial cells in addition to other neurotransmitters. Many substances are implicated in the modulation of the GnRH pulse generator, such as sex steroids, insulin, IGF-I, norepinephrine, dopamine, GABA, and opioids. Ovarian hyperandrogenism is driven by LH, and the effect is amplified by increased sensitivity to LH. The cause of excess adrenal androgen production is unknown, but hyperinsulinemia may play a role. From 50% to 70% of PCOS patients have insulin resistance. Although muscle and adipose tissue are insulin resistant, ovaries, adrenals, liver, skin, and hair remain sensitive. Insulin resistance may be the first manifestation of the metabolic syndrome in many PCOS patients. PCOS women are at increased risk for diabetes, dyslipidemia, cardiovascular disease, and endometrial cancer. To exclude other causes of hyperandrogenic anovulation, one should obtain levels of: testosterone, DHEAS, 17hydroxyprogesterone, and 24-hour urinary free cortisol if Cushing’s syndrome is suspected. Rarely, acromegaly may present as a PCOS-like picture. The 2-hour OGTT is the preferred method for diabetes detection. A fasting and 2-hour insulin level will detect insulin resistance or pancreatic insufficiency, respectively. Oral contraceptives plus anti-androgens are an effective therapy for patients with hirsutism and irregular menses. Insulin-lowering agents appear to be an effective adjunct for hyperinsulinemic women attempting conception. However, optimal dosing and safety profiles need further study.

REFERENCES

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1. Stein IF, Levinthal M: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181–191, 1935. 2. Farquhar CM, Birdsall M, Manning P, et al: The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women. Austral NZ J Obstet Gynaecol 34:67–72, 1994. 3. Polson DW, Adams J, Wadsworth J, Franks S: Polycystic ovaries—a common finding in normal women. Lancet 1:870–872, 1988. 4. Zawadski JK, Dunaif A: Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. In Dunaif A, Givens J, Haseltine F, Merriam G (eds). Polycystic Ovary Syndrome. Boston, Blackwell Scientific, 1992, pp 377–384. 5. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25, 2004. 6. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al: Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeast United States: A prospective study. J Clin Endocrinol Metab 83:3078–3082, 1998. 7. O’Driscoll J, Mamtora H, Higginson J, et al: A prospective study of the prevalence of clear-cut endocrine disorders and polycystic ovaries

8. 9.

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11. 12.

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in 350 patients presenting with hirsutism or androgenic alopecia. Clin Endocrinol 41:231–236, 1994. Hatch R, Rosenfield R, Kim M, Tredway D: Hirsutism: Implications, etiology, and management. Am J Obstet Gynecol 140:815–830, 1981. Carmina E, Koyama T, Chang L, et al: Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 167:1807–1812, 1992. Betti R, Bencini P, Lodi A, et al: Incidence of polycystic ovaries in patients with late-onset or persistent acne: Hormonal reports. Dermatologica 181:109–111, 1990. Cela E, Robertson C, Rush K, et al: Prevalence of polycystic ovaries in women with androgenic alopecia. Eur J Endocrinol 149:439–442, 2003. Carmina E, Lobo R: Polycystic ovary syndrome (PCOS): Arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab 84:1897–1899, 1999. Dunaif A, Graf M: Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 83:23–29, 1989. Arner P: Control of lipolysis and its relevance to development of obesity in man. Diabetes/Metab Rev 4:507–515, 1988.

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38. Prevot V, Croix D, Bouret S, et al: Definitive evidence for the existence of morphological plasticity in the external zone of the median eminence during the rat estrous cycle: Implication of neuroglio-endothelial interactions in gonadotropin-releasing hormone release. Neuroscience 94:809–819, 1999. 39. Wetsel WC, Valenca M, Merchenthaler I, et al: Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons. Proc Natl Acad Sci 89:4149–4153, 1992. 40. Daniels T, Berga S: Resistance of gonadotropin releasing hormone drive to sex steroid-induced suppression in hyperandrogenic anovulation. J Clin Endocrinol Metab 82:4179–4183, 1997. 41. Kalro BN, Loucks TL, Berga SL: Neuromodulation in polycystic ovary syndrome. Infertil Reprod Med Clin 14:529–555, 2003. 42. Kamberi IA, Mical RS, Porter JC: Hypophysial portal vessel infusion: In vivo demonstration of LRF, FRF, and PIF in pituitary stalk plasma. Endocrinology 89:1042–1046, 1971. 43. Findell PR, Wong KH, Jackman JK, Daniels DV: β1-Adrenergic and dopamine (D1) receptors coupled to adenylyl cyclase activation in GT1 gonadotropin-releasing hormone neurosecretory cells. Endocrinology 132:682–688, 1993. 44. Leblanc H, Lachelin GC, Abu-Fadil S, Yen SS: Effects of dopamine infusion on pituitary hormone secretion in humans. J Clin Endocrinol Metab 43:668–674, 1976. 45. Quigley ME, Rakoff JS, Yen SS: Increased luteinizing hormone sensitivity to dopamine inhibition in polycystic ovary syndrome. J Clin Endocrinol Metab 52:231–234, 1981. 46. Judd SJ, Rigg LA, Yen SS: The effects of ovariectomy and estrogen treatment on the dopamine inhibition of gonadotropin and prolactin release. J Clin Endocrinol Metab 49:182–184, 1979. 47. Spruce BA, Kendall-Taylor P, Dunlop W, et al: The effect of bromocriptine in the polycystic ovary syndrome. Clin Endocrinol 20:481–488, 1984. 48. Lobo R, Shoupe D, Chang SP, Campeau J: The control of bioactive luteinizing hormone secretion in women with polycystic ovary syndrome. Am J Obstet Gynecol 148:423–428, 1984. 49. Pons S, Torres-Aleman I: Estradiol modulates insulin-like growth factor I receptors and binding proteins in neurons from the hypthalamus. J Neuroendocrinol 5:267–271, 1993. 50. Daftary S, Gore A: Developmental changes in hypothalamic insulinlike growth factor-1: Relationship to gonadotropin-releasing hormone neurons. Endocrinology 144:2034–2045, 2003. 51. Longo KM, Sun Y, Gore A: Insulin-like growth factor-1 effects on gonadotropin-releasing hormone biosynthesis in GT1-7 cells. Endocrinology 139:1125–1132, 1998. 52. Roth C, Jung H, Kim K, et al: Involvement of γ amino butyric acid (GABA) in the postnatal function of the GnRH pulse generator as determined on the basis of GnRH and GnRH receptor gene expression in the hypothalamus and the pituitary. Exper Clin Endocrinol Diabetes 105:353–358, 1997. 53. Snowden EU, Khan-Dawood FS, Dawood MY: The effect of naloxone on endogenous opioid regulation of pituitary gonadotropins and prolactin during the menstrual cycle. J Clin Endocrinol Metab 59:298–302, 1984. 54. Eagleson C, Gingrich M, Pastor C, et al: Polycystic ovarian syndrome: Evidence that flutamide restores sensitivity of the gonadotropinreleasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 85:4047–4052, 2000. 55. de Ziegler D, Steingold K, Cedars M, et al: Recovery of hormone secretion after chronic gonadotropin-releasing hormone agonist administration in women with polycystic ovarian disease. J Clin Endocrinol Metab 68:1111–1117, 1989. 56. Barnes R: Pathophysiology of ovarian steroid secretion in polycystic ovary syndrome. Semin Reprod Endocrinol 15:159–168, 1997. 57. Bergh C, Carlsson B, Olsson JH, et al: Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin. Fertil Steril 59:323–331, 1993. 58. el-Roeiy A, Chen X, Roberts VJ, et al: Expression of the genes encoding the insulin-like growth factors (IGF-I and II), the IGF and insulin receptors, and IGF-binding proteins 1-6 and the localization of

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WHO Consultation, part 1: Diagnosis and classification of diabetes mellitus. WHO, 1999. www.who.int/diabetes/currentpublication/en Talbott E, Zborowski J, Rager J, et al: Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab 89:5454–5461, 2004. 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 57:505–513, 1992. Wild RA, Painter PC, Coulson PB, et al: Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab 61:946–951, 1985. Dahlgren E, Janson PO, Johansson S, et al: Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand 71:599–604, 1992. Guzick S, Talbott E, Sutton-Tyrrell K, et al: Carotid atherosclerosis in women with polycystic ovary syndrome: Initial results from a casecontrol study. Am J Obstet Gynecol 174:1224–1229, 1996. Yildiz B, Haznedaroglu I, Kirazli S, Bayraktar M: Global fibrinolytic capacity is decreased in polycystic ovary syndrome, suggesting a prothrombotic state. J Clin Endocrinol Metab 87:3871–3875, 2002. Pierpoint T, McKeigue P, Isaacs A, et al: Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 51:581–586, 1998. 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 3:101–105, 2000. Potischman N, Hoover R, Brinton L, et al: Case-control study of endogenous steroid hormones and endometrial cancer. J Natl Cancer Inst 88:1127–1135, 1996. Konishi I, Koshiyama M, Mandai M, et al: Increased expression of LH/hCG receptors in endometrial hyperplasia and carcinoma in anovulatory women. Gynecol Oncol 65:273–280,1997. Anderson K, Sellers T, Chen P, et al: Association of Stein-Leventhal syndrome with the incidence of postmenopausal breast carcinoma in a large prospective study of women in Iowa. Cancer 79:494–499, 1997. Koskinen P, Penttila T, Anttila L, et al: Optimal use of hormone determinations in the biochemical diagnosis of the polycystic ovary syndrome. Fertil Steril 65:517–522, 1996. Legro R, Kunselman A, Dodson W, 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 84:165–169, 1999. Moller DE, Flier JS: Insulin resistance—mechanisms, syndrome, and implications. NEJM 325:938–948, 1991. Legro R, Finegood D, Dunaif A: A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 83:2694–2698, 1998. Ducluzeau P, Cousin P, Malvoisin E, et al: Glucose-to-insulin ratio rather than sex hormone-binding globulin and adiponectin levels is the best predictor of insulin resistance in nonobese women with polycystic ovary syndrome. J Clin Endocrinol Metab 88:3626–3631, 2003. Carnevale Schiance G, Rossi A, Sainaghi P, et al: The significance of impaired fasting glucose versus impaired glucose tolerance. Diabetes Care 26:1333–1337, 2003. Kauffman RP, Baker VM, DiMarino P, et al: Polycystic ovarian syndrome and insulin resistance in white and Mexian American women: A comparison of two distinct populations. Am J Obstet Gynecol 187:1362–1369, 2002. Legro R, Castracane VD, Kauffman RP: Detecting insulin resistance in polycystic ovary syndrome: Purposes and pitfalls. Obstet Gynecol Surv 59:141–154, 2004. Guzick D, Wing R, Smith D, et al: Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 61:598–604, 1994.

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Chapter 15 Polycystic Ovary Syndrome 100. Korytkowski M, Mokan M, Horwitz M, Berga S: Metabolic effects of oral contraceptives in women with polycystic ovary syndrome. J Clin Endocrinol Metab 80:3327–3334, 1995. 101. Cumming D, Yang J, Rebar R, Yen S: Treatment of hirsutism with spironolactone. JAMA 247:1295–1298, 1982. 102. De Leo V, Lanzetta D, D’Antona D, et al: Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 83:99–102, 1998. 103. Inzucchi S, Maggs D, Spollett G, et al: Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. NEJM 338:867–872, 1998. 104. Genazzani A, Battaglia C, Malavasi B, et al: Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril 81:114–119, 2004. 105. Azziz R, Ehrmann D, Legro R, et al: Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: A multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86:1626–1632, 2001. 106. Nestler J, Daniela J, Evans W, Pasquali R: Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. NEJM 338:1876–1880, 1998.

107. Vandermolen D, Ratts V, Evans W, et al: Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 75:310–315, 2001. 108. Mitwally M, Kuscu N, Yalcinkaya T: High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome. Hum Reprod 14:2700–2703, 1999. 109. Jakubowicz D, Iuorno M, Jakubowicz S, et al: Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 87:524–529, 2002. 110. Glueck C, Wang P, Kobayashi S, et al: Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 77:520–525, 2002. 111. De Leo V, La Marca A, Petraglia F: Insulin-lowering agents in the management of polycystic ovary syndrome. Endocrine Rev 24:633–667, 2003. 112. Garber A, Duncan T, Goodman A, et al: Efficacy of metformin in type II diabetes: Results of a double-blind, placebo-controlled, dose–response trial. Am J Med 103:491–497, 1997.

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16

Amenorrhea J. Ricardo Loret de Mola

INTRODUCTION Disorders of the menstrual cycle are one of the most common reproductive problems seen in a gynecologic practice. The absence of a menstrual period is a frequent symptom of underlying pathology of either the reproductive tract or the hypothalamic-pituitary-ovarian axis. This chapter examines both primary and secondary amenorrhea. Although some of the etiologies for these two conditions overlap, the most common causes and thus the diagnostic approaches used for the two are very different. For this reason, primary and secondary amenorrhea are considered separately in terms of etiology, diagnosis, and management. Each section concludes with a comprehensive diagnostic approach.

DEFINITIONS In common medical usage, amenorrhea refers to the abnormal cessation of menses.1 Physiologic amenorrhea exists before puberty, during pregnancy and lactation, and after menopause. However, these physiologic causes are not included in the standard amenorrhea classifications. Amenorrhea can be divided into two major groups based on presentation: primary or secondary amenorrhea (Table 16-1).2,3 Although many of the causes of primary and secondary amenorrhea are similar, the most likely causes, and thus the diagnostic approach, are distinct.

is diagnosed depends on the presence or absence of secondary sexual characteristics. In the absence of increased growth or development of secondary sexual characteristics, primary amenorrhea is diagnosed when the patient has no menses by age 13. In the presence of normal growth and development of secondary sexual characteristics, the diagnosis of primary amenorrhea is reserved for patients who have no menstruation by age 15. The incidence of primary amenorrhea in the United States is less than 0.1%. The majority of patients with primary amenorrhea will be found to have either gonadal dysgenesis (49%) or müllerian agenesis (16%).4

Secondary Amenorrhea Secondary amenorrhea refers to cessation of menses after establishment of menstruation for reasons other than pregnancy, lactation, or menopause. By convention, the diagnosis is applied after menses have been absent for a length of time equivalent to at least 3 of the previous menstrual cycle intervals or 6 months. The incidence of secondary amenorrhea not due to pregnancy, lactation, or menopause is approximately 4%.5,6 Although the list of causes for amenorrhea is quite extensive (Table 16-2), it appears that this list will continue to grow or be modified as more sophisticated genetic testing becomes available and the genetic understanding of human disease expands. The majority of patients with amenorrhea will have premature ovarian failure, hyperprolactinemia, hypothalamic amenorrhea, or polycystic ovary syndrome (PCOS).

Primary Amenorrhea Primary amenorrhea is the absence of menstruation in a woman who has never menstruated. Because children do not normally menstruate before puberty, the age at which primary amenorrhea

Table 16-1 Definitions of Primary and Secondary Amenorrhea Primary Amenorrhea No menstruation in a woman who has never menstruated by • age 13 in the absence of growth and development of secondary sexual characteristics, or • age 15 with normal growth and development of secondary sexual characteristics Secondary Amenorrhea Any woman who has been regularly menstruating with the absence of menses for either ≥ 3 of the previous cycle intervals, or 6 months

Classification The most widely accepted classification of amenorrhea was published by the World Health Organization (WHO) and divides amenorrhea into three groups (Table 16-3).3 This WHO amenorrhea classification is designed to help the practicing clinician summarize the causes of amenorrhea to assist in evaluating the condition. Group I include individuals who lack endogenous estrogen production, in association with normal or low follicle-stimulating hormone (FSH) levels, and no evidence of hypothalamic-pituitary pathology or elevated prolactin levels. Group II is associated with evidence of estrogen production and normal levels of prolactin and FSH. Finally, Group III involves elevated serum FSH levels that indicate gonadal failure.7 Although amenorrhea can occur among patients with sexual ambiguity or virilization, it is rarely the cause for initial consultation.8

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Section 3 Adult Reproductive Endocrinology Table 16-2 Classification of Amenorrhea, Both Primary and Secondary3 I.

Anatomic defects (outflow tract) A. Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) B. Complete androgen resistance (testicular feminization) C. Intrauterine synechiae (Asherman syndrome) D. Imperforate hymen E. Transverse vaginal septum F. Cervical agenesis—isolated G. Cervical stenosis—iatrogenic H. Vaginal agenesis—isolated I. Endometrial hypoplasia or aplasia—congenital

II. Primary hypogonadism A. Gonadal dysgenesis 1. Abnormal karyotype (Incomplete gonadal dysgenesis) a. Turner syndrome 45,X b. Mosaicism 2. Normal karyotype a. Pure gonadal dysgenesis i. 46,XX ii. 46,XY (Swyer syndrome) B. Gonadal agenesis C. Enzymatic deficiency 1. 17α-Hydroxylase deficiency 2. 17,20-Lyase deficiency 3. Aromatase deficiency D. Premature ovarian failure 1. Idiopathic 2. Injury a. Chemotherapy b. Radiation c. Mumps oophoritis 3. Resistant ovary a. Idiopathic III. Hypothalamic causes A. Dysfunctional 1. Stress 2. Exercise 3. Nutrition-related a. Weight loss, diet, malnutrition b. Eating disorders (anorexia nervosa, bulimia) 4. Pseudocyesis B. Other disorders 1. Isolated gonadotropin deficiency a. Kallmann syndrome b. Idiopathic hypogonadotropic hypogonadism 2. Infection a. Tuberculosis b. Syphilis c. Encephalitis/meningitis d. Sarcoidosis 3. Chronic debilitating disease 4. Tumors a. Craniopharyngioma b. Germinoma c. Hamartoma d. Langerhans cell histiocytosis e. Teratoma f. Endodermal sinus tumor g. Metastatic carcinoma IV. Pituitary causes A. Tumors 1. Prolactinomas 2. Other hormone-secreting pituitary tumor (corticotropin, thyrotropinstimulating hormone, growth hormone, gonadotropin) a. Mutations of FSH receptor b. Mutations of LH receptor c. Fragile X syndrome 3. Autoimmune disease 4. Galactosemia V. Other endocrine gland disorders A. Adrenal disease 1. Adult-onset adrenal hyperplasia 2. Cushing syndrome B. Thyroid disease 1. Hypothyroidism 2. Hyperthyroidism

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Table 16-2 Classification of Amenorrhea, Both Primary and Secondary3—cont’d C. Ovarian tumors 1. Granulosa-theca cell tumors 2. Brenner tumors 3. Cystic teratomas 4. Mucinous/serous cystadenomas 5. Krukenberg tumors 6. Nonfunctional tumors (craniopharyngioma) 7. Metastatic carcinoma D. Space-occupying lesions 1. Empty sella 2. Arterial aneurysm E. Necrosis 1. Sheehan syndrome 2. Panhypopituitarism F. Inflammatory/infiltrative 1. Sarcoidosis 2. Hemochromatosis 3. Lymphocytic hypophysitis G. Gonadotropin mutations (FSH) VI. Multifactorial causes A. Polycystic ovary syndrome

Table 16-3 World Health Organization (WHO) Classification of Amenorrhea Characteristic

Group I

Group II

Group III

Estrogen

Low

Normal

Low

FSH

Low or normal

Normal

High

Prolactin

Normal

Normal

Hypothalamus/ pituitary

No pathology

Example

Hypogonadotropic hypogonadism

Polycystic ovary syndrome (PCOS)

Gonadal failure

PRIMARY AMENORRHEA The etiologies of primary amenorrhea are multiple and diverse (Tables 16-4 and 16-5). The four most common causes of primary amenorrhea have been reported to be the following:4 (1) Gonadal dysgenesis (almost half of all cases) (2) Müllerian agenesis (i.e., congenital absence of the uterus and vagina) (3) Hypothalamic disorders, including those related to exercise and nutrition (4) Constitutional delay of puberty Other causes of primary amenorrhea, while less common, include outflow obstructions (e.g., imperforate hymen, transverse vaginal septum), androgen insensitivity syndrome, and inborn defects in gonadotropin secretion or response. Several of these are examined in this chapter; others are discussed in separate chapters.

Gonadal Dysgenesis The term gonadal dysgenesis is used globally to refer to all forms of abnormal gonads, which can occur in individuals with normal

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Chapter 16 Amenorrhea Table 16-4 Common Causes of Primary Amenorrhea Category

Frequency

Normal Secondary Sexual Development Müllerian agenesis Androgen insensitivity Constitutional delay Outlet obstruction (e.g., vaginal septum, imperforate hymen)

(~1/3 of total) 10% 9% 8% 3%

Absent Secondary Sexual Development High FSH (gonadal dysgenesis) Abnormal karyotype (e.g., 46,XO, mosaic) 46,XX 46,XY Low FSH Hypothalamic disorders Constitutional delay Hyperandrogenic conditions (e.g., PCOS, CAH) Pituitary adenomas

(~2/3 of total) 20% 15% 5% 8% 10% 6% 5%

Adapted from Practice Committee of ASRM: Current evaluation of amenorrhea. Fertil Steril 82(Suppl 1):33-S39, 2004.

karyotypes (46,XX; 46,XY) as well as a variety of abnormal or mosaic states, most commonly Turner’s syndrome (45,XO). The gonads are usually streaks of fibrous tissue. Pure Gonadal Dysgenesis

Pure gonadal dysgenesis refers to phenotypically female individuals with streak gonads and normal female external genitalia and normal müllerian structures whose karyotype can be either 46,XY (Swyer syndrome) or 46,XX. This heterogeneous condition results from a structural abnormality on the Y chromosome, a mutation in the SRY gene, or a mutation in an autosomal gene. Mixed Gonadal Dysgenesis

Mixed gonadal dysgenesis refers to individuals with defective gonadal development secondary to a chromosomal mosaic variant. Their karyotypes show partial sex chromosome monosomy with an absence or abnormality of the second sex chromosome, with 45,XO/46,XY being the most common. Their phenotypes range from phenotypic female to pseudohermaphrodite to phenotypic male, depending on the ratio of 45,XO cells to those with normal (46,XX or 46,XY) karyotypes in each gonad. These patients present with abnormal sex differentiation. There can be a streak

gonad on one side and a dysgenetic gonad or normal testicle on the other and with concurrent ipsilateral Wolffian or müllerian development. Most of these individuals have short stature, and one third will show characteristics of Turner’s syndrome. The majority of patients with gonadal dysgenesis will never have menses. This group of patients make up 40% of cases of primary amenorrhea, and 40% will have an abnormal karyotype. This abnormal karyotype will be Turner’s syndrome (46,XO) 50% of the time and a mosaicism such as XO/XY 25% of the time. Patients who present with gonadal dysgenesis and a normal karyotype need to be assessed for a variety of other conditions, such as neurosensory deafness and fragile X syndrome. These clinical associations are particularly true when familial premature ovarian failure is identified.9

General Principles of X Chromosome Genetic Disorders Short stature is the result of a mutation of the SHOX gene (short stature homeobox-containing gene). The gene is located on the pseudoautosomal region of the X chromosome, and two normal copies are required for the development of normal stature. Isolated deletions of portions of the X chromosome have also been reported. Deletions affecting Xp11 result in ovarian failure in about half of women. Deletions involving the q arm of the X chromosome also usually result in ovarian failure. Even in those who achieve normal menstruation, fertility is rare. When the deletion on the X chromosome is more distal (Xp21 region), the phenotype is generally milder. However, secondary amenorrhea or infertility is common. Most women with Xp deletions are short, regardless of their ovarian function, and present with a Turner’s syndrome-like phenotype. The molecular mechanism responsible for ovarian failure in these cases is due to loss of a putative ovarian determinant gene necessary for ovarian development, increasing follicular atresia, but not to the extent of that observed in patients with Turner’s syndrome. Translocations of the X chromosome, although extremely rare, may cause amenorrhea depending on the location of breakpoints. In a balanced X translocation one X chromosome is normal, and the other is an X autosome translocation chromosome. X inactivation is not usually random so that the normal X is usually inactivated. If the translocated chromosome were inactivated, the autosome would also be inactivated, making the

Table 16-5 Genital Tract Abnormalities Associated with Amenorrhea Asherman’s Syndrome

Müllerian Anomalies

Müllerian Agenesis

Androgen Insensitivity

Severe Hyperandrogenemia/ Insulinemia

Karyotype

46,XX

46,XX

46,XX

46,XY

46,XX

Heredity

Not hereditary

Not known

Not known

Maternal-linked recessive, 25% risk of affected child, 50% risk of carrier in women

Not known, probably multifactorial

Sexual hair

Normal female

Normal female

Normal female

Absent or sparse

Hirsutism with male pattern distribution

Testosterone

Normal female

Normal female

Normal female

Normal male range

High normal female range

Other anomalies

None

Frequent, mostly urinary

Frequent, mostly urinary

Rare

None

Gonadal neoplasia

Normal incidence

Normal incidence

Normal incidence

5% incidence of malignant tumor

Normal incidence

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Section 3 Adult Reproductive Endocrinology karyotype lethal. Nearly all males and half of the females with X autosome translocations are sterile.10 Turner’s Syndrome

It is known that specific genes in the X chromosome are essential for normal functioning of the ovaries.11 It appears that both X chromosomes with normally functioning genes need to be present in the oocytes to prevent the formation of a streak gonad. Turner’s syndrome (45,XO) is the most common cause of gonadal dysgenesis. It is usually caused by nondisjunction of the sex chromosomes and occurs in approximately 1 out of 2500 live births. In some cases, Turner’s syndrome occurs in patients with normal karyotypes (46,XX) when a genetic abnormality results in one of the X chromosomes not being fully functional. The characteristic physical features common to females with Turner’s syndrome include short stature, somatic abnormalities (webbed neck, shield chest, increased angle at the elbow known as cubitus valgus, cardiovascular abnormalities), and prepubertal status associated with elevated gonadotropins.12 Patients with Turner’s syndrome require special attention to the autoimmune disorders and renal anomalies that are frequently found with the condition. All patients with Turner’s syndrome should seek expert cardiology consultation and screening, including chest X-ray and echocardiography, at the time of diagnosis. Annual cardiac examinations, including evaluation of blood pressure, and repeated screening at 3- to 5-year intervals if the initial screening reveals no abnormalities. When the cardiac echo is abnormal or the ascending aorta cannot be visualized, magnetic resonance imaging (MRI) of the chest should be performed in all patients.12 Due to the absence of one of the X chromosomes, these patients have streak gonads with complete lack of ovarian follicle development. The absence of sex hormone production from the ovary in early adolescence results in the absence of puberty and primary amenorrhea. Patients with variations of the syndrome can present with some clinical features but not all of the characteristic physical findings. For this reason, Turner’s syndrome should be suspected in every adolescent with primary amenorrhea, sexual infantilism, and poor growth during the teenage years. If the serum FSH is elevated in such a patient, a karyotype should be obtained. Even if the FSH is normal, a karyotype should be obtained to rule out mosaicism in adolescents with poor growth after puberty (i.e., 25% of ideal body weight), body image disturbances, and an intense fear of becoming overweight and refusal to take action to increase the weight. The overall incidence of anorexia ranges from 0.64 per 100,000 to 1.12 per 100,000. It is extremely important for the clinician to recognize early signs of these disorders so that appropriate intervention and treatment can be obtained. The mortality associated with anorexia is as high as 9%, usually secondary to cardiac arrhythmia precipitated by electrolyte abnormalities and diminished heart muscle mass. Suicide is also more common. The clinical features of bulimia and anorexia are listed in Tables 16-8 and 16-9.

Table 16-8 Common Features of Bulimia

Anorexia nervosa is associated with multiple neuroendocrine abnormalities (Table 16-10). As a result of decreased caloric intake, thyroxine (T4) conversion to triiodothyronine (T3) is decreased, resulting in lowered basal metabolism. As a result, thyroxine is converted to an inactive isoform, reverse triiodothyronine (reverse T3). Profound hypothalamic dysfunction is manifest by hypothermia and impaired secretion of vasopressin that can result in partial diabetes insipidus with the inability to concentrate urine. Hyperactivation of the HPA axis results in hypersecretion of cortisol, but manifestations of hypercortisolism are rarely present due to number of decreased cellular glucocorticoid receptors. These patients also have increased central opioid activity. Bulimia and anorexia result in a prepubertal pattern of LH similar to patients with functional hypothalamic amenorrhea secretion, presumably due to a marked decrease in GnRH secretion. With weight gain, patients with anorexia will resume Table 16-9 Common Features of Anorexia Nervosa Preoccupation with handling of food Bulimic behavior Calorie counting Distortion of body self-image Hyperactivity Obsessive-compulsive personality Increased incidence of past sexual abuse Amenorrhea Constipation Coarse, dry skin Soft, lanugo-type hair Hypothermia with defective thermoregulation Mild bradycardia Cardiac arrhythmias Hypotension Hypokalemia secondary to diuretic or laxative abuse Osteopenia Increased serum beta-carotene levels Anemia, leukopenia Elevated hepatic enzymes

Table 16-10 Neuroendocrine Abnormalities Associated with Anorexia Nervosa Diminished GnRH LH pulsatile frequency and amplitude Low blood LH and FSH levels Impaired corticotropin response to CRH stimulation testing

Irregular menstrual cycles

Resistance to dexamethasone suppression

Dental enamel erosion

Increased corticotropin levels

Enlargement of salivary glands

Increased 24-hour urinary free cortisol levels

Acute irritation of esophageal mucosa

Normal prolactin level

Esophageal or gastric rupture

Normal TSH levels with high reverse T3 and low T3 levels

Hypokalemia

Elevated GH levels

Aspiration pneumonia

Decreased IGF-I levels

Ipecac poisoning

Diabetes insipidus

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Section 3 Adult Reproductive Endocrinology normal patterns of LH secretion and may have normal or supranormal responses to GnRH. Despite return to normal body weight, up to 50% remain anovulatory. As in all energy deprivation states, leptin plays a critical role in the disruption of the hypothalamic function that results in amenorrhea. Leptin is a protein hormone secreted by adipose tissue and has an important role in adaptation to starvation. Leptin-deficient ob/ob mice and leptin-resistant db/db mice show obesity and hypogonadotropic hypogonadism. However, the principal role of leptin is in caloric deprivation; it acts as the signal from the periphery to the brain about energy deficit. This energy deficit is signaled to the hypothalamicpituitary axis through decreased leptin levels. Leptin may have a role in the other neuroendocrine abnormalities such as thyroid and insulin-like growth factor-I (IGF-I) seen in anorexics and in other energy-deficient states such as excessive exercise.29 Evaluation of Hypothalamic Amenorrhea

Because this is a diagnosis of exclusion, significant organic diseases must be excluded (see Table 16-2). A detailed interview may identify a stressful event or emotional crisis (divorce, relationship breakup, death of a friend or relative) preceding the amenorrhea. Other interpersonal and environmental stressors may also be present, such as academic pressures, job stresses, or psychosexual problems. A careful review of the patient’s current lifestyle, including exercise intensity, dietary choices, and the use of sedatives or hypnotics, may be helpful in characterizing the psychogenic stress components.30 Patients with hypothalamic amenorrhea will have a history of normal menarche and regular menstrual cycles between 26 and 35 days in length. These women typically are intelligent, highachievers who are usually thin or of normal body weight. The physical examination should focus on identifying galactorrhea, thyroid dysfunction, and evidence of hyperandrogenemia (i.e., acne, hirsutism). Oral examination may identify the peculiar dentition or enlarged salivary glands of a bulimic patient. The pelvic examination should be normal except for a thinned vaginal mucosa or absent cervical mucus, which are characteristics of hypoestrogenism. Despite these findings, these patients do not usually experience hot flushes. Laboratory evaluation should include measurement of serum LH, FSH, prolactin, thyrotropin, and estradiol. LH and FSH can be either low or normal, and estradiol levels will be either low or within the lower limits of normal. Most of the other pituitary hormones should be in the normal range. In many patients, the progestin challenge test (medroxyprogesterone acetate 10 mg for 7 days) will not result in uterine bleeding. This test is a bioassay for the absence of estrogen priming of the endometrium and reflects the low circulating levels of estradiol. Clinical Management of Hypothalamic Amenorrhea

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The first step in clinical management is to identify and treat environmental stressors. Appropriate support and counseling often helps patients develop coping mechanisms that allow them to live healthier lifestyles. In patients with eating disorders and in many athletes, dietary consultation is extremely helpful. After lifestyle modification, spontaneous recovery of menstrual function will occur in 70% to 80% of patients. For patients

who continue to have oligomenorrhea, periodic evaluation of menstrual status every 4 to 6 months is prudent. The primary medical concerns for these patients are infertility and bone loss. Athletes have been characterized as having the “female athlete triad” of amenorrhea, osteoporosis, and eating disorders. Management of these patients should emphasize measurement of bone density, dietary and psychological counseling, weight change, and calcium intake. One goal of therapy may be to decrease the level of exercise, improve the diet, and achieve weight gain. For others, exercise may not induce amenorrhea but may be associated with longer menstrual cycles, luteal phase defects, and intermenstrual spotting. These reproductive defects may be reversible with a decrease in exercise level or intensity. Infertility

In patients who desire fertility but fail to resume normal cycles, ovulation induction is indicated. Clomiphene citrate (25 to 50 mg for 5 days) can be attempted, but this approach will rarely induce ovulation in patients with hypothalamic amenorrhea. In contrast, human menopausal gonadotropin is usually highly successful for inducing ovulation. These patients are generally exquisitely sensitive to human menopausal gonadotropins, and thus treatment should be started at the lowest dose. Some centers use a modified insulin pump to administer intravenous pulsatile GnRH at a dose of 5 μg every 90 minutes. This approach will successfully induce ovulation after a 13- to 14-day treatment period. Pump therapy is associated with ovulation rates of greater than 90%, with generation of a single dominant ovarian follicle in most cases, and lower rates of ovarian hyperstimulation. After ovulation, the corpus luteum should be supported with either GnRH or human chorionic gonadotropin (1500 units intramuscularly or 2500 units subcutaneously) every 3 days for four doses. Supplemental progesterone can also be used. Bone Loss

The greatest long-term health risk is bone loss that can put the patient at risk for osteoporosis, particularly later in life. In athletes with hypothalamic amenorrhea, the type of exercise activity significantly affects the overall osteogenesis. In young women with persistent hypoestrogenism, the bone mass can decrease at a rate of 2% to 5% per year for the first 3 to 5 years. The primary cause of bone loss in these patients is hypoestrogenemia, and thus patients not desiring fertility will benefit from hormone replacement therapy. Bone loss is most sensitive to estrogen.31,32 Although several forms of hormone replacement have been described, placing young women on oral contraceptives has been the treatment of choice. Although many women prefer to have menses in association with hormone replacement, athletes who find this to be inconvenient can be safely kept on continuous hormone replacement or birth control pills. Periodic measurements of mineral bone density are worthwhile to monitor the progress of patients both from a dietary and hormone replacement point of view. Dual energy X-ray absorptiometry (DEXA) is often helpful in convincing patients to begin estrogen therapy. The use of bisphosphonates in women of reproductive age should be carefully considered, given their accumulation in bone and unknown effects on a fetus in cases where fertility is being sought.

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Chapter 16 Amenorrhea Treatment of Anorexia Nervosa

Therapeutic approaches to anorexia nervosa include behavior modification, group therapy, and individual psychotherapy. Generally, a team approach consisting of a psychiatrist and a general medicine specialist with expertise in eating disorders is desirable. Because of the high mortality rate and the significant morbidity associated with anorexia, it is important to obtain psychiatric consultation and follow-up in all patients with eating disorders. The long-term success rates for treatment of anorexia nervosa and bulimia remain low. Postcontraception Amenorrhea

Amenorrhea after long-term contraception use remains a concern, but the issues of concern have changed. In the past, use of highdose (>50 μg ethinyl estradiol) oral contraceptives was associated with prolonged amenorrhea after discontinuation. With modern low-dose oral contraceptives, amenorrhea is uncommon, but reversible cycle disturbances after discontinuing oral contraceptives can last up to 9 months or longer.33 Fortunately, oral contraceptives do not affect fertility in the long term. Amenorrhea that continues more than 2 months after discontinuation of an oral contraceptive should trigger an investigation for other causes of amenorrhea. A more common problem has become amenorrhea after the intramuscular use of medroxyprogesterone acetate (Depo-Provera) for contraception. Amenorrhea is common after discontinuation of this type of contraception, and the return to baseline fertility takes an average 10 months.34 For this reason, investigation for amenorrhea after discontinuation of depot medroxyprogesterone should be limited until 12 months after the last injection.

Hyperandrogenic States Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is one of the most common causes of ovulation dysfunction (see Chapter 19). Although this complex syndrome has a wide range of clinical manifestations, amenorrhea was one of the primary manifestations first described by Stein and Leventhal in 1935 along with infertility and enlarged ovaries.35 Contemporary series suggest that only about 25% of patients with PCOS will have amenorrhea.36 The pathology, diagnosis, and treatment of PCOS is discussed in depth in Chapter 15. Other Hyperandrogenic States

Other hypoandrogenic states that mimic PCOS can also result in amenorrhea. Probably the most serious of these conditions are ovarian and adrenal tumors. Likewise, Cushing’s syndrome can cause amenorrhea secondary to increased androgens. Another cause is adult-onset congenital adrenal hyperplasia. The basis of the workup to exclude these conditions includes measurement of serum androgens, including total testosterone, DHEAS, and 17-hydroxyprogesterone. Imaging of the ovaries and, in some cases, adrenal glands is also important. This details of this evaluation are given in Chapter 18.

Disorders of the Anterior Pituitary Pituitary tumors commonly interfere with normal reproduction. Small pituitary tumors can present clinically as irregular or

absent menses or galactorrhea. Less commonly, large pituitary tumors manifest as headaches and compression of the optic chiasm and bitemporal hemianopsia related to their growth in a confined anatomic space. The most common pituitary tumor is the prolactin-secreting adenoma, which accounts for almost 70% of all pituitary adenomas. The second most commonly encountered pituitary tumor is a nonfunctioning pituitary adenoma, which constitutes at least 25% of all pituitary tumors. Less common pituitary tumors secrete growth hormone, corticotropin, thyrotropin, FSH, or LH. These tumors increase prolactin levels by compressing the pituitary stalk and interfering with the release of dopamine, which acts as a prolactin inhibiting factor. Amenorrhea results in addition to diseases caused by other pituitary tumors, including acromegaly (growth hormone-secreting tumors), Cushing’s disease (corticotropin-secreting tumors), or hyperthyroidism (thyrotropin-secreting tumors). Diagnosis and management of these tumors is discussed in depth in Chapter 22. Prolactin-Secreting Adenomas

Prolactin-secreting adenomas are the most common pituitary tumors, accounting for half of all pituitary adenomas found at autopsy. Classification has been attempted by a variety of different histologic findings; however, the most useful form of classification is according to function. Hyperprolactinemia is associated with decreased estradiol concentrations as well as amenorrhea or oligomenorrhea. In women with hyperprolactinemia, the prevalence of pituitary tumor is 50% to 60%,37 and the likelihood of a pituitary tumor is unrelated to the level of prolactin found.37 The poor correlation between tumor size and serum prolactin indicates that MRI or computed tomography (CT) scanning of the pituitary should be performed whenever serum prolactin levels are consistently elevated.38 Although the exact incidence of these tumors is unknown, autopsy series have shown the presence of microadenomas to range from 9% to 27%.39,40 The distribution of these types of tumors appears equal among gender. Empty Sella Syndrome

This syndrome refers to a congenital incompleteness of the diaphragm of the sella turcica, allowing for extension of the subarachnoid space into the pituitary fossa. This can also occur secondary to surgery, radiation therapy, or infarction of a pituitary tumor. This anatomic abnormality is found in approximately 5% of autopsies, with a high predominance in women. Empty sella is found in 4% to 16% of patients with amenorrhea-galactorrhea.41 Galactorrhea and elevated serum prolactin levels can be seen. Annual surveillance with serum prolactin levels is sufficient since they rarely develop prolactinomas. The purpose of treatment is alleviation of symptoms. Postpartum Pituitary Necrosis (Sheehan’s Syndrome)

Postpartum pituitary necrosis is usually preceded by a history of severe obstetrical hemorrhage with hypotension, circulatory collapse, and shock.42 After fluid resuscitation of the patient, this condition may be manifested by clinical evidence of partial or panhypopituitarism. Simmonds was the first to describe this clinical syndrome although the most complete description has been attributed to Sheehan. This condition constitutes an endocrine emergency that can be life-threatening.

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Section 3 Adult Reproductive Endocrinology The pathophysiology of this process is not entirely clear. With pregnancy, there is an increase in blood supply to the pituitary bed and the pituitary gland enlarges. During the period of profound hypotension, Sheehan postulated that occlusive spasm of the arteries that supply the pituitary and stalk occurs. This leads to venous stasis and thrombosis of the pituitary portal vessels, causing a variable degree of pituitary ischemia and cell death. Many patients initially present with a failure to have breast engorgement and lactation due to a deficiency in prolactin secretion. These women may also have other anterior pituitary deficiencies. The posterior pituitary is usually spared because it is less dependent on the portal blood supply. In some patients, the absence of corticotropin secretion leads to inadequate cortisol secretion, resulting in postural hypotension, nausea, vomiting, and lethargy. Hypothyroidism may be noted later in this syndrome. Recovery of pituitary function has been reported in a few cases. Post-traumatic Hypopituitarism

This condition can arise after severe head trauma as a result of a sudden deceleration of the head and occult damage to the pituitary stalk or hypothalamus during a motor vehicle accident. Trauma may also be associated with a basal skull fracture or an episode of unconsciousness. These individuals will often manifest a delay from injury to presentation and may display evidence of partial hypopituitarism or panhypopituitarism. These symptoms can include amenorrhea, galactorrhea, hypogonadism, loss of axillary and pubic hair, anorexia, and weight loss. In these patients, evaluation of adrenal function is most critical because adrenal failure is life-threatening. The diagnostic evaluation and management is similar to that described for Sheehan’s syndrome. Pituitary Apoplexy

This medical emergency is characterized by an acute infarction of the pituitary gland. Patients will complain of a sudden onset of a severe retro-orbital headache and visual disturbances that may be accompanied by lethargy or loss of consciousness. These symptoms may mimic other neurologic emergencies such as hypertensive encephalopathy, cavernous sinus thrombosis, ruptured aneurysm, or basilar artery occlusion. CT or MRI may indicate hemorrhagic changes in the pituitary sella region. Patients with pituitary tumors are at higher risk for this complication. For some patients, neurosurgical consultation and emergency decompression may become necessary. Provocative testing as described for Sheehan’s syndrome should be performed to evaluate for multiple pituitary deficits. Appropriate replacement of target tissue hormones should be instituted based on testing. Postirradiation Hypopituitarism

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Exposure to therapeutic radiation sources for treatment of midline tumors of the central nervous system can place patients at increased risk for delayed development of hypopituitarism. In general, sensitivity to radiation is greatest for gonadotrophs, followed by corticotrophs and thyrotrophs. The onset of pituitary deficiencies may be insidious but can occur within 1 year of radiotherapy. Periodic assessment of hypothalamic-pituitary function should be performed for an indefinite period of time, and appropriate replacement hormone therapy should be instituted as these deficiencies develop.

Evaluation of Pituitary Adenomas

The clinical manifestations of these adenomas are usually more obvious in women, due to the disruption of menses. The most common symptoms of a prolactin-secreting adenoma in women are galactorrhea, irregular periods, headaches, and infertility. Men can experience hypogonadism due to these tumors, but the tumors are usually large and produce high serum prolactin levels. Approximately one third of women with amenorrhea will have elevated prolactin levels; one third of women with galactorrhea and elevated prolactin levels will have normal menses and one third of women will have a high prolactin level without galactorrhea.43 As many as a third of patients with secondary amenorrhea will have a prolactinoma and when associated with galactorrhea, half of the patients will have normal findings on imaging of the sella turcica.43,44 The apparent clinical difficulty in associating clinical symptoms, laboratory values, and sella turcica imaging is the fact that there is tremendous variability in the detection of prolactin in clinical assays. The immunoreactivity of clinical assays usually detects the small form of prolactin, which also has more biologic activity. Big forms of prolactin can also be secreted by pituitary adenomas and, since this prolactin type cannot usually be detected by the immunoassays, the diagnosis of a pituitary adenoma may be missed. Therefore, whenever the clinical scenario of galactorrhea is present, particularly in a patient with irregular menstruation, imaging of the pituitary gland must be considered and clinical intervention should be instituted.45,46 Some patients with high serum prolactin levels can also have what is referred to as a “high-dose hook effect” where large amounts of prolactin prevent accurate assessment by the immunoassay. Dilutions of serum samples are able to detect the abnormality.47 The mechanism by which prolactin causes oligomenorrhea and amenorrhea is due to the inhibition of pulsatile secretion of GnRH by elevated prolactin.48,49 The measurement of thyrotropin should be included as part of the evaluation. Although prolactin levels associated with hypothyroidism are generally less than 100 ng/mL, these levels can induce galactorrhea. Hyperprolactinemia in hypothyroidism is the result of increased thyrotropin-releasing hormone (TRH) stimulation of the pituitary gland. TRH is a potent stimulant of prolactin-secreting cells. The extent of pituitary deficiencies can be characterized by provocative testing with combined intravenous injection of the hypothalamic releasing factors GnRH, TRH, growth hormone releasing hormone, and CRH.50 Management of Pituitary Adenomas

The use of dopamine agonists such as bromocriptine lowers the circulating levels of prolactin and restores the normal response of the ovary to gonadotropins and restores normal menstrual function. The treatment with bromocriptine, a dopamine agonist, inhibits pituitary prolactin secretion. This medication is associated with many side effects; 10% of patients cannot tolerate the medication and will discontinue it. Most patients complain of nausea, headache, and faintness, usually due to orthostatic hypotension. Other side effects include dizziness, fatigue, nasal congestion, vomiting, and abdominal cramps, which can be diminshed by starting the patient on a low dose of the medication and slowly increasing it. Some patients can benefit from vaginal administration of bromocriptine to avoid the

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Chapter 16 Amenorrhea gastrointestinal side effects.51 Vaginal administration is effective largely by avoiding the first pass through the liver. There is no evidence that bromocriptine harms the fetus. However, most clinicians recommend discontinuing the medication during pregnancy.52 More than 80% of patients with amenorrhea and galactorrhea in association with hyperprolactinemia will have their menses restored 5 to 7 weeks after therapy is started.53 The cessation of galactorrhea is much slower than the restoration of menses, and complete cessation of galactorrhea occurs in half of patients after 4 months of use. Up to 75% of patients who stop the treatment will develop symptoms again.54 It is possible for macroadenomas to regress with bromocriptine treatment, but it requires higher doses and a longer period of use. Most patients have a rapid shrinkage in the first 3 months of therapy followed by a slower reduction.55 Patients who initially present with serum prolactin levels over 1000 ng/mL have tumors that invade into their cavernous sinuses. These individuals usually have inoperable tumors and require long-term suppression with dopamine agonists. Bromocriptine can also be used for patients who have failed surgery and radiation therapy. Cabergoline is an alternative to bromocriptine. Side effects seem to develop less frequently and the medication is taken once or twice weekly. Due to a limited experience on fetal safety, this agent should be used with caution in patients who are trying to conceive.56-58 Transsphenoidal surgery has also been used to treat pituitary adenomas. Symptom resolution is achieved in 30% of patients with macroadenomas and 70% of patients with microadenomas; this is highly dependent on the experience of the neurosurgeon.59 Tumor recurrence is high, especially after surgery for macroadenoma. Potential postoperative complications include panhypopituitarism, meningitis, cerebrospinal fluid leaks, and diabetes insipidus. The high success rate of medical therapy, recurrence of disease, and potential complications of surgery have limited the use of surgical intervention to patients who have failed medical therapy. Radiation therapy is less satisfactory than surgery for the treatment of pituitary adenomas, and the response is very slow. Under specific circumstances radiation can be delivered with a gamma knife procedure. Patients who respond to treatment of hyperprolactinemia can breast-feed if desired and usually can experience normal lactation without fear of tumor growth. There is only a small chance of growth of most pituitary tumors during pregnancy. Up to 5% of patients will have tumor enlargement, which is usually asymptomatic; less than 2% will develop symptoms.60 Most symptomatic patients present with headaches, which usually precede any visual abnormalities. During pregnancy there is normal pituitary growth, typically due to the increased size of the prolactin-secreting cells. Insufficient blood supply to the adenoma may cause this infarct. Occasionally patients may have restoration of normal menses from tumor infarction in pregnancy or postpartum. Surveillance during pregnancy with monthly visual field examinations or serum prolactin measurements has not been clinically useful. Patients who become symptomatic should be assessed and treated. Most patients will respond to bromocriptine, and it is very uncommon to require termination of pregnancy or neurosurgery.61 Dopamine agonists used during pregnancy do not affect decidual secretion of prolactin, which is under control of estrogen and progesterone rather than dopamine.

Cushing’s Disease and Acromegaly

Although amenorrhea and/or galactorrhea are usually encountered with pituitary prolactinomas, these symptoms may also precede corticotropin- or growth hormone-secreting tumors. If the patient presents clinical symptoms of glucocorticoid excess suggestive of Cushing’s disease, a corticotropin serum level and a 24-hour urine collection for free cortisol should be ordered. Excessive production of growth hormone can rarely occur in children and is referred to as gigantism. In adults excessive production of growth hormone from a pituitary tumor is called acromegaly. After the final height is achieved, the excessive growth of this syndrome is restricted to the acral areas, such as hands, feet, and facial features. Excessive sweating and fatigue are common. If the patient presents with signs and symptoms of acromegaly, a serum IGF-I level is the most appropriate test. This evaluation can be performed on a random blood test. On the contrary, growth hormone levels are only of value if obtained during an oral glucose tolerance test. The expected suppression of growth hormone with a glucose load is not seen. Glucose intolerance and hypertension are commonly found with both acromegaly and Cushing’s disease. Because the initial presentation of acromegaly can be amenorrhea, an elevated serum prolactin level, and a macroadenoma (>10 mm in diameter) on MRI, a serum IGF-I should be obtained in all patients who present with these findings.

Premature Ovarian Failure Premature ovarian failure is defined as amenorrhea with persistent estrogen deficiency and elevated FSH levels before age 40. This affects at least 1% of women.62,63 Most causes of premature ovarian failure are easily identified, such as chemotherapy and radiation therapy for cancer. Premature ovarian failure is usually irreversible, although spontaneous recovery of ovarian function can occur. Premature ovarian failure is a common cause of secondary amenorrhea, accounting for 4% to 18% of cases.64 This topic is examined in depth in Chapter 20. The etiology for the majority of patients with premature ovarian failure is unknown. However, for patients younger than age 30 presenting with amenorrhea, a karyotype should be obtained to rule out sex chromosome translocation, short arm deletions, or persistence of an occult Y chromosome, because these conditions are associated with an increased risk of ovarian malignancies. Some experts recommend that all patients with premature ovarian failure have a chromosomal analysis. However, in patients with amenorrhea secondary to premature ovarian failure, the single most common karyotype is XX (see Table 16-6). Gonadal Dysgenesis

Rare patients with gonadal dysgenesis may go through normal puberty and present with secondary amenorrhea, almost always before age 30. Women with secondary amenorrhea as a result of gonadal dysgenesis will usually have a normal 46,XX karyotype, although some will be found to have deletions, 47,XXX, or 46,XO. Patients who present with gonadal dysgenesis and a normal karyotype need to be assessed for a variety of other conditions, such as neurosensory deafness (Perrault’s syndrome), as well as fragile X syndrome, the most common genetic cause of developmental disorders. About 16% of women who are carriers of the

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Section 3 Adult Reproductive Endocrinology premutation allele for fragile X syndrome experience premature ovarian failure, particularly when familial premature ovarian failure or mental retardation is identified.9 When women with sporadic premature ovarian failure are screened, approximately 3% will be premutation carriers. Some females with premutation alleles may be affected with mild degrees of mental deficiency or learning disability. There is also an association of premature ovarian failure with autosomal-dominant eyelid abnormalities. This is known as blepharophimosis-ptosis-epicanthus inversus syndrome. This syndrome is caused by a mutation in FOXL2, which is a transcription gene factor found on chromosome 3.65,66 Several other autosomal disorders have been associated with ovarian failure; these will produce elevations of FSH without necessarily having oocyte depletion. Some of these include mutations of the phosphomannomutase 2 (PMM2) genes, the galactose-1-phosphate uridyltransferase (GALT) gene, the FSH receptor gene, and the autoimmune regulator gene (ARE), which is responsible for polyendocrinopathy-candidiasis-ectodermal dystrophy.67 Autoimmune Causes

A common form of premature ovarian failure is due to autoimmune disease. Up to 40% of women with premature ovarian failure may have autoimmune abnormalities, most commonly autoimmune thyroiditis resulting in hypothyroidism.68,69 Premature ovarian failure is also more common in women with insulin-dependent diabetes, myasthenia gravis, and parathyroid disease than in healthy women.70 In 10% to 60% of cases of Addison’s disease, autoimmune ovarian failure may also be present. Because these individuals are at increased risk for endocrine autoimmune conditions, patients should be evaluated every other year for occurrence of these abnormalities so early intervention can be achieved. Patients with unexplained premature ovarian failure should have a complete evaluation to exclude other autoimmune disorders; tests to perform include tests for calcium, phosphorus, fasting glucose, adrenal antibodies to 21-hydroxylase enzyme, free T4, thyrotropin, and thyroid antibodies. This evaluation should be repeated on a yearly or every other year basis.71 Screening for antiovarian antibodies is not warranted because the assays have poor sensitivity and specificity. Patients should be screened for adrenal disease with an evaluation for antiadrenal antibodies. If that test is positive, more sophisticated testing such as a corticotropin stimulation test is necessary. A fasting morning serum cortisol is not sufficiently sensitive. Premature Ovarian Failure: Other Causes

246

Although elevated serum FSH levels are virtually synonymous with ovarian disorders, there are uncommon conditions that can raise FSH but are associated not with a primary ovarian problem but a central problem. These include pituitary adenomas that secrete FSH or specific enzyme defects such as 17-hydroxylase deficiency (P450c17) or galactose-1-phosphate uridyl transferase deficiency (galactosemia). There have been a few reports of single gonadotropin deficiency; the measurement of both LH and FSH together will uncover these unusual disorders. In premature ovarian failure you will always find elevations of both hormones; a single elevation is suspicious.72 Most of these abnormalities are due to

single-gene or amino acid substitutions. In these cases, an MRI of the pituitary will also uncover a pituitary adenoma that secretes these hormones, particularly if associated with an elevated α-subunit. However, these tumors are generally not associated with amenorrhea. There can also be mutations of the receptors for gonadotropins; these patients are diagnosed with resistant or insensitive ovary syndrome. These patients generally have secondary amenorrhea with normal secondary sexual characteristics and do not respond to gonadotropins and have small antral follicles on ultrasound.73 Mutations for the human FSH receptor gene have also been identified, both in females74 and males. Females display hypergonadotropic hypogonadism from FSH resistance. The phenotype ranges from absent to normal breast development and primary or secondary amenorrhea. This is a relatively uncommon finding, but is found predominantly in certain populations such as Finland (1% of females are heterozygotes). Mutations of the LH receptor in 46,XX females consist of normal sexual development and amenorrhea.26 Serum LH may be normal to increased, FSH is normal, follicular phase estradiol levels are normal, and progesterone is low. The uterus is small and the ovaries are consistent with anovulation. Diagnosis of Premature Ovarian Failure

The initial screen, as in all cases of amenorrhea, is with serum thyrotropin, prolactin, and FSH levels. The diagnosis of premature ovarian failure is made in the presence of elevated serum FSH, normal serum prolactin, and normal serum thyrotropin. Estradiol will also be decreased, and thus progesterone challenge will not result in withdrawal bleeding. Ovarian biopsies are usually not necessary in patients with premature ovarian failure. The costs and risks of surgical intervention are substantial, and they do not change patient management. A transvaginal ultrasound to assess antral follicle count and ovarian volume may be useful. Management of Premature Ovarian Failure

Patients with ovarian failure should be offered estrogen and progesterone replacement to maintain their secondary sexual characteristics and reduce the risk of osteoporosis. This can be easily achieved with combined oral contraceptives until the age of natural menopause as long as no contraindications to combined oral contraceptives are met. Some women who take lowdose exogenous estrogen therapy with a progestin, who have some ovarian follicles left with premature ovarian failure, can have spontaneous ovulation and conception is possible in rare cases.75

Disorders of the Genital Tract Although disorders of the genital tract are one of the less common cause of secondary amenorrhea, they are usually discovered relatively early in the diagnostic workup. Intrauterine adhesions (i.e., Asherman’s syndrome), although relatively common, accounts for only 7% of women presenting with secondary amenorrhea. Another infrequent cause of amenorrhea is outflow obstruction secondary to cervical stenosis. This is usually due to treatment of cervical dysplasia with modalities such as cryosurgery, electrocautery, or cold knife cone biopsy.

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Chapter 16 Amenorrhea Asherman’s Syndrome

Asherman’s syndrome is commonly used to describe the presence of intrauterine adhesions (or synechiae), most commonly secondary to uterine surgery. Patients are found to have Asherman’s syndrome after undergoing aggressive curettage for postpartum bleeding, after removal of multiple submucosal fibroids, or after metroplasty.76 Recently uterine artery embolization has also been associated with the development of Asherman’s syndrome; although its mechanism is not well understood, it is believed to be secondary to ischemia associated with the embolization procedure.77 Although the syndrome was first described as amenorrhea secondary to intrauterine synechiae, the presence of hypomenorrhea or amenorrhea is not considered a requirement for making this diagnosis today.76,78 Typically, the diagnosis is made when synechiae are seen at the time of a hysterosalpingogram. Adhesions can be isolated or diffuse dense scarring. Amenorrhea is most commonly seen with diffuse scarring. Regardless of bleeding pattern, patients typically have normal ovarian function and normal changes in their basal body temperature. Management of Asherman’s Syndrome

Asherman’s syndrome is treated with hysteroscopy, by lysing the synechiae with scissors, cautery, or laser. To prevent the reformation of adhesions, patients in the past have had an intrauterine device or a pediatric Foley catheter placed inside the uterine

cavity in the postoperative period. More recently, a balloon uterine stent that mimics the normal shape of the uterus has been developed. The balloon is typically kept inside the uterus for 7 to 10 days. Oral antibiotics are administered for variable lengths of time, typically for the length of treatment or a few days more. For patients who complain of cramping, nonsteroidal anti-inflammatory drugs are usually helpful. Although little prospective data are available, most clinicians give the patient 4 to 6 weeks of oral therapy with conjugated estrogens (2.5 mg) to regenerate the endometrium. This is followed by progestin to induce withdrawal bleed. If the initial therapy is unsuccessful, patients sometimes have to undergo multiple surgeries until menstruation is restored. Some authors report a subsequent pregnancy rate of 70% to 80% if menses can be restored, although this is sometimes difficult in severe cases. Patients who become pregnant may be at increased risk for complications, including premature labor, placenta accreta, placental previa, and postpartum hemorrhage.

Diagnostic Approach for Secondary Amenorrhea Evaluation of the woman with secondary amenorrhea begins with a careful history to detect sometimes subtle symptoms of one of a wide variety of conditions that can bring a halt to menses (Fig. 16-2). Physical examination will sometimes give hints of the most likely etiologies. Initial laboratory evaluation is an

History Physical examination

Hirsutism Acne

Laboratory evaluation

Progestin challenge No bleeding

Beta-hCG

TSH

Prolactin

FSH

Estrogen plus progestin challenge No bleeding

(FSH, E2 normal)

Estradiol Positive

Pregnancy

High

Hypothyroidism

Further evaluation required Asherman's Syndrome

High

Low or normal FSH, low E2

High FSH, low E2

Pituitary adenoma Hypothalamic dysfunction

Premature ovarian failure

Testosterone DHEAS 17 hydroxyprogesterone

High

PCOS or other hyperandrogenic condition Figure 16-2

Flow diagram in the evaluation of women with secondary amenorrhea, showing major decision points.

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Section 3 Adult Reproductive Endocrinology important step, not only to exclude physiologic causes of amenorrhea (e.g., pregnancy), but also to detect subtle hormonal conditions that often have no other symptoms or physical signs. Progestin challenge is then used to detect genital tract disorders and hypoestrogenemic states. By the second visit, enough information can be gathered to pursue more directed diagnostic tests to come up with a definite diagnosis.

Laboratory Evaluation

Basic to every history for women with amenorrhea is the menstrual history, sexual activity, and means of contraception. Years of irregular menses suggest PCOS but do not exclude pregnancy. Several modern means of contraception are prone to iatrogenic amenorrhea. In young women, eating and exercise habits must be explored. Although hypothalamic amenorrhea is common in underweight young women, so is unintended pregnancy. Young women are also at greater risk for premature ovarian failure related to abnormal karyotype. Genital tract disorders will almost always be accompanied by a history of gynecologic surgery, especially after a pregnancy. However, postpartum hemorrhage necessitating uterine curettage also brings up the possibility of Sheehan’s syndrome. The history should identify subtle symptoms of endocrinologic or systemic disorders, such as vaginal dryness associated with premature ovarian failure, galactorrhea often associated with hyperprolactinemia, and the increased hair growth often seem in women with PCOS. Systemic diseases often have associated symptoms, such as the weight gain associated with both hypothyroidism and Cushing’s syndrome. Acne and increased midline hair are often signs of hyperandrogenic conditions such as PCOS or adult-onset congenital adrenal hyperplasia. Clearly, many of these symptoms overlap and it is often tempting to prematurely jump to the diagnosis in a patient with classic symptoms of a common disorder. For this reason, it is important to let the history guide the additional tests, while not omitting parts of the basic workup.

All patients presenting with secondary amenorrhea should have an initial set of laboratory studies, including a pregnancy test and thyrotropin, prolactin, and FSH levels. A positive pregnancy test will initiate a workup for pregnancy to determine location and viability. Elevated thyrotropin or prolactin levels indicate a need to evaluate the patient further for hypothyroidism or pituitary adenoma, respectively. The results of the FSH measurement must be determined in relationship to other test results. An elevated FSH is an indication for further evaluation for premature ovarian failure. A normal or low FSH can be normal in patients with PCOS, and these patients will normally have withdrawal bleeding after a progestin challenge. In the presence of hypoestrogenemia as evidenced by low serum estradiol and failure to bleed after progestin challenge, either a low or normal FSH are abnormal and require an evaluation for hypothalamic disorders. Evaluation of androgens is indicated in women with amenorrhea and any sign of androgen excess such as hirsutism or acne. Although many women with PCOS will have modestly elevated androgens (see Chapter 15), the most important objective of measuring androgens in women with apparent PCOS is exclusion of other causes of hyperandrogenic amenorrhea, most notably androgen-producing tumors of the ovary and adrenal glands, Cushing’s syndrome, and adult-onset adrenal hyperplasia. Some women with elevated androgens will have minimal signs. This uncommon situation should be considered in women who do not appear to be hypoestrogenemic but do not bleed after progestin challenge. Evaluating both estradiol and androgen levels in these patients can sometimes help make the diagnosis.

Physical Examination

Progestin Challenge Test

The physical examination will often give obvious or subtle hints of the underlying cause of secondary amenorrhea. Patients with PCOS will often be overweight with increased hair on the upper lip, chin, chest, and inner thighs. These signs tend to occur at the time of menarche and are more pronounced in adolescents with adult-onset congenital adrenal hyperplasia. Sudden and dramatic hirsutism suggests an ovarian or adrenal tumor. Short stature and Turner’s syndrome can suggest premature ovarian failure with a genetic basis. Endocrinologic and systemic diseases often, but not always, have classic signs. Galactorrhea on breast examination suggests hyperprolactinemia, although only one third of women with elevated prolactin level will have this finding. Cushing’s syndrome is often associated with central obesity, moon face, abdominal striae, and “buffalo hump.” Gynecologic examination is occasionally illustrative in women with secondary amenorrhea. During speculum examination, significant stenosis of the external cervix or vaginal atrophy associated with hypoestrogenemia can be obvious. Bimanual examination will often detect the enlarged uterus of pregnancy, but less commonly the bilaterally enlarged ovaries seen in PCOS.

A traditional step early in the evaluation of secondary amenorrhea is the progestin challenge test. With a normal outflow tract and the presence of normal levels of circulating estrogen, menses will usually be induced by administering synthetic or natural progesterone. This can be in the form or medroxyprogesterone 10 mg a day for 7 days, intramuscular progesterone in oil 200 mg, or micronized progesterone 200 mg once a day for 7 days. Any amount of bleeding or spotting that occurs up to 7 days after the last progestin pill is considered to be a normal progestin challenge. Lack of withdrawal bleeding after a progestin challenge requires further evaluation. If not already evaluated, determination of serum FSH and estradiol is important to exclude premature ovarian failure or occult hypothalamic amenorrhea. Even in women with no clinical signs of androgen excess, serum total testosterone and DHEAS should be measured, because high levels of androgens can result in endometrial atrophy, thus preventing withdrawal bleeding. Failure to bleed after a progestin challenge is usually the result of estrogen deficiency or Asherman’s syndrome. To differentiate between these two, the patient should be pretreated

History

248

As with the history, the physical examination should be used to guide the accessory tests. However, because many causes of secondary amenorrhea will not be obvious on physical examination, a comprehensive, stepwise approach to the basic workup is important.

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Chapter 16 Amenorrhea with estrogen (e.g., conjugated estrogens 1.25 mg daily for 6 to 8 weeks) and the progestin challenge should be repeated. Patients who do not bleed after administration of both estrogen and progestin are likely to have an anatomic problem that is preventing menses.

●

●

Imaging

Transvaginal ultrasound is perhaps the most common modality used to image the pelvic organs. In patients with secondary amenorrhea, this approach will rarely be helpful. Polycystic ovaries can often be seen in patients with PCOS. However, their absence does not exclude this diagnosis. Most anatomic abnormalities that cause amenorrhea, such as intrauterine adhesions, are difficult to see by ultrasound. Saline infusion sonohysterogram is more accurate. Hysterosalpingogram is typically used to visualize intrauterine adhesions. However, it should be performed in the evaluation of secondary amenorrhea only in patients who have a history of a predisposing factor.

●

●

●

●

Surgical Evaluation

The etiology of secondary amenorrhea can usually be determined without surgical evaluation. In some cases, diagnostic hysteroscopy may be necessary to assess the endometrial cavity when imaging modalities give ambiguous results.

●

●

PEARLS ●

The most common causes of primary amenorrhea are gonadal dysgenesis (almost half of all cases), müllerian agenesis (i.e.,

●

congenital absence of the uterus and vagina), hypothalamic disorders, and constitutional delay of puberty. The most common causes of secondary amenorrhea are premature ovarian failure, hyperprolactinemia, hypothalamic amenorrhea, and PCOS. The investigation of amenorrhea starts with three serum hormonal measurements: FSH, thyrotropin, and prolactin. Women with disorders of the genital tract (e.g., müllerian anomalies) have normal serum FSH, thyrotropin, and prolactin levels. The differential diagnosis for a blind vaginal pouch include müllerian agenesis and androgen insensitivity syndrome. Approximately 30% of patients with müllerian anomalies will have urinary tract anomalies, such as pelvic kidney, horseshoe kidney, unilateral renal agenesis, hydronephrosis, and ureteral duplication. Another 10% to 12% will have skeletal anomalies mostly associated with the spine. Forty percent of cases of primary amenorrhea have gonadal dysgenesis, and at least half of these patients have abnormal karyotypes. The diagnosis of Turner’s syndrome should be suspected in every young woman with sexual infantilism or poor growth after puberty, because these patients can present without the characteristic physical findings. The most common symptoms of a prolactin-secreting adenoma in women are galactorrhea, irregular periods, headaches, and infertility. Causes of hypothalamic amenorrhea are often related to energy deprivation syndromes, such as anorexia or stress.

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Chapter 16 Amenorrhea 77. Davies C, Gibson M, Holt EM, Torrie EPH: Amenorrhea secondary to endometrial ablation and Asherman’s syndrome following uterine artery embolization. Clin Radiology 57:317–318, 2002.

78. Asherman JC: Amenorrhoea traumatica (atretica). J Obstet Gynecol Br Empire 55:23–30, 1948.

USEFUL WEB SITES • Asherman’s syndrome: An excellent source of information for physicians, families, and patients can be found at http://www.ashermans.org/. • An interesting internet site for patients with müllerian anomalies can be found at http://health.groups.yahoo.com/group/MullerianAnomalies/. Another patient resource can be found at http://www.inletmedical.org/ html/uterine_abnormality.htm. • An excellent resource is the Androgen Insensitivity Syndrome Support Group, which can be accessed at www.medhelp.org/www/ais/.

• A very strong patient advocacy group for patients with Turner’s syndrome can be found at http://www.turner-syndrome-us.org/. • An excellent support group for patients who are XY females is http://www.xyxo.org/. • An excellent link to patient support groups, literature, and ongoing research studies in premature ovarian failure can be found at http://www.pofsupport.org/.

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17

Lactation and Galactorrhea Elizabeth Ann Kennard and Elizabeth M. Hurd

INTRODUCTION Lactation is one of the most important physiologic processes necessary for the survival of mammalian offspring in the absence of human intervention. Breast milk contains species-specific nutrients and immune factors that allow for the appropriate growth and development of newborns. For breastfeeding to be successful, the mammary glands must develop and transform into milk-producing organs by a hormone-driven process referred to as lactogenesis. An understanding of this process has taken on increasing importance as the tremendous benefits of breastfeeding have become widely known in the past two decades. Galactorrhea, in its broadest sense, refers to the spontaneous flow of milk from the nipple at any time other than during breastfeeding. Derived from the Greek, galactorrhea literally means “milk flow.” Physiologic galactorrhea is experienced by many pregnant women late in gestation, as well as during the first few weeks or months after delivery when not breastfeeding or after cessation of breastfeeding. Clinically, the term galactorrhea is used to refer to abnormal or inappropriate secretion of breast milk or a milklike fluid. This term often applies to milk secretion that occurs more than 6 months after either cessation of breastfeeding or delivery when not breastfeeding or in a woman who has never been pregnant. However, it is important to be aware that nonphysiologic galactorrhea has no universally agreed-upon definition. Nonphysiologic galactorrhea can span the continuum from an incidental finding on examination to a significant social problem for the patient. The discharge may be unilateral or bilateral and it may occur spontaneously or only with nipple stimulation. Galactorrhea must be differentiated from a nipple discharge other than milk. The etiology can be idiopathic or related to any of a number of potentially serious underlying or iatrogenic causes. This chapter begins with a review of the normal physiology of the breast and lactation. The various etiologies of pathologic galactorrhea are discussed, followed by a discussion of evaluation, treatment, and long-term prognosis for women with this problem.

PROLACTIN A thorough comprehension of prolactin is required to understand both lactation and galactorrhea. Prolactin is responsible for the primary endocrine control of breast secretions, although multiple other hormones also influence breast milk production. Prolactin is a 198-amino acid polypeptide hormone secreted in pulsatile fashion from the anterior pituitary (adenohypophysis) by

specific cells referred to as lactotrophs.1 These cells have a common origin with the growth hormone-secreting cells (i.e., somatotrophs). Both prolactin and growth hormone are classified as somatomammotropic hormones based on their structural similarities. Due to its structural similarity to growth hormone, prolactin was the last pituitary hormone to be isolated. Prolactin has a short half-life of only 20 minutes and exists in heterogeneous forms, including big prolactin, a dimeric glycosylated form, and big big prolactin.2,3 Secretion has a circadian rhythm, with a higher average level of serum prolactin during sleep, especially during the rapid eye movement phase. The prolactin receptor is a member of the cytokine receptor family. It is a single transmembrane polypeptide found in multiple tissues in addition to the mammary glands, including the liver, adrenal glands, lungs, testes, and ovaries.4 The effects of prolactin in many of these tissues remains unknown.5

Neuroendocrinology of Prolactin Secretion The control of prolactin secretion by the anterior pituitary lies within the hypothalamus and is predominantly inhibitory. However, the hypothalamus releases both prolactin-inhibiting factors (PIF) and prolactin-releasing factors (PRF) that modulate the secretion of prolactin.6 Prolactin-inhibiting factors are released by the hypothalamus into the hypothalamo-hypophyseal portal system. Although other compounds have been shown to have inhibitory activity, dopamine appears to be the most important PIF.7 Interruption of the tuberoinfundibular tract and blocking dopamine receptors with “gene knockout” techniques both result in high prolactin levels.8 Gonadotropin-associated peptide and γ-aminobutyric acid are also PIFs.9 Prolactin secretion is regulated by a negative feedback loop wherein prolactin, acting via prolactin receptors in the median eminence, stimulates dopamine secretion.10 Dopamine acts via the adenylyl cyclase pathway to reduce prolactin secretion from the pituitary lactotrophs. The predominant dopamine receptor in the adenohypophysis is D2 (DRD2). Binding of dopamine to this receptor decreases cellular adenylyl cyclase activity and cyclic adenosine monophosphate. Although the major control mechanism for prolactin is inhibitory, the hypothalamus also releases PRFs, which stimulate lactotrophs to secrete prolactin (Table 17-1). The primary physiologic PRF appears to be vasoactive intestinal peptide. However, there appear to be two more clinically relevant PRFs.11,12 The ability of thyrotropin-releasing hormone (TRH) to act as a PRF is believed to be the basis of the association between hypothyroidism

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Section 3 Adult Reproductive Endocrinology Table 17-1 Prolactin Releasing Factors

Table 17-2 Hormones Required for Normal Mammary Development

Thyrotropin-releasing hormone

Estrogen

Serotonin

Progesterone

Vasoactive intestinal peptide

Prolactin

Opioids

Cortisol

Growth hormone-releasing hormone

Insulin

Gonadotropin-releasing hormone

Thyroxine Growth hormone

and hyperprolactinemia, a condition that resolves with thyroid hormone replacement. Serotonin appears to be another PRF; use of any of the various selective serotonin reuptake inhibitors (SSRIs) is commonly associated with hyperprolactinemia.

LACTATION The process of lactation requires normal breast development followed by appropriate hormonal and mechanical stimulation of the breast.

Breast Development Prenatal

Normal development in utero requires fetal exposure to many hormones, including estrogens, progesterone, prolactin, insulin, cortisol, thyroxine, and growth hormone (Table 17-2). The endocrine system is essential for the proper development and function of the mammary glands.13,14 Gene knockout studies have demonstrated the importance of each of these hormones in fetal mammary gland development.15. These hormones work through normal hormone–receptor interactions using local growth factors in many cases.16,17

Puberty

At puberty, estradiol is the major influence on breast development, and the breast contains both α and β estrogen receptors. However, multiple hormones are necessary for normal development, including all the hormones necessary for normal in utero development (see Table 17-2). Under the influence of rising estradiol levels at puberty, the breast increases in size and the areola gains pigmentation.18 Most breast development at puberty is adipocyte differentiation under the influence of estrogens. Estrogens stimulate the lactiferous ducts to branch extensively. The terminal alveoli unit, however, is rudimentary.

The Mature Breast Anatomy

The breasts consist of glands, fat, and connective tissue. The basic glandular unit consists of ducts and secretory lobules (Fig. 17-1). Twenty or more lactiferous ducts converge on the nipple. Each large duct is connected to smaller branching ducts and eventually lobules. The ducts are lined by a cuboidal or columnar epithelium, at the base of which are myoepithelial cells. Each lobule contains alveoli, milk glands lined by epithelium.19,20 In a nonactive state,

Nipple areolar complex

Lobules

Lactiferous sinus

Nipple

Sebaceous gland

Gland of Montgomery

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Figure 17-1 The breast and nipple–areolar complex. Distal ducts are lined by epithelial and myoephithelial cells. The breast lobules empty into lactiferous ducts, which terminate at the nipple. The glands of Montgomery are associated with sebaceous glands and terminate on the areola. (From Powell DE: The normal breast: Structure, function and epidemiology. In Powell DB, Stelling CB. The Diagnosis and Detection of Breast Disease. Mosby, 1995,)

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Chapter 17 Lactation and Galactorrhea the ductules often have only rudimentary terminal alveoli that secrete milk.

of the alveolar cells first leads to colostrum formation. Within the next 2 to 3 days, there is a relatively rapid onset of mature milk production.24

Cyclic Changes During the Menstrual Cycle

Breast changes occur with the different phases of the menstrual cycle. In the luteal phase, breast stromal water content and density increases under the influence of increased levels of circulating estrogen and progesterone. Clinically, the breasts become larger and fuller. On mammogram, breast tissue becomes more fibrous and dense, and thus more opaque. The “cloudy” mammography images make it difficult to detect small abnormalities in premenopausal women. Cell proliferation is also increased in the late luteal phase.

Pregnancy Breast development and lactogenesis during pregnancy occurs under the influence of multiple hormones, most notably prolactin, estrogen, and progesterone. Prolactin is secreted in large amounts by the decidua, and levels will be 5 to 10 times normal by the end of the first trimester.21 Under the influence of increased estrogen, the pituitary lactotrophs undergo hyperplasia. After delivery, prolactin declines to a normal baseline by 6 weeks postpartum and then pulses with breastfeeding. Lactogenesis

Final differentiation of the breast into a lactating organ occurs during pregnancy. Lactogenesis is a three-stage process whereby mammary glands develop the ability to produce and secrete milk.22 Starting in early pregnancy and ending within a week of parturition, the mammary glands are hormonally transformed from an undifferentiated state to a fully differentiated state with an established supply of mature milk. Stage I Lactogenesis

During this stage, mammary glands become competent to secrete milk. This stage begins early in gestation and is nearly complete by midpregnancy. As a result of rising levels of estrogen, progesterone, prolactin, and human placental lactogen, the terminal duct lobular units expand and secretory cells begin to differentiate. Prolactin induces the transcription of β-casein and lactalbumin genes.23 Mammary cells start accumulating large numbers of fat droplets. The character of secreted glandular fluid changes, with increases in lactose, total protein, and immunoglobulin concentrations and decreases in sodium and chloride concentrations. The mammary glands remain quiescent as a result of elevated estrogen and progesterone levels, but are prepared to initiate milk production around parturition. Stage II Lactogenesis

This stage begins at the time of birth and ends with the establishment of an appropriate milk supply. Delivery of the placenta results in a sudden drop in circulating progesterone levels. At the same time, both glucocorticoid and prolactin levels increase. This leads to increased synthesis of lactose. Lactose draws water by osmosis into the secretory vesicles. At the same time, synthesis of other milk components (e.g., nutrients and minerals) is increased under the influence of maternal insulin, growth hormone, cortisol, and parathyroid hormone. Secretion

Stage III Lactogenesis

The last phase of lactogenesis, also referred to as galactopoiesis or simply lactation, is defined as secretion and continued production of mature milk by the mammary glands once lactation has been established. Lactation occurs in response to sensory signals from suckling transmitted to the paraventricular and supraoptic nuclei in the brain. This results in release of oxytocin from the posterior pituitary. Oxytocin causes mammary myoepithelial cell contraction, resulting in milk letdown. As long as prolactin and oxytocin secretion are maintained and milk is removed from the mammary glands, milk production will be maintained. Milk production appears to require the presence of other hormones as well, including insulin and glucocorticoids. Suckling by the nursing young is the best-known physiologic stimulus of prolactin secretion. The mechanism of this classic neuroendocrine reflex appears to be decreased release of dopamine (a PIF) into portal blood.25 Breastfeeding

In nature, species-specific breast milk is necessary for survival of the neonate, because it is the only bioavailable source for the neonate of water, organic nutrients, and minerals. For human infants, breast milk gives the best opportunity for ideal growth and development because it contains a species-specific assortment of important nutrients and bioactive substances. These elements are critical during early developmental periods, especially for the brain, immune system, and intestinal tract. Colostrum, the first milk produced after parturition, is lower in fat than mature milk, but is higher in carbohydrates, protein, and antibodies. Mature milk is higher in calories as a result of higher fat content, but also contains antibodies and other bioactive factors. When human milk is unavailable, modern infant formulas are acceptable but incomplete substitutes. Most commonly made from cow’s milk or soybeans, formulas are similar to human milk in terms of water, fat, carbohydrates, and calories, but are devoid of antibodies and other bioactive factors. The exceptional benefits of human breast milk compared to formulas are so numerous that the American Academy of Pediatrics policy statement is that “pediatricians and other health care professionals should recommend human milk for all infants in whom breastfeeding is not specifically contraindicated.”26 Breastfeeding and Anovulation

Breastfeeding is associated with decreased ovarian function for a variable period of time. This is clinically manifested as anovluation, amenorrhea, hypoestrogenemia, and some degree of vaginal atrophy. The underlying mechanism of breastfeeding-related anovulation is related to the ability of suckling and prolactin release to inhibit gonadotropin-releasing hormone (GnRH) release. The amount of GnRH suppression varies with the amount and frequency of breastfeeding, use of infant supplements, and the weight and nutritional health of the mother. As a result of these variables, the length of time a breastfeeding woman will have amenorrhea is highly variable, and women should not rely on lactation to prevent pregnancy.

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Section 3 Adult Reproductive Endocrinology As many as 10% of breastfeeding women will ovulate within 10 weeks of giving birth.27 Two thirds of women who breastfeed for more than 9 months will resume ovulation and menstruation during that time. A small fraction of breastfeeding women will remain anovulatory and amenorrheic for more than 1 year. Involution

After cessation of breastfeeding (or after delivery in women not breastfeeding), postlactation changes result in involution of ducts and alveoli by apoptosis. Involution is a process whereby the mammary glands regress from their lactogenic state, resulting in a progressive decline and ultimate cessation of milk production. Prolactin levels will return to normal within 2 weeks of parturition if breastfeeding does not occur. After breastfeeding has been established, cessation of milk removal from the mammary glands will lead to rapid changes in the mammary tissue. Involution is complete in an average of 40 days after breastfeeding is stopped. Apoptosis of a large percentage of the alveolar cells and a remodeling of the mammary glands results in a return of the mammary glands to a mature quiescent state, although they never return to their prepregnant state.

GALACTORRHEA Nonphysiologic galactorrhea is a common problem that has been estimated to occur in approximately one fourth of all previously parous women sometime during their reproductive life. The condition is most common in women between ages 20 and 35 and is less common in nulligravid women.28 The most common pathologic condition resulting in galactorrhea is hyperprolactinemia, which has several possible underlying causes (Tables 17-3 and 17-4). Table 17-3 Pathologic Etiologies of Hyperprolactinemia Central nervous system disorders Pituitary tumors/lesions Adenomas (most common: prolactinomas, gonadotroph or nonfunctioning adenomas) Empty sella syndrome Hypothalamic tumors Craniopharyngioma Astrocytoma Hypophysitis Autoimmune Infections (e.g., tuberculosis, schistosomiasis) Sarcoidosis Hypothyroidism Chest wall irritation Thoracotomy Herpes zoster Atopic dermatitis Burns Breast surgery or tumors Thoracic neoplasms Ectopic prolactin secretion Bronchogenic carcinoma Renal adenocarcinoma Hypernephroma Gonadoblastoma

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Hyperprolactinemia Hyperprolactinemia occurs in less than 1% of the general population. When patients present with secondary amenorrhea, approximately 30% will be found to have hyperprolactinemia. When patients present with both galactorrhea and amenorrhea, 75% will have hyperprolactinemia. Approximately 30% of these patients will be found to have prolactin-secreting tumors.

Clinical Manifestations of Hyperprolactinemia The most common presenting symptoms of hyperprolactinemia are galactorrhea, infertility, menstrual dysfunction, and headaches. Galactorrhea is seen in more than 80% of hyperprolactinemic patients. Hyperprolactinemia is known to be causally related to several pathologic conditions (see Table 17-3). As noted, a physiologic response to hyperprolactinemia is anovulation.29,30 High levels of prolactin inhibit the pulsatile release of GnRH, thereby reducing pituitary release of both luteinizing hormone (LH) and folliclestimulating hormone (FSH). The LH surge is also inhibited. There is evidence that high serum prolactin levels also have a direct effect on the ovary.28 Hyperprolactinemia inhibits androgen synthesis, thereby reducing substrate for estrogen formation, and may block aromatase activity. All of these effects lead to hypoestrogenism and explain the disrupted or absent menstrual cycles in women with high prolactin levels. Elevated serum prolactin levels have a luteolytic effect that can disrupt the cycle. Elevated prolactin levels should be considered in the differential diagnosis of luteal phase disorders.

ETIOLOGIES OF HYPERPROLACTINEMIA Galactorrhea is most commonly a normal response of the breast to a normal or abnormal endocrine signal (i.e., hyperprolactinemia). Once elevated prolactin is detected, the goal of the clinician is to determine the underlying cause. After pregnancy is excluded, the clinician must assess the patient for drug causes, thyroid disease, Table 17-4 Drug Class Associated with Galactorrhea Neuroleptics Butyrophenones Phenothiazines Risperidone Antidepressants Selective serotonin reuptake inhibitors Tricyclic antidepressants Anti-emetics Metoclopramide Cardiovascular drugs Methyldopa Reserpine Verapamil Opiates Codeine, morphine, heroin Histamine(H2)-receptor antagonists Cimetidine

Decreased prolactin metabolism Renal failure Cirrhosis

Stimulation of lactotrophs High-dose oral contraceptives

Pseudocysesis false pregnancy

The listed drugs are only examples and do not represent a complete list

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Chapter 17 Lactation and Galactorrhea anatomic breast or chest wall abnormalities, and pituitary disorders (see Table 17-3).

Hypothyroidism

Whenever investigating hyperprolactinemia, clinicians should exclude an unrecognized early pregnancy. As discussed, the primary physiologic function of prolactin is to induce breast development and lactogenesis during pregnancy. By the end of the first trimester, prolactin levels will be 5 to 10 times the nonpregnant levels.

Hypothyroidism, even if subclinical, may result in elevated prolactin levels. When levels of circulating thyroxine are low, the lack of negative feedback on the hypothalamus results in increased release of thyrotropin-releasing hormone (TRH) into the portal circulation. As thyrotrophs are stimulated to release thyrotropin, lactotrophs are stimulated to release prolactin. This cross-reactivity is thought to be related to the embryologic derivation of both of these cell types from the same precursor cells.33 Thyroid replacement will uniformly reduce both thyrotropin and prolactin release, and alleviate the associated galactorrhea.34

Activities that Stimulate Prolactin Release

Chest Wall Lesions

When evaluating a patient’s serum prolactin levels, it is important to be aware of activities that can stimulate a temporary increase in prolactin through normal physiologic mechanisms. These include sleeping, eating, sexual intercourse, breast or chest stimulation, and stress. For this reason, if a borderline elevation of serum prolactin is detected on initial evaluation, it is prudent to avoid these stimulants by repeating the prolactin determination in the morning after fasting remote from any breast stimulation to avoid expensive evaluation of a fallacious prolactin elevation.31

Because chest stimulation can result in elevations of prolactin, it isn’t surprising that trauma or lesions of the chest wall may result in hyperprolactinemia and galactorrhea.35 Tumors, herpes zoster, spinal cord injury, and other lesions have been associated with hyperprolactinemia.36

Central Nervous System Disorders

Decreased Prolactin Metabolism

Physiologic Causes Pregnancy

Pituitary Adenomas

Pituitary adenomas can result in hyperprolactinemia by two different mechanisms. Prolactinomas, which account for approximately 70% of pituitary adenomas, secrete prolactin and are the most common cause of very high serum prolactin levels (usually >100 μg/L). Other types of pituitary adenomas result in hyperprolactinemia by a completely different mechanism. Clinically nonfunctioning adenomas usually originate from gonadotroph cells. They represent almost 30% of pituitary adenomas. Less common adenomas are those that originate from the somatotrophs (produce growth hormone), corticotrophs (secrete corticotropin), or thyrotrophs (secrete thyrotropin). The gonadotroph adenomas incommonly secrete FSH or LH. These tumors increase prolactin by compressing the pituitary stalk and interfering with the release of dopamine, the putative PIF. As a result of decreased exposure of the lactotrophs to the inhibitory influence of dopamine, prolactin levels increase, usually to the range of 30 to 100 μg/L. The nonfunctioning tumors usually present with neurologic symptoms rather than symptoms related to the hyperprolactinemia. These include visual impairment (bitemporal hemianopsia) and headache. Large tumors of the hypothalamus may also cause compression of the portal system that carries the prolactin inhibitors. Structural lesions such as empty sella syndrome or a cyst of Rathke’s pouch can also cause hyperprolactinemia and associated galactorrhea.32 The diagnosis and treatment of pituitary abnormalities are addressed in Chapter 22. Any disease that causes pituitary inflammation can result in hyperprolactinemia, probably as a result of decreased dopamine effect on lactotrophs. Uncommon causes of hypophysitis include autoimmune disease, infections (e.g., tuberculosis, schistosomiasis), and sarcoidosis.

Ectopic Prolactin Production

Rarely, malignant tumors have been reported to secrete prolactin, resulting in hyperprolactinemia. A list of some reported tumor types is given in Table 17-3.

Because most prolactin is excreted by the kidneys, renal disease is associated with galactorrhea due to high prolactin levels resulting from decreased excretion. This effect disappears once normal renal function is restored via transplant.37 Elevated prolactin has long been associated with cirrhosis of the liver, although the mechanisms for this remain unclear. Medications

Many psychotropic medications have been shown to cause galactorrhea via elevations of prolactin (see Table 17-4). The mechanism by which dopamine blocking agents (such as phenothiazines) increase prolactin is obvious, because they result in decreased exposure of lactotrophs to dopamine. It is less obvious how other centrally acting drugs increase prolactin levels, but this side effect is common with major neuroleptics such as haloperidol and antidepressants, including the tricyclics and the SSRIs.38–42 The SSRIs are probably the most frequent drug class associated with increased serum prolactin. Other commonly used drugs associated with hyperprolactinemia include antihypertensive medications such as methyldopa and verapamil.43 Protease inhibitors used for the treatment of human immunodeficiency virus infections have also been associated with hyperprolactinemia.44 The list of other medications associated with hyperprolactinemia is extensive. For this reason, the clinician should consult the product information for any medications being taken by women found to have hyperprolactinemia to determine if they could be associated with the galactorrhea.

EVALUATION OF GALACTORRHEA A general approach to the investigation and management of galactorrhea is outlined in Fig 17-2.

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Section 3 Adult Reproductive Endocrinology

History and Physical Exam

Palpable mass or discharge not consistent with milk

Evaluate with mammogram/ needle aspiration/breast surgeon referral

Figure 17-2

Galactorrhea/normal menses

TSH, PRL, pregnancy test

TSH and PRL

Normal

Elevated PRLx2

Elevated TSH

Elevated PRLx2

Observe

Pituitary image

Treat hypothyroidism

Pituitary image

Treat or observe

Repeat TSH, PRL

Pregnant

Treat hyperprolactinemia

Flow diagram for the evaluation of galactorrhea.

History It is important to determine the time of onset, duration, and frequency of galactorrhea. The amount and quality of the discharge should be defined as well as whether the leakage is spontaneous or needs to be induced. Galactorrhea associated with hyperprolactinemia is usually bilateral and spontaneous. Gynecologic history should include menstrual and contraception history, with special attention to the possibility of pregnancy. Obstetric history should include number of pregnancies, time since last delivery, menstrual cycle data, and medications. General symptoms can often give clues to underlying diseases associated with hyperprolactinemia. Symptoms of hypothyroidism include lethargy, weight gain, heat or cold intolerance, and nail and skin changes. Brain tumors are often associated with headaches and visual symptoms. History or symptoms of underlying renal or liver disease should be elicited. Finally, any history of chest lesion or trauma should be noted.

Physical Examination

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Galactorrhea/amenorrhea

The physical examination of the breast for the presence of masses and discharge should be performed. An important objective is to differentiate galactorrhea from other pathology. A dark or bloody secretion is clearly not milk, and a local cause should be sought. Palpable masses should be evaluated following normal protocols for this finding. The clinician should attempt to express the discharge or ask the patient to demonstrate the galactorrhea. The fluid may be milky, tan, green, or clear but should not be bloody. Placing a

drop of the fluid under the microscope and visualizing multiple fat droplets can easily verify galactorrhea. The presence of a bloody discharge or fluid is not galactorrhea and should prompt consideration of ductogram or other localized evaluation to rule out malignancy. An examination for galactorrhea should also include assessment for thyroid disorders, including palpation of the thyroid, and neurologic assessment, including visual fields.

Diagnostic Tests Serum Prolactin Levels

In the nonpregnant woman, the range of normal prolactin levels is from 1 to 20 ng/mL. There is a diurnal variation, such that prolactin levels are higher during sleep. During pregnancy, prolactin levels normally increase to as high as 300 ng/mL. Prolactin levels can be temporarily increased by breast stimulation related to medical or self-examination or sexual activity. However, in the nonpregnant patient, routine breast examination does not acutely alter serum prolactin levels, and thus measurement. If prolactin is elevated, the test should be repeated fasting and in the morning, when it would be expected to be lowest. The patient should be instructed to abstain from any breast or nipple stimulation immediately prior to the test. Other Laboratory Tests

Whenever hyperprolactinemia is suspected, a urine or blood pregnancy test and a serum thyrotropin level should be evaluated simultaneously with a serum prolactin level. In women at risk for kidney disease, a serum creatinine level should also be evaluated.

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Chapter 17 Lactation and Galactorrhea Imaging Studies

In the presence of reproducible hyperprolactinemia, evaluation of the pituitary and hypothalamus with magnetic resonance imagining is indicated to check for an intracranial lesion. Computed tomography can be used, but has the disadvantage of lower resolution. The most common brain tumor in women with hyperprolactinemia is a benign pituitary adenoma. These are classified as being either a microadenoma (1 cm). Their treatment and prognosis are discussed in Chapter 22. Postmenopausal women with no evidence of pituitary or hypothalamic lesions should be further evaluated with a chest radiogram and a mammogram, because hyperprolactinemia has been associated with both breast and lung cancer.

TREATMENT FOR GALACTORRHEA RELATED TO HYPERPROLACTINEMIA When galactorrhea is found to be a symptom of significant pathology, the treatment of the underlying problem becomes paramount. Many women will have resolution of their galactorrhea with appropriate therapy that normalizes their prolactin levels. When women are found to have a pituitary microadenoma or idiopathic hyperprolactinemia, the treatment decision is usually made based on the symptoms the patient is having. The most common symptoms associated with hyperprolactinemia are excessive galactorrhea, infertility, and hypoestrogenemic amenorrhea.

Indications for Treatment Excessive Galactorrhea

Galactorrhea itself is not a dangerous condition but can have significant impact on lifestyle if excessive. Whereas most women with minimal galactorrhea rarely request treatment for symptoms alone, women who have enough leakage to keep their clothing moist will often request treatment to avoid social embarrassment and/or the skin disorders associated with chronic dampness, including excoriation and fungal infections. Infertility

Women unable to achieve pregnancy found to have galactorrhea and hyperprolactinemia are at risk for ovulation dysfunction that can range from subclinical to obvious anovulation and amenorrhea. If a pituitary adenoma is diagnosed, the prognosis of this lesion during pregnancy should be discussed prior to therapy. Treatment with dopamine agonists will often result in pregnancy without further treatment.

increase estrogen will increase bone mass in these women.46 However, eumenorrheic women with galactorrhea demonstrate normal bone density and do not require treatment for this indication.47

Treatment Options The treatment of hyperprolactinemia is covered fully in Chapter 22. In brief, elevated prolactin levels related to pituitary causes can usually be decreased to the normal range using a dopamine agonist. In most cases, this will result in resolution of galactorrhea, associated menstrual abnormalities, and infertility. If infertility persists with normalized prolactin, ovulation induction medications may be used successfully in these patients.48 Conversely, if pregnancy is not desired, care must be taken to avoid pregnancy when hyperprolactinemia is corrected because a previously anovulatory patient has an 80% chance of becoming ovulatory after 6 months or less of treatment.49 If pregnancy is not desired, oral contraceptives can be used, especially if menstrual abnormalities persist. Oral contraceptives with higher levels of ethinyl estradiol (i.e., ≥ 50 μg) have been associated with galactorrhea and hyperprolactinemia.50 However, modern oral contraceptives (i.e., ≤ 35 μg) can be used in women with hyperprolactinemia with no measurable risk of enlargement of pituitary lesions.51 Galactorrhea not associated with elevated prolactin is uncommon. In the absence of other lesions, it is believed that some women have an increased sensitivity to normal levels of prolactin. Other women are thought to have elevated levels of abnormal prolactin that is not measured using normal assays. If these women have indications for treatment, a trial of dopamine agonist therapy is warranted.

PEARLS ●

●

●

●

●

●

Hypoestrogenemic Amenorrhea

●

Menstrual abnormalities in women with galactorrhea and hyperprolactinemia are often the result of hypoestrogenemia. The most significant long-term medical problem associated with this condition is decreased bone mineral density due to their hypoestrogenic state.45 Treatment to lower prolactin and thus

●

Lactation is a complex multistep process under hormonal control. Breast milk is a neonate’s best source of water, organic nutrients, minerals, and bioactive substances. Pregnancy and hypothyroidism should be excluded in women with hyperprolactinemia. Galactorrhea of endocrine origin is often associated with amenorrhea. Galactorrhea associated with a normal menstrual cycle and a normal serum prolactin level is usually not associated with a pituitary tumor. Centrally acting drugs associated with galactorrhea include antipsychotics, antidepressants (e.g., imipramines, SSRIs) opiates, histamine (H2) receptor antagonists (e.g., cimetidine), and calcium channel blockers. The highest levels of serum prolactin are usually related to pituitary prolactinomas; lower levels can be seen with any lesion that compresses the pituitary stalk. Treating hyperprolactinemia with dopamine agonists will resolve galactorrhea and usually result in normalized menstrual cycles and fertility.

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1. Veldhuis JD, Johnson L: Operating characteristics of the hypothalamopituitary-gonadal axis in men: Circadian, ultradian, and pulsatile release of prolactin and its temporal coupling with luteinizing hormone. J Clin Endocrinol Metab 67:116–123, 1988. 2. Garnier PE, Aubert ML, Kaplan ASL, et al: Heterogeneity of pituitary and plasma prolactin in man: Decreased affinity of “bigA” prolactin in a radioreceptor assay and evidence for its secretion. Endocrinology 47:1273–1279, 1978. 3. Whitaker MD, Klee GG, Kao PC, et al: Demonstration of biological activity of prolactin molecular weight variants in human sera. J Clin Endocrinol Metab 58:826–830, 1983. 4. Bole-Feysot C, Goffin V, Edery M, et al: Prolactin (PRL) and its receptor: Actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocrine Rev 19:225–268, 1998. 5. Ben-Jonathan N, Mershon JL, Allen DL, Steinmetz RW: Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocrine Rev 17:639, 1996. 6. Lawrence RA, Lawrence RM: Breastfeeding: A Guide for the Medical Profession, 6th ed. St. Louis, Elsevier/CV Mosby, 2005. 7. Mogg RJ, Samson WK: Interactions of dopaminergic and peptidergic factors in the control of prolactin release. Endocrinology 126:728–735, 1990. 8. Kelly MA, Rubinstein M, Asa SL, et al: Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 19:103–113, 1997. 9. Lamberts SWJ, Macleod RM: Studies on the mechanism of the GABAmediated inhibition of prolactin secretion. Proc Soc Exp Biol Med 158:10–13, 1978. 10. Clemens JA, Meites J: Inhibition by hypothalamic prolactin implants of prolactin secretion, mammary growth and luteal function. Endocrinology 2:878–881, 1968. 11. Tashjian Jr AH, Barowsky NJ, Jensen DK: Thyrotropin releasing hormone: Direct evidence for stimulation of prolactin production by pituitary cells in culture. Biochem Biophys Res Commun 43:516–623, 1971. 12. Clemens JA, Sawyer BD, Cerimele B: Further evidence that serotonin is a neurotransmitter involved in the control of prolactin secretion. Endocrinology 100:692–698, 1977. 13. Forsyth IA: Variation among species in the endocrine control of mammary growth and function: The roles of prolactin, growth hormone, and placental lactogen. J Dairy Sci 69:886–903, 1986. 14. Schams D, Kohlenberg S, Amselgruber W, et al: Expression and localization of oestrogen and progesterone receptors in the bovine mammary gland during development, function, and involution. J Endocrinol 177:305–317, 2003. 15. Grimm SL, Seagroves TN, Kabotyanski EB, et al: Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development. Mol Endocrinol 16:2675–2691, 2002. 16. Hovey RC, Harris J, Hadsell DL, et al: Local insulin-like growth factorII mediates prolactin-induced mammary gland development. Mol Endocrinol 17:460–471, 2002. 17. Stull MA, Rowzee AM, Loladze AV, Wood TL: Growth factor regulation of cell cycles progression in mammary epithelial cells. J Mammary Gland Biol Neoplasia 9:15–26, 2004. 18. Rosen JM, Humphreys R, Krnacik S, et al: The regulation of mammary gland development by hormones, growth factors and oncogenes. Prog Clin Biol Res 387:95–111, 1994. 19. McManaman JL, Neville MC: Mammary physiology and milk secretion. Advanced Drug Deliv Rev 55:629–641, 2003. 20. Clark R: Introduction and overview: Sex steroids in the mammary gland. J Mammary Gland Biol Neoplasia 5:245–250, 2000. 21. Tyson JE, Friesen HG: Factors influencing the secretion of human prolactin and growth hormone in menstrual and gestational women. Am J Obstet Gynecol 116:377–387, 1973. 22. Neville MC, Keller RP, Seacat J, et al: Studies in human lactation: Milk volumes in lactating women during the onset of lactation and full lactation. Am J Clin Nutr 48:1375–1386, 1988.

23. Schmitt-Ney M, Doppler W, Ball RK, Groner B: β-Casein gene promoter activity is regulated by the hormone mediated relief of transcriptional repression and a mammary-gland-specific nuclear factor. Mol Cell Biol 11:3745–3755, 1991. 24. Birkenfeld A, Kase NG: Functional anatomy and physiology of the female breast. Obstet Gynecol Clin North Am 21:433–445, 1994. 25. Freeman ME, Kanyicska B, Lerant A, Nagy G: Prolactin: Structure, function, and regulation of secretion. Physiol Rev 80:1523–1631, 2000. 26. Gartner LM, Morton J, Lawrence RA, et al., for the American Academy of Pediatrics Section on Breastfeeding: Breastfeeding and the use of human milk. Pediatrics 115:496–506, 2005. 27. Campbell MR, Gray RH: Characteristics and determinants of postpartum ovarian function in women in the United States. Am J Obstet Gynecol 169:55, 1993. 28. Benjamin F: Normal lactation and galactorrhea. Clin Obstet Gynecol 37:887–897, 1994. 29. Sauder SE, Frager M, Case GD, et al: Abnormal patterns of pulsatile luteinizing hormone secretion in women with hyperprolactinemia and amenorrhea: Responses to bromocriptine. J Clin Endocrinol Metab 59:941–948, 1984. 30. Cheung CY: Prolactin suppresses luteinizing hormone secretion and pituitary responsiveness to luteinizing hormone-releasing hormone by a direct action at the anterior pituitary. Endocrinology 113:632–638, 1983. 31. Fujimoto VY, Clifton DK, Cohen NL, et al: Variability of serum prolactin and progesterone levels in normal women: The relevance of single hormone measurements in the clinical setting. Obstet Gynecol 76:71–87, 1990. 32. Simard MF: Pituitary tumor endocrinopathies and their endocrine evaluation. Neurosurg Clin North Am 14:41–54, 2003. 33. Jacobs LS, Snyder PJ, Wilber JF, et al: Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. J Clin Endocrinol Metab 39:6–17, 1974. 34. Tolino A, Nicotra M, Romano L, et al: Subclinical hypothyroidism and hyperprolactinemia. Acta Eur Fertil 22:275–277, 1991. 35. Boyd AE, Spare S, Bower B, et al: Neurogenic galactorrheaamenorrhea. J Clin Endocrinol Metab 47:1374–1377, 1978. 36. Yarkony GM, Novick AK, Roth EJ, et al: Galactorrhea: A complication of spinal cord injury. Arch Phys Med Rehabil 73:878–880, 1992. 37. Lim VS, Kathpalia SC, Frohman LA: Hyperprolactinemia and impaired pituitary response to suppression and stimulation in chronic renal failure: Reversal after transplantation. J Clin Endocrinol Metab 48:101–107, 1979. 38. Pollock A, McLaren EH: Serum prolactin concentration in patients taking neuroleptic drugs. Clin Endocrinol 49:513–516, 1998. 39. Lawson DM, Gala RR: The influence of adrenergic, dopaminergic, cholinergic and serotoninergic drugs on plasma prolactin levels in ovariectomized, estrogen-treated rats. Endocrinology 96:313–318, 1975. 40. Molitch ME: Antipsychotic drug-induced hyperprolactinemia: Clinical implications. Endocrine Pract 6:479–481, 2000. 41. Slater SL, Lipper S, Schiling DJ, Murphy DL: Elevation of polasma prolactin by monoamine-oxidase inhibitors. Lancet 2:275–276, 1977. 42. Sherman L, Fisher A, Klass E, Markowitz S: Pharmacologic causes of hyperprolactinemia. Semin Reprod Endocrinol 2:31, 1984. 43. Gluskin LE, Strasberg B, Shah JH: Verapamil-induced hyperprolactinemia and galactorrhea. Ann Intern Med 95:66–67, 1981. 44. Luzzati R, Crosato IM, Mascioli M, et al: Galactorrhea and hyperprolactinemia associated with HIV postexposure chemoprophylaxis. AIDS 16:1306–1307, 2002. 45. Klibanski A, Neer RM, Beitins IZ, et al: Decreased bone density in hyperprolactinemic women. NEJM 303:1511–1514, 1982. 46. Klibanski A, Greenspan SL: Increase in bone mass after treatment of hyperprolactinemic amenorrhea. NEJM 315:542–546, 1986. 47. Ciccarelli E, Savino L, Carlevatto V, et al: Vertebral bone density in non-amenorrhoeic hyperprolactinaemic women. Clin Endocrinol 28:1–6, 1988.

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Chapter 17 Lactation and Galactorrhea 48. Farine D, Dor J, Lupovici N, et al: Conception rate after gonadotropin therapy in hyperprolactinemia and normoprolactinemia. Obstet Gynecol 65:658–660, 1985. 49. Vance ML, Thorner MO: Prolactinomas. Endocrinol Metab North Am 16:731–753, 1987. 50. Luciano AA, Sherman BM, Chapler FK, et al: Hyperprolactinemia and contraception: A prospective study. Obstet Gynecol 65:506–510, 1985.

51. Testa G, Vegetti W, Motta T, et al: Two-year treatment with oral contraceptives in hyperprolactinemic patients. Contraception 58:69–73, 1998. 52. Powell DE, Stelling CB: The normal breast: Structure, function and epidemiology. In The Diagnosis and Detection of Breast Disease. St. Louis, Mosby, 1994.

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18

Hirsutism Cynthia Abacan and Charles Faiman

INTRODUCTION Hirsutism refers to excessive hair growth in areas of the body under androgen control. Although hirsutism may occur in both men and women, it is typically only a problem for women. The areas in which normally only postpubescent males have terminal hair growth include the upper lip, chin, chest, back, buttocks, and inner thigh. Hirsutism is a cosmetic concern from the patient’s perspective. Various studies have shown an increased prevalence of social fear and depression among hirsute women.1,2 Whether or not these psychological symptoms have a neuroendocrine basis remains to be elucidated.3 The old adage that “Even a single hair casts its own shadow” may help the clinician deal with the problem objectively. Indeed, even minor degrees of hirsutism may have major consequences on self-image in certain individuals. Hirsutism needs to be differentiated from hypertrichosis. Hypertrichosis, referring to a diffuse increase in fine (vellus) hair that is not androgen dependent, may be congenital or associated with other medical conditions such as hypothyroidism or porphyria or may be associated with certain medications4,5 (Table 18-1). From a practical viewpoint, hirsutism is most often the manifestation of an underlying benign process. However, the association of androgen excess with insulin resistance and its concomitant metabolic consequences is of increasing concern.

used and the population studied. There is a wide degree of variation of what is considered normal hair growth. It is influenced heavily by the woman’s race and cultural background. It is generally accepted that women of Mediterranean origin have more body hair per unit area than Asians of the mongolian race. Traditionally, hirsutism has been quantified according to criteria established by Ferriman and Gallwey.8 In this system, nine body areas sensitive to androgen are graded from 0 (absent), through 1 (minimal terminal hair) to 4 (frank virilization). In this scoring system, the minimum score is 0 and the maximum is 36. In their study of 161 women, Ferriman and Gallwey noted that 9.9% had a score of greater than 5, 4.3% had a score above 7, and 1.2% obtained a score above 10. In general, a score of 8 or more has been considered to represent hirsutism. Various investigators have modified this scoring system over the years.9,10 Hirsutism scores vary widely among women of different ethnic origins (Table 18-2). Consequently, a numeric cutoff point for hirsutism needs to be defined in the context of the population of interest. In clinical practice, the use of a standardized scoring system is impractical. It is limited by subjective variability as well as varying cutoff points depending on ethnicity.5,11 From a practical point of view, hirsutism may be classified simply as mild, moderate, or severe. Specifying the affected areas is helpful in following the response to therapy.

PREVALENCE

THE HAIR FOLLICLE AND HAIR GROWTH CYCLE

It has been estimated that between 5% and 15% of women surveyed are affected with hirsutism, although the exact prevalence remains uncertain.6,7 These estimates depend on the criteria

The hair follicle is composed of dermal and epidermal components.12 Together with the arrector pili muscles and sebaceous glands, it forms the pilosebaceous unit. In androgen-sensitive

Table 18-1 Disorders and Drugs Causing Hypertrichosis

Table 18-2 Prevalence of Hirsutism in General Population Surveys

Disorders

Drugs

Thyroid disorders

Diphenylhydantoin

Population

Anorexia nervosa

Diazoxide

8% 7.1%

Knochenhauer ES, et al.158

Minoxidil

174 white women 195 black women

≥ 6

Dermatologic disorders

Cyclosporine

145 white women

≥8

7.1%

Asuncion M, et al.159

Streptomycin

4780 Kashmiri women ≥ 6

Prolonged administration of cortisone

531 Thai women

Penicillamine Psoralens

*Ferriman-Gallwey Score8

Criterion for Prevalence Hirsutism* of Hirsutism Authors

≥3

10.5%

Zargar AH, et al.160

2%

Cheedwadhanaraks S, et al.11

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Section 3 Adult Reproductive Endocrinology areas, each pilosebaceous unit has the capacity to differentiate into a terminal hair or into a sebaceous follicle. There are three main types of human hair follicles. These have been classified according to the size and depth of the follicle13:

Adrenal Glands

Ovaries

• Vellus hair follicles—fine, soft, and poorly pigmented hair found in most areas of the body • Medium follicles—thicker than vellus hair, penetrating deeper into the dermis, pigmented, and present in the upper arms, lower legs, and in the transitional zone between thick and fine hair regions • Terminal follicles—large, thick, pigmented hair, penetrating into the entire skin layer and found in the scalp, axillae, and pubic areas. In men, these are also found in the face and chest. The hair follicle undergoes repetitive cycles of growth postnatally.14 In fact, the hair growth cycle has been described as a recapitulation of embryogenesis.15 The hair cycle includes three phases: telogen (resting), anagen (growth), and catagen (shortening). In humans, hair growth occurs in a mosaic pattern, where the activity of each follicle is independent of its neighbors.15 In human scalp hair, 85% to 90% of the hair follicles are in anagen, 13% are in telogen, and less than 1% are in catagen at any given time.16 Factors mediating the close relationship between the epidermal and dermal components of the hair follicle are the subject of increasing studies. Different growth factors have been implicated in the control of hair development—epidermal growth factor, fibroblast growth factor, tumor necrosis factor-β, and insulin-like growth factors.17–20 Hair growth is therefore the culmination of interactions between an organism’s genetic make-up influenced by environmental signals from the endocrine and paracrine environment. Although the morphologic changes in the hair growth cycle are well documented, the molecular mechanisms underlying the regulation of the phases of hair growth are still not well understood.

ANDROGENS AND HAIR GROWTH Hirsutism is caused by high circulating androgen levels and/or by an increased sensitivity of the hair follicle to androgen exposure. Androgen excess has been described as the most frequent endocrine disorder in women of reproductive age.21 It is believed to occur in 75% to 85% of women with hirsutism.7 Hirsutism is only one of the clinical signs of androgen excess, which also includes androgenic alopecia, acne, and infertility.22 Much of our current knowledge about the role of androgens in adult human hair growth is based on the early observations of individuals with testicular feminization (androgen resistance) syndrome or with pseudovaginal perineoscrotal hypospadias (now known as steroid 5α-reductase 2 deficiency) or those who underwent castration. All of these conditions are characterized by decreased to absent androgen level or action, leading to variations in hair growth pattern observed phenotypically.

Androgen Production and Metabolism In women, direct secretion from the ovaries and the adrenal glands

264 accounts for 30% to 50% of circulating testosterone (Fig. 18-1).

30%-50% Circulating Testosterone 50%-70%

Peripheral conversion of androgen precursors in skin, liver and adipose tissue

Figure 18-1

Testosterone production in premenopausal women.

Table 18-3 Role of SHBG in the Regulation of Free Estrogen and Testosterone High estrogen state: free estrogen increases and free testosterone decreases Normal estrogenic state: balance High androgen state: free estrogen decreases and free testosterone increases

The rest arises from peripheral conversion of androgen precursors to testosterone, mainly in the skin, liver, and adipose tissue.23 Androgen precursors include androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). Testosterone is the most important circulating androgen. It is present either protein-bound or free in the circulation. Approximately 98% to 99% of plasma testosterone is protein bound—with higher affinity to sex hormone-binding globulin (SHBG) and more loosely to the larger pool of albumin and other proteins. Various factors affect the hepatic production of SHBG. Androgens, insulin, and growth hormone lower SHBG levels, whereas estrogens and thyroid hormone excess result in increased SHBG levels.24 Because of the greater affinity of SHBG to testosterone compared to estradiol, changes in SHBG concentration produce a much greater alteration in the percentage of unbound testosterone than of unbound estradiol. This relationship has been characterized as a see-saw, with SHBG as the fulcrum whose position moves in response to estrogens and androgens (Table 18-3).25 In this way the balance between the levels of free estrogen and free testosterone is determined by the amount of SHBG, whose concentration is determined by these hormones. Accordingly, SHBG acts to amplify the tissue exposure and response to androgen/estrogen balance.

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Chapter 18 Hirsutism The free fraction of plasma testosterone is the biologically active portion. It is believed to enter the target cell by passive diffusion and then binds to the nuclear androgen receptor. Androgen binding leads to an allosteric conformational change, which in turn leads to receptor dimerization, nuclear transport, and target DNA interaction.26–28 These events culminate in target gene transcription. Both testosterone and dihydrotestosterone bind to the same receptor but with different affinities, that for dihydrotestosterone being much greater than that for testosterone.29 The affinity for DHEA and androstenedione is markedly less.30

Site of Androgen Action in the Skin The skin is a major site for the peripheral conversion of weak androgen precursors to active androgens.30 DHEA and DHEAS have little androgenic activity. However, these may be converted to androstenedione and subsequently to testosterone in the adrenal glands and in the peripheral tissues. The active androgen in the skin is dihydrotestosterone.23 Conversion from the testosterone precursor is catalyzed by the enzyme 5α-reductase. Two forms of 5α-reductase are known. Type 1 is found mainly in nongenital skin; the gene responsible is found on chromosome 5. Type 2, encoded on chromosome 2, is primarily found in androgen target tissue such as the prostate, epididymis, seminal vesicle, and genital skin.31 The two types share 50% homology. Dermal papilla cells taken from androgen-dependent areas such as the beard have been demonstrated to express a greater number of androgen receptors as compared to nonbalding scalp cells.15 Higher levels of 5α-reductase activity have also been demonstrated in beard cells.32 The varying sites of expression of the androgen receptor in the different cell types in the skin likely account for the diverse effects of androgens in the skin. These likely account for the disparity in hair distribution and thickness observed among hirsute individuals with similar androgen levels. The increased sensitivity of the pilosebaceous unit to normal levels of androgen is believed to be due to enhanced peripheral 5α-reductase activity, polymorphisms of the androgen receptor, or altered androgen metabolism.

ETIOLOGY OF HIRSUTISM Hirsutism is a sign of increased androgen level or increased sensitivity of the hair follicles to androgen. Hyperandrogenemia is seen in 85% of patients with moderately severe hirsutism.6 Hirsutism may be idiopathic or due to androgen excess from either the ovary or the adrenal gland. Conditions associated with androgen excess from the ovaries include polycystic ovary syndrome (PCOS), hyperthecosis, and androgen-secreting ovarian tumors. Adrenal causes of androgen excess include Cushing’s syndrome, congenital adrenal hyperplasia (CAH), and androgen-secreting tumors. Most hirsute women will have PCOS33,34 (Fig. 18-2).

Idiopathic Hirsutism The most widely accepted definition of idiopathic hirsutism includes normal androgen levels and normal ovulatory function in a hirsute patient.35 Using these criteria, the prevalence of

PCOS IH

0.2% 0.7% 2.6% 3.8% 11.2%

HAIRAN-S 21-NCCAH 21-CAH

82%

Androgen-secreting Neoplasm

Figure 18-2 Causes of androgen excess. PCOS, polycystic ovary syndrome; IH, idiopathic hirsutism (includes patients with normal or elevated androgens without a specific diagnosis); HAIRAN, hyperandrogenic insulin-resistant acanthosis nigricans; 21-NCCAH, 21-hydroxylase deficient nonclassic congenital adrenal hyperplasia; 21-CAH, 21-hydroxylase deficient classic adrenal hyperplasia. (Data from Azziz R, et al: Androgen excess in women: Experience with over 1000 consecutive patients. JCEM 89:453–462, 2004).

idiopathic hirsutism has been estimated to be between 5% and 15%.36,37 Among 64 hirsute women claiming regular menses at intervals shorter than 35 days, 25 (39%) had an anovulatory cycle documented by a day 22 to 24 serum progesterone level of less than 4 ng/mL.36

Polycystic Ovary Syndrome Although initially described in 1935 by Stein and Leventhal, a uniform definition for PCOS still does not exist.38 At the recent joint meeting of the European Society for Human Reproduction and the American Society of Reproductive Medicine, it was suggested that the diagnosis of PCOS is met when at least two of the three following elements are present: hyperandrogenism, chronic anovulation, and polycystic ovaries.39 The different diagnostic criteria for PCOS reflect the heterogeneous nature of this disorder. PCOS is still a diagnosis of exclusion. The prevalence of PCOS is estimated to be at 5% to 7% of reproductive age women.40 It is the most common cause of anovulatory infertility. Polycystic ovary syndrome needs to be distinguished from polycystic ovaries alone. Although most women with PCOS have polycystic ovaries, a substantial population of normal women does as well. Polycystic ovarian morphology may be found in 20% or more of women of reproductive age.41,42 The significance of polycystic ovaries alone is unclear given that it seems to have no impact on fertility.43 Women with PCOS present with some or all of the following clinical features: oligomenorrhea, infertility, hirsutism, acne, alopecia, or obesity. It is important to remember that the syndrome has multiple components—reproductive, metabolic, and cardiovascular—that have health implications throughout the woman’s life.44 Insulin resistance, which refers to the diminished ability of insulin to exert its metabolic effects, is now thought to play a central role in PCOS.45,46 Beta-cell dysfunction, independent of insulin resistance, is also thought to contribute to the pathogenesis of the complications of PCOS.47 Women with PCOS have higher basal insulin concentrations and an increased prevalence of central

265

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Section 3 Adult Reproductive Endocrinology obesity, type 2 diabetes mellitus, and hypertension.48 An estimated 50% to 70% of women with PCOS have insulin resistance.49 Not surprisingly, insulin resistance in women with PCOS is associated with obesity but may also be present in lean women with PCOS.50–52 The consequent hyperinsulinemia is believed to lead to androgen excess through several mechanisms: (1) stimulation of ovarian androgen production, (2) stimulation of adrenal androgen biosynthesis, (3) stimulation of luteinizing hormone (LH) release, and (4) decreasing hepatic SHBG production.53–56 Differentiating those women with PCOS with insulin resistance from those without insulin resistance therefore becomes important given the metabolic consequences and required surveillance for these women.57–59 Considering the paucity of data on the use of simple laboratory markers of insulin resistance in predicting risks and therapeutic response in women with PCOS, it is recommended that the best clinical approach may be the heightened surveillance in all patients for the clinical sequelae of insulin resistance, such as glucose intolerance, dyslipidemia, and hypertension.60

Congenital Adrenal Hyperplasia CAH is a family of autosomal recessive disorders resulting from deficiency in one of the five enzymes necessary for the biosynthesis of cortisol and aldosterone.61 Clinical features depend on the degree of the enzyme defect. The classic forms of neonatal virilization result from a severe enzyme deficiency. Nonclassic forms, due to a less severe enzyme deficiency, may result in delayed signs of androgen excess. In this chapter, the three enzyme deficiencies that result in features of postnatal androgen excess are discussed (see Chapter 2 for details on steroidogenesis). 21-Hydroxylase Deficiency

This enzyme deficiency accounts for the majority (90% to 95%) of CAH cases.61,62 There is a wide variability in phenotypic expression, depending on the extent of the enzyme impairment. All the various forms of 21-hydroxylase deficiency are caused by either homozygous or compound heterozygous mutations in the CYP21A2 gene. The incidence is estimated to be 1:15,000 live births for the severe classic form of CAH.63 The prevalence is higher in certain ethnic groups, such as the Ashkenazi Jews. Nonclassic 21-hydroxylase deficiency (21-OHD) has been reported to occur in from 1% to 10% of hyperandrogenic women.64 Affected individuals produce normal amounts of cortisol and aldosterone at the expense of elevated sex hormone precursors. Onset of symptoms is variable. Some may present with premature pubarche; others may be diagnosed after puberty when they present with symptoms resulting from androgen excess—menstrual irregularity, hirsutism, acne, or infertility. They are clinically indistinguishable from women with PCOS. Up to 50% of affected women (with nonclassic 21-OHD) have been reported to have polycystic ovaries on ultrasound examination.65 Serum androgen levels are comparable with those seen in PCOS as well.66 Measurement of 17-hydroxyprogesterone (basal or stimulated) currently is the main test used to diagnose nonclassic 21-OHD. 11␤-Hydroxylase Deficiency

This is the second most common cause of CAH, seen in about 5%

266 to 8% of cases.63 Clinical features are similar to the virilizing form

of CAH. However, hypertension is a clinical feature believed to be due to the excess production of the mineralocorticoid deoxycorticosterone. Hypokalemia may be seen as well. Mild, late-onset presentations have been reported. Diagnosis is based on the response to a corticotropin stimulation test similar to 21-OHD; however, in this condition, deoxycorticosterone and 11-deoxycortisol are elevated. 3␤-Hydroxysteroid Dehydrogenase Deficiency

This is a rare form of CAH due to mutations within the HSD3B2 gene. Salt-losing and nonsalt-losing types have been identified. The diagnosis is established by demonstrating an increased corticotropin-stimulated ratio of Δ5-17-hydroxypregnenolone to 17-hydroxyprogesterone or to cortisol.

Androgen-secreting Tumors Adrenal Tumors

A purely androgen-secreting adrenal tumor is rare. More frequently, a mixed picture of Cushing’s syndrome with virilization is seen in adults.67 In a review of cases of androgen excess seen in the Mayo Clinic from 1946 to 2002, 11 female patients were identified to have pure androgen-secreting adrenal tumors. Five of these were malignant.68 Malignant tumors were bigger (9.8 cm vs. 4.2 cm) and heavier (232 g vs. 44 g). Surprisingly, mortality was reported in only one patient, a finding in marked contrast to the lower survival rates observed in other forms of adrenocortical carcinoma.69 Ovarian Tumors

Androgen-secreting ovarian tumors are also rare.70 Sertoli-Leydig cell tumors are the most common virilizing ovarian tumor and account for 0.5% of all ovarian neoplasms; however, even nonfunctional ovarian tumors may cause hyperandrogenism, probably mediated by stimulation of stromal cells adjacent to the tumor.71,72

Ovarian Hyperthecosis Hyperthecosis refers to the nests of luteinized theca in the ovarian stroma. There is a considerable clinical overlap between patients with PCOS and those with ovarian hyperthecosis. The latter, however, often present with a more severe form of hyperandrogenism with associated virilization. Laboratory evaluation typically shows a normal serum DHEAS level with extremely elevated testosterone levels, often greater than 200 ng/dL.71

Hyperandrogenism, Insulin Resistance, and Acanthosis Nigricans (HAIRAN) Syndrome A unique disorder of severe insulin resistance associated with hyperandrogenism, HAIRAN syndrome is becoming more widely recognized. It is characterized as follows:73 (1) early age of onset of hyperandrogenism, (2) acanthosis nigricans, (3) marked insulin resistance, (4) positive correlation of the severity of the insulin resistance with the severity of androgen excess, (5) ovarian source for the androgen overproduction, and (6) ovarian hyperthecosis. Most affected women will have normal glucose concentration at the expense of markedly elevated levels of circulating insulin (>80 μU/mL fasting insulin and/or

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Chapter 18 Hirsutism >500 μU/mL after an oral glucose challenge).7 The molecular cause of the insulin resistance in patients with HAIRAN syndrome is still not well understood.

Cushing’s Syndrome

the patient’s benefit and satisfaction. Most underlying etiologies for hirsutism are benign, considering that it may take months to even years of androgen exposure to transform vellus hair to terminal hair.81 Onset of Symptoms

The reported incidence of hirsutism in patients with Cushing’s syndrome is 64% to 81%.74 However, Cushing’s syndrome is a rare cause of hirsutism. Increased adrenal androgen production may accompany the increased production of cortisol. The onset of hirsutism is often distinct from menarche. There may also be increased growth of lanugo hair as a result of the hypercortisolism.75

Increased androgen exposure of the pilosebaceous unit occurs at puberty. Hence, hirsutism often starts at around this time or a few years thereafter. On occasion, it may accompany an early adrenarche. Not infrequently, increased facial hair development in women occurs postmenopausally. It is thought to result from the altered estrogen/androgen balance.82 Rapid hair growth of recent onset should be viewed with suspicion.

Hyperprolactinemia

Extent of Hair Growth

Elevated prolactin levels have been noted in some hirsute women. In a study of 158 women with hirsutism, elevated prolactin was noted in 6% of the women.76 The exact relationship between hyperprolactinemia and hirsutism is still unclear. It is postulated that elevated prolactin level may increase androgen production via an effect on the adrenal cortex. Use of dopamine agonists in hirsute, hyperprolactinemic women has been shown not only to reduce serum androgen levels, but also to improve hirsutism scores.77 On the other hand, the use of bromocriptine in women with PCOS but without hyperprolactinemia has not been demonstrated to alter serum androgen levels.78

Drug-Induced Hirsutism Multiple medications have been implicated in hirsutism. Anabolic steroids such as danazol, oral contraceptives containing progestins that are 19-nortestosterone derivatives, and medications that can increase serum prolactin have been implicated.4 Among 19-nortestosterone derivatives, first-generation (norethynodrel) and second-generation progestins (norethindrone and its metabolites; levonorgestrel and its derivatives) are more androgenic than the third-generation progestins (desogestrel and norgestimate).79 With the increasing use of testosterone replacement in postmenopausal women, iatrogenic hirsutism will likely occur more frequently.80

APPROACH TO THE PATIENT WITH HIRSUTISM Patients’ Goals In evaluating hirsutism, it is important to find out what is of most concern for the patient. Often, cosmetic concerns are paramount. On the other hand, some women will present because of concern for the metabolic complications often thought to be associated with hirsutism. It is becoming widely appreciated that hypertension, dyslipidemia, and type 2 diabetes mellitus are increasingly recognized to be closely linked to PCOS.

History A thorough history is necessary in the evaluation of a woman with hirsutism. Recognizing the patient’s concerns and goals for the visit will allow the physician to tailor the eventual therapy to

The patient will often volunteer the areas of concern, particularly if these involve the face or the chin. However, areas that can be covered by clothing are often overlooked. Hence, one also needs to ask about hair growth in the upper chest, around the areolae, in the upper abdomen, buttocks, and the lateral area of the pubis to the inner thighs. Hair growth in the upper back also needs to be assessed because it is not noticeable to the patient. Knowledge of the method and frequency of depilation is helpful. This gives the clinician an idea of the severity of the hirsutism as well as efficacy of therapy. The clinician may make a false impression of the severity of the problem because a number of women may go to their doctor’s office with the areas of concern recently waxed or shaved. Associated Symptoms Acne

Androgen action on the pilosebaceous unit leads to increased sebum production. Sebum production is important in the process of acne development. As is the case with hirsutism, estrogen and androgen appear to have opposing roles in this process. Alopecia

Androgenic alopecia, another distressing condition associated with androgen excess, needs to be differentiated from other types of alopecia. Different patterns of hair loss have been described:83 • Progressive thinning of the crown with preservation of the frontal hairline • Male-pattern form with bitemporal recession. Virilization

Rapid progression of hirsutism associated with virilization is suggestive of an androgen-secreting neoplasm of the ovary or the adrenal gland. Deepening of the voice, increased muscle mass, increased libido, and clitoral enlargement are clues suggestive of androgen excess. Menstrual History

Oligomenorrhea is one of the features of PCOS. In adolescents, oligomenorrhea that persists after the first few years from the menarche may be an early sign of PCOS.30 Regular menses, however, do not predict normal androgen status in hirsute women. Although 40% of hirsute women will have regular menses, on evaluation, half of these women will be found to have elevated levels of one or more androgens.84

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Section 3 Adult Reproductive Endocrinology Regular menses do not prove normal androgen status or reliably normal ovulatory/luteal function. In one study, 39% of women reporting normal menstrual cycles actually had oligoovulation/anovulation when basal body temperature and day 22 to 24 progesterone levels were measured.36

Signs of Virilization

Weight Changes

Abdominal and Pelvic Examination

Weight gain and distribution need to be assessed. Central obesity is seen in patients with Cushing’s syndrome. Obese women with PCOS have a greater prevalence (73% vs. 56%) of hirsutism compared to nonobese women with PCOS.85 Obesity tends to enhance the androgenic state by two mechanisms:29 (1) the resultant insulin resistance and hyperinsulinemia leads to lowered hepatic SHBG production, in turn resulting in increased levels of free testosterone, and (2) the activation of androgenic precursors in the peripheral tissues is enhanced.

Presence of a neoplasm may be suggested by a mass palpable either in the abdominal area or in the pelvic region. Clitorimegaly can be defined by a clitoral index (length × width) of greater than 35 mm2 or a length greater than 10 mm.87

Deepening of the voice and changes in muscle mass and distribution may be observed. Loss of breast tissue and subcutaneous fat may lead to loss of the normal female body contour in some women.

DIAGNOSTIC TESTS Usually a few serum hormone determinations is all that is required to arrive at a diagnosis. However, under certain clinical circumstances dynamic endocrine testing and special imaging is required.

Family History

An increased prevalence of hirsutism, acne, and male-pattern balding has been observed in relatives of hirsute women.10 Among families of women diagnosed with PCOS, an autosomal dominant pattern of inheritance has been reported for the inheritance of polycystic ovaries and premature male-pattern balding.86 Whether this familial clustering is due to the genetic pattern of the underlying disorder or to some other factor is still unclear. Ethnicity

Ethnic differences in hair quantity and distribution need to be kept in mind. Clearly, the criteria for assessing hirsutism among women of different racial background need to be adjusted and individualized (see Table 18-2). Drug History

Anabolic steroids such as testosterone and danazol can cause hirsutism. The other classes of drugs that can be associated with hirsutism are those that elevate prolactin, such as the phenothiazines (e.g., chlorpromazine), gastrointestinal motility drugs (e.g., metoclopramide), and some antihypertensive medications (e.g., methyldopa).

Physical Examination

Laboratory Tests Testosterone

Measurement of total and/or free testosterone is useful in the evaluation of any state of androgen excess. Although there have been considerable improvements in the commercially available assays for measuring total serum testosterone, there is still a wide degree of between-kit variability, especially in samples from women.88 It is important to keep in mind that an accurate measurement of free testosterone is highly dependent on an accurate assay for total testosterone.89,90 Consequently, it is important for a clinician to be familiar with the assay used and the normal ranges in the laboratory. Total testosterone value above 200 ng/dL has been suggested to signify an androgen-secreting neoplasm.91 However, in a more recent review, Friedman and colleagues92 followed 18 women with serum testosterone level greater than 200 ng/dL (7 nmol/L) for 5 years. Only two women were diagnosed with an androgen-secreting neoplasm. Most of the women were overweight. Conversely, if virilization is present even in the setting of only a modest elevation in serum testosterone, then further workup is warranted. It remains possible that small neoplasms are not being detected by conventional means (i.e., computed tomography [CT] scan of adrenal glands, transvaginal ultrasound of the ovaries).

Skin

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A thorough examination of androgen-sensitive areas is warranted when evaluating a woman with concerns regarding hirsutism. Hirsutism needs to be differentiated from hypertrichosis. The latter is manifested by increased vellus hair over the whole body. The conditions causing hypertrichosis have been mentioned previously. Noting the sites involved and the severity of involvement will allow the physician to document response to therapy. Acanthosis nigricans is a hyperpigmented, velvety reactive skin change often associated with insulin resistance. It is usually found in flexural areas such as the posterior neck, axillae, and inguinal regions. In cases of rapid development of acanthosis nigricans, an occult malignancy (most commonly gastrointestinal or pulmonary) needs to be sought. Plethora, telangiectasia, and violaceous abdominal striae are characteristic skin findings in Cushing’s syndrome. Acne and androgenic alopecia may also be present.

Dehydroepiandrosterone Sulfate

Dehyroepiandrosterone sulfate is primarily produced by the adrenal glands; hence, it is a good marker for adrenal androgen production. Although a weak androgen, its main importance in androgen excess states is to provide a pool of precursor for testosterone formation in the periphery. It is frequently elevated in anovulatory women.93 Levels decline with age but with marked individual variability.94 DHEAS values greater than 700 μg/dL (24.3 μmol/L) are suggestive of a virilizing adrenal tumor.4 Testing for Congenital Adrenal Hyperplasia

As previously mentioned, most cases of CAH are due to 21-hydroxylase deficiency. Nonclassic 21-OHD is often clinically indistinguishable from PCOS. An unstimulated early-morning follicular phase 17-hydroxyprogesterone determination has been recommended as a screening tool for this condition because a value

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Chapter 18 Hirsutism of less than 2 ng/dL has been shown to have a negative predictive value of 100%.95 Patients who have 17-hydroxyprogesterone levels greater than or equal to 2 ng/dL should proceed to a corticotropin stimulation test. Measuring 17-hydroxyprogesterone level at baseline and 60 minutes after an intravenous injection of 250 μg of synthetic corticotropin is used to establish the diagnosis of late-onset 21-hydroxylase deficiency Post-stimulation values greater than 10 ng/mL (30.3 nmol/L) constitute a positive test.66 Testing for Cushing’s Syndrome

In those hirsute women with other clinical signs suggestive of hypercortisolism, screening for Cushing’s syndrome is warranted. A 24-hour urine free cortisol is widely used to establish the presence of Cushing’s syndrome. The concomitant measurement of creatinine in the urine sample ensures the adequacy of the collection. Sensitivity ranging from 95% to 100% and specificity from 94% to 98% has been cited by other authors.97 Other screening tests include low-dose (1 mg) overnight dexamethasone suppression testing, midnight serum cortisol, and midnight salivary cortisol. To date, there is no specific protocol advocated or one test shown as being clearly superior to the others in confirming the diagnosis of Cushing’s syndrome. Most clinicians will use a combination of these tests. Once the diagnosis is confirmed, additional tests are required to establish the specific etiology of Cushing’s syndrome. Referral to a center that deals with such patients is usually recommended. Hyperprolactinemia

Hyperprolactinemia has been associated with hirsutism. Consequently, a serum prolactin level should be measured in the workup for hirsutism, particularly in those hirsute women with irregular menstrual cycles. A review of the patient’s medications is warranted to rule these out. Elevated prolactin level may also be seen in association with untreated hypothyroidism as a cause of the hyperprolactinemia warranting a screening thyrotropin test as well. Magnetic resonance imaging of the hypothalamicpituitary region may be warranted. Serum Luteinizing Hormone and Follicle-Stimulating Hormone

Measurements of serum LH and follicle-stimulating hormone (FSH) are of little clinical utility in most cases of hirsutism. A disproportionate increase in serum LH as compared to FSH has been observed frequently in women with PCOS.97 A LH:FSH ratio of greater than 3 has been used by some to indicate PCOS; however, a ratio lesss than 3 does not exclude the diagnosis. Women with irregular or absent menses suspected of ovarian failure are an exception to this principle. In these women, measurement of serum FSH is important to exclude ovarian failure.

Imaging Studies Ultrasonography

The diagnosis of PCOS is often established on clinical grounds with minimal supportive laboratory data. Polycystic ovaries using ultrasonography are not found in all women with PCOS; conversely, as many as 20% to 25% of normal women may have polycystic ovaries on ultrasound. Some women with CAH and adrenal tumors may also have polycystic ovaries. Hence, ultrasound is most often utilized when an ovarian neoplasm is suspected. The positive predictive value of ultrasound for adnexal

malignancy is cited to be 73%, with a negative predictive value of 91%.98 Transvaginal ultrasonography is the preferred method of imaging the ovary with the principal aim of lateralizing the lesion. Adrenal Imaging

Due to the rarity of androgen-secreting adrenal tumors, adrenal imaging is not indicated unless there is a strong suspicion for an adrenal neoplasm. Incidental adrenal masses (“incidentalomas”) are found in 1% to 4% of abdominal imaging studies of patients without suspected adrenal pathology.99 In postmortem autopsies, incidental adrenal masses are seen in up to 8.7% of unselected populations.100 If clinically indicated CT or MRI are quite sensitive for detecting adrenal tumors. Ovarian and Adrenal Venous Sampling

In cases in which adrenal and ovarian imaging fail to identify a source for excessive androgen levels, biochemical analysis of blood samples from the adrenal and ovarian veins have been advocated by some authors.101 However, use of this technique should be restricted to centers experienced in its use.102

MANAGEMENT Treatment of hirsutism is directed toward the underlying etiology. It also needs to be tailored to the patient’s goal for therapy. Often a combination of mechanical therapy targeting local manifestations of hirsutism and pharmacologic therapy aimed toward the underlying cause are used. Treatment options can be broadly divided into (1) mechanical/local removal of unwanted hair, (2) androgen suppression, and (3) blockade of peripheral androgen action. Before beginning treatment, it is important to inform the patient that improvement in hair growth may not be noticeable for at least 6 months due to the intrinsically long half-life of the hair follicle. Beyond the directed therapy for hirsutism, the management of a hirsute patient should also consider the consequences of chronic anovulation and the increased cardiovascular risk from possible insulin resistance. Chronic anovulation is associated with endometrial hyperplasia or carcinoma as well as dysfunctional uterine bleeding. Insulin resistance associated with most cases of PCOS increases the risk for development of type 2 diabetes mellitus, hypertension, dyslipidemia, and coronary artery disease. Consequently, diet, exercise and a weight loss program need to be incorporated into the treatment plan for women with PCOS.

Hair Removal Nonpharmacologic measures of hair removal include waxing, shaving, plucking, bleaching, and use of depilatory creams as well as electrosurgical methods such as electrolysis and laser therapy. Most of these methods are effective transiently; none treats the underlying etiology. Shaving, epilation (plucking and waxing), chemical depilation, and bleaching are all safe, easy, and inexpensive. Shaving is not popular among women for facial hair removal because of the unsightly stubble that occurs once regrowth occurs. Mild skin irritation either due to local trauma or to chemical reaction may occur with any of these methods.103,104 Hair removal is achieved in electrolysis by delivering an electric current to the hair follicle using a probe. This is a slow,

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Section 3 Adult Reproductive Endocrinology expensive, and often painful process. Scarring, as well as hypopigmetnation and hyperpigmentation, have been reported to occur.105 Laser Hair Removal

Laser hair removal targets the melanin in the hair bulb.103 It is based on the principle that selective thermal injury is achieved only in the target capable of absorbing the specific wavelength used for a given amount of time.106 Only hair in the anagen phase is susceptible to injury from the lasers. Different lasers are available, such as the ruby, alexandrite, diodide, and neodymium;yttrium-aluminum-garnet (Nd:YAG) lasers. These appear to be equally efficacious.105 More studies with longer follow-up are needed to be able to define their role conclusively. Topical Agents Eflornithine

Eflornithine (Vaniqa) is a topical agent that inhibits ornithine decarboxylase—a rate-limiting enzyme in the biosynthesis of polyamines.104 Reduction in hair growth rates have been reported in 32% of patients who used this product as compared to placebo.4 Its effects may last up to 8 weeks after the therapy is discontinued.103 Side effects reported include stinging, tingling, and rash.

Androgen Suppression Oral Contraceptive Pills

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Like gonadotropin-releasing hormone (GnRH) analogs, exogenous estrogen and progesterone in oral contraceptives inhibit gonadotropin secretion, leading to decreased ovarian androgen production. In addition, oral contraceptives have also been shown to increase SHBG levels and to decrease adrenal production of androgens and their precursors.107–109 All of these make oral contraceptives ideal for use in hirsute women with hyperandrogenism. In general, 60% to 100% of hirsute women show improvement with oral contraceptive use. Currently, low-dose estrogen formulations in almost all the oral contraceptives available in the United States have circumvented the adverse effects associated with high estrogen content while demonstrating comparable reduction in androgen level and improvement in hair growth.110 However, there are differences in the oral progestins available. Not all oral progestins are purely progestational, and most of these have been shown to have androgenic activity.79 In the older oral contraceptive pills, lowering the progestin dose minimized its androgenic side effects. Currently, newer progestins with improved progesterone-receptor selectivity are available. These include norgestimate, desogestrel, and gestodene.111 Oral contraceptives formulations containing these newer progestins have been shown to be efficacious in the treatment of hirsutism.112,113 Drosperinone is a new progestin contained in one oral contraceptive pill as well as in an agent used for hormone replacement therapy. It is an analog of spironolactone that has both anti-mineralocorticoid and progestogenic properties. In most hirsute women treated with 30 μg ethinyl estradiol plus 3 mg drosperinone for 12 cycles, hirsutism scores improved from the sixth cycle onward.114 However, no direct comparative trials with other oral contraceptive pills have been reported.

Gonadotropin-releasing Hormone Agonists

GnRH is a hypothalamic decapeptide hormone released in a pulsatile fashion and regulates the production and release of both LH and FSH from the anterior pituitary gland.115 GnRH and its agonists have been used either to stimulate the pituitary-gonadal axis (an acute event) or to down-regulate the GnRH receptor by continuous exposure, leading to gonadotropin/gonadal suppression (chemical castration).116,117 Several studies have shown the efficacy of using GnRH agonists in the treatment of hirsutism.118 Treatment of hirsute women with nafarelin for 6 months results in significant decreases in serum gonadotropin, testosterone, free testosterone, and androstenedione levels, as well as significant decreases in hirsutism scores.119 However, cost of therapy and clinical consequences of hypoestrogenism—such as hot flashes and decreased bone mineral density—limit its usefulness. Currently, their use is not recommended for first-line therapy of hirsutism. Combination of GnRH agonists with estrogen therapy has ameliorated the side effects from hypoestrogenism. In a comparative study of leuprolide plus estrogen versus an oral contraceptive pill for the treatment of hirsutism, the combination of leuprolide plus estrogen demonstrated a more rapid improvement in hirsutism.120 Glucocorticoids

Glucocorticoid treatment lowers adrenal androgen production. However, its efficacy in treating hirsutism is limited. Low doses need to be used to avoid side effects such as weight gain, osteoporosis, glucose intolerance, and adrenal suppression. Even in women with late-onset CAH, the results of treating hirsutism with glucocorticoids are often disappointing. In a comparative study of cyproterone acetate versus hydrocortisone in treating hirsutism in women with this condition,121 a 54% reduction in hirsutism score was noted in cyproterone acetate-treated patients versus a 26% reduction noted in the hydrocortisone group after 1 year. However, hydrocortisone has a shorter halflife as compared to prednisone or dexamethasone, which may have accounted for these results. The latter two agents are preferred in this condition. The commonly used dosage for prednisone is 2.5 mg twice a day, whereas for dexamethasone, it is 0.125–0.25 mg at bedtime. Higher doses are not recommended. Insulin Sensitizers

Insulin resistance, with its consequent hyperinsulinemia, plays an important role in the pathogenesis of PCOS. Hyperinsulinemia has been shown to increase ovarian androgen production122,123 and to decrease the production of SHBG.56 Dietary weight loss in obese women with PCOS has been shown to improve insulin resistance and reduce hyperandrogenism with consequent decreased hirsutism and improved ovulation, and fertility rates.124,125 On the other hand, metformin is an effective treatment for anovulation in women with PCOS.126 Metformin is a biguanide that lowers glucose in the presence of insulin by reducing hepatic gluconeogenesis and increasing peripheral cellular glucose uptake.127 Metformin also reduces levels of free testosterone, which has been attributed to increased SHBG levels rather than decreased total serum testosterone levels.128–130 There is also the question of whether it is the weight loss from the anorectic effects of metformin rather than an independent effect of metformin that leads to improvement in free testosterone levels.131

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Chapter 18 Hirsutism Metformin has been shown to improve hirsutism in several but not all studies.131–134 In a 12-month study comparing metformin with ethinyl estradiol/cyproterone acetate, metformin resulted in a greater reduction in the hirsutism score.135 In another study, the opposite was observed.136 Currently, the use of metformin in doses between 1.5 and 2.0 g/day is recommended to ameliorate hirsutism in the PCOS population.135,137 Thiazolidinedione compounds comprise another class of insulin-sensitizing drugs, which are selective ligands of the nuclear transcription factor peroxisome-proliferator-activated-receptor γ (PPARγ). These enhance glucose uptake mainly in adipose and muscle tissues. Two drugs are currently available—rosiglitazone and pioglitazone. The Food and Drug Administration (FDA) withdrew troglitazone, the first available thiazolidinedione, from the market in 1999 because of hepatotoxicity. Earlier studies done using troglitazone in PCOS demonstrated significant reductions in mean serum free testosterone levels, improvement in ovulatory frequency, and improvement in hirsutism scores.138–140 Similarly, small studies using rosiglitazone or pioglitazone showed improved ovulatory rates and insulin sensitivity.141–144 Results of hormonal assessments were variable but only two studies using pioglitazone alone and in combination with metformin showed an increase in SHBG levels.143,145 Overall, measures to improve insulin resistance are important in the management of hirsute women with underlying PCOS. However, one should keep in mind that metformin is in pregnancy category B (drugs that have been used during human pregnancy and do not appear to cause major birth defects or those in which animal studies show no risk), whereas rosiglitazone and pioglitazone are category C (drugs that are either more likely to cause problems to the mother or fetus or are still lacking human data). Consequently, current use of thiazolidinediones in women desirous of pregnancy is not recommended.

Peripheral Androgen Blockade Blocking the binding of testosterone and dihydrotestosterone to the androgen receptor is an effective way of treating hirsutism. Currently, there are several medications included in this class. However, all have teratogenic potential and should be used in conjunction with adequate contraception in women of childbearing age. Spironolactone

The aldosterone antagonist spironolactone also competes with testosterone and dihydrotestosterone for the androgen receptor. Spironolactone (50 to 200 mg/day) will reduce the quantity and quality of facial hair growth in the majority of women with moderate to severe hirsutism.146 The maximal effect is noted by 6 months and maintained at 12 months of treatment. It was equally effective in treating hirsutism in women with either idiopathic or PCOS-related hirsutism. Reduction in ovarian androgen production was observed, whereas it had no effect on adrenal androgen or cortisol levels. Diuresis was limited to the first few days of treatment. A similar reduction in total testosterone has been demonstrated in doses of 100 mg/day to 200 mg/day of spironolactone.147 Anagen hair shaft diameters decreased in both groups (19% and 30%, respectively). Although no direct comparative trial with an oral contraceptive and spironolactone is available,

combination therapy has been shown to significantly improve hirsutism and reduce serum total and free testosterone levels.148 Furthermore, the addition of an oral contraceptive will decrease the frequency one of the side effects of spironolactone that could decrease compliance: irregular menstrual cycles. Side effects commonly associated with spironolactone include gastrointestinal discomfort, polyuria, nocturia, fatigue, headaches, irregular menstrual bleeding, decreased libido, and atopic reactions.24 Hyperkalemia is uncommon in women with normal renal function. Flutamide

An agent used for the hormonal treatment of prostate cancer, flutamide is effective in the treatment of hirsutism.149 In a study of 18 hirsute women treated with flutamide 125 mg three times a day for 12 months,150 hirsutism scores were markedly improved in all women, with concomitant reduction in serum androgen levels. It is also more effective than spironolactone in treating hirsutism, with reduction in hirsutism scores to almost normal after 6 months of therapy with flutamide versus only a 30% reduction in women treated with spironolactone.151 Major concerns include the expense and rare hepatotoxicity, which can sometimes be fatal.152 Consequently, its use for hirsutism is currently off-label; it is not approved for this use by the FDA. Cyproterone Acetate

Cyproterone acetate is an antiandrogen as well as a progestin. It is used as a part of an oral contraceptive or added to an estrogen or an oral contraceptive pill.153 It reduces circulating testosterone and androstenedione levels by suppressing LH.7 In the periphery, it inhibits androgen binding to its receptor.121 In a prospective, randomized trial comparing low dose flutamide, finasteride, ketoconazole, and cyproterone acetate–estrogen in treating hirsutism, cyproterone acetate–estrogen and flutamide were noted to be the most efficacious.154 The cyproterone acetate–estrogen combination reduced hair growth most rapidly. However, cases of fatal hepatitis have also been reported in association with use of cyproterone acetate. Currently, it is not available in the United States. Finasteride

Finasteride is an inhibitor of type 2 5α-reductase and is currently approved for the treatment of benign prostatic hyperplasia.155 It has also been approved for the treatment of androgenic alopecia in men at a dose of 1 mg/day. In a study of 27 women with idiopathic hirsutism,156 treatment with finasteride 5 mg/day alone or in combination with an oral contraceptive for 6 months showed significant improvement in clinical hirsutism scores. No change in serum androgen levels was noted in the finasteride only group. However, the group that received combination therapy showed decreased dihydrotestosterone levels. Finasteride treatment appears to be as effective as spironolactone in treating hirsutism.157 In a prospective study comparing low-dose flutamide, finasteride, ketoconazole, and cyproterone acetate–estrogen regimens, improvement in hirsutism scores was smaller in the group receiving finasteride.154,157 That group was also slowest in decreasing hair growth rate. However, it was the best tolerated among the four regimens. The FDA has not approved finasteride for use in hirsutism.

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Section 3 Adult Reproductive Endocrinology CONCLUSION

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Hirsutism is a common reason for women to seek medical attention. Most often, it results from conditions that are benign. The history and physical examination will often provide the clinician enough clues as to the possible underlying etiology. Simple screening tests using serum total and/or free testosterone, DHEAS, and follicular-phase 17-hydroxyprogesterone will direct the clinician as to the most likely etiology. In women with associated oligomenorrhea and/or infertility, a serum prolactin and thyrotropin level should be assessed as well. Most women with hirsutism have PCOS. With the recognition of the increased risk for the development of diabetes, hypertension, and hyperlipidemia in this population, an increased surveillance for the detection of any of these conditions is warranted. Ultimately, the patient’s goal for the consultation must direct the therapy as well. In some women, simple reassurance of the benign nature of this condition may be enough. In others, a combination of mechanical methods and pharmacologic agents may be needed. Whatever the treatment option chosen, it must be emphasized that noticeable improvement in hair growth occurs slowly.

●

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PEARLS ●

In women, direct secretion from the ovaries and the adrenal glands accounts for 30% to 50% of circulating testosterone. The rest arises from peripheral conversion of androgen precursors.

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Approximately 98% to 99% of plasma testosterone is protein bound—with higher affinity to SHBG. Androgens, insulin, and growth hormone lower SHBG levels, whereas estrogens and thyroid hormone excess result in increased SHBG levels. Rapid progression of hirsutism associated with virilization is suggestive of an androgen-secreting neoplasm of the ovary or the adrenal gland. Regular menses do not predict normal androgen status in hirsute women. PCOS is responsible for most cases of hirsutism. Androgen-secreting neoplasms are uncommon and usually present with new onset of symptoms that are rapidly progressive. Serum testosterone >200 ng/dL (7 nmol/L) and DHEAS values greater than 700 μg/dL (24.3 μmol/L) are suggestive but not diagnostic of a tumor. Most patients with these serum levels will not have tumors. An unstimulated early-morning follicular phase 17-hydroxyprogesterone determination is recommended as a screening tool for CAH; a value of 90 kg, infertility with nulliparity, or PCOS).51,56,58–60 For women who do not wish to have cyclic menses, hypomenorrhea or amenorrhea can be induced with continuous systemic progestin therapy using a depot progestin preparation, progestin implants, or continuous local administration via a progesterone-containing intrauterine system.

Hirsutism Women with hyperandrogenic anovulation (PCOS) frequently experience acne or hirsutism. In women desiring pregnancy, mechanical hair removal is the only appropriate option given the concern regarding antiandrogen therapy in pregnancy. However, for those who are not attempting conception, various combination therapies are available, some of which provide simultaneous contraception and cycle control. The most effective treatment for hirsutism usually involves a combination of weight loss (where appropriate), mechanical hair removal, and medical therapy. The latter usually involves androgen suppression (e.g., oral contraceptives) and/or specific antiandrogen therapy (e.g., with spironolactone, cyproterone acetate, flutamide, or finasteride).

Ovarian Failure Fertility is often still a concern for young women with hypergonadotropism (see Chapter 20). However, women with rising FSH levels, diminished ovarian reserve, or premature ovarian failure are rarely suitable candidates for ovulation induction therapy.60 Depending on age and other factors, there is a small chance of spontaneous conception during occasional ovulatory cycles. Approximately 5% to 10% of young women with premature ovarian failure conceive spontaneously if they enter into a remission after the diagnosis. Beyond this, oocyte donation offers the only realistic possibility of achieving a pregnancy.10,11 Women with rising FSH levels have a presumptive diagnosis of impending ovarian failure, but may still have a relatively normal menstrual pattern and few other symptoms. Although they generally require no specific therapy, they may benefit from counseling about cardiovascular and bone health, including a healthy diet, regular weight-bearing and muscle strengthening

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Chapter 19 Anovulation and Ovulatory Dysfunction exercise, smoking cessation, modest alcohol intake, and appropriate intake of calcium and vitamin D. As ovarian function declines and eventually ceases, women with premature ovarian failure may benefit from measures aimed at menstrual cycle control, endometrial protection, relief of hypoestrogenic symptoms, and osteoporosis prevention. Either cyclic OCs or traditional estrogen/progestin hormone replacement therapy can be used for this purpose, although OCs may achieve better cycle control in cases where some residual ovarian function persists. Young women who are still hoping for the possibility of a remission and a pregnancy may be better served by low-dose hormone replacement therapy using micronized estradiol and progesterone. Such low-dose regimens are not likely to inhibit or mask the return of spontaneous ovulation during a remission, nor do they pose safety concerns about inadvertent exposure during an early pregnancy because they involve hormones identical to those produced by the human ovary.

Long-term Health Issues Traditionally, the focus of gynecologic treatment in women with PCOS has been on infertility, hirsutism, and menstrual irregularity. However, women with hyperandrogenism and PCOS are also at risk for long-term health sequelae, including

android obesity, diabetes, dyslipidemia, hypertension, and heart disease. Many women with PCOS present early in their reproductive years, giving gynecologists a unique opportunity to modify long-term health consequences by encouraging interventions aimed at controlling weight and insulin resistance. Counseling can be offered about lifestyle modifications, including regular exercise, healthy body weight, healthy eating habits, and smoking cessation.

PEARLS ●

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Ovulatory dysfunction is a spectrum of disorders ranging from amenorrhea to frequent, irregular, and/or heavy menses. Rule out underlying disorders that require specific treatment or have other health implications. The menstrual cycle may serve as a barometer of general health. PCOS is the most common form of ovulatory dysfunction, but many women have a normal workup with no clear etiology for anovulation. Offer individualized therapy based on the presenting symptoms, the desire for pregnancy or the need for contraception, and the associated symptoms (e.g., hirsutism). Arrange follow-up and monitor long-term health consequences.

REFERENCES 1. Lobo RA, Carmina E: The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med 132:989–993, 2000. 2. Knobil E: The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53–88, 1980. 3. Moschos S, Chan JL, Mantzoros CS: Leptin and reproduction: A review. Fertil Steril 77:433–444, 2002. 4. Welt CK, Chan JL, Bullen J, et al: Recombinant human leptin in women with hypothalamic amenorrhea. NEJM 351:987–997, 2004. 5. Altchek A: Dysfunctional uterine bleeding in adolescence. Clin Obstet Gynecol 20:633–650, 1977. 6. Scott RT Jr, Hofmann GE: Prognostic assessment of ovarian reserve. Fertil Steril 63:1–11, 1995. 7. Sherman BM, Korenman SG: Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest 55:699–706, 1975. 8. Coulam CB, Adamson SC, Annegers JF: Incidence of premature ovarian failure. Obstet Gynecol 67:604–606, 1986. 9. Anasti JN: Premature ovarian failure: An update. Fertil Steril 70:1–15, 1998. 10. van Kasteren YM, Schoemaker J: Premature ovarian failure: A systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 5:483–492, 1999. 11. Kalantaridou SN, Nelson LM: Premature ovarian failure is not premature menopause. Ann NY Acad Sci 900:393–402, 2000. 12. Dunaif A: Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis. Endocr Rev 18:774–800, 1997. 13. Perkins RB, Hall JE, Martin KA: Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea. Hum Reprod 16:2198–2205, 2001. 14. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25, 2004. 15. Pasquali R, Pelusi C, Genghini S, et al: Obesity and reproductive disorders in women. Hum Reprod Update 9:359–372, 2003. 16. Rich-Edwards J, Goldman M, Willet W, et al: Adolescent body mass index and infertility caused by ovulatory dysfunction. Am J Obstet Gynecol 71:171–177, 1994.

17. Lake J, Power C, Cole T: Women’s reproductive health—the role of body mass index in early and adult life. Int J Obesity 21:432–438, 1997. 18. VonShoultz B, Calstrom K: On the regulation of sex-hormone binding globulin. A challenge of old dogma and outlines of an alternative mechanism. J Steroid Biochem 32:327–334, 1989. 19. Monroe SE, Levine L, Chang RJ, et al: Prolactin-secreting pituitary adenomas. V. Increased gonadotroph responsivity in hyperprolactinemic women with pituitary adenomas. J Clin Endocrinol Metab 52:1171–1178, 1981. 20. Speiser PW, White PC: Congenital adrenal hyperplasia. NEJM 349:776–788, 2003. 21. Barnes RB, Rosenfield RL, Ehrmann DA, et al: Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: Evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab 79:1328–1333, 1994. 22. Noyes RW, Hertig AT, Rock JR: Dating the endometrial biopsy. Fertil Steril 1:3–25, 1950. 23. Tavaniotou A, Albano C, Smitz J, Devroey P: Impact of ovarian stimulation on corpus luteum function and embryonic implantation. J Reprod Immunol 55:123–130, 2000. 24. Li TC, Cooke ID: Evaluation of the luteal phase. Hum Reprod 6:484–499, 1991. 25. Jordan J, Craig K, Clifton DK, Soules MR: Luteal phase defect: The sensitivity and specificity of diagnostic methods in common clinical use. Fertil Steril 62:54–62, 1994. 26. Davis OK, Berkeley AS, Naus GJ, et al: The incidence of luteal phase defect in normal, fertile women, determined by serial endometrial biopsies. Fertil Steril 51:582–586, 1989. 27. Stone S, Khamashta MA, Nelson-Piercy C: Nonsteroidal antiinflammatory drugs and reversible female infertility: Is there a link? Drug Safety 25:545–551, 2002. 28. Murdoch WJ, Cavender JL: Effect of indomethacin on the vascular architecture of preovulatory ovine follicles: Possible implication in the luteinized unruptured follicle syndrome. Fertil Steril 51:153–155, 1989. 29. Evers JL: The luteinized unruptured follicle syndrome. Baillieres Clin Obstet Gynaecol 7:363–387, 1993. 30. Scheenjes E, te Velde ER, Kremer J: Inspection of the ovaries and steroids in serum and peritoneal fluid at various time intervals after

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ovulation in fertile women: Implications for the luteinized unruptured follicle syndrome. Fertil Steril 54:38–41, 1990. Glatstein IZ, Harlow BL, Hornstein MD: Practice patterns among reproductive endocrinologists: Further aspects of the infertility evaluation. Fertil Steril 70:263–269, 1998. McNeely MJ, Soules MR: The diagnosis of luteal phase deficiency: A critical review. Fertil Steril 50:1–15, 1988. Duggan MA, Brashert P, Ostor A, et al: The accuracy and interobserver reproducibility of endometrial dating. Pathology 33:292–7, 2001. Daya S, Ward S, Burrows E: Progesterone profiles in luteal phase defect cycles and outcome of progesterone treatment in patients with recurrent spontaneous abortion. Am J Obstet Gynecol 158:225–232, 1988. Filicori M, Butler JP, Crowley Jr WF: Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest 73:1638–1647, 1984. Ferriman D, Gallwey J: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447, 1961. Speroff L, Glass RH, Kase NG: Clinical Gynecologic Endocrinology and Infertility. Baltimore, Williams and Wilkins, 1999, pp 421–485. Clark AM, Thornley B, Tomlinson L, et al: Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 13:1502–1505, 1998. Kiddy DS, Hamilton-Fairley D, Bush A, et al: Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 36:105–111, 1992. American Society for Reproductive Medicine Committee Opinion: Use of clomiphene citrate in women. Fertil Steril 80:1302–1308, 2003. Garcia J, Jones GS, Wentz AC: The use of clomiphene citrate. Fertil Steril 28:707–717, 1977. Fluker MR, Wang IY, Rowe TC: An extended 10–day course of clomiphene citrate (CC) in women with CC-resistant ovulatory disorders. Fertil Steril 66:761–764, 1996. Eijkemans MJ, Habbema JD, Fauser BC: Characteristics of the best prognostic evidence: An example on prediction of outcome after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. Semin Reprod Med 21:39–47, 2003. Mitwally MF, Casper RF: Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 75:305–309, 2001. de Ziegler D: The dawning of the non-cancer uses of aromatase inhibitors in gynaecology. Hum Reprod 18:1598–1602, 2003.

46. Al-Omari WR, Sulaiman WR, Al-Hadithi N: Comparison of two aromatase inhibitors in women with clomiphene-resistant polycystic ovary syndrome. Int J Gynaecol Obstet 85:289–291, 2004. 47. Costello MF, Eden JA: A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril 79:1–13, 2003. 48. Lord JM, Flight IH, Norman RJ: Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 2003:CD003053. 49. Fluker MR, Urman B, Mackinnon M, et al: Exogenous gonadotropin therapy in World Health Organization groups I and II ovulatory disorders. Obstet Gynecol 83:189–196, 1994. 50. Mulders AG, Laven JS, Eijkemans MJ, et al: Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: A meta-analysis. Hum Reprod Update 9:429–449, 2003. 51. Farquhar CM, Lethaby A, Sowter M, et al: An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol 181:525–529, 1999. 52. van der Vange N, Blankenstein MA, Kloosterboer HJ, et al: Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception 41:345–352, 1990. 53. Gordon GG, Southren AL, Tochimoto S, et al: Effect of medroxyprogesterone acetate (Provera) on the metabolism and biological activity of testosterone. J Clin Endocrinol Metab 30:449–456, 1970. 54. Coulam CB, Annegers JF, Kranz JS: Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol 61:403–407, 1983. 55. Cheung AP: Ultrasound and menstrual history in predicting endometrial hyperplasia in polycystic ovary syndrome. Obstet Gynecol 98:325–331, 2001. 56. Ballard-Barbash R, Swanson CA: Body weight: Estimation of risk for breast and endometrial cancers. Am J Clin Nutr 63:437S–441S, 1996. 57. Balen A: Polycystic ovary syndrome and cancer. Hum Reprod Update 7:522–525, 2001. 58. Gibson M: Reproductive health and polycystic ovary syndrome. Am J Med 98:67S–75S, 1995. 59. Munro MG: Abnormal uterine bleeding in the reproductive years. Part I—pathogenesis and clinical investigation. J Am Assoc Gynecol Laparosc 6:393–416, 1999. 60. Scott RT, Opsahl MS, Leonardi MR, et al: Life table analysis of pregnancy rates in a general infertility population relative to ovarian reserve and patient age. Hum Reprod 10:1706–1710, 1995.

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20

Premature Ovarian Failure Khalid Ataya

INTRODUCTION Premature ovarian failure is defined as hypergonadotropic hypogonadism before age 40. Premature ovarian failure is commonly but not uniformly associated with depletion of ovarian follicles, as is seen in menopause. It results in cessation of regular menses. This condition affects approximately 1% of all women, with 90% of cases occurring between ages 30 and 40. Premature ovarian failure will be found in 10% to 28% of women presenting with primary amenorrhea and 4% to 18% of women presenting with secondary amenorrhea.1 In some cases, the etiology is identical to menopause and thus represents the occurrence of a normal physiologic process at an unusually young age. However, in many cases, the underlying cause is an identifiable pathology. The goal of the clinician is to diagnose and, if possible, treat any ongoing pathologic conditions. Equally important is to help the affected woman reach any unfulfilled reproductive goals via assisted reproductive technologies and psychologically adjust to her condition. Finally, the clinician must ensure that the patient does not suffer the adverse sequelae of prolonged estrogen deprivation, most notably genital atrophy and osteoporosis. This chapter describes normal ovarian development and gradual loss of function. Premature ovarian failure is described, including the various known causes and its standard evaluation. Finally, long-term management is covered.

OVARIAN EMBRYOLOGY The primordial germ cells are known to originate from the endoderm of the yolk sac. These cells can be identified histologically as early as the end of the third week of gestation and migrate to the genital ridge.2 By 8 weeks of intrauterine life, persistent mitosis increases the total number of oogonia to 600,000.3 From this point on, the oogonial endowment is subject to three simultaneous ongoing processes: mitosis, meiosis, and oogonial atresia. At approximately 20 weeks’ gestation, the ovaries possess the maximal complement of up to 6 million to 8 million primary oocytes, approximately two thirds of which have entered and arrested in the prophase of the first meiotic division.1 From midgestation onward, relentless and irreversible attrition progressively diminishes the germ cell endowment of the gonad.4 Some of the oogonia depart from the mitotic cycle to enter the prophase of the first meiotic division between weeks 8 and 13 of fetal life. This change marks the conversion of these cells to primary oocytes well before actual follicle formation.

A role for steroids has been suggested in the control of ovarian primordial follicle assembly and early follicular development.5 It is generally presumed that usually no oogonia are present at birth. Unconfirmed data from mice has challenged this concept, however.6 These investigators have challenged the dogma that germline stem cells are not present and follicular renewal does not occur in the postnatal mammalian ovary. Only 1 million germ cells are present at birth.7 This decreases further to approximately 300,000 by the onset of puberty. Of these follicles, only 400 to 500 (i.e., less than 1% of the total) ovulate in the course of a reproductive lifespan.8 Once formed, the primary oocyte persists in prophase of the first meiotic division until the time of ovulation, when meiosis is resumed and the first polar body is formed and extruded. It is generally presumed that a granulosa cell-derived putative meiosis inhibitor is in play. This hypothesis is based on the observation that denuded (granulosa-free) oocytes are capable of spontaneously completing meiotic maturation in vitro. The primary oocyte is converted into a secondary oocyte by completion of the first meiotic metaphase and formation of the first polar body, before actual ovulation but after the luteinizing hormone (LH) surge. At ovulation, the secondary oocyte and the surrounding granulosa cells (cumulus oophorus) are extruded.

NORMAL OVARIAN AGING Ovarian aging, ultimately leading to ovarian failure and menopause, is a continuum. An early sign is a poor response to ovarian stimulation, followed by menstrual irregularities and eventually ending in cessation of ovarian follicle function. The time interval between the loss of menstrual regularity and the menopause is approximately 6 years, regardless of age at menopause.9 Consistent with this is the finding that the age of last delivery for Canadian women in the nineteenth century showed the same variation as the age of menopause but occurred 10 years earlier.10

Loss of Fertility and Ovarian Aging Natural fertility is known to decline with maternal age. Normal women experience their peak fertility in their early 20s, and an accelerated decline is observed after age 35, as recorded in natural populations around the world.11 The risk of clinical miscarriage and fetal aneuploidy both increase with maternal age, with a steep rise in the late 30s.12,13 The cause of age-related deterioration of oocyte quality is generally accepted to be

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Section 3 Adult Reproductive Endocrinology meiotic nondisjunction due to accumulation of damage in DNA and the microtubules of the meiotic spindle.10 Elevation of early follicular phase follicle-stimulating hormone (FSH) is a hallmark of diminishing ovarian follicular reserve, heralding the menopause transition.14 Elevated FSH levels noted in the premenopause are believed to cause a more rapid recruitment of the cohort of preantral follicles.15 Thus, a period of accelerated oocyte depletion begins until nearcomplete exhaustion of the follicles.16 Poor response to ovarian stimulation most likely represents women in a stage between onset of accelerated decline and total loss of fertility, whereas nonresponse corresponds to a total loss of fertility.17 The basis of the link between a poor response and an early menopause lies in the physiology of follicular development and depletion in the ovary. It has been suggested that the size of the antral follicle cohort is a reflection of the actual resting follicle pool.18–21 “Poor responders” also become menopausal earlier.22,23

Table 20-1 Causes of Premature Ovarian Failure Genetic X chromosome-related Abnormal chromosome number Gene deletions Fragile-X permutations Single-gene mutations Galactosemia Gonadotropin receptor defects Inhibin defects Steroidogenesis enzyme defects Other Genetic syndromes Polyglandular autoimmune syndromes BPEI (blepharophimosis, ptosis, and epicanthus inversis) syndrome Myotonia dystrophica Perrault’s syndrome (congenital deafness) Ataxia-telangiectasia Autoimmune Isolated ovarian disorder Polyglandular autoimmune syndromes 1 and 2 Infectious

Menopause The clinical sequelae of physiologic ovarian failure is menopause, which is defined as the permanent cessation of menses. The median age of menopause in the United States is 51 years, with menopause occurring before age 40 for 1% of women and beyond age 60 for another 1%.24 Despite a progressive prolongation in the mean age of the population and a trend toward accelerated menarche, the age of menopause has remained relatively unaffected over the last century.25 Evidence suggests that the time of the natural menopause is under strong genetic control, although environmental factors can play a significant role.26

PATHOPHYSIOLOGY OF PREMATURE OVARIAN FAILURE

Iatrogenic Chemotherapy Radiation Repetitive ovarian surgery Environmental toxins Idiopathic

Gonadotropin Receptor Polymorphism

A mutation of the FSH receptor has been described in a subset of patients with premature ovarian failure.31 This is associated with loss in receptor function and appears confined to specific families in the Finnish population. A defect in the LH receptor gene associated with ovarian resistance has also been described.32 Inhibin Polymorphism

Premature ovarian failure is the absence of ovarian function before age 40. Although it can be the result of a physiologic process at an unusually young age, it is often due to a broad range of underlying etiologies. Regardless of etiology, the clinical results are decreased fertility, and hypoestrogenemia ultimately manifesting as amenorrhea. In most cases, the etiology of premature ovarian failure will not be clear, and the majority of cases occur sporadically. However, there is a genetic component in some woman, and the risk of premature ovarian failure in a woman with a first-degree relative with premature ovarian failure is between 4% and 30%.27,28 Multiple known etiologies of premature ovarian failure are presented here (Table 20-1).

Genetic Causes Genetic errors such as single-gene defects, abnormalities in the sex chromosomes, and other poorly defined genetic diseases have been associated with premature ovarian failure. The list of potential disorders associated with premature ovarian failure is extensive; however, some general patterns have been observed. Single-Gene Defects

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Single-gene defects may give rise to ovarian failure. These include mutations of FSH and LH receptors, inhibin, and galactosemia, among others.29,30

Mutations in the inhibin α and β genes have been associated with relatively severe symptoms of premature ovarian failure. Amenorrhea usually develops by the second decade of life in 7% of patients exhibiting this mutation, compared to 0.7% of controls.33 Galactosemia

In females affected with this autosomal recessive disorder, the incidence of premature ovarian failure is at least 80%.34 A relevant murine model suggests that this might be due to a decrease in the germ cell number during fetal oogenesis.35 Mutations of the galactose-1-phosphate uridyltransferase gene can also result in premature ovarian failure because of ovarian accumulation of galactose metabolites at toxic levels.36 Other possible mechanisms contributing to premature ovarian failure in these patients include defective isoforms of FSH, and follicular dysfunction that may be related to interference with nucleotide sugar metabolism and the synthesis of galactose-containing glycoproteins and glycolipids consequent to the enzymatic defect.1,37 Other Genetic Abnormalities

Several autosomal loci have been implicated in premature ovarian failure.38 For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, whereby lesions result in decreased follicles. Deficiencies of 17α-hydroxylase and 17,20-desmolase are associated with primary amenorrhea, sexual

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Chapter 20 Premature Ovarian Failure infantilism, and hypertension.1 The impaired steroidogenesis results in loss of negative feedback and elevation in the endogenous FSH. This in turn has been implicated in recruiting larger cohorts of follicles, resulting in an accelerated exhaustion of the oocyte complement.14–16 HLA-DR3-linked predisposition to premature ovarian failure with autoimmune polyglandular endocrinopathies has been demonstrated.39 Autoimmune polyglandular syndromes are a series of disorders characterized by autoimmunity against two or more endocrine organs. BPEI syndrome (blepharophimosis, ptosis, and epicanthus inversis), an autosomal dominant disorder mapped to chromosome 3q, is associated with development of premature ovarian failure.40,41 Myotonia dystrophica, secondary to a mutation of a gene located on chromosome 19, may be associated with premature ovarian failure.41 Moreover, the genes FRAXA and POF1B have been implicated in premature ovarian failure.42 Autosomal disorders such as mutations of the phosphomannomutase 2 (PMM2) gene have been identified in patients with premature ovarian failure.43 Perrault’s syndrome, with deafness and familial autosomal recessive premature ovarian failure, has also been described.44 Sex Chromosome Abnormalities

Specific sex chromosome anomalies may be identified in some patients presenting with premature ovarian failure.45 Among them, 45,X and 47,XXY are most prevalent, followed by variable mosaicism.46 The X chromosome contains genes critical to ovarian function. It is generally believed that the Y chromosome directs the indifferent gonad toward testicular differentiation and that differentiation toward ovarian differentiation requires less specific gene activation. It is clear that both X chromosomes are required to maintain the function of the ovary. The critical region spans Xq13-26.1 Proximal deletions (Xq13-21) can be associated with primary amenorrhea while the more distal ones are associated with premature ovarian failure. Genes termed POF1 and POF2 have been localized to Xq21.3-27 and Xq13.3-q21.1, respectively.1 The age at menopause is significantly younger with the latter. Deletions in these genes are typically not associated with short stature. Within the short arm of the X chromosome, some regions have been associated with risk for premature ovarian failure. The chance of having an abnormal karyotype increases with earlier age of onset of the ovarian failure.45 A chromosomal analysis is recommended for patients younger than age 30 because of increased risk of a gonadal tumor associated with the presence of a Y chromosome.47–49 Swyer syndrome, with 46,XY chromosome compliment and a uterus, may result from a defective Y chromosome and usually presents with primary amenorrhea. The frequency of Y chromosome material detected by polymerase chain reaction is high in Turner’s syndrome (12.2%), but the occurrence of a gonadal tumor among these Y-positive patients is low (7% to 10%).50 It has been estimated that 75% of premature ovarian failure patients presenting with primary amenorrhea have a 45,X or mosaic chromosome patterns.51 Fragile X syndrome premutation carriers, typically with mental retardation and developmental delay, intention tremor, ataxia, or dementia, are at an increased risk for premature ovarian failure, with an incidence of 16% to 21%.52 A higher risk for premature

ovarian failure (28%) has been proposed for carriers inheriting the premutation from the father, compared to a 4% risk when inherited from the mother.53 Expansion of a triplet repeat within exon 1 of the FMR1 X-linked gene causes the fragile X syndrome. Expansions of between 50 and 200 repeats are premutations. Evidence suggests that female carriers of premutations in the FMR1 gene are at increased risk of premature ovarian failure. Although it is difficult to be obtain precise information, the risk has been reported to be between 22% and 26%.54

Autoimmune Etiologies Autoimmune premature ovarian failure can be isolated or part of the polyglandular autoimmune syndromes (see Table 20-1).55,56 These syndromes are associated with ovarian failure in more than 60% of patients. Polyglandular autoimmune syndrome type1 is rare, occurs before adulthood, and is inherited in an autosomal recessive manner; its components include hypoparathyroidism, mucocutaneous candidiasis, hypoadrenalism, and primary hypogonadism. The adrenal autoimmunity is directed against the side chain cleavage and the 17-hydroxylase enzymes. Polyglandular autoimmune syndrome type 2 is more common, usually occurs in adults, has a female preponderance, and has a polygenic inheritance related to HLA-DR3 and HLA-DR4; its components include adrenal insufficiency, autoimmune thyroid disease, type 1 diabetes mellitus, and gonadal failure. The adrenal defect involves antibodies to the enzyme 21-hydoxylase. A spectrum of other autoimmune disorders has been recognized in patients with premature ovarian failure, including vitiligo, myasthenia gravis, Sjögren syndrome, systemic lupus erythematosus, celiac disease, rheumatoid arthritis, and pernicious anemia. Histologic evidence of lymphocytic oophoritis has been demonstrated in 11% of patients with premature ovarian failure; 78% of these patients were positive for steroid cell antibodies, suggesting an immune-mediated insult to the ovaries.57 The lympocytic infiltration seems to spare the primordial follicles. A loss of the regulatory/suppressive CD4+ cells may be the underlying mechanism for premature ovarian failure in patients with thymic aplasia, resulting in an exaggerated autoimmune damage to various organs, including the ovary.58 Circulating immunoglobulins that inhibit the binding of FSH to its receptor have been described.59 In a prospective clinical trial of 119 women with karyotypically normal spontaneous premature ovarian failure, testing for hypothyroidism (27%) and diabetes (3%) was judged to be worthwhile. It was suggested that tests for other possible associated diseases be based on associated clinical presentation.60 Steroid cell autoantibodies seen in Addison’s disease may crossreact with the theca interna/granulosa layers of the ovarian follicles, and their presence is a marker for the association of Addison’s disease and premature ovarian failure. Steroidogenesis enzymes can be targets of autoantibodies. Three percent of women with premature ovarian failure develop adrenal insufficiency (a 300-fold increase compared with the general population). Symptoms could include anorexia, weight loss, vague abdominal pain, weakness, fatigue, salt craving, and skin hyperpigmentation. The lack of consensus on ovary-specific antibodies as markers for ovarian autoimmunity has clinical and research consequences.

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Section 3 Adult Reproductive Endocrinology Variations in detection of ovarian autoantibodies are likely to be due to study design elements such as antibody test format and antigen preparation, in addition to the multiplicity of intraovarian targets potentially involved in ovarian autoimmunity, including ovarian cellular elements and oocyte-related antigens.61 Many studies only assess one target antigen, leaving individuals with ovarian autoimmunity unidentified.

Infectious Agents A rare type of infection related to premature ovarian failure is mumps oophoritis. It appears that this aberration in menstrual function and fertility may be related to the time during which the infection occurs as well as to the severity of the infection. In addition, it is apparent that mumps oophoritis may be a more frequent cause of premature ovarian failure than commonly suspected.62,63

Iatrogenic Etiologies

supply, with resulting ischemia. Multiple procedures on the same ovary can have a negative cumulative effect. The intraovarian use of electrocautery and other tissue destruction modalities may reduce the number of viable ovarian follicles.

Environmental Toxins Smoking, among other environmental factors, has been shown to accelerate the onset of menopause by approximately 2 years.80

Idiopathic Etiologies Many women with premature ovarian failure may have none of the above etiologies. Population-based studies have suggested an association between various epidemiologic parameters and risk of premature ovarian failure. A low socioeconomic status, a higher education level and nulliparity,81 a higher body mass index and anthropometric measurements have all been proposed risk factors for developing premature ovarian failure in different populations.82

Chemotherapy

Many chemotherapeutic agents used for the treatment of malignancies are toxic to the ovaries and cause ovarian failure. Chemotherapy is associated with exaggerated attrition of ovarian follicles through alteration of DNA, direct destruction of dividing granulosa cells, and damage to the oocytes.1,64–73 These effects may be preventable, as discussed in the Management of Premature Ovarian Failure section in this chapter. Radiation

The effect of radiation depends on age and the X-ray dose.74,75 Duration of time over which exposure occurs may also be important. Steroid levels begin to fall and gonadotropins rise within 2 weeks after radiation of the ovaries. Young women exposed to radiation are less likely to have immediate and permanent ovarian failure, possibly because of the higher number of oocytes present at younger ages. The risk of premature ovarian failure can be reduced in women undergoing pelvic irradiation by laparoscopically transposing the ovaries out of the pelvis before radiation.76 The risk does not appear to be reduced by treatment with hormone modulators before irradiation.77 The sensitivity of the cells to the adverse influences is related to the nature of the agent, the dose, and the patient’s age at the time of exposure; the younger the patient, the lesser the likelihood of complete cessation of gonad function as an immediate sequel to therapy.1,78 The duration of exposure to toxic agents may also be relevant. Resumption of menses and pregnancy have been reported after radiotherapy and chemotherapy.79 Surgery

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Surgical or vascular injury to the ovary may reduce the number of available ovarian follicles. Ovarian torsion and its effects on blood supply reduction may contribute to the damage. Operative laparoscopy has become a more commonly done procedure by an increasing number of surgical specialties. Direct surgical injury to the ovarian vessels within or outside the ovary can have deleterious effects. Destruction of intraovarian lesions such as endometriomas or other ovarian cysts may reduce intraovarian regional blood

Premature Ovarian Failure and Fertility It is important to appreciate that in premature ovarian failure, despite the occurrence of amenorrhea and elevation of the FSH levels, residual oocytes may still exist, albeit in significantly diminished numbers.1 Therefore the term premature menopause is not correct. Residual follicles, when present, usually exhibit episodic function, as opposed to the virtually inert oocyte–granulosa units seen in age-appropriate menopause.83 As many as 20% of women with premature ovarian failure will exhibit sporadic ovulatory cycles.84 Indeed, pregnancies have been reported in up to 8% of patients.85

DIAGNOSIS OF PREMATURE OVARIAN FAILURE Premature ovarian failure should be suspected in any woman younger than age 40 who presents with either amenorrhea or signs of hypoestrogenemia and menstrual irregularity. These women may go through a normal puberty and a variable period of cyclic menses followed by oligomenorrhea and amenorrhea (Table 20-2). Therefore, premature ovarian failure should always be included in the differential diagnosis of anovulation.

History and Physical Examination History and physical examination may reveal symptoms and signs of estrogen deficiency, such as hot flashes and urogenital atrophy with attenuated vaginal rugae and scant cervical mucus. The underlying ovarian defect may be manifest at varying ages, depending on the number of functional follicles left in the ovaries. The different symptoms may be regarded as phases in a process similar to perimenopausal change regardless of the actual age of the patient. If loss of follicles occurs rapidly before puberty, primary amenorrhea and lack of secondary sexual development ensue. The degree to which the adult phenotype develops and when the amenorrhea occurs depend on whether follicle loss took place before, during, or after puberty.

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Chapter 20 Premature Ovarian Failure Table 20-2 Potential Clinical Symptoms and Signs of Premature Ovarian Failure

goiter should be pursued. Evaluation for neurosensory deafness and a detailed eye examination should be considered. Hyperpigmentation, postural hypotension, and vitiligo may be signs of associated adrenal disease.

Younger than age 40 Gynecologic history Irregular menses or amenorrhea Anovulation or oligo-ovulation Hot flashes Urogenital atrophy Sexual infantilism Family history Mental retardation Premature ovarian failure Personal history Autoimmune disease Mumps infection Exposure to toxic agents (radiation, chemotherapy) Associated symptoms Fatigue Weight loss Anorexia Nausea Postural dizziness and salt craving Neurosensory deafness Dry eyes

Deafness can be suggestive of Perrault’s syndrome.44 There also appears to be an association of premature ovarian failure with dry eye syndrome.86 Family history of premature ovarian failure and familial mental retardation should be obtained. The risk of FMR1 mutation in patients with premature ovarian failure and no family history is approximately 6%. In patients with a family history of premature ovarian failure the risk is higher. History of mumps infection should be obtained. Exposure to radiation, chemotherapy, tobacco products, and other environmental toxins may result in accelerated ovarian follicular loss and should be noted. All prior ovarian surgeries should be documented. Fatigue, weight loss, anorexia, nausea, postural dizziness, and salt craving may suggest adrenal insufficiency. Most patients have normal results on physical examination except for urogenital atrophy (Table 20-3). However, features of Turner’s syndrome, such as short stature, low posterior hairline, high arched palate, shield chest with widely spaced nipples, and short fourth and fifth metacarpals, should be sought. Evidence of possible associated autoimmune diseases such as ptosis and

Table 20-3 Possible Physical Findings in Premature Ovarian Failure Short stature

Laboratory Evaluation Menopausal serum FSH levels (>40 IU/L) on at least two occasions in a woman younger than age 40 are sufficient for the diagnosis of premature ovarian failure. Any woman with irregular menses for 3 consecutive months requires FSH, estradiol, prolactin, and thyrotropin measurements to rule out premature ovarian failure among other hormonal etiologies. The progestin challenge test can be misleading in the early stages of premature ovarian failure. Significant levels of circulating estradiol can be present in women with little residual ovarian function. Once premature ovarian failure is diagnosed, the patient should be evaluated for associated autoimmune disorders. Testing for antiovarian antibodies is considered to be unreliable at this time. Far more critical is testing for antiadrenal antibodies. If they are positive further testing of adrenal function is necessary (Table 20-4). The most sensitive test is the corticotropin stimulation test. Women with premature ovarian failure are at increased risk of autoimmune thyroid disease. For this reason, thyrotropin, T4, and thyroid peroxidase autoantibodies should be obtained. Other tests for autoimmune disease include a sedimentation rate, complete blood count with differential, antinuclear antibody, and rheumatoid factor. Other tests to consider under specific circumstances are a fasting glucose test to check for diabetes mellitus, calcium and phosphorus to exclude hypoparathyroidism, pregnenolone to evaluate 17-hydroxylase deficiency in sexually infantile hypertensive women, and galactose-1-phosphate to evaluate for galactosemia. A karyotype is necessary to evaluate X chromosome abnormalities and the presence of Y chromosome material. Although most cases occur before age 30, some authorities feel that all patients with premature ovarian failure should have a karyotype. Testing for premutation in the FMR1 gene would identify fragile X pedigrees. In amenorrheic women who desire fertility, FSH, LH, and estradiol should be measured weekly for a month to detect any remaining ovarian follicular activity. The lack of significant rise of estradiol or decrease of FSH suggests irreversible ovarian failure, especially in the absence of any demonstrable antral follicles on ultrasound.82 Alternatively, indirect information about the remaining ovarian reserve of follicles in women with some menstrual function may

Low posterior hairline High arched palate Shield chest Widely spaced nipples Short 4th and 5th metacarpal Absence of vaginal rugae

Table 20-4 Suggested Initial Screening Tests for Associated Medical Disorders

Ptosis

Antiadrenal antibodies (adrenal disease) If positive, screen with corticotropin stimulation test

Goiter

Fasting glucose (diabetes)

Skin hyperpigmentation

Thyrotropin T4, antithyroid antibodies (thyroid disease)

Postural hypotension

Calcium and phosphorus (parathyroid disease)

Vitiligo

Complete blood count (pernicious anemia)

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Section 3 Adult Reproductive Endocrinology be obtained by measuring day 3 FSH and estradiol,23,87–89 performing a clomiphene challenge test,90 and obtaining an ultrasonographic antral follicle count.91

Ovarian Biopsies Ovarian biopsies are not necessary for clinical care. When done as part of a research protocol in women with premature ovarian failure, ovarian biopsies show either no follicles or a small number of follicles, sometimes with lymphocytic perifollicular infiltration consistent with an autoimmune process. In patients with the resistant ovary syndrome, many small follicles are found with little progress in folliculogenesis.82

Imaging In primary amenorrhea associated with hypergonadotropic hypogonadism and sexual infantilism, the ovarian remnants may exist as streaks, and transvaginal ultrasonography usually cannot detect any ovaries. Follicular cysts and pregnancies have been demonstrated in a subset of patients with high gonadotropin levels and menstrual irregularities diagnosed with premature ovarian failure. Pelvic ultrasonography for antral follicle count has been used as an indirect indicator of ovarian follicle reserve.91 Antral follicles will appear as round or oval echo-free structures up to 5 to 10 mm in diameter. Pelvic ultrasonography will sometimes reveal remaining follicles in patients 6 years after a diagnosis.90 Bone density should be performed as a baseline and as frequently as needed thereafter. However, it is critical to understand that the results need to be interpreted in light of the patient’s age (see Chapters 24 and 25). Treatment protocols may need to be modified to ensure that osteoporosis does not become a problem.

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Probably the most important lifestyle event for primary prevention is to stop smoking. Very little can be done to prevent premature ovarian failure caused by cytogenetic or infectious etiologies. Laparoscopic transposition of ovaries out of the pelvis before radiation reduces the risk of premature ovarian failure.92,76 This risk does not appear reduced by prior treatment with hormone modulators.77 Predictable ovarian failure related to premature ovarian aging, such as with familial premature ovarian failure, may allow several preventive intervention options, most of which remain experimental at this time. For the 10% of women in the general population who are expected to become menopausal by age 45, the critical point of 25,000 resting follicles would probably be reached 13 years earlier. By age 32, these women would begin a rapid decline of fertility and possibly have total loss of fertility by age 36. In the years following the diagnosis at age 32 or younger, these women will have a reproductive potential similar to a 37-year-old woman and could experience increased incidence of dizygotic twinning,93–95 increased incidence of aneuploidy88,96 and miscarriage,89 subfertility,90,97 and a relatively poor response to ovarian stimulation.

Under this scenario of fixed time intervals between premenopausal reproductive milestones, menstrual cycles may continue to be regular for 6 to 8 more years following the diagnosis of reduced ovarian follicular reserve.9,10,16, 98–101 The diagnosis may be suspected by finding reduced antral follicle counts,18-21,87 elevated FSH on the third day of menses and after a clomiphene challenge test, and lower inhibin B levels.23,88–90 There seems to be a large overlap between basal FSH levels of older and younger women, however.102 Variants of FSH receptor genotype were associated with different basal FSH levels and variable responses to ovarian stimulation with gonadotropins. A mildly elevated basal FSH level does not necessarily mean early ovarian aging.98,103–105 Serum antimüllerian hormone has been suggested as another marker.106,107 It is hoped that “DNA fingerprints” that identify women with a genetic predisposition to early ovarian aging may become available.10 For women at risk, it is wise to advise them to complete their families as soon as possible. For socioeconomic and career priority reasons, some of these women may elect to postpone childbearing, however. The details of surgical and nonsurgical options to preserve oocytes from being prematurely lost because of chemotherapy or premature ovarian aging are presented elsewhere in this book (see Chapter 32). The surgical approach involves excising some ovarian tissue followed by variable laboratory manipulation of the tissue. The birth of a healthy child from a frozen-thawed ovarian autograft in a 32-year-old woman with Hodgkin’s disease was reported recently.107 Crucial factors in the rapid depletion of the primordial follicles observed in the transplant can be attributed to the still rudimentary technical steps of tissue harvesting, preparation, and localization of the graft. The risk of reintroducing cancer cells through the grafted ovarian tissue calls for an extremely careful selection of patients for this still experimental treatment.108 The nonsurgical approach involves the use of hormonal manipulation to halt follicle depletion related to age or chemotherapy.72,73,109–112 Nuclear cloning techniques could also generate oocytes from stem cells.113 The recently described oogonia stem cells in postnatal ovaries, if confirmed, could also open new horizons in this arena.114 The nonsurgical approach seems to be preferred by a larger number of young American women.114

Counseling Patients determined to have premature ovarian failure should receive psychological, endocrinologic, and genetic counseling regarding the implications of their disease (Table 20-5).

Fertility Prognosis Pregnancies have been reported in women with premature ovarian failure and high gonadotropin levels.115 It has been Table 20-5 Premature Ovarian Failure Patients Referred for Genetic Counseling Women with a family history of premature ovarian failure Women with premature ovarian failure and a chromosomal abnormality Women with premature ovarian failure and family history of mental retardation

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Chapter 20 Premature Ovarian Failure suggested that approximately one half of young women who have 46,XX spontaneous premature ovarian failure have ovarian follicles remaining in the ovary.116 These follicles function intermittently and unpredictably, and pregnancies can occur without intervention. At present, there are no proven therapies that will improve follicular function for these women. Premature ovarian failure patients still have a 5% to 10% chance to conceive after diagnosis.117 A randomized trial of hormone replacement in this setting showed that folliculogenesis occurred often but was less frequently followed by ovulation and even less frequently by pregnancy (up to 14%). Controlled trials have failed to demonstrate any success with any treatment in excess of the placebo.118,119 Estrogen therapy did not improve the rate of folliculogenesis, ovulation, or pregnancy.118 The clinician should inform premature ovarian failure patients that there is a small likelihood of spontaneous pregnancy. Women desirous of achieving pregnancy are still best served by donor oocytes120; an increased susceptibility to poor ovarian response exists when utilizing a related donor. It has been suggested that corticosteroid treatment may result in normalization of serum gonadotropins, increasing serum estradiol, ultrasonographic evidence of follicular growth, and conception, especially in women with premature ovarian failure associated with autoimmune disease.121 However, this treatment is considered experimental.

Hormone Replacement The diagnosis of premature ovarian failure results in multiple profound ramifications, including psychological devastation,122 multisystem effects of estrogen deprivation such as osteoporosis,123,124 cardiovascular morbidity,123,125 depression, and cognitive difficulties.126 Bone mineral density scores of approximately 1 standard deviation below the mean for age-comparable women have been demonstrated in patients with premature ovarian failure, despite taking estrogen replacement,1 with a 2.6fold increase in risk for hip fractures. A higher mortality rate in association with diminishing age of menses cessation has been reported.127 Snowdown and colleagues127 found an odds ratio (OR) for mortality of 1.95 (CI, 1.24–3.07) for women developing premature ovarian failure. The excess mortality was associated with coronary artery disease and stroke. This persists despite use of estrogen replacement, with the OR for mortality being 3.33 (CI, 1.14–9.72) for patients ever using estrogen replacement therapy. Women in specific pathophysiological subgroups of premature ovarian failure (i.e., autoimmune, X chromosome-related) may be more susceptible to vascular disease on the basis of the underlying defect that caused the premature ovarian failure. Other women with premature ovarian failure (i.e., chemotherapy- or radiationinduced) may be more prone to long-term diseases and mor-

tality by virtue of their primary disease that necessitated chemoradiation therapy. Hormone replacement therapy, as an “antidote” for aging in women, is becoming a less compelling option as results accumulate and alternative nonhormonal medications demonstrate efficacy against the common diseases of aging. The safety, dose, administration route, and appropriateness of selection criteria of hormonal and nonhormonal interventions are discussed elsewhere in this book and for the most part are applicable to premature ovarian failure. Typically these patients require higher doses, such as 100 μg estradiol transdermal patch to give a serum estradiol level of 100 pg/mL. Cyclic progesterone is also required. Alternatively, because of the relatively younger group age and the possibility of unpredictable ovulation, the use of birth control pills may be appropriate if the patient is not interested in pregnancy. Adequate calcium intake, vitamin D, and exercise should be reinforced. In general, treatment of premature ovarian failure should be directed toward its specific cause, if possible. Associated disease processes affecting other glands or tissues (such as thyroid and adrenals) should be addressed as well.

CONCLUSION Multiple etiologies can result in premature ovarian failure before age 40. Some of these lend themselves to possible fertility preservation technologies advanced over the past decade. Of all women, 10% may become menopausal by age 45 and these may have experienced an accelerated decline of fertility before age 32. These women may be considered to have early ovarian aging in spite of having menstrual function. Appropriate clinical history, ultrasound, and hormonal testing may help identify these asymptomatic patients at risk.

PEARLS ●

●

●

● ●

●

● ●

Premature ovarian failure is not synonymous with premature menopause. The most common ascertainable causes of premature ovarian failure are genetic and autoimmune. Premature ovarian failure is associated with a higher risk for the occurrence of familial fragile X syndrome. It is important to exclude autoimmune disorders. Premature ovarian failure is associated with a higher probability of other autoimmune phenomena, such as autoimmune thyroid and adrenal disease. Testing for antiovarian antibodies is not indicated because of poor reproducibility of the assays. A karyotype should be obtained in women under age 40. Higher doses of hormone replacement therapy may be required because of the young age of patients.

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Section 3 Adult Reproductive Endocrinology 107. Donnez J, Dolmans MM, Demylle D, et al: Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 364:1405–1410, 2004. 108. Baird DT, Webb R, Campbell BK, et al: Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at –196°C. Endocrinology 140:462–471, 1999. 109. Ataya K, Gitiforooz H: Progesterone and LHRH agonists delay the rate of ovarian follicle loss in rhesus monkeys. Presented to the American Society of Human Genetics, 50th Annual Meeting in Philadelphia, October 2000. 110. Ataya KM: Postponing menopause in rhesus monkeys using LHRH agonist + progesterone by altering the dynamics of follicle growth and atresia. Presented at the Society of Gynecological Investigation, Conference in Toronto, March 2001. 111. Ataya KM: LHRH agonist does not retard physiologic ovarian follicle loss in rhesus monkeys. Presented at the Society of Gynecological Investigation, Conference in Toronto, March 2001. 112. Blumenfeld Z: Ovarian cryopreservation versus ovarian suppression by GnRH analogues: Primum non nocere. Hum Reprod 19:1924–1925, 2004. 113. Hubner K, Fuhrmann G, Christenson LK, et al: Derivation of oocytes from mouse embryonic stem cells. Science 300:1251–1256, 2003. 114. Ataya K, McMullen S: Attitude of American young women towards delaying reproductive aging. Presented to the North American Menopause Society, 11th Annual Meeting in Orlando, Florida, September 2000. 115. Ataya KM, Mudawwar F, Allam C, Karam K: Hyper-gonadotropism with pregnancy. Am J Obstet Gynecol 146:341–343, 1983. 116. Nelson LM, Bakalov VK: Mechanisms of follicular dysfunction in 46,XX spontaneous premature ovarian failure. Endocrinol Metab Clin North Am 32:313–337, 2003.

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117. van Kasteren YM, Schoemaker J: Premature ovarian failure: A systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 5:583–592, 1999. 118. Taylor A, Adams J, Mulder J, et al: A randomized, controlled trial of estradiol replacement therapy in women with hypergonadotropic amenorrhea. J Clin Endocrinol Metab 81:3615–3621, 1996. 119. Lieman H, Santoro N: Premature ovarian failure: A modern approach to diagnosis and treatment. Endocrinologist 7:314–321, 1997. 120. Sauer MV, Paulson RJ, Macaso TM, et al: Oocyte and pre-embryo donation to women with ovarian failure: An extended clinical trial. Fertil Steril 55:39–43, 1991. 121. Orshan SA, Furniss KK, Forst C, Santoro N: The lived experience of premature ovarian failure. JOGNN 30:202–208, 2001. 122. Conway GS: Premature ovarian failure. Curr Opin Obstet Gynecol 9:202–206, 1997. 123. Pouilles JM, Tremolliers F, Bonneu M, Ribot C: Influence of early age at menopause on vertebral bone mass. J Bone Min Res 9:311–315, 1994. 124. Joakimsen O, Bonaa KH, Stensland BE, Jacobsen BK: “Populationbased study of age at menopause and ultrasound assessed carotid atherosclerosis: The Tromso study. J Clin Epidemiol 53:525–530, 2000. 125. Shepard JE: Effects of estrogen on cognition, mood and degenerative brain diseases. J Am Pharmaceut Assoc 41:221–228, 2001. 126. Cooper GS, Sandler DP: Age at natural menopause and mortality. Ann Epidemiol 8:229–235, 1998. 127. Snowdown DA, Kane RL, Beeson WL, Burke GL, et al: Is early natural menopause a biological marker of health and aging? Am J Public Health 79:709–714, 1989.

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Section 3 Adult Reproductive Endocrinology Chapter

21

Abnormal Uterine Bleeding William W. Hurd, Geoffrey D. Towers, and Gary Ventolini

BACKGROUND AND DEFINITIONS Abnormal uterine bleeding (AUB) is among the most common diagnostic and therapeutic challenges faced by gynecologists. Complaints of AUB account for more than a third of gynecology visits.1 An indication of how difficult this problem can be to treat is that AUB remains the indication for half the hysterectomies performed in the United States. The inability to find any pathologic abnormality in 20% of these hysterectomy specimens suggests that AUB is often caused by potentially treatable hormonal or systemic conditions.2 Each gynecologist needs to develop an approach to AUB that is expedient, cost-effective, and successful. Focused evaluation and appropriate treatment depend on knowing the most likely causes of AUB and their most common presenting symptoms.

Abnormal Uterine Bleeding Terminology The following descriptive terms are often used to describe AUB: ● ●

●

● ●

●

● ●

Definition Abnormal uterine bleeding is an all-inclusive term used to describe any uterine bleeding outside the parameters of normal menstruation that occurs during the reproductive years. It does not include bleeding that originates lower in the genital tract (i.e., the vagina or vulva). It usually does include bleeding originating from either the uterine fundus or cervix, because these causes are difficult to distinguish clinically, and should both be considered in all patients presenting with bleeding from the uterus. Abnormal bleeding can occur during childhood or after the menopause. However, because the differential diagnoses and thus the diagnostic approach are markedly different during these time periods, bleeding in these age groups is considered separately in Chapters 13 and 24.

Normal Menstruation Exactly what is considered normal menstruation is somewhat subjective and often varies between individual women and certainly between cultures. However, normal menstruation (eumenorrhea) can be defined as bleeding that occurs after ovulatory cycles every 21 to 35 days, lasts 3 to 7 days, and is not excessive. The total amount of blood lost during a normal menstrual period has been found to be no more than 80 mL, although this is difficult to estimate clinically, because much of the menstrual effluent is dissolved endometrium.3 Normal menses do not cause severe pain, do not include passage of identifiable clots, and do not require the patient to change pads or tampons more than once per hour. It follows that AUB is any bleeding that falls outside these parameters.

●

●

Dysmenorrhea—painful menstruation Polymenorrhea—frequent menstruation with bleeding intervals shorter than 21 days Menorrhagia—excessive menstrual bleeding, in terms of flow (>80 mL) and/or duration (>7 days). This implies regular ovulatory cycles. Metrorrhagia—irregular menstruation intervals Menometrorrhagia—irregular menstruation intervals with excessive flow and/or duration Oligomenorrhea—menstruation fewer than 9 times per year (i.e., average bleeding intervals >40 days) Hypomenorrhea—very light or short duration menstruation Intermenstrual bleeding—uterine bleeding in between apparently ovulatory menses Amenorrhea —absence of menses for at least 6 months, or three cycles Postmenopausal bleeding—uterine bleeding more than 12 months after cessation of menses.

These various types of characteristic bleeding patterns can give clues as to the etiology and help guide the diagnostic workup. However, because of the marked variation in presentation and the common existence of multiple potential causes of bleeding, presentation alone cannot be used clinically to exclude common conditions. Dysfunctional Uterine Bleeding: An Obsolete Diagnostic Term

Dysfunctional uterine bleeding is a traditional term that was used for years to refer to excessive uterine bleeding in cases where no uterine pathology could be identified.4 However, the development of a greater understanding of AUB and the continuing development of more sophisticated diagnostic techniques has made this term outdated. In most cases, bleeding unrelated to uterine pathology can be determined to be due to chronic anovulation (polycystic ovary syndrome and related conditions), exogenous steroid hormones (contraceptives or hormone replacement therapy), or hemostatic disorders (e.g., von Willebrand’s disease). In many cases that would have been referred to as dysfunctional uterine bleeding in the past, modern diagnostic techniques identify uterine or systemic pathologies that (1) result in anovulation (e.g., hypothyroidism), (2) result from anovulation (e.g., endometrial hyperplasia or cancer), or (3) coexist with anovulatory bleeding but may or may not be causal (e.g., leiomyomata).

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Section 3 Adult Reproductive Endocrinology Table 21-1 Common Uterine Conditions Associated with Abnormal Uterine Bleeding Pregnancy Early normal pregnancy Spontaneous abortion Ectopic pregnancy Gestational trophoblastic disease Infection Pelvic inflammatory disease Endometritis Cervicitis

spontaneous abortion, whereas the remaining half will ultimately prove to have a viable pregnancy. Ectopic pregnancies, which currently make up 2% of all pregnancies, will commonly present with AUB as one of the symptoms as well.7 Gestational trophoblastic disease is another pregnancy-related problem that presents as AUB in more than 80% of cases.8 Pregnancy must be ruled out in every case of AUB in reproductive-age women, no matter how obvious any alternative causal diagnoses might be.

Uterine Pathology An important and expected priority for gynecologists is to precisely identify uterine pathology that might contribute to uterine bleeding (see Table 21-1). Most of these diagnoses can be determined to be related to infection and neoplasm. An additional common uterine pathology related to AUB is adenomyosis.

Neoplasms Benign Leiomyoma Endometrial polyps Endocervical polyps Malignant Endometrial carcinoma Cervical carcinoma Adenomyosis

Infection Table 21-2 Incidence of Endometrial Polyps and the Risk of Associated Malignancies as a Function of Age. Age Group (Years of age)

Incidence of Endometrial Polyps

Risk of Associated Malignancy

25–35

9%

2%

36–45

27%

11%

46–55

29%

15%

56–65

18%

17%

>65

17%

55%

Data from Hileeto D, Fadare O, Martel M, Zheng W: Age-dependent association of endometrial polyps with increased risk of cancer involvement. World J Surg Oncol 3:8, 2005.

Clinically, treatment will always be the most effective when specific causes of AUB can be identified. Because grouping widely divergent causes of AUB together in a poorly defined group is unlikely to improve diagnosis or treatment, a national consensus group has recently concluded that dysfunctional uterine bleeding no longer has any usefulness in clinical medicine.5

ABNORMAL UTERINE BLEEDING CAUSED BY UTERINE CONDITIONS Different causes of AUB can be grouped according to their basic pathophysiology (Tables 21-1 and 21-2). The clinician must keep in mind that any individual patient can simultaneously have two or more causes of uterine bleeding. For this reason, the workup must evaluate patients simultaneously for the most likely and most serious anatomic and systemic etiologies based on clinical presentation.

Pregnancy

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Normal pregnancies, spontaneous abortions, and ectopic pregnancies together represent the most common causes of AUB in the reproductive-age group. First-trimester bleeding occurs in up to 25% of all pregnancies and is associated with an increased risk of several common complications.6 In approximately half of these cases, bleeding will be an early symptom of impending

Infection is a surprisingly common cause of AUB and is often the basis of what appears to be AUB. In obvious cases of pelvic inflammatory disease (see Chapter 33), approximately 40% of the patients will present with vaginal bleeding.9 An underrecognized cause of uterine bleeding is endometritis. Although chronic endometritis was classically diagnosed only when plasma cells were found on endometrial biopsy, recent studies have found an association between AUB and reactive changes in the surface endometrium, but no association with the presence of a particular type of inflammatory cell.10 Other studies have verified that subclinical endometritis is a common finding in patients diagnosed with AUB and can be related to any of a number of pathogens.11 Cervicitis is another common cause of AUB characterized by postcoital spotting. In addition to common sexually transmitted diseases (i.e., chlamydia and gonorrhea), other vaginal flora and pathogens can be involved.12 Postcoital bleeding is the most common presenting symptom in women found to have chlamydia infections.13 Neoplasms

AUB can be a marker for gynecologic neoplasms. These neoplasms can be benign (e.g., leiomyoma, endometrial or endocervical polyps) or malignant (e.g., endometrial or cervical carcinoma). Focal intracavitary lesions account for up to 40% of cases of AUB.14 Ovarian neoplasms can indirectly cause irregular bleeding by interfering with ovulation Some of the most common neoplasms known to cause AUB are reviewed here. Leiomyomas

These benign myometrial tumors are remarkably common and by age 50 can be found in nearly 70% of white women and more than 80% of black women on ultrasonographic examination.15 However, many of these leiomyomas are subclinical, and estimates of symptomatic leiomyomas range from 20% to 40%. Menorrhagia is more likely to be related to those lying immediately adjacent to the endometrium (e.g., submucosal or intracavitary). This is in contrast to the majority of leiomyomas that are located within the wall of the uterus (intramural), immediately adjacent to the uterine serosa (subserosal), or attached to the external uterine surface by a stalk (pedunculated).

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Chapter 21 Abnormal Uterine Bleeding Endometrial Polyps

Adenomyosis

Endometrial polyps are localized overgrowths of the endometrium that project into the uterine cavity. Such polyps may be broadbased (sessile) or pedunculated. Endometrial polyps are surprisingly common in both premenopausal and postmenopausal women, and are found in at least 20% of women undergoing hysteroscopy or hysterectomy.16 The incidence of these polyps rises steadily with increasing age, peaks in the fifth decade of life, and gradually declines after menopause. Studies have found that from 5% to 33% of premenopausal women complaining of AUB will be found to have endometrial polyps.17,18 Endometrial polyps are commonly found in patients with a long history of anovulatory bleeding, suggesting that polyps might be the result of chronic anovulation in some women. Polyps are also found in women complaining of postmenstrual spotting or bleeding in ovulatory cycles or during cyclic hormonal therapy. Although endometrial polyps in premenopausal women are usually benign, the risk of associated endometrial malignancy increases significantly with age, such that in women older than age 65 the risk of malignancy is greater than 50% (see Table 21-2).16 In one pathologic study of 513 women with endometrial polyps, associated carcinomas were endometrioid in 58, serous in 6, carcinosarcoma in 1, and clear cell in 1.16

Adenomyosis is the benign invasion of endometrium into the myometrium. Microscopic examination of the uterus reveals endometrial glands and stroma deep within the endometrium surrounded by hypertrophic and hyperplastic myometrium. This histopathologic diagnosis is made on careful microscopic evaluation of uterine specimens in more than 60% of hysterectomy specimens.22 Clinically, two thirds of patients with adenomyosis will complain of menorrhagia and dysmenorrhea, and pelvic examination usually reveals a diffusely enlarged and tender uterus. Diagnostic tests that are suggestive of adenomyosis include transvaginal ultrasonography and magnetic resonance imaging (MRI). The sensitivity for ultrasonography probably approaches 50%, and the sensitivity of MRI ranges from 80% to 100%.22,23 Hopefully, more effective diagnostic tests and treatment besides hysterectomy will be developed in the future.

Endometrial Cancer

The single most important disease to identify early in the evaluation of a perimenopausal or postmenopausal woman is endometrial cancer. In women age 40 to 49, the incidence of endometrial carcinoma is 36 per 100,000.19 After the menopause, approximately 10% of women with AUB will be found to have endometrial cancer, and the incidence increases with each decade of life thereafter. Endocervical Polyps

These soft, fleshy growths originate from the mucosal surface of the endocervical canal. They usually hang from a stalk and protrude through the cervical os, although some are broad based. They usually range in size from 3 to 20 mm, but are occasionally even larger. The cause of endocervical polyps is unclear, but they are known to be more frequent in women on oral contraceptives or with chronic cervicitis. Microscopically, endocervical polyps consist of a vascular core surrounded by a glandular mucous membrane and may be covered completely or partially with stratified squamous epithelium. In some cases, the connective tissue core may be relatively fibrous. Endocervical polyps removed from women taking oral contraceptives often show a pattern of microglandular hyperplasia.20 Endocervical polyps are relatively common in sexually active women and are rare before menarche. Many endocervical polyps are asymptomatic and are discovered incidentally on visual examination of the cervix. When symptomatic, these polyps usually manifest as intramenstrual or postcoital spotting. Cervical Cancer

As many as 17% of women presenting with postcoital spotting will be found to have cervical dysplasia; 4% will have invasive cancer.21 In the absence of a visible lesion, Papanicolaou smears and colposcopy (if indicated) are important diagnostic tools. In the presence of a visible cervical lesion, biopsy is the most important technique for confirming the clinical diagnosis.

ABNORMAL UTERINE BLEEDING UNRELATED TO UTERINE PATHOLOGY Many women experience heavy or irregular menstrual bleeding that is not caused by an underlying anatomic abnormality of the uterus. Although anovulatory bleeding is one of the most common underlying causes, a number of other unrelated causes, such as exogenous hormones and bleeding disorders, must also be considered (Table 21-3).

Table 21-3 Causes of Abnormal Uterine Bleeding Unrelated to Uterine Pathology* Exogenous hormones Hormone contraceptives Hormone replacement therapy Ovulation defects Physiologic oligo-ovulation Perimenarchal Perimenopausal Polycystic ovary syndrome Hyperandrogenic states Congenital adrenal hyperplasia, adult-onset Cushing’s syndrome Ovarian and adrenal tumors Systemic diseases that interfere with ovulation Hypothyroidism Hyperprolactinemia Renal failure Liver disease Endometrial atrophy Menopause Premature ovarian failure Hypogonadotropic hypogonadism Exogenous progestins Hyperandrogenemia Coagulopathy Hereditary bleeding disorders Von Willebrand disease Disorders of platelet function and fibrinolysis Acquired bleeding abnormalities Idiopathic thrombocytopenia purpura Leukemia Aplastic anemia Anticoagulation therapy *Referred to as “dysfunctional uterine bleeding” in the past.

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Section 3 Adult Reproductive Endocrinology Exogenous Hormones Hormonal therapy has become one of the most common causes of AUB. Irregular bleeding is one of the most common symptoms in women receiving contraceptive therapy and hormone replacement therapy (HRT) and is the most common reason for discontinuation of these therapies. Hormone Contraceptives

Today, approximately 10 million women in the United States use some type of hormonal contraception, including combination oral contraceptives, progestin-only pills, depot medroxyprogesterone acetate injections, progestin-containing intrauterine devices, subdermal levonorgestrel implants, transdermal combination hormone patches, and intravaginal rings (see Chapter 26). In addition to being a common reason to visit primary care physicians, AUB is a major cause of contraception discontinuation and subsequent unplanned pregnancy. During the first 3 months of combination oral contraceptive use, as many as one third of women will experience AUB. For the majority of women, the most effective treatment approach is patient reassurance and watchful waiting. As the uterus adapts to the new regimen of hormonal exposure, the monthly withdrawal bleeding becomes regular, lighter, and less painful than natural menstruation in most women. If abnormal bleeding persists beyond 3 months, other common causes should be excluded. In young sexually active women, sexually transmitted diseases should be excluded; in one study, almost one third of women on oral contraceptives who experienced abnormal bleeding were found to have otherwise asymptomatic Chlamydia trachomatis infections.24 If no cause for AUB other than hormonal therapy is found, treatment options include the use of supplemental estrogen and changing to an oral contraceptive with a different formulation with a different progestin or higher estrogen content (see Chapter 26). Women using progestin-only contraceptives have an even greater risk of continued AUB than those using combined oral contraceptives. Prolonged exposure to progestins results in a microscopic condition sometimes called pseudoatrophy (see Endometrial Atrophy in this chapter). When reassurance is not sufficient, administration of supplemental estrogen during bleeding episodes is sometimes useful. Hormone Replacement Therapy

300

Hormone replacement therapy (HRT) after the menopause is a common iatrogenic cause of AUB. Unopposed daily estrogen therapy is associated with the highest rates of irregular bleeding and subsequent discontinuation of therapy.25 The addition of sequential or continuous oral progestins is associated with decreased irregular bleeding and reduced rate of endometrial hyperplasia. Sequential progestins result in the lowest rate of irregular bleeding during the first year of therapy, but the rate for sequential and continuous therapy is similar thereafter. Each selective estrogen receptor modulator (SERM) is associated with a distinctive risk of AUB, which varies according to their effect on the endometrium. Tamoxifen, the first SERM used clinically as adjuvant treatment for breast cancer, exhibits antiestrogenic activity in the breast but stimulates the endometrium.26 As a result, tamoxifen has an incidence of postmenopausal vaginal bleeding similar to unopposed estrogen and likewise

increases the risk of endometrial pathology, including endometrial polyps, hyperplasia, and cancer. Raloxifene, a SERM approved for the prevention of osteoporosis, has little if any estrogenic effect on the uterus, resulting in atrophic endometrium.27 As a result, the risk of vaginal bleeding for women taking raloxifene is not increased compared to women not taking any form of HRT.

Ovulation Defects Abnormal or absent ovulation is one of the most common causes of AUB during the reproductive years. A brief description of normal menstrual physiology (which is covered in depth in Chapter 1) is helpful in understanding anovulation as an underlying cause of AUB. Normal Menstruation

Each month, the endometrium of normally ovulating women is exposed to physiologic levels of estradiol (50 to 250 pg/mL) accompanied for the last 14 days of each cycle by progesterone (midluteal phase >12 nmol/L). The result is a structurally stable endometrium 5 to 20 mm thick as measured by transvaginal ultrasound. Withdrawal of progesterone and estrogen results in menstruation, which involves the breakdown and uniform shedding of much of the functional layer of the endometrium, which is enzymatically dissolved by matrix metalloproteinases.28 Normal menses occur every 28±7 days, with duration of flow of 4±2 days and a blood loss of 40±40 mL.29 Hemostasis is achieved by a combination of normal coagulation mechanisms and vasoconstriction of the spiral arterioles. Oligo-ovulation and Anovulation

Irregularity or absence of ovulation is surprisingly common among reproductive-age women not using hormonal contraception. In the perimenarchal years, adolescents often have a number of anovulatory cycles as part of the maturation process, but only occasionally do they complain of clinically significant AUB. In the years immediately preceding menopause, anovulatory cycles again become more common for many women. These episodes of endometrial exposure to unopposed estrogen increase the risk of not only AUB, but also endometrial hyperplasia and endometrial cancer. During the intervening years, both chronic and intermittent intervals of anovulation can occur, often as the result of treatable underlying conditions. Mechanism of Anovulatory Bleeding

Anovulation results in AUB as a result of chronic exposure of the endometrium to estrogen without the benefit of cyclic exposure to postovulatory progesterone. Endometrium thus exposed to unopposed estrogen becomes abnormally thickened and structurally incompetent. The result is asynchronous shedding of portions of the endometrium unaccompanied by vasoconstriction. The bleeding associated with unopposed estrogen exposure is often heavy. Because the blood has not been lysed by endometrial enzymes, blood clots are often passed, resulting in increased menstrual cramping in many women. Prolonged periods of bleeding also appear to predispose to subclinical endometritis, which exacerbates bleeding further and is often unresponsive to hormonal therapy.

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Chapter 21 Abnormal Uterine Bleeding Polycystic Ovary Syndrome

The most common causes of chronic anovulation are grouped together under a constellation of symptoms referred to as polycystic ovary syndrome (PCOS) (see Chapter 15). PCOS is a heterogeneous endocrine and metabolic disorder that affects 6% to 10% of reproductive-age women.30 This syndrome is diagnosed when a woman without an underlying condition is found to have two out of the following three criteria: (1) oligo-ovulation or anovulation, (2) hyperandrogenism and/or hyperandrogenemia, and (3) polycystic ovaries.31 These women have circulating estrogen levels in the normal range but anovulatory progesterone levels. Polycystic ovary syndrome is often the result of insulin resistance.30 In today’s culture, insulin resistance is often related to obesity. However, not all women with PCOS have insulin resistance and obesity. Insulin resistance is a common but not universal metabolic disorder underlying PCOS.32 The mechanism whereby insulin resistance results in PCOS is fascinating.33 Insulin increases production of androgens by both the ovaries (primarily androstenedione and testosterone) and adrenal gland (primarily dihydroepiandrosterone). In the ovary, insulin increases androgen secretion by thecal cells in an LHdependent process and ovarian stroma cells. These increased androgens contribute to the hirsutism and may contribute to the increased body mass often seen in PCOS patients. These androgens can be aromatized peripherally in both fat and muscle to estrogens (primarily estrone), which acts on the pituitary to increase secretion of LH, which in turn stimulates the ovaries to secrete more androgens in concert with insulin. The resulting positive feedback loop is believed to be the cause of many cases of PCOS. The accuracy of this interpretation is supported by the observation that in many overweight patients, either weight loss or the use of an insulin-sensitizing agent (e.g., metformin) will simultaneously improve insulin resistance and restore regular ovulatory cycles.33 Systemic Diseases That Can Mimic PCOS

Some patients who are oligo-ovulatory or anovulatory have an underlying systemic disease, and these patients can be clinically indistinguishable from PCOS. Although some diseases can be detected with appropriate testing, not all of these systemic conditions can be treated such that the symptoms of PCOS completely resolve. Conditions that can result in signs and symptoms identical to PCOS can be divided into two groups. The first group includes conditions that cause hyperandrogenemia, which can in turn interfere with ovulation and result in a clinical picture identical to PCOS.34 These include adult-onset congenital adrenal hyperplasia, Cushing’s syndrome and disease, and androgen-secreting neoplasms of the ovary or adrenal gland. Adult-onset congenital adrenal hyperplasia should be suspected whenever PCOS symptoms occur simultaneously with menarche. Cushing’s and androgen-secreting tumors should be suspected when hyperandrogenism and ovulation dysfunction present rapidly in a woman with previously normal menstrual cycles. Evaluation and management of these specific syndromes are discussed in Chapters 18 and 22. The second group consists of any systemic condition that can interrupt ovulation. Both hypothyroidism and hyperprolactinemia are relatively common conditions that may have no symptoms other than interference with ovulation. Simple blood tests can

screen for these conditions in the initial evaluation of apparent PCOS. In addition, any serious systemic disease can interfere with ovulation—most notably, renal failure and chronic liver disease. Both of these systemic disorders can affect hemostasis. Patients with serious systemic diseases usually manifest significant symptoms in addition to ovulatory dysfunction and AUB.35

Endometrial Atrophy Endometrial atrophy from any cause can result in AUB, usually described as spotting. The significance of this type of AUB is that it is indistinguishable from the earliest symptoms of endometrial cancer and thus must be carefully evaluated in the perimenopausal and postmenopausal woman. Hypoestrogenemia most commonly occurs as a result of surgical or natural menopause. Although natural menopause occurs at an average age of approximately 51 years, 2% of women undergo premature menopause before age 40 years. Hypoestrogenemia also occurs in women with normal ovaries who lack gonadal hormonal stimulation because of pituitary or hypothalamic pathology, descriptively grouped together as hypogonadotropic hypogonadism. Causes of this condition include hypothalamic amenorrhea, usually secondary to conditions such as anorexia nervosa, repetitive or prolonged strenuous exercise, or starvation, and the relatively uncommon pituitary failure. Hypoestrogenemia can also be secondary to hyperprolactinemia. Histology

Histologically, hypoestrogenemia leads to atrophy of both endometrial glands and stroma. Scanty, small glands are seen in dense stroma. The result is thin endometrium less than 5 mm thick on transvaginal ultrasonography. Prolonged exposure to exogenous progestins, with or without estrogen, can also result in endometrial atrophy. Long-term use of combination oral contraceptives results in poorly developed glands lined by a single layer of low columnar to cuboidal cells. Secretory changes are minimal, but stromal decidualization is present; the result is discordance between small inactive glands and decidualized stroma. Numerous granular lymphocytes are often present. Progestin-only contraception results in endometrial atrophy with sparse, narrow glands lined by flattened epithelium in a spindle-cell stroma but no decidual reaction. Women with hyperandrogenemia can develop a similar clinical and histologic picture.

Coagulopathy A surprisingly common cause of menorrhagia is one of several inborn or acquired conditions that interfere with normal hemostatic mechanisms in the case of vascular interruption. Hereditary Bleeding Disorders

Von Willebrand’s disease and less common disorders of platelet function and fibrinolysis are characterized by excessive menstrual bleeding that begins at menarche and is usually regular. As many as 20% of adolescents who present with menorrhagia significant enough to cause anemia or hospitalization have a bleeding disorder, and thus should undergo an evaluation for coagulopathy. However, it is important to remember that most AUB in this age group is probably due to anovulation.36

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Section 3 Adult Reproductive Endocrinology The most common bleeding disorder is von Willebrand’s disease, which affects 1% to 2% of the population.37 This hereditary deficiency (or abnormality) of the von Willebrand factor (vWF) results in decreased platelet adherence. Von Willebrand factor interacts with platelets to form a platelet plug. A fibrin clot will then form on this plug. There are three main types of von Willebrand’s disease. The mild form (type 1) is responsible for more than 70% of cases and is an absolute decrease in the protein. The mechanism by which an abnormal factor leads to bleeding at the level of the endometrium is unclear. The vast majority of women with von Willebrand’s disease report AUB, specifically menorrhagia. The prevalence of this disorder in adult women with menorrhagia can range from 7% to 20%. Other inherited conditions include thrombocytopenias and rare clotting factor deficiencies (e.g., factor I, II, V, VII, X, XI, XIII deficiencies). Acquired Bleeding Disorders

New onset of extremely heavy menses not amenable to hormonal therapy can sometimes be related to acquired bleeding abnormalities causing accelerated platelet destruction, such as idiopathic thrombocytopenic purpura (ITP), hematologic diseases affecting platelet production, such as leukemia, or hematologic diseases affecting platelet function (thrombocytopathies). Other systemic disorders such as sepsis and liver disorders can also cause an acquired hemostatic disorder resulting in bleeding. Anticoagulant Therapy

Excessive bleeding can sometimes be a significant problem for woman taking anticoagulant therapy, such as warfarin or heparin. Fortunately, most women taking anticoagulants do not have problems with AUB, which is considered to be an adverse reaction to anticoagulant therapy. Life-threatening genital bleeding in women taking anticoagulants is rare but may require emergency hysterectomy.38

CLINICAL EVALUATION OF ABNORMAL UTERINE BLEEDING When evaluating a woman with AUB, the workup should be tailored according to age and presentation in order to be the most expedient and cost-effective (see Table 21-1). At the same time, the clinician must be aware of common causes of AUB that might not be clinically obvious but still must be excluded. An important fact to keep in mind is that AUB can often have more than one cause. Sometimes subtle comorbid conditions, such as anovulation and secondary endometritis, make singlefactor therapy surprisingly ineffective.11 In other women, obvious causes of chronic anovulation can be associated with endometrial hyperplasia and/or cancer. Careful evaluation of the patient for multiple simultaneous causes of AUB is requisite.

History

302

A careful history is the most important factor in determining the appropriate diagnostic approach. This should include the usual and recent menstrual patterns, the extent of recent bleeding, sexual activity, and contraception. A personal or family history of a bleeding disorder should be documented. Important questions include symptoms of pregnancy, infection, changes in body hair, excessive bleeding, and systemic disease. Current medication

and information about previous Pap smears are also important. The review of systems should include subtle symptoms of systemic disease, such as weight gain or loss, abdominal swelling, somnolence, and nipple discharge. Pregnancy

In reproductive-age women, the presence of signs and symptoms of pregnancy is important to ascertain. Current contraceptive methods and past pregnancy history are likewise important. Characterization of Bleeding

Once pregnancy is excluded, the amount and character of the bleeding is the most important information. Careful, stepwise retrospective questioning will usually give a clear picture of the bleeding pattern over the previous days, months, and even years. In nonemergency cases, the use of a prospective menstrual calendar is an excellent way to document the problem as well as the response to therapy (Fig. 21-1). It is important to determine when the bleeding problems were first noticed, because menorrhagia starting at menarche should alert the clinician to the possibility of an underlying bleeding disorder. The amount of bleeding is probably the most difficult to determine, because normal or heavy menstrual bleeding can be very subjective. For research purposes, menorrhagia can be

Year:

Menstrual Cycle Record

Month: Day:

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Enter appropriate letter in proper calendar day square:

Figure 21-1

Menstrual calendar.

S = Spotting B = Bleeding T = Pill taken

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Chapter 21 Abnormal Uterine Bleeding defined as a monthly blood loss of more than 80 mL on three consecutive menses as measured by the alkali hematin method.39 Unfortunately, this type of accurate evaluation is neither costeffective nor readily available. Clinically, menorrhagia can be defined as bleeding on the heaviest day requiring changing soaked sanitary pads or tampons more than once every 2 hours, or using more than one sanitary pad at a time. The presence and size of blood clots passed vaginally is important, because normal menstrual effluent is made up of dissolved endometrium and nonclotting blood. Another objective measure of the problem is the amount of days lost from school or work over the past several months.

testosterone and DHEAS. All women older than age 40 should have an endometrial biopsy after pregnancy is excluded to detect endometrial hyperplasia or cancer. Polycystic ovary syndrome and adult-onset congenital adrenal hyperplasia may sometimes be indistinguishable by clinical presentation, with both disorders often characterized by hirsutism, acne, menstrual abnormalities, and infertility.41 Unfortunately, no discriminatory screening test exists for this heterologous condition, most commonly caused by 21-hydroxylase or 11β-hydroxylase deficiency. If ovulation dysfunction and signs of androgen excess begin at the time of puberty, these women should be investigated appropriately (see Chapters 18 and 22).

Symptoms of Hemostatic Disorders

Hemostatic Disorders

In adolescents with menorrhagia, it is important to determine any past history of excess bleeding during surgical, dental, or obstetric procedures because this has been found to be predictive of von Willebrand’s disease.40 Surprisingly, in this same study epistaxis and easy bruising were not clearly discriminatory symptoms.

Patients with the new onset of significant menorrhagia should be evaluated for bleeding disorders with prothrombin time, activated partial thromboplastin time, and bleeding time.42 Any patient with a history of menorrhagia since menarche, especially with a history of surgical- or dental-related bleeding or postpartum hemorrhage, should be evaluated for hereditable bleeding disorders. These tests will include specific tests for von Willebrand’s disease such as vWF antigen, vWF functional activity (ristocetin cofactor activity), and factor VIII level. These levels can fluctuate; therefore, the tests should be repeated if clinical suspicion is high. Normal ranges should be adjusted for the observation that vWF levels are 25% lower in women with blood type O compared with other blood groups. Some centers offer a screening test referred to as a “platelet function assay” before performing detailed von Willebrand testing. Further studies such as platelet aggregation studies may be required.42 If these studies are negative, factor XI level and euglobulin clot lysis time can be evaluated.

Physical Examination The physical examination is intended to detect both gynecologic and systemic diseases. Special care should be taken to document the presence of hirsutism, acne or other signs of excess androgens, and galactorrhea. The pelvic examination begins with a speculum examination to inspect the cervicx for polyps or for signs of infection or inflammation. A bimanual examination is important to determine uterine size, adnexal masses, and the presence and character of any tenderness.

Laboratory Testing Laboratory evaluation is an important part of the initial evaluation of all patients with AUB (Table 21-4). However, rather than ordering every possibly helpful test at the first visit, laboratory tests should be obtained in a stepwise fashion based on presentation (see Fig. 21-1). The most important test for all reproductive-age women complaining of AUB is a β-human chorionic gonadotropin (hCG) test for pregnancy. For all but the most insignificant bleeding, a complete blood count (CBC), including platelets, is important to detect significant anemia and disorders of platelet production or survival. Unless precluded by extremely heavy bleeding, a Pap smear should be performed on any woman who has not had one within the past year. For patients with apparent oligoovulation or anovulation, thyrotropin and prolactin will detect subtle pituitary function disorders in which AUB might be seen as the earliest symptom. Because cervical and uterine infections are common, cervical tests for gonorrhea and chlamydia are helpful in women with intermenstrual spotting, as well as in any woman at risk for these infections. Several patient groups will require additional ancillary tests. Obese patients with apparent AUB are at increased risk for Type 2 diabetes. Several authors recommend measurement of hemoglobin A1c (HbA1c) as a good diabetes screen that does not require fasting or a return visit for a provocative test. Patients with hirsutism or other evidence of androgen excess should be screened for ovarian and adrenal malignancies with total

Table 21-4 Laboratory Testing for Abnormal Uterine Bleeding All patients Pregnancy test Complete blood count (including platelets) Papanicolaou smear Cervical tests for gonorrhea and chlamydia Anovulation Thyrotropin Prolactin Obesity Type 2 diabetes screen: HgA1c Hirsutism Testosterone Dihydroepiandrosterone sulfate Over age 40 Endometrial biopsy New-onset menorrhagia40 Prothrombin time Activated partial thromboplastin time Bleeding time Menorrhagia since menarche40 Above plus: Iron profile Serum creatinine Factor VIII level vWF antigen Ristocetin cofactor Platelet aggregation studies If the above are negative, consider: Factor XI level Euglobulin clot lysis time

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Section 3 Adult Reproductive Endocrinology Malignancies and Premalignancies Endometrial Biopsy

The incidence of endometrial carcinoma in women between ages 40 and 49 has been reported to be as high as 36 per 100,000.43 The risk after menopause continues to increase. For this reason, once pregnancy has been excluded, an endometrial biopsy should be obtained in all women older than age 40 who present with AUB.

Imaging and Hysteroscopy Before the past two decades, our ability to determine the size of the uterus and visualize the uterine cavity was limited. In addition to the bimanual pelvic examination, the only other available methods were hysterosalpingogram (HSG) and dilation and curettage (D&C). Although the radiation exposure and discomfort associated with HSG are both acceptable, this technique effectively identifies only marked abnormalities of the uterine cavity. Lesions less than 1 cm in size are often missed. Likewise, the previously blind procedure of D&C gave the operator only the roughest idea of the depth and contour of the uterine cavity. Intrauterine findings at the time of hysterectomy were often a surprise. In obese patients in whom bimanual examinations are difficult, unexpected ovarian masses at laparotomy were commonplace. Transvaginal Ultrasonography

Today, transvaginal ultrasonography and sonohysterography has made unexpected findings at surgery rare (see Chapter 30). Ultrasonography and sonohysterography have become an important step in the evaluation of AUB (Fig. 21-2). Transvaginal ultrasonography can accurately determine uterine size and configuration, and can reveal the nature of both palpable and nonpalpable adnexal masses. Knowledge before surgery about the size and location of leiomyoma and the potential that an ovarian mass might be malignant is invaluable. Sonohysterography can be used to accurately visualize most intrauterine abnormities once pregnancy has been excluded. Accurate evaluation of the uterine cavity is of the greatest importance for the evaluation and treatment of AUB. This almost painless procedure involves injection of sterile saline into the uterus while a transvaginal sonogram is performed. When the uterine cavity is distended with saline, intracavitary lesions (e.g., polyps, fibroids, cancer) as small as 3 mm can be clearly seen. Office Hysteroscopy

Office hysteroscopy (see Chapter 42) is another excellent outpatient method for visualizing the uterine cavity. The discomfort and risk is also somewhat greater than with sonohysterography, and the procedure can be difficult in the presence of cervical stenosis or when the cervix is difficult to visualize. However, the color photographs of the lesion can be very instructive for patients.

MANAGEMENT OF ABNORMAL UTERINE BLEEDING Treatment of AUB Unrelated to Pregnancy or Uterine Pathology 304

When pregnancy or a uterine condition is found to be the cause of AUB, specific treatment options are required that are

described in other chapters. In more than half the cases, it will be determined that the bleeding is unrelated to pregnancy or uterine abnormalities. Treatment for these cases consists of correcting any underlying systemic abnormalities when possible and returning the endometrium to a functional status with exogenous hormone therapy when necessary. The simplest case might be hypothyroidism, where simple thyroid hormone replacement will restore normal ovulation in most cases (see Chapter 22). Hyperprolactinemia requires careful evaluation and monitoring (see Chapter 22). In some cases, what appears clinically as PCOS is actually an adrenal enzyme deficiency that can be treated with steroid replacement (see Chapter 22). As noted below in the section “Ovulation Induction,” even idiopathic PCOS can often be treated as a systemic condition related to insulin resistance. Treatment of Women with Coagulopathy

Women with von Willebrand’s disease who complain of menorrhagia can often be successfully treated with long-term oral contraceptive therapy.43 Other medical treatments used by hematologists for acute episodes include desmopressin acetate, antifibrinolytic agents, and plasma-derived concentrates of vWF.43

Emergency Treatment of Anovulatory Bleeding The most important aspect of management of anovulatory bleeding is the expedient cessation of bleeding. The first objective of all therapy is to achieve structural stability of the endometrium as quickly as possible. In women who do not desire pregnancy, the next goal is to promote universal, synchronous endometrial shedding at regular intervals or stop menstruation altogether. These goals are accomplished with some combination of estrogen and/or progestin given parenterally or orally according to the patient’s medical condition. Hemodynamic Stabilization

Some patients will present with life-threatening uterine bleeding. Although hemorrhagic shock is uncommon secondary to AUB, critically low hemoglobin levels are not, especially in perimenopausal or postmenopausal women at increased risk for cardiac symptoms secondary to severe anemia. Concurrently with establishing that bleeding is unrelated to pregnancy or an anatomic pathology, the hemodynamically unstable patient should be resuscitated with intravenous fluids and blood replacement as indicated. Expedient Evaluation

After appropriate laboratory tests (i.e., CBC and β-hCG) have been obtained, the most important part of the initial evaluation is transvaginal ultrasonography. If sonohysterography is attempted, it is important to remember that intrauterine clots are often impossible to differentiate from anatomic lesions such as leiomyoma or polyps. An endometrial biopsy is another important part of the evaluation in all women over age 40 unless an emergency D&C is planned. However, hormonal therapy does not have to be delayed until histologic diagnosis has been made. Dilation and Curettage

In cases where massive uterine bleeding is life-threatening, D&C is the most expedient way to stop blood flow and determine the

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Chapter 21 Abnormal Uterine Bleeding History and Physical

Intial lab evaluation: • CBC, platelet count • β-hCG • Pap smear

Transvaginal ultrasonography Sonohysterography

Pregnancy

Transvaginal ultrasonography

Endometrial pathology

• Viable • Spontaneous abortion • Ectopic • Molar

• Biopsy • Hysteroscopy

Cervical lesion

Myometrial pathology: • Leiomyoma • Adenomyosis

Normal uterus

Biopsy

Taking hormonal therapy

Regular menses (assume ovulatory)

Irregular menses (anovulatory)

Intermenstrual spotting

Excessive menses

Lab evaluation: • Chlamydia • Gonorrhea

Lab evaluation: • Bleeding disorders

Lab evaluation: • Thyrotropin • Prolactin • Hemoglobin A1c Signs of androgen excess: • Testosterone (total) • DHEAS

Endometrial biopsy if >40 years old Figure 21-2

Algorithm for evaluating women with abnormal uterine bleeding.

existence of endometrial pathology when present. The disadvantage of this surgical approach is risk of anesthesia, which is dependent on the patient’s overall medical condition, and the small surgical risk. Although cost should always be a consideration in modern medicine, the usually fast and effective resolution of bleeding often allows discharge within 24 hours. Thus, the cost of surgery may actually be less than the cost of several days’ hospitalization required for the medical treatment discussed in the following. However, D&C has no long-term therapeutic effect; therefore, long-term treatment must be initiated. In most cases of AUB, medical management can be safely used as the first line of treatment.

Intravenous Estrogen Therapy

In many cases where the bleeding is not dangerously brisk, it can be improved overnight by administration of intravenous conjugated estrogens, 25 mg given every 4 hours until bleeding stops. When studied in adolescents, it was found that intravenous conjugated estrogen therapy stopped acute bleeding in 90% of cases.36 Those that do not show signs of improvement in their bleeding within 8 hours required D&C. This therapy might seem paradoxical for use in anyone who is bleeding because of prolonged unopposed estrogen effect on the endometrium. However, its effectiveness has been demonstrated in a well-designed study. In theory, estrogen acutely

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Section 3 Adult Reproductive Endocrinology Table 21-5 “Taper” Oral Contraceptive Therapy for Abnormal Uterine Bleeding* Day

Frequency

1–2

One tablet 4 times daily

3–4

One tablet 3 times daily

5–19

One tablet daily

20–25

Expect menses

26

Start oral contraceptives at standard dosage

devices, nonsteroidal anti-inflammatory drugs (NSAIDs), and danazol. In Europe, tranexamic acid, an antifibrinolytic agent, has been used to treat many women with AUB. It has been reported to be very effective in a recent Cochrane Review. Now considered to be the treatment of choice for menorrhagia in Europe, it is given during the first 5 days of menses. The original worry that it would increase thromboembolic risk has not been confirmed. Another antifibrinolytic that has been used effectively is aminocaproic acid. Finally, gonadotropin-releasing hormone (GnRH) analogues can also be used on a temporary basis.

*Regimen for low-dose (30 mcg ethinyl estradiol), monophasic oral contraceptives

Endometrial Synchronization

decreases uterine bleeding related to asynchronous shedding by stimulating clotting at capillary level and promoting vasoconstriction of spiral vessels. This therapy is often associated with nausea, and intravenous or oral antiemetics (oral or intravenous promethazine [Phenergan], 10 mg) should be given simultaneously. Oral High-Dose Combined Hormonal Therapy

Once bleeding has slowed to that consistent with heavy menses or less, “taper” therapy with oral contraceptives can be started (Table 21-5). This approach is also ideal for women with heavy bleeding who do not require hospitalization for stabilization and observation. Like the intravenous estrogen therapy, nausea is a common problem with this treatment and should be treated preemptively with oral antiemetics to optimize compliance. Women at Increased Risk for Cardiovascular Disease or Venous Thrombosis

It is well appreciated that estrogen-containing oral contraceptives are relatively contraindicated in any women at increased risk for cardiovascular disease or venous thrombosis. This includes women with a history of thromboembolic disease and woman over age 35 who have additional risk factors (e.g., cigarette smoking, hypertension, diabetes). Although no studies have been published using short-term, high-dose intravenous or oral estrogen in these patients, at least one case of fatal pulmonary thromboembolism has been reported with intravenous therapy.44 Certainly, highdose estrogen therapy should be used in these patients only if the benefits outweigh the risks.

Long-term Treatment of AUB

306

Effective long-term medical therapy for AUB can sometimes be difficult. Two approaches are discussed that might improve the medical therapy: synchronization of the endometrium at the beginning of therapy and diagnosis and treatment of subclinical endometritis. The long-term approach chosen for treatment for AUB depends on the underlying condition being treated and the woman’s reproductive desires. For anovulatory women wishing to become pregnant, ovulation induction is usually the most appropriate treatment. Women who do not desire pregnancy can use lowdose oral contraceptives. If contraception is not required, cyclic progestins can be used for the first 14 days of each month. For women who are ovulatory but have heavy or prolonged menses, both hormonal and nonhormonal therapy is available. In addition to oral contraceptives and cyclic progestins, some women will have excellent responses to progestin-containing intrauterine

In women with chronic irregular bleeding, it is helpful to synchronize the entire endometrium prior to starting cyclic hormones. This may reduce breakthrough bleeding with subsequent therapy. Two approaches for this can be used. A relatively safe method is the use of the potent progestin medroxyprogesterone in a dose of 10 mg/day for a full 14 days. This will usually abate the presenting bleeding episode within 2 to 3 days, and help decrease the endometrial height before withdrawal bleeding. Alternatively, “taper” therapy with oral contraceptives can be used for women presenting with heavy, prolonged bleeding. The patient should be advised that she might have moderately heavy bleeding within 1 to 2 days of stopping the medroxyprogesterone. Oral contraceptives should be started on the Sunday after this withdrawal bleeding. Iron supplementation should also be started in any patient with anemia. The patient should also be cautioned that occasional breakthrough bleeding is to be expected during the first 3 months of oral contraceptive use or if a pill is missed or taken late. Subclinical Endometritis

It has been recently observed that the most frequent histologic finding in endometrial biopsies of women with AUB is chronic endometritis.45 This suggests that when apparently anovulatory AUB does not respond to progestin withdrawal, subclinical endometritis might be a coexisting disorder that must be addressed. Although few studies have evaluated the role of subclinical endometritis in AUB, several have suggested a relationship. In one study, 81% of patients with irregular bleeding or vaginal discharge had positive endometrial cultures for Mobiluncus, and treatment with metronidazole resolved their irregular bleeding.46 In another study of 100 hysterectomies performed for irregular bleeding or fibroids, 25% of the endometrial cavities were found to harbor organisms, including Gardnerella vaginalis, Enterobacter, and Streptococcus agalactiae.47 Finally, a study of college-age women presenting with abnormal bleeding while on oral contraceptives found that 29% were infected with Chlamydia.48 Together, these data suggest that subclinical endometrial infections might play a role in many women with AUB. Cervical evaluation for common pathogens (i.e., chlamydia and gonorrhea) followed by specific therapy is important. In women with negative cultures who do not respond to cyclic hormonal therapy, empiric therapy with a broad-spectrum antibiotic (e.g., metronidazole or a cephalosporin) might also be reasonable, although prospective studies remain to be performed. Ovulation Induction

When fertility is desired, restoration of ovulation is paramount. This can be accomplished in many cases by restoring the hormonal

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Chapter 21 Abnormal Uterine Bleeding milieu to a more normal state. In the case of hyperprolactinemia, lowering prolactin levels with the use of a dopamine agonist will often result in ovulation and pregnancy (see Chapter 22). In the case of PCOS, recent studies have demonstrated that lowering insulin levels with an insulin-sensitizing drug (e.g., metformin hydrochloride) will often restore ovulation and result in pregnancy in many cases (see Chapter 37). While waiting for these therapies to result in resumption of ovulation and normal menses, monthly induction of withdrawal bleeding with oral progestin is important to avoid continued AUB. In women not using contraceptives, the use of micronized progesterone (100 to 200 mg daily for 14 days) will result in reasonable withdrawal bleeding and be safe should pregnancy occur. For patients who do not resume ovulation with systemic therapy, induction of ovulation is attempted using clomiphene citrate or injectable medications as required (see Chapter 37). Oral Contraceptives

Combination oral contraceptives have been used for decades to decrease both the duration and amount of menstrual flow and dysmenorrhea.49 More recently, it has been found that extending the number of consecutive days of active pills could decrease the annual number of menses, thus minimizing menstrual-related symptoms even further.50 A consequence of this is the marketing of extended-cycle oral contraceptives that have 3 months of active pills instead of 3 weeks and thus extend the time between menses, such that the patient only has 4 cycles per year. Unfortunately, this regimen has greater risk of spotting and breakthrough bleeding than those using monthly cycles. Progestins

Progestins (e.g., 10 mg medroxyprogesterone, 200 mg micronized progesterone) can be administered daily from day 15 to 26 of each cycle to regulate menses in anovulatory patients. This safe and effective approach has none of the side effects or risks associated with oral estrogens and can be used in women of all ages. Progestins given in this manner also prevent endometrial hyperplasia and cancer. In some women, progestins also result in “premenstrual” symptoms, including mood changes or depression, nausea, breast tenderness, and bloating. In menorrhagia (ovulatory AUB) luteal phase progestins have been shown to be less effective than other medications, including NSAIDs. Longer courses such as 21 days of therapy may be required.51 Luteal phase progestin therapy is less effective than tranexamic acid, danazol, or the progesterone-releasing intrauterine system (IUS). Progestin therapy for 21 days of the cycle (e.g., day 5 to day 26) is more effective.

approximately 2 weeks by pituitary down-regulation, hypoestrogenemia, and complete cessation of menses. GnRH antagonists avoid this flare, but have only recently become available and their clinical utility remains to be determined. All GnRH analogues are associated with symptoms of acute estrogen deprivation, most notably hot flashes, and bone loss that is to some degree irreversible after 6 months of use. For these reasons and because of expense, the GnRH analogues are rarely used for long-term treatment of AUB. Levonorgestrel-Containing Intrauterine System

The levonorgestrel-containing IUS, developed originally for contraception, is effective for the treatment of both menorrhagia and dysmenorrhea (see Chapter 27). The local release of levonorgestrel into the uterine cavity suppresses endometrial growth and has been shown to decrease menstrual blood loss by as much as 97%.53 Although many women complain of intermenstrual bleeding during the first few months of use, as many as 20% will have amenorrhea after a year. Even though the progestins are administered locally, some women complain of systemic side effects, such as breast tenderness. Although the initial cost of the levonorgestrel-containing IUS is high compared to other medical treatment, these devices are now approved for 10 years of uninterrupted use and are thus very cost-effective for longterm therapy. Danazol

This synthetic derivative of testosterone has been shown to be effective for menorrhagia in doses between 200 and 400 mg. However, the androgenic side effects, need for barrier contraception, and the need to take the medication daily for long periods of time limit its use. Desmopressin

This drug is useful in decreasing bleeding in women with von Willebrand’s disease. It increases factor VIII and vWF. It has several potential routes of administration, such as intravenous, subcutaneous, and intranasal. Its main side effects are vasomotor; potential hyponatremia is associated with its use. Hormone Replacement Therapy

Some women older than age 40 with ovulatory dysfunction will also complain of symptoms of reduced estrogen production, such as hot flashes or sleep disturbances. Many of these women treated with continuous estrogen and cyclic progestin therapy will obtain symptomatic relief; up to 90% will respond with predictable progesterone withdrawal bleeding.54 The potential increased risk of venous thrombosis, cardiovascular disease, and breast cancer should be discussed with the patient.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs have long been used to reduce dysmenorrhea as well as the amount of menstrual flow, at least in part by inhibiting prostaglandin synthesis.52 Although studies are limited, NSAIDs appear to be an effective way to treat AUB in ovulatory women (menorrhagia). NSAIDs should not be used for women with von Willebrand’s disease or a platelet dysfunction. GnRH Analogues

Continuous administration of a GnRH antagonist results in increased ovarian stimulation (referred to as a flare) followed in

Surgical Treatment for Abnormal Uterine Bleeding without Uterine Pathology If medical management of AUB is unsuccessful and the woman is not interested in childbearing, surgical therapies, including endometrial ablation and hysterectomy, are often utilized. Endometrial ablation is the least invasive surgical procedure available and has been shown to result in less morbidity and shorter recovery periods and be more cost-effective than hysterectomy in the short term (see Chapter 42). Because women who undergo

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Section 3 Adult Reproductive Endocrinology endometrial ablation can have residual active endometrium, they should receive progestin if they are prescribed estrogen hormone replacement therapy after menopause. Hysterectomy remains a reasonable option for some women with AUB who fail medical management. As many as 20% of women who undergo endometrial ablation will subsequently undergo hysterectomy within 5 years, and some studies demonstrated a higher satisfaction rate in women who initially underwent hysterectomy rather than endometrial ablation.55,56

PEARLS ●

● ●

●

CONCLUSION AUB remains one of the most challenging gynecologic problems. Every gynecologist must have comprehensive knowledge of the most common causes of this problem. Appropriate diagnostic workup begins with a careful history, followed by indicated laboratory and imaging tests. Medical treatment improves symptoms for the majority of women with AUB. Surgical evaluation and treatment for AUB remain important aspects of gynecologic care.

●

●

●

● ●

Investigation of abnormal uterine bleeding should include an initial evaluation to rule out pregnancy and cervical pathology followed by anatomic assessment of the uterus and uterine cavity by ultrasound and possible sonohysterogram or biopsy. Irregular (nonovulatory) cycles are often due to PCOS. A patient with completely normal results on investigation with ovulatory cycles should be investigated for von Willebrand’s disease. The treatment of choice is NSAIDs or oral contraceptives. Patients with anovulatory bleeding may respond to cyclic progestins. Ovulatory AUB may require a longer course of therapy. The norgestrel-containing intrauterine system is an effective option if the more conservative treatment options fail. Desmopressin is very effective for patients with von Willebrand’s disease. Intravenous estrogens are effective for acute bleeding. D&C may be effective for an acute bleed but has no long-term benefit.

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Chapter 21 Abnormal Uterine Bleeding 31. Zawadski JK, Dunaif A: Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. In Dunaif A, Givens JR, Haseltine FP, Merriam GE. Polycystic Ovary Syndrome. Boston, Blackwell Scientific, 1992, pp 377–384. 32. Lakhani K, Prelevic G, Seifalian A, et al: Polycystic ovary syndrome, diabetes and cardiovascular disease: Risks and risk factors. J Obstet Gynaecol 24:613–621, 2004. 33. Pugeat M, Ducluzeau PH: Insulin resistance, polycystic ovary syndrome and metformin. Drugs 58(Suppl 1):41–46, 1999. 34. Chang RJ: A practical approach to the diagnosis of polycystic ovary syndrome. Am J Obstet Gynecol 191:713–717, 2004. 35. Holley JL: The hypothalamic-pituitary axis in men and women with chronic kidney disease. Adv Chronic Kidney Dis 11:337–341, 2004. 36. Falcone T, Desjardins C, Bourque J, et al: Dysfunctional uterine bleeding in adolescents. J Reprod Med 39:761–764, 1994. 37. Bravender T, Emans SJ: Menstrual disorders: Dysfunctional uterine bleeding. Pediatr Clin North Am 46:545–553, 1999. 38. Minakuchi K, Hirai K, Kawamura N, et al: Case of hemorrhagic shock due to hypermenorrhea during anticoagulant therapy. Arch Gynecol Obstet 264:99–100, 2000. 39. Woo YL, White B, Corbally R, et al: Von Willebrand’s disease: An important cause of dysfunctional uterine bleeding. Blood Coagul Fibrinolysis 13:89–93, 2002. 40. Kouides PA: Menorrhagia from a haematologist’s point of view. Part I: Initial evaluation. Haemophilia 8:330–338, 2002. 41. Sahin Y, Kelestimur F: The frequency of late-onset 21-hydroxylase and 11 β-hydroxylase deficiency in women with polycystic ovary syndrome. Eur J Endocrinol 137:670–674, 1997. 42. Kouides PA: Evaluation of abnormal bleeding in women. Curr Hematol Rep 1:11–18, 2002. 43. ACOG Practice Bulletin: Management of anovulatory bleeding. Int J Gynaecol Obstet 72:263–271, 2001.

44. Zreik TG, Odunsi K, Cass I, et al: A case of fatal pulmonary thromboembolism associated with the use of intravenous estrogen therapy. Fertil Steril 71:373–375, 1999. 45. Ferenczy A: Pathophysiology of endometrial bleeding. Maturitas 45:1–14, 2003. 46. Larsson PG, Bergman B, Forsum U, Pahlson C: Treatment of bacterial vaginosis in women with vaginal bleeding complications or discharge and harboring Mobiluncus. Gynecol Obstet Invest 29:296–300,1990. 47. Moller BR, Kristiansen FV, Thorsen P, et al: Sterility of the uterine cavity. Acta Obstet Gynecol Scand 74:216–219, 1995. 48. Krettek JE, Arkin SI, Chaisilwattana P, Monif GR: Chlamydia trachomatis in patients who used oral contraceptives and had intermenstrual spotting. Obstet Gynecol 81:728–731, 1993. 49. Sulak PJ: The career woman and oral contraceptive use. Int J Fertil 36(Suppl 2):90–97, 1991. 50. Sulak PJ, Cressman BE, Waldrop E, et al. Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms. Obstet Gynecol 89:179–183, 1997. 51. Lethaby A, Irbine G, Cameron I: Cyclical progestogens for heavy menstrual bleeding. Cochrane Database Syst Rev 3, 2005, CD001016. 52. Higham JM: The medical management of menorrhagia. Br J Hosp Med 45:19–21, 1991. 53. Hurskainen R, Teperi J, Rissanen P, et al: Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: Randomized trial 5 year follow up. JAMA 291:1456–1463, 2004. 54. Strickland DM, Hammond TL: Postmenopausal estrogen replacement in a large gynecologic practice. Am J Gynecol Health 2:26–31, 1988 55. Comino R, Torrejon R: Hysterectomy after endometrial ablationresection. J Am Assoc Gynecol Laparosc 11:495–499, 2004. 56. Lethaby A, Shepperd S, Cooke I, Farquhar C: Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000;CD000329.

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Section 3 Adult Reproductive Endocrinology Chapter

22

Management of Pituitary, Adrenal, and Thyroid Disease S. Sethu K. Reddy and Maria Fleseriu

INTRODUCTION The reproductive system is often affected by disorders of other endocrine glands, such as the pituitary, thyroid, and adrenal glands. Classic endocrine disorders bear the name of distinguished physicians such as Harvey Cushing, who in 1932 described a syndrome that included disruption of the menstrual cycle, truncal obesity, hypertension, and hirsutism. Obstetricians and gynecologists require an understanding of the physiologic adjustments of different endocrine glands in pregnancy to assess potential endocrine disorders. This chapter gives the general principles of clinical presentation, investigation, and management of the most common endocrine disorders associated with reproductive dysfunction.

PITUITARY DISORDERS Anatomy The pituitary gland weighs from 500 to 1000 mg and sits in the sella turcica immediately behind the sphenoid sinus. It has anterior and posterior bony walls and a bony floor. Above is a layer of dura (diaphragma sella) and then the optic chiasma, hypothalamus, and third ventricle. Laterally on each side is the cavernous sinus, inclusive of the internal carotid artery and cranial nerves III, IV, V1, V2, and VI. The optic chiasma may be in front of (15%), above (80%), or behind the sella (5%). Within this optic chiasma, nerve fibers from the nasal half of the retina cross over to the opposite optic tract while those from the temporal half remain uncrossed. The close association of the pituitary gland with the optic chiasma explains the visual symptoms associated with expanding masses in this region.1 The median eminence is an intensely vascular component at the baseline of the hypothalamus that forms the floor of the third ventricle. The pituitary stalk arises from the median eminence. The hypothalamus extends anteriorly to the optic chiasma and posteriorly to the mammillary bodies. It was not until the mid-1960s that hypothalamic releasing hormones were isolated and identified (Table 22-1).

Physiology Thyrotropin-releasing hormone (TRH) was the first releasing hormone to be identified. In subsequent years, other releasing hormones were identified. Of note, prolactin is under tonic inhibitory influence, with dopamine acting as a prolactin releaseinhibiting factor. Magnetic resonance imaging (MRI) is the best

method for visualization of hypothalamic–pitutiary anatomy, because the optic chiasma, vascular structures, and tumor extension to the cavernous sinuses can be well visualized on MRI compared to other imaging techniques.

Pituitary Tumors Pituitary tumors may present with either hypofunction or hyperfunction, as well as symptoms directly related to the mass effect of the tumor (Table 22-2). Since the advent of computed tomography (CT), microadenomas have been arbitrarily designated as equal to or less than 10 mm in diameter and macroadenomas as greater than 10 mm in diameter. They are invariably benign, with no sex predilection. Pituitary adenomas are rarely associated with parathyroid and pancreatic hyperplasia or neoplasia as part of the multiple endocrine neoplasia type I (MEN I) syndrome. Pituitary carcinomas are rare, but metastases from other solid malignancies can occur more frequently.2

PITUITARY ADENOMAS Approximately 50% of pituitary adenomas are prolactinomas, 15% are growth hormone (GH)-producing, 10% are corticotropinproducing, and less than 1% secrete thyrotropin. Nonfunctioning pituitary adenomas, or more appropriately named nonsecretory adenomas represent about 25% of pituitary tumors. Most of

Table 22-1 Pituitary Hormones, Hypothalamic Hormones, and Other Regulatory Factors Pituitary Hormones

Hypothalamic Hormones

Other Regulatory Factors

Thyrotropin

TRH

T4, T3, dopamine, Pit-1

Corticotropin

CRH

ADH, adrenaline, cortisol

Luteinizing hormone

LH-RH

Estrogen, progesterone, testosterone

Follicle-stimulating hormone

LH-RH

Activin, estrogen, inhibin, follistatin, testosterone

Growth hormone

GH-RH

Somatostatin, estrogens, T4, Pit-1

Prolactin

PRF

Dopamine, TRH, Pit-1, estrogen, serotonin, vasoactive intestinal peptide, GnRH-associated peptide

TRH, thyrotropin-releasing hormone; CRH, corticotropin-releasing hormone; LH-RH, luteinizing hormone-releasing hormone; GH-RH, growth hormone-releasing hormone; PRF, prolactin-releasing factor; Pit-1, pituitary-specific transcription factor; ADH, antidiuretic hormone.

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Section 3 Adult Reproductive Endocrinology Table 22-2 Clinical Manifestations of Pituitary Tumors Endocrine Effects Mass Effects

Hyperpituitarism

Hypopituitarism

Headaches

GH: acromegaly

GH: short stature in children, increased fat mass, decreased strength and well-being in adults

Chiasmal syndrome

Prolactin: hyperprolactinemia

Prolactin: failure of postpartum lactation

Hypothalamic syndrome

Corticotropin: Cushing’s disease Nelson’s syndrome

Corticotropin: hypocortisolism

Disturbances of thirst, appetite, satiety, sleep, and temperature regulation

LH/FSH: gonadal dysfunction or silent α-subunit secretion

LH or FSH: hypogonadism

Diabetes insipidus

Thyrotropin hyperthyroidism

Thyrotropin: hypothyroidism

SIADH Obstructive hydrocephalus Cranial nerves III, IV, V1, V2, and VI dysfunction Temporal lobe dysfunction Nasopharyngeal mass CSF rhinorrhea SIADH = syndrome of inappropriate antidiuretic hormone; GH = growth hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone.

these adenomas on morphologic examination reveal granules containing hormones, typically components of glycoprotein hormones. Autopsy studies suggest that up to 20% of normal individuals harbor incidental pituitary microadenomas that are pathologically similar in distribution to those that present clinically.3 Impingement on the optic chiasma or its branches by pituitary pathology may result in visual field defects, with the most common being bitemporal hemianopsia. Lateral extension of the pituitary mass to the cavernous sinuses may result in diplopia, ptosis, or altered facial sensation. Among the cranial nerves, palsy of CN III is the most common. Premenopausal women often present with smaller pituitary tumors because they seek medical attention once altered menses are noted. The initial workup for most suspected adenomas should be limited and should include a serum prolactin and insulin-like growth factor-I (IGF-I) level. Other screening tests may be performed depending on clinical features.

Prolactinoma Prolactin Physiology

The pituitary content of prolactin is approximately 100 μg but can increase 10- to 20-fold during pregnancy and lactation. Although breast tissue is the most important target organ for prolactin, prolactin receptors have been identified in various tissues, including the liver, kidney, ovaries, testes, prostate, and seminal vesicles. Dopamine is the major inhibitor of prolactin secretion, and any mechanisms that interrupt dopamine transport from the hypothalamus or reduce dopamine activity in the pituitary can lead to elevated levels of serum prolactin. Estrogens, TRH, and serotonin increase prolactin levels. Whereas H2 receptors inhibit prolactin secretion, H1 receptors stimulate its secretion. Hyperprolactinemia

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Hyperprolactinemia is the most common pituitary disorder. Estrogen therapy in the past was suggested as a cause of

prolactinoma formation, but careful case-cohort studies have found no evidence that oral contraceptives induce development of prolactinomas. Clonal analysis of tumor DNA indicates that prolactinomas are monoclonal in origin. Hyperprolactinemia impairs pulsatile gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) release, likely through alteration in hypothalamic luteinizing hormonereleasing hormone (LHRH) secretion. Women of reproductive age usually present with oligomenorrhea, amenorrhea, galactorrhea, and infertility. Those with longstanding amenorrhea are less likely to have galactorrhea secondary to longstanding estrogen deficiency. Postmenopausal women and men usually come to medical attention because of a mass effect, such as headaches and visual field defects.4 Many men with hyperprolactinemia do not report any sexual dysfunction, but once treated effectively for hyperprolactinemia, the majority realize the presence of problems, including decreased libido and erectile dysfunction. Men with longstanding hypogonadism may have decreased beard and body hair, with soft but usually normal-size testes. If hypogonadism starts before completion of puberty, testes will be small. Patients with microadenomas have higher frequency of headaches compared to control subjects. Drug history is an important part of the initial evaluation of patients with elevated prolactin level, because some medications are associated with hyperprolactinemia and their discontinuation (if possible) will avoid any further, often expensive, workup. Other common conditions associated with elevated prolactin levels include pregnancy and hypothyroidism (Table 22-3). The prolactin level usually correlates well with the size of the tumor. Serum prolactin level above 200 μg/L is almost always indicative of a prolactin-producing pituitary tumor. However, a serum prolactin level below 200 μg/L can be seen in the presence of a large pituitary adenoma, because stalk compression from an adenoma that does not secrete prolactin can also cause hyperprolactinemia. Stimulatory tests, including the TRH stimulation test, which are performed to determine whether an

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease Table 22-4 Clinical Signs and Symptoms of Acromegaly

Table 22-3 Differential Diagnosis of Hyperprolactinemia Physiologic

Pathologic

Pharmacologic

Coarsening of facial features

Pregnancy

Prolactinoma

TRH

Prominent jaw and frontal sinus

Postpartum

Acromegaly (25%)

Psychotropic medications

Broadening of hands and feet

Newborn

Hypothalamic disorders

Phenothiazines

Hyperhidrosis

Stress

“Chiari-Frommel”

Reserpine

Macroglossia

Hypoglycemia

Craniopharyngioma

Methyldopa

Signs of hypopituitarism

Sleep

Metastatic disease

Estrogen therapy

Diabetes mellitus (10%–25%)

Postprandial hypoglycemia

Pituitary stalk secretion or compression

Metoclopramide, cimetidine (especially intravenous)

Skin tags (screening for colonic polyps required)

Intercourse

Hypothyroidism

Opiates

Cardiomyopathy (50%–80%)

Nipple stimulation

Renal failure

Verapamil

Carpal tunnel syndrome

Liver disease

Some SSRIs, including fluoxetine and fluvoxamine

Sleep apnea (5%)

Chest wall trauma (burns, shingles) SSRI = Selective serotonin reuptake inhibitor.

elevated prolactin is a result of a prolactinoma, are nonspecific and cannot be used to diagnose or exclude a tumor. Large prolactinomas may be associated with a falsely low prolactin level. Dilution of serum will reveal the markedly elevated prolactin levels. Observational studies in patients with microadenomas indicate that serum prolactin concentration or adenoma size increases in only a minority of patients; indeed, serum prolactin deceases in a majority of patients over time. Details of the relationship between prolactin adenomas and amenorrhea are found in Chapter 16. Treatment

Dopamine agonists are now the first-line treatment for prolactinoma, because surgical resection is curative only in a minority of patients and is associated with a high risk of side effects and recurrence in all patients. Bromocriptine mesylate (Parlodel), pergolide mesylate (Permax), and cabergoline (Dostinex) are potent inhibitors of prolactin secretion, and their use often results in tumor shrinkage. Suppression of prolactin secretion by dopamine agonists depends on the number and affinity of dopamine receptors on lactotrope adenoma. There is usually a substantial decrease in prolactin level even when serum prolactin levels do not normalize. These medications should be initiated slowly, because side effects often occur at the beginning of treatment. The most common side effects of dopamine agonists include nausea, headache, dizziness, nasal congestion, and constipation. In men treated for prolactinomas, it may take up to 6 months before testosterone increases and normal sexual function is restored. Prolactin appears to have an independent effect on libido in men, because exogenous testosterone works poorly in restoring libido in those who continue to have elevated prolactin levels. Although patients with microadenomas or those without evidence of a pituitary tumor can sometimes be followed without therapy, patients with macroadenomas always need to be treated. Occasionally a patient with microadenoma or no definite pituitary

Hypertension (25%–30%)

tumor has no increase in prolactin concentration once the dopamine agonist is discontinued. For this reason, it would be reasonable to try a “drug holiday” after several years of therapy with close follow-up. Medical therapy during pregnancy often stirs debate about the continuation of bromocriptine. Tumor-related complications are seen in about 15% of pregnancies and in only 5% of women with microadenomas. A sensible approach would be to stop bromocriptine when pregnancy begins, and then follow the clinical status with serum prolactin levels and visual field examinations. If there is significant worsening in clinical status, bromocriptine could be reinstituted. The adenoma can be followed yearly by MRI, increasing the duration between imaging studies if size is stable.5 Transsphenoidal surgery is reserved for patients with disease refractory to medical therapy. Even in patients with a mass effect, including visual field defects, dopamine agonists are the first line of therapy, because a rapid improvement in symptoms is observed in the majority of patients. The main advantage of surgery is avoidance of chronic medical therapy. Radiation therapy may be considered for patients who poorly tolerate dopamine agonists and who will likely not be cured by surgery (e.g., tumor invasion of cavernous sinuses).

Acromegaly Acromegaly may occur at a rate of 3 to 4 cases per million per year, with mean age at diagnosis of 40 years in men and 45 years in women. The GH-secreting tumors tend to be more aggressive in younger patients. Classical clinical features are listed in Table 22-4. More than 95% of cases of acromegaly are caused by GH-secreting pituitary tumors. In rare cases, they are caused by ectopic GH-releasing hormone (GH-RH) secretion, mainly carcinoids and pancreatic islet cell tumors. Patients with acromegaly have a 3.5-fold increased mortality rate, with cardiovascular disease being the most common cause of death. Somatotrope adenomas appear to be monoclonal in origin. A gsp mutation in a GspIa subunit in GH cells, leading to continuous GH secretion, has been shown to cause acromegaly.6 Due to the pulsatile nature of GH secretion, random GH levels can overlap in acromegalic patients and controls. Therefore, a single GH level is usually inadequate to establish the diagnosis.

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Section 3 Adult Reproductive Endocrinology Insulin-like growth factor-I has a longer plasma half-life than GH and is an excellent initial screening test for those suspected to have acromegaly. An elevated IGF-I level in a clinical setting suggestive of acromegaly almost always confirms the diagnosis. Patients with poorly controlled diabetes and malnutrition may have falsely low serum IGF-I levels. The oral glucose tolerance test remains the gold standard test to confirm the diagnosis. Normal individuals suppress their GH level to less than 1 μg/L (using chemiluminescent assays) within 2 hours after ingestion of 100 grams of oral glucose solution. With respect to women’s health, one should note that GH-secreting tumors may also cosecrete prolactin; thus, women may present with symptoms of hyperprolactinemia and only subtle symptoms of acromegaly. This cosecretion may occur over several years. The patient may initially present with high prolactin levels and several years later may start secreting excess GH. Particular attention to early detection of cardiovascular disease should be made, because it is the primary cause of mortality in these patients. Patients with acromegaly have increased risk of colon polyps with potential for increased risk of malignancy, affecting their life expectancy. For this reason they should undergo colonoscopy every 3 to 5 years until more outcome data are available. It is not clear if more rigorous screening for a variety of cancers, including breast, lung, or prostate cancer, is indicated. Treatment

314

The primary aims of treatment include relief of the symptoms, reduction of tumor bulk, normalization of IGF-I and GH dynamics, and prevention of tumor regrowth. Medical treatment of acromegaly has gained significance since the limitations of radiation and surgical therapy have become evident. Somatostatin analogues are the most effective medical therapy available for acromegaly. Octreotide therapy has significantly changed the management of acromegaly with lowering and normalization of IGF-I in 90% and 65% of patients, respectively. Octreotide is usually given as a subcutaneous injection three times per day. The long-acting octreotide (Sandostatin LAR) has been approved by the U.S. Food and Drug Administration (FDA) for medical therapy of acromegaly as a monthly intramuscular injection. Long-term observations of patients on somatostatin analogues have shown no evidence for tachyphylaxis. Some degree of tumor shrinkage is expected in up to 50% of patients, although in most cases there is less than 50% shrinkage in tumor size. The most common side effects are gastrointestinal, including diarrhea, abdominal pain, and nausea. The most serious side effect of somatostatin analogues is cholelithiasis, seen in up to 25% of patients. Its long-term management is similar to that for cholelithiasis in the general population, and routine ultrasonographic screening is not indicated. There have been very few reports of the use of a somatostatin analogue during pregnancy.7,8 Normalization of IGF-I is seen in only 10% to 15% of patients treated with dopamine agonists and is more likely with pituitary tumors secreting both GH and prolactin. Surgical approach is the treatment of choice in those presenting with pituitary microadenoma or when tumor is confined to the sella, with cure rates up to 90%. However, patients with acromegaly who have a macroadenoma will have a surgical cure less than 50% of the

time. Even in those not cured by surgery, tumor debulking usually results in improvement of symptoms and lowering of IGF-I levels. Radiation therapy almost always induces a decrease in size of the tumor and GH level but often fails to normalize IGF-I levels. In view of its low efficacy, high risk of hypopituitarism, and the lack of knowledge about its long-term effect on neuropsychiatric functions, radiation therapy should be reserved for those not responsive to other treatment modalities. Radiosurgery (gamma knife) seems to be superior to conventional radiation therapy, but large studies on efficacy and long-term safety profile are lacking. The most important recent development in the treatment of acromegaly is the introduction of a novel GH receptor antagonist. This is a recombinant modified GH molecule conjugated with polyethyleneglycol (PEG), which prevents the GH receptor from dimerization. In clinical practice, although pituitary-derived GH levels increase by a third, serum IGF-I levels are normalized in more than 90% of patients. This drug (Pegvisomant) is currently administered as a daily subcutaneous injection of approximately 1 mL. Theoretical concerns exist for pituitary tumor growth but have not been substantiated.

Cushing’s Disease Corticotropin-secreting pituitary adenoma is the most common cause of endogenous Cushing’s syndrome (60%), with the rest being adrenal (25%) or ectopic (15%) in origin. The term Cushing’s disease refers specifically to a pituitary tumor as the cause. Signs and symptoms suggestive of hypercortisolism are listed in Table 22-5. Many signs and symptoms of Cushing’s disease are nonspecific, including hypertension, abnormal glucose tolerance, menstrual irregularities, and psychiatric disturbances, including depression. Most women with Cushing’s disease have reduced fertility.9 Women with Cushing’s disease typically have fine facial lanugo hair and may have acne and temporal scalp hair loss secondary

Table 22-5 Signs and Symptoms of Cushing’s Syndrome Clinical Feature

Approximate Prevalence (%)

Obesity General

80–95

Truncal

45–80

Hypertension

75–90

Menstrual disorders

75–95

Osteopenia

75–85

Facial plethora

70–90

Hirsutism

70–80

Impotence/decreased libido

65–95

Neuropsychiatric symptoms

60–95

Striae

50–70

Glucose intolerance

40–90

Weakness

30–90

Bruising

30–70

Kidney stones

15–20

Headache

10–50

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease Suspect Cushing Syndrome Obtain 24 hr UFC and/or 1 mg ON DST

UFC > 150% ULN/ AM cortisol > 5 μg/dl CHECK AM ACTH

UFC Normal AM cortisol < 1.8 μg/dl

Supressed ACTH

Normal or Elevated ACTH

Abd. CT Scan

8 mg ON DST CRH stim. test

an undetectable or low corticotropin level is consistent with adrenal etiology, low-normal corticotropin may be seen in both ectopic Cushing’s syndrome and corticotropin-secreting pituitary tumor. The CRH stimulation test is used to differentiate between the two. Although corticotropin levels tend to be higher in those with ectopic Cushing’s syndrome compared to patients with pituitary disease, there is considerable overlap. The high-dose dexamethasone test or the CRH stimulation test is helpful in differentiation of the two disorders. Cortisol levels are not suppressed with the high-dose (8 mg) dexamethasone test in patients with ectopic corticotropin syndrome, and CRH stimulation may not lead to a further rise in corticotropin.10 The gold standard test to differentiate pituitary Cushing’s syndrome from ectopic corticotropin-producing tumor is inferior petrosal sinus sampling. This test should be performed by an experienced neuroradiologist; it is essential to note that it cannot be used to make the diagnosis of Cushing’s syndrome. Ectopic Corticotropin Syndrome

Normal ACTH response AM cortisol reduced >50%

Flat ACTH response

MRI Sella

CXR, Abd. CT, Lung CT

Figure 22-1 Laboratory investigation of a patient with a clinical suspicion of Cushing’s syndrome. ULN, upper limit of normal; ON DST, overnight dexamethasone suppression test; UFC, urinary free cortisol; CRH, corticotropin-releasing hormone; CXR, chest x-ray; MRI, magnetic resonance imaging; Abd. CT, abdominal computed tomography.

to increased adrenal androgen secretion. There is usually a 3- to 6-year delay in diagnosis of patients with Cushing’s disease, and it may be possible to date the onset of the disease by determining which scars are pigmented due to excess secretion of corticotropin and other melanotropins. Diagnosis

Twenty-four hour urinary free cortisol measurement is the single best test for diagnosis of Cushing’s syndrome (Fig. 22-1). Because of the significant overlap between normal individuals and those with Cushing’s syndrome, random serum cortisol has no role in the diagnosis of Cushing’s syndrome. A 1-mg overnight dexamethasone suppression test with a morning cortisol level below 1.8 μg/dL virtually rules out the disease but is associated with an up to 40% false-positive rate. A combination of low-dose dexamethasone suppression test and corticotropin-releasing hormone (CRH) stimulation test has been shown to have 100% diagnostic accuracy in a National Institutes of Health study. This test may have a significant value in establishing the diagnosis in those with pseudo-Cushing’s and elevated 24-hour urinary free cortisol. Other tests useful in establishing the diagnosis of Cushing’s disease include midnight serum and salivary cortisol (see Fig. 22-1). Once the diagnosis of Cushing’s syndrome has been established, the next step is to find out whether cortisol hypersecretion is corticotropin dependent (see Fig. 22-1). Although

The most important differential diagnosis of Cushing’s disease is ectopic production of corticotropin. Ectopic ACTH syndrome is the most frequent and best studied of the ectopic hormone syndromes. Most tumors associated with ectopic corticotropin syndrome are carcinomas and have a poor prognosis. They usually present as a rapid-onset syndrome (within 6 months) associated with profound muscle weakness, hyperpigmentation, hypertension, hypokalemia, and edema. Hyperpigmentation is thought to be due to cosecretion of β-melanocyte-stimulating hormone, one of the byproducts of corticotropin synthesis. Some benign tumors, such as carcinoids or islet cell tumors, have been shown to cause ectopic corticotropin syndrome and are difficult to differentiate from pituitary causes of Cushing’s syndrome. This difficulty is increased by radiologic investigations of the sella that are often negative or show a microadenoma, which is seen in up to 20% of autopsy series in normal individuals. Treatment

Surgical (transsphenoidal) removal of corticotropin-secreting pituitary tumor is the treatment of choice. Availability of an experienced surgeon is crucial, with an 80% to 90% remission rate after surgery. An undetectable postoperative cortisol level with the patient not taking steroids is considered to be an excellent marker for long-term cure. A period of temporary adrenal insufficiency follows successful surgery, usually lasting 6 to 8 months, but possibly as long as 2 years. For those not cured by the surgery, other options include second operation and radiation therapy. Patients whose tumor is unresponsive to these therapies may then be offered medical or surgical adrenalectomy. Ectopic corticotropin-producing tumors should be resected if possible. Octreotide may inhibit ectopic corticotropin secretion. Mitotane (Lysodren) is perhaps the most effective adrenolytic agent. Other medications, such as aminoglutethimide (Cytadren), ketoconazole (Nizoral), or metyrapone (Metapyrone), are useful as temporizing agents only. The glucocorticoid antagonist mifepristone (RU-486) is a promising therapy that appears to have few side effects. One difficulty is that one cannot rely on cortisol measurements to follow the effect of mifepristone. This agent blocks cortisol action but may be associated with actual higher levels of circulating cortisol.

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Section 3 Adult Reproductive Endocrinology Nonsecretory and Glycoprotein-Secreting Pituitary Adenomas

except in those with pituitary infarction. Isolated deficiencies of various anterior pituitary hormones have also been described.

Nonsecretory Adenomas

Growth Hormone Deficiency

Nonsecretory or glycoprotein-secreting tumors are usually clinically silent because they are inefficient in secreting hormones and lack a clinically recognizable syndrome. They usually come to attention because of manifestations of a mass lesion, including headache and visual field defect. Patients may present with varying degrees of hypopituitarism due to the mass effect. Glycoprotein-secreting Adenomas

Rarely, pituitary adenomas can secret glycoproteins, including FSH, LH, or thyrotropin. An FSH adenoma may cause amenorrhea in a woman, or an LH adenoma may cause precocious puberty in a boy. Diagnosis is confirmed by measurement of either intact glycoprotein hormones or their α and β subunits. Levels of the α subunit tend to be inappropriately elevated, compared with those of the intact hormone itself.11 Thyrotropin-secreting Pituitary Adenomas

The clinical picture in patients with thyrotropin-secreting pituitary adenoma includes pituitary mass lesion, hyperthyroidism, and goiter. Their most important biochemical feature is elevation of thyroid hormone levels in the presence of normal or elevated thyrotropin level. For this reason, any patient presenting with endogenous hyperthyroidism and an elevated or normal thyrotropin level should be further evaluated for the presence of a thyrotropin-secreting pituitary adenoma. Elevations in serum prolactin and α subunit of thyrotropin are in favor of a thyrotropic adenoma and against thyroid hormone resistance syndrome, which can also elevate the thyrotropin level. Treatment

The transsphenoidal surgical approach is standard for this type of adenoma, especially if visual function is abnormal. Surgery is rarely curative because of the size of adenoma on presentation, and usually radiation therapy is needed as an adjunct. Octreotide may be helpful in reducing hormone secretion, but further studies are required to assess if it has any effect on tumor size. Dopamine agonists such as bromocriptine have been used in high doses, but clinical responses (i.e., changes in tumor size or visual symptoms) occur in less than 10% of patients. Long-acting gonadotropin-releasing hormone (GnRH) agonists and antagonists may reduce secretion of FSH and LH by tumors but do not reduce tumor size. In summary, the efficacy of medical therapy in patients with nonfunctional or glycoproteinsecreting pituitary adenoma is not established but is used in an attempt to reduce tumor hypersecretion and size after unsuccessful surgery.

HYPOPITUITARISM

316

Pituitary adenomas are the most common cause of hypopituitarism, but other causes, including parasellar diseases, pituitary surgery, or radiation therapy, are possible. Head injury must also be considered. Pituitary hormone deficiency secondary to a mass effect usually occurs in the following order: GH, LH, FSH, thyrotropin, corticotropin, and prolactin. Prolactin deficiency is uncommon

Growth hormone deficiency is now recognized as a pathologic state in adults, and many patients with GH deficiency now receive GH replacement. GH deficiency may contribute to increased mortality in patients with hypopituitarism, with cardiovascular disease being the most common cause of mortality. The symptoms of GH deficiency in adults are subtle and include decreased muscle strength and exercise tolerance and reduced sense of well-being (e.g., diminished libido, social isolation). Patients with GH deficiency have increased body fat, particularly intra-abdominal fat, a well as decreased lean body mass compared to normal adults. Some patients have decreased bone mineral density, which may improve with GH replacement. A trial of GH replacement in adults with documented GH deficiency and symptoms or metabolic abnormalities suggestive of GH deficiency is indicated. The most common side effects of GH therapy include fluid retention, carpal tunnel syndrome, and arthralgia. These side effects are usually dose-related and improve with dose reduction.

Gonadotropin Deficiency Gonadotropin deficiency may be secondary to a pituitary defect, hypothalamic deficiency of GnRH, or a functional abnormality such as hyperprolactinemia, anorexia nervosa, and severe disease state. In women gonadotropin deficiency causes infertility and menstrual disorders, including amenorrhea. It is often associated with lack of libido and dyspareunia. In men hypogonadism is diagnosed less often, because decreased libido and impotence may be considered as a function of aging. Hypogonadism is often diagnosed retrospectively when the patient presents with a mass effect. Osteopenia is a consequence of longstanding hypogonadism and usually responds to hormone replacement therapy.

Corticotropin Deficiency The symptoms of secondary adrenal insufficiency from corticotropin deficiency are similar to primary adrenal insufficiency with one important difference. Mineralocorticoid secretion is mainly regulated by the renin and angiotensin system and is preserved in patients with pituitary disorders. For this reason the symptoms are more chronic in nature and commonly include malaise, loss of energy, and anorexia. Hyperkalemia is not a feature of secondary adrenal insufficiency. An acute illness may precipitate vascular collapse, hypoglycemia, and coma.

Thyrotropin Deficiency Thyrotropin deficiency is a relatively late finding in patients with pituitary disorders, with symptoms being similar to those seen with primary hypothyroidism, including malaise, leg cramps, lack of energy, and cold intolerance. The degree of hypothyroidism depends on the duration of thyrotropin deficiency.

Causes of Hypopituitarism Lymphocytic Hypophysitis

Lymphocytic hypophysitis is an autoimmune disease often presenting in women during or after pregnancy. The clinical

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease manifestations are secondary to hypopituitarism or adrenal insufficiency or are due to a pituitary mass effect. Serum prolactin is elevated in half of patients but may be decreased. Antipituitary antibodies are present in some patients, and other autoimmune endocrine disorders, including Hashimoto’s thyroiditis and Addison’s disease, have been seen by others.12 The diagnosis may be suspected on clinical grounds in a pregnant or postpartum woman. However, surgical biopsy is needed for confirmation of diagnosis. The natural history of lymphocytic hypophysitis is variable, worsening or improving spontaneously. Some patients recover fully, while others may need selective hormone replacement. For this reason, patients need to be assessed at regular intervals to determine the necessity of continued hormone replacement. Adequate hormone replacement therapy is crucial. Although lymphocytic hypophysitis is a chronic inflammatory process, probably of autoimmune etiology, anti-inflammatory corticosteroid treatment has not been systematically used so far. Thirteen patients in the literature were treated with a mean daily dose of 27.5 mg methylprednisolone equivalent for a mean time of 4.75 months. Lasting improvements, both endocrinologic and neuroradiologic, occurred in 15%. Transient improvements, primarily neurologic, occurred in 62% of cases. Relapse of symptoms occurred days to a few months after discontinuation of corticosteroid therapy. Recent experience from Germany suggests that one should be cautiously optimistic about high-dose steroid therapy. MRI findings improved in 88% of patients treated with high-dose steroids, but clinical normalization was quite variable, with none achieving complete recovery.13 Surgery for mass effect in lymphocytic hypophysitis can lead to rapid relief of neurologic symptoms, but endocrinologic improvement was seldom reported. Indications for surgery are the presence of gross chiasma compression, ineffectiveness of corticosteroid therapy, and the impossibility of establishing the diagnosis of lymphocytic hypophysitis with sufficient certainty by conservative evaluation.14 Empty Sella Syndrome

The diagnosis of empty sella syndrome has become increasingly more common, owing to the prevalent use of CT and MRI of the brain for headaches or other symptoms. Pituitary fossa enlargement is secondary to communication between the pituitary fossa and subarachnoid space, which causes remodeling and enlargement of the sella. Primary empty sella syndrome is the result of a congenital diaphragmatic defect; secondary empty sella syndrome may result from previous surgery, irradiation, or infarction of a preexisting tumor. Most patients have no pituitary dysfunction, but a wide spectrum of pituitary deficiencies have been described, especially in those with secondary empty sella syndrome. Coexisting tumors may occur. Management is usually with reassurance and hormone replacement, if necessary. Surgery is only necessary if visual field defects occur or if cerebrospinal fluid rhinorrhea is present. Pituitary Apoplexy

Pituitary apoplexy is an endocrine emergency resulting from hemorrhagic infarction of the pituitary usually associated with a preexisting pituitary tumor. A variety of predisposing conditions,

including bleeding disorders, diabetes mellitus, pituitary radiation, pneumoencephalography, mechanical ventilation, and trauma, have been described. The clinical manifestations of this syndrome are related to rapid expansion and compression of the pituitary gland and the perisellar structures leading to hypopituitarism, visual field defect, and cranial nerve palsies. Extravasation of blood or necrotic tissue into the subarachnoid space may cause clouding of consciousness, meningismus, and fever. If pituitary apoplexy is suspected, anterior pituitary insufficiency should be presumed and the patient must be treated accordingly. The glucocorticoid dose must be adequate for the degree of stress and presumptive cerebral edema. Any evidence of sudden visual field defects, oculomotor palsies, hypothalamic compression, or coma should lead to immediate surgical decompression. The recovery of a variety of pituitary hormone deficiencies after surgery has been documented; all patients should be reevaluated for possible recovery of their pituitary hormone axes. Sheehan’s Syndrome

Sheehan’s syndrome is the result of ischemic infarction of the normal pituitary gland, leading to hypopituitarism secondary to postpartum hemorrhage and hypotension.15 Patients have a history of failure to lactate postpartum, failure to resume menses, cold intolerance, or fatigue. Some women may have an acute crisis mimicking apoplexy within 30 days postpartum. There is often subclinical central diabetes insipidus.16

ADRENAL GLAND DISORDERS Anatomy and Physiology The adrenal gland consists of the medulla and the cortex. The cortex is further divided into the zona reticularis, the zona fasciculata, and the zona glomerulosa. The medulla produces norepinephrine and epinephrine. The zonae fasciculata and reticularis produce cortisol and androgens, mainly dehydroepiandrosterone sulfate (DHEAS). The zona glomerulosa produces aldosterone. As a result of the absence of 17-hydroxylase in the zonal glomerulosa, cortisol and androgens cannot be produced in that layer. The zonae reticularis and fasciculata are under the control of corticotropin released by the pituitary gland in response to hypothalamic CRH. CRH in turn is regulated by cortisol-negative feedback, stress, and a circadian rhythm. Besides increasing the synthesis of cortisol, corticotropin is trophic for the adrenal gland so that a lack of corticotropin results in atrophy of the zonae fasciculata and reticularis. Although corticotropin has some effect on aldosterone production, the zona glomerulosa is predominantly under the control of renin. Understanding the anatomy and physiology of the adrenal gland is crucial to understanding its hypofunction and hyperfunction.17

Adrenal Insufficiency Etiology

Clinical adrenal insufficiency results from hypofunction of the adrenal cortex. This may be due to destruction of the adrenal gland itself, referred to as Addison’s disease or primary adrenal insufficiency. Alternatively, it may be due to a lack of either corticotropin (i.e., secondary adrenal insufficiency) or CRH.18

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Section 3 Adult Reproductive Endocrinology Table 22-6 Other Causes of Primary Adrenal Insufficiency in Adults Infection Viral Human immunodeficiency virus (HIV) Mycobacterial Fungal Hemorrhage/infarction Anticoagulants/coagulopathy Sepsis

secondary adrenal insufficiency. Therefore, hyperkalemia and profound dehydration with orthostatic hypotension are seen in primary adrenal insufficiency only. Likewise, hyperpigmentation of the skin or mucous membranes (secondary to increased corticotropin) is seen in primary adrenal insufficiency only. The absence of hyperkalemia or hyperpigmentation does not exclude adrenal insufficiency. In addition to hyponatremia and hyperkalemia, laboratory abnormalities in adrenal insufficiency may include hypoglycemia (usually chronic), hypercalcemia, eosinophilia, and lymphocytosis.

Thrombosis

Diagnosis

Metastatic cancer: breast, lung, gastrointestinal, renal Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis Adrenoleukodystrophy/adrenomyeloneuropathy Disorder seen in young men (X-linked)—abnormal accumulation of verylong-chain fatty acids in adrenal cortex, brain, testes, and liver Central nervous system demyelination

Table 22-7 Adrenal Insufficiency Signs and Symptoms Primary

Secondary

Cortisol deficiency Anorexia/nausea/vomiting Weight loss/fatigue Myalgia/arthralgia Hypotension Hyponatremia

Yes

Yes

Androgen deficiency Loss of axillary and pubic hair (usually women only)

Yes

Yes

Aldosterone deficiency Hyperkalemia Orthostasis

Yes

No

Corticotropin excess Hyperpigmentation

Yes

No

The most common cause of Addison’s disease in adults (80%) is autoimmune destruction of the adrenal gland. This is often seen in association with other autoimmune diseases, including Hashimoto’s thyroiditis, Graves’ disease, or type 1 diabetes mellitus. Adrenal insufficiency in this setting is known as type II autoimmune polyglandular syndrome. Type I autoimmune polyglandular syndrome, more commonly seen in children, consists of Addison’s disease, hypoparathyroidism, and mucocutaneous candidiasis. Other causes associated with adrenal insufficiency are listed in Table 22-6. Currently, acquired immunodeficiency syndrome is the most common cause of infectious adrenal destruction, and the antiphospholipid syndrome (lupus anticoagulant) is increasingly being recognized as a cause of adrenal hemorrhage. Secondary adrenal insufficiency is a result of adrenal gland atrophy from corticotropin deficiency. This most often results from pituitary corticotroph atrophy owing to previous exogenous glucocorticoid use,19 hypopituitarism, or isolated corticotropin deficiency (usually postpartum). Clinical Presentation

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The underlying etiology of adrenal insufficiency determines the clinical presentation (Table 22-7). Under the regulation of corticotropin, cortisol and adrenal androgens are lost in both primary and secondary adrenal insufficiency. Aldosterone production, predominantly regulated by renin, remains intact in

The diagnosis of adrenal insufficiency is made by demonstrating diminished responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to stimulation. A morning cortisol value less than 3 μg/dL (assuming normal cortisol-binding globulin) can be sufficient to make the diagnosis. However, the cosyntropin (Cortrosyn or corticotropin) stimulation test is usually required and is the gold standard. In this test a baseline serum cortisol is obtained and then cosyntropin 250 μg is given intramuscularly or intravenously. The serum cortisol level is drawn again after 30 to 60 minutes. A rise in the cortisol level to 18 μg/dL is a normal response. If an abnormal response is obtained, a corticotropin level then determines primary (high corticotropin) versus secondary disease (normal or low corticotropin). In secondary adrenal insufficiency, however, the corticotropin stimulation test is not always abnormal. Adequate corticotropin may be present to prevent adrenal gland atrophy, thereby resulting in a response to the supraphysiologic dose of corticotropin used in the test. However, the HPA axis may not be able to respond to stress. In patients with suspected secondary adrenal insufficiency and a normal corticotropin stimulation test, CRH is now available to assess corticotropin response. In addition, the insulin tolerance test or the metyrapone test evaluate the integrity of the HPA axis by its response to hypoglycemia or inhibited cortisol synthesis, respectively. Although not widely used, some investigators find that a 1 μg corticotropin stimulation test may be more sensitive at detecting mild adrenal insufficiency.20 Treatment

The treatment of adrenal insufficiency is replacement of the deficient hormones. The following agents may be used in treating adrenal insufficiency: ● ● ●

Hydrocortisone, 30 mg daily Prednisone, 7.5 mg daily Dexamethasone, 0.75 mg daily

Cortisol 20 mg in the morning and 10 mg in the evening, or prednisone, 5 to 7.5 mg daily, provides dramatic relief of symptoms. However, to prevent Cushing’s syndrome, the smallest dose needed to control the patient’s symptoms should be used. For a minor illness, the glucocorticoid dose should be doubled for as short a time as needed. For a major stress, parenteral hydrocortisone, 200 to 400 mg daily, is given initially and then rapidly tapered. Aldosterone replacement is required in primary adrenal insufficiency only and is given as fludrocortisone acetate (Florinef Acetate), 0.05 to 0.2 mg daily. The dose is adjusted according to the blood pressure and potassium level. Renin levels may be required to assess plasma volume. Adrenal androgens are not replaced.21

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease In undiagnosed patients with suspected adrenal crisis, dexamethasone, 2 to 4 mg intravenously or intramuscularly, should be given along with saline and glucose. Dexamethasone does not interfere with the cortisol assay. The corticotropin stimulation test should then be done as soon as possible. In the management of secondary adrenal insufficiency caused by previous exogenous steroids, glucocorticoids with short halflives (usually cortisone) should be given. Typically larger doses are used in the morning and smaller doses in the evening. The evening doses are gradually tapered, as symptoms permit, to allow overnight hypothalamic-pituitary “desuppression” and a rise in corticotropin level. This leads to a return of adrenal gland function. When morning cortisol reaches 10 μg/dL, replacement glucocorticoid can generally be discontinued. Stress glucocorticoids, however, should be given until result of the corticotropin stimulation test is normal. Recovery of the HPA axis from glucocorticoid suppression generally requires 6 to 12 months. Pregnancy and Adrenal Insufficiency

Because the excess estrogens in pregnancy can result in increased synthesis of cortisol binding globulin, the doses of cortisone or prednisone may need to be increased modestly. Dosing is empiric since there is no good blood test to titrate the steroid replacement. One must avoid overreplacement as well.

Hypoaldosteronism Hypoaldosteronism results from decreased aldosterone production by the zona glomerulosa of the adrenal cortex. This may be due to deficient renin stimulation or defective aldosterone production despite renin stimulation. In adults, the most common cause of primary hypoaldosteronism is adrenal insufficiency. Renal insufficiency (or type 4 renal tubular acidosis) is the most common cause of secondary hypoaldosteronism. Children and young adults may have adrenal cortex enzyme deficiencies causing hypoaldosteronism. The symptoms and signs of mineralocorticoid deficiency include hyperkalemia and metabolic acidosis. Blood pressure may be low, normal, or high. Serum sodium may be normal or low. If necessary, the diagnosis may be established by aldosterone levels that fail to rise with standing or volume depletion with diuretics. Treatment involves mineralocorticoid replacement with fludrocortisone, 0.05 to 0.2 mg daily, with dose adjustments based on blood pressure and potassium levels. Patients with hypertension or congestive heart failure are treated with loop diuretics.

Late-Onset Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia (CAH), due to deficiency of an enzyme in the cortisol synthesis pathway, occurs in three variant forms: ● ● ●

Classic CAH Simple virilizing CAH Late-onset CAH.

Late-onset CAH results in relative cortisol deficiency and increased corticotropin levels. Cortisol production is normalized but at the expense of adrenal hyperplasia and increased androgens. Therefore, late-onset CAH presents with peripubertal (or later)

evidence of androgen excess (acne, hirsutism, menstrual irregularities, infertility) and adrenal hyperplasia or nodules. Adrenal insufficiency is not present. The most common (relative) enzyme deficiency is 21-hydroxylase, resulting in an accumulation of 17-hydroxyprogesterone (17-OHP). In this case, screening for late-onset CAH should be performed before the follicular phase and may include the following: ● ●

Random early-morning follicular phase 17-OHP Stimulated (by cosyntropin) 17-OHP.

Women with severe forms of CAH tend to have reduced fertility rates because of oligo-ovulation. Successful conception requires careful endocrine monitoring and often ovulation induction.22 Late-Onset CAH and Pregnancy

Fertility rates may be lower in women with CAH, but with successful medical management, women, especially those with 21-hydroxylase deficiency, may conceive.23 From a fetal and neonatal standpoint, accurate prenatal diagnosis of 21-hydroxylase deficiency and 11β-hydroxylase deficiency is necessary to allow for prenatal treatment using dexamethasone in an attempt to minimize clinical problems in the neonate. Dexamethasone can cross the placenta and suppress fetal adrenal steroidogenesis and potentially prevent masculinization of affected female fetuses.24 Large quantities of estrogen are produced during normal human pregnancy, and, after the first 3 to 4 weeks of gestation, the placenta produces nearly all of the estrogen. The major precursor for estrogen production is DHEAS, which is synthesized in the fetal adrenal gland. The adrenals of the human fetus at term are as large as those of adults, weighing 8 to 10 g or more. The fetal adrenals are principally composed of an inner fetal zone that accounts for 85% of the total volume. The outer zone, the neocortex, develops into the mature adrenal cortex, which is only 15% of the total volume. The capacity of the fetal adrenals for steroidogenesis is enormous, and near term, the fetal adrenals secrete 100 to 200 mg of the steroid per day. The total daily steroid production by the adrenals in an unstressed adult is approximately 35 mg.25 In addition to its role in providing precursors for placental estrogen formation, the fetal adrenal cortex may participate in the events that lead to the initiation of labor and maturation of the fetal lungs. Corticotropin levels in human fetal blood decline as gestation progresses, but the adrenals continue to grow in late gestation. The trophic stimulus for the fetal adrenal may not be corticotropin, and the pattern of steroids secreted by the fetal adrenal is also different. Therefore, a trophic role has been proposed for other hormones, including GH, human chorionic gonadotropin (hCG), prolactin, and human placental lactogen. More than 90% of the estradiol and estriol and 85% or more of the progesterone formed in the trophoblast are secreted into the maternal compartment. The net transfer of steroids to maternal blood is approximately 10 times that of the net transfer to fetal blood. Only a small amount of the steroids in the maternal circulation reach the fetal compartment in normal pregnancy. For example, a small amount of cortisol in maternal plasma crosses the placenta, both because the reentry pathway dominates and because cortisol within the trophoblast is converted to cortisone

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Section 3 Adult Reproductive Endocrinology by 11β -hydroxysteroid dehydrogenase. Circulating 19-carbon steroids in the maternal compartment, such as DHEAS, DHEA, androstenedione, and testosterone, do not reach the fetal compartment because of the presence of aromatase enzymes of the syncytiotrophoblast that are used for the conversion of 19-carbon steroids to estrogens. This mechanism protects the female fetus from possible virilization in women who may be hyperandrogenic during pregnancy.

Cushing’s Syndrome Pathophysiology

Cushing’s syndrome is a result of glucocorticoid excess. Endogenously, this may be due to increased corticotropin secretion by the pituitary gland (Cushing’s disease) or ectopically or to autonomous cortisol secretion by an adrenal tumor. The most common cause of Cushing’s syndrome, however, is exogenous use of glucocorticoids.

A repeat urinary free cortisol with alcohol abstention should be normal. If necessary, the low-dose dexamethasone suppression test may document true hypercortisolism. Dexamethasone 0.5 mg orally is administered every 6 hours for 48 hours, while a 24-hour urinary free cortisol including 17-hydroxysteroids (17-OHCS) is collected before and on the second day of dexamethasone. Failure to suppress 24-hour urine 17-OHCS to less than 4 mg or the urinary free cortisol to less than 25 μg suggests pathologic hypercortisolism, although pseudo-Cushing’s states occasionally cannot be suppressed. The urine 17-OHCS level is less essential because of the advent of the urinary free cortisol. Once true Cushing’s syndrome has been documented, a corticotropin level separates corticotropin-dependent from corticotropin-independent disease. The corticotropin-dependent hypercortisol diseases and syndromes are: ●

Clinical Presentation

The clinical features of Cushing’s syndrome are listed in Table 22-5. With respect to specificity for Cushing’s syndrome, thinning of the skin, purple striae, and bruising are the best clinical signs. Hypokalemia, edema, and hyperpigmentation are more commonly seen in ectopic corticotropin secretion, in which corticotropin and cortisol levels tend to be much higher. If a pregnant woman is in a hypercortisolemic state due to exogenous glucocorticoid therapy, the fetus is at potential risk of hypoadrenalism and one needs to forewarn the neonatologist. Diagnosis

The diagnosis of Cushing’s syndrome revolves around the inability to suppress the HPA axis. Two screening tests are employed: ● ●

24-hour urine collection for free cortisol and creatinine Overnight dexamethasone suppression test, in which dexamethasone 1 mg is given at 11 p.m. and a serum cortisol is drawn the following morning. A cortisol level less than 1.8 μg/dL is a normal (or negative) response.

The 24-hour urinary free cortisol and creatinine is more specific but is also more cumbersome. The value may be elevated in depression, acute illness, and alcoholism. The 1-mg overnight dexamethasone suppression test is easy to perform but falsepositive and false-negative responses are common. Causes of a false-positive test result include increased cortisolbinding globulin (high circulating estrogen), depression, acute illness, and alcoholism. Drugs that increase the metabolism of dexamethasone (rifampin, phenobarbital, and phenytoin) may also result in a false-positive response. False-negative test results may be seen in Cushing’s disease or cyclic intermittent Cushing’s syndrome. Differential Diagnosis

320

Figure 22-1 will allow confirmation of hypercortisolism and assessment of potential causes. If an abnormal result is obtained by either the 24-hour urinary free cortisol or the 1-mg overnight dexamethasone suppression test, the pseudo-Cushing’s state of alcoholism or endogenous depression should first be sought by a careful history, physical examination, and laboratory evaluation.

● ●

Cushing’s disease ectopic corticotropin production ectopic CRH production

The corticotropin-independent hypercortisol diseases and syndromes are: ● ● ● ●

adrenal adenoma adrenal carcinoma nodular adrenal hyperplasia exogenous glucocorticoids.

A low corticotropin level prompts CT of the adrenal to look for a tumor or nodules. A normal or elevated corticotropin value suggests Cushing’s disease or ectopic corticotropin production; these can be differentiated by the high-dose (8 mg) overnight dexamethasone suppression test. If a morning cortisol level suppresses by 50% in response to 8 mg of dexamethasone the evening before, the diagnosis is presumed to be Cushing’s disease. However, the specificity is not 100%. Many occult bronchial carcinoid tumors with corticotropin secretion can suppress in response to high-dose dexamethasone. Magnetic resonance imaging is not a definitive means for distinguishing pituitary from nonpituitary tumors, because 50% of Cushing’s disease patients have occult pituitary adenomas. Furthermore, up to 10% of patients may have false-positive pituitary scans (pituitary “incidentaloma”). Inferior petrosal sinus sampling (enhanced with CRH) may be necessary; an elevated sinus-to-peripheral corticotropin gradient suggests Cushing’s disease. Treatment

It should be apparent that the diagnostic workup for Cushing’s syndrome can have many pitfalls. False-positive screening tests, pseudo-Cushing’s states, modest specificity of the high-dose dexamethasone suppression test, and limitations of pituitary imaging can all lead to an erroneous diagnosis. It is important to correctly diagnose Cushing’s disease because the most appropriate treatment is transsphenoidal pituitary adenomectomy performed by an experienced neurosurgeon, although radiation therapy, ketoconazole (Nizoral), or bilateral adrenalectomy may be needed in some cases. Resection of the underlying tumor or chemotherapy is the treatment for adrenal neoplasia and ectopic corticotropin production.

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease Cushing’s Syndrome and Pregnancy

Although the clinical diagnosis may be difficult during pregnancy, one should seek out catabolic signs. There is also a greater likelihood of diabetes, worsening hypertension, cardiomyopathy, and psychological and muscular symptoms. The diagnostic testing, such as low- and high-dose dexamethasone testing, remains the same. One should remember that with higher cortisol binding globulin levels, the usual serum (total) cortisol levels may be falsely high.26 Poor wound healing should be anticipated as well as prolonged bleeding from any surgical procedures. Treatment is the same as for the nonpregnant state although surgical intervention such as adrenalectomy, if required, should be performed early in the second trimester. Occasionally, ketoconazole27 has been used to medically control the hypercortisolism without adverse effects on the mother or the baby. Adrenal insufficiency can occur postoperatively and therefore preventive therapy should be initiated.28

Hyperaldosteronism Excess aldosterone results in hyperaldosteronism with hypertension, hypokalemia, and metabolic alkalosis. This may be associated with Cushing’s syndrome, particularly in patients with adrenal carcinoma. Isolated primary hyperaldosteronism, marked by an elevated aldosterone level and suppressed plasma renin activity, accounts for 1% to 2% of patients with hypertension; the presence of spontaneous hypokalemia or a serum potassium level less than 3.0 mEq/L on diuretics should prompt an evaluation.29 The ratio of aldosterone (ng/dL) to plasma renin activity (ng/mL/h) is a simple screening test. However, first hypokalemia must be corrected and interfering drugs, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, and beta blockers, discontinued. A ratio greater than 20 is quite sensitive but not specific. Because the ratio can swing widely with small changes in plasma renin activity, some rely on 24-hour urinary aldosterone levels as an indicator of excess aldosterone secretion. The saline suppression test confirms the diagnosis. The test involves determination of aldosterone and plasma renin activity before and after administration of 2 L of normal saline. Normal patients suppress aldosterone to less than 5 ng/dL. A persistently elevated aldosterone-to-plasma renin activity ratio after captopril (Capoten) may also be used to confirm the diagnosis. The next step is to differentiate adrenal adenoma from hyperplasia. An adenoma can be differentiated by CT findings, increased 18-hydroxycorticosterone levels, or bilateral adrenal vein catheterization. Spironolactone (Aldactone), an aldosterone antagonist, is the treatment of choice for patients with hyperplasia, small adenomas, or contraindications to surgery.30

methasone suppresses corticotropin and subsequently excess aldosterone production. In patients with suppressed plasma renin activity and low aldosterone levels, a mineralocorticoid other than aldosterone is present. In the syndrome of apparent mineralocorticoid excess, seen in young adults, the mineralocorticoid has been identified as cortisol (which normally has little mineralocorticoid effect). Normally, cortisol is inactivated to cortisone in the renal tubular cell by 11β-hydroxysteroid dehydrogenase. Deficiency of this enzyme allows cortisol to bind to the mineralocorticoid receptor, resulting in hypertension, hypokalemia, and suppressed plasma renin activity. Natural licorice (glycyrrhizic acid) is known to inhibit 11β-hydroxysteroid dehydrogenase, thus explaining licorice-induced hypermineralocorticoidism. Excess sodium itself serves to suppress plasma renin activity and causes hypertension in Liddle’s syndrome. In this familial syndrome, constitutive activation of the kidney’s epithelial sodium channel results in increased sodium resorption and potassium excretion independently of any mineralocorticoid. Spironolactone is therefore ineffective; triamterene (Dyrenium) is the treatment of choice. Primary hyperaldosteronism is rarely observed in pregnancy.31 Plasma aldosterone levels may be normally elevated in pregnancy and urinary potassium level may be lower than that in nonpregnant patients with hyperaldosteronism due to the effects of progesterone. Plasma renin levels should be decreased in patients with primary hyperaldosteronism. In a healthy pregnancy, plasma renin activity is usually increased and decreases in the setting of primary hyperaldosteronism.32 Another dynamic test that may be used is stimulation of renin production by positioning the patient upright. In pregnant patients, prolonged standing results in a modest increase in plasma renin activity.33 If the renin activity remains suppressed, this is suggestive of primary hyperaldosteronism. Imaging studies are necessary to localize adrenal adenomas. MRI is the preferred imaging method in pregnant women. If an adrenal adenoma is detected, unilateral adrenalectomy is the treatment of choice. Cases of successful adrenalectomy in the second trimester have been reported. The goals of medical therapy should be adequate control of blood pressure and replacement of potassium. Spironolactone and ACE inhibitors are contraindicated in pregnant patients. Methyldopa, beta blockers, and calcium channel blockers can be used. Dexamethasone-suppressible hyperaldosteronism (or glucocorticoid-remediable aldosteronism) seems to be associated with a higher likelihood of exacerbation of hypertension during pregnancy.34 There does not appear to be a higher incidence of preeclampsia.

Other Mineralocorticoid Excess Syndromes

Pheochromocytoma

The pathogenesis of several mineralocorticoid excess syndromes has recently been elucidated. Dexamethasone-suppressible hyperaldosteronism is an entity that should be suspected in a young patient with elevated aldosterone levels, suppressed renin activity, and an appropriate family history of hypertension and premature strokes. Through the development of a hybrid gene, the enzyme that catalyzes the final steps of aldosterone synthesis becomes regulated by corticotropin. Treatment with dexa-

Pheochromocytoma accounts for approximately 0.1% of hypertensive patients. This tumor should be especially suspected in multiple endocrine neoplasia type II (MEN IIA and MEN IIB), in which case the disease is frequently bilateral. Clinical Presentation

The triad of headaches, palpitations, and diaphoresis in the presence of hypertension is classic for pheochromocytoma.

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Section 3 Adult Reproductive Endocrinology Table 22-8 Signs and Symptoms of Pheochromocytoma Classic symptoms Headaches, palpitations, and diaphoresis Postural hypotension Tachycardia Weight loss Pallor Hyperglycemia Anxiety Nausea/vomiting Constipation Tremulousness

Other signs and symptoms are listed in Table 22-8. More frequently recognized are silent pheochromocytomas presenting as adrenal incidentalomas. Cocaine abuse may be mistaken for pheochromocytoma. Diagnosis

Screening for pheochromocytoma consists of a 24-hour urine collection for catecholamines and metanephrines. Plasma catecholamines may also be useful; plasma norepinephrine levels greater than 2,000 pg/mL are specific for pheochromocytoma. Borderline or indeterminate results require further testing. The clonidine (Catapres) suppression test is used to confirm the diagnosis in patients with indeterminate urine or plasma studies. The test involves the measurement of plasma catecholamines before and 3 hours after 0.3 mg of oral clonidine. A normal response is a plasma norepinephrine level less than 500 pg/mL or a 50% decrease from baseline. Plasma metanephrines is also an excellent screening tool. The glucagon stimulation test may also be used. An increase in blood pressure and plasma catecholamines strongly suggests pheochromocytoma. However, the sensitivity of this test is limited, and it is potentially dangerous (hypertensive crisis). Chromogranin A, a neuropeptide secreted with the catecholamines, is sensitive for pheochromocytoma but has poor specificity. It is elevated with even minor degrees of renal insufficiency and cosecreted with many hormones. Once the diagnosis is biochemically established, radiographic localization is indicated. Although CT is the initial choice, MRI may be especially useful because pheochromocytoma can be markedly hyperintense (white) on T2-weighted images. Scanning with iodine-131-labeled metaiodobenzylguanidine (MIBG) is most specific and is particularly useful for extra-adrenal (10%) and malignant metastatic tumors (10%).

mortality rates of 48% and 54.4%, respectively, in the late 1960s35 dropped to 17% and 26%, respectively, by the late 1980s.36 In a 1999 review of patients with pheochromocytoma in pregnancy, the maternal and fetal mortality rates were 4% and 11%, respectively. Antenatal diagnosis of pheochromocytoma reduced the maternal mortality rate to 2%.37 Pregnant patients with pheochromocytoma usually present with severe and fluctuating hypertension. The most common associated symptoms are headache, perspiration, palpitation, and tachycardia. Other signs and symptoms may include arrhythmias, postural hypotension, chest or abdominal pain, visual disturbance, convulsions, and sudden collapse. A history of multiple endocrine neoplasia type II (MEN II), familial pheochromocytoma, von Hippel-Lindau syndrome, or retinal angiomatosis should increase clinical suspicion. Preoperative management with alpha-adrenergic blockade (e.g., phenoxybenzamine) is safe in pregnancy. Combined alpha and beta blockers (e.g., labetalol) have also been used in pregnancy without adverse fetal effects. Beta blockade should not be used without prior alpha blockade because unopposed alphaadrenergic activity may lead to vasoconstriction and a hypertensive crisis. Surgical intervention should be performed before 24 weeks’ gestation, after achieving adequate alpha blockade. After 24 weeks’ gestation, uterine size makes abdominal exploration and access to the tumor difficult. Optimum results are obtained if surgery is delayed until fetal maturity is reached.38 At that time, with adequate alpha blockade, elective cesarean delivery may be performed, followed immediately by adrenal exploration. Vaginal delivery appears to be higher risk than cesarean delivery. Some authors have reported success with alpha and beta blockade from the beginning of the second trimester to term, with good fetal outcomes. Malignant pheochromocytoma may recur in pregnancy. Lifelong monitoring is necessary in all patients, with extra caution in those who are pregnant.

Incidentally Discovered Adrenal Mass Incidental adrenal masses are common, detected in approximately 2% of patients having abdominal CT scan. The differential diagnosis of such masses is listed in Table 22-9. Management of an incidentaloma is controversial; clinical judgment is required. Patients should first be clinically evaluated for evidence of adrenal hormone production (cortisol, androgens, aldosterone, catecholamines). If the tumor appears to be clinically

Table 22-9 Differential Diagnosis of Incidentally Found Adrenal Masses Functioning or nonfunctioning adenoma

Treatment

Functioning or nonfunctioning carcinoma

Treatment of a pheochromocytoma is resection after appropriate operative preparation (volume loading and adrenergic receptor blockade). Calcium channel blockers may also be effective.

Pheochromocytoma Metastasis from tumors at other sites (especially malignant melanoma, lung, breast, and gastrointestinal cancers) Myelolipoma Cyst

Pheochromocytoma and Pregnancy

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Pheochromocytoma in a pregnant woman is life-threatening, but the prognosis appears to be improving. Maternal and fetal

Focal enlargement in hyperplastic gland (e.g., Cushing’s disease, congenital adrenal hyperplasia) Pseudoadrenal mass arising from nearby organs

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease nonfunctional, most endocrinologists would still screen biochemically for pheochromocytoma.39 Several investigators also recommend dexamethasone suppression testing to exclude preclinical Cushing’s syndrome. These patients will not have the classic signs or symptoms of hypercortisolism but will have evidence of HPA axis dysfunction, such as loss of diurnal rhythm. The long-term implications of preclinical Cushing’s syndrome are unknown, and the optimal management is therefore controversial; however, at a minimum, these patients need to be identified before adrenal surgery because postoperative adrenal insufficiency may develop. Despite an absence of hormone excess, nonfunctional tumors greater than 4 to 6 cm should be resected owing to an increased risk of malignancy. Nonfunctional tumors measuring 4 cm and smaller can be further evaluated radiographically to determine the likelihood of benign disease. The attenuation value, obtained from a noncontrast CT scan, is a measure of a tumor’s lipid content. A value less than 10 Hounsfield units (HU) suggests fat density and is specific for adenoma. Masses of indeterminate attenuation value (10 to 20 HU) can be further classified by MRI. Masses inconsistent with adenoma on CT or MRI require repeated follow-up with CT to assess growth or fine-needle aspiration biopsy.40 A biopsy, however, is rarely necessary.

THYROID GLAND DISORDERS The thyroid gland is situated in the neck, anterior to the trachea, between the cricoid cartilage and the suprasternal notch. It has two lobes connected by an isthmus and in adults it usually weighs 10 to 20 grams.

Thyroid Physiology Synthesis and Secretion of Thyroid Hormone

Thyroid hormone synthesis involves six major steps: 1. Active transport of iodide across the basement membrane into the thyroid cell. The thyroid concentrates inorganic iodide from the extracellular fluid by an active process that is influenced by both thyrotropin and an autoregulatory system. Iodide transport can be inhibited by anions, as perchlorate and thiocyanate, and this mechanism has sometimes been therapeutically used to quickly correct severe hyperthyroidism in patients not manageable by other treatment. 2. Oxidation of iodide and iodination of tyrosyl residues in the thyroid gland. 3. Coupling of iodothyrosine. The two main thyroid hormones are T4 (thyroxine, 3,5,3′,5′-tetraiodo-L-thyronine) and T3 (3,5,3′-triiodothyronine). T4 and T3 form within thyroglobulin by a coupling reaction catalized by thyroid peroxidase. The thyroid can store several weeks’ supply of thyroid hormone in the thyroglobulin pool. 4. Proteolysis of thyroglobulin with release of free iodothyronines and iodothyrosines. 5. Deiodination of iodotyrosines in the thyroid cell and reuse of iodide.

6. Intrathyroidal 5′ deiodination of T4 to T3. Approximately 25% of circulating T3 is derived from direct secretion; the remainder comes from peripheral conversion. Iodine is a major component of thyroid hormone. Thus, adequate iodide intake is necessary for normal thyroid hormone synthesis. The minimum dietary requirement of iodide is about 75 μg/day; the daily iodine intake varies between 200 and 500 μg/day in the United States. Iodide absorption is efficient, and most of the iodide is removed by the thyroid and kidneys. Thyroid Hormone Transport

Thyroid hormones are transported in serum bound to carrier proteins, with only 0.03% to 0.04% of T4 and 0.3% to 0.4% of T3 being free and active. Thyroid-binding globulin (TBG) is the primary binding protein (about 75%); other binding proteins are TBPA (≈15% of T4 binding) and albumin (≈10% of T4). T3 is bound primarily to TBG. Changes in TBG concentration result in almost parallel changes in thyroid hormone concentrations, but the amount of free hormone does not change. Any alterations in the affinities of these globulins for thyroid hormone can cause significant alterations in the binding capacities, leading to changes in the ratio of free to bound thyroid hormone. TBG can be abnormal under several clinical circumstances. Congenital Thyroid Hormone Binding Protein Abnormalities

In a recent study of 15,000 consecutive patients over a period of 4 years, congenital complete TBG deficiency was reported in 1/2500 live births and partial deficiency in 1/200. TBG excess is found in 1/15,000 live births.41 Familial dysalbuminemic hyperthyroxinemia is a familial autosomal dominant syndrome caused by abnormal albumin with an increased affinity for T4 resulting in elevated serum total T4 but normal thyrotropin level. Familial dysalbuminemic hyperthyroxinemia is the most common cause of inherited euthyroid hyperthyroxinemia. Whenever there is a large discrepancy between the actual versus expected T4 in a situation of a normal thyrotropin, a binding protein abnormality is the most likely etiology. Current recommendations of using a thyrotropin level only as a screening test may result in the clinician missing these biochemical anomalies. Other causes of TBG abnormalities are pregnancy, estrogen therapy, acute hepatitis, and human immunodefieciency virus infection. Metabolism of Thyroid Hormones

T4 is metabolized by initial deiodination to T3 or reverse T3 and then later by further deiodination. The cytochrome P450 system in the liver is responsible for approximately 25% of hormone disposal. Drugs that stimulate the cytochrome P450 enzymes (phenytoin, phenobarbital, carbamazepine, rifampin) can increase thyroid hormone metabolism and clearance. In a euthyroid patient, this can be compensated by an increase in thyrotropin secretion, but in a hypothyroid patient on thyroid hormone therapy, doses would have to be increased. Several studies have demonstrated that there are two separate 5′- deiodinase enzymes and one 5-deiodinase. The type I 5′-deiodinase is primarily localized in the liver and kidney. The type II 5′-deiodinase is present in the anterior pituitary and has a much higher affinity for T4. The type II 5′-deiodinase is present in the central nervous system, placenta, and skin and it is the predominant deiodinase in the fetus.42

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Section 3 Adult Reproductive Endocrinology Approximately 80 to 90 μg of T4 is secreted daily and T3 secretion is approximately 20 to 30 μg/day. The rest comes from peripheral conversion. During illnesses, conversion of T4 can be routed preferentially to reverse T3.

Table 22-10 Screening Recommendations for Thyroid Disease Screening Recommendations

Hormone Receptors

The generally accepted concept is that T4 is a prohormone that is converted to T3, which then interacts with the nuclear receptor. Some recent work suggests that T4 may directly interact with cell membrane proteins, resulting in rapid, calcium-dependent actions. In the future, one could envision selective thyroid hormone receptor modulators, analogous to the selective estrogen receptor modulators (SERM) such as tamoxifen and raloxifene.

Physiologic Effects of Thyroid Hormone Thyroid hormone influences almost all tissues of the body, and some consider them tissue growth factors. Protein synthesis and catabolism is stimulated, and this is probably responsible for some of the calorigenic effect of thyroid hormone. Thyroid hormone also affects carbohydrate metabolism, increasing epinephrine effects in stimulating glycogenolysis and gluconeogenesis and enhancing the rate of intestinal glucose absorption. Thyroid hormone affects catabolism of all lipoproteins. Hypothyroidism can thus lead to increased levels of any of the lipoproteins, including low-density, very low-density, intermediate-density, and high-density lipoproteins. Pituitary Regulation of Thyroid Activity

Thyroid hormone synthesis and secretion is tightly regulated by pituitary thyrotropin and thus this becomes a sensitive indicator of thyroid hormone excess or deficiency. More importantly, the thyrotropin level also tells us how the pituitary perceives the thyroid status instead of relying on our own imprecise clinical impression.

Prevalence of Thyroid Disease

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The National Health and Nutrition Examination Survey (NHANES III)43 measured serum thyrotropin, total serum T4, and antithyroid antibodies in a sample representative for geographic distribution of U.S. population. The prevalence of hypothyroidism was 4.3% (0.3% clinical and 4.0% subclinical) and the prevalence of hyperthyroidism was 1.3% (0.5% clinical and 0.7% subclinical). It should be noted that mean serum thyrotropin in a healthy population was 1.5 mU/L. Thyrotropin levels were higher in females compared to males, higher in the white population than African Americans or Mexican Americans. Women were also more likely to have antithyroid antibodies. In 2004, the U.S. Preventive Health Task Force44 felt that there was insufficient “good strength” evidence to support testing or routine screening of thyroid function in the general population (Table 22-10). Most experts agree that although controversial, screening is warranted in women over age 35, men over age 65, and as routine screening in women at their first prenatal visit.45,46 The main areas of disagreement between the U.S. Preventive Task Force in 2004 and the joint statement by several endocrine associations in 200547 are

● ●

●

Organization

Routine screening for subclinical thyroid disease in adults, pregnant women, and women contemplating pregnancy

2005

Consensus statement of the American Association of Clinical Endocrinologists, The Endocrine Society, and American Thyroid Association47

Uncertain whether screening for subclinical thyroid dysfunction in nonpregnant adults is beneficial

2004

U.S. Preventive Services Task Force44

Against routine treatment of subclinical thyroid dysfunction Insufficient evidence to support population-based screening

2004

U.S. Preventive Services Task Force44

Levels of thyrotropin or free T4 should be monitored in pregnant patients with preexistent disease No need to measure TFTS in hypermesis Insufficient data to warrant routine screening of asymptomatic pregnant women

2002

American College of Obstetricians and Gynecologists45

Women and men over age 35, every 3 years

2000

American Thyroid Association107

routine screening for subclinical disease in general population routine screening for subclinical disease in women who are pregnant or planning pregnancy routine treatment of patients with subclinical hypothyroidism with thyrotropin between 4.5 and 10 mU/L.

Until more evidence is gathered through major clinical trials, patient preference will also have an important role in the decision making together with the best clinical judgment from the practicing physician.

Thyroid Disease and Fertility Menometrorrhagia may be evident in mild to moderate hypothyroidism, and amenorrhea may be observed with severe hypothyroidism. There may be disorders of ovulation or conception with hypothyroidism. Occasionally, with severe hypothyroidism, prolactin levels may be elevated, resulting in reduced LH and FSH secretion, leading to absent menses. Autoimmune ovarian problems can coexist with hypothyroidism, which may result in premature ovarian failure. Endometriosis has also been reported in antibody-positive women. Hyperthyroidism may also be associated with irregular or absent menses, and infertility is common. Thyroid disease should be considered in patients undergoing investigation for menstrual problems48 or infertility.49 A recent prospective study by Poppe and colleagues of more than 400 infertile women showed a higher prevalence of autoimmune thyroid disease (18%), determined by the presence of antimicrosomal antibodies, compared with controls (8%).50 A Finnish study reported an overall prevalence of hypothyroidism of 4% in infertile women.51 Fortunately, once treated adequately, neither hypothyroidism nor hyperthyroidism has a major impact on fertility. The potential effect of treatment of relative thyroid hormone deficiency on infertility is unknown.52 One intervention trial in

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease women with recurrent abortions, mild thyroid dysfunction, and positive antimicrosomal antibodies53 showed that early supplementation with thyroid hormone favorably affects the outcome of pregnancy. It is unknown whether treatment of women with antithyroid antibodies but normal thyrotropin levels can lead to better outcomes. Systematic screening54 should be considered in all women with a female cause of infertility.55

Subclinical Hypothyroidism

Table 22-11 Causes of Hypothyroidism Primary Agenesis Destruction of the gland Surgical removal Irradiation—therapeutic radioiodine or external irradiation Autoimmune disease (Hashimoto’s thyroiditis) Idiopathic atrophy Infiltrative process (as in scleroderma, Reidel’s thyroiditis) Inhibition of synthesis and release of thyroid hormone Iodine deficiency Excess iodide in susceptible individuals Drugs—interferon, lithium, amiodarone Inherited enzyme defects Transient Subacute thyroiditis Postpartum thyroiditis Silent thyroiditis

Subclinical hypothyroidism is defined as an elevated serum thyrotropin level associated with normal total or free levels of T4 and T3 in the absence of symptoms. The thyrotropin level is usually less than 10 μU/mL. It has been also called mild hypothyroidism, preclinical hypothyroidism, mild thyroid failure, and compensated hypothyroidism.56 The natural history of subclinical hypothyroidism is variable.57 In some individuals, the thyrotropin level will be normal several months later or may remain unchanged. This may be due to laboratory error or to transient silent thyroiditis. The patient may also develop overt hypothyroidism, which occurs at a rate of about 5% per year in patients with raised thyrotropin levels and detectable antithyroid antibodies.58 In some subjects with high titers of antithyroid antibodies, the risk of progression to overt disease may be closer to 20% per year.59 Consideration of these possible outcomes60 affects the decision about whether to treat or to observe without treatment.61

able to radioactive ablation, because they do not cause permanent hypothyroidism and thus would constitute a therapeutic/ diagnostic trial.

Potential Benefits of Treating Subclinical Hypothyroidism

Hypothyroidism

Treatment may prevent progression to overt hypothyroidism, which is estimated to be 2.6% in women with increased thyrotropin levels and 4.3% if antimicrosomal antibodies are present as well. The risk of cardiovascular disease may be decreased if the lipid profile is affected,62 even though several studies failed to show a clear association between cardiovascular disease and hypothyroidism.63 There may be an improvement of symptoms if present.64

Subclinical Hyperthyroidism Subclinical hyperthyroidism is defined as a suppressed serum thyrotropin level associated with normal total or free levels of T4 and T3. The prevalence (2%) is much lower compared with subclinical hypothyroidism. With or without a goiter, it is often difficult to make a definitive diagnosis, even with additional tests. If the thyrotropin level is not detectable or is at the lowest limit of normal, it is unlikely that the patient is hyperthyroid. If the thyrotropin level is only slightly below the normal range (i.e., 0.1 to 0.3 μU/mL), this is most likely a transient abnormality and should be monitored rather than treated. If the individual is truly hyperthyroid, there will be potential increased risk of atrial fibrillation, osteoporosis, and changes in heart contractility. Nevertheless, the abnormal test results may be a result of nonthyroidal illness and concomitant medication, underlying autonomous thyroid function, or the initial phase of thyroiditis. It would be reasonable to repeat thyroid function tests in 8 to 12 weeks. Normalization would indicate likely recovery from nonthyroidal illness or thyroiditis. If the initial pattern persists, the choice should be made between a trial of antithyroid drugs and close clinical follow-up. Antithyroid drugs would be prefer-

Secondary Pituitary disease—tumors, surgery or irradiation, infiltrative disorders, Sheehan’s syndrome, trauma, genetic forms of combined pituitary hormone deficiencies Hypothalamic disease

Hypothyroidism is a common disease, especially in women, with a 1% to 2% prevalence (up to 10% in those older than age 65).43,56,65 Congenital hypothyroidism is one of the most frequent congenital diseases, with an incidence of 1/4000 newborns. Table 22-11 lists the causes of hypothyroidism. Clinical Features

The symptoms are generally related not only to the pathogenesis of hypothyroidism, duration, and severity, but also to the age of the patient. The symptoms and signs of thyroid disease are ubiquitous and often nonspecific. Armed with a high index of suspicion, one can more easily document the clinical manifestations of thyroid disease. Hypothyroidism may manifest as modest weight gain; cold intolerance; fatigue; dry, falling hair; facial puffiness; macroglossia; slow, guttural speech; muscle aches; depression; reduced memory; somnolence; sleep apnea; constipation; galactorrhea; and a menstrual disorder such as menorrhagia. Clinical signs include dry and yellow skin, eyelid edema, puffy hands and swelling of feet, cold extremities, dry skin and brittle nails, coarse hair, slow speech, delayed relaxation phase of deep tendon reflexes, bradycardia, and serous cavity effusions. Despite popular belief weight gain is minimal and is due mostly to fluid retention. Since autoimmune processes play a major role in thyroid disorders, one should often look for other autoimmune disorders in the patient and enquire about family history of thyroid and other autoimmune disorders, especially in female relatives. Smoking increases the metabolic effects of hypothyroidism in a dose-dependent way. Thyroid gland examination should include the size, symmetry, consistency, tenderness, nodularity, mobility, vascularity, and any

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Section 3 Adult Reproductive Endocrinology associated lymphadenopathy. The presence of goiter is not essential for diagnosis. Laboratory Tests

The best screening test for both hypothyroidism and hyperthyroidism is the level of thyrotropin (TSH). The thyrotropin response to decreasing free T4 levels is hyperbolic. Once the patient is hypothyroid, thyrotropin rises beyond the normal range, but subsequent drops in free T4 levels can result in exponential rise in thyrotropin levels. Although the thyrotropin level is helpful in making the diagnosis of hypothyroidism, the levels of TSH do not correlate with the severity of the hypothyroidism. Once an abnormal TSH level is detected, one should confirm the diagnosis with measurement of free T4 or T3 levels. Total T4 reflects bound and free T4. T4 uptake is an estimate of binding that correlates with the amount of TBG. The free thyroxine index is a calculated value (product of total T4 and the T4 uptake). The free T4 is a direct immunoassay detecting unbound T4. This is a more economical method compared to the more accurate but laborious dialysis assay. Total T3 and free T3 are additional tests that are not immediately necessary for thyroid evaluation. Thyroglobulin levels may be high, indicating inflammation or damage to the thyroid gland, and may be low in situations of excessive exogenous thyroid hormone administration. Antithyroid Antibodies

Microsomal antibodies (or thyroid perioxisomal antibodies) usually represent underlying Hashimoto’s thyroiditis. Approximately 5% to 15% of euthyroid women and up to 2% of euthyroid men have antithyroid antibodies and these patients have an increased risk of developing thyroid dysfunction. Thyroglobulin antibodies may also be present in Hashimoto’s thyroiditis (autoimmune thyroiditis). In scenarios where thyroglobulin levels are being monitored, the presence of thyroglobulin antibodies may interfere with the thyroglobulin assay, resulting in falsely low or falsely high levels of thyroglobulin. Thyrotropin receptor antibodies are antibodies that bind to the thyrotropin receptor. Their presence signifies Graves’ disease. Some antibodies may be stimulatory, such as thyroid-stimulating immunoglobulin; others may be inhibitory (thyroid binding inhibitory immunoglobulin. Antithyroid antibodies may cross the placenta and can cause transient thyroid dysfunction in the fetus. Other Diagnostic Methods

The thyroid ultrasound examination is now widely available and is the best delineator of thyroid structure. A radioactive iodide scan can determine which areas of the thyroid are able to trap and organify iodide. Radioactive iodide uptake is a numerical (not visual) measure, describing the percentage of iodide that is being taken up specifically by the thyroid tissue. Measurements can be typically made 4 hours or later after the isotope (131I or 125I) is administered. Lipids

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An association between hypothyroidism and lipid disorder has been observed for decades, but the exact effects are still unknown. In a study on 295 patients with overt hypothyroidism, just 8.5% had a normal lipid profile.66 However, in another study of hypothyroidism in hypercholesterolemic patients (cholesterol level

over 200 mg/dL) the prevalence of overt hypothyroidism was 1.3% and subclinical hypothyroidism 11.2%.67 The effects of replacement with thyroxine are even more controversial. T4 replacement can reduce LDL cholesterol by 11% to 36%, depending on the degree of basal LDL elevation.63 Myxedema Coma

Myxedema coma is now extremely rare due to much earlier diagnosis of hypothyroidism. The patients have profound hypothermia, bradycardia, and typical skin and facial changes; mortality is close to 100% with or without treatment. Aggressive treatment with intravenous T4 (up to 500 μg) with possible addition of T3 can reduce mortality.68 Treatment

The thyroid hormone replacement preparations available are: ● ● ●

sodium levothyroxine dessicated thyroid synthetic T3 or synthetic T4/T3 combination.

The most commonly used preparation is levothyroxine, usually with a daily replacement of 1.6 μg/kg. Thyroid function tests should be assessed at 2 months, then 6 months, and then annually to monitor compliance and dosage requirements. The dosage is smaller if the patient still has residual thyroid function. Due to its short half-life, T3 is used before some diagnostic tests. There are some data indicating that adding T3 to T4 treatment will improve mood and quality of life, but other studies don’t show any beneficial effect.69 The medication should be taken at least 1 hour from a meal. Medications such as calcium, soy, iron, aluminum, and cholestyramine can interfere with the absorption or metabolism of levothyroxine, and they should be separated by 4 hours from the thyroid hormone. In elderly patients, with or without cardiac disease, a lower dose (12.5 to 25 μg/day) is started and increased slowly, by 25 μg/day every 4 to 6 weeks. Special consideration should be taken when treating pregnant women with preexistent hypothyroidism (see “Thyroid Disease in Pregnancy” in this chapter) and to treat adrenal insufficiency first in secondary hypothyroidism. The interchangeability of thyroxine products has been closely watched for several decades, but in 2004, the American Association of Clinical Endocrinologists, The Endocrine Society (TES), and the American Thyroid Association issued a joint statement addressing the introduction to the market of several generic levothyroxine products that had been approved by the U.S. Food and Drug Administration (FDA).70 The main concern was related to the FDA’s method in determining bioequivalence. Bioequivalence establishes therapeutic equivalence; this would be better reflected with an endocrine endpoint, such as serum thyrotropin, but this measurement was not used by the FDA. Thus the difference in some preparations was large (33% [uncorrected] and 12.5% to 25% [corrected for baseline values]). The panel recommended not substituting thyroxine preparations for one another, but if it is clinically indicated, then it suggested monitoring thyrotropin at 6 weeks. Estrogen Therapy

In women with hypothyroidism, estrogen therapy may increase thyroxine requirements.71 The serum TBG concentration

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease Table 22-12 Causes of Thyroid Hormone Overproduction Primary thyroid overproduction Thyrotropin-independent Graves’ disease Toxic multinodular goiter Toxic adenoma Metastatic thyroid carcinoma hCG-mediated thyrotoxicosis Iodide excess (jodbasedow) Thyrotropin-dependent Thyrotropin-mediated thyrotoxicosis (thyrotropin adenoma) Pituitary resistance to T4 and T3

Table 22-13 Symptoms and Signs of Thyrotoxicosis Symptoms (listed in order of prevalence)

Emotional nervousness, irritability Tremulousness Insomnia or decreased sleep requirement Palpitations or pounding of the heart Heat intolerance, sweating Weight loss with increased appetite Increased frequency of stools Polyuria Oligomenorrhea; menstrual irregularity or amenorrhea Decreased fertility Prominence of eyes, puffiness of lids Pain or irritation of eyes Blurred or double vision, decreasing acuity, decreased motility Dyspnea Less frequently, orthopnea, paroxysmal tachycardia, anginal pain

Physical Examination (listed in order of prevalence)

Tachycardia, overactive heart, widened pulse pressure, bounding pulse Goiter/thrill and bruit Fine, warm, moist skin Coarse or thinning hair Oncholysis (Plummer’s nails) Tremulousness, hyperreflexia Exophthalmos, lid edema, chemosis, extraocular muscle weakness Congestive heart failure, paroxysmal tachycardia or fibrillation Hyperkinetic behavior, thought, and speech Lymphadenopathy and occasional splenomegaly Prominence of eyes, lid lag, globe lag Decreased visual acuity, scotomata, papilledema, retinal hemorrhage, edema Pretibial myxedema Acropachy Hyperpigmentation or vitiligo Hypokalemic periodic paralysis

Thyroid destruction Subacute painful thyroiditis Painless and postpartum thyroiditis Amiodarone-induced thyroiditis Nonthyroidal excess Thyrotoxicosis factitia—excessive dose Struma ovari

increases at 6 weeks in response to estrogen, reaching a peak at 12 weeks. Serum T4 level rises in parallel. Estrogen increases serum TBG levels by increasing hepatic biosynthesis. Androgens decrease serum TBG levels.

Hyperthyroidism Hyperthyroidism may be a result of either overproduction of thyroid hormone or destruction of the thyroid gland. One may also see hyperthyroidism from exogenous (oral intake) or ectopic synthesis of thyroid hormone (struma ovari) (Table 22-12). Clinical Examination

Hyperthyroidism may manifest as involuntary weight loss; occasional hyperphagia; thin, brittle hair; reduced ability to concentrate; personality change; initial hypomanic symptoms followed by fatigue; insomnia; increased sweating; heat intolerance; fine tremor; proximal muscle weakness; tachyarrhythmia; more frequent bowel movements; lighter menses with reduced rate of ovulation; thin, brittle nails; and eye stare and lid lag. The presence of proptosis on ocular examination or pretibial myxedema (a nonpitting edema of the shins) strongly suggests Graves’ disease72 (Table 22-13). The differential diagnosis is listed in Table 22-14. Laboratory Evaluation

Finding a suppressed thyrotropin level with an elevated T4 or T3 level confirms the diagnosis of hyperthyroidism. New generations of thyrotropin assays can detect levels as low as 0.002 IU/mL. Truly hyperthyroid patients will have low thyrotropin levels that are in this range or most likely undetectable. The presence of thyrotropin receptor antibodies indicates Graves’ disease but by themselves do not indicate hyperthyroidism. Radioactive iodine uptake can help determine if the thyroid is autonomously overactive. This procedure can be performed in a nonpregnant woman but is not an option in a pregnant woman.

Family history of any thyroid disease, especially Graves’ disease Italicized items are more specific for Graves’ disease.

Table 22-14 Differential Diagnosis of Hyperthyroid Symptoms Acute psychosis Severe illness High-altitude exposure Selenium deficiency Medications Amphetamnes Iodide administration Amiodarone Gallbladder contrast High doses of propranolol Prednisone Estrogen withdrawal

Treatment Antithyroid Drugs

Thionamides, including propylthiouracil (PTU) and methimazole, are approved by the FDA for the treatment of hyperthyroidism. Both inhibit thyroid hormone synthesis by interfering with thyroid peroxidase-mediated iodination of tyrosine residues in thyroglobulin, an important step in the synthesis of T4 and T3.

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Section 3 Adult Reproductive Endocrinology PTU has an additional effect in blocking the conversion of T4 to T3. The medications may also have direct immunosuppressive effects in the thyroid, accounting for some of their effects in Graves’ disease.73 Personal preference has usually determined the initial choice of antithyroid medication. Recently methimazole has become the treatment of choice due to its better side effect profile and once-a-day schedule. The usual starting dose of methimazole is 15 to 30 mg; of PTU is 300 mg daily. After starting the treatment, close follow-up testing at 4 weeks is recommended and then every 4 to 6 weeks until euthyroidism is achieved. Some authors prefer using high doses first to block the gland and supplement with exogenous thyroid hormones,74 but these benefits have not been replicated in North America.75 There do not appear to be any good predictors of clinical remission or response to antithyroid drugs. Typically antithyroid medication is used for between 12 and 18 months. Once the medication is stopped, relapse occurs, usually within the first 3 to 6 months, but remission may last as much as 40 years. Side Effects of Antithyroid Drugs

Antithyroid drugs have a variety of minor side effects, such as skin reactions, arthralgias, gastrointestinal effects, and sialadenitis. Almost all patients taking antithyroid drugs will have transient elevation of liver transaminases within the first 2 to 6 weeks. The most fearful side effect is agranulocytosis, thought to occur in 0.3% of cases, mostly at the beginning of the treatment (first 3 months). A complete blood count is recommended after initiating therapy, but follow-up tests are not helpful because the agranulocytosis is idiosyncratic. However, all patients should be aware of this risk and should be told to stop the drug and seek urgent medical therapy if they develop sudden fever or sore throat without explanation. Rarer side effects include hepatic necrosis, vasculitis, and cholestasis.76 Radioactive Iodine

Radioactive iodine is used to definitively treat patients with hyperthyroidism.77 This will result in subsequent hypothyroidism. Radioiodine has not been shown to cause infertility or birth defects but certainly can cause fetal hypothyroidism, especially if given after the first trimester.

Thyroid Disease and Pregnancy Glinoer reported a higher miscarriage rate in patients from Belgium with antithyroid antibodies.78 However, it is unclear whether this represents a cause-effect relationship.79 A retrospective study published in 2005 reviewing 17,000 women delivering in one center found that pregnancies in women with subclinical hypothyroidism were three times more likely to be complicated by placental abruption (relative risk [RR]: 3) and two times more predisposed to premature birth (RR, 1.8).80 Thyroid Function in Pregnancy

Thyroid disorders are observed 4 to 5 times more frequently in women than in men. Consequently, physicians should be aware of the physiologic changes of thyroid function in pregnancy. Pregnancy results in a number of physiologic changes81: ●

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●

an increase in TBG due to higher levels of estrogen alterations in the requirements for iodine and an increase in urinary iodine excretion. In iodine-deficient areas, the thyroid

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size enlarges but increasing iodine intake by 200 μg/day may prevent goitrogenic changes. changes in autoimmune regulation placenta has a role in deiodination of iodothyronines due to an increase in type II deiodinase. This leads to high reverse T3. an increase in hCG has an effect on the maternal thyroid that peaks near the end of first trimester. An increase in hCG by 10,000 U/L lowers thyrotropin by 0.1 μU/mL and raises free T4 by 0.6 pmol/L.

Total thyroid hormone (T4) is increased mostly in the first half of gestation due to a profound increase in TBG. Serum T4 levels increase between 6 and 12 weeks and slowly after that; T3 rise is more progressive. Serum T4 has a 20-fold higher affinity for TBG than T3, so the ratio between T4 and T3 is constant. The changes in TBG imply that the extrathyroidal T4 pool must increase to ensure the same free hormone level. The daily increased secretion is between 1% and 3 % until it reaches a steady state and then returns to previous levels. The free levels of T3 and T4 are maintained usually in a normal range. The indirect calculated free T4 indices are not very reliable in pregnancy. The hormonal output is regulated through the normal pituitary–thyroid feedback by thyrotropin stimulation that is minor in a patient with a normal thyroid gland.82 However, these physiologic adjustments can be “stressed” in women with any predisposition to thyroid disease. Human chorionic gonadotropin is a weak thyroid stimulator that can bind to the thyrotropin receptor. If hCG is markedly elevated (as may happen normally in a twin pregnancy) or is a more potent molecular variant, serum free T4 concentrations may increase to hyperthyroid range with temporary thyrotropin suppression.83 Immunology of Normal Pregnancy

It has been observed that most immune disorders improve during pregnancy. One cause has been postulated to be the absence of expression of the classic class I or II major histocompatibility complex (MHC) antigens on the placenta. These MHC antigens are needed to present antigenic peptides to cytotoxic cells and T-helper cells. The placenta produces human leukocyte antigen G, which binds natural killer cells and activates CD8+ T cells. The placental trophoblast cells express a Fas ligand that mediates apoptosis of Fas-expressing maternal lymphocytes, resulting in protection of the fetus. There are many conflicting data regarding the effect of pregnancy on T cells and B cells, with a profound interest in the Th2/Th1 ratio, which seems to be elevated in pregnancy.84 During pregnancy, there is also there is a large drop in antibody levels with no parallel reduction in B-cell number. Their reduced activity is correlated to the sex steroids. Within 6 months of delivery, total imunoglobulin G as well as autoantibodies rise above prepregnancy levels and we see an exacerbation of almost all autoimmune disorders. Fetal Thyroid Function

The fetal thyroid begins to function after 10 to 12 weeks of pregnancy. Thyroid hormones (mostly from the fetal thyroid and a negligible amount from the mother’s thyroid) are important for development of the fetal nervous system. Iodine in the mother’s diet readily crosses the placenta and is used by

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease the fetal thyroid gland to make thyroid hormone. Iodine deficiency can cause newborn hypothyroidism or mental retardation (cretinism) and is a major world health problem in underdeveloped countries. Because there is an overabundance of iodine in the American diet, disorders caused by a lack of dietary iodine rarely occur here. Low thyroid hormone concentrations in early gestation may be associated with lower IQ in children age 5 to 7.85 Some of the altered physiological development86 was also found in biochemically euthyroid women with elevated antimicrosomal antibodies.87 Planning Pregnancy for Women with Thyroid Disease

In patients with hypothyroidism the therapeutic aim is to maintain the thyrotropin level in the normal range, preferable close to 1 to 2 μU/mL.88 If a woman is hyperthyroid before pregnancy, medical treatment with PTU should be started.89 Clearly, radioactive iodine is contraindicated in pregnancy, and nonpregnant women should be advised to avoid conception for 6 to 12 months after the treatment. If a woman conceives while taking PTU the medication can be continued but adjusted to allow the thyroid hormone levels to be at the upper end of normal. Hypothyroidism in Pregnancy

Overt hypothyroidism is present in 0.3% to 0.7% of pregnancies and subclinical hypothyroidism in up to 2.5%. L-thyroxine is safe and is well absorbed during pregnancy. Some women require higher doses during their pregnancy. Physicians generally monitor the thyrotropin level two or three times during the pregnancy to detect even mild hypothyroidism and increase the L-thyroxine dose, if necessary. Several publications have shown that 35% to 62% of women with autoimmune hypothyroidism and up to 70% to 100% of athyroid women require an increase of levothyroxine dosage. A prospective study of 19 women found that an increase in the levothyroxine dose was necessary during 17 pregnancies.90 The mean levothyroxine requirement increased 47% during the first half of pregnancy (median onset of increase, 8 weeks’ gestation) and plateaued by week 16. This increased dose was maintained and required until delivery.

Hyperthyroidism in Pregnancy

Thyrotoxicosis (hyperthyroidism) during pregnancy, most often due to Graves’ disease, presents a challenge for diagnosis and treatment because of unique fetal and maternal considerations. The risk of miscarriage and stillbirth is increased if thyrotoxicosis goes untreated, and the overall risks to mother and baby further increase if the disease persists or is first recognized late in pregnancy.91 The main disorders that present with symptoms and signs of hyperthyroidism in pregnancy include Graves’ disease, silent thyroiditis, hyperemesis gravidarum, and molar pregnancy (Table 22-15). The diagnosis of hyperthyroidism is suggested by specific physical signs, such as prominent eyes, enlarged thyroid gland, and exaggerated reflexes, and is confirmed by markedly elevated serum thyroid hormone levels and a suppressed thyrotropin level. Radioactive investigations are not performed. However, because there is no fetal thyroid activity until after the end of the first trimester, there is very little iodide trapping by the fetus in early pregnancy. Later in pregnancy radioactive iodine can destroy the fetal thyroid, but this is probably not a sufficient reason to end the pregnancy, because recognition and treatment of hypothyroidism shortly after delivery usually ensures normal growth and development in the child. The treatment of choice for thyrotoxicosis during pregnancy is antithyroid medication, either PTU or methimazole,92 because radioactive iodine cannot be used. PTU remains the drug of choice, because methimazole has been associated with rare cases of aplasia cutis in some infants.93 The initial goal is to control the hyperthyroidism and then use the lowest medication dose possible to maintain serum thyroid hormone levels in the high normal range. In this way smaller doses of medications are used and thus are less likely to cause fetal hypothyroidism. If a mild allergy to one of these medications develops, the other medication may be substituted. If there is a problem with taking pills or more severe drug allergy, thyroidectomy may be performed during the second trimester but is rarely necessary. The natural course of hyperthyroidism in pregnancy is for the disease to become milder or remit totally near term.94 In many

Table 22-15 Gestational Hyperthyroidism Causes

Clinical Findings

Laboratory Evaluation

Usual Course of Disease

Graves’ Disease

Heat intolerance and tachycardia Clinically hyperthyroid

High T4 and T3 Suppressed thyrotropin Anti-thyrotropin receptor antibodies

Usually responds well to treatment during pregnancy and worsens after delivery

Gestational transient thyrotoxicosis (GTT); most severe form is hyperemesis gravidarum

Less dramatic hyperthyroidism than Graves’ disease Dramatic nausea and weight loss Vomiting not related to degree of hyperthyroidism Prevalence is much higher than that of Graves’ disease

GTT is directly related to both the amplitude and duration of peak hCG Thyrotropin low but not undetectable Thyroid hormone levels are high normal Absent thyrotropin receptor antibodies

Thyrotoxicosis transiently during the first half of gestation Therapy usually not required Suppressed thyrotropin may lag weeks after normalization of T4

Silent thyroiditis

Presence of goiter, no bruit Clinically hyperthyroid

T3/T4 ratio is normal Absent thyrotropin receptor antibodies

Diagnosis may be difficult

Molar pregnancy

Midly hyperthyroid Sonographic findings of molar pregnancy

Extremely high hCG levels Absent thyrotropin receptor antibodies

Resolves with removal of molar pregnancy

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Section 3 Adult Reproductive Endocrinology patients antithyroid medications can be tapered to low levels or even discontinued. For those patients who are not so fortunate, it is important to maintain control of the hyperthyroidism throughout pregnancy to avoid severe thyrotoxicosis (thyroid storm) developing during labor and delivery.94 If this does develop, additional acute treatment with beta-adrenergic blockers such as propranolol (Inderal) and high doses of nonradioactive iodine are used. Long-term treatment with these agents is not advised in pregnancy, because beta blockers have been associated with fetal bradycardia and occasionally intrauterine growth retardation.95 In lactating mothers, both PTU and methimazole can be safely used, their concentration in breast milk being small, with no effects on thyroid functions in the breastfed infant.96 Fetal Thyroid Disease

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Antithyroid medications, nonradioactive iodine, and maternal thyroid antibodies can all cross the placenta and cause hypothyroidism in the fetus. Nonradioactive iodine, which is present in some medications, including some cough medications, can cause a goiter in the fetus, making delivery difficult or causing respiratory obstruction. For this reason, iodine-containing drugs should never be used in pregnancy except in the case of thyroid storm. Unfortunately, there is no simple blood test to assess fetal thyroid function, although measurements of thyroid hormone or thyrotropin levels in the amniotic fluid sac have been used in research studies.97 Plain X-rays sometimes show delayed bone development in fetal hypothyroidism, but this test is usually not recommended. Screening for hypothyroidism at birth, now done routinely in North America on all babies, identifies the need for early short- or longterm thyroxine treatment, with excellent long-term follow-up results. Fetal thyrotoxicosis (hyperthyroidism) occurs occasionally due to transfer of maternal thyroid-stimulating antibodies across the placenta. Most often, the mother herself has hyperthyroidism, which is being treated with antithyroid drugs that also passively treat the baby by crossing the placenta. Sometimes, however, the mother’s thyrotoxicosis occurred in the past and was controlled by either radioactive iodine treatment or an operation in which the mother’s thyroid gland was removed. In such a situation the mother has less thyroid tissue and cannot be hyperthyroid, even though she continues to have thyroid-stimulating antibodies in her blood. Because the mother is well, fetal thyrotoxicosis may not be suspected. Clues to the presence of fetal hyperthyroidism are fetal heart rate consistently above the normal limit of 160 beats per minute and the presence of high levels of thyroid-stimulating antibodies in the mother’s blood. Recently, it has been suggested that ultrasonography of the fetal thyroid gland may be helpful in assessing fetal thyroid size.98 All women with a history of Graves’ disease should be tested for thyroid-stimulating antibodies late in pregnancy.99 The consequences of untreated fetal thyrotoxicosis include low birth weight and head size, fetal distress in labor, and neonatal heart failure and respiratory distress. Administration of antithyroid drugs to the mother during pregnancy can treat the baby in this situation. Close follow-up and continued treatment is required after delivery.

Postpartum Thyroid Disease in the Mother Preexisting Thyroid Disease

For preexisting hypothyroidism, thyroid hormone treatment is continued after delivery and breastfeeding is encouraged. Thyroid hormones do not pass into breast milk in significant amounts. Graves’ disease is prone to relapse or worsen in the postpartum period. If that happens, antithyroid drugs can be started or their dose increased, or radioactive iodine can be given if the mother is not breastfeeding. Women taking PTU may breastfeed, because little of this drug crosses into the milk. Nursing is also possible for women who take methimazole, although more of this drug is secreted into breast milk. In both cases the baby’s thyroid function should be monitored. Definitive therapy with radioactive iodine should be considered, although many breastfeeding women will wish to postpone this, because some of the mother’s radioiodine crosses into her baby through the breast milk. Postpartum Thyroiditis

Postpartum thyroiditis may occur in 8% to 10% of women.100 Thyroiditis also occurs in the nonpostpartum period, as well as in men, and is probably an autoimmune thyroid disease related to Hashimoto’s thyroiditis.101 Typically, it consists of a temporary period of hyperthyroidism lasting from 6 weeks to 3 months postpartum, followed by hypothyroidism occurring between 3 and 9 months after delivery. Women at risk include those with a previous history of postpartum thyroiditis or those who can be shown to have thyroid autoantibodies.102 Usually, no treatment or only symptomatic treatment is required for the hyperthyroid phase, and a short course of thyroxine treatment for 6 to 12 months is sufficient for the hypothyroid phase. Some women who do not recover from the hypothyroid phase will require long-term thyroid replacement therapy.103 During the first 3 months after delivery, symptoms of fatigue, depression, and impairment of memory and concentration are common and often unrelated to a woman’s thyroid hormone level. Symptoms can mimic postpartum depression and thus a high index of suspicion is needed to rule out hypothyroidism.104 It is reasonable to perform a thyrotropin level in those women who do experience emotional disorders following pregnancy.

Solitary Thyroid Nodule and Thyroid Cancer in Pregnancy A thyroid nodule may be discovered during the pregnancy, and the best way to investigate this would be an ultrasound-guided fine needle aspiration biopsy because this results in a better biopsy yield and the ultrasound can document a baseline assessment of size of the nodule. If results of the examination of the biopsy specimen is suspicious or suggestive of malignancy, necessary surgery can be performed in the second trimester; if the nodule is discovered late in pregnancy, surgery can be deferred until the postpartum period.105 History of thyroid cancer and radioactive iodide administration does not preclude conception. One normally advises a year of avoiding pregnancy after a high-dose radioactive iodine therapy for thyroid cancer. Pregnancy has not been shown to affect the course of thyroid cancer.106

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

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The multiple endocrine neoplasia (MEN) syndromes are rare, but their recognition is crucial because it is important for treatment of the patient and recognition of their affected family members. The MEN syndromes are autosomal dominant in nature. It is essential that the treating physician be alert about their various clinical presentations and use the available molecular DNA testing for their confirmation. MEN syndromes have been divided into MEN type I and MEN type II. MEN type I includes pituitary, parathyroid, and pancreatic islet cell tumors; invariably hyperparathyroidism is the initial presenting disorder. Alterations in the menin gene (a tumor suppressor gene) have been implicated. MEN type II includes medullary carcinoma of the thyroid, hyperparathyroidism, and pheochromocytomas. Medullary carcinoma of the thyroid is often the initial illness in this syndrome. A mutation of the RET proto-oncogene appears to be strongly correlated with the presence of disease in MEN type II.

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Approximately 50% of pituitary adenomas are prolactinomas, 15% are GH-producing, 10% are corticotropin-producing, and less than 1% secrete thyrotropin. Nonfunctioning pituitary adenomas, more appropriately named nonsecretory adenomas, represent approximately 25% of pituitary tumors. The initial workup for most suspected adenomas should be limited and should include serum prolactin and insulinlike growth factor (IGF-I) level. Dopamine is the major inhibitor of prolactin secretion. Estrogens, thyrotropin-releasing hormone, and serotonin increase prolactin levels. Drugs, pregnancy, and hypothyroid disease are common causes of elevated prolactin levels. Serum prolactin level above 200 μg/L is almost always indicative of a prolactin-producing pituitary tumor. Dopamine agonists are now the first-line treatment for prolactin adenomas. During pregnancy bromocriptine can be discontinued; then the clinical status, serum prolactin levels, and visual field examinations can be followed. More than 95% of cases of acromegaly is caused by GH-secreting pituitary tumors. A single GH level is usually inadequate to establish the diagnosis of acromegaly. IGF-1 is the initial screening test for those suspected to have acromegaly. Somatostatin analogues are the most effective medical therapy available for acromegaly. Corticotropin-secreting pituitary adenoma is the most common cause of endogenous Cushing’s syndrome (60%), with the rest being adrenal (25%) or ectopic (15%) in origin.

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Twenty-four-hour urinary free cortisol measurement is the single best test for diagnosis of Cushing’s syndrome. Surgical (transsphenoidal) removal of corticotropin-secreting pituitary tumor is the treatment of choice for Cushing’s disease. Nonsecretory or glycoprotein-secreting tumors are usually clinically silent and they usually come to attention because of manifestations of mass lesion, including headache and visual field defect. Pituitary adenomas are the most common cause of hypopituitarism. Clinical adrenal insufficiency may be due to destruction of the adrenal gland itself, referred to as Addison’s disease or primary adrenal insufficiency. Clinical adrenal insufficiency may less commonly be due to a lack of either corticotropin (i.e., secondary adrenal insufficiency) or CRH. The most common cause of Addison’s disease in adults (80%) is autoimmune destruction of the adrenal gland. The cosyntropin (Cortrosyn or corticotropin) stimulation test is the gold standard for the diagnosis of adrenal insufficiency. The triad of headaches, palpitations, and diaphoresis in the presence of hypertension is classic for pheochromocytoma. The mean serum thyrotropin level in the healthy population is 1.5 mU/L, but the ranges of normal reported by laboratories are wide. Menometrorrhagia may be evident in mild to moderate hypothyroidism, and amenorrhea may be observed with severe hypothyroidism. Subclinical hypothyroidism is defined as an elevated serum thyrotropin level associated with normal total or free levels of T4 and T3 in the absence of symptoms. The best screening test for both hypothyroidism and hyperthyroidism is the level of thyrotropin. Once an abnormal thyrotropin level is detected, one should confirm the diagnosis with measurement of free T4 or T3 levels. Microsomal antibodies (or thyroid perioxisomal antibodies) usually represent underlying Hashimoto’s thyroiditis. Thyrotropin receptor antibodies are antibodies that bind to the thyrotropin receptor. Their presence signifies Graves’ disease. Antithyroid antibodies may cross the placenta and can cause transient thyroid dysfunction in the fetus. Total thyroid hormone (T4) is increased mostly in the first half of gestation due to a profound increase in thyroid-binding globulin. In pregnant patients with hypothyroidism the therapeutic aim is to maintain the thyrotropin level in the normal range, preferable close to 1 to 2 μU/mL. Many women with autoimmune hypothyroidism or athyroid women require an increase of levothyroxine dosage during pregnancy. The main disorders that present with symptoms and signs of hyperthyroidism in pregnancy include Graves’ disease, silent thyroiditis, hyperemesis gravidarum, and molar pregnancy. The treatment of thyrotoxicosis during pregnancy is propylthiouracil.

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Chapter 22 Management of Pituitary, Adrenal, and Thyroid Disease 53. Vaquero E, Lazzarin N, De Carolis C, et al: Mild thyroid abnormalities and recurrent spontaneous abortion: Diagnostic and therapeutical approach. Am J Reprod Immunol 43:204–208, 2000. 54. Spong CY: Subclinical hypothyroidism: Should all pregnant women be screened? Obstet Gynecol 105:235–236, 2005. 55. Hollowell J, LaFranchi S, Smallridge R, et al: 2004 where do we go from here? Summary of working group discussions on thyroid function and gestational outcomes. Thyroid 15:72–76, 2005. 56. Canaris G, Manowitz N, Mayor G, Ridgway E: The Colorado thyroid disease prevalence study. Arch Intern Med 160:526–534, 2000. 57. Cooper DS: Subclinical thyroid disease: Consensus or conundrum? Clin Endocrinol 60:410–412, 2004. 58. Cooper D: Clinical practice. Subclinical hypothyroidism. NEJM 345:260–265, 2001. 59. Diez JJ, Iglesias P: Spontaneous subclinical hypothyroidism in patients older than 55 years: An analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab 89:4890–4897, 2004. 60. Tuzcu A, Bahceci M, Gokalp D, et al: Subclinical hypothyroidism may be associated with elevated high-sensitive C-reactive protein (low grade inflammation) and fasting hyperinsulinemia. Endocrine J 52:89, 2005. 61. Hueston WJ, Pearson WS: Subclinical hypothyroidism and the risk of hypercholesterolemia. Ann Family Med 2:351–355, 2004. 62. Canturk Z, Cetinarslan B, Tarkun I, et al: Lipid profile and lipoprotein A as a risk factor for cardiovascular disease in women with subclinical hypothyroidism. Endocrine Res 29:307–316, 2003. 63. Biondi B, Klein I: Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 24:1–13, 2004. 64. Rodondi N, Newman A, Vittinghoff E, et al: Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 165:2460–2466, 2005. 65. Tunbridge W, Evered D, Hall R, et al: The spectrum of thyroid disease in a community: The Whickham survey. Clin Endocrinol 7:481–493, 1977. 66. O’Brien T, Dinneen S, O’Brien P, Palumbo P: Hyperlipidemia in patients with primary and secondary hypothyroidism. Mayo Clinic Proc 68:860–866, 1993. 67. Bruckert E, De Gennes J, Dairou F, Turpin G: [Frequency of hypothyroidism in a population of hyperlipidemic subjects]. Presse Medicale 22:57–60, 1993. 68. Hylander B, Rosenqvist U: Treatment of myxoedema coma—factors associated with fatal outcome. Acta Endocrinologica 108:65–71, 1985. 69. Sawka A, Gerstein H, Marriott M, et al: Does a combination regimen of thyroxine (T4) and 3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 88:4551–4555, 2003. 70. Joint statement on the U.S. Food and Drug Administration’s decision regarding bioequivalence of levothyroxine sodium. Thyroid 14:486, 2004. 71. Arafah BM: Increased need for thyroxine in women with hypothyroidism during estrogen therapy. NEJM 344:1743–1749, 2001. 72. Weetman A: Graves’ disease. NEJM 343:1236–1248, 2000. 73. Cooper D: Antithyroid drugs. NEJM 352:905–917, 2005. 74. Hashizume K, Ichikawa K, Sakurai A, et al: Administration of thyroxine in treated Graves’ disease. Effects on the level of antibodies to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism. NEJM 324:947–953, 1991. 75. Rittmaster RS, Abbott EC, Douglas R: Effect of methimazole, with or without L-thyroxine, on remission rates in Graves’ disease. J Clin Endocrinol Metab 83:814–818, 1998. 76. Abraham P, Avenell A, Watson W, et al: Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database Syst Rev 2004: CD003420. 77. Cooper DS: Hyperthyroidism. Lancet 362:459–468, 2003. 78. Glinoer D: Thyroid autoimmunity and spontaneous abortion. Fertil Steril 72:373–374, 1999.

79. Haddow J: Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 106:198–199, 2005. 80. Casey BM, Dashe JS, Wells CE, et al: Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 105:239–245, 2005. 81. Larsen PR, Schlumberger MJ, Hay ID: Thyroid. In Wilson JD, Foster DW (eds). Williams Textbook of Endocrinology, 9th ed. Philadelphia, WB Saunders, 1998, pp 249–340. 82. Mandel S, Spencer C, Hollowell J: Are detection and treatment of thyroid insufficiency in pregnancy feasible? Thyroid 15:44–53, 2005. 83. Hershman JM: Physiological and pathological aspects of the effect of human chorionic gonadotropin on the thyroid. Best Prac Res Clin Endocrinol Metab 18:249–265, 2004. 84. Lazarus J, Parkes A, Premawardhana L: Postpartum thyroiditis. Autoimmunity 35:169–173, 2002. 85. LaFranchi S, Haddow J, Hollowell J: Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes? Thyroid 15:60–71, 2005. 86. Pop VJ, Kuijpens JL, van Baar AL, et al: Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 50:149–155, 1999. 87. Morreale de Escobar G, Obregon MJ, Escobar del Rey F: Role of thyroid hormone during early brain development. Eur J Endocrinol 151(Suppl 3):U25–U37, 2004. 88. Mandel S: Hypothyroidism and chronic autoimmune thyroiditis in the pregnant state: Maternal aspects. Best Pract Res Clin Endocrinol Metab 18:213–224, 2004. 89. Neale D, Burrow G: Thyroid disease in pregnancy. Obstet Gynecol Clin North Am 31:893–905, 2004. 90. Alexander E, Marqusee E, Lawrence J, et al: Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. NEJM 351:241–249, 2004. 91. Davis L, Lucas M, Hankins G, et al: Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 160:63–70, 1989. 92. Wing D, Millar L, Koonings P, et al: A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 170:90–95, 1994. 93. Milham S: Scalp defects in infants of mothers treated for hyperthyroidism with methimazole or carbimazole during pregnancy. Teratology 32:321, 1985. 94. Amino N, Tanizawa O, Mori H, et al: Aggravation of thyrotoxicosis in early pregnancy and after delivery in Graves’ disease. J Clin Endocrinol Metab 55:108–112, 1982. 95. Pruyn SC, Phelan PJ, Buchanan GC: Long-term propranolol therapy in pregnancy: Maternal and fetal outcome. Am J Obstet Gynecol 135:485–489, 1979. 96. Azizi F, Bahrainian M, Khamseh M, Khoshniat M: Intellectual development and thyroid function in children who were breast-fed by thyrotoxic mothers taking methimazole. J Pediatr Endocrinol Metab 16:1239–1243, 2003. 97. Nachum ZRY, Weiner E, Shalev E: Graves’ disease in pregnancy: Prospective evaluation of a selective invasive treatment protocol. Am J Obstet Gynecol 189:159–165, 2003. 98. Luton D, Le Gac I, Vuillard E, et al: Management of Graves’ disease during pregnancy: The key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 90:6093–6098, 2005. 99. Glinoer D: Management of hypo- and hyperthyroidism during pregnancy. Growth Hormone IGF Res 13(Suppl A):S45–S54, 2003. 100. Lazarus JH: Thyroid dysfunction: Reproduction and postpartum thyroiditis. Semin Reprod Med 20:381–388, 2002. 101. Pearce E, Farwell A, Braverman L: Thyroiditis. NEJM 348:2646–2655, 2003. 102. Hayslip C, Fein H, O'Donnell V, et al: The value of serum antimicrosomal antibody testing in screening for symptomatic postpartum thyroid dysfunction. Am J Obstet Gynecol 159:203–209, 1988. 103. Amino N, Mori H, Iwatani Y, et al: High prevalence of transient postpartum thyrotoxicosis and hypothyroidism. NEJM 306:849–852, 1982. 104. McCoy SJ, Beal JM, Watson GH: Endocrine factors and postpartum depression. A selected review. J Reprod Med 48:402-408, 2003.

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107. Ladenson P, Singer P, Ain K, et al: American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med 160:1573–1575, 2000.

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23

Premenstrual Syndrome and Menstrual-Related Disorders Robert L. Reid and Allison M. Case

INTRODUCTION Premenstrual syndrome (PMS) has emerged over the past 25 years as a clinical entity in search of a precise pathophysiologic explanation. A condition rarely discussed in medical texts before the 1980s, PMS can lead to major distress that interferes with day-to-day activities and disrupts interpersonal relationships. The literature on PMS has focused almost entirely on women with adverse premenstrual experiences. Some women experience well-defined medical conditions, such as migraine, epilepsy, irritable bowel syndrome, and asthma, that are linked to, and exacerbated by, the hormonal fluctuations of the menstrual cycle. However, there is evidence that 5% to 15% of women may experience positive changes in the premenstruum.1 Clinicians now understand the need to discriminate between the usual premenstrual experience of ovulatory women (wherein premenstrual molimina forewarn of impending menstruation) and PMS. This chapter reviews our current understanding of menstrual-related conditions, including PMS.

DEFINITION AND PREVALENCE Molimina Molimina are symptoms, such as breast pain, swelling, bloating, acne, and constipation, that foreshadow impending menstruation. Some or all of these symptoms are estimated to occur in 80% to 90% of women of reproductive age. Approximately 30% to 40% of women report these symptoms to be distressing enough that they would seek a remedy if one were available. Swelling of the extremities and abdominal bloating are molimina reported by 60% of women, although objective documentation of weight gain is usually lacking.2,3 Cyclic breast symptoms affect 70% of women, with 22% reporting moderate to extreme discomfort.4

Premenstrual Syndrome Premenstrual syndrome is defined as the cyclic recurrence in the luteal phase of the menstrual cycle of a combination of distressing physical, psychological, and/or behavioral changes of sufficient severity to result in deterioration of interpersonal relationships and/or interference with normal activities.5 This definition emphasizes the fact that a diagnosis of PMS should rely not only on the presence of typical premenstrual symptoms, but also on a level of severity enough to disrupt normal function. The term PMS should be reserved for a more severe constellation of symptoms, mostly psychiatric, that leads to major interference with day-to-day activities and interpersonal relationships.6 Women

with this degree of symptoms probably comprise 3% to 5% of women in their reproductive years. 7–10

Premenstrual Dysphoric Disorder In the psychiatric literature, the term premenstrual dysphoric disorder (PMDD) is used to indicate the most serious premenstrual disturbances that are associated with deterioration in functioning. PMDD is characterized by depressed or labile mood, anxiety, irritability, anger, and other symptoms occurring exclusively during the 2 weeks preceding menses. According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV), the symptoms must be severe enough to interfere with occupational and social functioning (Table 23-1).11 This sets PMDD apart from the more common PMS, as a severely distressing and disabling condition that requires treatment.

EPIDEMIOLOGY PMS-like behavior has been reported both in humans and in nonhuman primates that demonstrate menstrual cyclicity. In the nonhuman primate, zoologists have noted premenstrual changes in behavior and appetite similar to those reported by women with PMS.12,13 The availability of effective contraception since midway through the twentieth century has meant that repeated cycles of pregnancy and lactation were no longer the biological destiny of women in the developed world—and as a direct result the expected number of menstrual cycles in a woman’s lifetime increased from as few as 50 to as many as 500, with a commensurate increase in menstrual cycle-related disorders. Little is known about the inheritance of PMS. However, there is support for a genetic predisposition. Surveys have found that as many as 70% of daughters of affected mothers were themselves PMS sufferers, whereas 63% of daughters of unaffected mothers were symptom-free.14 The common belief that PMS is a disorder of the older woman may have stemmed from the fact that mood swings in the teen are less likely to be considered an effect of menstrual cyclicity and more likely to be attributed to the “hormonal swings and heartbreaks” of adolescence. There are clear examples of teens who developed severe PMS shortly after puberty. PMS sufferers often relate that symptoms become progressively worse over time and since women have increasing contact with healthcare providers for nonpregnancy-related concerns in their later reproductive years, this may account for the preponderance of older women seeking help for PMS.

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Section 3 Adult Reproductive Endocrinology Table 23-1 Diagnostic Criteria for Premenstrual Dysphoric Disorder (PMDD) 1. Timing of symptoms Symptoms are present during the last week of the luteal phase, remit within the first few days of menses, and are absent during the week following menses. The symptoms occur during most, if not all, menstrual cycles. 2. Symptoms At least five symptoms are required, including at least one of the first four symptoms: ● markedly depressed mood ● marked anxiety ● marked affective lability ● persistent and marked anger ● decreased interest in usual activities ● lethargy ● marked change in appetite ● hypersomnia or insomnia ● a sense of being overwhelmed or out of control physical symptoms 3. Severity The symptoms markedly interfere with work, school, social activities, and relationships with others. 4. Other disorders Rule out that the disorder is not merely an exacerbation of a major affective, panic dysthymic, or personality disorder, although PMDD can be superimposed on any of these disorders. 5. Confirmation of the disorder The above criteria must be confirmed by prospective daily self-rating for two consecutive menstrual cycles. Adapted from: American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, D.C. APA, 1994.

Premenstrual syndrome disappears during suppression of the ovarian cycle; for example, during hypothalamic amenorrhea due to excessive physical, or nutritional stress, during lactational amenorrhea, during pregnancy, and after menopause—either natural or induced.15,16 Interestingly, hormone therapy employing sequential progestin sometimes triggers PMS symptoms in susceptible women, whereas continuous combination hormone replacement therapy is not associated with these changes.17,18 Contrary to popular belief, there is no convincing evidence that the risk of PMS increases after pregnancy or tubal ligation. This belief probably originated when PMS symptoms reappeared and seemed acutely worse after the hormonal “protection” of preexisting pregnancy.

DIAGNOSIS History

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Physicians should make an effort to enquire about PMS symptoms as part of the menstrual and reproductive history of all women of reproductive age. For the woman with few symptoms, this provides education about PMS and may forestall fears that she is “losing her mind” should symptoms emerge in the later reproductive years. For the woman with significant symptoms this will create the opportunity for counseling and reassurance and will set the stage for establishing the diagnosis. A typical PMS sufferer may describe being a productive worker and/or a great mother for most of the month. Sometime after ovulation, however, she awakens in the morning with feelings of anger, anxiety, or sadness. At work she may experience feelings of paranoia and wonder if coworkers are conspiring against her. She may report difficulty concentrating or overreacting to minor

Table 23-2 Key Elements of a Prospective Symptom Record Used for the Diagnosis of PMS 1. Daily listing of symptoms 2. Ratings of symptom severity throughout the month 3. Timing of symptoms in relation to menstruation 4. Rating of baseline symptom severity during the follicular phase

day-to-day provocations. Though feeling inexplicably depressed, she may know inwardly that she has little in her life about which to be sad. She may report that minor things that her spouse says or that her children do are enough to trigger an exaggerated reaction at home. Although she may want to be held and comforted at such times, she reports that she cannot stand to be touched. She may try to isolate herself at these times. Occasionally depression, anger and aggression, or anxiety may be extreme, resulting in concerns for the welfare of the affected woman or her family. Caution is needed in immediately accepting such a typical history as diagnostic of PMS. Researchers have found that many psychiatric conditions worsen premenstrually, a situation referred to as premenstrual magnification. Hence, an individual with an underlying psychiatric disorder may recall and relate the symptoms that were most severe in the premenstrual week, while ignoring the lower level of symptoms that exist throughout the month.19 Prospective Symptom Record

The clinician can have confidence in the diagnosis only by obtaining a prospective symptom record over a 1- to 2-month period. Any calendar used for this purpose must obtain information on four key areas: symptoms, severity, timing in relation to the menstrual cycle, and baseline level of symptoms in the follicular phase (Table 23-2). Information should be sought about stresses related to the woman’s occupation and family life, because these may tend to exacerbate PMS. Past medical and psychiatric diagnoses may be relevant in that a variety of medical and psychiatric disorders may show premenstrual exacerbation. Typically PMS symptoms appear after ovulation and worsen progressively leading up to menstruation. Approximately 5% to 10% of PMS sufferers experience a brief burst of typical PMS symptoms coincident with the midcycle fall in estradiol that accompanies ovulation20 (Fig. 23-1). PMS symptoms resolve at varying rates after onset of menstruation. In some women there is almost immediate relief from psychiatric symptoms with the onset of bleeding; for others the return to normal is more gradual. The most severely affected women report symptoms onset shortly after ovulation (2 weeks before menstruation), resolving at the end of menstruation. Such individuals typically report having only one “good week” per month (Fig. 23-2).21 If this pattern is longstanding it becomes harder and harder for interpersonal relationships to rebound during the good week, with the result that their condition may start to take on the appearance of a chronic mood disorder. Whenever charting leaves the diagnosis in doubt, a 3-month trial of medical ovarian suppression will usually provide a definitive answer. One example of a symptom calendar is the Prospective Record of the Impact and Severity of Menstrual symptoms (PRISM)

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Chapter 23 Premenstrual Syndrome and Menstrual-Related Disorders Figure 23-1 Circulating gonadotropin, estradiol, and progesterone concentrations correlated to symptom severity in a woman with midcycle and premenstrual PMS symptoms— so-called pattern C PMS. Daily Menstrual Distress Questionnaire (MDQ) score reflects PMS symptom severity throughout the menstrual cycle. (From Reid RL: Endogenous opioid activity and the premenstrual syndrome. Lancet 2:786, 1983.)

300 PMS

LH (ng/ml)

LH

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100

0

Estradiol Progesterone

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10

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16 18

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A B C D Ovulation Figure 23-2 Four common patterns of PMS symptomatology in relation to the menstrual cycle. Note that in every case symptoms commence after ovulation. (From Reid RL: Premenstrual syndrome. In DeGroot L (ed). Endotext.com. Available at www.endotext.org. Accessed 20 December 2004.)

28

2

4

being evaluated for PMS. However, there are no characteristic physical findings in women with PMS. When seen in the follicular phase of the cycle, PMS sufferers typically appear entirely normal. Premenstrually, a woman presenting with an acute episode of PMS may appear anxious, tearful, or angry depending on the nature of her symptom complex. Organic causes of PMS-like symptoms must be ruled out. Marked fatigue may result from anemia, leukemia, hypothyroidism, or diuretic-induced potassium deficiency. Headaches may be due to intracranial lesions. Women attending PMS clinics have been found to have brain tumors, anemia, leukemia, thyroid dysfunction, gastrointestinal disorders, pelvic tumors including endometriosis, and other recurrent premenstrual phenomena, such as arthritis, asthma, epilepsy, and pneumothorax.16

Diagnostic Tests 5

calendar (Figs. 23-3 and 23-4). This instrument allows rapid visual confirmation of the nature, timing, and severity of menstrual cycle-related symptomatology and at the same time provides information on life stressors and current use of PMS therapies. Positive premenstrual changes associated with enhanced mood or performance are reported by up to 15% of women. Increased energy, excitement, and well-being have been associated with increased activity, heightened sexuality, and improved performance on certain types of tasks during the premenstrual phase.1

There is no endocrine test that helps in establishing the diagnosis in most circumstances. In a woman in whom the natural ovarian cycle has been disguised following hysterectomy a serum progesterone determination at the time of symptoms may help to confirm the link between symptoms and the luteal phase of the cycle. At times a complete blood count and/or sensitive thyrotropin level may be indicated to rule out anemia, leukemia, or thyroid dysfunction as an explanation for symptoms.

ETIOLOGY Physical Examination

A thorough physical examination, including gynecologic examination, is recommended in the assessment of all women

Since the 1950s a wide range of etiologic theories have been advanced to explain the varied manifestations of PMS. PMS has

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Section 3 Adult Reproductive Endocrinology PRISM CALENDAR BLEEDING Day of Menstrual Cycle

Name Baseline Weight On Day 1

lbs. or kg. (circle one)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1718 19 20 2122 232425 26 27 2829 30 3132 33 3435 36 3738 39 4041 42 43 44 45 46 47 48 49

Month May Date WEIGHT CHANGE SYMPTOMS Irritable Fatigue Inward anger Labile mood (crying) Depressed Restless Anxious Insomnia Lack of control Edema or rings tight Breast tenderness Abdominal bloating Bowels const(c) loose (l) Appetite up⇑ down⇓ Sex drive up⇑ down⇓ Chills(C) Sweats (S) Headaches Crave,sweets,salt Feel unattractive Guilty Unreasonable behavior Low self-image Nausea Menstrual cramps LIFESTYLE IMPACT Aggressive Physically towards others Verbally Wish to be alone Neglect housework Time off work Disoganized, distractable Accident prone/clumsy Uneasy about driving Suicidal thoughts Stayed at home Increased use of alcohol LIFE EVENTS Negative experience Positive experience Social activities Vigorous exercise MEDICATIONS Vitamin B6 ASA

Figure 23-3 One example of a Prospective Record of the Impact and Severity of Menstrual symptoms, the PRISM calendar, developed by Reid and Maddocks. (From Reid RL: Premenstrual syndrome. Curr Prob Obstet Gynecol Fertil 8:1–57, 1985.)

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been attributed to altered levels or ratios of estrogen and progesterone, androgen excess, fluid retention, endogenous hormone allergy, vitamin and trace element deficiencies, prolactin excess, hypoglycemia, bacterial and yeast infections, thyroid dysfunction, endogenous opiate addiction and withdrawal, abnormal metabolism of essential fatty acids leading to prosta-

glandin E1 deficiency, and altered calcium metabolism, to mention a few.15 As with other areas of confusion and uncertainty, the area of PMS is an attractive one for those promoting unorthodox treatments for personal gain. Many of the theories that underlie such interventions lack biologic plausibility and appear to have

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Chapter 23 Premenstrual Syndrome and Menstrual-Related Disorders Name

PRISM

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C ALEN D A R BLEEDING Day of Menstrual Cycle

lbs. or kg. (circle one)

x x

x x x x x x x

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1718 19 20 2122 232425 26 27 2829 30 3132 33 3435 36 3738 39 4041 42 43 44 45 46 47 48 49

Month May Date WEIGHT CHANGE SYMPTOMS Irritable Fatigue Inward anger Labile mood (crying) Depressed Restless Anxious Insomnia Lack of control Edema or rings tight Breast tenderness Abdominal bloating Bowels const(c) loose (l) Appetite up⇑ down⇓ Sex drive up⇑ down⇓ Chills(C) Sweats (S) Headaches Crave,sweets,salt Feel unattractive Guilty Unreasonable behavior Low self-image Nausea Menstrual cramps LIFESTYLE IMPACT Aggressive Physically towards others Verbally Wish to be alone Neglect housework Time off work Disoganized, distractable Accident prone/clumsy Uneasy about driving Suicidal thoughts Stayed at home Increased use of alcohol LIFE EVENTS Negative experience Positive experience Social activities Vigorous exercise MEDICATIONS Vitamin B6 ASA

Figure 23-4

c

x

Visual inspection of a completed PRISM calendar reveals a pattern of symptoms consistent with PMS.

emerged as a means to market specific therapeutic products. Conscientious investigators have expended much effort to rigorously evaluate the promotional claims of others. Randomized, controlled trials have failed to confirm the efficacy of most of these purported treatments. Other theories, while having some biologic plausibility, have not or cannot be confirmed with available diagnostic techniques. No one theory has gained universal acceptance, although consensus

is developing that in some susceptible women normal swings in gonadal hormones22 appear to mediate changes in the activity of central neurotransmitters such as serotonin, which in turn incite profound changes in mood and behavior.23 Others have speculated a role for steroid-induced modulation of γ-aminobutyric acid receptors in the brain.24 Although it is likely that many of the physical symptoms (breast tenderness, bloating, constipation) are the direct effect of gonadal steroids, it is intriguing that

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Section 3 Adult Reproductive Endocrinology her life, and her loved ones is essential in choosing the level of intervention most appropriate to her situation.

Brain serotonin activity Estrogen Progesterone

Lifestyle Modification Strategies Communication Strategies

Menses

Critical level for

Depression Anger Anxiety

Figure 23-5 A hypothetical depiction of the interrelationship between gonadal steroid fluctuations and central changes in serotonin activity to explain the timing of symptoms in PMS. When serotonin levels or activity fall below an arbitrary level (which may be influenced by stress, heredity, or other factors), symptoms of anger, anxiety, or depression may emerge (depicted by gray areas). (From Reid RL: Premenstrual syndrome. In DeGroot L (ed). Endotext.com. Available at www.endotext.org. Accessed 20 December 2004.)

treatment of PMS with selective serotonin reuptake inhibitors (SSRIs) will ameliorate the severity of not only psychological, but also physical complaints.25 Several lines of evidence from clinical medicine support this interrelationship between estrogen or lack of estrogen effect (perhaps mediated by progestin-induced depletion of estrogen receptors) and central serotonergic activity.23 Estrogen has been shown to alleviate clinical depression in hypoestrogenic women in double-blind clinical trials.26,27 The addition of sequential progestin therapy to estrogen replacement triggers characteristic PMS-like mood disturbance in some susceptible postmenopausal women.17 Anti-estrogens given for ovulation induction may, at times, provoke profound mood disruption. Women with PMS show a surprisingly high frequency of premenstrual and menstrual hot flashes (85% of PMS sufferers vs. 15% of non-PMS controls) that are typical of those experienced by menopausal women.28,29 SSRIs have been shown to relieve hot flashes in breast cancer survivors made menopausal by chemotherapy.30 In each of these circumstances a decrease in exposure to estrogen has been linked to mood disturbance and in each case a decrease in serotonin activity (inferred from the response to SSRIs) appears to be the proximate cause (Fig. 23-5).

THERAPY

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Women who experience PMS typically report that they have tried numerous over-the-counter PMS remedies with little effect before seeking professional help. The type of health professional they consult will often define different courses of intervention at the outset—for example, a psychologist may well focus on communication, stress reduction, or assertiveness training, whereas other health practitioners may turn initially to medical interventions. No single approach works in all situations, and a careful assessment of the impact of symptoms on the woman,

When an individual is suffering to a degree that requires more than simple counseling and reassurance, measures aimed at lifestyle modification should first be explored. She should be encouraged to discuss the problem with those individuals who are central to her life, including spouse, other family members, or a sympathetic coworker. Often confrontations can be avoided if an understanding spouse or friend recognizes the cause for her upset and defers discussion of the controversial subject until another time. Strategies for stress reduction can be helpful. Communication and assertiveness may be improved with counseling. Group counseling in a program supervised by a clinical psychologist may be invaluable. Although it is useful for PMS sufferers to learn to anticipate times in the month when vulnerability to emotional upset and confrontation may be greatest, the strategy of making important decisions “only on the good days,” as espoused in some PMS clinics, falls apart if premenstrual symptoms last for more than just a few days per month. For some women premenstrual symptoms may last for a full 3 weeks, and advising them to restrict their important activities to the remaining days of the month is neither helpful nor warranted. Interventions aimed at reducing symptoms are more appropriate in this circumstance. Diet

There is a paucity of evidence to support a dietary approach to the control of PMS,31 although there are a few simple dietary measures that may afford a measure of relief for the afflicted woman. Most women with PMS, despite feelings of bloating and tension, show no absolute increase in weight, no change in girth, and no signs of peripheral edema.3 PMS sufferers commonly report cravings for salty and sweet foods, and these dietary alterations may account for unusual cases of premenstrual edema.32 Sudden shifts from low-sodium, low-carbohydrate intake to a diet high in these constituents can account for weight gain of as much as 5 kg in 24 hours.33 For this reason reduction in the intake of salt and refined carbohydrates may help prevent edema and swelling in occasional women with this manifestation of PMS. Although a link between methylxanthine intake and premenstrual breast pain has been suggested, available data are not convincing.34,35 Nevertheless, a reduction in the intake of caffeine may prove useful in women in whom tension, anxiety, and insomnia predominate. Several lines of evidence indicate that there is a tendency to increased alcohol intake premenstrually,36 and women should be cautioned that excessive use of alcohol is frequently an antecedent factor in marital discord. Anecdotal evidence suggests that small, more frequent meals may occasionally alleviate mood swings. Based on recent evidence that cellular uptake of glucose may be impaired premenstrually, there is at least some theoretical basis for this dietary recommendation.37 Carbohydrates may exhibit mood-altering effects through a number of mechanisms,38 yet attempts to improve premenstrual symptoms through dietary supplements have not been successful.39,40 Calcium supplemen-

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Chapter 23 Premenstrual Syndrome and Menstrual-Related Disorders tation has been shown to be marginally superior to placebo in a randomized, placebo-controlled trial.41

physical and some psychological manifestations of PMS with an improvement in health-related quality of life.49,50

Exercise

Pyridoxine

Regular aerobic exercise may relieve PMS symptoms, at least temporarily, in many women,42,43 and it should be recommended as part of an overall program of lifestyle modification. Some women with PMS report that exercise is an outlet for the inward anger and aggression that characterizes their symptomatology.

Published data in regard to the efficacy of pyridoxine (vitamin B6) have been contradictory51; however, this medication in proper dosages (100 mg daily) is, at worst, a safe placebo that becomes one part of an overall management plan for women with distressing molimina that should include lifestyle modification and changes in diet. Patients should be cautioned that these medications do not work for all women and that increasing the dose of pyridoxine in an effort to achieve complete relief of symptoms may lead to peripheral neuropathy. Pyridoxine should be discontinued if there is evidence of tingling or numbness of the extremities.

Medical Interventions The primary factor directing the selection of therapy should be the intensity and impact of premenstrual symptoms. Symptoms that are causing major disruption to quality of life rarely respond to lifestyle modification alone, and efforts to push this approach often do nothing more than delay effective therapy. Conversely, minor symptoms or symptoms that are short-lived each month seldom justify major medical interventions. Many times other gynecologic symptoms, such as dysmenorrhea or menorrhagia, coexist with PMS; if this is the case it is prudent to try existing therapies that may benefit more than one concern. Nonsteroidal anti-inflammatory drugs (NSAIDs) or oral contraceptives are an excellent first-line therapy in these circumstances.

Diuretics

The routine use of diuretics in the treatment of PMS should be abandoned. Most women show only random weight fluctuations during the menstrual cycle despite the common sensation of bloating. Spironolactone has been reported to alleviate symptoms in some PMS sufferers.52 Anxiolytics

Mefenamic acid (500 mg three times daily) in the premenstrual and menstrual weeks has outperformed placebo for the treatment of PMS in some but not all clinical trials.44,45 Mefenamic acid is contraindicated in women with known sensitivity to aspirin or those at risk for peptic ulcers.

Some women report overriding symptoms of anxiety and tension or insomnia in the premenstrual week.53 New short-acting anxiolytics or hypnotics such as alprazolam (0.25 mg twice daily) or triazolam (0.25 mg at bedtime), respectively, may be prescribed sparingly for such individuals.54,55 Buspirone has also proven useful for anxiety and may be particularly helpful in circumstances where SSRIs evoke sexual dysfunction.56

Oral Contraceptives

Antidepressant Therapy

Despite being one of the most commonly used medications among women of reproductive age, oral contraceptive steroids have been given to women with premenstrual complaints for 40 years without a clear understanding of what to expect in terms of symptom duration or severity. Contraceptive steroids will reduce menstrual cramps and flow and by so doing may improve the entire premenstrual/menstrual experience for some women. However, the very reason that some women stop oral contraceptives is that it seems to provoke a worsening of premenstrual complaints; some reports suggest that premenstrual symptoms may have an earlier onset in the cycle in some affected women using standard oral contraceptives. The first systematic studies to examine the effects of oral contraceptives on PMS did not find differences in PMS symptoms between oral contraceptive users and nonusers, nor were there significant differences between agents with differing progestational potencies.46,47 Monophasic and triphasic preparations showed similar rates of symptomatology.48 A new oral contraceptive preparation containing a novel progestin with diuretic effects (drospirenone) has undergone the most rigorous testing in normal women and women with strictly defined PMDD. The dosage of progestin in each pill is said to be the equivalent to 25 mg of spironolactone. Alhough the evidence supporting a role for fluid retention as an etiologic component of PMS is lacking,3 many women are distressed by feelings of bloating and edema. In controlled clinical trials this new oral contraceptive has been shown to offer relief to some

A range of newer antidepressant medications that augment central serotonin activity have been shown to alleviate severe PMS.57,58 Because these agents will also relieve endogenous depression, a pretreatment diagnosis achieved by prospective charting is very important. For patients in whom psychiatric symptoms predominate, antidepressant therapy may provide excellent results (Fig. 23-6). SSRIs, such as fluoxetine, sertraline, paroxetine,

Nonsteroidal Anti-inflammatory Drugs

Brain serotonin activity Estrogen Progesterone

Menses SSRI effect

Brain serotonin activity

remains above critical threshold

Figure 23-6 Hypothetical depiction of how drugs that elevate serotonin activity can alleviate PMS. (From Reid RL: Premenstrual syndrome. In DeGroot L (ed). Endotext.com. Available at www.endotext.org. Accessed 1 January 2005.)

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Section 3 Adult Reproductive Endocrinology fluvoxamine, and velafaxine (a serotonin and norepinephrine reuptake inhibitor), have all been successfully employed. Symptom profiles may help in selecting the most appropriate agent (i.e., fluoxetine in patients in whom fatigue and depression predominate; sertraline if insomnia, irritability, and anxiety are paramount). SSRIs have been associated with loss of libido and anorgasmia, which are particularly distressing to this patient population, and appropriate pretreatment counseling is essential. Tricyclic antidepressants (TCAs) have not generally been effective, with the exception of clomipramine, a TCA with strong serotoninergic activity. Intolerance to the side effects of TCAs is common. Most PMS sufferers would prefer to medicate themselves only during the symptomatic phase of the menstrual cycle. Recent studies have demonstrated that luteal phase therapy may be effective for many women with PMS.59 Practically speaking, a trial of SSRI therapy should be commenced with continuous use. After a woman has determined the optimal response that can be achieved with continuous therapy, it is reasonable for her to try luteal phase-only therapy to determine if the benefit is maintained. Unfortunately, several follow-up studies have demonstrated the rapid recurrence of severe PMS attended by significant social disruption after cessation of therapy with SSRIs.60,61 Practically speaking this would mean that if this line of therapy is chosen extended treatment may be required. Gonadotropin-Releasing Hormone Agonists

Many women express reservations about the need to take SSRIs on a long-term basis. Other women find there is some loss of spontaneous emotion while using psychotropic medications; still others report that the side effects are intolerable. A different approach to the management of severe PMS has been to suppress the ovarian cycle, which is thought to incite the changes in central neurotransmitters that underlie the manifestations of PMS (Fig. 23-7). Gonadotropin-releasing hormone (GnRH) agonists effect rapid medical ovarian suppression, thereby inducing a pseudomenopause and affording relief from

Estrogen Medical Ovarian Suppression GnRH agonist and estrogen addback

Brain serotonin activity

Critical threshold below which psychiatric symptoms appear

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Figure 23-7 Hypothetical depiction of how medical or surgical elimination of ovarian steroid fluctuations can stabilize central serotonin activity and eliminate PMS. (From Reid RL: Premenstrual syndrome. In DeGroot L (ed). Endotext.com. Available at www.endotext.org. Accessed 1 January 2005.)

PMS.62 This approach is unsatisfactory in the long term not only because of the troublesome menopausal symptoms it evokes, but also because it creates an increased risk for osteoporosis and possibly ischemic heart disease. When combined with hormone replacement therapy GnRH agonists afford excellent relief from premenstrual symptoms without the attendant risks and symptoms resulting from premature menopause. The major drawback to this therapeutic approach is the expense of medication and the need for the patient to take multiple medications on a long-term basis. Other Medical Therapy

Neither progestin therapy63,64 nor oil of evening primrose65 have been shown to be efficacious for PMS in controlled clinical trials.

Medical Management of Specific Symptoms Premenstrual Mastalgia

Premenstrual mastalgia, which affects up to 70% of women in reproductive age, may occur in isolation from other PMS symptoms and, as such, should be considered a moliminal symptom. Low doses of danazol, the synthetic analog of ethinyltestosterone, can bring about dramatic relief of mastalgia in most women.66 This medication is given at a dose of 100 mg daily for several cycles followed by maintenance doses of 50 mg daily in the luteal phase only. Higher doses of danazol (400 mg daily) may be required to relieve other PMS symptoms.67 Mastalgia may also respond to tamoxifen, a selective estrogen receptor modulator, at a dose of 10 mg daily.68 Diuretics, medroxyprogesterone acetate, and pyridoxine have not been shown to help mastalgia.

Surgical Therapy Medical approaches to PMS should be exhausted before consideration of surgery (hysterectomy and oophorectomy) for debilitating PMS. Observational trials have shown this therapy to be effective.69,70 For the woman in whom there is unequivocal documentation that premenstrual symptoms are severe and disruptive to lifestyle and relationships and in whom conservative medical therapies have failed (either due to lack of response, intolerable side effects, or prohibitive cost), the effect of medical ovarian suppression should be tested. At times this therapy (a GnRH agonist and continuous combination hormone replacement therapy) can be maintained until menopause with satisfactory symptom control. Some women, despite complete relief of symptoms, cannot afford to or choose not to take this combination of medications for prolonged intervals (as long as 10 to 15 years from diagnosis until menopause in some cases). In these specific circumstances a surgical option may be considered. In the circumstance where family is complete and permanent contraception is desired, the pros and cons of oophorectomy for lasting relief from premenstrual symptomatology should be discussed with the patient. In many women the progestin component of hormone replacement therapy when given sequentially may induce an apparent recrudescence of PMS-like symptoms and when given continuously may result in unwanted irregular bleeding. Accordingly, hysterectomy at the time of oophorectomy is a consideration that allows subsequent replacement with low-dose estrogen alone.

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Chapter 23 Premenstrual Syndrome and Menstrual-Related Disorders Table 23-3 Mechanisms and Management of Menstrual Cycle-related Effects on Common Medical Conditions Medical Condition

Mechanism

Management

Menstrual Migraine Migraines occurring only on day 1 of menstruation ± 2 days

Estrogen withdrawal

Symptomatic: ergotamine, analgesics, antiemetics, triptans Prophylactic: Estrogen (percutaneous patch or gel; oral) Cycle suppression (continuous OC, GnRH agonist) Triptans

Catamenial Epilepsy Epilepsy that worsens or occurs exclusively at menstruation

Decreased progesterone = lowered seizure threshold Altered drug metabolism

Symptomatic: Measure anticonvulsant levels and alter dose accordingly Prophylactic: Progesterone (oral, I.M.) Continuous combination OC Progestin-only OC

Premenstrual Asthma Premenstrual and/or menstrual asthma exacerbations

Progesterone-induced hyperventilation and alterations in airway responsiveness

Symptomatic: Optimize usual asthma medications Prophylactic: GnRH agonist (if lifethreatening)

Irritable Bowel Syndrome Premenstrual and/or menstrual exacerbations

Progesterone-induced changes in gut motility

Symptomatic: Antispasmodics, promotility agents, bulk-forming laxatives Serotonin-receptor antagonists Prophylactic: GnRH agonist (severe cases)

Diabetes Premenstrual and/or menstrual alterations in glycemic control

Changes in carbohydrate metabolism by unknown mechanism Altered eating control or patterns

Symptomatic: Adjust insulin accordingly Prophylactic: Awareness of altered control; adjust insulin accordingly

OC, oral contraceptive; GnRH, gonadotropin-releasing hormone

EFFECTS OF THE MENSTRUAL CYCLE ON COMMON MEDICAL CONDITIONS Menstrual Migraine There is compelling evidence supporting a relationship between reproductive hormones, particularly estrogen, and migraine headache. Table 23-3 gives an overview of mechanisms and management of menstrual cycle-related effects on common medical conditions. Migraine and Other Hormonal Events

Migraine headaches are two to three times more common in women than men,71 and their frequency increases considerably after menarche.72 Although 60% of migrainous women link attacks to menstruation,71 only 7% to 14% of women have true menstrual migraine. These women experience migraine headaches, usually without aura, almost exclusively during menses (generally day 1 ± 2 days)73,74 and are virtually free of migraines at other times of the cycle, with the exception of a small percentage of

women who experience a brief exacerbation associated with ovulation.71,72 Approximately 70% of women who experience menstrual migraine will improve during pregnancy, especially the second and third trimesters.74,75 These women may experience migraine in the postpartum period, associated with falling estrogen levels.76 Menopause and the climacteric, a time of declining estrogen levels, have a variable effect on migraine, although most women do show a decline in frequency of migraine after menopause.74,77 Oral contraceptives have variable effects on migraine frequency. Similar to menstrual migraine, some oral contraceptive users experience headaches only during the pill-free or placebo days.74,78 Role of Sex Steroids in Headache

Migraines are vascular headaches, associated with a vasoconstrictive phase followed by vasodilatation.79 Estrogen withdrawal is likely responsible for initiating some or all of these vascular effects on intracranial vessels.72,80 Estrogen affects headache by altering neurovascular activity in the brain. Exposure to migraine “triggers” in susceptible patients results in intracerebral release of serotonin, which stimulates dilation of intracerebral vessels. Vessel dilatation activates perivascular neurons, which in turn activate the trigeminal nucleus that results in headache pain. Peripheral serotonin levels affect a patient’s susceptibility to migraine triggers. High estrogen levels are associated with high peripheral serotonin levels, which reduce headache susceptibility. Conversely, when estrogen levels fall, as occurs with menses, ovulation, and postpartum, peripheral serotonin levels also decrease, increasing headache susceptibility and frequency.71,81 Cycling of estrogen levels and prepriming with high levels of estrogen is required for declining estrogen levels to modify peripheral serotonin levels and headache activity.74 In women with menstrual migraine, the onset of headache appears to be triggered by an abrupt decline in serum estrogen levels, rather than by any absolute level. Estrogen administration can preclude the expected migraine attack until the estrogen is discontinued.80,82–84 Progesterone administration, while delaying menstrual flow, does not prevent the occurrence of migraine at the expected time.80 Treatment of Menstrual Migraine

Effective treatment of menstrual migraine depends first on accurate diagnosis of migraine and on establishing a link between attacks and menstruation. This is best accomplished by prospective recording of migraine attacks and menstrual periods by the patient herself for at least 3 months. During this time, symptomatic relief of acute migraine attacks with the usual migraine therapies (ergotamine, analgesics, anti-inflammatory medications, antiemetics) can be offered. NSAIDs can also be used prophylactically, starting 2 days before menses and continuing for 4 to 6 days.85 These are particularly useful if the woman also experiences significant dysmenorrhea.74 The development of the triptans, serotonin receptor agonists, has significantly improved the management of migraine headaches.86 These medications selectively activate serotonin receptors on intracranial blood vessels and the trigeminal nerve, causing vasoconstriction of abnormally dilated intracranial vessels and inhibition of neurogenic inflammation.87 Acute attacks of menstrual migraine respond well to sumatriptan. Short-term prophylaxis with sumatriptan (2.5 mg three times daily) for 5

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Section 3 Adult Reproductive Endocrinology consecutive perimenstrual days has also proven effective in treating menstrual migraine,88,89 although the cost-effectiveness and long-term safety of this regimen requires further study.87 Prophylactic hormonal therapy to stabilize estrogen levels is indicated for women with menstrual migraine who do not experience adequate relief from symptomatic treatment.82–84,90,91 Estrogen can be administered either orally or percutaneously as a 50- or 100-μg transdermal patch or 1.5 mg of percutaneous estradiol gel.74,92 Percutaneous estrogen may be more effective because there is less variation in serum estrogen levels compared to oral preparations.74 Estrogen should be started in the late luteal phase, at least 48 hours before the anticipated onset of migraine, and should be continued for 4 to 6 days. Estradiol (1 mg) taken sublingually immediately at the onset of the headache may interrupt the usual progression to migraine.93 Medications that suppress the hypothalamic-pituitary-ovarian axis have been successful for treatment of women whose menstrual migraines are refractory to the usual therapies. The combination oral contraceptive pill can be given continuously for 3 to 4 months, followed by a withdrawal bleed and symptomatic treatment of any resulting migraine attack.91 A new 28-day oral contraceptive that maintains continuous, albeit lower, estrogen administration rather than placebo for the last 7 days is currently being developed and may be very useful for women experiencing menstrual migraine or migraine on the oral contraceptive during the usual pill-free or placebo week. Gonadotropin-releasing hormone agonists are a useful tool for both diagnosis and treatment of menstrual migraine but should be tried only after all other possible treatments have been exhausted. A recent report demonstrated dramatic success in treating menstrual migraine with GnRH agonists, combined with continuous low-dose estrogen replacement therapy.94 Women who respond to this treatment typically can expect to experience long-term relief after surgical oophorectomy with low-dose estrogen replacement therapy. Concomitant hysterectomy, although unnecessary for migraine prevention, simplifies subsequent hormone therapy, if necessary for menopausal symptoms. This “definitive” therapy should only be offered to the woman with recalcitrant menstrual migraine who has completed her childbearing.

Catamenial Epilepsy

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The term catamenial is derived from the Greek word Katamenios, which means monthly, because historically the cyclic nature of epileptic attacks was thought to be due to the cycles of the moon.95 Catamenial epilepsy is observed in 10% to 70% of epileptic women.95,96 As in menstrual migraine, the wide range in reported incidence is due to the lack of a generally accepted definition.96 Strictly defined, catamenial epilepsy is epilepsy that occurs at or worsens around menstruation, such that at least 75% of seizures occur over the 10 days beginning 4 days before menses, representing a sixfold increase in daily seizure frequency.95–97 Whereas up to 70% of epileptic women claim that their seizures are exacerbated by menstruation,96 true catamenial epilepsy can be objectively demonstrated in approximately 12%.96 Menstrual exacerbations occur with all types of seizures, although they may be more common in women with focal

epilepsy rather than generalized seizures.95 Three distinct patterns of catamenial epilepsy have been described in women with ovulatory cycles: perimenstrual, periovulatory, and luteal.98 In the most common, perimenstrual pattern, seizure frequency is greatest during the menstrual phase (day −3 to +3) compared to the midfollicular and midluteal phases. The periovulatory pattern is characterized by increased seizure frequency during the ovulatory (midcycle) phase, compared to the midfollicular and midluteal phases. In the luteal pattern, seizure frequency is greatest in the ovulatory, midluteal, and menstrual phases, compared to the midfollicular phase. Women with anovulatory cycles tend to experience an overall increase in seizure frequency throughout their cycle, compared to women with ovulatory cycles. This is very likely due to the overall lower progesterone levels that are consistent with anovulation. In contrast to the pattern seen in ovulatory women, seizures are significantly less common during menses compared with the remainder of the cycle in anovulatory women.99 Some women with epilepsy appear to be at increased risk for ovulatory dysfunction. One study identified anovulatory cycles in 35% of women with temporal lobe epilepsy, compared with 8% of controls.100 Other reproductive endocrine disorders, including polycystic ovary syndrome, hyperprolactinemia, and premature ovarian failure, appear to have a higher prevalence in women with epilepsy.101,102 Pathophysiology of Catamenial Epilepsy

Catamenial epilepsy is believed to result from cyclic alterations in both ovarian hormone levels and drug metabolism. Seizure threshold is increased by progesterone and decreased by estrogen.103 A decrease in the progesterone level, or in the progesterone to estrogen ratio, correlates with increased seizure activity.104 Seizure frequency has been shown to increase during two specific times in the menstrual cycle. The first corresponds to the rapid decrease in progesterone just prior to menses, and the second to the elevation of estrogen prior to ovulation.103 An increase in seizure frequency has also been demonstrated during anovulatory cycles when progesterone levels are relatively low.105 Altered metabolism of anticonvulsants at different times in the cycle is well established.95,106 The decrease in estrogen and progesterone at menstruation is believed to stimulate the release of hepatic monoxygenase enzymes, which accelerates anticonvulsant metabolism and increases the risk for breakthrough seizures.95,106 Treatment of catamenial epilepsy should include measurement of serum levels of anticonvulsants during times of seizure exacerbation. A supplemental daily dose of seizure medication at the time of exacerbation may improve seizure control.107 Treatment of Catamenial Epilepsy

Accurate prospective documentation of seizures in relation to menstrual periods is essential for diagnosis and before specific treatment. Many investigators have shown progesterone therapy to be beneficial.104,105,108–112 Medroxyprogesterone acetate given orally (10–40 mg daily) or intramuscularly (150 mg q 6–12 weeks) has been the most widely studied.104,105 In addition to its antiepileptic properties, progesterone given in this fashion may also reduce seizure frequency by suppressing gonadotropin release, which, in turn, lowers estrogen levels.108 More recently, natural

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Chapter 23 Premenstrual Syndrome and Menstrual-Related Disorders micronized progesterone has also proven effective treatment in some women. In one study, eight women with temporal lobe epilepsy were treated with progesterone vaginal suppositories, 50 to 400 mg every 12 hours, during the phase of highest seizure frequency. The average monthly seizure frequency declined by 68%, and overall 75% of women had fewer seizures during the 3-month study period.110,111 In another larger study of 36 women treated with sublingual progesterone, focal and generalized seizures were reduced by 68% and 57%, respectively, and 4 patients became seizure-free.113 The effects of combined oral contraceptives on seizure frequency have been inconsistent, with seizure exacerbation occurring on pill-free days in some reports.104 Uninterrupted combination oral contraceptives or the progestin-only oral contraceptive may be preferable in women with epilepsy because they result in continuous progestin exposure.114 There are few studies describing the use of GnRH agonists for the treatment of catamenial epilepsy refractory to other therapies.115,116 Although these drugs are generally effective at reducing seizure frequency, their effects on bone demineralization may preclude long-term use.

Premenstrual Asthma Up to 40% of women with asthma experience an increased frequency and severity of asthma symptoms premenstrually or at menstruation.117,118 Gibbs and coworkers119 objectively confirmed the worsening of asthmatic symptoms premenstrually by documenting significant decreases in peak expiratory flow rates. There is also some evidence that women are more likely to be hospitalized premenstrually for asthma complications, including respiratory failure.120–122 The precise etiology of premenstrual asthma remains elusive but may be related to changing levels of progesterone or prostaglandins. Progesterone level increases steadily after ovulation and falls abruptly in the days prior to menstruation. Its relaxant effect on smooth muscle contractility may contribute to cyclic changes in airway responsiveness.123 Progesterone-stimulated hyperventilation may further influence asthma, leading to symptomatic deterioration and dyspnea. A subjective increase in asthma symptoms, along with an objective increase in peak expiratory flow rates, has been demonstrated in women with premenstrual asthma; however, an associated deterioration in airway reactivity has not been shown.124 There is also no relationship between airway function and absolute levels of progesterone. Although some prostaglandins have bronchoconstrictive effects, studies have failed to show any relationship between endogenous prostaglandin synthesis and premenstrual asthma.125 Menstrual cycle-related alterations in immune mechanisms have also been suggested.126 It has been suggested that premenstrual asthma may in part be due to altered perception or heightened awareness of symptoms, perhaps related to PMS.117 An association has been reported between premenstrual asthma and symptom scores for PMS and dysmenorrhea.121 Both estrogen and progesterone can alter β2-adrenoceptor function and regulation, thereby potentiating the brochorelaxant effects of catecholamines. There are cyclic changes in β2-adrenoceptors during the menstrual cycle in normal women,

with up-regulation of receptors during the luteal phase, most likely related to progesterone.127 Interestingly, this cyclic change is lost in asthmatic women, who demonstrate a paradoxical down-regulation of receptors when exposed to progesterone.127 The altered β2-adrenoceptor function and regulation may reduce response to both endogenous and exogenous bronchdilators, thereby contributing to premenstrual asthma exacerbations.117 Treatment of Premenstrual Asthma

Proper management of premenstrual asthma requires an accurate diagnosis. A detailed history of the timing of exacerbations, accompanied by a patient diary of symptoms and peak expiratory flow rates is useful. The majority of patients will respond to increased dosages of the usual asthma medications (betaadrenergic agonists, anticholinergics, and corticosteroids) during the luteal phase.117,123 Intramuscular progesterone was shown to be effective in three women with severe, refractory premenstrual asthma, eliminating the decrease in peak flow rate, as well as reducing total corticosteroid requirement.128 Exogenously administered estradiol did not ameliorate severe premenstrual asthma in a randomized clinical trial.129 There are two reports of the successful use of a GnRH agonist for women with recurrent menstrual-related status asthmaticus.130,131 The improvements seen with high-dose progesterone and GnRH agonists may be due to the resulting profound suppression of ovarian hormone production. Although there has been interest in the use of oral contraceptives in women with premenstrual asthma, the existing studies have shown highly variable effects on asthma symptoms.132-134

Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a common functional bowel disorder, diagnosed clinically by the triad of chronic or recurrent abdominal pain, altered bowel habits, and the absence of a structural or biochemical abnormality.135,136 Up to one third of otherwise asymptomatic women report an increase in gastrointestinal symptoms before and during menstruation.137 Reports of constipation during the progesterone-dominant luteal phase and loose stools or diarrhea at the onset of menses are common. Almost 50% of women with IBS will report a similar increase in bowel symptoms, such as abdominal pain, diarrhea, and constipation.136-138 Progesterone has well-documented effects on the gastrointestinal system, including a reduction in lower esophageal sphincter tone and delayed gastric emptying.139 Delayed gastrointestinal transit time in women, particularly during the luteal phase, has also been demonstrated.140 Abrupt progesterone withdrawal may trigger an increase in bowel activity. Progesterone may also act as an endogenous antagonist of enteric nerve function.141 A recent study has shown that the exacerbation of IBS symptomatology at menses is associated with an increase in rectal sensitivity in women with IBS. A control group of healthy female volunteers did not demonstrate any changes in rectal sensitivity in relation to their menstrual cycles.142 Gastrointestinal symptoms, such as abdominal pain, diarrhea, and constipation, are consistently reported by women with IBS.137,143,144 The most dramatic changes in bowel symptoms occur at the start of menstrual flow, a time when the levels of progesterone fall, and prostaglandin E2 and F2α, powerful

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Section 3 Adult Reproductive Endocrinology stimulants of colonic contractility, rise.136 Patients with IBS, in whom the colon is hyperresponsive to a variety of stimuli, may have an exaggerated colonic response to prostaglandins released during menstruation.136 Treatment of Irritable Bowel Syndrome

Treatment of IBS is generally symptomatic, including antispasmodics, promotility agents, and bulk-forming laxatives. The theory of prostaglandin involvement in menstrual-related exacerbations of IBS raises the possibility of treatment with prostaglandin synthesis inhibitors. Although there are other effective drug therapies for IBS, including antispasmodics and the newer serotonin receptor antagonists,145 studies investigating the efficacies of these therapies in women with menstrual exacerbations of IBS are lacking. There have been several reports of successful treatment of severe, menstrually exacerbated IBS with GnRH agonists.146 With the menstrual cycle completely eliminated, these women experience significant and progressive improvement in bowel symptoms. Interestingly, many of these women experienced transient recurrence of their symptoms during the progestin phase of the estrogen and progestin addback therapy given to minimize the long-term adverse effects associated with GnRH agonists.146 It is likely that GnRH agonists have direct effects on the enteric nervous system, in addition to their indirect effects on the gut, mediated through ovarian hormone suppression.147 This possibility is supported by limited evidence that GnRH agonists provide relief from IBS in men and postmenopausal women.146 The expense and potential adverse effects of these medications will preclude prolonged use in most circumstances. Rarely, if dramatic relief results from a trial of ovarian suppression, oophorectomy may have a therapeutic role.

Diabetes

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Menstrual cycle-related alterations in glycemic control during the luteal and premenstrual phases in some women with insulindependent diabetes (IDDM) have been reported.148–150 In one observational study of 406 women with IDDM, 67% reported changes in blood glucose control and 70% reported changes during menstruation. These changes were most pronounced in women experiencing PMS or sweet cravings during this time.151,152 Deterioration in glycemic control, diabetic ketoacidosis, severe insulin reactions, and hypoglycemic episodes may occur more frequently around menstruation.153 In one exceptional case, insulin resistance and ketoacidosis recurred exclusively during menstruation.154 Altered insulin receptor binding and affinity at different times during the menstrual cycle have been reported in some155–157 but not all studies.158 Attempts to identify the hormones responsible for menstrual cycle-related changes in carbohydrate metabolism have produced conflicting results. Impaired glucose tolerance during the luteal phase is reported in healthy women without diabetes.159 Studies on the effects of oral contraceptives and progestational agents on carbohydrate metabolism also show variable effects.160–162 It is possible that even small effects of estrogen and progesterone on glucose homeostasis are exaggerated in diabetic women, in whom the normal feedback regulation between plasma glucose levels and insulin secretion is lost.149

Poor eating behavior, such as binging or increased intake of sweets, is described by many women in the luteal phase and premenstrually152 and is another possible cause for loss of glycemic control in women with diabetes. Diabetic women should be counseled regarding the possibility of altered glycemic control. They need to recognize and anticipate changes in their eating patterns. Regular glucose monitoring, with appropriate anticipatory adjustment of insulin dosage and dietary intake, is a useful management strategy.97 Ovarian suppression with GnRH agonists has been used successfully in women with recurrent life-threatening complications, such as recurrent severe insulin reactions or ketoacidosis associated with specific phases of the menstrual cycle.150

Arthritis Symptoms of rheumatoid arthritis often improve in the luteal phase when ovarian steroid production is maximal. Similarly, improvement is seen during pregnancy with exacerbation postpartum.163 A subjective increase in morning stiffness and arthritic pain during menstruation and the early follicular phase has been shown.164 Rudge and colleagues objectively documented menstrual cycle-related variations in rheumatoid arthritis by demonstrating a significant decline in mean grip strength at the start of menstruation.165 Similarly, finger joint size peaked within 6 days of the start of menses, corresponding in many cases with increased body weight.165 The abrupt decline of ovarian steroidogenesis resulting from involution of the corpus luteum is thought to be responsible for “menstrual arthritis,” a rare condition in which arthritis occurs exclusively at the time of menses.166 Cyclic alterations in rheumatoid arthritis may be attributable to menstrual cyclicity in the immune response.97 Both estrogen and progesterone have anti-inflammatory properties that may ameliorate arthritic symptoms.167 Premenstrual exacerbation of symptoms has also been attributed to altered pain perception associated with premenstrual mood alterations.165 Estrogen, either alone168 or in combination oral contraceptives,169,170 has proved beneficial for some women with rheumatoid arthritis. Oral contraceptives may delay onset of rheumatoid arthritis but do not prevent its occurrence.171,172 Estrogen therapy in postmenopausal women does not appear to protect against the occurrence of rheumatoid arthritis.168

Other Disorders The previous discussion describes the effects of the menstrual cycle on several relatively common disorders. Several rare conditions also show menstrual variation in severity. There are numerous case reports of catamenial pneumothorax, the occurrence of recurrent spontaneous pneumothorax exclusively associated with menses, possibly the result of pleural or diaphragmatic endometriosis.173,174 This has been successfully treated with GnRH agonists.175 There is some evidence that acute appendicitis presents more frequently in the luteal phase,176,177 although this could be due to the misdiagnosis of right lower quadrant pain resulting from corpus luteal cysts, leading to unnecessary appendectomy. Other disorders exacerbated by the postovulatory and premenstrual phases of the menstrual cycle include acne, endocrine allergy and anaphylaxis, hereditary angio-

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Chapter 23 Premenstrual Syndrome and Menstrual-Related Disorders edema, erythema multiforme, urticaria, aphthous ulcers, Behçet’s syndrome, acute intermittent porphyria, paroxysmal supraventricular tachycardia, glaucoma, and multiple sclerosis.123,178–182 GnRH agonists have been used for some of these conditions, in particular for recurrent anaphylaxis and acute intermittent porphyria, when symptoms are severe or disabling.183–185 In contrast to these disorders, myasthenia gravis generally improves premenstrually.186 Although one early report indicated better outcomes if breast surgery was performed in the luteal phase,187 subsequent investigators have been unable to confirm this finding.188

An Approach to Menstrual Cycle-Related Exacerbations of Medical Conditions Exacerbation of certain medical conditions at specific times during the menstrual cycle is a well-recognized phenomenon. The importance of prospective recording of symptoms in relation to the menstrual cycle to facilitate the diagnosis and treatment of menstrual cycle-related exacerbations cannot be overestimated. Where appropriate, cyclic alteration of symptomatic therapy may be sufficient for treatment. If such measures prove ineffectual, a trial of medical ovulation suppression may be warranted. If a dramatic benefit results, consideration should be given to ongoing therapy with a GnRH agonist and steroid “addback,” or to a cheaper alternative such as Depo-Provera or danazol. If these medical approaches are impractical due to cost or side effects, and the woman’s fertility aspirations have been met, consideration of hysterectomy and bilateral oophorectomy with ongoing estrogen replacement therapy is a final option.

PEARLS ●

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CONCLUSION ●

The recognition of recurrent menstrual cycle-related exacerbations of a medical disorder allows consideration of innovative treatments that alter or suppress ovarian hormone production. Elimination of ovarian cyclicity may provide dramatic relief for some women in whom standard therapies prove less than ideal.

●

PMS is a term that should be reserved for a more severe constellation of symptoms—mostly psychiatric—that leads to major interference with day-to-day activities and interpersonal relationships. Only by obtaining a prospective symptom record over a 1- to 2-month period can the clinician have confidence in the diagnosis of PMS. The most severely affected women report symptoms onset shortly after ovulation (2 weeks before menstruation), resolving at the end of menstruation. In some susceptible women, normal swings in gonadal hormones appear to mediate changes in the activity of central neurotransmitters such as serotonin that in turn incite profound changes in mood and behavior. Neither progestin therapy nor oil of evening primrose have been shown to be efficacious for PMS in controlled clinical trials. A range of newer antidepressant medications that augment central serotonin activity have been shown to alleviate severe PMS. In women with menstrual migraine, the onset of headache appears to be triggered by an abrupt decline in serum estrogen levels, rather than by any absolute level. Prophylactic hormonal therapy to stabilize estrogen levels is indicated for women with menstrual migraine who do not experience adequate relief from symptomatic treatment. Menstrual exacerbations occur with all types of seizures, although they may be more common in women with focal epilepsy, rather than generalized seizures. Menstrual cycle-related alterations in glycemic control during the luteal and premenstrual phases in some women with insulin-dependent diabetes (IDDM) have been reported. Symptoms of rheumatoid arthritis often improve in the luteal phase when ovarian steroid production is maximal.

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Chapter 23 Premenstrual Syndrome and Menstrual-Related Disorders 175. Slabbynck H, Laureys M, Impens N, et al: Recurring catamenial pneumothorax treated with a GnRH analogue. Chest 100:851, 1991. 176. Arnbjonsson E: Acute appendicitis risk in various phases of the menstrual cycle. Acta Chir Scand 149:603–605, 1983. 177. Arnbjornsson E: The influence of oral contraceptives on the frequency of acute appendicitis in different phases of the menstrual cycle. Surg Gynecol Obstet 158:464–466, 1984. 178. Dalton K: Influence of menstruation on glaucoma. Br J Ophthal 51:692–695, 1967. 179. Smith R, Studd JW: A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J Royal Soc Med 85:612–613, 1992. 180. Caughey SC, Margesson LJ, Reid RL: Erythema multiforme with ulcerative stomatitis at menstruation. Can J Obstet Gynecol 112–113, 1990. 181. Howard RE: Premenstrual urticaria and dermatographism. JAMA 245:1068, 1981. 182. Rosano GMC, Leonardo F, Sarrel P, et al: Cyclical variation in paroxysmal supraventricular tachycardia in women. Lancet 347:786–788, 1996.

183. Anderson KE, Spitz IM, Sassa S, et al: Prevention of cyclical attacks of acute intermittent porphyria with a long-acting agonist of luteinizing hormone-releasing hormone. NEJM 311:643–645, 1984. 184. Meggs WJ, Pescovitz OH, Metcalfe D, et al: Progesterone sensitivity as a cause of recurrent anaphylaxis. NEJM 311:1236–1238, 1984. 185. Slater JE, Raphael G, Cutler GB, et al: Recurrent anaphylaxis in menstruating women: Treatment with a luteinizing hormone-releasing hormone agonist: A preliminary report. Obstet Gynecol 70:542–546, 1987. 186. Vijayan N, Vijayan VK, Dreyfuss PM: Acetylcholinesterase activity and menstrual remissions in myasthenia gravis. J Neurol Neurosurg Psychiatry 40:1060–1065, 1977. 187. Badue RA: Timing of surgery during the cycle and breast cancer survival. Lancet 337:1261, 1991. 188. Wobbes T, Thomas CM, Segers MF, et al: The phase of the menstrual cycle has no influence on the disease-free survival of patients with mammary carcinoma. Br J Cancer 69:599–600, 1994.

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Section 3 Adult Reproductive Endocrinology Chapter

24

Menopause Francisco Arredondo and James H. Liu

INTRODUCTION Natural menopause occurs between ages 45 and 55, with a median age of 51 for women in industrialized countries.1 Available evidence suggests that in less-developed countries with lower socioeconomic and nutritional level this event takes place earlier.2,3 These differences in onset of menopause support the hypothesis that menopause might not only be genetic, but may also be a biological marker echoing society’s longevity. The significant medical and technologic gains of the past century in medicine and to some extent, the constant betterment of living standards, have yielded an improvement in life expectancy. In some countries increases of more than 40 years of life expectancy have been observed during the past 100 years alone.4 The life expectancy for women at birth in the United States is age 79.9.5 As a consequence of this demographic evolution, a large proportion of the female population will spend more than one third of their lives after the menopause. In 1950 there were 220 million women in the world older than age 50. More than half of these women lived in the so-called developed world (112 million). In 1990, there were 467 million women older than age 50 around the globe, and by 2030 this number is expected to approach 1.2 billion. Roughly three out of four of these menopausal women will be in the developing world (total of 912 million).6 At a national level, the U.S. Census Bureau calculated a total of 35.5 million women older than age 50 during the 1990 census, and by 1997 the menopausal population in the United States represented almost 30% of the total female population. By 2030, the menopausal population in the United States is expected to reach 66.5 million, representing 38% of the female population and 20 % of the entire population.7 These demographic changes will reflect an “inverted pyramid” phenomenon in certain countries. In this scenario, the elderly to nonelderly population ratio will significantly change, with obvious challenging consequences in the economic balance between productivity and expenditure. For these reasons understanding the menopausal state, associated diseases, and its full impact to society are fundamental for health providers and health policy makers. The present chapter aims at providing an overview of this challenge.

MENOPAUSE PHYSIOLOGY AND PATHOPHYSIOLOGY The supply of primordial follicles in the female gonad is predetermined before birth and diminishes with age until the gonad

is unable to provide enough mature follicles to sustain menstrual cyclicity.8 The peak number of germ cell count is found at 20 weeks’ gestation, with decreased numbers at birth and puberty. Based on the number of follicles at three successive stages of development, which were obtained by counting follicles in histologic sections of ovaries from 52 normal women, a mathematical model was developed to describe the rates of growth and death of ovarian follicles in human ovaries between ages 19 and 50.9 While the number of oocytes dwindles throughout a woman’s life,10 there seems to be a transition at age 38 when the rate of follicle disappearance is augmented considerably with age. As a consequence, an estimated total of 1500 follicles remain at age 50 from the 300,000 present at age 19. This high death rate of small follicles appears to be responsible for advancing the timing of ovarian failure, and therefore of menopause, to midlife in our species.

Age of Menopause The mean age of menopause in normal women in the United States ranges between age 50 and 52.11 This number was based on a cross-sectional study, which is associated with recall bias. However, these findings have been confirmed in a large prospective cohort study of middle-aged women: the Massachusetts Women’s Health Study. The cohort of 2570 women that was followed confirmed that the median age of natural menopause was 51.3 years with a mean difference of 1.8 years between current smokers and nonsmokers. This study also showed that smokers not only show an earlier menopause, but also a shorter perimenopause.12 In other parts of the world, population-based surveys have shown earlier onset of menopause. For example, the median age of onset of menopause was 48 in a survey of 742 United Arab Emirates women.13 In certain regions of India, such as the state of Himachal Pradesh, the mean age of onset of menopause can be as low as 43.5 years, according to data from 500 postmenopausal women.14

Factors Affecting the Onset of Menopause Table 24-1 includes several factors that have been linked with an earlier onset of menopause. Among these factors, smoking has been the most often linked environmental agent to early age of onset of menopause. However, these studies have been inconclusive with regard to duration and intensity of smoking. Midgette and Baron concluded after a review of 14 studies that the risk of being menopausal was approximately doubled for current smokers compared with nonsmokers among women age 44 to

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Section 3 Adult Reproductive Endocrinology 55.15 However, in 2004 van Asselt and colleagues, using data from a Dutch population-based cohort of 5544 women, assessed the effect of smoking duration and intensity on age at menopause, correcting for the chronologic age-dependency of the variables concerned. After their modeling they concluded like previous researchers that smoking lowers the menopausal age. However, the reduction in the menopausal age appears not to be dependent on smoking duration, and it appears that smoking cigarettes could have an effect only around the time of menopause itself.16 In other words, the number of cigarettes smoked during perimenopause is apparently more significant than smoking history as the culprit of earlier age of onset of menopause among smoking women. Women treated with total abdominal hysterectomy appear to be at risk of early menopause. Concurrent unilateral oophorectomy was associated with an even earlier onset. However, previous tubal ligation does not influence the age of menopause.

percent of apoptosis occurs at the small antral follicle stage of 2.1 to 5 mm. On the other hand, atresia of the resting follicles in the human fetus seems to be set off by a process of necrosis rather than apoptosis.20 It seems clear now that the age-related decline in ovarian function in women is the result of the decline in both quantity and quality of the resting ovarian follicle pool. Recently a total of 182 resting follicles from a young cadre of women (age 25–32) were compared with 81 resting follicles from an older group (age 38–45) for signs of age-related changes by transmission-electron microscopy. De Bruin and colleagues concluded that, in resting follicles, the morphologic changes with age are different from the changes seen in quality decline by atresia.20 The morphologic changes with age specifically comprise the mitochondria, the dilated smooth endoplasmic reticulum, and the Golgi complex.

Genetic Contribution The age of natural menopause is determined by the interplay of genetic and environmental factors.21 There are cross-sectional22 and case-control23 population studies suggesting the existence of genetic variability in the age of menopause to be as high as 70%. However, a study conducted in the Netherlands in 164 motherdaughter pairs with a natural menopausal age estimated a hereditability of 44% (95% confidence interval [CI] 36%–50%). The authors conclude that these estimates are more accurate than those of previous studies that were done in twins and siblings because siblings shared many environmental factors.24

Time Course of Oocyte Pool Depletion It is estimated that the entire process from initiation of follicle growth until complete maturation and finally ovulation takes months.17,18 The majority of follicles will experience atresia by apoptosis at some point in their developmental process.19 Fifty

Table 24-1 Factors Associated with Earlier Onset of Menopause

STAGES OF REPRODUCTIVE AGING

Smoking Genetic factors Family history of early menopause

Until recently there was an absence of a relevant organized nomenclature system for the different stages of female reproductive aging. With this in mind the Stages of Reproductive Aging Workshop (STRAW) was held in Park City, Utah on July 23 and 24, 2001 (Fig. 24-1). As noted in Figure 24-1 the anchor for the staging system is the final menstrual period (FMP). Five stages occur before and two after this anchor point. Stages −5 to −3 cover the reproductive period; stages −2 and −1 are the menopausal transition; and stages +1 and +2 are the postmenopause.

Pelvic surgery Total abdominal hysterectomy Unilateral oophorectomy Metabolic factors Type 1 diabetes mellitus Galactose consumption Galactose-1-phosphate uridyl transferase deficiency Ovulation patterns Nulliparity Shorter menstrual cycles Nonuse of birth control pills

Stages:

-5

Terminology

-4

-3

Reproductive Early

Peak

Late

Final Menstrual Period (FMP) 0 -2 -1 +1 +2 Menopausal Postmenopause Transition Early Late* Early* Late Perimenopause

Menstrual cycles:

Endocrine:

354

variable

variable to regular normal FSH

variable

regular

↑FSH

a 1 yr

variable ≥ 2 skipped variable cycle length cycles and (>7 days an interval of amenorrhea different from normal) (≥60 days)

Amen x 12 mos

Duration of Stage:

until demise

none

↑FSH

↑FSH

*Stages most likely characterized by vasomotor symptoms

b 4 yrs

↑= elevated

Figure 24-1 The STRAW staging system. (From Soules MR: Executive Summary of STRAW, 2001.25–27)

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Chapter 24 Menopause Among the most concrete achievements of STRAW was the development of clear and specific nomenclature, which was previously vague and confusing in the literature. The authors of STRAW recognize that this is a draft and these concepts might evolve as knowledge advances.25-27

Menopausal Transition Stage −2 (early) and −1 (late) encompass the menopausal transition and are defined by menstrual cycle and endocrine changes. The menopausal transition begins with variation in menstrual cycle length in a woman who has a monotropic follicle-stimulating hormone (FSH) rise and ends with the FMP (not able to be recognized until after 12 months of amenorrhea).

Postmenopause Stage +1 (early) and +2 (late) encompass the postmenopause. The early postmenopause is defined as the 5 years after the FMP. The participants agreed this interval is relevant because it encompasses a further dampening of ovarian hormone function to a permanent level as well as accelerated bone loss. Stage +1 was further subdivided into segment a, the first 12 months after the FMP, and segment b, the next 4 years. Stage +2 has a definite beginning but its duration varies, because it ends with death. Further divisions may be warranted as women live longer and more information is accumulated.

during menopause. It is also one of the most puzzling symptoms of menopause, because the etiology and physiology remain incompletely understood.28 It is thought to be the result of a hypothalamic dysregulation from estrogen withdrawal that culminates in peripheral vasodilation and increase in blood flow. This results in heat loss and a decrease in core body temperature. The hypothalamic dysfunction is also manifested by simultaneous pulse of LH and presumably gonadotropin-releasing hormone (GnRH) that is coincident with the hot flash. Hot flash, hot flush, night sweats, and vasomotor symptoms are words frequently used to express the same experience. Hot flashes are defined subjectively as the recurrent transient sensation of heat that can be accompanied by palpitations, perspiration, chills, shivering, and feeling of anxiety. It is then a heat dissipation response that habitually begins in the face, neck, and chest and often becomes generalized.29 Although menopause is the most common cause of hot flashes, other causes should be considered. Fever is by far the most common cause of hot flashes, especially when coupled with a night sweat; thus, if during an episode of hot flashes the oral temperature is elevated the cause of the fever should be sought. In general we can divide the potential causes of hot flashes into seven categories: systemic diseases, neurologic, alcohol– medication interaction, drugs, food additives, eating, and miscellaneous30 (Fig. 24-2). However, is important to emphasize that these other causes are much less common than those associated with hypoestrogenemia.

Perimenopause Perimenopause literally means “about or around the menopause.” It begins with stage −2 and ends 12 months after the FMP. The climacteric is a popular but vague term that we recommend be used synonymously with perimenopause. Generally speaking, the terms perimenopause and climacteric should be used only with patients and in the lay press and not in scientific papers.

CLINICAL SIGNS AND SYMPTOMS OF MENOPAUSE The diagnosis of menopause can be established when the absolute level of serum FSH is elevated. The threshold for the diagnosis of menopause will vary according to the assay employed. In any event, the level will be two standard deviations above the normal value of a reproductive-age woman on cycle day 3. The luteinizing hormone (LH) level is of little value in the evaluation or diagnosis of menopause. The clinical diagnosis of menopause is established retrospectively once a patient has had more than 12 months of amenorrhea in conjunction with vasomotor symptoms such as hot flashes and headaches. At this point the patient has made the transition in the STRAW classification from −1 to +1.The range of symptoms due to immediate estrogen deficiency in women during STRAW stages −1 to +1 includes hot flashes and urogenital changes (see Table 24-1).25–27

Hot Flashes The vasomotor flush is the most characteristic trait of estrogen deficiency. It is experienced at least once in 75% of women

Systemic Diseases

The most common systemic disorders associated with hot flashes are carcinoid syndrome, mastocytosis, pheochromocytoma, medullary thyroid carcinoma, pancreatic carcinoma, and renal cell carcinoma. Carcinoid Syndrome

These are mainly neuroendocrine tumors of the bowel. They may also be found in the bronchus, pancreatic islets, retroperitoneum, liver,31 and even in the ovary.32 They probably arise from gastrointestinal or bronchopulmonary pluripotential stem cells.33 The carcinoid syndrome clinically has a classic triad of diarrhea, flushing, and valvular heart lesions. Skin flushing is the most common sign and is present in more than 90% of patients. The mechanism of flushing is at least partially due to serotonin release, but other substances, such as kinin, substance P, neurotensin, and prostaglandin, may play a role.33 Mastocytosis

Mast cell proliferations can be limited to the skin (cutaneous) or can be spread to extracutaneous tissues (systematic). Vasomotorlike symptoms may be present in these patients because the mast cell granules contain a number of acid hydrolases, leukotrienes, histamine, heparin, and slow-reacting substance.34 Pheochromocytoma

These tumors often arise from the adrenal medulla. Most of their clinical characteristics are due to the production, storage, and secretion of catecholamines. The hallmark sign in these patients is hypertension, which is present in 60% of patients. A significant number of them suffer hot flashes. Documenting increased urinary catecholamines makes the diagnosis.35

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Section 3 Adult Reproductive Endocrinology Figure 24-2 Differential diagnosis of flushing. (Adapted from Mohyi D: Differential diagnosis of hot flashes. Maturitas 27:203–214, 1997.)

Hot Flashes Differential Diagnosis

Systemic diseases

ETOH

Drugs

Neurologic

Carcinoid Syndrome

Metronidazole

Bromocriptine

Anxiety

Mastocytosis

Ketoconazole

Tamoxifen

Migraine

Pheochromocytoma

Chlorpropamide

Nicotinic acid

Parkinson's Disease

Medullary thyroid cancer

Cephalosporins

Opiates

Spinal cord lesions

Panreatic cancer

Calcium blockers

Brain tumors

Renal cell cancer

Cholinergic drugs

Emotional blushing

Food Additives

Eating

Miscellaneous

Monosodium glutamate

Hot beverages

Sodium nitrate

Auriculotemporal flushing

Sulfites

Gustatory flushing Dumping Syndrome

Medullary Carcinoma of the Thyroid

Medullary carcinoma of the thyroid is a malignant tumor that originates from the parafollicular or thyroid C cells. These tumor cells typically produce an early biochemical signal (hypersecretion of calcitonin).36 This cancer can occur sporadically, but many times is inherited in an autosomal dominant way as a part of the syndrome multiple endocrine neoplasia type 2.37 Other bioactive substances that can be secreted by medullary carcinomas and may be responsible for the vasomotor symptoms include corticotropin, corticotropin-releasing hormone, and prostaglandins.30

symptoms when combined with alcohol.38 Others, such as calcium channel blockers, have a direct impact on the vessels.39 On the other hand, tamoxifen or bromocriptine produce hot flashes by triggering different mediators. Vasodilators (nitroglycerin, prostaglandins), calcium channel blockers, nicotinic acid, opiates (i.e., morphine), amyl nitrite, cholinergic drugs, bromocriptine, thyrotropin-releasing hormone, tamoxifen, clomiphene, triamcinolone, and cyclosporine are the most commonly cited medications. Food Additives and Eating Habits

Neurologic Flushing

Anxiety or emotional blushing, migraines, Parkinson’s disease, spinal cord lesions (autonomic hyporeflexia), and brain tumors are associated with hot flashes. Alcohol–Medication Interaction

356

Alcohol and numerous drugs are associated with vasomotor symptoms. In some cases the drug is not the real vasoactive agent, but rather a metabolite or another mediator triggered by the drug ingested. Some drugs will only create vasomotor

Monosodium glutamate, sodium nitrite, and sulfites are the most common food additives associated with hot flashes. Hot beverages, auriculotemporal flushing (cheese, chocolate, lemon, highly spicy foods), gustatory flushing (chewing chili pepper), and dumping syndrome (seen in patients after gastric surgery and triggered by a meal, hot fluid, or hypertonic glucose) are examples of symptoms associated with ingesting food or beverage. The main limitation in our ability to assess the value of a treatment for hot flashes is the lack of an objective measure. This complex task is due to the current inability to reliably

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Chapter 24 Menopause identify when a hot flash has taken place. The main objective method used today, sternal skin conductance monitoring, has some limitations, but the main weakness is the failure of sternal skin conductance to provide any information on duration, intensity, and interference with patient activities. Therefore, all data are derived from imperfect methods.28

Morbidity Associated with Hot Flashes Sleep Disturbances

The relationship between hot flashes and interference with sleep is controversial. Multiple epidemiologic studies have shown an association between awakening and arousal from sleep and hot flashes in menopausal women.40–42 This has led to the commonly held conception that hot flashes and night sweats cause awakening, which subsequently creates fatigue, and possibly decreases performance and quality of life.43 The flaw in these studies is that these hypotheses have not been properly tested in controlled laboratory investigations. Also, neither of these investigations screened out patients with apnea and other sleep disturbances that are also prevalent in menopause and may represent a confounder factor. Recently, Freedman and Roehrs studied 31 patients between ages 46 and 51 who were classified into three groups: premenopausal asymptomatic (cycling), postmenopausal asymptomatic (asymptomatic), and postmenopausal symptomatic (symptomatic). They then assessed several outcome measures: sleep electroencephalogram recordings, sternal skin conductance to record hot flashes, multiple sleep latency tests to assess sleepiness, simple and divided attention performance tests, and sleep and fatigue questionnaires. There were no significant differences among the three groups on any sleep variable. Of the awakenings taking place within 2 minutes of a hot flash, 55.2% happened before the hot flash, 40% after the hot flash, and 5% simultaneously. Of arousals taking place within 2 minutes of a hot flash, 46.7% occurred before, 46.7% after, and 5.6% simultaneously. There were no significant group differences on any self-report measure or on any performance measure. They concluded that there is no evidence that hot flashes produce sleep disturbances in symptomatic postmenopausal women.44

Migraines There is sufficient observational data to suggest a link between hormones and migraines.45,46 However, the relationship between menopause and migraine is still being debated. Observational studies suggest that migraine worsens just before menopause and improves after cessation of menses in approximately two thirds of cases. Neri, in a sample of 556 postmenopausal patients, studied the prevalence and characteristics of headaches in this cohort and found that many of them had migraine with aura. Interestingly, women with prior migraine generally improved with the onset of spontaneous menopause. In contrast, women with bilateral oophorectomy usually experienced worsening of their migraines.47 More recently, a cross-sectional, community-based study of 1436 women using the 1988 International Headache Society Criteria showed the highest prevalence of migraines in the perimenopausal group (31%) and the lowest (7%) in the postmenopausal group.48

Urogenital Changes The lack of estrogen has been associated with a decrease in the moisture of the genital tissues. The persistent dryness of the vaginal mucosal surfaces may lead to symptoms of vaginitis, pruritus, dyspareunia, and even stenosis. Other symptoms that may be related to estrogen deprivation in the urogenital tissues are dysuria, urgency incontinence, and urinary frequency. It is unclear whether all these symptoms are related to the lack of estrogen or are part of the degenerative process of aging. It is postulated that changes in estrogen levels change the quality of the collagen content and the connective tissues in the urogenital area.49 More controversial are data suggesting that lack of estrogen increases the likelihood of menopausal women to experience recurrent urinary tract infections (UTIs). A randomized, placebocontrolled trial of vaginal estrogen in 93 postmenopausal women demonstrated that patients being treated could reduce their number of UTIs per year. This study observed 0.5 episodes of UTI in the treatment groups versus 5.9 episodes in the placebo group.50 On the other hand data from the Heart and Estrogen/ Progestin Replacement Study (HERS) showed that urinary tract infection frequency was higher in the group randomized to hormone treatment, although the difference was not statistically significant (odds ratio, 1.16; 95% CI, 0.99–1.37).51 However conflicting these results are, from the clinician’s point of view it seems prudent to attempt a trial of vaginal estrogen therapy to address several of these postmenopausal urogenital symptoms. It should be considered in the presence of a vaginal pH greater than 4.5. Like FSH, elevated vaginal pH appears to be a good predictor of estrogen status.52,53

LONG-TERM MORBIDITY ASSOCIATED WITH POSTMENOPAUSAL STATUS The two major long-term risks associated with menopause are osteoporosis and cardiovascular disease.

Osteoporosis Chapter 25 reviews osteoporosis in detail. In this section we discuss its relationship as a long-term risk factor in menopausal women. The demographic changes and longevity increase described at the beginning of this chapter, coupled with the fact that osteoporosis rises dramatically with age, makes osteoporosis a serious economic burden for healthcare systems in our society.54 The estimated total direct expenditures (hospitals and nursing homes) for osteoporotic and associated fractures was $17 billion in 2001 ($47 million each day).55 The National Osteoporosis Foundation estimates that 50% of white women will suffer at least one osteoporosis-related fracture in their remaining lifetime. At least 90% of hip and spine fractures among elderly women can be attributed to osteoporosis.56 These statistics are the result of an accelerated decline in bone mass after menopause. However, this decline begins at approximately age 35 when a disparity between bone formation and bone resorption begins to occur. After menopause there are two periods of net bone loss: an accelerated stage that begins with the onset of menopause (1 to 3 years) and continues for 5 to 8 years57 (STRAW 0, 1, and 2) and a prolonged, slower stage of bone loss that remains throughout STRAW 2. The initial accelerated phase may account for bone loss of up to 30%.58

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Section 3 Adult Reproductive Endocrinology The three most common osteoporotic related fractures are hip, vertebral, and wrist. The most common are vertebral fractures, accounting for 700,000 cases a year in the United States.55 These should be suspected in postmenopausal women with back pain, loss of height, and kyphosis. In one observational study of 7223 postmenopausal women over age 65, patients with radiographically detected vertebral fractures were found to have significantly more limited-activity days, whether they were symptomatic or not.59 These data should raise awareness for the clinician of the decreased quality of life that menopausal patients may experience even with asymptomatic fractures. The second most common fracture is hip fracture, accounting for 300,000 cases a year in the United States.55 These are without doubt the more serious consequence of osteoporosis in postmenopausal women. One in 5 women will die within 1 year after fracture, and 1 in 2 will have permanent loss of function.60 Lastly, distal forearm fractures occur in 250,000 patients a year in the United States.55 Only half of the patients who suffer these fractures recover full function of the arm in 6 months.61

Cardiovascular Disease

358

The American Heart Association has designated cardiovascular disease a “silent epidemic.” Despite the overall decline in the mortality rate due to cardiovascular disease in the United States, the absolute number of deaths due to cardiovascular disease is actually increasing.62 This is in part due to the demographic changes in our society described in the introduction of this chapter. Cardiovascular disease, which encompasses heart attacks and strokes, is responsible each year for more deaths than all other causes combined in postmenopausal women.62,63 The burden and threat of this disease during menopause is in part due to the discrepancy among the reality of the problem and the perception of its magnitude by both physicians and patients. Nothing exemplifies this better than a 1995 Gallup survey, which revealed that 4 out of 5 women ages 45 to 75 were unaware that cardiovascular disease was the first cause of death for their age group. Instead most of the women quoted cancer, specifically breast cancer, as their most probable cause of death. In reality this represents only 4% of the causes of death in this age group. The primary care physicians questioned did not do very well either; 32% of them did not know that heart disease was the main cause of death in this age group of women.64 The incidence of cardiovascular disease and particularly myocardial infarction dramatically increases after menopause and approximates the mortality of this entity in men.65,66 Furthermore, bilateral oophorectomy or premature ovarian failure increases the risk of cardiovascular disease beyond that of natural menopause.67 Despite this seemingly logical association between estrogen cardioprotection and other coherent data from observational studies, the Women’s Health Initiative (WHI) group of trials and the HERS have found no role for estrogen as a primary or secondary prevention for cardiovascular disease in postmenopausal women. Very sound evidence from epidemiologic studies and clinical research make evident that the best tools are preventive measures and lifestyle habit modifications: smoking cessation, blood pressure control, lowering cholesterol, and promoting exercise.

MEDICAL TREATMENT OF MENOPAUSE The results of the Women’s Health Initiative study (WHI) have altered the principles of medical practice in menopausal women. We have changed from the concept of prevention of chronic diseases encompassed in the term hormone replacement therapy to the concept of hormone therapy. Thus, the U.S. Food and Drug Administration (FDA) and professional organizations such as the American College of Obstetricians and Gynecologists recommend the use of estrogen-containing medications to be restricted to the treatment of vasomotor and vaginal symptoms. They also affirm that the lowest effective dose be prescribed for the shortest duration of time.68–70

Principles of Hormone Therapy During the past three decades the clinical opinion on the use of estrogen during menopause has changed dramatically. Initially, estrogen was recommended as a short-term treatment for menopausal symptoms. Later, on the basis of observational studies, estrogen was given for long-term prevention of heart disease and an improved quality of life. The WHI hormone therapy trial, however, demonstrated that estrogen was not effective for the prevention of cardiovascular disease. Key Findings from the Women’s Health Initiative

The WHI was a group of clinical trials designed to examine the impact of hormone therapy on cardiovascular disease and breast cancer, the effect of low-fat diet on breast and colon cancer, and the impact of vitamin D in calcium supplementation on fractures and colon cancer.71 These trials included: ●

●

●

●

●

A randomized, controlled trial of 16,608 asymptomatic postmenopausal women ages 50 to 79 with a uterus comparing conjugated estrogens (0.625 mg) and a progestin, medroxyprogesterone (2.5 mg), daily versus placebo. The primary outcome measure of this trial was coronary heart disease and breast cancer. The secondary outcome measures were stroke, congestive heart failure, angina, peripheral vascular disease, coronary revascularization, pulmonary embolism, deep venous thrombosis, ovarian cancer, endometrial cancer, hip fractures, diabetes mellitus requiring therapy, death from any cause, and quality of life measures. A randomized, controlled trial on 10,739 asymptomatic postmenopausal women age 50 to 79 without a uterus (hysterectomized) comparing conjugated estrogens (0.625 mg/day) versus placebo. A dietary modification randomized, controlled trial of 48,837 postmenopausal women age 50 to 79 to either sustained lowfat (20%) or self-determined diet. The primary outcome measures were breast and colorectal cancer. The secondary outcome measures included stroke, congestive heart failure, angina, peripheral vascular disease, coronary revascularization, ovarian cancer, endometrial cancer, hip fractures, diabetes mellitus requiring therapy, and death from any cause. A calcium/vitamin D supplementation diet trial of 38,282 postmenopausal women where the primary outcome measure was hip fractures and the secondary outcome measures were death from any cause, breast cancer, and colon cancer. A cohort observation group of 93,676 postmenopausal patients.

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Chapter 24 Menopause Table 24-2 Women’s Health Initiative Findings: Outcomes Associated with Use of Combined Estrogen and Progestin and Estrogen Alone in Healthy Postmenopausal Women, Aged 50 to 79 Years Estrogen and Progestin

Outcome

RR (95% CI)

Estrogen*

Average Absolute Risk Difference†,‡

RR (95% CI)

Average Absolute Risk Difference†

Cardiovascular Deep venous thrombosis Pulmonary embolism Coronary heart disease Ischemic stroke

2.07 2.13 1.24 1.44

(1.49–2.87) (1.39–3.25) (1.00–1.54) (1.09–1.90)

13 8 7 8

1.47 1.34 0.91 1.39

(1.04–2.08) (0.87–2.06) (0.75–1.12) (1.10–1.77)

6 11 −5 12

Cancer Breast Colorectal Ovarian Endometrial

1.24 0.63 1.58 0.81

(1.02–1.50) (0.43–0.92) (0.77–3.24) (0.48–1.36)

8 −6 8 −4

0.77 (0.59–1.01) 1.08 (0.75–1.55) NYR N/A

−7 1 NYR N/A

Other Probable dementia§ All fractures Hip fractures

2.05 (1.21–3.48) 0.76 (0.69–0.83) 0.67 (0.47–0.96)

23 −44 −5

NYR 0.70 (0.63–0.79) 0.61 (0.41–0.91)

12 −56 −6

Mortality

0.98 (0.82–1.18)

−1

1.04 (0.88–1.22)

+3

Abbreviations: RR, relative risk compared to placebo; CI, confidence interval; N/A, not applicable (hysterectomized women); NYR, not yet reported. *Hysterectomized †Annual per 10,000 women ‡Compared to placebo group §Women aged 65 to 79

In May 2002 the clinical trial that aimed to assess the cardiovascular effects of estrogen and progestin therapy in postmenopausal women with intact uterus was halted. The Data and Safety Monitoring Board reported that the estrogen/progestin treatment group had an increased risk of cardiovascular disease, thromboembolism, and breast cancer after 5.2 years of followup.72 In 2004, after 6.8 years of follow-up, the estrogen-only trial was halted.73 In this clinical trial, estrogen-only treatment demonstrated an increase risk of strokes similar to the one found in the estrogen/progestin clinical trial previously halted. They also reported a lack of benefit on cardiovascular disease incidents and a probable increase in dementia. The risks and benefits findings of the WHI are summarized in Table 24-2.74 The WHI findings should not be generalized to the whole menopausal population, but rather to the population studied and the specific treatment used in the trial. Some researchers argue that there might be a difference in the thromboembolic risk among the different estrogen compositions. It should be emphasized that the WHI trial did not intend to evaluate the effects of estrogen or estrogen/progestin on vasomotor symptoms; therefore, these results must be translated into the specific needs of our patients when they request relief for hot flashes or other postmenopausal symptoms. It is also critical to point out that the rate of serious adverse events in patients treated with estrogen therapy is low, calculated to be 2 out of 1000 women treated per year.75 Healthcare providers and patients must balance the benefits of estrogen treatment versus the risk for adverse events. Today, more than ever, the concept of individualized menopausal care should be applied in the clinical setting. The WHI hormone trial is the first randomized, controlled trial that demonstrates that estrogen actually decreases the risk of fractures in a low-risk population. However, when all the

risks and benefits are weighted, it can be concluded in this study that estrogens are not indicated as a preventive measure in postmenopausal women and the potential harm outweighs the potential benefit. Thus, at the present time, use of estrogen should be limited to the treatment of symptomatic menopausal women for the shortest possible time at the lowest dose. Key Findings of the Heart and Estrogen/Progestin Replacement Study

Whereas the WHI aimed to test the hypothesis that hormone therapy prevented cardiovascular disease in healthy postmenopausal women (primary prevention), the Heart and Estrogen/ Progestin Replacement Study (HERS) intended to evaluate whether hormone therapy decreased the risk of coronary heart disease in postmenopausal women with established coronary disease. In this randomized trial, all the 2763 postmenopausal women had uterus and were allocated to either placebo (n = 1383) or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily (n = 1380).76,77 The primary outcome measures were nonfatal myocardial infarction and death from coronary heart disease. The results of the HERS trial have been reported in two publications: HERS and HERS II. The HERS report is the result of randomized, blinded, placebo-controlled trial for 4.1 years; the HERS II reflects the unblinded follow-up for 2.7 more years.76,77 Both of the studies demonstrated that in patients with established heart disease, the use of estrogen and progestin does not prevent additional cardiovascular events. There were no differences in the primary or secondary outcomes of patients in the placebo or the treatment group. The conclusion of HERS and HERS II is that postmenopausal hormone therapy should not be recommended for the purpose of reducing the risk of cardiovascular events. Table 24-3 shows a comparison between the WHI and HERS trials.

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Section 3 Adult Reproductive Endocrinology Table 24-3 Comparison of Findings of the Women’s Health Initiative Study (WHI) and the Heart and Estrogen/Progestin Replacement Study (HERS) WHI-Cardiac Heart Disease by Year of Follow-Up

HERS-Risk of Cardiac Events

Estrogen-Progestin (n=8000)

Placebo

Hazard Ratio & Confidence Interval

Estrogen-Progestin (n=1383)

Placebo (n=1380)

Relative Hazard (Risk) & Confidence Interval

1

42 cases

23 cases

1.81 (1.09–3.01)

57 cases

38 cases

1.52 (1.01–2.29)

2

38

3

19

28

1.34 (0.82–2.18)

47

48

1.00 (0.67–1.49)

15

1.27 (0.64–2.50)

35

41

4

0.87 (0.55–1.37)

32

25

1.25 (0.74–2.12)

33

49

0.67 (0.43–1.04)

5

29

19

1.45 (0.81–2.59)

1.06 (0.69–1.62)

>6

28

37

0.70 (0.42–1.14)

0.98 (0.72–1.34)

Year

Table 24-4 Incidence of Invasive Breast Cancer in Relation to Recency of Use of Hormone Replacement Therapy HRT Use at Baseline

Cases/Population

Never users

2894/392,757

Current users

Relative Risk (95% FCI)* 1.00 (0.97–1.04)

3202/285,987

1.66 (1.60–1.72)

Last use 27 kg/m2) had a relative risk of anovulatory infertility of 3.1 compared to women closer to their ideal body weight (BMI 20–25 kg/m2). At the same time, women with a BMI lower than 17 kg/m2 had a relative risk of anovulatory infertility of 1.6. Although the relative risk of anovulation was highest in obese women, it was also significantly increased in underweight women as well.

Stress It is difficult to specifically assess the contribution of social stress to infertility. Several studies have clearly demonstrated that stress is associated with poorer outcomes with assisted reproductive technology (ART).

INITIAL EVALUATION OF THE INFERTILE COUPLE The initial evaluation is by far the most important interview the caregiver will ever have with the infertile couple for several reasons. First, as with any initial visit, it is the primary information gathering occurrence the caregiver will share with the patients. The first evaluation will help identify the specific causes of infertility and suggest the appropriate treatment. As previously stated, with proper evaluation and treatment, the majority of women will become pregnant, and proper categorization will assist in this greatly. Second, it serves as the beginning of a partnership between caregiver and the couple that will hopefully lead to conception. The first visit helps lay down the sense of understanding and trust necessary between physician and patients, especially in such an emotionally charged situation as infertility. This understanding is vital to overcome much of the misinformation that has been gained by the patients from friends, relatives, and the mass media. Third, the patients should understand from the initial counseling session that although they have presented asking for medical advice concerning their infertility, the eventual therapeutic decisions are solely theirs to make. In the age of in vitro fertilization/embryo transfer (IVF/ET), intracytoplasmic sperm injection (ICSI), ovum donation, and the other ARTs, there are medical solutions for nearly every cause of infertility or subfertility. The patients have to realize, however, that the ultimate decision concerning what therapies are personally acceptable to them lies only within their hands. They are in control of both the direction and the intensity of suggested therapy and should be counseled to such an extent starting at the first meeting. Last, this initial evaluation should lay down the guidelines of possibility to the patients. Not all therapies will work in all patients and not all patients will become pregnant regardless of the therapy. The couple should be given a concise outline of the possibilities of care and all of the information necessary to make an intelligent decision concerning their options. When the patients

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Section 6 Infertility and Recurrent Pregnancy Loss are allowed to have such an involvement in decision making, it allows them to more easily accept the failure of any individual therapy and helps them reach closure if success is never attained.

Treating the Infertile Couple A special emphasis must be placed on treatment of the patients as a couple and not as unique individuals. The path to fertility is most certainly a dual venture that the patients must travel together. It should be strongly encouraged that both partners are present at every visit whenever possible, especially the initial evaluation. By having both patients present, it is possible to more fully understand the general attitudes concerning their infertility and their reaction to each specific therapy. It is certainly easier to answer all of their questions when they are present together. It is also easier to evaluate the frustration level of each patient if the physician sees both of them together. Treatment failures compound the general sense of failure the couples already bear and can be identified and eased by seeing the patients jointly. Talking to the patients as a pair may help them more fully understand all of the intricacies and general risks of their care, and the physician can answer any questions either of them may have concerning their options, the physician’s recommendations, and their frustrations.

Primary Elements of the Initial Infertility Evaluation The initial evaluation consists of seven primary elements (Table 34-4). It is recommended that the entire initial evaluation should be completed before direct recommendations concerning treatment are suggested to the patients. Most patients will accept a temporary delay in their therapies while full evaluation of all aspects of their clinical state is accomplished far easier than they do frequent changes in their protocol interspersed with intermittent testing and analysis.

know the answers to, especially those about family history, (2) have collated the data from other physicians concerning testing already performed and other therapies attempted, and (3) be able to better understand the nature of the first evaluation prior to their arrival. There are several versions of preprinted questionnaires available either through the American Society for Reproductive Medicine (ASRM) or from many of the pharmaceutical companies that produce the medications used in ovulation induction. In the female partner, the relevant medical history concerning the causes and the nature of infertility covers a broad range of subjects.22,23 Attention to detail during this collection of data is imperative.

Demographics It is important to determine where the patient has lived. Extragenital Mycobacterium tuberculosis infections remain one of the most common causes of pelvic inflammatory disease in the third world.24–26 In areas where tuberculosis is an endemic disease, such as Vietnam and the Philippines, tuberculus epididymitis and salpingitis are common. If recent diagnostic testing has not been done, placement of an intermediate purified protein derivative (iPPD) should be performed and the results drive further investigation. Even in the United States, up to 2% to 5% of tubal disease can be tubercular in nature.27 With any suspicion of tubercular disease, further evaluation of the female genital tract, such as endometrial biopsy and evaluation of the fallopian tubes, should be performed.

Menstrual History Information should be obtained about the following subjects: ● ●

HISTORY The data collected as part of a careful medical history will often identify signs and symptoms of a specific disease or cause and focus the evaluation on the factors responsible for the infertility. Many of the answers to the questions that should be asked, especially those concerning medical and family history and any previous evaluations, are more fully answered when the patients are specifically prepared to answer them. Sending a questionnaire to the patients before their initial evaluation is strongly recommended. By filling out these data sheets before their initial visit, the patients will be forced to (1) find out the answers to the questions that they do not immediately

● ● ●

● ● ●

●

Table 34-4 Initial Infertility Evaluation History Physical examination

●

Semen analysis

●

onset of menses development of secondary sexual characteristics, such as the development of breasts (thelarche), pubic hair (pubarche) and axillary hair, and the prepubertal growth spurt (adrenarche). If any of these events have been delayed or were aberrant in nature or timing, different diagnostic questions must be raised. cycle length and characteristics onset and severity of dysmenorrhea timing of dysmenorrhea pain in relation to cycle (e.g.,the pain of endometriosis frequently decreases with the actual onset of menstrual bleeding) mitigating factors or agents that decrease the dysmenorrhea factors that make the dysmenorrhea worse onset and severity of dysuria, especially when it occurs with the onset of menses. Endometriotic lesions of the bladder can cause significant dysuria at the time of menses. onset and severity of dyschezia. Endometriotic lesions of the rectosigmoid colon can cause significant pain at the time of menses. The nature of the stool may also change markedly. with an increase in the frequency of bowel movements and changes in the nature of the stool.28,29 presence or absence of midcycle spotting presence or absence of premenstrual symptoms

Tests of hormonal status

510

Assessment of tubal patency

Gynecologic History

Tests of ovulatory status

Gynecologic questioning should include questions about the following subjects:

Assessment of luteinization

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Chapter 34 Female Infertility ● ●

●

●

●

previous sexually transmitted diseases previous use of an intrauterine device (IUD). The association of Actinomyces israelii infections and use of IUDs has been well-documented30,31 and further evaluation such as an endometrial biopsy or evaluation of the fallopian tubes should be considered. previous abnormal Pap smear. The risks factors for human papillomavirus infection of the cervix and subsequent cervical intraepithelial neoplasia are identical as those for a previously undiagnosed sexually transmitted disease. A previous evaluation for an abnormal Pap smear should increase the degree of suspicion of concomitant tubal disease. Additionally, the diagnostic and therapeutic surgeries associated with abnormal Pap smears, such as a cold-knife cauterization or loop electrosurgical excision procedure (LEEP), can lead to cervical scar formation and stenosis and therefore cervical factor infertility. previous instrumentations of the cervical os, such as a dilatation for curettage. Any instrumentation of the os can tear the collagenous fibers of the cervix and hence lead to cervical factor infertility. previous use of hormonal contraception, including duration of use and time of discontinuation

Surgical History Past surgery, its indications, and outcomes, especially abdominal surgery, can be important. Surgeries should be listed and considered regardless of the organ system involved or the seeming lack of anatomic association with reproduction. Developmental abnormalities of the reproductive tract can frequently be associated with those of other anatomic sites.

Family History Many common genetically determined diseases, such as congenital adrenal hyperplasia, can have a significant effect on ovulation and fecundity. Such family information would be helpful in determining the need for further provocative testing of the proband. Include questions about the following: ● ● ●

●

Obstetric History Although this portion is short in women with primary infertility, couples with secondary infertility should be carefully questioned about the following subjects: ●

●

●

●

●

● ●

gravity, parity, pregnancy outcomes, and any associated complications length of time necessary to conceive each pregnancy event. This becomes especially important if the female patient has had pregnancy events with partners other than the one she is currently being evaluated with. mode of delivery with each successful pregnancy event. One of the indications for cesarean delivery is malpresentation; a common cause of malpresentation can be a müllerian anomaly.32 mode of treatment of each unsuccessful pregnancy event. Was instrumentation of the uterus used during the care of these previous losses? Instrumentation even in the best hands can lead to the formation of adhesions and the likelihood of Asherman’s syndrome. partner history. Who was the partner involved in each of the previous pregnancy events? It cannot be assumed that the current partner, the one presenting for care, was involved in these previous pregnancies. duration of infertility results of any previous evaluation and treatment of infertility

Medical History

number and age of siblings whether any or all of her siblings have children whether any or all of her siblings had any difficulty in having children her mother’s age and age of her menopause and cause (i.e., was it a natural menopause or one surgically induced?) If surgically induced, what was the indication for this surgery? Did she have difficulty in conceiving, and if so what therapies were used to achieve success?

Questions should be raised about a familial history of any of the following problems in any population: ● ● ● ● ● ●

thyroid disease atherosclerotic cardiovascular disease cancer diabetes mellitus birth defects heritable diseases. The question must be investigated as to whether there is a significant genetic risk to any child that would potentially be created through medical intervention. Populations at specific risk for genetic disease should be appropriately screened at the time of the initial evaluation per recommendations made by the ASRM (Table 34-5). Table 34-5 Genetic Screening for Various Ethnic Groups Ethnic Group

Disorder

Screening Test

Ashkenazi Jews

Tay-Sachs disease Canavan disease

Decreased serum hexosaminidase A or molecular analysis DNA analysis to detect most common alleles

African Americans

Sickle cell anemia

Presence of sickle cell hemoglobin, confirmatory hemoglobin electrophoresis

Mediterranean populations

Beta-thalassemia

Mean corpuscular volume (MCV) < 80%, followed by hemoglobin

Southeast Asians Chinese

Alpha-thalassemia

Hemoglobin electrophoresis if mean corpuscular volume < 80%

Whites of European descent Ashkenazi Jews

Cystic fibrosis

DNA analysis of specified panel of 25 CFTR gene mutations

electrophoresis

Past or current medical conditions for which the patients have been under the care of a physician can be very important; the couple should be questioned about the following: ● ● ●

●

any prescription medications either is currently taking past medical admissions to the hospital history of common communicable diseases, such as rubella, rubeola, varicella, and mumps allergies

Adapted from American Society for Reproductive Medicine: Appendix A: Minimal genetic screening for gamete donors. In 2004 Compendium of ASRM practice committee and ethics committee reports. Fertil Steril 82:S22–S23, 2004.

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Several environmental exposures covered in this section are known to have adverse effects on fertility. This part of the assessment should include questions about the following: ●

●

● ● ●

occupation and the possibility of toxic exposures in the workplace use of tobacco. Smoking can have a marked negative effect on fecundity.33–35 Smoking cessation should be discussed within the context of any medical evaluation use of alcohol use of recreational or illicit drugs use of herbal preparations, vitamin supplements, or megavitamins

The utilization of herbal preparations in the United States has reached epidemic proportions. As much as 32% of the population as a whole use some type of herbal preparation purchased over the counter,36 but less than 8% will volunteer these substances when asked openly what medications they are taking.37 Many of these products have ingredients that contain active hormones, estrogen disrupters, vasoactive amines, or antiinflammatory ingredients, all of which can have a marked effect on both the menstrual cycle and fecundity. Not all of these products are contraindicated; their ingredients should be examined by the physician for possible effects on reproduction. There are many on-line (www.pda.com or www.NaturalData base.com) and print compendiums that outline the specific nature of the herbal and vitamin ingredients of these over-the-counter supplements.38,39

Nutritional History The nutritional status of the patient should be obtained. It should be determined if the patient is taking adequate amounts of folic acid, calcium, and vitamin D. Patients should be aware of the dangers of environmental contamination in the food chain, such as mercury contamination in certain types of fresh fish.

Sexual History Coital Frequency and Timing

512

It is important to be aware of the association of coital timing and the probability of successful conception (Fig. 34-1). Because activated sperm can last for up to 80 hours in the female reproductive tract,40,41 it has long been a general recommendation that intercourse occur at specific times during the menstrual cycle to ensure that at the time of expected ovulation there will be capacitated sperm available for fertilization. There can, however, be a significant diminution of both cycle and overall fecundity rates if coitus becomes too frequent.42,43 It is important to remember that coitus is usually a spontaneous expression of love between two individuals. If their love-making is placed on too specific a timed schedule, it can lead to significant performance anxiety, sexual dysfunction, and a worsening of the problem at hand. This will in turn greatly increase the already high frustration level borne by the couple. Consequently, unless there is marked male factor infertility present, there can be no clear medical justification for advising the avoidance of coitus at any time. It should be suggested to the patients that they make love at least twice a week from the cessation of menses.

Sexual Dysfunction

Whether sexual dysfunction is caused by a specific organic disease, the treatment of that disease, or the use of self-prescribed substances that interfere with sexual performance, this data should be gleaned at the outset of the evaluation. Many substances, such as many blood pressure medications, alcohol, and many recreational drugs, can lead to both erectile dysfunction in the male and desire phase sexual dysfunction in the female. Dyspareunia

Questions concerning painful intercourse should be specific to typify the type of dysfunction that this pain represents. Is the pain insertional in nature? A lack of lubrication at the initiation of coitus and the pain that it can engender does not necessarily represent the presence of an organic problem specific to the reproductive tract. Do the patients utilize an artificial lubricant on a regular basis? Although most commercially available vaginal lubricants are not spermicidal in their basic nature, their use can form an amalgam with the semen placed into the vagina during ejaculation. This may lead to a decrease in sperm motility and the number of sperm that enter the cervix. It should be suggested to the patients that alternative methods of increasing vaginal lubrication be used during times of high relative fecundity. Is there deep thrust dyspareunia? Deep thrust dyspareunia can be a very common gynecologic problem, but it is usually an episodic or intermittent complaint.44 The etiology of this symptom stems from the relative immobility of the pelvic organs and arises from rapid stretching of the uterosacral and cardinal ligaments due to the sudden movement of the cervical/uterine unit during coitus. It can also be caused by direct pressure on nodular lesions of endometriosis in the uterosacral ligaments or in the pouch of Douglas. Deep thrust dyspareunia should raise the suspicion of an organic disease, such as endometriosis or adenomyosis.45–48 Is there increased pain with orgasm? Orgasm is physiologic, typified by rhythmic contractions of the orgasmic platform and the uterus, created involuntarily by localized vasocongestion and myotonia.49 These contractions have a recorded rhythmicity of approximately 0.8 seconds, as the tension increment is released in the orgasmic platform, but accumulates slowly and more irregularly in the uterine corpus. The eventual strength of these

0.4 Probability of conception

Social History

0.3 0.2 0.1 20 -10

-8

-6

-4

-2

0

2

Day of intercourse Figure 34-1 Probability of conception according to day of coitus in relation to the day of basal body temperature (BBT) rise. Day 0 indicates day of BBT rise. (Data from From Royston JP: The probability of conception and day of timed intercourse. Biometrics 38:397, 1982.)

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Chapter 34 Female Infertility uterine contractions may be 4 to 5 times the baseline to peak intensity of a labor contraction.50 Localized production of prostaglandins and endoperoxidases in both endometriosis and adenomyosis can intensify these contractions and cause sensitization of C-afferent nerve fibers in the pelvis, thereby eliciting greater pain with each of these individual contractions.51 Marked pain with orgasm may therefore be a diagnostic suggestion of organic disease of the reproductive tract.52 Sexual Orientation

In the United States alone, an estimated 2.3 million women identify themselves as lesbians.53 Many of these women will present for medical therapy of this absolute male factor infertility, either alone or with a partner. Traditionally, many physicians have altered their history taking and diagnostic regimen in lesbian populations due to the seeming absence of significant risk factors for pelvic inflammatory disease and other sexually transmitted diseases. However, this is not always the case. Numerous studies have reported that 53% to 99% of women who identify themselves as lesbians have at some time had sex with men, and 25% to 30% of these women continue to have sex with men.54 Up to 25% of this population has been pregnant at one time, and more than 60% of those who had been pregnant report having one or more induced abortions.55 Consequently, whereas treatment of a lesbian patient or couple may lead to differing legal and ethical pathways, it is not an indication for an altered history taking or medical evaluation. Erroneous assumptions about the reproductive health and history of lesbians may place them at increased risk for delayed detection of risk factors and adverse outcomes. This in turn may decrease the success rates of any suggested therapy. Sexual orientation should be established at the initial evaluation, but the workup should remain standardized.

REVIEW OF SYSTEMS Several portions of the general review of systems must be stressed in the evaluation of the infertile female. Each is indicative of a specific hormonal or physiologic abnormality that can be closely associated with anovulation and hence with infertility or subfertility.

Visual Changes The most common presenting feature in space-occupying lesions of the pituitary, such as craniopharyngioma and macroadenomas, is visual impairment (70%).62 As the size of the pituitary increases, the relatively small area of the sella turcica forces the gland superiorly toward the optic chiasma. Compression of the optic nerve at the optic chiasma most commonly may cause bitemporal hemianopsia, or bilateral loss of the peripheral visual fields, although total blindness due to optic atrophy can occur rarely. Confrontational visual fields can be evaluated during the patient’s physical examination to evaluate any complaint of visual field abnormality.

Changes in Weight As in all of medicine, radical changes in weight in either direction may be indicative of an underlying organic problem and should be appropriately investigated.

Heat and Cold Intolerance Temperature intolerance is a common clinical feature of both hypothyroidism63 and hyperthyroidism.64 Both extremes of altered thyroxine secretion have been shown to cause menstrual irregularities and anovulation, as outlined in Chapter 19.

PHYSICAL EXAMINATION In the female partner, the physical examination may reveal pertinent medical facts that may directly affect efforts at reaching the appropriate diagnosis. Several portions of the general physical examination should be specifically stressed in the evaluation of the infertile female.

Weight and Body Mass Index The connection between increased BMI and anovulatory infertility has been discussed in this chapter under Causes of Infertility and Subfertility. Documentation of patient’s vital statistics are generally more comparable across large populations when determined as a BMI rather than a simple listing of absolute body weight and height. For example, 200 pounds is significantly different when compacted into patients of differing heights. Standardized charts for calculation of BMI are available from the ASRM.65

Headaches Patients should be questioned to find out both the frequency of self-medication with nonsteroidal anti-inflammatory drugs (NSAIDs) and the dosage taken. Headaches can be associated with pituitary lesions, such as craniopharyngiomas56,57 and prolactinomas.58,59 Prolactinomas are relatively common causes of anovulation. Each can cause hormonal derangements that lead to anovulation and infertility. Additionally, frequent headaches of any etiology may lead a patient to self-medicate with large doses of over-the-counter NSAIDs. It has been suggested that at high doses, these medications can interfere with the inflammatory processes of ovulation and implantation.60,61 Patients should also be advised to avoid taking these medications during their therapeutic protocols to prevent these abnormalities.

Thyroid Abnormalities As outlined elsewhere in this text, abnormalities of the thyroid gland can have a marked effect on the menstrual cycle and hence on fecundity. The thyroid gland is one of the largest of the endocrine glands and lies in the anterior neck, immediately below the prominence of the thyroid cartilage. The thyroid is made up of two distinct lobes joined by a thin band of connective tissue called the isthmus. The right lobe of the thyroid is normally significantly more vascular than the left and hence is often the larger of the two lobes.66 Consequently, the right lobe is more often enlarged in disorders associated with a diffuse increase in size.67 The gland itself can be examined in many manners. Many medical students are taught to examine the gland from behind

513

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Section 6 Infertility and Recurrent Pregnancy Loss the patient with the tips of the fingers, having the patient swallow to feel the gland in its entirety. It may be less stressful to the patient and more clinically accurate to stand directly in front of her and examine the gland directly with the tips of your dominant hand. In this manner, the tactile sense of the fingertips can be underscored by the visual references of the sternocleidomastoid muscles. It additionally allows the clinician to stand in full view of the patient and decreases the anxiety associated with the examination.

abnormal. What is abnormal to one examiner may not be to another. Standardized scoring systems such as the FerrimanGallwey72 scale and its modifications73 are useful to quantify the growth of hair. They remain limited by their subjective nature and the wide variability in score assignment and are therefore of little actual clinical use, but they can trigger a recognition of possible hyperandrogenism to help guide the direction of your laboratory examination of the patient. Acanthosis Nigricans

Breast Examination As the primary care physicians for the majority of American women, especially those of reproductive age, gynecologists have long been well-versed in the proper screening for and the evaluation of breast disease. Several aspects of the examination of the breast bear special mention in this case. Asymmetry of the Breasts

It is quite common to have some dyssymmetry in the breasts.68 This should, however, be a developmental finding and not an ongoing and progressive finding. Increasing dyssymmetry in the relative sizes of the breasts may be associated with hyperprolactinemia and organic diseases, such as varicella zoster, that in turn can lead to hyperprolactinemia.69 Most patients are aware of any relative inequality in the size and shape of their breasts, and any dyssymmetry should be directly questioned at the time of the examination. Galactorrhea

Galactorrhea is the active secretion of breast milk at a physiologically inappropriate time (i.e., a time other than during pregnancy or when the patient is actively breastfeeding a child). Usually white in color, breast milk can be differentiated from a pathologic discharge in several manners. First, secretions that have been hormonally induced usually arise from multiple ductal openings and are commonly found bilaterally. Pathologic discharges, on the other hand, are elicited from single ducts and are primarily unilateral in nature. Second, the discharge can be plated on a slide and examined and stained with Congo Red dye to detect the presence of fat globules.70 The specimen generally does not need to be sent for cytologic evaluation unless there is a suspicion of breast disease.

Abdomen The abdomen should be evaluated for evidence of an organic disease that can have a negative effect on fecundity. As an example, the violaceous striae associated with Cushing’s syndrome can be noted on the skin of the abdomen and over the hips.71 Finding these purplish streaks or marked central obesity would thereby suggest an evaluation for hypercortisolemia. Obesity itself should also trigger concern for the effects of BMI on fertility.

Skin Hirsutism

514

The overgrowth of terminal hair is succinctly discussed in Chapter 18. Briefly however, there are tremendous differences in the simple connotation of the term an overgrowth of hair. What is deemed abnormal by a patient may not be physiologically

Acanthosis nigricans is characterized by hyperpigmented, velvety plaques in body folds such as the neck and axilla, although other areas can be involved as well. The formation of these characteristic plaques is stimulated by hyperinsulinemia, often the consequence of obesity-associated insulin resistance. Because insulin resistance is associated with polycystic ovary syndrome, the finding of acanthosis nigricans is an indication for further investigation. The HAIR-AN syndrome is used to refer to patients with the clinical association of hyperandrogenism, insulin resistance, and acanthosis nigricans. Tattooing and Body Piercing

These forms of self-expression have become remarkably common over the past decade for both men and women. Once regarded as deviant or markedly rebellious behavior, such body decoration has grown to such popularity that it must now be considered a mainstream expression.74 More than 26% of female college students have a tattoo, and nearly 60% have pierced some part of their bodies.75 The vast popularity of such body decoration has led to an explosion of commercial tattoo and body piercing establishments. Legal regulation unfortunately remains almost completely lacking. Two aspects of this behavior that must be considered in the evaluation of the infertile female. First, tattooing and body piercing have the potential to cause infection. Most bacterial infections are rarely serious and can be treated with antibiotics, but sexually transmitted diseases, such as syphilis, have been reported.76 Potential viral infections can be far more serious. A direct causeand-effect relationship has associated these practices with the transmission of blood-borne viral pathogens, including hepatitis B virus (HBV), hepatitis C virus (HCV), HIV-1, and HIV-2.77–79 The vertical transmission of all of these diseases may have been frequently reported and can have disastrous effects on both the mother and the fetus. Because the fertility evaluation is being performed for the sole purpose of hopefully creating a fetus and hence placing it at risk for the possible vertical transmission of serious infection, any patient with a tattoo or body piercing must be screened appropriately. If the tattoo or body piercing occurred more than 1 year before the examination, convalescent titers for viral infection are sufficient.80 If less than 1 year has elapsed, repetition of such viral screening should be considered at that anniversary. Second, piercing of the breast, such as the placement of nipple rings, must certainly be considered a substantial stimulation to prolactin secretion. Otherwise healthy-appearing women with regular cyclic menses with nipple rings may induce galactorrhea and clinically significant hyperprolactinemia.81 Discovery of such body jewelry should trigger screening of prolactin secretion. Patients should also be appropriately

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Chapter 34 Female Infertility counseled concerning the potential hormonal effects and be left to decide for themselves about the possible removal of this body adornment.

Gynecologic Examination The primary purpose of the gynecologic examination is to identify abnormal reproductive anatomy. Abnormalities in the examination suggest specific organic disease states or structural anomalies that can have marked effects on fecundity. These, in turn, focus the evaluation and direct further investigation into the causes of the patient’s complaint. Important abnormalities readily identifiable by gynecologic examination are discussed here. Clitorimegaly

In the nonerect state, the clitoris is generally 0.5 to 1.5 cm in length and partially covered by a prepuce or hood of skin. Although no consistent standard exists for clitorimegaly, it can be liberally defined as length greater than 20 mm or width greater than 10 mm. Developmental endogenous or exogenous abnormalities of the clitoris are rare. In most cases, enlargement is due to inappropriate androgen exposure. Identification of abnormal breadth and length of the clitoris will require questions about the possible ingestion of exogenous androgens or possible exposure in utero to androgenic substances taken by the patient’s mother, and will certainly tailor part of the endocrinologic screening. When clitorimegaly appears to be present on examination of the external genitalia, the clitoris must be measured. When a paper tape is used, it should be placed underneath the clitoral hood to measure its entire length, and extreme care must be used to avoid making a paper cut to the organ. A less irritating manner of measuring the length is to wet a cotton tip swab, gently place it underneath the clitoral hood, and slip it to the base of the organ. A finger can demarcate the clitoral tip; then the cotton tip swab can be held against the paper tape to define the clitoral length. Cervix Abnormalities of the Cervical Os

The traditional descriptions of the cervical os as being either parous or nulliparous are at best imprecise. There is such variation to the diameter and caliber of cervical ostia across populations that there is often no obvious distinction between individual women in these groups. The most common cervical abnormality associated with decreased fertility is cervical stenosis. Cervical stenosis decreases fertility apparently by diminishing the mucus bridge from the vagina to the endocervix necessary for sperm transport. The earliest therapeutic approaches used in the past for this problem include cervical dilation and intraperitoneal insemination. Intrauterine insemination (IUI) using washed sperm has proven to be an excellent treatment for this condition.

In the not too distant past, cervical malformations were commonly linked to in utero exposure to diethylstilbestrol (DES), which was frequently prescribed to pregnant women from the 1940s through the early 1970s to prevent miscarriages. Although in utero DES exposure is unlikely in younger women, an woman in her midthirties or older found to have a cervical malformation should be questioned about possible in utero exposure. Cervical Motion Tenderness

Cervical motion tenderness is sometimes elicited by gentle lateral movement of the cervix. Gently moving the cervix toward the patient’s right can cause the structures of the right adnexae to be stretched in the contralateral direction. An opposite movement will stretch the other adnexae. Cervical motion tenderness can be associated with either active or antecedent pelvic infection. Its physiologic basis is that movement of the cervix causes movement of the adnexae as well. If the fallopian tubes or ovaries are actively infected, this will cause sliding of inflamed parietal peritoneum on another surface, thereby causing the internal equivalent of rebound tenderness. Consequently if cervical motion during the bimanual examination elicits a painful response, an active pelvic infection should be suspected. However, other causes of cervical motion tenderness should also be considered. An important cause of cervical motion tenderness is pelvic adhesions. The adnexa can be adhered to surrounding pelvic structures as a result of previous infection or endometriosis. Even in the absence of adhesions, endometriosis can cause cervical motion tenderness when it involves pelvic structures attached to the cervix, including the vaginal apex, the uterosacral ligaments and cardinal ligaments, and the inferior portion of the broad ligaments. Abnormal Deflection of the Cervix

When the vaginal speculum is opened and the cervix visualized, it should be pointing directly down the middle of the vagina. This is because the normal structures attached bilaterally to the uterus and cervix are equal in size. Lateral deflection of the cervix can indicate that the supporting structures are shorter on one side than those on the other side. Anatomic inequalities such as this include (1) developmental abnormality such as müllerian anomaly, (2) iatrogenic changes such as surgical or obstetrical trauma, or (3) postinflammatory changes such as the damage caused by pelvic infections or endometriosis. Marked cervical deflection should increase the suspicion of organic disease and can be an indication for further radiologic or surgical evaluation of the reproductive tract. Anterior or posterior deflection of the cervix, in contrast to lateral deflection, is usually a normal variant. Anteflexion of the uterus causes posterior cervix deflection and vice versa. Contrary to popular opinion, retroflexion of the uterus is not associated with decreased fecundity. Rather, it is a normal variant found in approximately one third of women.

Abnormalities of the Ectocervix

Uterus and Adnexa Uterine Abnormalities

Malformations of the cervix can include transverse ridges, cervical collars, hoods, coxcombs, pseudopolyps, and cervical hypoplasia and agenesis.82 These uncommon malformations can be idiopathic developmental imperfections or the results of obstetrical trauma and surgery.

The bimanual examination can often identify uterine abnormalities associated with decreased fecundity, including leiomyomata, adenomyosis, or müllerian anomalies (Table 34-6). Findings such as uterine enlargement, irregularity, or tenderness are often indications for further evaluation.

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Section 6 Infertility and Recurrent Pregnancy Loss Table 34-6 Abnormalities that Can be Suspected Based on Bimanual Pelvic Examination

Table 34-7 Elements of the Infertility Evaluation Tests

Uterus

Leiomyomata Adenomyosis Müllerian anomalies Pregnancy

Fallopian tubes

Hydrosalpinx Pyosalpinx Ectopic pregnancy Hydatid cyst of Morgagni Tubo-ovarian abscess Tubo-ovarian complex Pelvic adhesive disease

Ovary

Corpus luteum Graafian follicle Residual follicular cyst Endometrioma Sclerocystic ovaries Tubo-ovarian abscess Tubo-ovarian complex

Adnexal Abnormalities

Any adnexal abnormality found during the pelvic examination should be further evaluated. The most common abnormalities found on bimanual examination that can affect fertility are listed in Table 34-6. Specific discussion of these entities can be found elsewhere in the text.

DIAGNOSTIC TESTING After the completion of a thorough medical history and physical examination, further testing is required and can be subdivided into two categories: (1) preconception screening that should be performed on every woman considering pregnancy and (2) the basic infertility evaluation that will further direct evaluation and treatment. Based on these tests or specific findings in the medical history or the physical examination, it may be necessary to perform more directed and invasive diagnostic procedures as well. An outline of such testing is listed in Table 34-7.

Preconception Screening Papanicolaou Smear

The American College of Obstetricians and Gynecologists, (ACOG) recommendations for cervical cytology screening should be followed.83 If a recent evaluation has not occurred, a Pap smear should be obtained and the results documented. If the length of infertility treatment should be spread over a period longer than a year or if the patients return for further treatment after an intervening pregnancy, the clinician can maintain a current record of Pap smear screening. Blood Type and Screen

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Blood typing and determination of Rh factor is required in all female patients considering pregnancy, if not already known.84 In Rh-negative women, antibody testing and appropriate typing of her partner are also recommended to prevent significant alloimmunization in any potential fetus created through these therapies.

Preconception Screening

Current Pap smear ABO, Rh factor typing Immunity Rubella titer Varicella convalescent titers (patients with uncertain history of infection) Appropriate genetic screening (see Table 34-5) Sexually transmitted diseases All patients VDRL/RPR Hepatitis B surface antigen (HBsAg) Chlamydia (RNA/DNA-based testing) High-risk patients Hepatitis C antibody (HCA) Gonorrhea HIV 1 and 2 Donor gametes or ART patients All tests above, plus: Cytomegalovirus (CMV) Human T-cell lymphocyte virus (HTLV) Types I and II

Infertility Testing

Semen analysis Ovulatory function Thyrotropin Prolactin Basal body temperature chart Midluteal serum progesterone Urinary LH surge detection Androgen excess Total testosterone DHEAS 17-OH progesterone, if indicated Suspicion of Cushing’s syndrome 24-hour urine for free cortisol Advanced maternal age Day 3 FSH Clomiphene citrate challenge test (CCCT) Imaging studies Vaginal ultrasonography Sonohysterography Hysterosalpingography Diagnostic laparoscopy

Rubella and Varicella Immunity

Determination of a rubella titer is recommended in all patients of childbearing age with no evidence of immunity.85,86 If a woman is found to lack immunity to rubella, she can be immunized on discovery. To date there has been no case of reported congenital rubella syndrome directly attributable to vaccination with the attenuated live virus. Regardless, the current recommendations of the CDC are for a delay of 3 months before conception due to the theoretical risk of the immunization.86 Varicella infection is uncommon in pregnancy, occurring in 0.4 to 0.7 per 1000 patients.87,88 Due to such a low incidence, recommendations for screening for varicella immunity are controversial. Universal screening has been shown not to be costeffective.89 On the other hand, the CDC considers nonpregnant women of childbearing age as a high-risk group and recommends their vaccination.90 Considering both of these factors, it is reasonable to screen infertile women actively attempting conception who have an uncertain history of past varicella infection and subsequently

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Chapter 34 Female Infertility vaccinate the seronegative among them. As with rubella vaccination, the chance of congenital varicella syndrome from inappropriate vaccination during pregnancy is very low.91 A 3-month delay of conception is also recommended after varicella immunization. Genetic Screening

The ACOG, the ASRM, and the American College of Medical Genetics recommend that appropriate genetic screening be offered to couples as part of preconception counseling.92–94 Many of these recommendations have been made in very specific populations in which carrier status for autosomal recessive disease is more common. It seems reasonable, however, to broaden this screening to autosomal recessive diseases that have higher incidences in whatever ethnic group you are evaluating. Table 34-5 lists the recommended genetic screens for some of the more common ethnic groups encountered in the United States. Testing can be performed either concurrently or sequentially, depending on the mechanism of insurance reimbursement and patient preference. Concurrent testing screens both partners simultaneously. Sequential testing screens one partner, and the second is tested only if the first is identified as a carrier. Either methodology is reasonable in most cases. Sexually Transmitted Diseases

Screening of women for sexually transmitted diseases is an important part of the infertility evaluation to detect current infections and determine women at increased risk of having pelvic adhesions related to previous infections, even in women determined to be at low risk based on history and physical examination. If donor gametes or any of the ARTs are being considered, screening of both partners is required.95 The current recommendations of the CDC for screening of pregnant women can be used as a guide to screening the infertile female.96 These recommendations call for screening all pregnant women for syphilis (Venereal Disease Research Laboratory [VDRL] or the rapid plasma reagent [RPR]), hepatitis B (hepatitis B surface antigen [HbsAg]), and Chlamydia (either RNA- or DNA-based testing). Women at moderate or high risk for sexually transmitted diseases should also be screened for gonorrhea (either culture or DNA-based testing), hepatitis C (hepatitis C antibody) and HIV-1 and 2 (ELISA). Due to the current medicolegal environment, screening for HIV should be done on a voluntary basis after consent has been obtained. For couples considering the use of donor gametes or use of ART, the ASRM recommends thorough testing of both the man and the woman. Screening tests include those listed, with the addition of cytomegalovirus (CMV) antibody and human T-cell lymphocyte virus (HTLV) types I and II.80,97,98

INFERTILITY EVALUATION Semen Analysis The evaluation of the male member of the infertile couple is unusual in that it begins with a laboratory test rather than a physical examination. The semen analysis is the foundation of screening for male infertility problems. This test provides important information about both sperm quality and quantity but does not assess sperm function.

The semen sample is analyzed for volume, viscosity, pH and color of the ejaculate, sperm concentration, motility, morphology, forward progression of the sperm, and the presence of white or red blood cells suggestive of infection. These tests are usually performed manually in a specialized laboratory, although computerassisted semen analysis has also been used. Men with persistently abnormal semen analyses should be sent to a urologist with a special interest in infertility for further evaluation. The complete evaluation of the male is covered in Chapter 35.

Tubal and Peritoneal Factors Ultrasonography

An excellent adjunct to the physical examination is transvaginal ultrasonography (see Chapter 30). Skilled examination can elicit the complete anatomy of the cervix, the endometrium, the myometrium, the fallopian tubes, the ovaries, the adnexae and the pouch of Douglas.99,100 Appropriate consultation or referral to those fully trained in such evaluations, as outlined by the guidelines of the American Institute of Ultrasound in Medicine, is strongly recommended. Conditions diagnosed by ultrasound include uterine anomalies, hydrosalpinges, and endometriomas. Because these conditions might not be detectable on physical examination and are often treatable, transvaginal ultrasound is recommended by some infertility specialists before proceeding with specific treatment. Sonohysterography and Sonohysterosalpingography

Sonohysterography is an ultrasound-based test similar to hysterosalpingography (HSG) in that a fluid medium is instilled through the cervix to evaluate the reproductive anatomy. This technique has long been used for the delineation of subtle endometrial and intracavitary lesions, such as polyps, fibroids, and endometrial cancers. Sonohysterosalpingography is a ultrasonographic technique recently developed to evaluate tubal patency by the addition of special media and power Doppler imaging or three-dimensional sonography instrumentation.101,102 Until the accuracy of this procedure can be improved, it remains an experimental procedure. Hysterosalpingography

HSG is a radiographic evaluation that allows visualization of the inside of the uterus and tubes (see Chapter 29).103 Radiographic contrast dye, either water or oil based, is injected into the uterine cavity through the vagina and cervix. The dye fills the uterine cavity and spills into the abdominal cavity if the fallopian tubes are open. An HSG will usually reveal the presence of endometrial polyps, submucous fibroids, intrauterine adhesions (synechia), uterine and vaginal septa uterine cavity abnormalities, or the aftereffect of genital tuberculosis. Many of these problems are readily visible with transvaginal ultrasound as well. More importantly, HSG can determine whether the fallopian tubes are open or blocked and whether the blockage is located proximally, at the junction of the tube and the uterus, or distally, which usually manifests as a hydrosalpinx. If tubal ligation reversal is planned, HSG will demonstrate the point at which the tubes are blocked. In some cases, HSG will detect pelvic adhesions, although pelvic adhesions are often missed with this technique.

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Section 6 Infertility and Recurrent Pregnancy Loss

Diagnostic Laparoscopy

Laparoscopy is an important part of the diagnostic testing for many infertile women (see Chapter 44). It is the only way to accurately diagnose the extent of endometriosis and intraperitoneal adhesions. It is also an accurate way to accurately identify abnormalities of the uterus, fallopian tubes, and ovaries. Laparoscopy has the added advantage of being a therapeutic modality whenever endometriosis or pelvic adhesions are diagnosed. This simultaneous diagnosis and treatment adds little risk or expense to the procedure but has been well documented to improve pregnancy rates, even in mild cases. Laparoscopy has traditionally been a part of the basic female infertility evaluation. However, because of the cost and small but real risks of surgery, laparoscopy is not always performed before a trial of treatment for other causes of infertility, such as ovulatory dysfunction or male factor infertility. Most reproductive endocrinology and infertility specialists advocate doing laparoscopy in women at high risk of endometriosis or pelvic adhesions based on the results of the history and physical examination or at some time before using gonadotropins for superovulation.

Evaluation of Ovulation The only absolute proof of ovulation is conception. For practical purposes all other diagnostic tests are indirect evidence. Women who have regular menstrual cycles and have significant moliminal symptoms, such as breast tenderness, bloating, and dysmenorrhea, are most likely ovulatory. However, more accurate determination of ovulatory function is an important part of an infertility investigation. Basal Body Temperature Charts

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A basal body temperature (BBT) chart, the most traditional method for documenting ovulation, is based on the general effects of progesterone on core basal body temperature. For this test, the woman takes her temperature every morning and plots the results on graph paper. A sustained midcycle rise in temperature indicates that ovulation has probably occurred (Fig. 34-2). At rest, the BBT generally fluctuates between 97.0° and 98.0°F during the follicular phase of the menstrual cycle. Progesterone levels greater than 5 ng/mL raise the hypothalamic setpoint for basal temperature by approximately 0.6°F. Synthetic progestins, such as medroxyprogesterone acetate and norethindrone acetate, cause this same thermogenic effect. For greatest accuracy, the BBT needs to be a measurement of the basal temperature at rest before arising from bed in the morning.105 A digital thermometer is most commonly used, although an oral thermometer with a scale able to differentiate temperature to tenths of a degree will suffice. In most ovulatory women, a sustained rise in BBT is indicative of ovulation. This can occur anywhere between 1 to 5 days after the midcycle surge in luteinizing hormone (LH) and up to 4 full days after ovulation has already occurred.106 If care is not taken to minimize muscular activity before taking the temperature or the temperature rise is gradual, ovulation may

not be predicted until well after the oocyte has been released from the ovary. Classic studies on ovulation prediction and use of the BBT revealed that only 95% of biphasic cycles are ovulatory, and only 80% of monophasic cycles are actually anovulatory.107,108 This indicates a 5% false-positive rate and a 20% false-negative rate. The advantages of the BBT chart are that it is inexpensive and allows patients to become directly involved in their own care. Previous months’ data can be extrapolated in an effort to appropriately time coitus, which can be recorded on the same chart for retrospective evaluation. The disadvantage of BBTs is that they can be difficult to accurately interpret and cannot be used to prospectively predict the exact day of ovulation. The BBT remains a good method for many couples to understand their individual reproductive cycles early in the course of evaluation. As therapy progresses, they are often replaced with urinary LH detection kits or transvaginal ultrasonographic detection of preovulatory follicle growth. Serum Progesterone

Another method for documenting that ovulation has occurred is the measurement of serum progesterone levels. With the resolution of the corpus luteum from the previous menstrual cycle, serum progesterone levels remain below 1 ng/mL during most of the follicular phase. They rise during the late follicular phase to 1 to 2 ng/mL, an increase partially responsible for the change in pituitary sensitivity to gonadotropin-releasing hormone (GnRH) that creates the midcycle LH surge.109 After ovulation, progesterone levels rise steadily until they peak 7 to 8 days after ovulation. Any level of serum progesterone greater than 3 ng/mL provides reliable evidence that luteinization of the follicle, and hence ovulation, has occurred.110 A midluteal level of greater than 12 ng/mL is generally considered to be evidence of adequate ovulation and thus the absence of a luteal phase defect related to suboptimal progesterone levels. There are several ways to determine the appropriate time to measure midluteal progesterone levels. In the past, serum progesterone level was measured on day 21 of the menstrual cycle, based on the classic 28-day menstrual cycle.111 Unfortunately, normal menstrual cycles can often be much longer than this. The average cycle length of an individual patient can be used to determine the day likely to be 7 days before her next menses, which should correspond to the best date to measure midluteal progesterone. Basal Body Temperature Chart 99 Oral Temperature

Although the primary purpose of the hysterosalpingogram is not therapeutic, both oil- and water-soluble media have been shown to increase subsequent pregnancy rates by as much as fourfold.104

98.5 98 97.5 97 96.5 96 1

3

5

7

9

11 13 15 17 19 21 23 Day of Cycle

Figure 34-2

Basal body temperature (BBT) chart.

25

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Chapter 34 Female Infertility Probably the best way to time measurement of midluteal progesterone is with the use of a urinary LH kit. Assuming that ovulation will occur within 24 to 36 hours of the beginning of the LH surge detected in the urine, midluteal serum progesterone can best be measured 7 to 8 hours after detection of the surge. Although measurement of serum progesterone levels can be used as a documentation of ovulation and an adequate luteal phase, like the BBT, this test cannot be used to prospectively predict when ovulation will occur. Another concern is that, in some women, luteinization and progesterone production might occur without the actual release of the oocyte, a condition known as luteinized unruptured follicle syndrome.112,113 Many clinicians do not believe that this condition occurs often enough to be of clinical concern.

The endometrial biopsy is no longer recommended as part of the standard infertility evaluation. In the past, the endometrial biopsy was used as a test of luteinization and ovulation based on the known effects of progesterone secretion on the endometrium, much like a luteal phase serum progesterone level.120 Although painful and costly, this office test was once considered the gold standard for the diagnosis of luteal phase deficiency.111 However, a large multicenter study showed convincingly that out-of-phase biopsy does not discriminate between fertile and infertile women.121 Although not a standard part of the modern infertility evaluation, the endometrial biopsy remains a vital research technique in the study of the ultrastructure of the endometrium and its receptivity to embryonic implantation.

Urinary LH Measurements

Evaluating Hormonal Causes of Ovulation Dysfunction

The midcycle LH surge is the harbinger of the coming ovulation. For this reason, detection of a midcycle LH rise in the urine can predict ovulation before it happens. There are several nonprescription products available designed specifically to detect the LH surge in urine. They are simple colorimetric tests designed to change color when the urinary LH concentration exceeds a specific threshold. This threshold is specifically designed to be exceeded only at levels associated with the midcycle LH surge. To consistently detect the timing of LH surge, testing must be performed daily, generally starting 2 to 3 days before the expected day of ovulation. Assuming the standard 28-day cycle, testing should therefore begin around cycle day 12. Because the LH surge is a succinct event, generally lasting only between 48 to 50 hours, in the majority of cycles testing will only be positive on 1 day. Occasionally it will remain positive for a second day, but because the purpose of the test is to determine the start of the surge, once it is detected, testing can be stopped. Because it is a colorimetric test based on an absolute concentration, test results will vary both by the time of the day they are taken and by the patient’s general volume of fluid intake. Patients should be advised not to limit their fluid intake, just to limit it in the time immediately before the time they intend to perform the test. The first urine of the day should not be used for this test. Due to many factors, women in the northern hemisphere generally start their LH surge early in the morning. Because it takes several hours for LH to subsequently appear in the urine, the best results correlate with testing done in the late afternoon or early evening (1600 to 2200 hours).114,115 Testing twice a day will greatly decrease false-negative results but is not really necessary if testing is done regularly and at a standardized time. Ovulation will generally follow an afternoon or early evening urinary detection of LH within 14 to 26 hours.116 Consequently, if these tests are being used to time coitus or an IUI, the day after the first positive test will have the highest success rate.117 Although the accuracy of many of these ovulation predictor kits can vary, the most accurate kits predict ovulation within the next 24 to 48 hours with 90% accuracy.116,118,119 Most kits are comparatively easy to read, noninvasive, and relatively inexpensive, generally costing around $30 to $35/month. The disadvantage is that accurately reading them can be difficult for some patients.

Endometrial Biopsy

Thyrotropin

Hypothyroidism, a relatively common problem in women, can present as ovulation dysfunction with few other symptoms. The simplest screening test for hypothyroidism is the measurement of thyrotropin. It is reflective of all feedback to the central nervous system and is an excellent direct measure of thyroid health. Consequently, a thyrotropin level should be drawn at the initial evaluation. When the thyrotropin is elevated, this is suggestive of hypothyroidism and should be followed with measurement of free T4 or free thyroxine index.122 When thyrotropin is abnormally low, it can be a reflection of hyperthyroidism. Further testing is required to verify this diagnosis. Prolactin

Hyperprolactinemia can cause menstrual disruption, oligomenorrhea, amenorrhea, and consequently infertility.123,124 Hyperprolactinemia is another relatively common clinical entity and can be caused by a myriad of pathologic processes. Prolactin-secreting adenomas are the most common pituitary tumor in women.125 There has been some concern in the past that prolactin evaluation after a breast examination might lead to spurious elevation since breast or nipple stimulation can markedly increase serum prolactin levels during pregnancy.126 In some patients, breast augmentation can increase serum prolactin concentrations.127 However, in the nonpregnant patient, routine breast examination does not acutely alter serum prolactin levels.128 Consequently, prolactin measurements can be drawn immediately after the initial infertility evaluation with little fear of spurious elevation. It should also be remembered that thyrotropin-releasing hormone (TRH) is a potent prolactin-stimulating substance.129 Because TRH as well as thyrotropin is elevated in hypothyroid states, prolactin secretion will also be elevated in such circumstances. To avoid confusion, thyrotropin and prolactin levels should be drawn together and under the specifications outlined here.

Cervical Factor Cervical factor accounts for approximately 5% of all clinical referrals for infertility.19 This is not surprising because the narrow cervix is the site where the greatest reduction in the number of sperm allowed to progress further into the female reproductive tract occurs. Of the 40 to 100 million sperm contained in an

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Section 6 Infertility and Recurrent Pregnancy Loss average ejaculate, only a small percentage manages to enter the uterus and proceed to the point of fertilization in the tubal ampulla. The ability of adequate number of sperm to traverse the cervix is dependent on both the diameter of the cervical os and the quantity and quality of the cervical mucus. Postcoital Test

Perhaps one of the oldest diagnostic tests for infertility is the postcoital test, first described by J. Marion Simms in 1866.130 This test for cervical factor infertility evaluates the amount and quality of cervical mucus and is usually performed 2 to 12 hours after coitus immediately before ovulation. Appropriate timing is assumed to be 24 hours after the urinary detection of an LH surge or 24 hours after intramuscular administration of human chorionic gonadotropin to induce ovulation. Performing the postcoital test either too early or too late can result in spuriously poor results. To perform a postcoital test, a vaginal speculum is placed and cervical mucus is obtained using forceps or an 18-gauge angiocatheter attached to a syringe. The mucus is evaluated for consistency, ferning, and stretchiness (spinnbarkeit) and is microscopically evaluated for number of motile sperm and cellularity. The postcoital test is no longer considered to be an important part of the infertility evaluation. One reason is that the sperm count is the only factor evaluated with a postcoital test that has been found to be predictive of pregnancy.130,131 Another reason for the fall from favor of the postcoital test is that the results rarely alter treatment decisions. If the postcoital test is repeatedly abnormal, the patient is treated with IUI, the most effective treatment for cervical factor fertility. If the postcoital test is normal, most patients are still treated with IUI, because it is also an effective treatment for unexplained infertility and improves pregnancy rates over other forms of insemination regardless of the cause of infertility.132

Androgen Excess

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The signs and symptoms of hyperandrogenism can be elicited during the initial history and physical examination. When androgen excess is suspected, the patient should be screened to exclude ovarian or adrenal tumors by measuring serum androgens. Although both of these organs produce a range of androgens, tumors should be suspected if there is a de novo or rapid evolution of clinical hyperandrogenism rather than by any particular serum androgen level. Imaging studies for androgen tumors include transvaginal ultrasonography and computed tomography or magnetic resonance imaging of the adrenals. Elevated serum testosterone or dehydroepiandrosterone sulfate is often due to polycystic ovary syndrome (see Chapter 15). Some clinicians suggest that free testosterone might be a better diagnostic measurement of hyperandrogenicity than total testosterone.133 This is because the overwhelming majority of testosterone is bound to either sex-hormone binding globulin or albumin, and the androgenic effects of testosterone are created solely by the remaining 1% free testosterone. Measuring free testosterone is not necessary because there is an excellent direct correlation between total and free testosterone levels.134 Patients with elevated total testosterone will uniformly have elevated free testosterone as well.

Nonclassic congenital adrenal hyperplasia should be considered in women with hyperandrogenism and a significant family history of subfertility or infertility. In non-Jewish white populations, 1% to 5% of hyperandrogenic women are deficient in the activity of adrenal enzymes necessary to produce cortisol, most commonly 21-hydroxylase.135 The disorder is genetic and transmitted as an autosomal recessive trait. The best screening test for nonclassic congenital adrenal hyperplasia remains measurement of 17OHprogesterone.136

The Evaluation of Ovarian Reserve The age-related decline in fertility is primarily due to the relentless and progressive diminution of oocyte quality. Not only do the number of remaining ovarian follicles decline with age, those remaining become progressively less sensitive to the gonadotropin stimulation necessary for their maturation and ovulation. There consequently comes a time in every female’s reproductive life when it becomes exceedingly difficult to achieve a pregnancy with her own oocytes. The past two decades have seen remarkable progress in the study of the mechanisms of reproductive aging. All of these studies have attempted to generally describe the relative size and quality of the remaining ovarian pool. Two of them deserve mention here. Day 3 FSH

As the quality of the remaining oocyte pool decreases, the amount of follicle-stimulating hormone (FSH) secreted by the pituitary can be expected to progressively increase to drive the failing ovary harder. An early follicular, or basal, FSH drawn on cycle day 3 can have predictive value on the possibility of fertility.137–139 When basal FSH levels are elevated, especially above 10 to 15 IU/L, success with even the most provocative therapies, including in vitro fertilization, is greatly diminished.140 Clomiphene Citrate Challenge Test

The clomiphene citrate challenge test (CCCT) is a provocative examination of endocrine dynamics that is an even more sensitive test of ovarian reserve than basal FSH measurements.141 In this test a basal FSH level is measured on day 3 of the cycle. The patient is then given clomiphene citrate, 100 mg daily on days 5 to 9. The FSH level is again measured on cycle day 10. This test is considered abnormal if either day 3 or day 10 FSH levels are greater than 10 to 15 IU/L, depending on the laboratory. The CCCT is based on the two negative feedback mechanisms for the secretion of FSH from the ovary to the central nervous system: estrogen and inhibin B. When clomiphene citrate is given to women younger than age 35, it generally induces a transient increase in gonadotropin levels, with LH rising relatively more than FSH. This is due to the inhibitory effect of the large amount of inhibin B secreted by the granulosa cells of the developing follicles.142 When clomiphene citrate is given to a woman older than age 35 or one with diminishing ovarian reserve, the smaller follicular cohort results in significantly less feedback inhibition on FSH secretion.143 In this case elevations of either the basal and/or stimulated FSH levels are indicative of poor reproductive prognosis. Even with a normal basal FSH, a patient with an abnormally high day 10 value has a poorer prognosis.

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Chapter 34 Female Infertility Other Tests for Ovarian Reserve Other tests for ovarian reserve include serum inhibin, serum antimüllerian hormone, and antral follicle counts determined by ultrasonography. The serum tests are not generally available in most laboratories. The antral follicle count determines the number of follicles between 2 and 9 mm. There is a correlation with ART success and the number of antral follicles found at baseline ultrasound. Indications for Evaluation of Ovarian Reserve

Patients should undergo some evaluation of ovarian reserve in the following situations: ● ●

● ● ● ● ● ● ●

any patient older than age 35 any patient with a significant history of ovarian trauma due to surgery, infection, or endometriosis patients with unexplained infertility of any age smokers patients with a history of chemotherapy or radiation therapy patients with a significant history of autoimmune disease those with a family history of early menopause patients who have undergone a tubal ligation patients with a previous poor response to gonadotropin stimulation

TREATMENT The approach to treatment of the infertile couple is to first treat any abnormality discovered during the evaluation as specifically as possible. Previous and subsequent chapters in this textbook address the specific treatment of male factor infertility, tubal factors, endometriosis, cervical factors, ovulation induction, intrauterine insemination, and in vitro fertilization. If pregnancy is not achieved after normalization of any problems that have been diagnosed, the standard approach is to enhance fertility in a stepwise fashion, beginning with the least expensive, lowest technology treatment and progressing as needed to the most expensive, highest technology treatment that the couple desires until pregnancy is reached or the couple decides to no longer pursue the goal of conceiving a child. The most common alternatives are to adopt a child or remain childless. The physician’s role throughout this process is to assist the couple in making the best decisions they can about treatment, considering their medical conditions, emotional states, financial situation, and ultimate goals. When the couple achieves their initial goal of conceiving and giving birth to a healthy child, the physician’s work is complete. While the couple is in the midst of this often difficult endeavor or when they are unable to attain this goal, the physician’s attendance to their emotional needs or guidance in helping them reach an alternative goal becomes paramount.

Emotional Needs These emotional needs of the infertile couple should not be underestimated. By the time they arrive for their initial medical evaluation, most couples are frustrated by their failures to conceive, afraid that they will never be able to achieve success; many are self-recriminating. They often have a need to express their feelings of frustration to the physician and ancillary staff.

To meet the emotional needs of patients, it is important to acknowledge infertility as a medical and emotional struggle with a wide variety of stressors, including physical, financial, social, and marital.144 It is also important for clinicians and staff to be both sensitive and supportive to the couple. The importance and value of both members of the couple in the family and their involvement in treatment cannot be overemphasized. If there is evidence of significant emotional distress, the physician should be ready to offer help in terms of support groups or a professional infertility counselor. In addition to local resources, there are many national support organizations that can assist couples in satisfying their emotional needs, including RESOLVE (www.resolve.org), the American Fertility Association (www.theafa.org), and the American Society of Reproductive Medicine (ASRM)(www.asrm.org).

Adoption Even in the absence of a specific pathology, couples with more than a 3-year history of infertility have an increasingly poor prognosis. It is an important part of the role of the clinician to discuss the goals and options of the couples at regular intervals, especially with couples who fail to achieve success despite extensive diagnostic and therapeutic interventions. Many such couples can reach many of their goals through adoption. There are a wide range of choices in adoption. There are social agencies, private agencies, and agencies for international adoption. Social adoption is marked by a relatively low price tag, long lines and, if a healthy white child is desired, a very long wait. Older children, children of other or mixed lineage, and children with significant needs are easier to obtain. Private adoption is more specific, far more rapid, yet far more expensive. Additionally it is not legal in all states. There are numerous international organizations seeking adoptive parents for children in the third world. Clinics are usually able to direct patients toward any of these choices.

SUMMARY It must always be remembered that there are two primary goals of infertility therapy. The first is to achieve a pregnancy that leads to the delivery of a healthy infant. The second is to achieve emotional contentment regardless of conception. Infertility is a major life crisis to most patients. Its treatment involves significant temporal, economic, and emotional costs. When therapy fails, couples will go through the same standard phases of grief resolution they do when facing a death. The treating physician must continue to evaluate the couples and their needs to deal with their ongoing emotional distress. In all cases, the ultimate goal must be to assist them in returning to a happy and successful life, with or without childbearing.

PEARLS ●

●

The actual percentages by which individual factors are found to be the primary cause of infertility vary widely between studies. However, the most common primary diagnoses include male factor, tubal factor, endometriosis, ovulatory dysfunction, and cervical factor. Fecundity rates in women at age 20 approximate 20% per cycle. Subsequently, fertility rates decrease by 4% to 8% in

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women age 25 to 29, 15% to 19% lower by ages 30 to 34, 26% to 46% by ages 35 to 39, and 95% lower at ages 40 to 45. Proper history and physical examination is important to determine the cause of infertility. Initial screening includes evaluation for immunity to specific viruses, such as rubella and varicella, as well as screening for genetic disorders that may be specific to certain ethnic groups.

●

●

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Semen analysis, hysterosalpingography, and evaluation of ovulation with BBT or serum progesterone are the standard initial investigation for all infertility patients. An endometrial biopsy and the postcoital test are no longer considered basic tests for infertility. A test for ovarian reserve should be considered in all patients with idiopathic infertility, smokers, and patients over age 35.

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122. Spencer C, Eigen A, Shen D, et al: Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem 33:1391–1396, 1987. 123. Bohnet HG, Dahlen HG, Wutke W, Schneider HPG: Hyperprolactinemic anovulatory syndrome. J Clin Endocrinol Metab 42:132–143, 1976. 124. Moult PJA, Rees LH, Besser GM: Pulsatile gonadotropin secretion in hyperprolactinemic amenorrhoea and the response to bromocriptine therapy. Clin Endocrinol 16:153–162, 1982. 125. Yen SSC, Jaffe RB: Prolactin in human reproduction. In Yen SSC, Jaffe RB, Barbieri RL (eds). Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management, 4th ed. Philadelphia, WB Saunders, 1999, pp 273–274. 126. Hatjis CG, Morris M, Rose JC, et al: Oxytocin, vasopressin and prolactin responses associated with nipple stimulation. South Med J 82:193–196, 1989. 127. Hartmann BW, Laml T, Kirchengast S, et al: Hormonal breast augmentation: Prognostic relevance of insulin-like growth factor-I. Gynecol Endocrinol 12:123–127, 1998. 128. Hammond KR, Steinkampf MP, Boots LR, Blackwell RE: The effect of routine breast examination on serum prolactin levels. Fertil Steril 65:869–870, 1996. 129. Jacobs LS, Snyder PJ, Wilbur JF, et al: Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. J Clin Endocrinol Metab 33:966, 1971. 130. Glatstein IZ, Best CL, Palumbo A, et al: The reproducibility of the postcoital test: A prospective study. Obstet Gynecol 85:396–400, 1995. 131. Beltsos AN, Fisher S, Uhler ML, et al: The relationship of the postcoital test and semen characteristics to pregnancy rates in 200 presumed fertile couples. Int J Fertil Menopausal Stud 41:405–411, 1996. 132. Hurd WW, Randolph JF, Ansbacher R, et al: Comparison of intracervical, intrauterine, and intratubal techniques for donor insemination. Fertil Steril 59:339–342, 1993. 133. Loric S, Guechot J, Duron F, et al: Determination of testosterone in serum not bound by sex-hormone binding globulin: Diagnostic value in hirsute women. Clin Chem 34:1826–1829, 1988. 134. Schwartz U, Moltz L, Brotherton J, Hammerstein J: The diagnostic value of plasma free testosterone in non-tumorous and tumorous hyperandrogenism. Fertil Steril 40:66–72, 1983. 135. Azziz R, Dewailly D, Owerbach D: Clinical review 56: Non-classic adrenal hyperplasia: Current concepts. J Clin Endocrinol Metab 78:810–815, 1994. 136. American Society for Reproductive Medicine: The evaluation and treatment of androgen excess. Fertil Steril 82:S173–S180, 2004. 137. Scott RT, Toner JP, Mujasher SJ, et al: Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 51:651–654, 1989. 138. Toner JP, Philput CB, Jones GS, Muasher SJ: Basal follicle-stimulating hormone is a better predictor of in vitro fertilization performance than age. Fertil Steril 55:784–791, 1991. 139. Pearlstone AC, Fournet N, Gambone JC, et al: Ovulation induction in women over 40 and older: The importance of basal follicle-stimulating hormone level and chronological age. Fertil Steril 58:674–679, 1992. 140. Scott RT, Hofmann GE: Prognostic assessment of ovarian reserve. Fertil Steril 63:1–11, 1995. 141. Navot D, Rosenwaks Z, Margolioth EJ: Prognostic assessment of female fecundity. Lancet ii:645–647, 1987. 142. Hofmann GE, Danforth DR, Seifer DB: Inhibin-B: The physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening. Fertil Steril 69:474–477, 1998. 143. Yong PY, Baird DT, Thong KJ, et al: Prospective analysis of the relationships between the ovarian follicle cohort and basal FSH concentration, the inhibin response to exogenous FSH and ovarian follicle number at different stages of the normal menstrual cycle and after pituitary down-regulation. Hum Reprod 18:35–44, 2003. 144. Burns LH, Covington SN: When Infertility Strikes The Family: Helping The System Cope. Available at http://www.resolve.org/main/ national/familyfriend/strik.jsp. Accessed

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Evaluation of Male Infertility Dana A. Ohl, Timothy G. Schuster, and Susanne A. Quallich

INTRODUCTION A defect in male fertility can be found in up to 50% of couples with infertility. The male is the only cause of infertility in 30% of cases, and a combination of male and female factors can be found in another 20%.1 In the past, a combination of a lack of understanding of the pathophysiology of male infertility and a paucity of successful treatment modalities often led to neglect of the male in the evaluation process. In some cases women have undergone invasive testing and treatment before evaluation of their mate, only to find on subsequent semen analysis that the male partner was the source of the couple’s infertility. In other cases, the discovery of a markedly abnormal result on semen analysis has led to the immediate application of in vitro fertilization with intracytoplasmic sperm injection (IVF/ICSI) before a full evaluation of the male partner has been undertaken. In either case, the affected couple does not receive the optimal benefit of the extensive diagnostic and treatment modalities that have been developed for male infertility over the past 20 years. This chapter begins with an examination of the basic principles of male infertility. The standard and advanced diagnostic techniques are then detailed. Finally, the various treatment modalities and their effectiveness for specific diagnoses are elucidated.

GENERAL PRINCIPLES When male infertility is discovered, it is imperative for the man to be evaluated by a male infertility specialist before attempting pregnancy for several reasons. In some conditions, treatment modalities can improve the prospects of a couple achieving pregnancy. In others, careful evaluation will determine the presence of associated medical problems.2 For some couples with male infertility, genetic testing is essential to give prognostic information as to potential success and genetic risk assessment for the potential progeny to infertile couples considering treatment.3 In those men whose evaluation does not reveal a potentially treatable condition, contact with a male infertility specialist during the evaluation process completes the team that will implement comprehensive treatment plans that might include sperm retrieval with assisted reproductive technologies (ARTs).

Treatable Causes of Male Infertility Many men with male infertility will be found to have conditions amenable to surgical or medical treatment. Varicocele surgery has become more reliable and less invasive due to introduction of improved surgical techniques, such as the microsurgical

subinguinal approach.4,5 Surgical repair of epididymal obstructions has enjoyed higher success rates with introduction of invagination techniques.6 In men with clear-cut endocrinopathies, medical treatments are highly successful in improving fertility.7

Associated Medical Problems Male infertility increases the risk of other potentially dangerous medical problems, such as testicular cancer, spinal cord and brain tumors, genitourinary malformations, and chromosome aberrations.3 Men with severe oligospermia should be fully evaluated for these conditions before being directed toward attempts at pregnancy with IVF/ICSI. Failure to evaluate the male for these problems may delay the diagnosis of these potentially dangerous conditions.

Genetic Testing In recent years, our understanding of the genetics of male infertility has markedly improved. For example, it is now standard to perform Y-chromosome microdeletion testing in men with azoospermia or severe oligospermia, because aberrations in spermatogenesis have been linked to Y-chromosome microdeletions.2 Using this approach, an underlying genetic problem can be determined in many of these men whose abnormalities would have been designated as idiopathic in the past. Another example is congenital bilateral absence of vas deferens, which accounts for up to 5% of all male infertility. It has been observed that men with cystic fibrosis uniformly have this condition, but most men with congenital bilateral absence of vas deferens do not have the pulmonary or gastrointestinal problems indicative of cystic fibrosis. Subsequent research has shown that more than half of all men with congenital bilateral absence of vas deferens have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the same gene responsible for cystic fibrosis. In these cases, congenital bilateral absence of vas deferens is considered to be an atypical form of cystic fibrosis and is inherited in an autosomal recessive pattern.

PATHOPHYSIOLOGY The list of possible causes of male infertility is extensive (Table 35-1). Causative conditions and factors can almost always be identified by a detailed history, physical examination, and semen analysis. Some of the most common causes are explored below in more detail.

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Section 6 Infertility and Recurrent Pregnancy Loss Table 35-1 Male Infertility Etiologies Ejaculation Problems Anejaculation Retrograde ejaculation Sexual dysfunction Environmental High-temperature working environments Therapy-related Chemotherapy Radiation Medications Exogenous hormones Acquired Trauma Infection Prostatitis Epididymitis Orchitis Testicular cancer Systemic disease Hypothyroidism Immunologic Malignancies Anatomic Varicocele Obstructive azoospermia Vas deferens Epididymal Ejaculatory duct Developmental and Structural Specific genetic causes Klinefelter’s syndrome Cystic fibrosis Y-chromosome microdeletions Translocations Cryptorchidism Gonadal failure (hypergonadotropic hypogonadism) Sertoli cell only syndrome Impaired sperm transport (aperistalsis of vas deferens) Sperm Defects Spermatogenetic arrest Anomalies of sperm structure Hormonal Causes and Androgen Resistance Hypogonadotropic hypogonadism Hyperprolactinemia Congenital adrenal hyperplasia Androgen resistance syndrome Idiopathic

526

the inferior vena cava; and (3) the “nutcracker phenomenon,” caused by compression of the left renal vein between the superior mesenteric artery and aorta. The mechanism by which a varicocele causes impaired testicular function is poorly understood. It is well accepted that the presence of a varicocele is associated with progressive decline of testicular volume, impaired sperm quality, and loss of Leydig cell function.10 It has been shown that larger varicoceles are associated with greater impairment of testicular dysfunction compared to smaller varicoceles.11,12 Theories proposed to explain these observations include increased testicular temperature from loss of the countercurrent mechanism present in the normal spermatic cord, hypoxia, and reflux of renal or adrenal hormonal metabolites.13–15 Treatment

Several techniques exist to repair a varicocele, including surgical and radiographic intervention. These techniques are described in more detail in the subsequent chapter. Repair of a varicocele has been shown to improve spermatogenesis, increase Leydig cell function, and prevent further decline in testicular size.16–18 Many studies have evaluated the effectiveness of varicocele repair on improving pregnancy rates. However, most studies have been retrospective and poorly controlled. To date, only two randomized, prospective, case-controlled studies of varicocele have been performed. The first study randomized patients to surgical repair, radiographic embolization, or observation.19 Unfortunately, 48% of patients in this study had a grade 1 varicocele, for which repair is of questionable value. Although there was significant improvement in semen parameters in the patients receiving intervention, no difference was seen in pregnancy rates. The second study was a crossover design.20 A total of 45 couples underwent either immediate or delayed repair of a varicocele after 1 year of observation. Pregnancy rates were 60% during the first year for those undergoing immediate repair compared to 10% for those in the observation group. For the latter group, pregnancy rates increased to 44% during the subsequent year after repair.

Varicocele

Genetic Causes of Male Infertility

A varicocele is the single most commonly identified surgically treatable condition found in men with abnormal results on semen analysis. It has been reported that in asymptomatic men with a palpable varicocele, an abnormality on semen analysis will be found in 70%. A varicocele is present in approximately 35% to 40% of men with primary infertility and 80% of men with secondary infertility.8,9 However, not all men with a varicocele will be infertile, and this entity will be found in approximately 15% of all men. The majority of varicoceles will be found on the left side, but they can be either unilateral or bilateral. The etiology of a varicocele remains uncertain. The finding that more varicoceles occur on the left suggests they might be due to increased hydrostatic pressure in the internal spermatic veins. Related theories include: (1) the longer internal spermatic vein on the left compared to the right, resulting in increased hydrostatic pressure on the left; (2) the acute angle of insertion of the left internal spermatic vein into the left renal vein compared to the oblique insertion of the right internal spermatic vein into

A detailed discussion of the genetics of reproduction is given in Chapter 5. Klinefelter’s Syndrome

Klinefelter’s syndrome is a chromosomal aberration resulting in a genotype of 47,XXY in 90% of cases or the mosaic form of 46,XY/47,XXY in the remaining 10% of patients.21 Classically, men present as tall, eunuchoid appearance with azoospermia, gynecomastia, and small firm testes. However, a spectrum of presentations exists, especially in the mosaic form. Diagnosis is confirmed with a karyotype. Sperm extraction with ICSI has been reported in this patient population; however, couples should undergo preoperative counseling regarding risks of genetic transmission. Cystic Fibrosis

Cystic fibrosis is the most common autosomal recessive disorder in whites.22 It is associated with congenital bilateral absence of

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Chapter 35 Evaluation of Male Infertility the vas deferens in addition to pulmonary disease and exocrine pancreas dysfunction. Patients with this disease have mutations in the CFTR gene. This gene makes a protein responsible for chloride channel formation, and these mutations result in nonfunctioning channels. The mechanism by which these mutations result in degeneration of the developing vas deferens remains to be determined. An atypical form of cystic fibrosis should be suspected in any apparently healthy man with azoospermia and bilateral absence of the vas deferens on examination.22 More than half of these men will be found to have mutations in the CFTR gene. Because of the high carrier rate for cystic fibrosis in the population, all men with congenital bilateral absence of the vas deferens and their spouses should be screened for CFTR gene mutations. It is imperative that couples at risk for creating embryos with homozygous gene mutations for cystic fibrosis undergo genetic testing and counseling before proceeding with sperm harvesting and ICSI. Y-Chromosome Microdeletions

The long arm (q) of the Y chromosome contains three regions where mutations may lead to azoospermia or severe oligospermia. These genetic regions, termed azoospermia factors (AZF), have been subdivided into regions a, b, and c. Testing for Y-chromosome microdeletions should be considered in men with severe oligospermia or nonobstructive azoospermia. Successful pregnancies have been reported using ICSI for men with AZFc deletions; however, no patient with AZFa or AZFb deletions has been reported to have sperm on testicular biopsy.23–25 Although no somatic changes are evident in the offspring of patients with AZFc deletions, couples should be counseled that the genetic mutation will be transmitted to male progeny, who will face similar fertility issues in the future.

Ejaculatory Dysfunction Although relatively uncommon, ejaculatory dysfunction encompasses a large variety of disorders with individualized treatments. The entire spectrum of causes of ejaculatory dysfunctions cannot be covered in the scope of this chapter. However, some of the more common entities are explained here. Medications

Several classes of frequently used medications can cause ejaculatory dysfunction. The antiadrenergic properties of antihypertensives (e.g., methyldopa, doxazosin) can cause incomplete closure of the bladder neck, leading to retrograde ejaculation or in extreme cases failure of emission. Commonly used antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs]) and antipsychotics (e.g., thioridazine, clozapine) are also well-known causes of either delayed ejaculation or anejaculation.26,27 Diabetes Mellitus

Although erectile dysfunction is a more common finding in patients with diabetes mellitus, ejaculatory dysfunction may also be present due to the autonomic neuropathic effects on the sympathetic chain controlling the bladder neck. Difficulties with ejaculation or emission are present in up to 32% of diabetic patients.28

Spinal Cord Injury

Difficulties with ejaculation are reported in more than 80% of spinal cord injury patients.29 Because of the relatively young age of many of these patients, ejaculatory dysfunction represents a major cause of infertility after spinal cord injury.

Medications and Male Infertility In addition to ejaculatory dysfunction, several classes of medications can cause erectile dysfunction. Other medications can suppress germ cell function either directly or by disturbing the hypothalamic-pituitary-gonadal axis. Anabolic Steroids

Normal levels of intratesticular testosterone are essential for normal spermatogenesis, and these levels are significantly higher than peripheral testosterone levels.30 Use of anabolic steroids causes suppression of normal testicular feedback from the testes to the hypothalamus and pituitary, thus leading to decreased intratesticular testosterone levels and impaired spermatogenesis.31 Cessation of the exogenous androgens usually allows for resumption of normal spermatogenesis. However, there are case reports of continued disorders of the hypothalamic-pituitarygonadal axis after discontinuation of anabolic steroid use. Chemotherapy

Many chemotherapy agents are know to cause damage to germinal epithelium. As a general rule, the severity of gonadal toxicity is dose-dependent and is related to the class of chemotherapeutic agent used. Although some men will have recovery of spermatogenesis up to 5 years after treatment, a subset of men receiving chemotherapy will have permanent sterility.32 Before initiating chemotherapy there is currently no way to predict which men will have return of fertility. Consequently, sperm banking should be offered to all men before treatment.

EVALUATION OF THE MALE Male Partner History All evaluations of the infertile couple require a careful history from the male in addition to a semen analysis. In most infertility practices, physical examination of the male is performed only if the semen analysis is abnormal or if there is a history of some abnormality. An algorithm for the evaluation of male infertility is presented in Figure 35-1. General History

The general history of a male patient relative to the evaluation for male factor infertility should ascertain the duration of the couple’s attempts at pregnancy, if children have been born or a positive pregnancy test has occurred in this relationship or in another relationship before the current relationship, and the results of any prior semen analyses. It should be established that puberty started in the early or middle teens and was accompanied by normal physiologic male development. The clinician should also inquire about any previous evaluation and treatment for male or female factor infertility and should discuss any systemic illness within the past 6 months, particularly if it was a febrile illness.33 The review of systems should specifically include recent weight gain or loss, fevers, colds, sinus infections,

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Section 6 Infertility and Recurrent Pregnancy Loss Female evaluation Complaint of Infertility Male evaluation

Azoospermia or severe oligospermia (100 cases were included. NA: Not applicable

Distal tubal damage represents 85% of all cases of tubal infertility. The causes of distal tubal occlusion are PID, pelvic peritonitis, and previous surgery. A standardized method of operative report should be used. There are different scoring systems for distal tubal disease, but the most widely used is the ASRM classification for distal tubal occlusion (Fig. 47-12).27

obstruction of the fallopian tube. Some of these adhesions can appear as minimal agglutination between fimbriae. Gentle division with scissors should be performed. In more severe forms of fimbrial disease, the distal tube may be dilated but patent. The peritoneal adhesive bands are divided by laparoscopic scissors. The procedure can also be done by inserting two graspers into the tubal lumen and then spreading them apart. The procedure is repeated until the fimbria is opened. In severe cases, several interrupted sutures of 6-0 polyglactin to maintain the tubal opening are needed. The results of laparoscopic fimbrioplasty are depicted in Table 47-6.47–50

Salpingostomy

Salpingectomy

The procedure to open a distally occluded tube is called a terminal salpingostomy or salpingoneostomy. A systematic approach is required. First, any adhesions around the tubes should be liberated. The tube is then distended with dilute solution of contrast medium solution, which is injected through the intrauterine cannula (Figs. 47-13 and 47-14). The distended hydrosalpinx is then inspected. An opening on the hydrosalpinx along the avascular white line of the hydrosalpinx is created using laparoscopic scissors (Fig. 47-15). The tube is immobilized by uterine manipulation and with the help of laparoscopic forceps. Eversion of the mucosal flap can be achieved by suturing them in place with interrupted sutures of 6-0 polyglactin (Fig. 47-16). It can also be achieved by light coagulation of the serosal flap approximately 5 mm from the tubal margin. This leads to retraction of the mucosal flap, creating an eversion (Fig. 47-17). Depending on the degree of tubal damage, the overall pregnancy rate after salpingostomy is between 10% and 35% (Table 47-5). A meta-analysis found that increased term pregnancy rates and decreased ectopic rates were associated with microscopic salpingostomy compared to the macroscopic method.37 They also found that intrauterine pregnancy rates were significantly lower with the laparoscopic approach. However, this conclusion was based on the findings of four nonrandomized studies.

Several studies have shown the deleterious effect of hydrosalpinx on the outcome of IVF–embryo transfer (ET).51–55 Perhaps this is due to toxic agents in hydrosalpinx fluid that enter the uterine cavity and impair implantation. Meta-analysis of large retrospective series revealed that the IVF pregnancy rate in women with hydrosalpinx is half of those with tubal infertility of other causes, and the miscarriage rate is double.56,57 In attempt to improve the live birth rate of IVF treatment, it is recommended that the tubes be removed before IVF.58,59 In particular, hydrosalpinges that are visible on ultrasound should be removed. However, it is less certain if removal is necessary for mild cases seen only on HSG. Interestingly, salpingectomy or proximal tubal occlusion of a unilateral hydrosalpinx has been shown to increase spontaneous pregnancy rates.60 Treatment options for hydrosalpinx-related IVF include drainage, salpingostomy, proximal tubal ligation, and salpingectomy. Drainage of hydrosalpinx fluid can be performed by transvaginal needle aspiration under ultrasound guidance, either before the IVF cycle or at the time of oocyte retrieval. The efficacy of this technique is unclear. Furthermore, the fluid tends to reaccumulate after drainage. Salpingostomy is particularly appealing to young women with hydrosalpinx who do not wish their tubes removed because they wish to retain the potential for spontaneous conception. It carries the risk of reocclusion of the hydrosalpinx. Whether the rates of IVF pregnancy after salpingostomy are similar to those after salpingectomy is unknown. Occluding the proximal tube appears to be a reasonable alternative for women with hydrosalpinx undergoing IVF. Pregnancy rates after proximal tubal occlusion are similar to those

Although initial reports showed increased operative time, this may decrease as the technology improves.

Distal Tubal Occlusion

Fimbrioplasty

Fimbrioplasty is release of adhesions covering the fimbriae or the peritoneal bands surrounding the fimbria. The procedure is performed for fimbrial phimosis, which is an incomplete

703

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Section 7 Reproductive Surgery Figure 47-12 The American Society for Reproductive Medicine classification of distal tubal occlusion.

AMERICAN SOCIETY FOR REPRODUCTIVE MEDICINE CLASSIFICATION OF DISTAL TUBAL OCCLUSION Patient's Name G

Age

Chart#

Date P

Sp Ab

VTP

Ectopic

Infertile Yes

No

Other Significant History (i.e. surgery, infection,etc.) HSG

Sonography

Photography 10

Treatment (Surgical Procedures): Salpingostomy L

Laparotomy

3-5 cm 4 4 Moderately Thickened or Edematous 4 4 35% to 75% Preserved 4 4 Moderate 3 3 Moderately Dense (or Vascular) 2 2

Normal/Thin 1 1 Normal/ >75% Preserved 1 1 None/Minimal/Mild 1 1

Type of adhesions

Laparoscopy

RIGHT

>5 cm 6 6 Thick & Rigid 6 6 35% Preserved Adherent Mucosal Fold 6 6 Extensive 6 6 Dense 4 4

Additional Findings:

R

A. Terminal B. Ampullary

L

Drawing

R

Other:

Prognosis for Conception& Subsequent Viable Infant* Excellent (> 75%) Good (50-75%) Fair (25%-50%) Poor (< 25%) *Physician's judgment based upon adnexa with least amount of pathology. Recommended Followup Treatments:

704

after salpingectomy.61 In one retrospective study of patients undergoing IVF treatment, it was observed that management of hydrosalpinx by laparoscopic salpingectomy or by occluding the proximal tubes yielded statistically similar responses to an IVF–ET cycle.61 Occluding the proximal portion of the tubes is simpler and is a method of choice for women with severe pelvic adhesions. Recently some case reports have suggested a possible role for hysteroscopic tubal occlusion in patients with hydrosalpinx and severe pelvic disease at high risk for complications.

Salpingectomy has been shown to be effective. A randomized trial comparing laparoscopic salpingectomy to no treatment for hydrosalpinx before IVF found the pregnancy and delivery rates (37% and 29%, respectively) in the salpingectomy group were significantly higher than in the nontreated group (24% and 16%, respectively).59 It seems clear that salpingectomy is a worthwhile procedure before IVF.62 The technique of salpingectomy could affect the blood supply to the ovary; caution should be exercised when excising the tube.

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Chapter 47 Tubal Disease

Figure 47-13 Dense adhesions surrounding the tubes and ovaries. Chromopertubation revealed bilateral distal tubal occlusion.

Figure 47-14

Figure 47-16 with sutures.

Salpingostomy is completed by everting the mucosal flap

Figure 47-17

Salpingostomy has been completed.

The tube is grasped with a traumatic forceps.

Table 47-5 Reproductive Outcome after Laparoscopic Salpingostomy Figure 47-15 avascular line.

An opening is made with laparoscopic scissors at the

Prophylactic antibiotics may be all that is necessary to improve implantation rates in the presence of hydrosalpinx, at least in theory. It has been reported in a retrospective study that doxycycline treatment improved the IVF pregnancy rate.63 However, in general, a tubal occlusion procedure is recommended.

Periadnexal Adhesions Reproductive surgery can cause adhesion formation. Most surgery on reproductive organs is not performed for infertility but in women who have a disorder such as a myoma or ovarian cyst and

Author

Number of Patients

Intrauterine Pregnancies

Ectopic Pregnancies

Daniell et al, 198638

48

21%

10%

Canis et al, 199139

87

33%

7%

Dubuisson et al, 199440

90

32%

4%

Sasse et al, 199441

81

23%

14%

Dequesne, 199442

43

10 (20%)

Oh, 199643

82

35%

10%

Kasia et al, 199744

86

11%

6%

Milingos et al, 200045

61

23%

3%

139

32%

17%

Taylor et al, 200146

Only studies with >40 cases were included.

2 (4.6%)

705

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Section 7 Reproductive Surgery want to conceive in the future. Measures such as meticulous handling of the tissue, frequent irrigation with isotonic solution, gentle and minimal tissue handling, and good hemostasis decrease but do not eliminate adhesion formation. Adjunctive therapies, such as prophylactic antibiotics, intraperitoneal corticosteroids, and adhesion-preventing substances also fail to improve the reproductive performance of these women (see Chapter 52). Peritubal and periovarian adhesions impair fertility by interfering with gamete transfer and the ovum pickup mechanism. Removal of these adhesions is associated with improved fecundity. The ASRM (American Fertility Society) classification of adnexal adhesions is shown in Figure 47-18.27 Tulandi and

Table 47-6 Reproductive Outcome after Laparoscopic Fimbrioplasty Number of Patients

Author

Intrauterine Pregnancies

Ectopic Pregnancies

Dubuisson et al, 199047

31

35%

12.9%

Gomel & Erenus, 199048

40

48%

5%

Dequesne, 199442

63

64%

4.7%

Dlugi et al, 199449

113

20.3%

5.3%

Kasia et al, 199744

108

36%

Audebert et al, 199850

35

5.8%

74.3%

22.9%

THE AMERICAN FERTILITY SOCIETY CLASSIFICATION OF ADNEXAL ADHESIONS Patient's Name G

Age

Chart#

Date P

Sp Ab

VTP

Ectopic

Infertile Yes

No

Other Significant History (i.e. surgery, infection,etc.) HSG

Sonography

Photography

Laparoscopy

Laparotomy

TUBE

OVARY

2/3 Enclosure ADHESIONS R Filmy 1 2 4 4 8 16 Dense 2 4 1 L Filmy 4 8 16 Dense 1 2 4 R Filmy Dense 4* 8* 16 1 2 4 L Filmy 4* 16 Dense 8* * If the fimbriated end of the fallopian tube is completely enclosed, change the point assignment to 16. Prognosis Classification for Adnexal Adhesions LEFT

Additional Findings:

RIGHT

A. Minimal B. Mild C. Moderate D. Severe Treatment (Surgical Procedures):

L

Prognosis for Conception& Subsequent Viable Infant** Excellent (> 75%) Good (50-75%) Fair (25%-50%) Poor (< 25%) **Physician's judgment based upon adnexa with least amount of pathology. Recommended Followup Treatment:

706

Drawing

R

Figure 47-18 American Fertility Society (ASRM) classification of adnexal adhesions.

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Chapter 47 Tubal Disease colleagues evaluated pregnancy occurrence in infertile women with periadnexal adhesions.64 The pregnancy rate in women whose adhesions were lysed by laparotomy was higher than in those untreated. The cumulative probability of conception at 12 and 24 months follow-up were 8% and 13%, respectively, in the nontreated group and 40% and 42%, respectively, in the treated group. The ectopic pregnancy rate between the treated and nontreated group was similar. Intrinsic damage to the fallopian tube is more important in the development of ectopic pregnancy than the adhesions. Lysis of adhesions can be performed using laparoscopic scissors, electrocautery, or laser. The results are similar.65–68 The vascular type of adhesions should be coagulated first or vaporized with the laser. The procedure is performed by keeping the adhesions under tension with grasping forceps and divided. Filmy adhesions are divided, but dense adhesions should be excised. The overall pregnancy rate after laparoscopic salpingo-ovariolysis is 60% and the ectopic pregnancy rate is 5%.65 However, the pregnancy rate after salpingo-ovariolysis in women with severe and dense adhesions is poor (10% to 15%). These patients are better treated with IVF. In a retrospective study, there was no statistical difference between the cumulative conception rates of microsurgical and laparoscopic adhesiolysis after being stratified according to the duration of infertility.66 In addition, there was no difference in adhesion score after microsurgical and laparoscopic adhesiolysis. However, the laparoscopic approach has additional benefits, such as reduced postoperative pain, fast recovery, short hospital stay, and reduced risk of infection and thromboembolic accidents. The benefit of second-look laparoscopy was studied by Tulandi and coworkers in a randomized, prospective study.68 There was no increase in the pregnancy rate or decrease in the incidence of ectopic pregnancy after a second-look laparoscopy done 1 year after reproductive surgery.

However, it is often associated with false proximal occlusion, which could be due to tubal spasm or mucosal debris. As a result, nonvisualized tube is not synonymous with true occlusion, and it should be followed by selective tubal catheterization. If catheterization fails, patients are better treated with IVF. The most common cause of midtubal occlusion is iatrogenic after tubal sterilization. Reversal of tubal sterilization by reanastomosis is the most successful tubal reconstructive surgery. Also unlike IVF, several pregnancies could be achieved. Alternatively, patients, especially older women, can be offered assisted reproductive technology. In general, women with hydrosalpinx will have a better chance to conceive with IVF if the tube is removed. Hydrosalpinx fluid impairs implantation. Young women with tubal infertility who wish to conceive spontaneously can be offered reconstructive tubal surgery; this should be done by laparoscopy. Older premenopausal women and those with severe tubal damage should be offered IVF.

PEARLS Tubal disease remains one of the most common causes of infertility. HSG remains the best approach to evaluation of tubal disease. Proximal tubal occlusion is commonly found on HSG and may resolve spontaneously. Therefore a repeat HSG is recommended before attempt at correction. The best method for correction of proximal tubal occlusion is by fluoroscopic or hysteroscopic cannulation. Midtubal occlusion is typically caused by a previous tubal ligation and is amenable to reversal by laparoscopic technique. Distal tubal occlusion that is severe should be treated by IVF. However, less severe forms can be treated with surgery. Ectopic pregnancy is increased after tubal surgery. Hydrosalpinx that is severe, especially if visible on ultrasonography, should be removed before IVF.

●

● ●

●

●

●

● ●

CONCLUSIONS HSG remains the most widely used technique to evaluate tubal patency. It is simple, economical, and might lead to conception.

REFERENCES 1. Westrom L: Incidence, prevalence, and trends of acute pelvic inflammatory disease and its consequences in industrialized countries. Am J Obstet Gynecol 138:880–892, 1980. 2. DeCherney AH, Cholst I, Naftolin F: Structure and function of the fallopian tubes following exposure to diethylstilbestrol (DES) during gestation. Fertil Steril 36:741–745, 1981. 3. Novy M, Thurmond AS, Patton P, et al: Diagnosis of cornual obstruction by transcervical fallopian tube cannulation. Fertil Steril 50:434–440, 1988. 4. Hurd WW, Wyckoff ET, Reynolds DB, et al: Patient rotation and resolution of unilateral cornual obstruction during hysterosalpingography. Obstet Gynecol 101:1275–1278, 2003. 5. Steiner AZ, Meyer WR, Clark RL, Hartmann KE: Oil- Soluble contrast during hysterosalpingography in women with proven tubal patency. Obstet Gynecol 101:109–113, 2003. 6. Ekerhoved E, Fried G, Granberg S: An ultrasound-based approach to the assessment of infertility, including the evaluation of tubal patency. Best Pract Res Clin Obstet Gynecol 18:13–28, 2004. 7. Holz K, Becker R, Schurmann R: Ultrasound in the investigation of tubal patency. A meta-analysis of three comparative studies of Echovist-

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200 including 1007 women. Zentralblatt fur Gynekologie 119:366–373, 1997. Gordts S, Watrelot R, Campo R, Brosens I: Risk and outcome of bowel injury during transvaginal pelvic endoscopy. Fertil Steril 76:1238–1241, 2001. Brosens IA, Boeckx W, Delattin P, et al: Salpingoscopy: A new preoperative diagnostic tool in tubal surgery. BJOG 94:768–773, 1987. Marana R, Catalano GF, Muzii L, et al: The prognostic role of salpingoscopy in laparoscopic tubal surgery. Hum Reprod 14:2991–2995, 1999. Marchino GL, Gigante V, Gennarelli G, et al: Salpingoscopic and laparoscopic investigation in relation to fertility outcome. J Am Assoc Gynecol Laparosc 8:218–221, 2001. Gordts S, Campo R, Puttemans P, et al: A one-step outpatient endoscopy based approach. Hum Reprod 17:1684–1687, 2002. Kerin J, Daykhosky L, Segalowitz J, et al: A microendoscopic technique for visual exploration of the human fallopian tube from the uterotubal ostium to the fimbriae using a transvaginal approach. Fertil Steril 54:390–400, 1990.

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14. Surrey ES, Adamson GD, Surrey MW, et al: Introduction of new coaxial falloposcopy system: A multicenter feasibility study. J Am Assoc Gynecol Laparosc 4:473–478, 1997. 15. Pearlstone AC, Surrey ES, Kerin F: The linear everting catheter: A nonhysteroscopic transvaginal technique for access and microendoscopy of the fallopian tube. Fertil Steril 58:854–857, 1992. 16. Malik S: Genital tuberculosis and implantation in assisted reproduction. Rev Gynecol Pract 3:160–164, 2003. 17. Sulak PJ, Letterie GS, Coddington CC, et al: Histology of proximal tubal occlusion. Fertil Steril 48:437–440, 1987. 18. Ransom M, Garcia A: Surgical management of cornual–isthmic tubal obstruction. Fertil Steril 68:887–891, 1997. 19. Gillette WR, Herbison GP: Tubocornual anastomosis: Surgical considerations and coexistent infertility factors in determining the prognosis. Fertil Steril 51:241–246, 1989. 20. Donnez J, Casanas-Roux F, Nisolle-Pochet M, et al: Surgical management of tubal obstruction at the uterotubal junction. Acta Eur Fertil 18:5–9, 1987. 21. Lavy G, Diamond MP, DeCherney AH: Pregnancy following tubocornual anastomosis. Fertil Steril 46:21–25, 1986. 22. Gomel V: An odyssey through the oviduct. Fertil Steril 39:144–156, 1983. 23. Diamond E: A comparison of gross and microsurgical techniques for the repair of cornual occlusion in infertility: A retrospective study, 1968–1978. Fertil Steril 32:370–376, 1979. 24. Grant A: Infertility surgery of the oviduct. Fertil Steril 22:496–503, 1971. 25. Honere GM, Holden AE, Schenken RS: Pathophysiology and management of proximal tubal blockage. Fertil Steril 71:785–795, 1999. 26. Platz-Christensen JJ, Tronstad SE, Johansson O, Carlsson SA: Evaluation of regret after tubal sterilization. Int J Gynaecol Obstet 38:223–226, 1992. 27. American Fertility Society: Classification of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, müllerian anomalies and intrauterine adhesions. Fertil Steril 49:944–955, 1988. 28. Yoon TK, Sung HR, Kang HG, et al: Laparoscopic tubal anastomosis: Fertility outcome in 202 cases. Fertil Steril 72:1121–1126, 1999. 29. Hawkins J, Dube D, Kaplow M, Tulandi T: Cost analysis of tubal anastomosis by laparoscopy and by laparotomy. J Am Assoc Gynecol Laparosc 9:120–124, 2002. 30. DeCherney AH, Mezer HC, Naftolin F: Analysis of failure of microsurgical anastomosis after mid-segment, non-coagulation tubal ligation. Fertil Steril 39:618–622, 1983. 31. Paterson PJ: Factors influencing the success of microsurgical tuboplasty for sterilization reversal. Clin Reprod Fertil 3:57–64, 1985. 32. Lu ZY: Tubal anastomosis for reversal of sterilization with microsurgical technique in 246 women. Zhonghua Fu Chan Ke Za Zhi 24:203–205, 1989. 33. Kim SH, Shin CJ, Kim JC, et al: Microsurgical reversal of tubal sterilization: A report on 1118 cases. Fertil Steril 68:865–870, 1997. 34. Bisonette F, Lapensee L, Bouzayen R: Outpatient laparoscopic tubal anastomosis and subsequent fertility. Fertil Steril 72:549, 1999. 35. Dubuisson JB, Chapron CL: Single suture laparoscopic tubal reanastomosis. Curr Opin Obstet Gynecol 10:307–313, 1998. 36. Falcone T, Goldberg JM, Margossian H, Stevens L: Robotically assisted laparoscopic microsurgical tubal anastomosis: A human pilot study. Fertil Steril 73:1040–1042, 2000. 37. Watson A, Vandekerckhove P, Lilford R: Techniques for pelvic surgery in subfertility. Cochrane Database Syst Rev 2003; 3:CD000221. 38. Daniell JF, Diamond MP, McLaughlin DS, et al: Clinical results of terminal salpingostomy with the use of the CO2 laser: Report of the intra-abdominal laser study group. Fertil Steril 45:175–178, 1986. 39. Canis M, Mage G, Pouly JL, et al: Laparoscopic distal tuboplasty: Report of 87 cases and a four years experience. Fertil Steril 56: 616–621, 1991. 40. Dubuisson JP, Chapron C, Morice P, et al: Laparoscopic salpingostomy: Fertility results according to the tubal mucosal appearance. Hum Reprod 9:334– 339, 1994.

41. Sasse V, Karageorgieva E, Keckstein J: Laparoscopic treatment of distal tubal occlusion-reocclusion and pregnancy rate. J Am Assoc Gynecol Laparosc 1:S32, 1994. 42. Dequesne JG: CO2 laser laparoscopy in tubo-ovarian infertility. J Am Assoc Gynecol Laparosc 1:S10, 1994. 43. Oh ST: Tubal patency and conception rates with three methods of laparoscopic terminal salpingostomy. J Am Assoc Gynecol Laparosc 3:519–523, 1996. 44. Kasia J, Raiga J, Doh A, et al: Laparoscopic fimbrioplasty and neosalpingostomy: Experience of the Yaounde General Hospital, Cameroon (report of 194 cases). Eur J Obstet Gynecol Reprod Biol 73:71–77, 1997. 45. Milingos SD, Kallipolitis GK, Loutradis DC, et al: Laparoscopic treatment of hydrosalpinx: Factors affecting pregnancy rate. J Am Assoc Gynecol Laparosc 7:355–361, 2000. 46. Taylor RC, Berkowitz J, McComb PF: Role of laparoscopic salpingostomy in the treatment of hydrosalpinx. Fertil Steril 75:594–600, 2001. 47. Dubuisson PJ, Bouquet De Joliniere J, Aubriot FX, et al: Terminal tuboplasties by laparoscopy: 65 consecutive cases. Fertil Steril 54:401–403, 1990. 48. Gomel V, Erenus M: Prognostic value of the American Fertility Society’s (AFS) classification for distal tubal occlusion (DTO). In American Fertility Society 46th Annual Meeting program Supplement (p097). Washington, D.C., American Fertility Society, 1990, p S106. 49. Dlugi AM, Reddy S, Saleh WA, et al: Pregnancy rates after operative endoscopic treatment of total (neosalpingostomy) or near total (salpingostomy) distal tubal occlusion. Fertil Steril 62:913–920, 1994. 50. Audebert A, Pouly JL, Von Theobald P: Laparoscopic fimbrioplasty: An evaluation of 35 cases. Hum Reprod 13:1496–1499, 1998. 51. Anderson AN, Yue Z, Meng FJ, Petersen K: Low implantation rate after in vitro fertilization in patients with hydrosalpinges diagnosed by ultrasonography. Hum Reprod 9:1935–1938, 1994. 52. Strandell A, Waldenstrom NL, Hamberger L: Hydrosalpinx reduces in vitro fertilization/embryo transfer pregnancy rates. Hum Reprod 9:861–863, 1994. 53. Vandromme J, Chasse E, Lejeune B, et al: Hydrosalpinges in in vitro fertilization: An unfavorable feature. Hum Reprod 10:576–579, 1995. 54. Bedaiwy MA, Goldberg JM, Falcone T, et al: Relationship between oxidative stress and embryotoxicity of hydrosalpingeal fluid. Hum Reprod 17:601–604, 2002. 55. Bedaiwy MA, Falcone T, Goldberg JM, et al: The relationship between cytokines and the embryotoxicity of hydrosalpingeal fluid. J IVF Genet 22:171–176, 2005. 56. Blazar AS, Hogan JW, Seifer DB, et al: The impact of hydrosalpinx on successful pregnancy in tubal factor infertility treated by in vitro fertilization. Fertil Steril 67:517–520, 1997. 57. Camus E, Poncelet C, Goffinet F, et al: Pregnancy rates after in vitro fertilization in cases of tubal infertility with and without hydrosalpinx: A meta-analysis of published comparative studies. Hum Reprod 14:1243–1249, 1999. 58. Zeyneloglu HB, Arici A, Olive D: Adverse affects of hydrosalpinx on pregnancy rates after in vitro fertilization–embryo transfer. Fertil Steril 11:208–2084, 1998. 59. Strandell A, Lindhard A, Waldenstrom U, Thorburn J: Hydrosalpinx and IVF outcome: Cumulative results after salpingectomy in a randomized controlled trial. Hum Reprod 16:2403–2410, 2001. 60. Sagoskin AW, Lessey BA, Mottla GL, et al: Salpingectomy or proximal tubal occlusion of unilateral hydrosalpinx increases the potential for spontaneous pregnancy. Hum Reprod 18:2634–2637, 2003. 61. Surrey ES, Schoolcraft WB: Laparoscopic management of hydrosalpinges before in vitro fertilization–embryo transfer: Salpingectomy versus proximal tubal occlusion. Fertil Steril 75:612–617, 2001. 62. Johnson N, Mak W, Sowter M: Laparoscopic salpingectomy for women with hydrosalpinges enhances the success of IVF: A Cochrane review. Hum Reprod 17:543–548, 2002. 63. Hurst BS, Tucker KE, Awoniyi CA, Schlaff WD: Hydrosalpinx treated with extended doxycycline does not compromise the success of in vitro fertilization. Fertil Steril 75:1017–1019, 2001.

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Chapter 47 Tubal Disease 64. Tulandi T, Collins JA, Burrows E: Treatment-dependent and treatmentindependent pregnancy among women with periadenexal adhesions. Am J Obstet Gynecol 162:354–357, 1990. 65. Tulandi T, Bugnah M: Operative laparoscopy: Surgical modalities. Fertil Steril 63:237–245, 1995. 66. Saravelos HG, Li TC, Cooke ID: An analysis of the outcome of microsurgical and laparoscopic adhesiolysis for infertility. Hum Reprod 10:2887–2894, 1995.

67. Tulandi T: Salpingo-ovariolysis: A comparison between laser surgery and electrosurgery. Fertil Steril 45:489–491, 1986. 68. Tulandi T, Falcone T, Kafka I: Second-look operative laparoscopy one year following reproductive surgery. Fertil Steril 52:421–424, 1989.

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Section 7 Reproductive Surgery Chapter

48

Ectopic Pregnancy Beata Seeber and Kurt Barnhart

INTRODUCTION Ectopic pregnancy, the implantation of a fertilized ovum outside the endometrial cavity, is a curious phenomenon unique to primates. It does not occur in laboratory animals and has likewise not been reported in domestic or farm animals. In addition, no animal model of the disease exists. If undiagnosed or untreated, ectopic pregnancy may result in rupture of the fallopian tube and massive intraperitoneal hemorrhage. In the past decade, this phenomenon accounted for approximately 9% of maternal pregnancy-related deaths in the United States.1 Because ectopic pregnancy diagnosis and treatment has moved from an inpatient to an outpatient setting, there are no clear reporting standards, and the most up-to-date incidence rates and morbidity and mortality statistics date back to the mid-1990s.1 Fortunately, due to increased awareness of this problem by clinicians and the public, coupled with improved methods of diagnosis and treatment, the outcomes for women with ectopic pregnancy appear to be improving. Today, complications of ectopic pregnancy stem from misdiagnosis or delay in seeking medical care. It is no longer the case that the disease entity is missed due to a deficit in clinical knowledge or lack of means to diagnosis. Despite this, however, the condition continues to be a major cause of morbidity and mortality in reproductive-age women. This chapter reviews the epidemiology and pathophysiology of ectopic pregnancy, the clinical presentation and diagnosis of the disease, surgical and medical treatments, and reproductive outcomes.

EPIDEMIOLOGY It is estimated that about 2% of pregnancies in the United States are ectopic pregnancies. The number of ectopic pregnancies diagnosed in the United States continues to rise, with a sixfold increase documented between 1970 and 1992.2–4 In Europe, the prevalence of ectopic pregnancy appears stable in France, Sweden, and the Netherlands, but has continued to increase in Norway.4 U.S. healthcare statistics demonstrate that of the 108,800 patients diagnosed with ectopic pregnancy in 1992, 58,000 needed hospitalization, at a cost of $1.1 billion.5 Recent trends of outpatient treatment and decreased need for hospitalization have likely led to an underreporting of the condition and a consequent underestimation in U.S. government figures. The etiology of the observed increase in ectopic pregnancy prevalence appears to be multifaceted. An important factor

appears to be the recent rise in sexually transmitted diseases, leading to an increased incidence of clinical and subclinical tubal infections. Another contributing factor may be our improved ability to diagnose ectopic pregnancies earlier and more accurately. Finally, the increased utilization of assisted reproductive technologies is believed to play a role in this increased prevalence. The vast majority of ectopic pregnancies (more than 90%) occur in the tube, with 80% to 90% of these occurring in the ampullary region, 5% to 10% in the isthmic region, 5% in the fimbrial region, and about 2.4% located in the cornual (interstitial) region. The other sites include 3.2% in the ovary, 1.3% elsewhere in the abdomen, and less than 0.15% in the cervix.6–8

Etiology Ectopic pregnancies are believed to occur primarily as a result of factors that delay or prevent the passage of the fertilized egg into the uterine cavity. Partial or complete blockage of a fallopian tube may arrest the passing embryo in the fallopian tube lumen. Even if the tube is still patent, inflammation and infection may damage the endosalpinx of the tube. Resultant abnormalities in ciliary function are believed to impede transport of the embryo through the fallopian tube.9 The most common cause of such tubal damage is believed to be clinical or subclinical infections caused by Chlamydia trachomatis or Neisseria gonorrhoeae. It is hypothesized that in some cases embryo factors (including cytogenetic abnormalities) may lead to premature implantation in a nonendometrial site. However, recent studies that have examined the role of chromosome abnormalities in ectopic pregnancy have not supported earlier case reports of high proportions of genetically abnormal gestations at ectopic sites. Among 22 surgically excised tubal pregnancies, only one abnormal chromosomal complement was found.10 In a larger review of 62 karyotyped ectopic pregnancies, 4.8% showed chromosomal abnormalities, a figure which matched that expected for maternal and gestational age of the cases.11

Risk Factors Multiple risk factors have been consistently shown to be associated with ectopic pregnancies (Table 48-1).12 The strongest association has been found with prior pelvic inflammatory disease (PID), a prior history of ectopic pregnancy, and previous tubal surgery (including previous tubal ligation). These conditions are believed to alter tubal integrity and thus impede the migration of the fertilized ovum to the uterus. Weaker associations have been made between ectopic pregnancy and infertility (a possible marker in some patients for

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Section 7 Reproductive Surgery Table 48-1 Risk Factors for Ectopic Pregnancy Strong Associations Tubal surgery Pelvic inflammatory disease Prior ectopic pregnancy Weaker Associations Infertility Cigarette smoking Increasing age More than one lifetime sexual partner Abdominal or pelvic surgery Sexually transmitted diseases (gonorrhea and/or chlamydia) Intrauterine device use No Clear Association Oral contraceptive use Prior spontaneous miscarriage Prior elective termination of pregnancy Cesarean section

subclinical tubal infection), cigarette smoking (thought to affect tubal motility), increasing age, having more than one lifetime sexual partner, any pelvic or abdominal surgery (other than cesarean delivery), and a history of having a sexually transmitted disease. Although use of an intrauterine device (IUD) does not increase the risk of ectopic pregnancy compared to controls, women using an IUD found to have a positive pregnancy test are more likely to have an ectopic than an intrauterine pregnancy, in a manner similar to women who have had a tubal ligation.13 Unfortunately, the sensitivity of these risk factors is low, and as many as 50% of patients with proven ectopic pregnancies will have none.13 No clear association has been documented between ectopic pregnancy and oral contraceptive use, previous elective pregnancy termination or spontaneous miscarriage, or cesarean section.9,10 Improved Diagnosis

Diagnostic accuracy has improved as a result of more sensitive pregnancy tests and pelvic ultrasound. The advent of radioimmunoassay and specific antiserum to the beta-subunit of human chorionic gonadotropin (hCG) has allowed for the accurate quantification of β-hCG and the ability to closely follow its rise and fall.14 High-resolution transvaginal ultrasonography with Doppler flow imaging has led to improved visualization of adnexal masses, including ectopic pregnancies, at earlier gestational ages. Assisted Reproductive Technologies

Assisted reproductive technologies (ART) appear to increase the risk of ectopic pregnancies as a result of both preexisting pathology and effects inherent to these techniques. Not only do many subfertile women have tubal abnormalities, but ovulation induction also results in hormonal fluctuations that are hypothesized to alter tubal motility in some women. After oocyte retrieval, in vitro fertilization (IVF), and embryo transfer, the incidence of tubal pregnancy can be as high as 4.5%.15 Heterotopic Pregnancy

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IVF also appears to increase the incidence of simultaneous intrauterine and ectopic pregnancy, termed heterotopic pregnancy.16 In the late 1940s, the prevalence of heterotopic pregnancy

was estimated to be 1:30,000 pregnancies.17 The prevalence is now estimated to be 1:4000 pregnancies in the general population, and as high as 1:100 pregnancies resulting from IVF.15,18,19 This dramatic increase is believed to be the result of the increased risk of multiple pregnancies and the unknown effects on tubal motility, in combination with the invasive nature of ART. The clinician must be aware that although ultrasound verification of intrauterine pregnancy dramatically decreases the chance of an ectopic pregnancy, it does not completely rule it out, especially in patients whose pregnancy has resulted from ART.

Ruptured Ectopic Pregnancy Fallopian tube rupture secondary to ectopic pregnancy remains relatively common despite greater awareness of the disease and improved diagnostic modalities. This is because there is little or no correlation between tubal rupture time since last menstrual period, physical findings, symptoms or β-hCG level. In a large retrospective study of 700 women with ectopic pregnancies, the rupture rate was 34% and one third of patients had no symptoms prior to rupture.20 The primary risk factors for tubal rupture in this study were no prior history of ectopic pregnancy and multiparity. Likewise, there is little relationship between the onset of ectopic pregnancy symptoms and subsequent tubal rupture. In one study with an overall rupture rate of 32%, less than one fourth of the ruptures occurred within the first 48 hours of symptom onset.21 The remaining ruptures occurred at a fairly steady rate of 2.5% per 24 hours of untreated symptoms for the next 2 weeks. It is surprising that there is no correlation between tubal rupture and β-hCG levels. In one study, 11% of patients with ruptured ectopic pregnancies had β-hCG levels less than 100 IU/L.16 Even declining β-hCG levels are not clinically reassuring, because fallopian tube rupture can occur when serial β-hCG measurements demonstrate a dropping level, as well as when the β-hCG level is very low.22,23

PRESENTATION Symptoms The most common symptoms of ectopic pregnancy are abdominal or pelvic pain and vaginal bleeding or spotting in a patient with a positive pregnancy test. However, both the sensitivity and specificity of these symptoms for ectopic pregnancy are low. In some cases, these symptoms can be intermittent or even absent. Depending on their degree, these can sometimes be mistaken for a normal menstrual period or early pregnancy loss; thus some women may not initially report them to their physicians. Even though these symptoms may be due to other conditions, pain and bleeding during early pregnancy are always an indication to exclude ectopic pregnancy. Pain

Pain associated with an ectopic pregnancy can range from mild to severe and can be unilateral or bilateral. The pain is believed to be related to tubal distension from the proliferating chorionic villi and hemorrhage into the tubal lumen, as well as peritoneal irritation secondary to leakage of blood into the peritoneal cavity.

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Chapter 48 Ectopic Pregnancy Vaginal Bleeding

Vaginal bleeding occurs in more than 50% of ectopic pregnancies and can range from scant spotting to heavy bleeding. It is hypothesized that vaginal bleeding occurs because the thickened endometrial lining is not well supported by the abnormal hormonal milieu. Theoretically, lower β-hCG production associated with most ectopic pregnancies stimulates the corpus luteum to produce an inadequate amount of progesterone. Some patients may even report passing tissue vaginally. In such cases, it is important to keep in mind that a “decidual cast” from the endometrial cavity can easily be mistaken for tissue, and only microscopically confirmed chorionic villi should be used to confirm that the pregnancy was intrauterine.17

Physical Examination Findings on physical examination can vary dramatically and do not always correlate with the size of the ectopic pregnancy or whether or not it is ruptured. Patients with unruptured ectopic pregnancies usually have normal vital signs, although pain-related tachycardia is not uncommon. Lower abdominal tenderness on the affected side is common, but it may be found on the contralateral side as well, sometimes as a result of a corpus luteum cyst on that side. The clinician must keep in mind that a normal physical examination does not exclude an ectopic pregnancy. Pelvic Examination

On pelvic examination, inspection of the cervix will usually reveal a closed os, with or without bleeding. A vigorous bimanual examination in search of an adnexal mass is contraindicated if an ectopic pregnancy is suspected. In the presence of adnexal tenderness, the size and characterization of any adnexal masses is best determined by ultrasound. Bimanual pressure on a fragile ectopic pregnancy can result in rupture, converting a stable patient into a surgical emergency. Even when an ectopic pregnancy is present, an adnexal mass will be palpable in more than 10% of cases, and in one third of these cases, the mass will ultimately prove to be unrelated to the ectopic pregancy (e.g., a corpus luteum cyst).17

Ruptured Tubal Pregnancy Tubal rupture is often, but not always, associated with signs of peritoneal irritation, such as rebound tenderness and guarding. Hypotension and tachycardia are indications for immediate fluid resuscitation and expedient surgical intervention. Presumed hemoperitoneum can be confirmed by bedside transabdominal ultrasound, if it will not delay surgery.

DIAGNOSIS Early in pregnancy, it is often impossible to differentiate a viable pregnancy from an impending spontaneous abortion or an ectopic pregnancy. The diagnosis of an ectopic pregnancy is therefore a diagnosis of exclusion, utilizing modern noninvasive diagnostic approaches.

Ultrasonography The first step in evaluating a pregnancy is to determine viability. If the pregnancy is determined to be nonviable, the second step

is to differentiate between an abnormal intrauterine pregnancy (spontaneous abortion) and an ectopic pregnancy. Therefore, the first step in a diagnostic workup for ectopic pregnancy is to verify or exclude an intrauterine pregnancy (normal as well as abnormal), because the odds of heterotopic pregnancies are extremely low even after IVF. Intrauterine Pregnancy Confirmation

The confirmation of an intrauterine pregnancy requires the identification of a series of structures by vaginal ultrasound, including the gestational sac, yolk sac, and fetal pole with or without cardiac motion. The gestational sac is seen first and appears as a thick, echogenic rim surrounding a sonolucent center in an eccentric location of the endometrial stripe. This is often referred to as the double decidual sign. The yolk sac is a bright echogenic rim with a sonolucent center that can be seen by approximately 5 weeks’ gestational age. The fetal pole develops as a thickening along an edge of the yolk sac, with cardiac motion first seen around 51⁄2 to 6 weeks after the last menstrual period, even in the case of multiple gestations. The diagnostic accuracy of transvaginal ultrasound for identifying an intrauterine pregnancy approaches 100% in gestations greater than 51⁄2 weeks.24 A pseudosac may sometimes be mistaken for a gestational sac. This is a collection of fluid within the endometrial cavity that occurs due to bleeding from the decidualized endometrium when an extrauterine gestation is present. A pseudosac can usually be distinguished from a real gestational sac by its central location, filling the endometrial cavity itself. Adnexal Findings

Ectopic pregnancies can often be seen in the adnexa with vaginal ultrasound. The most common finding is an inhomogeneous mass, which has been reported to be visible in approximately half of patients with ectopic pregnancies in some series.25 Less commonly, a mass with a hyperechoic ring around the gestational sac can be seen. The ability to visualize an ectopic pregnancy is ultimately dependent on the quality of the ultrasound equipment and the experience of the sonographer. Even in the best of circumstances, no evidence of pregnancy either in the uterus or the adnexa is a common finding in patients subsequently proven to have an ectopic pregnancy.

Human Chorionic Gonadotropin Quantitative measurement of serum β-hCG is a very accurate method for determining gestational age in the first trimester of a normal pregnancy.26 This is extremely important in the diagnosis of ectopic pregnancy, because at the time of initial evaluation, many women will be unsure of their menstrual or conception dates; thus the exact gestational age is not known. The use of radioimmunoassay to measure serum β-hCG has greatly improved the time to obtain results as well as their accuracy. Discriminatory Zone

An important factor when determining the viability and location of a pregnancy by vaginal ultrasound is the discriminatory zone. The discriminatory zone is defined as that level of β-hCG at which a normal singleton intrauterine pregnancy can be visualized

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Section 7 Reproductive Surgery on transvaginal ultrasonography.28 At most institutions, the discriminatory zone for a singleton pregnancy when using transvaginal ultrasonography is between 1500 and 2500 mIU/mL (using the WHO Third International Standard, or International Reference Preparation).2 Each clinician will have to determine the discriminatory zone in their practice. Important variables include the type of β-hCG test used, the expertise of the ultrasonographer, and the quality of the ultrasound equipment. If the discriminatory zone is set too high, diagnosis of ectopic pregnancies will be delayed. If the discriminatory zone is set too low, the risk of intervening in a normal intrauterine pregnancy increases. This is especially important in patients who have become pregnant after ART, because multiple gestations can present with a β-hCG level well above the discriminatory zone long before an intrauterine pregnancy is visible by vaginal ultrasound. In practice, the discriminatory zone should be used as a guide rather than an absolute. In a symptomatic patient whose β-hCG is above the discriminatory zone but has no evidence of an intrauterine pregnancy, intervention is often warranted. In contrast, in an asymptomatic patient with this same scenario, repeat measurements will often demonstrate viability of normal, and sometimes multiple, gestations. Like all gray areas of medical diagnosis, patient education should be aimed at minimizing both anxiety and risk to the patient while waiting to make a definitive diagnosis. Serial ␤-hCG Determination

To distinguish a normal intrauterine pregnancy from a nonviable intrauterine or ectopic gestation, serial β-hCG determinations are performed. It is now well-established that the beta-hCG concentration rises almost linearly in the early weeks of a normally growing gestation, doubling every 1.4 to 2.1 days.27–29 Many clinicians rely on the rule of at least a 66% rise in β-hCG over 2 days based on earlier studies.27,30–33 More recent evidence suggests that the rise of β-hCG may be slower than previously reported, with 99% of all normal viable intrauterine pregnancies having an increase in β-hCG of at least 24% in 1 day and 53% in 2 days.34 Intervening when the 2-day rise in β-hCG is between 53% and 66% may result in the interruption of a viable pregnancy.

Uterine Cavity Sampling

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If the β-hCG level is not rising normally and is above the discriminatory zone, and an intrauterine pregnancy is not visualized by ultrasound, the diagnosis of an abnormal, nonviable gestation can be made with relative certainty. To differentiate between a spontaneous miscarriage and an ectopic pregnancy, the uterine cavity should be sampled to determine the presence or absence of chorionic villi. This is most commonly done by performing a dilation and curettage (D&C) in the operating room. Failure to accurately detect the presence of chorionic villi can lead to unnecessary surgical and medical interventions in women without an ectopic pregnancy. In cases where gross products of conception (gestational sac or fetal parts) are not visible, verification of the presence of chorionic villi can be a problem, because final diagnosis with a permanent pathologic specimen takes up to 24 hours. One solution is to obtain a frozen section at the time of D&C, which

has been shown to be very accurate in identifying products of conception, with almost no risk of false-positive results.35 Other techniques used to identify chorionic villi have not been found to be as sensitive. Floating the tissue obtained in saline solution will allow the trained gynecologist to identify villi in only 60% of cases where they can be identified histologically.36 The use of a stereomicroscope significantly improves the ability to identify chorionic villi, but is rarely available in common practice.37 Sampling of the uterine cavity with a pipelle biopsy instrument in an outpatient setting has been found to have relatively poor sensitivity of 30% to 63%.38,39 In the future, perhaps other forms of less invasive endometrial sampling, such as the handheld manual vacuum aspirator, will prove to have the necessary sensitivity for confirming products of conception.

Other Diagnostic Tests Other techniques have been used to diagnose ectopic pregnancy. Prior to accurate ultrasound, culdocentesis was used to diagnose acute intra-abdominal bleeding. For this often painful transvaginal technique, a spinal needle is placed though the posterior cul-de-sac to aspirate peritoneal fluid. The presence of clotting blood indicates hemoperitoneum secondary to acute bleeding, because blood that had been present for any period of time will have already lysed, and thus not clot. Today, the presumptive diagnosis of hemoperitoneum is made by transvaginal ultrasound whenever a hemodynamically compromised patient with a positive pregnancy test is found to have free intra-abdominal fluid. Serum progesterone levels have also been used to aid in the diagnosis of ectopic pregnancy. Overall, serum progesterone levels are lower in ectopic pregnancies than in intrauterine pregnancies.40 Levels less than 5 ng/mL are almost always (99.8%) associated with nonviable pregnancies, but these can be either abnormal intrauterine pregnancies (impending spontaneous abortion) or ectopic pregnancies.41 Conversely, progesterone levels of greater than 17.5 ng/mL are rarely associated with ectopic pregnancies, with only 8% of ectopic pregnancies falling into this category. Despite these strong correlations at either end of the concentration spectrum, serum progesterone levels have limited value in diagnosing ectopic pregnancies, because many patients’ values will fall between these extremes of values, where there is too much overlap to be discriminatory.42 In addition, serum progesterone levels are not readily available in many hospital laboratories on a “stat” basis, making the use of this test impractical in emergency situations. Other laboratory tests evaluated for usefulness in the diagnosis of ectopic pregnancy include vascular endothelial growth factor (VEGF), CA-125, fetal fibronectin, and creatine kinase.43–49 Like serum progesterone, overlapping ranges of values for normal and abnormal pregnancies have prevented any of these markers from being useful in distinguishing ectopic and nonectopic gestations. Using genomics approaches, other promising serum protein markers have been identified that may ultimately prove to be discriminatory between intrauterine and ectopic pregnancies.50

Algorithm for Diagnosis A simple diagnostic algorithm using ultrasound and serum β-hCG determinations can be helpful (Fig. 48-1).51 When a

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Chapter 48 Ectopic Pregnancy Figure 48-1 Diagnostic algorithm flow chart (adapted from Gracia CR, Barnhart KT: Diagnosing ectopic pregnancy: A decision analysis comparing six strategies. Obstet Gynecol 97:464-470, 2001.)

Early pregnancy with pain and bleeding

Ultrasound

IUP

Abnormal IUP

Nondiagnostic

Ectopic pregnancy

Expectant management

D&C vs. medical management with misoprostol

β-hCG

Treat EP

> Discriminatory

< Discriminatory

zone (no IUP)

zone

D&C

No chorionic villi

Treat EP (MTX vs. surgery)

Abnormal rise or fall

Chorionic villi

Serial β-hCG

Normal fall

Normal rise

No treatment

Ultrasound when β-hCG > discriminatory zone (back to top)

patient presents in early pregnancy with pain or uterine bleeding, the first step is transvaginal ultrasound. If a nonviable intrauterine pregnancy (e.g., impending spontaneous abortion) is visualized, standard management options are indicated based on symptomatology. Likewise, if an ectopic pregnancy is seen in the adnexa, treatment options are clear. If the ultrasound is nondiagnostic, revealing neither an intrauterine or ectopic pregnancy, and the β-hCG is below the discriminatory zone, the most likely diagnosis remains an intrauterine pregnancy, and viability needs to be determined. To distinguish between a growing intrauterine pregnancy and a nonviable gestation, serial β-hCG determinations are performed. As long as serial β-hCG levels rise appropriately, treatment remains expectant. If serial β-hCG levels rise at an abnormal rate, plateau, or drop, a nonviable pregnancy is diagnosed and a D&C is needed to differentiate between an abnormal intrauterine pregnancy and an ectopic pregnancy. Likewise, when vaginal ultrasound is nondiagnostic and the initial or subsequent β-hCG level is found to be well above the discriminatory zone, the next step for diagnosis and treatment of the symptomatic patient is D&C. Caution should be used in the asymptomatic patient with a β-hCG level at or slightly above the discriminatory zone, because viable multiple gestations can have β-hCG levels above the discriminatory zone before the time that an intrauterine pregnancy can be seen with vaginal ultrasound.

Identification of chorionic villi in the D&C specimen verifies the diagnosis of spontaneous abortion, and further treatment is rarely needed. Alternatively, inability to identify chorionic villi makes an ectopic pregnancy the most likely diagnosis. At this point, a decision must be made between either surgical or medical treatment. In some cases where no chorionic villi are found on D&C, the clinical history is suggestive of a complete spontaneous abortion before evacuation, with heavy vaginal bleeding with passage of tissue and an open cervix. In these cases, it is appropriate to manage the patient expectantly with re-evaluation of serum β-hCG levels 12 to 24 hours after evacuation. If the β-hCG level drops sharply from preoperative levels, a complete spontaneous abortion is the most likely diagnosis, although a resolving ectopic pregnancy (sometimes referred to as a tubal abortion) is also possible. Keep in mind that 35% of women with an ectopic pregnancy are diagnosed when the β-hCG level is falling.28 If the β-hCG level plateaus or continues to rise, an ectopic pregnancy is highly likely, and immediate treatment should be instituted. This approach can also be used when the clinical suspicion of ectopic pregnancy is low, but no pathologist is available for intraoperative examination of the D&C specimen. All patients for whom ectopic pregnancy was among the differential diagnoses should be followed with at least weekly β-hCG levels until β-hCG is no longer detectable in the serum.

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Section 7 Reproductive Surgery This may take up to several weeks, because a minimum decline in serial β-hCG concentration for a completed abortion ranges from 21% to 35% in 48 hours.52 A negative β-hCG value is the only sure way to confirm complete resolution of the ectopic pregnancy. There have been reports of tubal rupture with β-hCG levels as low as 5 mIU/mL.53 Of all women with ectopic pregnancies who present with symptoms, about 50% will have β-hCG levels above the discriminatory zone and are therefore diagnosed within a single evaluation.3 The remaining 50% of women with ectopic pregnancies who seek medical attention will be found to have β-hCG levels below the discriminatory zone, and ultrasound is usually nondiagnostic. At this point in time, the sensitivity of transvaginal ultrasound for the diagnosis of intrauterine pregnancy, spontaneous miscarriage, and ectopic pregnancy has been shown to be only 25% to 33% and the predictive value is low.54

Laparotomy versus Laparoscopy Laparoscopy has become the most common surgical approach to ectopic pregnancy, primarily due to the increased comfort level most gynecologic surgeons have gained with the laparoscopic approach. However, laparotomy remains the treatment of choice for the hemodynamically unstable patient with a ruptured ectopic pregnancy. Laparotomy versus laparoscopy for the treatment of ectopic pregnancy has been compared in three prospective, randomized trials.57–59 Each concluded that the laparoscopic approach is superior to laparotomy. Laparoscopy resulted in less blood loss, less analgesia requirement, and a shorter duration of hospital stay compared to laparotomy. Laparoscopy was also found to be less costly in all three trials. Not surprisingly, a Cochrane review of the surgical treatment of ectopic pregnancy likewise concluded that laparoscopy is the treatment of choice for eligible patients.60

Screening Asymptomatic Patients There may be some advantage to screening patients at high risk for ectopic pregnancy before the development of symptoms.55 Risk factors include previous history of ectopic pregnancy, tubal surgery, PID, sterilization, current IUD, and known tubal disease seen by hysterosalpingography or laparoscopy. In a study of 143 symptom-free women with these risk factors, screening was started before 7 weeks’ gestation with serial β-hCG measurements and ultrasound studies. In this particular study, 5.6% of the women were diagnosed with ectopic pregnancies. It is yet to be established that the potential benefits of this approach, including decreasing the risk of complications and patient reassurance, outweighed the drawbacks of false-positive diagnoses, increased costs, and increased emotional stress.56 For this reason, universal screening of women at increased risk for ectopic pregnancy cannot be recommended at this time.

TREATMENT Before the twentieth century, ectopic pregnancy was nearly always fatal, due to late diagnosis and absence of effective treatment options. Today, the primary goal of accurate and expeditious diagnosis is to limit morbidity and eliminate mortality associated with this condition. Early diagnosis of ectopic pregnancy makes a greater number of treatment options available to the physician and patient. Instead of the traditional treatment with laparotomy and fallopian tube resection (salpingectomy), clinically stable patients can often be treated with minimally invasive surgery (i.e., laparoscopy) and tubal conservation (salpingostomy). Alternatively, these patients may be candidates for medical therapy with methotrexate. In experienced hands, these modern treatment modalities appear to have comparable success rates, while maintaining the potential for future fertility.

Hemodynamic Stabilization

716

All patients suspected of having an ectopic pregnancy should have established adequate intravenous access for prompt crystalloid fluid hydration should intra-abdominal hemorrhage result in hemodynamic instability. Before surgery, the patient’s blood type should be determined and she should be cross-matched for several units of packed red blood cells in anticipation of further surgical losses.

Exploratory Laparotomy: The Unstable Patient

Exploratory laparotomy is still indicated for the treatment of the hemodynamically unstable patient in whom a ruptured fallopian tube has caused extensive intraperitoneal bleeding, leading to intravascular volume depletion. These patients present to the emergency room in distress, with hypotension and tachycardia; if intervention is not immediate, they may develop hypovolemic shock. Prompt evaluation and stabilization should be followed by expeditious surgery under general anesthesia. Although laparotomy is usually the most expedient approach, if hemodynamic stability can be reestablished with intravenous therapy, some experienced gynecologists find the laparoscopic approach satisfactory even with a ruptured ectopic pregnancy and associated hemoperitoneum as long as a large-bore (10-mm) suction– irrigator is available to allow adequate visualization of the pelvis. Regardless of approach, fluid and blood product replacement is the first priority in any patient exhibiting early signs of hemorrhagic shock. Large-bore IV lines should be placed, and the patient’s volume loss should be aggressively replaced. The patient should be cross-matched for at least 4 units of packed red blood cells before initiation of surgery, because additional volume losses may be expected once the abdomen is open and there is no pressure tamponade. Packed red blood cell transfusion should be initiated at the discretion of the anesthesiologist based on the patient’s physiologic condition and need for colloid fluid repletion, keeping in mind that young, healthy patients can usually tolerate anemia well. With every 4 units of packed red blood cells, 2 units of fresh frozen plasma are often transfused to replace clotting factors. The patient’s blood count and coagulation profile should be monitored closely throughout the case. Laparotomy via a pfannensteil incision will usually allow expeditious entry into the peritoneal cavity. On visualization of the pelvic structures, the site of implantation of the ectopic pregnancy should be immediately identified. A Kelly forceps (“clamp”) is then placed at the proximal portion of the fallopian tube, at the uterine cornu. This should virtually eliminate further blood loss, because most of the blood supply to the fallopian tube comes from branches of the uterine artery. A second Kelly clamp can then be placed along the mesosalpinx, meeting the end of the first clamp, so that all vessels within the mesosalpinx are occluded. Alternatively, a succession of Kelly clamps can be used to clamp the mesosalpinx as close to the tube as possible,

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Chapter 48 Ectopic Pregnancy Table 48-2 Salpingectomy via Laparotomy or Laparoscopy — Surgical Steps Suprapubic Pfannensteil incision made for laparotomy Fallopian tube elevated using Allis or Babcock clamp Mesosalpinx clamped with succession of Kelly clamps or hemostats, just below the fallopian tube Tube removed at site of uterine attachment close to cornua Interrupted 2-0 or 3-0 delayed-absorbable suture (e.g., Vicryl) used for closure of pedicles Inspection for hemostasis or Laparoscopic trocar ports placed (umbilical and at least 2 additional) for laparoscopic approach Fallopian tube grasped and elevated distally with endo-grasper Tube cauterized and then transected at cornual end, close to uterus Mesosalpinx coagulated with bipolar cautery and divided as close as possible to fallopian tube Dissection can proceed from cornual end to distal fimbria or from fimbriated end toward proximal tube Specimen placed in endoscopic bag and removed via large port site

as described by Damario and Rock.61 The entire tube and the ectopic gestation are then excised as one specimen. The pedicles are suture ligated with 2-0 or 3-0 vicryl or other synthetic absorbable suture. After assuring hemostasis, the pelvis should be evacuated of blood and clots, which can total up to several liters of blood loss (Table 48-2). Laparotomy can be the preferred approach for reasons other than hemodynamic instability. Other clinical indications include (1) multiple previous pelvic surgeries with documented or highly suspected extensive pelvic adhesions; (2) an underlying medical condition precluding laparoscopy; (3) an ectopic pregnancy that is outside the fallopian tube, in which case resection via laparoscopy is technically difficult; and (4) inadequate equipment or experience to safely remove the ectopic pregnancy laparoscopically.

Laparoscopic Approach Laparoscopy is the most common technique used for the surgical treatment of the majority of ectopic pregnancies. In general, at least three puncture sites are necessary to allow for adequate manipulation of the affected tube and the site of excision. This usually includes a laparoscope port placed at the umbilicus and two additional 5-mm instrument ports. One instrument port is placed in the midline 4 cm above the pubic symphysis, and a lateral port is place approximately 8 cm above the pubic symphysis and 8 cm lateral to the midline (to avoid the inferior epigastric vessels) on the side contralateral to the ectopic pregnancy. One of these incisions often needs to be enlarged to allow for the removal of the excised specimen, especially in the case of salpingectomy. An endoscopic pouch can be used to facilitate the collection of the specimen in the pelvis and ease its removal without fragmentation through a 10-mm port site. Salpingectomy

The surgical steps of laparoscopic salpingectomy are similar to those performed via laparotomy.56,62 Blood and clots present in the pelvis are removed with irrigation and suction so that the

involved tube can be adequately visualized. The involved tube is grasped near the end where cutting will be initiated. If possible, the tube is resected starting proximally at the uterine cornu and continuing until the fimbrial end is reached. With less than ideal exposure, resection can proceed in the opposite direction. Likely the easiest way to ensure tubal transection and closure at the uterine attachment is by using bipolar cautery. With the coagulation technique, the mesosalpinx is coagulated with bipolar cautery and then divided. If a single coagulation-cutting instrument is not available, this can be accomplished using bipolar forceps and then laparoscopic sheers. The mesosalpinx should be transected as close as possible to the fallopian tube so that vessels within the mesosalpinx, which are providing blood flow to the ovary, are not compromised. Other techniques for laparoscopic salpingectomy involve the use of endoscopic stapling devices as well as pretied endoscopic ligatures. Salpingostomy

Conservative surgical management of ectopic pregnancy can be accomplished by either salpingostomy or by segmental resection of the involved segment of fallopian tube. Segmental resection has mostly been used in patients with isthmic ectopic pregnancies because in this portion of the tube the lumen is narrower and the muscularis is thicker than in the ampullary region.63 This anatomic difference may lead to increased tubal obstruction after linear salpingostomy performed on this segment of the tube. The purpose of segmental resection is to retain the possibility of reanastomosis of the tubal segments using microsurgical technique, a procedure that may be undertaken either at the time of the initial surgery or during a subsequent surgery. The continued improved success of IVF, which is altogether able to bypass the fallopian tube, has made tubal reconstruction after ectopic pregnancy less utilized and not as practical. Salpingostomy, on the other hand, has become the standard procedure for laparoscopic resection of an ectopic pregnancy, although this technique can be performed via laparotomy as well. After identification of the ectopic gestation, the fallopian tube is immobilized by an atraumatic laparoscopic grasper. A 10- to 15-mm linear incision is then made on the antimesenteric surface of the fallopian tube, over the most distended portion of the tube. The linear incision can be made by laser, ultrasonic scalpel, unipolar needle cautery, or the tip of unipolar scissors. The ectopic pregnancy can then be removed by irrigating it out from the tube, or with blunt dissection, until the specimen protrudes through the opening and can be grasped for removal. The ectopic pregnancy tends to be found in the proximal portion of the distended fallopian tube, with blood clot and hemorrhage extending distally and accounting for most of the tubal enlargement. Therefore, it is important to ensure that all trophoblastic tissue is completely extracted from the tube, so as to not risk a persistent ectopic pregnancy. Tissues should be removed atraumatically because physical removal with surgical graspers may result in false plains, resulting in a greater incidence of retained trophoblastic tissue. Bleeding from the incision edge and ectopic pregnancy site can be controlled using bipolar or, if necessary, unipolar electrosurgery. Electrosurgery should be limited as much as possible to prevent further tubal damage. Another technique to minimize bleeding is to inject the tubal mesentery under the ectopic pregnancy before making the incision with 10 mL of a dilute

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Section 7 Reproductive Surgery Table 48-3 Laparoscopic Salpingostomy — Surgical Steps Laparoscopic trocar ports placed (umbilical, suprapubic, and at least one additional in lower quadrant contralateral to ectopic site) Evacuation of hemoperitoneum with suction irrigator Fallopian tube grasped and kept taut with atraumatic endo-grasper Laser, unipolar cautery, or edge of endosheers used to make linear salpingostomy incision along antimesenteric wall of tube Hydrodissection or gentle tubal compression to extrude products of conception Tissue placed in endoscopic bag and removed from abdominal cavity Irrigation of tube with minimal use of cautery (micro-tip best) Tube left open to heal by secondary intention

vasopressin solution (10 U in 50 mL physiologic saline solution).61 The temporary local vasospasm induced by this method is designed to minimize the need for electrosurgery and thus limit damage to tubal mucosa during ectopic pregnancy removal. After tissue removal and achievement of hemostasis, the tube is gently irrigated and left to close by secondary intention. The salpingostomy site closes effectively and rapidly by secondary intention with minimal risk of adhesions. Closing the salpingostomy with suture has not been shown to be beneficial during laparotomy or laparoscopy and might actually increase the risk of tissue ischemia and adhesion formation.64–66 A prospective study failed to show a difference between suturing and not suturing the salpingostomy site after laparoscopic removal of ectopic pregnancies in terms of tubal patency rates, postoperative adhesion rates, or cumulative pregnancy rates (Table 48-3).66 Whether performed by laparotomy or laparoscopy, the fertility outcome after linear salpingostomy is satisfactory. After salpingostomy performed by either approach, the intrauterine pregnancy rate is approximately 60% and the recurrent ectopic pregnancy rate is 15%.14 Comparisons of reproductive outcomes following different treatment approaches are discussed here. Persistent Ectopic Pregnancy

718

Although salpingostomy has a high success rate in terms of subsequent tubal patency and intrauterine pregnancy, incomplete resolution of the pregnancy, termed persistent ectopic pregnancy, occurs in 5% to 20% treated by this method.67–69 In one study, the risk of persistent ectopic pregnancy was double for patients treated with laparoscopic salpingostomy compared to patients treated with salpingostomy performed via laparotomy.14 After treating an ectopic pregnancy with salpingostomy, the β-hCG level should be checked on postoperative day 1. A decrease of less than 50% from the initial preoperative β-hCG level is associated with a relative risk of 3.51 for persistent products of conception.70 In this same series, there were no cases of persistent ectopic pregnancy when the postoperative day 1 β-hCG decreased by more than 76%. To ensure complete resolution of the ectopic pregnancy, the β-hCG level should be repeated weekly until it is no longer detectable. Failure of the β-hCG to drop to undetectable levels after surgery is an indication that active trophoblastic tissue has been left behind. Risk factors for developing a persistent ectopic pregnancy include a very early gestation, a small ectopic pregnancy of less than 2 cm, or a high concentration of β-hCG preoperatively.

Options for treatment of a persistent ectopic pregnancy include medical therapy or a second surgery. In general, if there are no signs indicating tubal rupture (which may occur even in the setting of a dropping β-hCG), medical treatment with methotrexate, using a single intramuscular dose, is preferable. Use of prophylactic methotrexate immediately after conservative surgery has been advocated by some and its use supported by one randomized trial, which showed a decrease in the rate of persistent ectopic pregnancy from 14.5% to 1.9% with singledose methotrexate (1 mg/kg IM).71 A recent decision-analysis found that prophylactic methotrexate resulted in fewer cases of tubal rupture and fewer procedures at a lower cost compared with observation alone.72 In a clinical setting where the rate of persistent ectopic pregnancy is greater than 9% with observation after surgery, the incidence of persistent ectopic pregnancy is less than 5% after prophylactic methotrexate, the probability of ectopic rupture is greater than 7.3% with persistent ectopic pregnancy, and the complication rate associated with prophylactic methotrexate is less than 18%, the use of prophylactic methotrexate optimizes the treatment. If these conditions are not met, observation alone is the better strategy. Until more data are available, following serial β-hCG levels without administering prophylactic methotrexate remains a reasonable strategy. Salpingectomy versus Salpingostomy

The decision to perform a salpingectomy as opposed to a salpingostomy in the surgical treatment of ectopic pregnancy is often difficult. If the tube is ruptured or appears extensively damaged, or in cases of large tubal pregnancies (>5 cm), salpingectomy is preferred and may be the only option. Similarly, if hemorrhage at the site of implantation cannot be controlled with conservative surgery, salpingectomy is appropriate because extensive coagulation of bleeding sites can result in extensive destruction of the tubal lumen. Women who have had a previous ectopic pregnancy at the same site and those who do not wish to be pregnant in the future are also candidates for salpingectomy. In these cases, the option of “ligating” the contralateral tube for contraceptive reasons should discussed with the patient prior to surgery. In patients who desire future fertility, the decision to perform salpingectomy or salpingostomy should be based on several additional considerations. Salpingectomy is often the preferred procedure in patients with extensive tubal adhesion or a history of previous tubal surgery, including tubal anastomosis. The risk for a repeat ectopic pregnancy is the same for a woman if the affected tube is removed or conserved because the risk factors for ectopic pregnancy usually affect both tubes. However, it is likely that conservation of the affected tube increases future fecundity. In women with a history of two or more ectopic pregnancies, early referral for IVF likely gives the best pregnancy success.

Medical Management with Methotrexate Methotrexate has proven to be a safe and effective method of treating ectopic pregnancy. First introduced in 1982, it has become a common mode of treatment for appropriately selected patients. The primary advantage to medical therapy is the chance to avoid the morbidity and risks associated with surgery. In addition to its use as primary treatment for ectopic pregnancy, methotrexate is

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Chapter 48 Ectopic Pregnancy also used for the treatment of persistent ectopic pregnancy after salpingostomy, as a prophylactic method to decrease the risk of persistent ectopic pregnancy after conservative surgery, and as a primary treatment of ectopic pregnancies in unusual locations.

readily referred to IVF for a presumed tubal factor, when one may not actually exist. In addition, the presumptive treatment of women at risk for ectopic pregnancy does not result in a reduction in cost, side effects, or time saved.76

Mechanism of Action

Indications and Contraindications

Methotrexate acts to inhibit rapidly dividing cells, specifically arresting mitosis of the cytotrophoblasts of the ectopic pregnancy. It is a folic acid antagonist that inhibits the enzyme dihydrofolate reductase. Dihydrofolate reductase reduces folate to tetrahydrofolate by the addition of single carbon groups, which are subsequently transferred in the synthesis of DNA and RNA precursors. By blocking this enzyme, methotrexate leads to the depletion of cofactors required for DNA and RNA synthesis. With interruption of both DNA and RNA synthesis and impairment of the synthesis of critical proteins necessary for cell survival, methotrexate targets cells in many parts of the cell cycle.73 Methotrexate also causes the buildup of dihydrofolate polyglutamates in the cell, which both acts as a toxic substance itself and prolongs the action of methotrexate within cells.73,74 Leucovorin (folinic acid) is sometimes used to “rescue” cells in which dihydrofolate reductase has been inactivated by methotrexate. This reduced form of folic acid enters cells via a carrier-mediated system and does not require reduction by dihydrofolate reductase for the conversion to active folate cofactors for DNA and RNA synthesis. For these reasons, leucovorin prevents some otherwise prohibitive side effects and allows for the administration of higher methotrexate doses. When treating an ectopic pregnancy with high-dose or multidose regimens of methotrexate, leucovorin rescue therapy is often added. Methotrexate is predominantly cleared by the kidney and excreted in the urine, so the medication should be used with great caution and with adjusted doses in patients with renal compromise.74

Methotrexate is an acceptable form of treatment for patients with ectopic pregnancy who have no evidence of tubal rupture, including hemodynamic instability or signs of hemoperitoneum. The patient must also be reliable enough to return as required for follow-up care. To minimize the risk of tubal rupture after the initiation of medical therapy, relative contraindications for the use of methotrexate have been described.77 Although not all clinicians agree, many avoid using methotrexate in the presence of an adnexal mass greater than 3.5 cm at its greatest dimension, fetal cardiac motion visible on ultrasound, or β-hCG greater than 15,000 mIU/mL.77 Absolute contraindications to methotrexate therapy include evidence of immunodeficiency, damage to organs that metabolize methotrexate (i.e., liver and kidney), preexisting conditions that could be exacerbated by methotrexate (e.g., peptic ulcer disease, blood dyscrasias, active pulmonary disease), and breastfeeding (Table 48-4).

Need for Definitive Diagnosis

Methotrexate Treatment Protocols

In an attempt to expedite treatment for women with abnormal pregnancies, some clinicians have used methotrexate presumptively before making a definitive diagnosis. The most common clinical scenarios where this practice is employed are (1) in the absence of signs of a normal intrauterine pregnancy and β-hCG above the discriminatory zone, and (2) with a pleateauing β-hCG level below the discriminatory zone. Although such a strategy does avoid invasive intervention, it is not recommended. Presumed diagnosis of ectopic pregnancy has been shown to be inaccurate about 40% of the time.75 Therefore, if methotrexate were used without prior confirmation of an ectopic pregnancy, a large number of patients would receive this chemotherapeutic agent unnecessarily. In addition, methotrexate has about a 30% failure rate when used for early pregnancy termination, so it may be inadequate treatment for an abnormal intrauterine pregnancy.75 Should the pregnancy ultimately prove to be viable, the risk of congential anomalies is significant, because methotrexate is a known teratogen. Another problem with presumptive treatment is that an incorrect diagnosis will lead to assignment of an erroneous diagnostic label to a patient, which may have implications for her future care: a patient with an ectopic pregnancy may be more

For the treatment of ectopic pregnancy with methotrexate, intramuscular injection is the preferred method of administration. Preliminary reports of oral administration have reported successful resolution of ectopic pregnancy, but this mode of administration is not well-studied.80

Pretreatment Evaluation

Certain baseline laboratory values should be evaluated before administering methotrexate. Patients should be screened with a complete blood count, liver function tests, and serum creatinine. A chest x-ray should be performed in women with a history of pulmonary disease due to their risk of developing interstitial pneumonitis. Patients should be excluded from medical treatment if they are found to have aspartate transaminase greater than 50 or 2 times normal; creatinine level greater than 1.3 to 1.5 mg/dL, white blood cell count less than 3,000/μL, or platelet count less than 100,000/μL.78,79

Table 48-4 Absolute Contraindications to Methotrexate Therapy Breastfeeding Overt or laboratory evidence of immunodeficiency Alcoholism, alcoholic liver disease, or other chronic liver disease Preexisting blood dyscrasias (bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia) Known sensitivity to methotrexate Active pulmonary disease Peptic ulcer disease Hepatic, renal, or hematologic dysfunction Adapted from ACOG: Medical Management of Tubal Pregnancy. Washington, DC, ACOG Practice Bulletin No. 3, 1998.

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Section 7 Reproductive Surgery The two most common regimens employed for the treatment of ectopic pregnancy are the multidose protocol and the singledose protocol. Under the multidose protocol, methotrexate is administered as the sodium salt at a dose of 1 mg/kg per day, intramuscularly, on days 1, 3, 5, and 7 of treatment.81 Due to the relatively large overall dose, leucovorin is used to prevent cell toxicity and is given at a dose of 0.1 mg/kg intramuscularly on alternating days (days 2, 4, 6, and 8). Patients receive up to four doses (1 methotrexate/1 leucovorin) until the β-hCG decreases by at least 15% on two consecutive measurements, 2 days apart. Consequently, some patients may only require one or two doses, and others need the full four-dose course. All patients need to be followed until the β-hCG is no longer detectable in the serum to confirm complete resolution of the ectopic gestation. In select cases, a second four-dose course may be given 1 week later if there is an increase or plateau in two consecutive β-hCG values; at such a point, however, most clinicians would proceed to surgical treatment. A single-dose regimen of methotrexate was more recently introduced, with the benefit of simplified administration and less frequent need for patient follow-up.82 Under this protocol, a patient is given an intramuscular methotrexate dose of 50 mg/m2 based on the patient’s body surface area: [Height(cm) × Weight(kg)] BSA (m ) = 3600 2

冢

冣

1⁄2

No leucovorin rescue is given. The single-dose regimen is somewhat of a misnomer because a second dose may be administered after 1 week if the β-hCG value does not decline by at least 15% between days 4 and 7 after initial methotrexate injection. It has been shown that using the single-dose protocol, approximately 20% of women require more than one dose to completely resolve their ectopic gestation.83 Again, once a treatment response has been documented with serially decreasing β-hCG levels, patients are followed with surveillance β-hCG measurements until no longer detectable in serum (Tables 48-5 and 48-6).

Table 48-5 Multidose Methotrexate Protocol Treatment Day

Laboratory Tests

Intervention

Pretreatment

β-hCG, CBC with differential, LFTs, creatinine, type and screen

Rule out SAB Rhogam if Rh-negative

1

β-hCG

MTX 1.0 mg/kg

2 3

LEU 0.1 mg/kg β-hCG

4 5

LEU 0.1 mg/kg β-hCG

6 7

720

MTX 1.0 mg/kg if 15% stop treatment and start surveillance. LEU 0.1 mg/kg

β-hCG

8

MYX 1.0 mg/kg if 15% stop treatment and start surveillance. LEU 0.1 mg/kg

Surveillance every 7 days (until β-hCG 60 U/mL

Ultrasound not suspicious

??? Surgical evaluation

Re-evaluate in 3 months

Diagnostic laparoscopy

Consider CT or MRI

Ultrasound suspicious Consider CT or MRI

Re-evaluate vs. diagnostic laparoscopy

Surgical evaluation

Figure 50-1 Algorithm for preoperative evaluation of an ovarian cyst. A distinction is made here between a diagnostic laparoscopy and surgical evaluation. Depending on surgeon skill, availability of gynecologic oncology backup, and overall clinical suspicion for malignancy, surgical evaluation could include laparoscopy, yet consideration should be given in these circumstances to performing a laparotomy.

evaluated with diagnostic laparoscopy. Laparoscopic treatment of the mass is appropriate in the absence of surgical evidence of malignancy. Women at high (10% or greater) risk of malignancy should be evaluated surgically, most commonly via laparotomy. In select circumstances, laparoscopy can be used for surgical evaluation, assuming that the laparoscopist has both the appropriate experience and gynecologic oncologist backup.

Intraoperative Tumor Rupture Intraoperative rupture of some ovarian cysts that are later found to be malignant is unavoidable, regardless of the preoperative criteria or surgical approached used. One study of 32 patients found an overall rate of tumor rupture of 25% for laparoscopy compared to 9% for laparotomy.31 This occurrence appears to worsen the patient’s prognosis, although there are conflicting data. Although some studies have found no impact of intraoperative tumor rupture on subsequent survival,32–34 others have shown decreased survival.35–38 The only prospective assessment of the impact of intraoperative tumor rupture found a significantly lower survival rate for women with stage I ovarian carcinoma after rupture, although not as low as for women whose tumor ruptured spontaneously before surgery.38 The greatest impact of intraoperative rupture was for serous tumors, where the 9-year survival rate declined from 86% to 50%. Furthermore, many oncologists will recommend chemotherapy after an intraoperative spill of a welldifferentiated stage I a cancer that usually would not have received such treatment. Certainly, spillage of cyst contents into the peritoneal cavity should be avoided when ovarian malignancy is a possibility.

Table 50-5 Surgical Staging for Ovarian Cancer Evaluate Is the tumor unilateral or bilateral? Does the tumor appear on the external surface of the ovary? Is the tumor capsule intact? Has the tumor ruptured? Biopsy Any suspicious lesions Three sites of pelvic peritoneum Cul-de-sac peritoneum Right and left abdominal gutter Undersurface of the right diaphragm Partial omentectomy Para-aortic and pelvic nodes Peritoneal washings

Surgical Staging Regardless of the surgical approach used to treat an ovarian malignancy, adequate surgical staging is imperative (Table 50-5). One study of 100 women with ovarian cancer referred to a gynecologic oncologist after surgical diagnosis found that only 25% had adequate staging.39 More than 30% were ultimately found to have more advanced stage disease than reported based on the initial surgery. One factor that contributes to inadequate staging at the initial surgery is the discordance between intraoperative frozen section and subsequent diagnosis based on permanent section. Making a diagnosis of borderline malignancy is especially difficult on frozen section. Several studies have documented a greater than 5% discordance between these two techniques.40,41

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Section 7 Reproductive Surgery The problem is that patients erroneously determined intraoperatively to have benign disease based on frozen section are unlikely to be adequately staged. In light of the inherent inaccuracy associated with frozen section, surgeons should consider staging patients with suspicious ovarian masses even if the interoperative diagnosis is benign. Moreover, surgeons should discuss intraoperative diagnostic limitations with their patients before surgery, irrespective of approach.

vessels. Many laparoscopic surgeons do not use the suprapubic site but rather place an accessory port just above the level of the umbilicus lateral to the rectus muscle on the patient’s left side. The latter approach allows the surgeon to operate comfortably with two hands. Specimen removal will often require placement of a 10-mm or greater port in one of the secondary sites. This larger port can be placed initially, or a 5-mm site can be dilated to 10 mm.

LAPAROSCOPY APPROACH FOR OVARIAN MASSES

Pelvic Washings and Peritoneal Cavity Inspection

Laparoscopic management of properly selected ovarian masses has become a standard part of modern obstetrics and gynecology.3 In one study of 396 women who underwent laparoscopy for a low-risk adnexal mass, only 2% of patients were ultimately found to have a malignancy.3 This low rate is related both to a low prevalence of malignancy among women with ovarian cysts in a general population and the efficacy of preoperative diagnostic testing. Because the possibility of a malignancy can never be eliminated preoperatively in patients with an ovarian mass, consideration should be given to obtaining consent for an open staging procedure in patients with a suspicious mass.

Oophorectomy versus Cystectomy Two approaches are commonly used for evaluation and treatment of ovarian cysts: oophorectomy and cystectomy. Oophorectomy, with or without removal of the fallopian tube, is the preferred approach for women no longer desiring fertility and for any lesion at moderate to high risk of being malignant to minimize the risk of intraperitoneal spillage. Cystectomy is preferred for low-risk ovarian lesions in women who want to preserve their fertility and young women with only one remaining ovary to preserve hormonal function. Incomplete removal of a cyst is not the procedure of choice but is sometimes necessary. In the case of a small cyst that appears to be functional in nature, aspiration of the cyst contents for cytology, followed by full-thickness biopsy of the cyst wall, is a reasonable technique to resolve the cyst while verifying that it is not a neoplasm. In the case of an endometrioma with no identifiable cyst wall that can be removed, aspiration of the chocolate cyst contents followed by ablation of the internal surface of the cyst may be necessary, but it is associated with an increased recurrence risk. In every case, a full-thickness biopsy of the cyst wall should be sent for pathologic evaluation.

Laparoscopic Setup

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Any standard laparoscopic technique can be used for entry. When dealing with a large lesion it is prudent to use an open laparoscopic technique or a left upper quadrant site. The latter is especially useful for removal of a mass in a pregnant patient. If an open umbilical technique is used, the mass can be removed through this port as well. During removal, the laparoscope is placed through one of the secondary ports to visualize the removal. Most laparoscopists use two or three secondary 5-mm ports for operative procedures. The most common configuration is a suprapubic port 3 to 4 cm above the pubic symphysis and lateral ports at McBurney’s point on the right and the corresponding Hurd’s point on the left, taking care to avoid the epigastric

Before beginning the operative procedure, pelvic washings should be collected. In the absence of ascites, 50 to 100 mL of saline solution is introduced into the peritoneal cavity and aspirated from the cul-de-sac, paracolic gutters, and beneath each hemidiaphragm. The abdominal cavity should be carefully inspected for signs of metastases by taking note of the appearance of the uterus, fallopian tubes, ovaries, cecum, paracolic gutters, colon, liver, gallbladder, diaphragm, omentum, and peritoneal surfaces. The ovarian capsule should be carefully inspected to determine if it is intact or has been penetrated by tumor. Any suspicious excrescences should be biopsied and sent for pathologic evaluation. If malignancy is encountered, a gynecologic oncologist should be consulted intraoperatively. If malignancy is encountered and an oncologist is not available, minimal tissue manipulations and irrigation of trocar sites is recommended. Prognosis is best with rapid reoperation.

Laparoscopic Oophorectomy Laparoscopic oophorectomy is an important technique to be mastered by obstetrician/gynecologists. In addition to minimizing the risk of intraperitoneal spill of ovarian cyst contents, special efforts need to be made to avoid ureteral injury. Knowing the course of the ureters and their relation to the ovarian blood vessels is essential. The ovarian artery originates from the abdominal aorta and courses with the ovarian vein and lymphatics through the infundibulopelvic ligament (i.e., ovarian suspensory ligament). At the superior end of the infundibulopelvic ligament, the ureter crosses beneath the ovarian vessels. The ureter then courses immediately beneath the ovary in the retroperitoneal space adjacent to the peritoneum. It is at these two locations that the ureter is at risk of injury during oophorectomy. The first step in a laparoscopic oophorectomy is to identify the ureter. If the ureter can be clearly identified transperitoneally by its peristalsis and found to be safely beneath the level of the infundibulopelvic ligament, oophorectomy can be performed without opening the pelvic sidewall peritoneum. However, in cases where the ureter cannot be seen because of obesity, adhesions, or thickened peritoneum, the pelvic sidewall peritoneum should be opened. The infundibulopelvic ligament is put on tension and the peritoneum is opened to identify the ureter. The ovarian vessels are skeletonized and occluded using one of a variety of techniques: bipolar cautery, ultrasonic scalpel, a stapling device, or an endoligature (Fig. 50-2). Careful dissection using scissors or one of these power sources is then used to isolate and occlude the utero-ovarian ligament, thereby separating the ovary and tube from their attachments. The dissection bed should be inspected for hemostasis before removal of the ovary from the peritoneal cavity. At the conclusion of laparoscopy, the

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A

B

B

Figure 50-2 A, The retroperitoneal space has been opened and the ovarian vessels are retracted laterally. The ureter is located on the medial leaf of the peritoneal incision. B, After isolation of the ovarian vessels from the surrounding structures, a bipolar device can be safely applied.

Figure 50-3 A, An incision is made on the ovarian cortex to identify the underlying cyst. B, The cortex is dissected off the cyst and the intact cyst is free.

hemostasis of all vascular pedicles should be reevaluated as the intra-abdominal insufflation pressure is decreased.

the ovarian tissue overlying the cyst must be carefully incised without rupturing the cyst. Having carefully inspected the ovary, a site on the ovary should be selected that appears (1) to have the thinnest layer between the cortex and the cyst wall and (2) to have good laparoscopic exposure. Some surgeons use monopolar cautery with the cutting current set at 10 amperes for this purpose. Others prefer gently incising the tissue with sharp scissors. Once a defect is made, the ovarian tissue is bluntly separated from the cyst wall (Fig. 50-3A). The ovarian cortex is held with a grasper and gently peeled away from the underlying cyst (see Fig. 50-3B). This can be facilitated with aid of water dissection from the laparoscopic suction–irrigator. In areas where connections between the cortex and cyst wall do not separate easily, sharp dissection should be used to avoid cyst rupture and spill.

Laparoscopic Ovarian Cystectomy For women with ovarian cysts at low risk of being malignant who desire to maintain their fertility, an ovarian cystectomy is often the best option. With the exception of functional cysts and endometriomas, the cyst wall of benign ovarian cysts can often be easily separated from the ovarian cortex and the cyst removed intact from the peritoneal cavity intact. The goal is to preserve as much normal ovarian cortex as possible, because this is the area containing primordial follicles. In cases where little ovarian tissue remains, the contribution of a small remnant to subsequent fertility and hormone secretion may be minimal. As with oophorectomy, ovarian cystectomy begins with collection of peritoneal washings and careful inspection of the peritoneum for signs of possible implants. Considerable finesse is then required to remove ovarian cysts intact without spillage. Ovarian cysts are ordinarily contained beneath a layer of ovarian epithelium that can be extremely thin. To begin a cystectomy,

Removal of the Ovary or Cyst from the Peritoneal Cavity Once the ovary or a cyst has been excised, the next challenge is to remove the specimen from the peritoneal cavity without

753

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Section 7 Reproductive Surgery spilling any cyst fluid into the peritoneal cavity. The ideal approach is to place the entire specimen intact into a retrieval bag for extraction. Retrieval Bags

Several types and sizes of retrieval bags are available. They can be grouped into two main categories: clear polymer bags and opaque fabric bags. The polymer bags have the advantage of easier intra-abdominal manipulation and better visibility, but are fragile and can be easily punctured or ruptured during extraction of the specimen. The fabric bags have more strength and thus cannot be ruptured, even if excessive force is applied while trying to remove a specimen larger than the port incision. They are somewhat more difficult to place into the abdomen and decrease visibility. In either case, it is important to select a bag big enough to hold the intact specimen whenever possible.

A

Cyst Aspiration and Morcellation in the Bag

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After the specimen is placed into the retrieval bag, the opening of the bag is drawn up into one of the port sleeves. A 10-mm suprapubic or lateral port is usually used, but the umbilical port can also be used if the laparoscope is first placed through an alternative port. The selected incision is encircled with absorbent material to prevent inadvertent fluid contamination of the subcutaneous tissue during specimen extraction. The port sleeve containing the bag opening is removed from the abdominal wall, thus delivering the bag opening through the trocar incision (Figure 50-4). At this point, ovarian cyst contents can be aspirated with little risk of spillage into the peritoneal cavity. Care must be taken to avoid puncturing a polymer bag with the aspiration needle. When the solid portion of the ovary is too large to deliver through the fascial incision, the resected tissue must be morcellated. Grasping and removing small pieces of the ovary with a Kocher forceps while the specimen remains within the intraabdominal portion of the bag can do this. Once enough tissue has been removed, the bag and the remaining contents can be delivered though the incision with gentle twisting traction. Excessive traction will rupture a polymer bag, releasing its contents into the peritoneal cavity. In some cases, the fascial incision must be extended. It is important to remember that most manufacturers of retrieval bags do not recommend morcellation within the bag but rather extending the incision to accommodate the intact removal of the cyst. An alternative method for removing large specimens is to use a colpotomy incision, because the vagina and peritoneum are more distensible than the abdominal wall muscle and fascia. After the specimen has been placed in a bag, a colpotomy incision can be performed laparoscopically with a power-cutting device while tenting the posterior cul-de-sac with a vaginal probe. The closed bag is transferred to a vaginal grasping instrument for removal. Alternatively, a 10-mm laparoscopic probe can be carefully placed through the posterior vaginal fornix so that the pneumoperitoneum is maintained and standard laparoscopic instruments can be used for removal. The colpotomy incision is closed either laparoscopically or transvaginally. After removal of a suspicious mass, a frozen section can be obtained to determine if it is malignant, although this is not as accurate as a permanent section. The approach for the remainder of the surgery can be based on the presumptive diagnosis. The

B Figure 50-4 The cyst is ruptured within a retrieval bag and morcellated without spill into the peritoneal cavity.

defect in the ovary is usually not closed. Suture on the cortex can increase adhesion formation. Occasionally with a large defect an interrupted stitch can be placed deep within the cavity to approximate the bivalve ovary. Treatment of Intraperitoneal Spill

If the contents of a suspicious ovarian cyst are spilled within the peritoneal cavity, the primary treatment is copious irrigation. It is not unusual to use more than 2 L of irrigation fluid to remove all visible cyst contents. Using warmed irrigation fluid will decrease the risk of hypothermia that is associated with large volumes of cool irrigation fluid. In the event that the mass is subsequently determined to be malignant, the gynecologic oncologist should be made aware that spillage has occurred. Large Cysts

Some ovarian cysts may be too large to fit into a retrieval bag before drainage. In this situation, drainage of the cyst before laparoscopic removal is necessary. Because the risk of malignancy increases with cyst size, the importance of minimizing intraperitoneal spill becomes even greater. Informed patient consent concerning this unavoidable risk is essential.

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B Figure 50-5 A, B, An endometrioma cyst wall is being dissected off the ovary. Note that most of the cortex is left intact. C, Bipolar coagulation is used for hemostasis and for destruction of any cystic tissue that was not removed.

C

Intraperitoneal aspiration of a large ovarian cyst can be performed with either a laparoscopic aspiration needle or the suction– irrigation cannulae placed directly through the abdominal wall. Intraperitoneal spillage can be minimized (but not completely prevented) by placing a pursestring suture around the aspiration site before puncture or by placing an endoligature over the drainage site after cyst decompression. After the ovarian cyst has been decompressed, it can be removed from the abdomen.

(Fig. 50-5A and B). Bleeding is common from the dissection bed, and bipolar cautery can be used to cauterize bleeding sites (see Fig. 50-5C). Excessive use of cautery can cause ovarian damage. The cyst wall is then placed in an endoscopic retrieval bag and extracted through a port incision. The specimen should be sent for microscopic evaluation, because malignancies can sometimes be indistinguishable from endometriomas. Excessive removal of ovarian tissue will diminish ovarian reserve.

Laparoscopic Endometrioma Resection Removal of an endometrioma is referred to as cystectomy, but the procedure is markedly different from that used for other ovarian cysts. Endometrioma cyst walls are usually densely adherent to the overlying ovarian tissue. This makes it difficult or impossible to find a surgical plane in many patients, and removing an endometrioma cyst wall intact is rarely possible. The first step in removal of an endometrioma is mobilization of the ovary from any adhesions to the pelvic sidewall or adjacent organs. Many endometriomas will rupture at this point and exude thick “chocolate” fluid. If the cyst remains intact, it will often rupture as the ovarian epithelium covering the cyst is incised. The edge of the cyst wall is separated from the ovarian tissue and is stripped using a combination of blunt and sharp dissection

CONCLUSION Laparoscopy has become the principal means to assess and manage low-risk pelvic masses in women. The laparoscopic approach has distinct advantages over laparotomy, including cost and patient comfort and recovery, and has been shown to be safe. The major concern about the laparoscopic approach is the risk of inadvertent intraperitoneal spillage of a gynecologic malignancy. The risk of this can be minimized by appropriate patient selection and careful surgical technique. Should a harmless-appearing cyst prove to be malignant, prompt and appropriate surgical management with the aid of a gynecologic oncologist is important to optimize long-term outcome.

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PEARLS ●

●

Most cysts in reproductive-age women are functional and require observation only. Most persistent cysts in reproductive-age women are benign and can be treated by laparoscopy with simple removal of the cyst.

●

●

● ●

Appropriate preoperative evaluation will minimize the inadvertent treatment of ovarian malignancies by laparoscopy. An attempt should be made to remove the cyst without rupture. The cyst should then be placed into a retrieval bag. Copious irrigation is required if rupture occurs. It is usually not necessary to suture the ovarian defect.

REFERENCES

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1. Majeed AW, Troy G, Nicholl JP, et al: Randomised, prospective, singleblind comparison of laparoscopic versus small-incision cholecystectomy. Lancet 347:989–994, 1996. 2. Guerriero S, Alcazar JL, Ajossa S, et al: Comparison of conventional color Doppler imaging and power Doppler imaging for the diagnosis of ovarian cancer: Results of a European study. Gynecol Oncol 83:299–304, 2001. 3. Havrilesky LJ, Peterson BL, Dryden DK, et al: Predictors of clinical outcomes in the laparoscopic management of adnexal masses. Obstet Gynecol 102:243–251, 2003. 4. Attaran M, Falcone T, Goldberg J: Endometriosis: Still tough to diagnose and treat. Cleve Clin J Med 69:647–653, 2002. 5. Norris HJ, Jensen RD: Relative frequency of ovarian neoplasms in children and adolescents. Cancer 30:713–719, 1972. 6. Koonings PP, Campbell K, Mishell DR Jr., Grimes DA: Relative frequency of primary ovarian neoplasms: A 10-year review. Obstet Gynecol 74:921–926, 1989 7. Huss M, Lafay-Pillet MC, Lecuru F, et al: [Granulomatous peritonitis after laparoscopic surgery of an ovarian dermoid cyst. Diagnosis, management, prevention: A case report]. J Gynecol Obstet Biol Reprod (Paris) 25:365–372, 1996. 8. Chen L, Nelson SD, Berek JS: Recurrent mature cystic teratoma presenting as a perihepatic mass. Obstet Gynecol 94:856, 1999. 9. Lin P, Falcone T, Tulandi T: Excision of ovarian dermoid cyst by laparoscopy and by laparotomy. Am J Obstet Gynecol 173:769–771, 1995. 10. Nezhat CR, Kalyoncu S, Nezhat CH, et al: Laparoscopic management of ovarian dermoid cysts: Ten years’ experience. JSLS 3:179–184, 1999. 11. Templeman CL, Hertweck SP, Scheetz JP, et al: The management of mature cystic teratomas in children and adolescents: A retrospective analysis. Hum Reprod 15:2669–2672, 2000. 12. Padilla LA, Radosevich DM, Milad MP: Accuracy of the pelvic examination in detecting adnexal masses. Obstet Gynecol 96:593–598, 2000. 13. Schutter EM, Kenemans P, Sohn C, et al: Diagnostic value of pelvic examination, ultrasound, and serum CA 125 in postmenopausal women with a pelvic mass. An international multicenter study. Cancer 74:1398–1406, 1994. 14. Guerriero S, Mallarini G, Ajossa S, et al: Transvaginal ultrasound and computed tomography combined with clinical parameters and CA-125 determinations in the differential diagnosis of persistent ovarian cysts in premenopausal women. Ultrasound Obstet Gynecol 9:339–343, 1997. 15. Andersen ES, Knudsen A, Rix P, Johansen B: Risk of malignancy index in the preoperative evaluation of patients with adnexal masses. Gynecol Oncol 90:109–112, 2003. 16. Finkler NJ, Benacerraf B, Lavin PT, et al: Comparison of serum CA 125, clinical impression, and ultrasound in the preoperative evaluation of ovarian masses. Obstet Gynecol 72:659–664, 1988. 17. Granberg S, Wikland M, Jansson I: Macroscopic characterization of ovarian tumors and the relation to the histological diagnosis: Criteria to be used for ultrasound evaluation. Gynecol Oncol 35:139–144, 1989. 18. Guerriero S, Ajossa S, Garau N, et al: Ultrasonography and color Doppler-based triage for adnexal masses to provide the most appropriate surgical approach. Am J Obstet Gynecol 192:401–406, 2005. 19. Davies AP, Jacobs I, Woolas R, et al: The adnexal mass: Benign or malignant? Evaluation of a risk of malignancy index. BJOG 100:927–931, 1993.

20. Strigini FA, Gadducci A, Del Bravo B, et al: Differential diagnosis of adnexal masses with transvaginal sonography, color flow imaging, and serum CA 125 assay in pre- and postmenopausal women. Gynecol Oncol 61:68–72, 1996. 21. Predanic M, Vlahos N, Pennisi JA, et al: Color and pulsed Doppler sonography, gray-scale imaging, and serum CA 125 in the assessment of adnexal disease. Obstet Gynecol 88:283–288, 1996. 22. Roman LD, Muderspach LI, Stein SM, et al: Pelvic examination, tumor marker level, and gray-scale and Doppler sonography in the prediction of pelvic cancer. Obstet Gynecol 89:493–500, 1997. 23. Alcazar JL, Jurado M: Using a logistic model to predict malignancy of adnexal masses based on menopausal status, ultrasound morphology, and color Doppler findings. Gynecol Oncol 69:146–150, 1998. 24. Guerriero S, Ajossa S, Risalvato A, et al: Diagnosis of adnexal malignancies by using color Doppler energy imaging as a secondary test in persistent masses. Ultrasound Obstet Gynecol 11:277–282, 1998. 25. Alcazar JL, Errasti T, Zornoza A, et al: Transvaginal color Doppler ultrasonography and CA-125 in suspicious adnexal masses. Int J Gynaecol Obstet 66:255–261, 1999. 26. Kobal B, Rakar S, Ribic-Pucelj M, et al: Pretreatment evaluation of adnexal tumors predicting ovarian cancer. Int J Gynecol Cancer 9:481–486, 1999. 27. Mol BW, Boll D, De Kanter M, et al: Distinguishing the benign and malignant adnexal mass: An external validation of prognostic models. Gynecol Oncol 80:162–167, 2001. 28. Mancuso A, De Vivo A, Triolo O, Irato S: The role of transvaginal ultrasonography and serum CA 125 assay combined with age and hormonal state in the differential diagnosis of pelvic masses. Eur J Gynaecol Oncol 25:207–210, 2004. 29. ACOG: The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. ACOG Committee Opinion no. 280, December 2002. Obstet Gynecol 100:1413–1416, 2002. 30. Im SS, Gordon AN, Buttin BM, et al: Validation of referral guidelines for women with pelvic masses. Obstet Gynecol 105:35–41, 2005. 31. Gal D, Lind L, Lovecchio JL, Kohn N: Comparative study of laparoscopy vs. laparotomy for adnexal surgery: Efficacy, safety, and cyst rupture. J Gynecol Surg 11:153–158, 1995. 32. Vergote I, De Brabanter J, Fyles A, et al: Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 357:176–182, 2001. 33. Sainz de la Cuesta R, Goff BA, Fuller AF Jr, et al: Prognostic importance of intraoperative rupture of malignant ovarian epithelial neoplasms. Obstet Gynecol 84:1–7, 1994. 34. Kodama S, Tanaka K, Tokunaga A, et al: Multivariate analysis of prognostic factors in patients with ovarian cancer stage I and II. Int J Gynaecol Obstet 56:147–153, 1997. 35. Dembo AJ, Davy M, Stenwig AE, et al: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75:263–273, 1990. 36. Ahmed FY, Wiltshaw E, A’Hern RP, et al: Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol 14:2968–2975, 1996. 37. Sjovall K, Nilsson B, Einhorn N: Different types of rupture of the tumor capsule and the impact on survival in early ovarian carcinoma. Int J Gynecol Cancer 4:333–336, 1994. 38. Mizuno M, Kikkawa F, Shibata K, et al: Long-term prognosis of stage I ovarian carcinoma. Prognostic importance of intraoperative rupture. Oncology 65:29–36, 2003.

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41. Boriboonhirunsarn D, Sermboon A: Accuracy of frozen section in the diagnosis of malignant ovarian tumor. J Obstet Gynaecol Res 30:394–399, 2004. 42. Cotran RS, Kumar V, Collins T, Robbins SL: Robbins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Company, 1999.

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Surgical Techniques for Management of Anomalies of the Müllerian Ducts and External Genitalia Marjan Attaran, Gita Gidwani, and Jonathan Ross

INTRODUCTION Malformations of the müllerian ducts and the external genitalia can have significant impact on both reproductive potential and sexual function. When a patient presents with such an abnormality, it is important to put significant thought and time into determining the correct diagnosis and subsequent treatment. This is particularly true for surgical management of external genitalia anomalies, where consequences, in terms of gender assignment and later sexual function, remain largely uncertain. This chapter begins with a review of the diagnostic and presurgical evaluation of these anomalies. The majority of the chapter deals with basic principles of surgical techniques used to correct these anomalies. The pathophysiology of genital anomalies is reviewed in Chapter 12.

CLASSIFICATION The classification of müllerian anomalies helps with both diagnosis and the comparison of outcomes after various modes of management. However, there is no single classification that encompasses all anomalies that have been reported in the literature.1–3 On the basis of pathophysiology, müllerian anomalies can be broadly classified into problems according to the developmental mechanism whose failure gave rise to the malformation. Anomalies can usually be classified as being related to (1) agenesis, (2) vertical fusion defects, or (3) lateral fusion defects.4 Agenesis of the uterus and vagina are relatively common abnormalities. Agenesis of other müllerian structures is extremely rare. Vertical fusion defects are usually the result of abnormal canalization of the vaginal plate and result in defects such as a transverse vaginal septum and imperforate hymen. Lateral fusion defects can be symmetrical or asymmetrical and include septum of the uterus and vagina, as well as unicornuate and bicornuate uteri and related abnormalities. The most accepted classification of uterine anomalies, published by the American Society for Reproductive Medicine (ASRM), places uterine anomalies into distinct groups based on anatomic configuration (Table 51-1).5 Because vaginal anomalies are not included in this classification, they must be described along with the uterine anomaly. This classification does not give insight into pathophysiology, but it is an effective way to communicate observations for purposes of treatment and prognosis.

MÜLLERIAN AGENESIS Clinical Presentation Müllerian agenesis (i.e., Mayer-Rokitansky-Küster-Hauser syndrome) was first described in 1829. Its incidence is reported to be 1 in every 5000 newborn females.6 Because the vagina and associated uterine structures do not develop with this disorder, it is a ASRM Class IA müllerian anomaly. Patients typically present during their adolescent years with complaint of primary amenorrhea. As a cause of primary amenorrhea, müllerian agenesis is second only to gonadal dysgenesis.7 Patients with müllerian agenesis will present with normal onset of puberty and appropriate secondary sexual characteristics, but apparently delayed menarche. They do not complain of cyclic pelvic pain like patients with obstructive müllerian anomalies. The external genitalia appear completely normal, with normal pubic hair growth and normal-size labia minora, which is in contrast to patients with complete androgen insensitivity syndrome. Hymeneal fringes may be evident, but the vaginal opening is absent. No pelvic masses suggestive of hematocolpos will be evident, which is in contrast to cases of complete transverse septum.

Table 51-1 ASRM Classification of Müllerian Anomalies I. Hypoplasia/Agenesis a. Vaginal b. Cervical c. Fundal d. Tubal e. Combined II. Unicornuate a. Communicating b. Noncommunicating c. No cavity d. No horn III. Didelphus IV. Bicornuate a. Complete b. Partial V. Septate a. Complete b. Partial VI. Arcuate VII. DES-related

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Section 7 Reproductive Surgery Because these patients have a 46,XX karyotype, normal ovaries will be present in the pelvis. Ovulation can be documented as a shift in basal body temperature. These patients’ hormonal levels are normal, and their cycle length based on hormonal studies varies from 30 to 34 days.8 In addition they may experience the monthly pain (mittelschmertz) that is indicative of ovulation.

Associated Anomalies Some but not all anomalies described can be extrapolated from the embryology.9–12 Hearing difficulties have been reported in patients with müllerian agenesis.10,11 A higher rate of auditory defects have been noted in general in patients with müllerian anomalies compared to those with normal müllerian structures.12 Müllerian agenesis is associated with renal and skeletal system anomalies. Renal abnormalities are noted in 40% of these patients. These include complete agenesis of a kidney, malposition of a kidney, and changes in renal structure.13 Skeletal abnormalities are noted in 12% of patients and include primarily spine defects followed by limb and rib defects.14 Patients with müllerian agenesis should be actively assessed for these associated anomalies.

Etiology The etiology of müllerian agenesis remains unknown. It appears to be influenced by multifactorial inheritance, and rare familial cases have been reported. It does not appear to be transmitted in an autosomal dominant inheritance pattern, because none of the female offspring of women with müllerian agenesis (born via in vitro fertilization [IVF] and surrogacy) have shown evidence of vaginal agenesis.9

Diagnosis Imaging

The diagnosis of müllerian agenesis is confirmed via imaging techniques. Abdominal ultrasonography will demonstrate the lack of uterus and existence of ovaries. The presence of a midline mass consistent with a blood collection usually indicates an obstructive müllerian anomaly. The distinction between müllerian agenesis and obstruction is extremely important, because an incorrect diagnosis can seriously jeopardize appropriate management. With the advent of magnetic resonance imaging (MRI), laparoscopy is no longer considered necessary to make this diagnosis. Typical findings in the pelvis include normal ovaries and fallopian tubes, and usually small müllerian remnants attached to the proximal portion of the fallopian tubes, that may be solid or have functioning endometrial tissue. Direct communication with the radiologist about the differential diagnosis before imaging studies is important. On occasion, the unsuspecting radiologist may interpret the small uterine remnants as a uterus. Careful attention to the very small dimensions of this structure will alert the physician to this possibility.

be reassured that her external genitalia appear normal and that she will be able to have a normal sex life after the creation of a normally functioning vagina. Although usually not voiced, the inability to subsequently bear children is a major disappointment to teenagers. Fortunately, with assisted reproductive technology procedures, including IVF and surrogacy, having her own genetic child will be an option for many of these young women.

CREATION OF A NEOVAGINA The first goal of treatment of müllerian agenesis is creation of a functional vagina to allow intercourse. Frank first proposed vaginal dilation with use of a dilator as a means of creating a neovagina in 1938.15 However, the surgical techniques of vaginoplasty remained the preferred methods for many years. The success of any technique depends in large part on the emotional maturity of the patient. Pretreatment counseling and continued support during treatment is important.

Vaginal Dilation The simplicity and ease of vaginal dilation and its significantly lower complication rate than surgical techniques dictates its use as initial form of therapy for most patients with müllerian agenesis. The American College of Obstetricians and Gynecologists recently released a committee opinion that recommends nonsurgical management of müllerian agenesis as the first mode of treatment.16 Frank’s technique of dilation involves actively placing pressure with the dilators against the vaginal dimple (Fig. 51-1). The patient is not only in an awkward position, but the hand applying the pressure can also become tired. In 1981, Ingram proposed the concept of passive dilation, where pressure is placed on the dilator by sitting on a bicycle seat.17 Roberts reported a success rate of 92% in women who dilated the vagina via the Ingram technique for 20 minutes three times a day.18 The average time to creation of a functional vagina was 11 months. This series demonstrated that an initial dimple less than 0.5 cm was all that was necessary to achieve adequate dilation. Interestingly, failure of this technique was not related to length of vaginal dimple but rather was more closely associated

Explaining the Diagnosis to the Patient

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The diagnosis, usually made in early adolescence, must be explained to the patient with great sensitivity. At a time when being like her peers is extremely important, knowledge of this diagnosis can be psychologically devastating. Each patient must

Figure 51-1

Examples of vaginal dilators of different sizes.

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Chapter 51 Surgical Management of the Müllerian Ducts and External Genitalia on the patient’s desires. The median age of starting treatment is 17 years.22 For appropriately selected motivated patients, the reported success rates are as high as 90%.23

Anterior abdominal wall

Vecchietti Procedure Bladder

Posterior direction

Peritoneal cavity

Giuseppe Vecchietti described this method of creating a neovagina in 1965.24 Similar to vaginal dilation, this method avoids the use of a graft. The Vecchietti procedure is a one-step procedure in which a neovagina is created in 7 days by continuous pressure on the vaginal dimple using an acrylic olive connected by retroperitoneal sutures to a spring-tension device on the lower abdomen. Although the original description of the Vecchietti procedure utilized laparotomy, this technique is currently performed laparoscopically.25,26 Procedure

Rectum

Figure 51-2 Schematic drawing of angle of dilator placement. The patient is viewed in lithotomy position and the axis is directed away from the bladder.

with the patient’s youth. Failure of this technique was more common in patients younger than age 18. Procedure

When the patient expresses a desire to proceed with therapy, she is shown the exact location of her vaginal dimple. The axis of dilator placement is also demonstrated (Fig. 51-2). The process is initiated by placement of the smallest dilator against the dimple. Pressure is kept on the distal aspect of the dilator by sitting on a stool while leaning slightly forward. When the dilator fits comfortably she moves to the next size dilator. The patient is instructed to use this technique a minimum of 20 minutes a day, two to three times a day. In motivated patients, a functional vagina can be created in as short as 12 weeks. Counseling and psychological support is integral to successful treatment.19–21 Patients are requested to return to the office frequently to monitor their progress, provide guidance, and have an opportunity to answer questions. Intercourse may be attempted when the largest dilator fits comfortably. Multiple types of graduated dilators, made of various materials, are present on the market. None have been found superior to the others. Patients may stop and reinitiate the dilation at any time without any negative long-term sequelae. Although most patients appear interested in initiating this therapy the summer before college when they are mature enough and motivated to create the vagina, the timing of therapy is purely dependent

The first step in this procedure is to use a sharp ligature carrier (similar to a Stamey needle) to insert one end of a suture through the retrohymeneal dimple into the peritoneal cavity between the bladder and the rectum under laparoscopic guidance. The other end of this number 2 polyglycolic acid suture is placed through a 3-cm acrylic olive and likewise inserted through the dimple into the peritoneal cavity using the sharp ligature carrier. The next step is to use a curved blunt ligature carrier to burrow retroperitoneally from a lateral suprapubic laparoscopic port site to the peritoneal fold between the bladder and the uterine rudiment. One end of the olive suture is placed through the eye of this curved ligature carrier and pulled retroperitoneally back through the abdominal wall port site incision. This procedure is repeated on the opposite side with the other end of the suture. After the laparoscope is removed and the abdominal wall incisions are closed, the ends of the suture are attached to a suprapubic Vecchietti spring-traction device located externally on the abdomen.25 Postoperatively, constant traction is applied to the perineal olive by daily readjustment of the tension of the sutures and traction device. The neovagina lengthens by 1 to 2 cm per day, such that a 10- to 12-cm vagina is created in 7 to 9 days. After creation of the vagina, the olive (now located at the apex of the neovagina) is removed and the patient is sent home with a vaginal mold in place. After surgery, it is important to initiate regular sexual intercourse or routinely use dilators to maintain vaginal length. Vecchietti reported a series of more than 500 patients with a success rate of 100% and only nine complications, including one bladder and one rectal fistula.27 Several smaller studies have subsequently been reported by other surgeons with similar outcomes.28,29 A 3-year follow-up study assessed the functional and psychological outcome in five patients.30 All five subjects reported having a functioning vagina allowing satisfactory intercourse and improvement in general well-being.

Vaginoplasty Techniques The traditional surgical management of vaginal agenesis is to create a vaginal space followed by placement of a lining to prevent stenosis. Multiple tissues and at least one manmade material have been used to line this cavity with varying degrees of success in preventing subsequent stenosis of the neovagina (Table 51-2).

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Section 7 Reproductive Surgery Table 51-2 Surgical Methods of Creating a Neovagina Dissection of a perineal space Split-thickness skin graft (McIndoe operation) Full-thickness skin graft Peritoneum (Davydov procedure) Amnion Muscle and skin flap Adhesion barriers Tissue expansion Bowel vaginoplasty Sigmoid colon Vulvovaginal pouch Williams vaginoplasty Traction on retrohymeneal fovea Vecchietti procedure

Figure 51-4 The initial transverse cut was made on the fibrous tissue and an initial space developed.

Figure 51-3

Skin graft is sutured around a mold.

McIndoe Procedure

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The most widely used surgical technique for creation of a neovagina is the McIndoe operation. The first step of the procedure is obtaining the split-thickness skin graft. The plastic surgery team typically acquires the skin graft from the buttock area, a location usually covered by clothing. The patient is placed in the prone position and the site is cleansed with an antiseptic solution and then soaked with an epinephrine saline gauze to allow vasoconstriction of small punctate bleeding sites. Mineral oil is applied to the donor site and the skin is held taut while the electrodermatome device is used to obtain a thick split-thickness skin graft. The skin graft should be 0.015 to 0.018 inch thick. After application of antiseptic solution, the donor site is covered with Op-Site, which is fixed in place by several stitches. Within 2 to 3 weeks the area heals with acceptable scarring. The skin graft is placed through a 1:5 ratio skin mesher. The purpose of meshing the skin is not to stretch it but rather to allow escape of any underlying blood clots or serous fluids. This skin graft is sutured around the mold with 4-0 absorbable suture (Fig. 51-3). The mold is covered completely, because any uncovered sites, whether due to lack of enough tissue or a gaping hole in the line of suture, tend to result in the formation of granulation tissue. Thus great care must be taken to obtain a sufficient amount of graft for this procedure.

The patient is placed in the dorsolithotomy position. A transverse incision is made in the vaginal vestibule, between the rectum and urethral openings (Fig. 51-4). In a patient who has not had prior surgery or radiation in the area, areolar tissue is now encountered. This tissue is easily dissected with either fingers or a Hagar dilator on either side of a median raphe (Fig. 51-5). The dissection is continued for at least the length of the mold without entering the peritoneal cavity. By cutting the median raphe, the two channels are then connected. If the dissection is performed in this manner, minimal bleeding is encountered. Any bleeding sites must be controlled meticulously to avoid lifting of the graft from the newly created vaginal wall and subsequent nonadherence and necrosis. After creation of the vaginal space, the mold covered with the skin graft is placed inside the cavity (Fig. 51-6). At the introitus, the skin graft is attached with several separate 3-0 absorbable stitches. To hold the mold in place, several loose nonreactive sutures such as 2-0 silk are used to approximate the labia minor in the midline. During the ensuing week, the patient is maintained on bed rest, broad-spectrum antibiotics, a low-residue diet, and an agent to decrease bowel motility. She also has an indwelling urinary catheter in place. On return to the operating room in 1 week, the mold is carefully removed. The vaginal cavity is irrigated with warm saline solution and the graft site is carefully assessed for any signs of necrosis or underlying hematoma. Another soft mold is then reinserted and kept in place for the next 3 months except during defecation and urination. Nighttime usage of the mold is recommended for the next 6 months. To prevent contracture of the vagina, the patient is instructed to reinsert the mold during extended times of sexual inactivity. Difficulty in dissecting the neovagina and increased probability of bleeding and fistula formation is encountered in the patient with a prior surgical procedure. Other problems that may be

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Figure 51-5 Placement of Hagar dilator to create space for the graft. The direction of the Hagar dilators is posterior.

Figure 51-6 The mold with the graft is placed in the space. Notice that the space to be created must accommodate the mold completely.

Figure 51-7

Hard glass mold.

Figure 51-8

Adjustable vaginal mold (Mentor, Minneapolis).

encountered include narrow subpubic arch, strong levators, shorter perineum, prior hymenectomy, and congenitally deep cul-de-sac.31 Because of concern regarding tissue necrosis from mold pressure and subsequent fistula formation, both rigid and soft molds have been used for this procedure (Figs. 51-7 and 51-8). Theoretically, soft molds decrease the risk of fistula formation that can result from avascular necrosis. A soft mold can be created by covering a foam rubber block with a condom.32 The foam is able to expand and fit the neovaginal space, thereby providing equal pressure throughout the canal. However, a report on the use of a rigid mold on 201 patients who underwent the McIndoe operation demonstrated a fistula formation rate of less than 1%.33 There is no study comparing the outcomes of soft versus rigid molds in this operation. Typically a rigid mold is used initially, but the patient is sent home with a soft mold in place. An 80% success rate has been reported with this procedure.34 Because success rates are highest in those patients that have not undergone prior vaginoplasty, patients must be counseled extensively before surgery regarding the need for prolonged use of the mold. Indeed, part of the presurgical assessment involves determination of patient maturity and motivation concerning the use of dilators. Lack of compliance with postoperative use of dilators will lead to contracture and diminishment of vaginal length.

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Section 7 Reproductive Surgery Surgical complications include postoperative infection and hemorrhage, failure of graft and formation of granulation tissue, and fistula formation. In general the incidence of complications are low: a rectal perforation rate of 1%, graft infection in 4%, and graft site infection of 5.5%.33 In a review of 50 patients, 2 rectovaginal fistulas and 1 graft failure were reported.31 Five patients required an additional operative procedure. Eighty-five percent of these patients considered their surgery to be a success. Long-term data on the McIndoe procedure, although limited, consistently indicate an improvement in quality of life. In a series of 44 patients who underwent a surgical procedure to create the vagina, 82% achieved a functional satisfactory postoperative result.35 Vaginal length varied from 3.5 to 15 cm. In another long-term study of women who underwent a McIndoe procedure, 79% of the patients reported improved quality of life, 91% remained sexually active, and 75% regularly achieved orgasm.36 The newly created vagina must be inspected at the time of the yearly pelvic examination and regular pap tests. Hair growth has been reported to be a problem with some skin grafts. Transformation to squamous cell carcinoma from skin graft has been described.37,38

of clothlike oxidized regenerated cellulose are wrapped around the mold and placed in the vagina in a manner similar to the McIndoe. The neovaginal space must be free of any bleeding. Epithelialization is noted to occur within 3 to 6 months. Small areas of granulation tissue may be seen at the apex of the vagina and resolve after application of silver nitrate. Average vaginal depth ranges from 6 to 12 cm. Continuous use of the mold is encouraged until complete epithelilization has occurred. A case series assessed the outcome of this technique on 10 patients with vaginal agenesis.46 Complete squamous epithelialization was noted within 1 to 4 months. When compared to a normal vagina, fern formation was noted and the vaginal pH was always acidic. However, none of the women complained of vaginal dryness or foul-smelling discharge. Patients who were sexually active did not report any problems. The advantages of use of oxidized regenerated cellulose include avoidance of any scars, readily available product, and low expense. In addition, the surgical procedure is simplified into a one-stage procedure. Although the reported data appear encouraging, confirmatory studies are required before use of oxidized regenerated cellulose can be recommended without any reservations. Amnion Lining

Peritoneal Graft: Davydov Procedure

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Amnion has also been used to line the neovagina cavity.47 Advantages include lack of a graft site, potential antibacterial effect, and lack of expression of histocompatibility antigens.48,49 Eight to 10 weeks after placement of amnion into the vaginal canal, the resulting epithelium was found to be “identical” to normal vaginal epithelium.50 However, concern about transmission of an infection with use of amnion has limited its use in the United States.

Use of the peritoneum to line the newly created vaginal space was popularized by Davydov, a Russian gynecologist, and first described by Rothman in the United States in 1972.39–41 In his original description, a laparotomy is performed after creation of the vaginal space, as described with the McIndoe operation. A cut is made on the peritoneum overlying the new vagina. Long sutures are applied to the anterior posterior and lateral sides of this peritoneum. The sutures are then pulled down through the vaginal space, thus pulling the peritoneum to the introitus. The edge of the peritoneum is then stitched to the mucosa of the introitus. Closing the peritoneum on the abdominal side then forms the top of the vagina. Several investigators have also described the laparoscopic modification of this procedure.42–44 This procedure may have several advantages compared to the traditional McIndoe. Contrary to skin grafts that leave visible scarring at the donor site, there is no outward sign of using a graft in the Davydov procedure. There appears to be no danger of lack of graft takes and no problem with hair growth. In Davydov’s first reported series, sexual intercourse was initiated within several weeks of surgery in all but one of his 30 patients. On follow-up, the length of the vagina was noted to be 8 to 11 cm. In a series of 18 patients who underwent the laparoscopic modification of this procedure, 85% reported being sexually satisfied during an 8- to 40-month follow-up. Although there was one report of a rectovaginal fistula 18 months after the surgery, there was no evidence of vault prolapse or enterocele formation. Minor granulation tissue was noted at the vaginal cuff, but the vault was primarily covered with squamous epithelium tissue.

These approaches are not procedures of choice for women with vaginal agenesis. However, they may be used for those who require vaginal reconstruction after exposure to radiation or multiple surgical procedures. The advantage of using a fullthickness skin flap is that it avoids the problem of contracture encountered with split-thickness grafts. The use of gracilis myocutaneous flaps and rectus abdominis myocutaneous flaps for vaginal reconstruction has been reported.51,52 This approach has been associated with a conspicuous scar and a higher failure rate. Wee and Joseph in Singapore designed flaps that maintained good blood supply and innervation.53 Known as a pudendal–thigh flap vaginoplasty, this technique has been particularly successful in patients with vulvar anomalies.54 In one study of patients with müllerian agenesis, 100% success in creating a functional vagina was reported.55 The patient’s own labia majora and labia minora have also been used to create a vagina.56 Tissue expansion has also been advocated to create labiovaginal flaps, which are then used to line the neovagina.57,58 Other modifications of this procedure have been reported.59,60

Adhesion Barrier Lining

Bowel Vaginoplasty

Jackson first described the use of an adhesion barrier to line the neovagina in 1994.45 Oxidized regenerated cellulose (Interceed; Johnson and Johnson Patient Care Inc, New Brunswick, N.J.) forms a gelatinous barrier on raw surfaces and thus prevents adhesion formation. After creation of the vaginal space, sheets

This is not a procedure of choice in women with vaginal agenesis. For this procedure, also known as a colocolpopoiesis, a portion of large bowel with its preserved vascular pedicle is sutured into the neovagina. In recent years, sigmoid colon use has been recommended.

Muscle and Skin Flap

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Chapter 51 Surgical Management of the Müllerian Ducts and External Genitalia Figure 51-9 Magnetic resonance image of functioning rudimentary bulbs.

metrial shedding, and development of endometriosis has been reported in these patients. Symptomatic müllerian bulbs should be removed either via laparotomy or laparoscopy.

Surgical Technique The procedure is started by placing traction on the ipsilateral uterine bulb. The round ligament is grasped, cut, and the peritoneum incised anteriorly, thereby creating a bladder flap. The retroperitoneal space is entered, the ureters identified, and the utero-ovarian ligaments transected. The dissection continues with identification and coagulation of the uterine arteries. Finally, the uterine remnants and the fibrous tissue connecting them are incised.

CERVICAL AGENESIS Figure 51-10

Pathologic specimen of the extirpated rudimentary bulbs.

Continuous use of dilators is not considered necessary, although constriction has been noted when ilium has been used. Success rates of up to 90% have been reported. Reported complications include profuse vaginal discharge, prolapse, introital stenosis, bowel obstruction, and colitis.61,62 Finally there is a report of a mucinous adenocarcinoma arising in a neovagina lined with the sigmoid colon.63 A laparoscopic modification of this procedure has also been described.64,65 Given the increased complication rates, it seems appropriate to reserve this treatment modality for complex situations where a prior vaginoplasty technique has failed or when there are multiple urogenital malformations.

OBSTRUCTED RUDIMENTARY UTERINE BULBS Patients with müllerian agenesis commonly have müllerian remnants noted on MRI or during a laparoscopy. The MRI has the added value of determining if any endometrial tissue exists within these remnants (Figs. 51-9 and 51-10). Patients with functional endometrial tissue may present after many asymptomatic years with cyclic pelvic pain secondary to monthly endo-

Cervical agenesis is a rare müllerian anomaly whose true incidence remains unknown despite many case reports in the literature.66 Various degrees of cervical abnormalities, ranging from dysgenesis to agenesis, have been described.67 The vagina may or may not be present in patients with cervical agenesis. In a series of 58 patients with cervical atresia, 48% had isolated congenital cervical atresia with a normal vagina.68 The rest of the patients had either a vaginal dimple or complete atresia.

Diagnosis Unlike some of the other müllerian anomalies, patients with cervical agenesis present very early in adolescence. Typically, patients present between ages 12 and 16 with a primary complaint of pelvic pain secondary to obstruction of flow from the uterus. Initially, the pain is cyclic, but it may evolve with time into continuous pain. It is not uncommon for such patients to have been evaluated by their pediatricians for other causes of abdominal pain. Although these girls have amenorrhea, this symptom fails to raise a red flag because the patients are so young at presentation that lack of menses is not concerning. Continuing menstruation in an obstructed uterus forms a hematometra, and possibly hematosalpinx, endometriosis, and adhesions in the pelvis (Figs. 51-11 and 51-12). Imaging of such a pelvis can easily lead to a misdiagnosis. Such patients have been taken to surgery for pain thought to be secondary to a pelvic mass, only to find that they have a congenital

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Section 7 Reproductive Surgery Management Pain Control

Figure 51-11

Schematic representation of cervical agenesis.

Pain control should be the first goal of treatment. Although analgesia may be required, severe pain will resolve within several days. Suppressive therapy is used to prevent further endometrial shedding until definitive surgery can be performed. Agents that are commonly used to achieve this suppression are continuous oral contraceptive pills, norethindrone acetate, depot-medroxyprogesterone acetate (DMPA), and gonadotropin-releasing hormone agonists or antagonists. Most adolescents are neither emotionally ready nor equipped to decide on a surgical course of action that may be as invasive as hysterectomy. Thus, if suppressive therapy with oral contraceptives or DMPA has provided pain relief, many may choose to hold off on definitive surgical therapy until they can fully understand the possible consequences. In addition, this alleviates the burden placed on parents to make a decision regarding their daughter’s reproductive future. Surgical Approach

Figure 51-12 Magnetic resonance image of cervical agenesis. The uterine cavity is distended with clots and no cervix is identified.

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anomaly. Although ultrasound may be helpful in looking for a cervix, one’s clinical suspicion must be communicated directly to the radiologist performing the procedure. MRI is very helpful in visualizing the cervix and can accurately determine its presence or absence.69–71 Patients with cervical agenesis who lack a vagina must be differentiated from those with a high obstructing vaginal septum. MRI is very helpful in making this differentiation by showing accumulation of blood in the upper vagina and a cervix in patients with a high transverse septum. Lack of a hematocolpos helps make the diagnosis of cervical agenesis or dysgenesis. Theoretically, MRI should detect absence of the cervix, but is unable to clearly differentiate among the various degrees of cervical dysgenesis.

There are no specific guidelines in the literature to determine the correct surgical procedure. It is clear, however, that each patient should be assessed individually. The definitive and safest treatment of cervical agenesis remains total abdominal hysterectomy. A hysterectomy would diminish continued physical pain and discomfort. In addition, with the advent of surrogate pregnancy, an early hysterectomy would potentially preserve more ovarian tissue, which may be used to achieve a pregnancy via surrogacy and IVF. On the other hand, it is a daunting decision to have a hysterectomy at a young age. The other surgical options for management of cervical dysgenesis are cervical canalization or uterovaginal anastomosis. There are many reports in the literature of cervical canalization and stent placement.72–74 Although success has been reported with establishment of menses, many patients will require reoperation secondary to fibrosis of the cervical tract and obstruction. In addition, pregnancy rates are very low. In a review of patients with cervical agenesis, 59% of those that underwent cervical canalization achieved normal menstruation. Four of the 23 who achieved cervical patency required multiple surgeries.68 The task is even more daunting if there is also a vaginal anomaly that requires reconstruction. There are several forms of cervical dysgenesis that are sometimes confused with agenesis.75 A hysterectomy may be considered in those patients with no evidence of a cervix, but canalization or uterovaginal anastomosis may be considered in those with a vagina and an obstructed cervix. Although preserving fertility is ultimately the goal of canalization procedures, sepsis and death have been reported subsequent to canalization.76 In addition, subsequent pregnancy rates are very low.73,77 The poor pregnancy rates may be attributed to several factors. Prolonged delay in diagnosis can lead to extensive endometriosis and scarring in the pelvis. Also, although canalization and stent placement may maintain an open pathway for menstruation, the lack of epithelization of the fistula not only increases the risk of fibrosis, but also may impede sperm migration into the uterus. The only pregnancy that was achieved in Rock’s series was one in whom a full-thickness skin graft was used in

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Chapter 51 Surgical Management of the Müllerian Ducts and External Genitalia Figure 51-13 The appearance of a bicornuate uterus at laparoscopy. Note the peritoneal band between the two horns.

the canalized area.75 More recently the use of bladder mucosa to line the newly created cervical canal was reported.72 After preoperative assessment and formation of the operative plan, the surgeon must be prepared to proceed with a concomitant vaginoplasty if indeed the patient suffers from vaginal atresia. The patient should have been preoperatively counseled regarding the need for prolonged use of a mold after surgery. Advances in artificial reproductive techniques have led to reports of pregnancies in patients with cervical agenesis. Thus, many patients are likely to choose effective continued endometrial suppression over a surgical solution in hopes of keeping a glimmer of reproductive hope. With the passage of time and attainment of adulthood, such patients may be better able to accept the diagnosis and its consequences.

UTERINE FUSION DEFECTS Uterine fusion defects include septate, bicornuate, and didelphic uteri. Patients with these isolated uterine anomalies are asymptomatic. The diagnosis is usually made during evaluation of infertility, recurrent pregnancy loss, or an obstetric complication. Correct diagnosis of these anomalies is of utmost importance, because their management varies significantly.78 The diagnosis is typically made based on evaluation of anatomy via imaging techniques, including ultrasonography, hysterosalpingography (HSG), and MRI or via laparoscopy and hysteroscopy. Although radiologic guidelines exist to differentiate these entities, the multitude varieties of these malformations can pose a significant challenge in making the correct diagnosis.

Septate Uterus Reproductive difficulties are encountered far more commonly in women with a septate uterus than any other uterine fusion defect. The septate uterus is associated with the highest spontaneous abortion rate of the uterine fusion defects. The management of uterine septum detected after an evaluation for recurrent pregnancy loss is hysteroscopic resection of the septum (see Chapter 43). However, the management of a septum found during an infertility investigation is less straightforward.78 Although the septum does not appear to cause infertility, the concern regarding possible spontaneous abortion after undergoing infertility treatment may be enough to justify hysteroscopic removal of the septum before infertility treatment. On a historical note, in the distant past a uterine septum was sometimes removed along with the midline section of the uterus via laparotomy using a Jones or Tompkins metroplasty procedure. These relatively extreme approaches have been completely supplanted by hysteroscopic septoplasty, described in Chapter 43.

Bicornuate Uterus The most frequently diagnosed uterine malformation is the bicornuate uterus (Fig. 51-13).79 This anomaly is usually discovered incidentally during an investigation for infertility or recurrent pregnancy loss. It is important to differentiate a bicornuate from a septate uterus. HSG alone cannot differentiate these entities, because this imaging approach cannot evaluate the external contour of the uterus. Laparoscopy was used primarily for this purpose in

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Section 7 Reproductive Surgery the recent past; modern imagining techniques, including ultrasonography and MRI, can adequately differentiate these two entities (see Chapter 31). Imaging criteria to differentiate septate and bicornuate uteri have been developed.80,81 A septate uterus has a flat or convex fundus or a fundal indentation less than 10 mm. The septum should be relatively thin, such that the angle between the medial borders of the hemicavities is smaller than 60 degrees. A bicornuate uterus has two distinct funduses with an intervening fundal indentation of at least 10 mm. In most cases, the angle between the medial borders of the hemicavities will be greater than 60 degrees. On MRI, a septate uterus will fail to show an intervening myometrium between the T2-hypointense septum that separates the endometrial cavities.80,81 In contrast, a bicornuate uterus will show two T2-hyperintense endometrial cavities, each with a junctional zone and myometrial band of intermediate signal intensity. Conception does not appear to be a problem in women with bicornuate uterus.78 However, higher rates of preterm delivery (19%) and spontaneous abortion (42%) have been reported.82 Uteroplacental insufficiency and cervical incompetence may play roles in the higher obstetric complications. Thus, the treatment options for bicornuate uterus may include Strassman metroplasty and cervical cerclage. Because the benefit of metroplasty has never been established in a controlled study, it is typically considered only after multiple pregnancy losses and complications.83 Surgical Technique: Strassman Metroplasty

The Strassmann metroplasty is the procedure of choice in the uncommon case where unification of a bicornuate uterus is indicated.13 Via laparotomy, a transverse incision is made across the fundus of the bicornuate uterus. The opened cavity is then repaired in an anteroposterior fashion. Because the subsequent length of gestation appears to increase after each pregnancy loss in patients with a bicornuate uterus (due to myometrial stretching or unknown factors), metroplasty is always the procedure of last resort.

Didelphic Uterus The didelphic uterus is defined as two completely separate uteri and cervices. It accounts for 10% of all uterine anomalies.79 On ultrasonography, the two bulbs of the uterus are distinctly noted and can be followed down to their individual cervices. Surgical correction is not indicated. In a long-term follow-up of 49 patients with didelphic uteri, 89% of those desiring pregnancy had at least one living child.84 The spontaneous miscarriage rate was 21%, and only one ectopic pregnancy occurred. The most common problem was preterm delivery, which occurred in 24% of pregnancies. Fortunately, only 7% of the infants weighed less than 1500 gm at birth. Breech presentation was noted in 51% of the infants, and thus the cesarean section rate is increased.

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Figure 51-14

Noncommunicating uterine horn seen at laparoscopy.

patient is unlikely to have severe dysmenorrhea. The diagnosis in these patients is usually made at the time of investigation for infertility, obstetric problems (including recurrent pregnancy loss), or at the time of cesarean section. In contrast, if a noncommunicating rudimentary horn is functioning, most patients will have severe dysmenorrhea unresponsive to medical therapy (Fig. 51-14).

Diagnosis Pelvic examination may reveal a deviated uterus or an adnexal mass. Ultrasonography will be consistent with a unicornuate uterus on one side, while the other side may be interpreted as a rudimentary horn, a pedunculated leiomyoma, or an ovarian endometrioma. HSG will show a unicornuate uterus and will often, but not always, demonstrate the presence of a communication with the rudimentary horn when present. In uncertain cases, an MRI is often useful in making a definitive diagnosis.

Management Management depends on whether the rudimentary horn is functional or communicating. A nonfunctioning, noncommunicating rudimentary horn does not need to be removed, as it will be asymptomatic and not put the patient at any risk. In contrast a functioning, noncommunicating rudimentary horn should be removed on diagnosis to alleviate the patient’s often severe dysmenorrhea and to avoid the risk of rupture, should a pregnancy occur in this horn.85 It would seem that a functioning, communicating rudimentary horn could be left in situ, since it is unlikely to be symptomatic for the patient. However, there is a risk of developing a pregnancy in such a horn, leading to subsequent rupture if undiagnosed.86 Therefore, surgical removal is recommended before attempting pregnancy.

UNICORNUATE UTERUS AND RUDIMENTARY HORN

Surgical Technique: Removal of a Rudimentary Horn

A unicornuate uterus may be associated with a communicating or noncommunicating rudimentary horn. In either case, patients will have monthly regular periods. If a rudimentary horn is communicating or noncommunicating but nonfunctioning, the

A rudimentary uterine horn can be removed via laparotomy or laparoscopy using similar techniques, depending on surgical experience.87 After gaining access to the pelvis, the round ligament of the rudimentary horn is identified, ligated, and divided. Access is gained into the retroperitoneal space, the ureter is identified,

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Chapter 51 Surgical Management of the Müllerian Ducts and External Genitalia and the bladder is dissected off the lower border of the rudimentary horn. The rudimentary horn should be removed together with the corresponding fallopian tube to avoid a future ectopic pregnancy in a blind residual tube via sperm transmigration. After disconnecting the tube from the mesosalpinx, the utero-ovarian ligament is transected so that the ovary can be spared. The rudimentary horn may share myometrial tissue with the unicornuate uterus or be attached by a band of fibrous tissue.87,88 In cases where the uterine horn is attached to the uterus with a fibrous band, the blood supply is found within this band. Coagulation and transection of the band is all that is required. In cases where the rudimentary horn is attached to the uterus via shared myometrium, the blood supply cannot be easily identified; thus the uterine artery ascending beneath the rudimentary horn should be identified and ligated. It may be difficult to find a plane of dissection between the horn and the uterus, but care must be taken to avoid entry into the cavity of the unicornuate uterus or compromising the integrity of the myometrial thickness. After this dissection, the myometrial defect should be carefully reapproximated with interrupted or continuous sutures to minimize the risk of uterine rupture during a subsequent pregnancy.

LONGITUDINAL VAGINAL SEPTUM A longitudinal vaginal septum can be either nonobstructing or obstructing. A nonobstructing vaginal septum is often asymptomatic and discovered at the time of a pelvic examination or childbirth. A woman with an obstructing vaginal septum often presents with increasingly severe dysmenorrhea and a unilateral vaginal mass.

The Nonobstructing Longitudinal Vaginal Septum Nonobstructing longitudinal vaginal septa account for 12% of the malformations of the vagina. Although most are asymptomatic, some patients complain of continued vaginal bleeding despite placement of a tampon, difficulty removing a tampon, or dyspareunia. These septa may be complete or partial and can exist in any portion of the vagina (Fig. 51-15). The communication can be extremely small and a septum can easily be missed during physical examination, especially if there is a dominant vaginal canal. Once the diagnosis is made, both the uterus and renal anatomy should be assessed for associated anomalies. In one study, 60% of patients with longitudinal vaginal septa were found to have a bicornuate uterus.89 Other investigators have noted a predominance of didelphic uteri in such cases.90 A longitudinal vaginal septum should be removed in patients with complaints of dyspareunia and those who desire to be able to effectively use a tampon. In cases of didelphic uteri, removal of the septum may be necessity to allow sufficient access to each cervix for Pap smears. Some obstetricians advocate removal of a longitudinal vaginal septum before delivery to avoid potential dystocia and laceration of the septum.89 The number of patients with vaginal septa who have had successful vaginal deliveries remains unknown. However, emergent resection of a vaginal septum at the time of delivery to resolve dystocia has been reported.91 It seems reasonable to remove a thick longitudinal septum before pregnancy or before delivery if discovered during pregnancy.

Figure 51-15

Nonobstructing longitudinal vaginal septum.

Surgical Technique

The goal of surgery is removal of a wedge of tissue without damaging the cervix, bladder, or rectum. A Foley catheter is placed in the bladder. Because longitudinal vaginal septa are well vascularized, the anterior border of the septum, followed by the posterior border, are removed using unipolar electrosurgery. Care must be taken not to remove the septum too close to the vaginal wall, because this will leave larger mucosa defects. The edges of these mucosal defects are reapproximated with 2-0 absorbable suture. Postoperative use of a vaginal mold is not necessary.

The Obstructing Longitudinal Vaginal Septum Women with an obstructing longitudinal septum usually present with normal-onset menarche and increasingly severe dysmenorrhea. These patients are most likely to have a didelphic uterus. One of the uteri has a patent outlet; the other is obstructed (Fig. 51-16).

Figure 51-16 An obstructing longitudinal septum usually presents as a bulge in the vagina.

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Transverse vaginal septum Figure 51-17

Placement of angiocath into the transverse septum.

If the obstruction is low in the vagina, eventually a bulge may be noted on examination of the lower canal. However, a higher obstruction may be completely missed with just visual inspection, which is frequently the case in an adolescent. Digital examination may reveal a tense bulge in the vaginal wall (Fig. 51-17). In many instances the bulge is found in the anterior portion of the vagina between the 12 o’clock and 3 o’clock positions or between the 9 o’clock and 12 o’clock positions due to the rotation of the two cervices. Ultrasonography of the pelvis will usually show a pelvic mass, which can be misleading unless a vaginal septum is considered in the differential diagnosis. MRI is the best imaging mode for definitively diagnosing this abnormality. Like other müllerian anomalies, a longitudinal vaginal septum is associated with renal abnormalities, including absent kidneys, pelvic kidneys, and double ureters.92 Some longitudinal septums will be found to be only partially obstructing and a small opening in the septum can be found during menses with close inspection. Symptoms may vary from irregular and prolonged bleeding to profuse vaginal discharge. Occasionally the pinpoint opening provides a pathway for organisms to access the obstructed vagina, leading to pelvic infection and pyocolpos. Physical examination is unlikely to reveal a tense bulge, but a slight fullness may sometimes be appreciated in the paravaginal area. Surgical Technique

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Accurate delineation of anatomy is a prerequisite for surgical excision of a noncommunicating longitudinal vaginal septum. The first step is to place a needle into the bulging vaginal wall to identify the correct plane of dissection. Once blood extrudes from the needle, the adjacent tissue is incised with electrocautery to gain access into the obstructed vagina. Allis clamps are placed on the edges of this incision and the cavity is assessed. When removing the medial border of this septum, care must be taken to avoid damaging the urethra and cervix. The septum should be removed in its entirety to allow easily access to the second cervix for Pap smears. The raw mucosal edges are approximated with 2-0 absorbable suture. Use of a vaginal mold

Figure 51-18

Angle of incision into septum.

after surgery is not necessary, because postresection stenosis is rare. In difficult cases, use of either a resectoscope or hysteroscope to remove a longitudinal vaginal septum has been described.93,94 The previously hidden cervix and obstructed vaginal canal will often appear abnormal. The cervix is usually flush with the vaginal fornix and often appears erythematous and glandular. Histologically, the obstructed vaginal canal and septum on its obstructed side will have columnar epithelium and glandular cypts.92 Some patients may complain of profuse vaginal discharge after removal of the septum. Metaplastic transformation of the vaginal mucosa to mature squamous epithelium can take many years. Simultaneous laparoscopy during removal of a vaginal septum is not recommended unless the diagnosis is unclear on MRI or imaging studies indicate concomitant pelvic masses. As in all cases of obstructive müllerian anomalies, endometriosis is frequently encountered, even if the septum is only partially obstucting.95,96 With the possible exception of endometriomas, excision of the endometriosis is not recommended because these lesions will regress after removal of the obstruction.95 The obstetric outcome of such patients is similar to that reported for patients with simple didelphic uterus. Pregnancy rates of 87% and live birth rates of 77% have been reported.92

TRANSVERSE VAGINAL SEPTUM The incidence of transverse vaginal septum appears to be between 1 in 21,000 to 1 in 72,000.67 A transverse vaginal septum may be located in the upper (46%), middle (40%), and lower (14%) third of the vagina.97,98 A transverse vaginal septum may be complete or incomplete and varies in thickness (Figs. 51-18 and 51-19).

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Figure 51-19 Reapproximation of distal and proximal vaginal mucosa after excision of the septum.

Presenting Symptoms Patients with a complete transverse vaginal septum generally present with a complaint of primary amenorrhea in early to midpuberty. Pelvic pain is a common, but not universal, presenting complaint. Patients with high transverse vaginal septa are most likely to experience pelvic pain, and the pain will manifest earlier than in patients with septa located lower in the vagina. This is believed to be secondary to decreased space for the hematocolpos that ensues after initiation of menses. Patients with an incomplete transverse vaginal septum may complain of profuse vaginal discharge, dyspareunia, inability to insert a tampon, or tearing during intercourse with resultant bleeding. If asymptomatic, it may not be discovered until a routine gynecologic examination. Very rarely a transverse vaginal septum may be detected in an infant or young child. In such instances, a mucocolpos can present as an abdominal mass.67 If large enough, this mass may cause ureteral obstruction with secondary hydronephrosis. Compression of the vena cava and cardiopulmonary failure has also been reported.

Diagnosis Manual and speculum examination provide the most important information for diagnosis of a transverse vaginal septum. If the septum is very low, a vaginal opening may not be appreciated on evaluation of the external genitalia. A low transverse vaginal septum can usually be differentiated from an imperforate hymen by visual inspection. By increasing intra-abdominal pressure and increasing the bulge of the imperforate hymen, the Valsalva maneuver may further assist in this differentiation. If an opening to the vagina is noted, a manual or speculum examination may reveal a higher location of the septum. A rectal examination is very helpful in detecting a hematocolpos, since the bulge is readily palpable. Transperineal and transabdominal ultrasonography can sometimes diagnose and determine the thickness of a transverse vaginal septum. However, in most cases an MRI of the pelvis will be required to differentiate a transverse vaginal septum from other müllerian anomalies such as cervical agenesis.

Figure 51-20 Complete transverse septum. Notice that there is no bulge with a Valsalva maneuver that would be seen with an imperforate hymen.

These patients should also be evaluated for associated anomalies, including aortic coarctation, atrial septal defects, urinary tract anomalies, and malformations of the lumbar spine.99

Surgical Technique Surgical removal of a transverse vaginal septum is recommended as soon as practical after diagnosis to avoid continued retrograde menstruation. Endometriosis is common in patients with a transverse vaginal septum. However, removal of endometriosis lesions is not recommended because relief of the obstruction leads to their spontaneous resolution. Delay in detection or treatment of a transverse vaginal septum may lead to impaired fertility secondary to irreversible pelvic adhesions, hematosalpinges, and endometriosis. In one long-term follow-up study of 19 patients with transverse septa, 47% became pregnant.99 However, a small study in Finland showed a significantly higher live birth rate in women who had undergone very early diagnosis and management of their transverse vaginal septa.100 The unfortunate consequence of very early surgical management is an increased rate of subsequent vaginal stenosis. This is most likely due to inconsistent use of vaginal dilators by young adolescents, which are a necessary part of treatment of a thick vaginal septum. An alternative to early surgery for very young patients is medical termination of monthly endometrial shedding using DMPA to postpone surgery.101 The young girl can be instructed to dilate the distal vagina to stretch the distal vaginal mucosa, potentially decreasing the need for a graft, and to prepare her for postoperative use of the dilator. The thickness and location of the septum will determine the best approach to surgery. Thin, low transverse vaginal septa are much easier to repair than thick, usually high septa. Surgical Technique: Thin Transverse Vaginal Septum

Transverse septa that are thin and low in the vagina can usually be excised without difficulty. If visually a slight bulge cannot be appreciated on examination, an angiocath needle is placed through the septum (Fig. 51-20). With return of thick blood

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Section 7 Reproductive Surgery During surgery, a bulge will not be seen in the presence of a thick transverse septum. The correct angle of dissection can be determined by inserting an angiocath needle into the hematocolpos under ultrasound guidance. In difficult cases, the septum can be approached transfundally via the uterus using laparoscopy and laparotomy.67 The dissection is carried out taking care to protect the bladder and rectum. A Foley catheter is placed into the bladder. As the loose areolar tissue is being dissected, the rectum is frequently examined to ensure the appropriate angle of dissection. If there is inadvertent entry into the bladder or the rectum, the procedure should be stopped and completed at a future date. After the cervix is visualized, the goal is to reapproximate the upper mucosal tissue to the lower vaginal mucosa. Z-plasty Technique

Figure 51-21

Schematic of obstructing longitudinal septum.

Figure 51-22

Partial transverse septum.

through the angiocath, the plane of dissection becomes clear. Access is gained into the upper vaginal cavity by perforating a bulging transverse septum with unipolar electrosurgery or scissors (Fig. 51-21). The septum is excised in its entirety and the upper vaginal mucosa is reapproximated to the lower vaginal mucosa using 2-0 absorbable suture (Fig. 51-22). In most instances, to prevent stenosis of the vagina, continual use of a mold is recommended for several weeks after surgery. Surgical Technique: Thick Transverse Vaginal Septum

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Managing thick transverse septa can be quite challenging. Before surgery, the patient must be prepared for prolonged use of a mold and possible split-thickness skin graft to line the vagina. The main concern is potential bowel injury; therefore, bowel preparation is recommended.

If a thick septum is completely incised, the distance between the vaginal mucosa of the proximal and distal portions of the vagina may be so great that the edges cannot be reapproximated without tension. For this reason, a Z-plasty technique, as first described by Garcia and colleagues, should be considered for correction of thick transverse vaginal septa or when the vagina is short.102 For this technique, four lower mucosal flaps are created by making oblique crossed incisions through the vaginal tissue on the perineal side of the transverse septum, taking great care to avoid injuring either the bladder or rectum.103 Four upper mucosal flaps are created by making oblique crossed incisions through the vaginal tissue on the hematocolpos side of the transverse septum. The upper and lower mucosal flaps are separated by sharp and blunt dissection and sutured together at their free edges to form a continuous Z-plasty. Excellent results have been noted on 13 patients who underwent this procedure.103 A vaginal mold must be used for 5 to 8 weeks after the procedure to avoid vaginal stenosis. If the girl is not sexually active, a dilator should be used at night for 6 to 8 additional months. The patient should be instructed in selfexamination and should return if she notices any signs of early stenosis. In cases of a thick septum where a Z-plasty technique is not used, a skin graft may be required. The technique utilized is similar to that described for the McIndoe procedure. Prolonged use of a mold is required postoperatively.

MANAGEMENT OF MALFORMATIONS OF THE EXTERNAL GENITALIA Anomalies of the external genitalia are uncommon but require extreme skill in both surgical technique and patient interaction. The assignment of gender is a critical responsibility of a physician. Chapter 12 outlines the pathophysiology and patient approach in detail.

Gender Assignment and Timing of Surgery Gender assignment and genital surgery for intersex patients remains controversial. Female genitoplasty performed in infancy can markedly complicate gender reassignment later in life. Gender dysphoria has been reported by some patients assigned a female gender of rearing based solely on anatomic considerations during

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Chapter 51 Surgical Management of the Müllerian Ducts and External Genitalia infancy.104 This gender dysphoria may be due to androgen imprinting of the fetal brain. However, the true incidence of gender dysphoria in intersex patients is unknown. The two common options for managing intersex patients are (1) early genital reconstruction, with corresponding assignment of gender, or (2) early assignment of gender of rearing with deferred genital surgery. The advantage of the first option of genital reconstruction in infancy is the unproven psychological benefit of undergoing genital surgery before the age of genital awareness. There is also a perception that healing is more rapid and complete when surgery is performed in infancy. The advantage of the second option is that it allows the patient to participate in the ultimate decisions regarding surgical intervention. Theoretically, this might minimize problems if the patient ultimately elects the gender opposite that assigned. It also allows patients satisfied with a female gender assignment the option of retaining a large clitoris rather than suffering the potential complications of clitoral reduction surgery. Before assigning a gender to an infant with ambiguous genitalia, a frank discussion regarding these issues should be undertaken with the family. A team approach should include the surgeon, an endocrinologist, and a psychiatrist/psychologist with interest in this area. The parents should be given every opportunity to deliberate on the issues and discuss the surgical, psychological, and social implications of each option with each member of the team. Although ethical concerns continue to intensify about early surgery, most surgeons ultimately abide by the parents’ decision.

A

Clitoromegaly Clitoromegaly in a newborn is an indication for a full intersex evaluation. Causes of clitoromegaly in a phenotypic female newborn include partial androgen insensitivity in XY individuals, mild congenital adrenal hyperplasia in XX individuals (Fig. 51-23), and a variety of other rare abnormalities. Therefore the first step in evaluating these patients is to determine the etiology of the clitoromegaly so that the primary problem may be addressed and appropriately managed.

B Figure 51-23 A, Preoperative image of a 6-month-old girl with congenital adrenal hyperplasia. B, A probe has been placed in the genitourinary sinus.

Surgical Technique: Reduction Clitoroplasty

Reduction clitoroplasty is often considered in patients with either isolated clitoromegaly or ambiguous genitalia. Once the cause of the clitoromegaly has been addressed and a decision has been made to proceed with reduction clitoroplasty, a full anatomic evaluation should be performed. Historically, the enlarged clitoris was managed with clitorectomy. However, concern regarding preservation of sexual function led to abandonment of resection in favor of clitoral recession. Clitoral recession was performed by folding the erectile bodies in an accordion fashion and recessing the glans under the pubic symphysis. However, these patients often suffered painful erections with sexual stimulation. This led to development of the reduction clitoroplasty approach. The goal of reduction clitoroplasty is to preserve sexual function by preserving the neural and vascular supply to the glans while excising most of the erectile tissue to prevent painful erections. The first step in reduction clitoroplasty is to identify the vaginal opening. Next, a circumcision is performed and the phallus completely degloved (Fig. 51-24). The circumcision can

Figure 51-24 A circumcision is performed and the phallus completely degloved. The Foley catheter is in the urethra and bladder.

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Section 7 Reproductive Surgery A

Clitoral hood

Figure 51-25 A, Lateral incisions are made in the erectile bodies ventral to the neurovascular bodies (see dashed line). B, The erectile tissue is separated from the dorsal tunica and urethral plate and excised.

Dorsal funix with neurovascular bundle

Preserved urethral plate

Corporal tissue to be excised

B

Labia minora

Figure 51-27 The skin flaps are brought down on either side to recreate the labia minora. Figure 51-26 The glans is recessed onto the pubic symphysis and secured with absorbable sutures. Skin flaps are created from the phallus skin.

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be brought across the urethral plate at the base of the shaft, preserving this tissue, which can be used as an anterior flap in the vaginoplasty if desired. The erectile tissue is then separated from the dorsal tunica vaginalis, on top of which run the neurovascular bundles (Fig. 51-25A). The erectile tissue is amputated at the crura and at the glans and excised, preserving the attachments of the dorsal tunica vaginalis and neurovascular bundles (Fig. 51-25B). The glans is then recessed onto the pubic symphysis and secured with absorbable sutures. Glans reduction may be undertaken by excising a ventral wedge of glans. However, this is rarely necessary and risks denervating the residual glans. A dorsal slit is made in the dorsal hood and the apex of this incision secured to the dorsal midline of the glans edge with

absorbable suture (Fig. 51-26). The skin flaps are then brought down on either side to recreate the labia minora (Fig. 51-27). The final result is shown in Figure 51-28. Simultaneous Vaginoplasty

Most patients with clitoromegaly will also have masculinization of the vaginal canal, which will ultimately require vaginoplasty. Although the timing of vaginoplasty is controversial, from a technical point of view, combining the vaginoplasty with the clitoral reduction will result in the best cosmetic outcome. A simple cutback or perineal flap vaginoplasty is most often employed in intersex patients. However, extremely virilized patients may require a more formal pull-through with or without surgical separation of the vagina and urethra. Regardless of the approach to vaginoplasty, the technique for reduction clitoroplasty remains the same.

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Chapter 51 Surgical Management of the Müllerian Ducts and External Genitalia children with preservation of the neurovascular bundle found that each had markedly abnormal clitoral sensation.107,109 In another study of sexually active women who had undergone nerve-sparing reduction clitoroplasty as infants, 2 of 3 patients had the worst possible score for orgasm difficulties. Clearly, detailed multicenter outcome studies of feminizing genitoplasty are needed. Until such studies are avaiable, parents and patients consenting to this procedure should be aware of the likely need for additional surgery later in life and the likelihood that even modern techniques may result in significant clitoral denervation and dissatisfaction with cosmetic outcomes.

PEARLS

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B Figure 51-28 the urethra.

Final result of reductive surgery. The Foley catheter is in ●

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Outcome Data

The little data available regarding the outcome of clitoral surgery does not support the routine application of this procedure during infancy. However, it must be kept in mind that the majority of patients thus far studied had surgery before the widespread acceptance of reduction clitoroplasty. Several small retrospective studies of patients assigned a female gender undergoing feminizing genitoplasty as infants have found a high incidence of sexual dysfunction, loss of clitoral sensation, anorgasmia, and dissatisfaction with cosmesis.104–108 One small series of women born with ambiguous genitalia found that those who underwent clitoral surgery as infants had significantly more sexual problems than a comparable group who did not.105 Cosmetic outcome is often poor after clitoral surgery performed during infancy and reoperation later is usually required.106 Nerve-sparing procedures do not appear to fare much better. A study of 6 women who had undergone clitoral reduction as

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Patients with müllerian agenesis typically present during their adolescent years with complaint of primary amenorrhea. Müllerian agenesis is associated with renal and skeletal system anomalies. With the advent of MRI, laparoscopy is no longer considered necessary to make the diagnosis of müllerian agenesis. The American College of Obstetricians and Gynecologists recently released a committee opinion that recommends nonsurgical management of müllerian agenesis as the first mode of treatment. The most widely used surgical technique for creation of a neovagina is the McIndoe operation. An 80% success rate has been reported with the McIndoe operation. Patients with cervical agenesis present between ages 12 and 16 with a primary complaint of pelvic pain secondary to obstruction of flow from the uterus. Patients with cervical agenesis who lack a vagina must be differentiated from those with a high obstructing vaginal septum. It is important to differentiate a bicornuate from a septate uterus. HSG alone cannot differentiate these entities. Conception does not appear to be a problem in women with bicornuate uterus. However, higher rates of preterm delivery and spontaneous abortion have been reported. A unicornuate uterus may be associated with a communicating or noncommunicating rudimentary horn. Women with an obstructing longitudinal septum usually present with normal onset menarche and increasingly severe dysmenorrhea. Patients with a complete transverse vaginal septum generally present with a complaint of primary amenorrhea in early to mid puberty. An alternative to early surgery for very young patients with a transverse vaginal septum is medical termination of monthly endometrial shedding using DMPA to postpone surgery. Reduction clitoroplasty is often considered in patients with either isolated clitoromegaly or ambiguous genitalia.

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Chapter 51 Surgical Management of the Müllerian Ducts and External Genitalia 52. McCraw JB, Massey FM, Shanklin KD, Horton CE: Vaginal reconstruction with gracilis myocutaneous flaps. Plast Reconstr Surg 58:176–183, 1976. 53. Wee JT, Joseph VT: A new technique of vaginal reconstruction using neurovascular pudendal-thigh flaps: A preliminary report. Plast Reconstr Surg 83:701–709, 1989. 54. Joseph VT: Pudendal–thigh flap vaginoplasty in the reconstruction of genital anomalies. J Pediatr Surg 32:62–65, 1997. 55. Monstrey S, Blondeel P, Van Landuyt K, et al: The versatility of the pudendal thigh fasciocutaneous flap used as an island flap. Plast Reconstr Surg 107:719–725, 2001. 56. Song R, Wang X, Zhou G: Reconstruction of the vagina with sensory function. Clin Plast Surg 9:105–108, 1982. 57. Belloli G, Campobasso P, Musi L: Labial skin-flap vaginoplasty using tissue expanders. Pediatr Surg Int 12:168–171, 1997. 58. Chudacoff RM, Alexander J, Alvero R, Segars JH: Tissue expansion vaginoplasty for treatment of congenital vaginal agenesis. Obstet Gynecol 87:865–868, 1996. 59. Fliegner JR: A simple surgical cure for congenital absence of the vagina. Aust NZ J Surg 56:505–508, 1986. 60. Fliengrer JR: Congenital atresia of the vagina. Surg Gynecol Obstet 165:387–391, 1987. 61. Parsons JK, Gearhart SL, Gearhart JP: Vaginal reconstruction utilizing sigmoid colon: Complications and long-term results. J Pediatr Surg 37:629–633, 2002. 62. Syed HA, Malone PS, Hitchcock RJ: Diversion colitis in children with colovaginoplasty. BJU Int 87:857–860, 2001. 63. Hiroi H, Yasugi T, Matsumoto K, et al: Mucinous adenocarcinoma arising in a neovagina using the sigmoid colon thirty years after operation: A case report. J Surg Oncol 77:61–64, 2001. 64. Darai E, Soriano D, Thoury A, Bouillot JL: Neovagina construction by combined laparoscopic-perineal sigmoid colpoplasty in a patient with Rokitansky syndrome. J Am Assoc Gynecol Laparosc 9:204–208, 2002. 65. Ota H, Tanaka J, Murakami M, et al: Laparoscopy-assisted ruge procedure for the creation of a neovagina in a patient with MayerRokitansky-Küster-Hauser syndrome. Fertil Steril 73:641–644, 2000. 66. Edmonds DK: Diagnosis, clinical presentation and mangement of cervical agenesis. In Gidwani G, Falcone T (eds). Congenital Malformations of the Female Genital Tract: Diagnosis and Management. Philadelphia, Lippincott Williams & Wilkins 1999, pp 169–176. 67. Rock J, Breech L: Surgery for anomalies of the müllerian ducts. In Rock JA, Jones HW 3rd (eds). Te Linde’s Operative Gynecology, 9th ed. Philadelphia, Lippincott Williams & Wilkins 2003, pp 705–752. 68. Fujimoto VY, Miller JH, Klein NA, Soules MR: Congenital cervical atresia: Report of seven cases and review of the literature. Am J Obstet Gynecol 177:1419–1425, 1997. 69. Letterie GS: Combined congenital absence of the vagina and cervix. Diagnosis with magnetic resonance imaging and surgical management. Gynecol Obstet Invest 46:65–67, 1998. 70. Markham SM, Parmley TH, Murphy AA, et al: Cervical agenesis combined with vaginal agenesis diagnosed by magnetic resonance imaging. Fertil Steril 48:143–145, 1987. 71. Reinhold C, Hricak H, Forstner R, et al: Primary amenorrhea: Evaluation with MR imaging. Radiology 203:383–390, 1997. 72. Bugmann P, Amaudruz M, Hanquinet S, et al: Uterocervicoplasty with a bladder mucosa layer for the treatment of complete cervical agenesis. Fertil Steril 77:831–835, 2002. 73. Deffarges JV, Haddad B, Musset R, Paniel BJ: Utero-vaginal anastomosis in women with uterine cervix atresia: Long-term follow-up and reproductive performance. A study of 18 cases. Hum Reprod 16:1722–1725, 2001. 74. Hovsepian DM, Auyeung A, Ratts VS: A combined surgical and radiologic technique for creating a functional neo-endocervical canal in a case of partial congenital cervical atresia. Fertil Steril 71:158–162, 1999. 75. Rock JA, Carpenter SE, Wheeless CR, Jones HW 3rd: The clinical management of maldevelopment of the uterine cervix. J Pelv Surg 1:129–133, 1995.

76. Casey AC, Laufer MR: Cervical agenesis: Septic death after surgery. Obstet Gynecol 90:706–707, 1997. 77. Jacob JH, Griffin WT: Surgical reconstruction of the congenitally atretic cervix: Two cases. Obstet Gynecol Surv 44:556–569, 1989. 78. Grimbizis GF, Camus M, Tarlatzis BC, et al: Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update 7:161–174, 2001. 79. Acien P: Incidence of müllerian defects in fertile and infertile women. Hum Reprod 12:1372–1376, 1997. 80. Pui MH: Imaging diagnosis of congenital uterine malformation. Comput Med Imaging Graph 28:425–433, 2004. 81. Krysiewicz S: Infertility in women: Diagnostic evaluation with hysterosalpingography and other imaging techniques. AJR 159:253–261, 1992. 82. Acien P: Reproductive performance of women with uterine malformations. Hum Reprod 8:122–126, 1993. 83. Patton PE: Anatomic uterine defects. Clin Obstet Gynecol 37:705–721, 1994. 84. Heinonen PK: Clinical implications of the didelphic uterus: Long-term follow-up of 49 cases. Eur J Obstet Gynecol Reprod Biol 91:183–190, 2000. 85. Jayasinghe Y, Rane A, Stalewski H, Grover S: The presentation and early diagnosis of the rudimentary uterine horn. Obstet Gynecol 105:1456–1467, 2005. 86. O’Leary JL, O’Leary JA: Rudimentary horn pregnancies. Obstet Gynecol 22:371, 1963. 87. Falcone T, Hemmings R, Kalife R: Laparoscopic management of a unicornuate uterus with a rudimentary horn. J Gynecol Surg 11:105–107, 1995. 88. Falcone T, Gidwani G, Paraiso M, et al: Anatomic variation in the rudimentary horns of a unicornuate uterus: Implications for laparoscopic surgery. Hum Reprod 12:263–265, 1997. 89. Haddad B, Louis-Sylvestre C, Poitout P, Paniel BJ: Longitudinal vaginal septum: A retrospective study of 202 cases. Eur J Obstet Gynecol Reprod Biol 74:197–199, 1997. 90. Heinonen PK: Longitudinal vaginal septum. Eur J Obstet Gynecol Reprod Biol 13:253–258, 1982. 91. Carey MP, Steinberg LH: Vaginal dystocia in a patient with a double uterus and a longitudinal vaginal septum. Aust NZ J Obstet Gynaecol 29:74–75, 1989. 92. Candiani GB, Fedele L, Candiani M: Double uterus, blind hemivagina, and ipsilateral renal agenesis: 36 cases and long-term follow-up. Obstet Gynecol 90:26–32, 1997. 93. Montevecchi L, Valle RF: Resectoscopic treatment of complete longitudinal vaginal septum. Int J Gynaecol Obstet 84:65–70, 2004. 94. Tsai EM, Chiang PH, Hsu SC, et al: Hysteroscopic resection of vaginal septum in an adolescent virgin with obstructed hemivagina. Hum Reprod 13:1500–1501, 1998. 95. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA: Endometriosis in association with uterine anomaly. Am J Obstet Gynecol 154:39–43, 1986. 96. Stassart JP, Nagel TC, Prem KA, Phipps WR: Uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis: The University of Minnesota experience. Fertil Steril 57:756–761, 1992. 97. Rock JA, Zacur HA, Dlugi AM, et al: Pregnancy success following surgical correction of imperforate hymen and complete transverse vaginal septum. Obstet Gynecol 59:448–451, 1982. 98. Lodi A: Contributo clinico stastico sulle malformazioni della vagina osservate mella. Clinica obstetricia e ginecologia di Milano dal 1906 al 1950. Ann Obstet Gynecol Med Perinatol 73:1246, 1951. 99. Rock JA, Zacur HA, Dlugi AM, et al: Pregnancy success following surgical correction of imperforate hymen and complete transverse vaginal septum. Obstet Gynecol 59:448–451, 1982. 100. Joki-Erkkila MM, Heinonen PK: Presenting and long-term clinical implications and fecundity in females with obstructing vaginal malformations. J Pediatr Adolesc Gynecol 16:307–312, 2003. 101. Hurst BS, Rock JA: Preoperative dilatation to facilitate repair of the high transverse vaginal septum. Fertil Steril 57:1351–1353, 1992.

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Section 7 Reproductive Surgery 102. Garcia RF: Z-plasty for correction of congenital transverse vaginal septum. Am J Obstet Gynecol 99:1164–1165, 1967. 103. Wierrani F, Bodner K, Spangler B, Grunberger W: “Z”-plasty of the transverse vaginal septum using Garcia’s procedure and the Grunberger modification. Fertil Steril 79:608–612, 2003. 104. Nelson CP, Gearhart JP: Current views on evaluation, management, and gender assignment of the intersex infant. Nat Clin Pract Urol 1:38–43, 2004. 105. Minto CL, Liao LM, Woodhouse CR, et al: The effect of clitoral surgery on sexual outcome in individuals who have intersex conditions with ambiguous genitalia: A cross-sectional study. Lancet 361:1252–1257, 2003.

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106. Creighton SM, Minto CL, Steele SJ: Objective cosmetic and anatomical outcomes at adolescence of feminising surgery for ambiguous genitalia done in childhood. Lancet 358:124–125, 2001. 107. Crouch NS, Minto CL, Laio LM, et al: Genital sensation after feminizing genitoplasty for congenital adrenal hyperplasia: A pilot study. BJU Int 93:135–138, 2004. 108. Creighton S: Surgery for intersex. J R Soc Med 94:218–220, 2001. 109. Gearhart JP, Burnett A, Owen JH: Measurement of pudendal evoked potentials during feminizing genitoplasty: Technique and applications. J Urol 153:486–487, 1995.

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52

Adhesion Prevention Mohamed F. Mitwally and Michael P. Diamond

INTRODUCTION The relevance of pelvic and peritoneal adhesions to the practice of reproductive endocrinology and infertility clearly relates to their association with infertility and chronic pelvic pain. In addition, postoperative adhesions are also responsible for significant complications, most notably adhesive bowel obstruction, and increase the difficulty of subsequent surgical procedures, which enhances the potential for intraoperative complications. Interestingly, the first case report of fatal intestinal obstruction caused by intra-abdominal adhesions was a woman who developed adhesions after removal of an ovarian tumor.1 Although the peritoneal cavity is of interest to the reproductive surgeon, postoperative adhesions also occur in other spaces, such as the pleural and pericardial cavities. This chapter first describes the scope and impact of pelvic adhesions, as well as the patholophysiology of their formation. This is followed by a careful examination of the complications and clinical conditions associated with adhesions. The final section is a thorough look at what is known about prevention.

HISTORICAL PERSPECTIVE Ancient Egyptians, known for their detailed descriptions of human anatomy, described pelvic adhesions several thousands years ago. Pleural adhesions were first described in the Babylonian Talmud in 440 A.D.2 Although adhesions caused by peritonitis have been recognized since the early 1700s, it was not until the widespread use of anesthesia in the mid-1800s when invasive abdominal procedures became more prevalent that the extent of the problems caused by intra-abdominal adhesions was realized. By the 1880s, the first published reports describing the use of adjuvants for adhesion prevention began to appear in the surgical literature. Over the next 100 years, a plethora of scientific reports and anecdotal accounts described the use of everything from amniotic fluid, bovine cecum, gold-beater’s skin, shark peritoneum, fish bladder, vitreous of calf ’s eyes, various gums, lubricants, fluids, gels, polymers, physical barriers, and a host of mechanical separation methods to prevent adhesions. Unfortunately, the results of most of these studies were equivocal, with no more than a small percentage of success. Even in this age of surgical sophistication and new operating room technology, our age-old nemesis, the intra-abdominal adhesion, remains a significant, long-term, and recurrent postoperative problem.3

DEFINITION, TYPE, AND EXTENT OF DISEASE Intra-abdominal adhesions are strands or membranes of fibrous tissue that can be attached to the various intra-abdominal organs, sometimes connecting them together (Fig. 52-1). The term adhesion in the medical field refers to the abnormal joining of anatomic structures at sites where no such anatomic attachment should exist. Adhesions usually develop in conjunction with surgery at sites of adhesiolysis and other operative sites, but also occur at “distant” sites where no surgical procedure was done. There are two general categories of adhesions, de novo and reformation. De novo adhesions occur at sites that did not previously have adhesions; reformation refers to adhesion formation at sites of previous adhesiolysis. To accurately describe the extent of peritoneal adhesions during clinical investigations, various scoring systems have been developed. Systematic assessment of adhesions is mandatory to decrease interobserver variation and to provide quantitative data corresponding to their extent and clinical significance.4 Most of the available scoring systems incorporate adhesion location, vascularity, and type (thickness). However, the current scoring systems suffer from the lack of validation for outcomes such as fertility, pain, and bowel obstruction, which makes the interpretation of the results of research related to adhesion development and prevention difficult. Thus, the question is often asked that if a study demonstrates a significant change in an adhesion score, does that reflect true clinical relevance in the extent of adhesive disease?

PREVALENCE OF DISEASE Despite the application of microsurgical technique and use of surgical adjuvants by experienced surgeons, the development of intraperitoneal postoperative adhesions is common. Currently, no serum marker or scanning technique is consistently able to identify adhesions, and a repeat operative procedure is required for evaluation.5 In a postmortem study of victims of motor vehicle accidents, intra-abdominal adhesions were encountered in 67% of individuals who had a history of abdominal operation.6 The prevalence among patients who had undergone major operations and multiple procedures was 81% and 93%, respectively. Most studies have shown that after an intra-abdominal operation, most patients

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Figure 52-1 Pelvic adhesions involving the uterus and bowel. This patient had a previous myomectomy.

developed adhesions. One study found that after merely one previous abdominal operation, 93% of patients had adhesions.7 On the other hand, intra-abdominal adhesions among patients who had never experienced a laparotomy were found in only 10.4%. Within 1 year of laparotomy, 1% of patients develop adhesionrelated intestinal obstruction;7 11% to 12% of them will suffer from recurrence later.8 In reports based on data from laparoscopies9 and autopsies,6 60% and 69% of women, respectively, had pelvic adhesions after previous abdominopelvic operations. Variation in the incidence of postoperative adhesions may be explained by differences in the extent of surgery, differences in the incidence or severity of prior surgery or other etiologic events, and in what each investigator considered to be a “significant” adhesion. It is important to emphasize that although some investigators believe all adhesions may not be clinically significant, others would emphasize that you cannot tell which adhesions will cause pain or contribute to bowel obstruction.

ECONOMIC IMPACT OF ADHESIONS

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The economic impact of adhesions as a complication of surgery is enormous. In the United States, 446,000 procedures were performed annually to remove abdominopelvic adhesions.10 This included 347,000 operations to release peritoneal adhesions and approximately 100,000 procedures to liberate intestinal adhesions. The cost of morbidity associated with adhesions is large.11 Few studies have been conducted to evaluate the financial impact of adhesion-related problems on the medical budget, and many of the studies could have underestimated the actual financial impact of adhesive disease by not considering the costs of performing diagnostic tests, consultations with other services such as gastroenterology, the increase in operative time required to free adhesions, and the complications due to inadvertent injury to other vital structures while freeing adhesions. In addition, a significant number of planned laparoscopic surgeries are converted to laparotomy because of failure to safely enter the

abdomen and achieve adequate pneumoperitoneum. Finally, there are costs associated with long-term morbidity such as adhesionrelated infertility and repeated admissions for bowel obstruction. The psychological impact of adhesion-related conditions that lead to loss of work might add to the economic burden. In the United States, an analysis of all hospitalizations for adhesions was performed using the 1988 National Hospital Discharge Survey. Of a total 281,982 hospitalizations, 51,100 were adhesion-related admissions. In total, there were more than 948,000 hospital-days of care, accounting for a cost of approximately $1.18 billion.10 In 1994, the same authors updated their database and found the annual overall cost to be approximately $1.3 billion. They also reported that lysis of adhesions was responsible for 1% of hospitalization in the United States.12 In a study that evaluated hospital discharge for adhesionrelated bowel obstruction between 1990 and 1996, the total number of patients increased from 115,067 in 1990 with a total length of hospitalization of 962,642 days to 139,716 patients with a total length of hospitalization of 885,396 days in 1996.13 The total costs increased steadily from $924 million in 1990 to $1.4 billion in 1996. Among those who were treated medically, there were 88,601 hospitalizations in 1990 and 110,817 in 1996, with a parallel increase of cost from $261 million in 1990 to $386 million in 1996. In the United Kingdom, Menzies and coworkers14 reviewed 110 hospital admissions resulting from adhesion-related smallbowel obstruction over a 2-year period. Of 110 admissions, surgical treatment was performed in 37% of patients and conservative management in the remaining patients. The total costs per admission were $7,521.28 (£4,677.41) and $2582.69 (£1,606.15) for the surgical and conservative treatment groups, respectively. In Sweden, Holmdhal and Riseberg15 conducted a cost analysis study on adhesion-related admission among all general surgeons. Collection of data was performed after the authors analyzed the questionnaire sent to all department heads of Swedish surgical units. There were a total of 6200 patients requiring hospitalizations, accounting for 3.5% of all laparotomies. They found that the total cost for adhesion-related hospitalization was $6.1 million US annually or close to $1 million US per million Swedish inhabitants (the population of Sweden is 8.5 million). Because of the difference in medical costs in various countries, meaningful comparisons are difficult. However, all studies suggest a huge financial impact of adhesion-related conditions to the healthcare system. Recently, Wilson16 calculated that a low-cost product with a 25% efficacy in preventing surgical adhesions could potentially generate a cost saving of £55 million over a 10-year period in the UK. In a prior study, they concluded that demonstrating the clinical effectiveness of adhesion reduction products in a randomized, controlled setting is unlikely to be feasible due to the large number of patients required. They suggested that products costing £200 (around $300 US) or more are unlikely to pay back their direct costs.17

COMPLICATIONS OF ADHESIONS Postoperative adhesions develop after virtually every transperitoneal operation, ranging from minimal scarring present on serosal surface to dense agglutination of nearly all structures. However, postoperative adhesions are much more common than

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Chapter 52 Adhesion Prevention symptoms would suggest; therefore, most adhesions probably do not lead to acute symptoms or clinical sequelae. In certain situations, adhesions may be of benefit. They may serve as adjuncts to the body’s natural defenses against intraabdominal insults and can be lifesaving in the postoperative period by localizing leakage from suture lines, isolating an inflammatory collection, or preventing the spread of infection. Other potential benefits include neovascularization of ischemic structures such as anastomoses. However, adhesions are associated with significant morbidity such as infertility, pain, and bowel obstruction.18

Reproductive Problems Adhesions play a significant role in the etiology of several reproductive disorders, including infertility, ectopic pregnancy, and recurrent pregnancy loss (intrauterine adhesions). From 15% to 20% of female infertility is caused by adhesions.19 Adhesions causing infertility or ectopic pregnancy may originate from endometriosis, infection such as pelvic inflammatory disease, appendicitis, or tuberculosis, as well as inflammatory bowel disease and surgery. More details on adhesions and infertility, ectopic pregnancy, and recurrent pregnancy loss are provided in other chapters of this text (see Chapters 34, 41, 47 and 48).

Intestinal Obstruction Adhesive intestinal obstruction is the most serious complication associated with peritoneal adhesions (Fig. 52-2). In addition to the significant pain, the condition can be life-threatening and in some cases fatal. In the early 20th century, most of the cases of intestinal obstruction were due to strangulated external hernias. As abdominal and gynecologic surgeries began to be performed more routinely, the number of intestinal obstructions caused by postsurgical adhesions increased and now has surpassed those produced secondary to hernias. This statistic, however, only holds true for the western world. In poorer regions of the world, the percentage of obstruction from hernias is still greater than that caused by adhesions.20 In advanced countries, adhesions account for intestinal obstructions in 49% to 74% of cases.21 Intestinal surgeries involving the left side of the colon and rectum, appendectomies, and gynecologic procedures are the three most common surgical procedures accounting for adhesionrelated intestinal obstruction.7 Both the extent and indication (e.g., cancer) of a gynecologic operation correlate significantly with the risk of postoperative intestinal obstruction. A Japanese group looked at the type of adhesions that caused intestinal obstruction and found that in 29% of cases, obstructive adhesions were small bowel to small bowel; in 48% the adhesions were small bowel to other abdominopelvic structures.22 Gynecologic malignancy increases the incidence of intestinal obstruction because more extensive operations are often required, and blockage by a tumor mass can occur. A report on 283 gynecologic patients treated for mechanical small-bowel obstruction showed that 175 (61.8%) were due to a primary or recurrent gynecologic malignancy, almost exclusively arising from the ovary.23 However, the second most common cause of obstruction was postoperative adhesions (41 patients, 14.5%), most of which followed an operation performed for a gynecologic cancer.23 Intestinal obstruction occurring in the immediate

Figure 52-2 Radiograph of intestinal obstruction-related bowel adhesions. This patient presented within 1 week of surgery with nausea and vomiting. Plain film of the abdomen in the supine and upright positions was obtained. The classic signs of a mechanical bowel obstruction are seen: large loops of bowel in ladder pattern with no gas in the colon. The gas–fluid levels are the classic sign of a small bowel obstruction.

postoperative period and those that follow treatment for earlystage ovarian cancer usually are related to adhesions, whereas delayed obstruction, especially that which occurs in the presence of advanced disease, is usually tumor-related, particularly if radiotherapy is administered.24 Although small-bowel obstruction on a gynecology service occurs most frequently in women with ovarian cancer, it can occur after other extensive pelvic operations, particularly ones associated with significant pelvic infection, such as surgery for tubo-ovarian abscess. It has been suggested that the two structures most commonly involved in adhesions associated with gynecologic surgery are the omentum and the distal small intestine.18 Short, obese women have a particular tendency to develop omental and small-bowel postoperative adhesions, perhaps in part related to longer, more difficult operative procedures.6 Because colonic adhesions are less common and the restricted mesentery can preclude twisting and kinking of the lumen, the colon is involved in adhesive obstruction only 2% to 10% as frequently as the small bowel.6 Among gynecology patients colonic obstruction usually is related to recurrent or persistent pelvic tumor causing extrinsic compression of the rectosigmoid colon.23,24 Adhesive intestinal obstruction after previous surgery can be early or late. According to the general surgery literature, 17% to 29% of intestinal obstruction cases occur within 1 month,25,26

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Section 7 Reproductive Surgery whereas the rest of the cases develop later, from 1 month to several decades after the surgery. After definitive operative management of an intestinal obstruction, the incidence of recurrence is approximately 14%. The factors contributing to occurrence or recurrence of intestinal obstruction are poorly understood.26,27 Fevang and colleagues studied a series of patients that included 500 patients who had a median follow-up of 10 years and a maximum follow-up time of 40 years after adhesive smallbowel obstruction.28 The cumulative recurrence rate for patients operated once for adhesive intestinal obstruction was 18% after 10 years and 29% at 30 years. For patients admitted several times for adhesive intestinal obstruction, the relative risk of recurrent adhesive intestinal obstruction increased with increasing number of prior episodes. The cumulative recurrence rate reached 81% for patients with four or more admissions. Other factors influencing the recurrence rate were the method of treatment of the last previous adhesive intestinal obstruction episode (conservative versus surgical) and the number of abdominal operations before the initial adhesive intestinal obstruction operation. Most recurrent adhesive small-bowel obstruction episodes occurred within 5 years after the previous one, but a considerable risk is still present 10 to 20 years after an adhesive small-bowel obstruction episode.28

The Conundrum of Chronic Pain Syndromes and Adhesions The issue of adhesion-related pain, including chronic pelvic and abdominal pain, dysmenorrhea, and dyspareunia, has been the subject for intense debate.29 There are three important questions that need to be addressed: Do adhesions cause pain? If yes, does the extent of adhesions correlate with the nature and severity of pain? Does adhesiolysis relieve adhesion-related pain? Adhesions May or May Not Cause Pain

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The question as to whether or not adhesions cause pain does not have an entirely satisfactory answer. In favor of this relationship are the findings that adhesions contain nerve fibers30 and are innervated with substance P-containing sensory neurons, suggesting that adhesions themselves are capable of generating pain stimuli and perhaps finally suggesting a mechanism to explain the pain associated with adhesions.31 However, some have criticized reports such as this because of the potential for “tenting” of normal peritoneum during adhesion excision, such that the nerves may have been in normal peritoneum. Additionally, the apparent absence of pain in some patients with massive adhesions in contrast to claims of intense pain by patients with only minimal adhesive disease has led many clinicians to doubt that adhesions alone are “enough” pathology to “cause” pain. Contributing to the confusion is the subjective nature of pain, the intrinsic difficulty in establishing reliable measures of clinical pain, and the lack of behavioral and psychological assessment in reports of pelvic pain in the gynecologic literature. Add to this the lack of noninvasive techniques for accurately observing or quantifying postoperative adhesion development. The magnitude of the problem is great. As many as 20% of patients with acute pelvic inflammatory disease will have chronic pain, much of which is felt to be associated with adhesions.32 It is possible that adhesions that restrict the free movement of pelvic organs would be implicated as a cause of chronic pelvic

pain.33 Approximately 20% to 50% of patients with chronic pain have pelvic adhesions.33,34 Adhesion Extent Does Not Correlate with Nature and Severity of Pain

Although several studies have suggested a significant association between adhesions and chronic pelvic pain, and the location of pain to reflect the site of adhesions, most of these studies failed to show a significant correlation between the extent of adhesions and the severity of pain.20 Similar observations have been made for the relationship between endometriosis and pain. Adhesiolysis Does Not Always Relieve Adhesion-Related Pain

Lysis of adhesions has been proposed as the therapeutic modality of choice for patients suffering from pelvic pain in association with adhesions, and some investigators report the resolution of chronic pain in individuals after lysis of adhesions, whereas others have not noted this effect consistently or have noticed only a very short period of benefit.35,36 Obviously, the “gold standard” study to determine the utility of adhesiolysis for pain relief would be a double-blinded, randomized trial with a control arm, which would control for adhesion reformation and de novo adhesion formation, and follow-up occurring past the point of the expected placebo effect of adhesiolysis surgery. Not surprisingly, such a study would be difficult to execute because of the need to recruit a large number of patients, to perform a second-look procedure to ascertain whether adhesion reformation occurred in those patients having pain relapse after adhesiolysis, and to debate the method to use to quantify patient pain.20 Probably the closest to this ideal study are reports by Swank and colleagues,37,38 who conducted both laparotomy and laparoscopy. Neither of these studies was able to demonstrate a significant benefit of adhesiolysis to the patient population as a whole, although trends were identified. Although each of these studies was randomized, the length of follow-up was limited, and neither included second-look laparoscopy so as to allow correction for new or persisting adhesions.

Other Problems Complicating Adhesions There are several other clinical implications of adhesions, including interference with intraperitoneal therapeutics and difficult repeat surgery. In an effort to improve both the response rates and the overall survival of patients with ovarian carcinoma, investigators have explored the safety and efficacy of antineoplastic agents delivered intraperitoneally for this malignancy. A major impediment to this innovative therapy is inadequate intraperitoneal distribution of drugs whenever extensive adhesions are present.39 Other adhesion-related complications of gynecologic surgery that do not affect fertility have not been well-studied. Voiding dysfunction, ureteral obstruction, and nonspecific gastrointestinal complaints may also be related to postoperative adhesion development.

PATHOPHYSIOLOGY OF ADHESION FORMATION Peritoneal Cavity Repair The abdominal cavity is lined by the peritoneum, which consists of a single layer of mesothelial cells, supported by a basement

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Chapter 52 Adhesion Prevention Table 52-1 The Temporal Relationship of Different Cell Types and Products in the Peritoneal Cavity (Days) after Surgical Injury First Appearance

Peak Levels

Disappearance

Polymorphonuclear cells

Day 1

Day 2

Day 4

Fibrin

Day 1

Day 2

After day 7

Mesothelial cells*

Day 1.5

Day 5–7

Macrophages

Day 1.5

Day 5

Blood vessels

Day 5.5

Day 6

After day 7

*Mesothelial cells covering the wound site; peak levels refers to re-epithelialization.

membrane and an underlying sheet of connective tissue. When it covers the abdominal wall it is called the parietal peritoneum and when it covers viscera it is called the visceral peritoneum. Peritoneal trauma results in mesothelial damage and is accompanied by inflammation. Mesothelial cells balloon and detach from the basal membrane, thereby creating denuded areas.40 Peritoneal injury due to surgery, irradiation, infection, or irritation initiates an inflammatory reaction that increases peritoneal fluid, including proteins and cells. This fibrinous exudate leads to formation of fibrin41 by activation of the coagulation cascade.42 Within this fibrinous exudate, polymorphonuclear cells, macrophages, fibroblasts, and mesothelial cells migrate, proliferate, or differentiate (Table 52-1). Macrophages increase in number and change functions from mainly phagocytosis into secretion of a variety of substances that cause differentiation of progenitor cells into mesothelial cells on the injured surface. Mesothelial cells form islands throughout the injured area, proliferate, and cover the denuded area in short periods of time, usually estimated to be within 5 to 7 days of injury.43 It is important to realize that this process occurs, not just at the edge of the denuded peritoneum, but throughout the surface of the injured area. All these cells, as well as fibroblasts that migrate from underlying tissues, release a variety of substances such as plasminogen system components, arachidonic acid metabolites, reactive oxygen species, cytokines, and growth factors such as interleukins, tumor necrosis factor-α, and transforming growth factors α and β. These factors modulate the process of peritoneal healing and adhesion development at different stages.44

Abnormal Repair The fibrinous exudate and fibrin deposition is an essential part of normal tissue repair, but its complete resolution is required for normal healing without adhesions. The degradation of fibrin is regulated by the plasminogen system. The inactive pro-enzyme plasminogen is converted into plasmin by tissue-type plasminogen activator or urokinase-type plasminogen activator in peritoneum (primarily tissue plasminogen activator [tPA]), which are inhibited by the plasminogen activator inhibitors 1 and 2. Plasmin degrades fibrin into fibrin degradation products. Plasmin can be directly inhibited by plasmin inhibitors (i.e., α2-macroglobulin,α2-antiplasmin, and α1-antitrypsin), but their role in peritoneal fibrinolysis is not well defined. Inhibition of plasminogen activator results in decreased fibrinolysis and allows formation of fibrin gel matrix, the scaffolding for the formation of an adhesion. This usually occurs over 5 to 8 days.

Fibroblasts will invade the fibrin matrix with extracellular matrix deposition, leading to peritoneal adhesions. In addition to fibroblast invasion and extracellular matrix deposition, the formation of new blood vessels has been universally claimed to be important in adhesion development as a means of resupplying oxygen and nutrients and removing metabolic waste.44 During peritoneal healing, cell–cell interactions between mesothelial cells, macrophages, and fibroblasts contribute to the healing of the peritoneum. Adhesion fibroblasts have developed a specific phenotype. Compared with normal peritoneal fibroblasts, adhesion fibroblasts have increased basal levels of collagen I, fibronectin, and other adhesion substances and decreased levels of tPA.45 Readers with greater interest in this area of investigation are referred to a more detailed review.46 To conclude, the balance between fibrin deposition and degradation in the initial days after surgery is critical in determining normal peritoneal healing or adhesion development. If fibrin is completely degraded, remesothelialization leading to normal peritoneal healing without adhesions will occur. In contrast, if fibrin is not completely degraded, it will serve as a scaffold for fibroblast ingrowth with subsequent extracellular matrix deposition and angiogenesis. After abdominal surgery and infection, however, the equilibrium between coagulation and fibrinolysis is disturbed in favor of the coagulation system.47–50

Risk Factors for Developing Adhesions As mentioned earlier, peritoneal repair and adhesion development is the net result of a balance between fibrin deposition as an outcome of the inflammatory process associated with peritoneal injury and fibrinolysis. Fibrinolysis plays a central role in the resolution of the inflammatory exudate, thereby minimizing the risk of adhesion development. This process has primarily been thought to be initiated by mesothelial cells in the region of tissue injury because fibrinolytic activity has been documented within normal mesothelium.51 However, tPA occurs in fibroblasts from human peritoneum and adhesions as well.52,53 Adequate blood supply is critical for normal fibrinolysis to occur. Peritoneal injury associated with ischemia interferes with fibrinolysis and leads to organization rather than resolution of the fibrin–cellular matrix.43 In the absence of ischemia, even large denuded areas of peritoneum usually will heal normally without developing adhesions.54,55 Agents that compromise blood flow within the area of tissue injury increase adhesion development. Thermal injury,56 infection,57 foreign body reaction (i.e., suture),57,58 radiationinduced endarteritis,59 and any other impediment to fibrin degradation increase intraperitoneal adhesions. The effect of electrocautery devoid of significant thermal injury or incomplete hemostasis on fibrinolysis and ultimately on adhesion development has not been adequately studied. Thus, the necessity to control small bleeding vessels and the optimal method to do such (cautery or suture) has yet to be defined. Only conflicting reports concerning these issues exist in the infertility literature.56,60 Fibrinolysis in the abdominal cavity is even more depressed in the presence of infection.61 Intraoperative tissue damage, infections, tissue ischemia, and intra-abdominal presence of foreign material, blood, or bile62,63 all have been shown to be potent causes of peritoneal adhesions. Foreign materials, such as glove powder,64 fluff from surgical

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Section 7 Reproductive Surgery packs (gauze lint),65 sutures,58,66 and material extruded from the digestive tract, cause a peritoneal inflammatory reaction, hence increasing the chance of adhesions.67

PREVENTION OF ADHESION DEVELOPMENT Although gynecologic surgery has been a major source of intraperitoneal adhesions and associated morbidity over the past century, most related complications, including adhesions, have been traditionally managed by general surgeons and related surgical subspecialties.68 However, with the establishment of the gynecologic subspecialties of reproductive endocrinology and infertility and gynecologic oncology, gynecologic surgeons developed a directed interest in adhesion development, prevention, and management. This interest is stimulated particularly for reproductive endocrinologists by the relationship between adhesions and impaired fertility4 and for gynecologic oncologists by the increased aptitude to perform all aspects of intestinal surgery,69 as well as the ability to deal with adhesion-related intestinal complications. As residency training programs in obstetrics and gynecology universally provide exposure to both of these subspecialties, all obstetricians and gynecologists should be familiar with the principles of adhesion development and their management.70 The focus of this review is on the pathophysiology of surgically induced adhesions and their prevention. The discussion on pathophysiology and the various approaches to decrease the chance of adhesions may not apply to adhesions that result from specific disease processes such as endometriosis, pelvic inflammatory disease, inflammatory bowel disease, and other adhesiogenic diseases.

Surgical Techniques Prevention of adhesion development starts by adopting adequate surgical techniques involving the application of microsurgical principles that enhance postoperative healing and minimize tissue insults that exacerbate inflammatory reactions. Such principles of microsurgical techniques, including gentle tissue handling, meticulous hemostasis, copious irrigation, prophylaxis against infection, limiting foreign body reaction, and preventing thermal injury, have all been described as means of decreasing adhesion development. These surgical principles apply to all types of operations because they can influence the risks of most complications associated with surgical procedures, not just adhesion development. Of course, application of these principles must be done in the context of the surgical procedure that needs to be conducted and appreciation of other surgical principles such as the need for adequate exposure and use of traction and countertraction. Surgery for, or associated with, peritonitis requires meticulous and thorough elimination of the source of contamination, treatment of infection, and debridement of the abdominal cavity; these are the cornerstones of such types of surgery for the prevention of surgical adhesions as well as intraperitoneal abscess formation. Hemostasis and Tissue Handling

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Achieving meticulous hemostasis and minimizing tissue handling without doubt constitute the two most important surgical

principles in minimizing adhesions. Although the presence of blood at the operative site increases postoperative adhesion development, it is important that hemostasis be achieved in a manner that devitalizes as little surrounding tissue as possible. When possible, the size of pedicles should be minimized and use of electrosurgery should be restricted to the actual bleeding site. With regard to tissue handling, manipulation of structures is required to achieve exposure and perform the procedure. However, tissue damage can often be minimized by the use of atraumatic graspers, moist (not dry) pads and, when feasible, grasping of tissue structures to be excised.4 Value of Precise Tissue Approximation

The value of tissue approximation, including peritoneal closure, is still a subject of intense debate without clearcut recommendations to be generalized. Traditionally, closure of the peritoneum was thought to possibly allow for (1) restoration of anatomy and approximation of tissues for healing; (2) reestablishment of the peritoneal barrier to reduce the risk of infection; (3) reduction of the risk of wound herniation or dehiscence; and (4) minimization of adhesion development.71 The Cochrane database examined the issue of peritoneal closure versus nonclosure in cesarean section. They concluded that there was “no significant difference in short-term morbidity from nonclosure of the peritoneum in cesarean section.”72 It is, however, important to appreciate that the conclusions drawn from cesarean section may not be applicable to general gynecologic surgery due to the obvious differences in the nature of the two surgery types. Although suturing the peritoneum appears to have a more anatomic result than leaving it to heal by secondary intention, the presence of ischemic tissue by sutures causes a predisposition to adhesion development.55 In animal models,73,74 laparotomy closure without peritoneal suturing healed with a lower incidence of adhesions to the wound compared with animals with peritoneal suturing. Postoperative adhesions at the site of closure of the pelvic peritoneum were responsible for bowel obstruction in 85% of cases, with adhesions to the anterior abdominal wall occurring in another 15%.75 Tulandi76 suggested that the currently available evidence suggests that peritoneal suturing is not only unnecessary, but could also be associated with a greater risk of small-bowel obstruction. Another important issue involving whether to precisely approximate tissues together or not is the ovarian cortex closure, such as in surgeries involving the removal of ovarian cysts and masses. In animal studies, suture closure of the ovarian cortex was associated with greater, not lesser, adhesion development.77 Use of Laparoscopy

It had been suggested, anecdotally, that procedures performed by laparoscopy, as opposed to laparotomy, might be less likely to be followed by the postoperative development of pelvic adhesions. Potential explanations included reductions in tissue drying, tissue manipulation, introduction of foreign materials, and abrasion of peritoneal sutures, as well as lack of packing of bowel.78,79 However, in a multicenter study evaluating adhesion reformation at a second-look procedure after laparoscopic adhesiolysis, adhesion reformation was identified in 66 of 68 subjects (97%).80 Laparoscopic adhesiolysis was able to significantly reduce the extent of pelvic adhesions to approximately half of what was present initially. De novo adhesion develop-

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Chapter 52 Adhesion Prevention ment occurred in only 8 (12%) of these 68 women, and in 11 (23%) of 47 available sites in those affected. This suggests that de novo adhesion development (not adhesion reformation) may occur less frequently after laparoscopic surgery, but confirmation of this hypothesis will require properly controlled studies. A recent study made the observation that the increased use of laparoscopy for abdominal procedures between 1988 and 1994 did not appear to be associated with a concomitant reduction in the hospitalization rate for adhesive intestinal obstruction, suggesting that although minimally invasive techniques may offer advantages such as decreased morbidity, whether such procedures actually reduce adhesion development remains unclear at this time.12 Laparoscopic adhesiolysis for adhesive intestinal obstruction has also come to the forefront81 and obviously offers similar advantages over laparotomy. However, there are no long-term results; thus, the question concerning decreased recurrence after laparoscopy compared with laparotomy requires further investigation.

Figure 52-3 sidewall.

Sharp dissection of dense adhesion of tube to the pelvic

CO2 Pneumoperitoneum-Enhanced Adhesion Development

Recently, the effects of carbon dioxide (CO2) pneumoperitoneum have become increasingly scrutinized.82–90 It has been hypothesized that CO2 pneumoperitoneum induces adverse effects, including hypercarbia, acidosis,88 hypothermia, and desiccation,89 as well as altered peritoneal fluid90 and morphology of the mesothelial cells.91 Adhesions have been found to increase with the duration of the pneumoperitoneum and with increased insufflation pressure in rabbits82 and mice.83 Potentially, such adhesions may be due to drying or cooling of tissues from insufflation gas flow; however, this remains controversial. Cooling has been suggested both to cause89 and reduce adhesions,84 while humidification of insufflation gas has been implicated in adhesion reduction85 or having no effect. The pneumoperitoneum-enhanced adhesion development has been suggested to be mediated by mesothelial hypoxia because similar effects were observed with helium pneumoperitoneum, and because the addition of 2% to 4% oxygen to both CO2 and helium pneumoperitoneum decreased adhesion development.83,86 Use of Energy Source

In general, there has been no evidence that use of a specific energy source per se (e.g., CO2 laser, bipolar electrocautery, unipolar electrocautery, harmonic scalpel) results in a greater reduction of adhesions or improvement in pregnancy outcome, compared with other surgical modalities.92–94 However, individual surgeons, based on their own experience, equipment availability, and preference, may find use of a particular modality to be most advantageous for the performance of these procedures.95–98 Technique for Treatment of Existing Adhesions to Prevent Adhesion Reformation

There is no single best method of dividing adhesions, in spite of dogma to the contrary. In some situations, particularly when the adhesions are flimsy and are easily separable, gentle blunt dissection may be the safest method. In other situations, when adhesions are dense and especially when important adjacent structures such as the urinary bladder are involved, blunt dissection or pulling on the small intestine results in tears of the bowel or adherent viscus. This happens primarily because the

tensile strength of the adhesions exceeds that required to maintain bowel or other visceral seromuscular layer intact. Consequently, when adhesions are dense, it is generally safer to use a sharp method of dissection (Fig. 52-3). Similarly, the role of adhesion incision versus excision has not been well studied. Although excision of adhesion bands may in many cases be intuitive so that the resulting raw surfaces will no longer be in apposition, it is perhaps better to leave raw surface area as small as possible, and therefore avoid denudation of visceral surfaces. In all situations, immediate recognition of enterotomy is important because if the operation is terminated without closing the defect, peritonitis will occur in the immediate postoperative period.99

Adhesion Development versus Adhesion Reformation Three groups have demonstrated fundamental differences between adhesion development and adhesion reformation in animal models. Holtz and associates100,101 described reduction in adhesion development with 32% dextran 70, but a similar inhibition of adhesion reformation could not be achieved with higher doses of dextran. Similarly, Elkins and coworkers102,103 observed a greater extent of adhesion reformation than adhesion formation after dextran treatment. Finally, Diamond and associates104,105 compared adhesion formation and reformation models and noted a greater extent of adhesions in the latter. Consistent with these observations, Diamond and Nezhat have proposed a classification of postsurgical adhesion development that differentiates de novo adhesion formation (type I) from adhesion reformation (type II) and subcategorizes each of these groups as to whether there was a lack of or presence of treatment of pathology106 at sites during the initial procedure. Importantly, a recent meta-analysis has validated this classification system by demonstrating increasing risk of adhesions in association with advanced stages.107 Such a system provides a method to assess efficacy of surgical techniques, new instrumentation, and antiadhesion adjuvant therapy.

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Section 7 Reproductive Surgery Second-Look Laparoscopy The value of second-look laparoscopy to promote fertility remains controversial. Multiple series have demonstrated that adhesiolysis in patients with preexisting adhesions results in pregnancy outcomes in inverse correlation with the extent/severity of the initial adhesions (i.e., the more adhesions initially, the less likely pregnancy will occur). Additionally, in other series, adhesiolysis has been shown to reduce the amount of adhesions, which will be identified in the future. The logical deduction from these statements is that secondlook laparoscopies will increase the pregnancy rate. However, well-designed studies examining the effect of early second-look laparoscopies on subsequent pregnancy outcome have not been performed. Advocates of second-look procedures propose several advantages: the ability to assess the efficacy of new surgical techniques, equipment, or adjuvants; the opportunity for the surgeon to assess the outcome of the surgical procedure; and a better opportunity for the patient to be counseled regarding next steps (e.g., recommending in vitro fertilization for patients with extensive adhesions). Nonetheless, these outcomes do not prove clinical benefits regarding pregnancy. Although Tulandi and colleagues were unable to identify a benefit of second-look laparoscopy 1 year after reproductive surgery, this study was limited by the lack of randomization and the differences in the initial surgeons.108 In contrast, when looking at adhesions as the endpoints, early second-look laparoscopy has been shown to reduce the presence of adhesions at the time of a “third-look” procedure.109 Additionally, reduced rates of ectopic pregnancy have been reported in women having second-look laparoscopies.110 If second-look laparoscopy is to be performed for assessment and possible management of postoperative adhesions, Swolin111 recommended that it be done early (6 to 8 weeks) to improve the possibility of lysis of postoperative adhesions. Subsequently, Raj and Hulka112 examined second-look laparoscopies performed up to 2 years after the initial procedure and demonstrated that bleeding was more common if the procedure was performed more than 12 weeks after surgery or sooner than 2 weeks after surgery. In the former case, bleeding was attributed to increased density and vascularity of the adhesions; in the latter, bleeding was attributed to granulation tissue.

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Table 52-2 Characteristics of an Ideal Antiadhesive Adjuvant Highly efficacious over range of conditions for which it will be utilized High safety profile No interference with tissue healing Easy to handle Easy to deliver Stays where placed Remains in abdominal cavity for sufficient time Will not promote infection Will not interfere with surgical procedure Treats large area Utilizable at open and endoscopic procedures Biosorbable Inexpensive

Table 52-3 Classes of Antiadhesion Agents Fibrinolytic agents Anticoagulants Anti-inflammatory agents Antibiotics Mechanical separation

inflammatory response.114 Hence, a single preventive measure, such as a physical barrier alone applied to one area, may not completely eliminate adhesion development throughout the abdominal cavity. In fact, the antiadhesion material barrier trials have used, as their endpoint, adhesion development at the site of barrier placement rather than at distant sites. Potential Mechanisms for Antiadhesion Barriers

Adjuvant Therapy

There are several different classes of antiadhesion barriers (Table 52-3). Approaches that have been suggested to minimize adhesion development involve one or more of the following mechanisms of action:

In addition to adopting microsurgical principles and optimal surgical techniques to reduce adhesion development, several other approaches have been suggested to help prevent and reduce the severity of adhesion development. Such approaches include the application of intraoperative devices and agents as well as the use of adjuvant medications to prevent adhesions. Table 52-2 includes a list of characteristics possessed by the ideal antiadhesive adjuvant. When reviewing the potential applications of adhesion barriers, it is important to distinguish the prevention of adhesions at the injury site versus other sites. It is not clear whether applying physical barriers to reduce adhesions at site of application can provide protection in areas other than the site of application.113 It has been shown that adhesions can readily develop at uninjured peritoneal sites distant from the midline incision and that a midline laparotomy initiates a generalized peritoneal

1. Reducing fibrin formation (anticoagulants and anti-inflammatory agents such as corticosteroids and nonsteroidal antiinflammatory medications) 2. Enhancing fibrin elimination (peritoneal lavage with fluids, and enzymatic degradation by fibrinolytic agents such as urokinase and recombinant plasminogen activator) 3. Mechanical separation of injured surfaces (peritoneal floatation by lavage fluid and instillation of high molecular-weight liquids and application of mechanical barriers such as Interceed, Gore-Tex Surgical Membrane, and Seprafilm) 4. Indirect mechanisms such as enhancement of intestinal motility to prevent establishment of adhesions and other agents under investigations that modulate mediators of the inflammatory response to peritoneal injury, such as immunomodulator, melatonin, and biodegradable polymers, as well as the use of antibiotics to reduce and eliminate infection.

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Chapter 52 Adhesion Prevention Table 52-4 Examples of Antiadhesion Barriers Oxidized regenerated cellulose (Interceed) FDA approved for laparotomy but not laparoscopy Requires meticulous hemostasis and removal of all irrigant fluids Hyaluronic acid and carboxymethylcellulose (Seprafilm) FDA approved Difficult application by laparoscopy 4% Icodextrin (Adept) FDA approved for laparoscopy but not laparotomy Expanded polytetrafluoroethylene (Gore-Tex surgical membrane) Not approved by the FDA for preventing pelvic adhesions Not biodegradable Requires suturing Ringer’s lactate Not approved by the FDA for preventing adhesions No studies showing human efficacy Dextran 70 (32%) Not FDA approved for preventing adhesions Significant complications such as coagulopathy

Table 52-4 gives some examples of various adjuvants that are generally used to prevent surgical adhesions.115,116 Several substances and materials have been studied and used over the years. These commercial adhesion-reducing substances are relatively expensive, with their cost ranging between $100 and $300 per unit. Although much has been written about use of these agents to prevent adhesion development, too little is known about the economic impact of adhesion-reducing agents on the healthcare system. It is important to stress the fact that a great deal of the available “evidence” involving prevention of adhesions comes from numerous animal studies that have examined various means of preventing postoperative intraperitoneal adhesions, usually in relation to tuboplasties and other infertility-related operations rather than extensive pelvic surgery. In addition, most of the controlled clinical trials of adhesion prevention in humans exist in the infertility literature rather than the gynecologic oncology literature. Although the relevance of these studies to the prevention of adhesions associated with extensive gynecologic surgery is unclear, one may conclude that adjuvants effective in the prevention of adhesions in one clinical setting (infertility surgery) may also be effective in another setting (extensive gynecologic surgery). Such an assumption awaits confirmation but may be false if there are differences in the metabolic, hemostatic, and infectious parameters associated with extensive surgery from those associated with infertility surgery. Moreover, with limited procedures, such as lysis of adhesions, there is no real injury to the underlying structures, as compared with radical operations, in which peritoneal trauma can be extensive. Human trials have not investigated the use of surgical adjuvants in preventing adhesions after radical pelvic surgery; therefore, it remains only speculative that this potential exists. Adhesions may simply represent the normal healing process after peritoneal injury. Indeed, with the degree of tissue destruction associated with radical operations, adhesion development may be physiologic rather than pathologic. Fortunately, animal studies and secondlook laparoscopies, once largely limited to the infertility arena, are now being used in gynecologic oncology research and operative procedures by other surgical specialties.18 Activation of the fibrinolytic system is considered beneficial in the prevention of intra-abdominal adhesions. In the late 19th

century, agents with potential fibrinolytic capacity, including liquor thiosinamine with sodium salicylate117 and oral phosphorus,2 were advocated. Streptokinase and streptodornase were the first agents with proven fibrinolytic properties that were effective in preventing adhesion development in rabbits and rats.118,119 The value of activation of the fibrinolytic system remains unproven in humans. Plasminogen Activator

Tissue plasminogen activator, the main plasminogen activator, has often been studied for prevention of adhesions. Although tPA proved to be effective, the risk of hemorrhage has been the main obstacle to its routine use. Anticoagulants such as heparin are also effective in adhesion prevention, although the use of local heparin in abdominal surgery remains controversial because of the risk of bleeding.120–124 Mechanical Separtion of Injured Surfaces

In the past decade several mechanical barriers have been developed. Membranes of oxidized regenerated cellulose,125,126 modified hyalouronic acid and carboxymethylcellulose, or expanded polytetrafluoroethylene127 were found to prevent the development of adhesions. All three coat the trauma site for the time (>7 days) required for re-epithelialization. Johns has reviewed the literature for the available evidence-based prevention of postoperative adhesions.128 He concluded that level 1 evidence supports the efficacy of three barrier methods for the prevention of postoperative adhesions: Interceed, Seprafilm, and Gore-Tex Surgical Membrane. Adhesions are not eliminated by these barriers, and the main debate is the clinical significance with the level of adhesions prevented. Furthermore, most of the efficacy is at the site of application. All three have limitations. Gore-Tex Surgical Membrane does not resorb and requires surgical removal or must be left in place permanently. Interceed and Seprafilm are biodegradable but also have significant practical limitations. Neither are approved for laparoscopy and their efficacy with this access is unproven. 4% Icodextrim is a recently approved adhesion reduction device that is a cornstarch-derived, water soluble branched glucose polymer. It is a solution that is applied intraperitoneally and is retaired in the peritoneal cavity for 3 to 4 days. Its effect is believed to be by hydroflotation. Hyaluronan

Hyaluronan-based agents have been shown to prevent adhesions after surgery. The potential of these agents to reduce intraabdominal adhesion in abdominal sepsis is a new promising concept. Hyaluronan-based antiadhesive agents, including modified hyaluronan–carboxymethylcellulose bioresorbable membrane and 0.4% hyaluronan solution, have been shown to be effective and safe for clinical application. Only the membrane, however, has been approved by the U.S. Food and Drug Administration (FDA) for use in benign diseases under noninfectious conditions.129 Methods of Unknown Benefit

Hydrofloatation, the use of large-volume isotonic solutions such as normal saline and Ringer’s lactate, has not been directly tested in randomized studies for preventing postsurgical adhesions. However, lack of benefit of crystalloids (and in fact statistically

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Section 7 Reproductive Surgery significant worsening) was demonstrated by a recent metaanalysis.107 Failure of effectiveness of crystalloids is due, at least in part, from the rapid absorption time. Most crystalloids are absorbed at approximately 30 to 60 mL/ hour. However, recent studies have suggested that these crystalloids remain in the peritoneal fluid longer.130 After the instillation of 300 mL of Ringer’s lactate solution, 78 mL was still present in the peritoneal cavity after 48 hours, compared with 30 mL in patients in the control group, in whom no Ringer’s lactate was left.130 By 96 hours there was no difference between the two groups. However, this is still too short a time to have a beneficial effect on adhesion formation. The disturbed equilibrium between fibrin synthesis and degradation leads to persistence of fibrinous adhesions. These will become ingrown with fibroblasts, and subsequent collagen deposition results in the development of permanent fibrous adhesions. Treatment with halofuginone, an inhibitor of collagen type I synthesis, decreases the development of experimentally induced surgical adhesions.131 Clinical trials have not been conducted yet. Anti-inflammatory drugs, including corticosteroids and prostaglandin synthetase inhibitors, have been tested for their ability to prevent adhesions.132–134 Down-regulation of the inflammatory response in this way, however, gave conflicting results. Swolin135 successfully reduced adhesion development in patients by applying intraperitoneal steroids, but others have reported equivocal or even deleterious effects.134 Dextran

Dextran 32% (Hyskon) has been approved by the FDA for uterine distension during operative hysteroscopy. However, randomized trials have shown conflicting results when this product has been used off-label for reduction of adhesions. This, in addition to the allergic reactions developing in some patients, markedly reduced the intra-abdominal use of Hyskon in gynecologic reconstructive surgery.

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Peritoneal adhesions occur in the majority of patients (more than 55%) that have had pelvic surgery. The peritoneum consists of a single layer of mesothelial cells that allows free movement of fluid. There are many events during a surgical procedure such as infection or foreign bodies that can cause adhesions. These events are thought to disturb the fibrinolytic process that is important in adhesion prevention. Mesothelial cells will start to cover a traumatized area of peritoneum by the third day. The predominant cell type in the peritoneal fluid by day 4 to 7 is the macrophage. The fibrin gel matrix that is formed after tissue injury is converted to an adhesion between day 5 and 8 after an injury. Adhesions are associated with infertility, chronic pain, and small-bowel obstrtuction. Adhesions also cause significant problems with subsequent surgical procedures, especially with peritoneal entry. This prolongs operative time. Surgical techniques that decrease adhesion formation are gentle tissue handling, excellent hemostasis, minimizing foreign bodies (including sutures), and decreasing ischemia with irrigation. Crystalloid solutions would not be expected to reduce adhesions because they are rapidly absorbed (35 to 65 mL/hour) before the peritoneal surface has completely repaired and covered with mesothelium, a process that takes up to 8 days.

REFERENCES

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1. Bryant T: Clinical lectures on intestinal obstruction. Med Tim Gaz 1:363–365, 1872. 2. Wiseman DM: Adhesion prevention: Past the future. In DiZerega G, DeCherney A, Diamond M, et al (ed). Peritoneal Surgery. New York, Springer, 2000, pp 401–417. 3. Becker JM, Stucchi AF: Intra-abdominal adhesion prevention: Are we getting any closer? Ann Surg 240:202–204, 2004. 4. Hulka JF, Omran K, Berger GS: Classification of adnexal adhesions: A proposal and evaluation of its prognostic value. Fertil Steril 30:661–665, 1978. 5. Diamond MP: Surgical aspects of infertility. In Sciarra JJ. Gynecology and Obstetrics Philadelphia, Harper and Row, 2004. 6. Weibel MA, Majno G: Peritoneal adhesions and their relation to abdominal surgery: A postmortem study. Am J Surg 126:345–353, 1973. 7. Menzies D, Ellis H: Intestinal obstruction from adhesion: How big is the problem? Ann R Coll Surg Engl 72:60–63, 1990. 8. Ellis H: The clinical significance of adhesions: Focus on intestinal obstruction. Eur J Surg Suppl 577:5–9, 1997. 9. Stovall TG, Elder RF, Ling FW: Predictors of pelvic adhesions. J Reprod Med 34:345–348, 1989. 10. Ray NF, Larsen JW, Stillman RJ, et al: Economic impact of hospitalizations for lower abdominal adhesiolysis in the United States in 1988. Surg Gynecol Obstet 176:271–276, 1993.

11. Al-Jaroudi D, Tulandi T: Adhesion prevention in gynecologic surgery. Obstet Gynecol Surv 59:360–367, 2004. 12. Ray NF, Denton WG, Thamer M, et al: Abdominal adhesiolysis: Inpatient care and expenditures in the United States in 1994. J Am Coll Surg 186:1–9, 1998. 13. Moscowitz I, Wexner S: Contributions of adhesions to the cost of health care. Health Care Financing Administration. MEDPAR Database 1990–1996. In DiZerega G, DeCherney A, Diamond M, et al (eds). Peritoneal Surgery. New York, Springer-Verlag, 2000. 14. Menzies D, Parker M, Hoare R, et al: Small bowel obstruction due to postoperative adhesions: Treatment patterns and associated costs in 110 hospital admissions. Ann R Coll Surg Engl 83:40–46, 2001. 15. Holmdhal L, Riseberg B: Adhesions: Prevention and complications in general surgery. Eur J Surg 163:169–174, 1997. 16. Wilson M: Cost and economics of adhesions. Hosp Med 65:343–347, 2004. 17. Wilson MS, Menzies D, Knight AD, Crowe AM: Demonstrating the clinical and cost effectiveness of adhesion reduction strategies. Colorectal Dis 4:355–360, 2002. 18. Monk BJ, Berman ML, Montz FJ: Adhesions after extensive gynecologic surgery: Clinical significance, etiology, and prevention. Am J Obstet Gynecol 170:1396–1403, 1994.

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Chapter 52 Adhesion Prevention 19. Hershlag A, Diamond MP, DeCherney AH: Adhesiolysis. Clin Obstet Gynecol 34:395–402, 1991. 20. Diamond MP, Freeman ML: Clinical implications of postsurgical adhesions. Hum Reprod Update 7:567–576, 2001. 21. Welch JP: Adhesions. In Welch JP (ed). Bowel Obstruction. Philadelphia, WB Saunders, 1990, pp 154–165. 22. Maetani S, Tobe T, Kashiwara S: Neglected role of torsion and constriction in pathogenesis of simple adhesive bowel obstruction. Br J Surg 71:127–130, 1984. 23. Krebs HB, Goplerud DR: Mechanical intestinal obstruction in patients with gynecologic disease: A review of 368 patients. Am J Obstet Gynecol 157:577–583, 1987. 24. Helmkamp BF, Kimmel J: Conservative management of small bowel obstruction. Am J Obstet Gynecol 152:677–679, 1985. 25. Miller EM, Winfield JM: Acute intestinal obstruction secondary to postoperative adhesions. Surgery 78:952–957, 1959. 26. Krook SS: Obstruction of the small intestine due to adhesions and bands. Acta Chir Scand 95:130–136, 1947. 27. Brightwell NL, McFee AS, Aust JB: Bowel obstruction and the long tube stent. Arch Surg 112:505–511, 1977. 28. Fevang BT, Fevang J, Lie SA, et al: Long-term prognosis after operation for adhesive small bowel obstruction. Ann Surg 240:193–201, 2004. 29. Hammoud A, Gago LA, Diamond MP: Adhesions in patients with chronic pelvic pain: A role for adhesiolysis? Fertil Steril 82:1483–1491, 2004. 30. Kligman I, Drachenberg C, Papadimitriou J, Katz E: Immunohistochemical demonstration of nerve fibers in pelvic adhesions. Obstet Gynecol 82:566–568, 1993. 31. Sulaiman H, Gabella G, Davis MC, et al: Presence and distribution of sensory nerve fibers in human peritoneal adhesions. Ann Surg 234:256–261, 2001. 32. Westrom L: Incidence, prevalence, and trends of acute pelvic inflammatory disease and its consequences in industrialized countries. Am J Obstet Gynecol 138:880–892, 1980. 33. Rapkin AJ: Adhesions and pelvic pain: A retrospective study. Obstet Gynecol 68:13–15, 1986. 34. Cunanan RG, Courey NG, Lippes J: Laparoscopic findings in patients with pelvic pain. Am J Obstet Gynecol 146:587–591, 1983. 35. Steege JF, Stout AL: Resolution of chronic pelvic pain after laparoscopic lysis of adhesions. Am J Obstet Gynecol 165:278–281, 1991. 36. Peters AAW, Trimbos-Kemper GCM, Admiraal C, Trimbos JB: A randomized clinical trial on the benfit of adhesiolysis in patients with intraperitoneal adhesions and chronic pelvic pain. BJOG 99:59–62, 1992. 37. Swank DJ, Van Erp WF, Repelaer Van Driel OJ, et al: A prospective analysis of predictive factors on the results of laparoscopic adhesiolysis in patients with chronic abdominal pain. Surg Laparosc Endosc Percutan Tech 13:88–94, 2003. 38. Swank DJ, Swank-Bordewijk SC, Hop WC, et al: Laparoscopic adhesiolysis in patients with chronic abdominal pain: A blinded randomised controlled multi-centre trial. Lancet 361:1247–1251, 2003 39. Markman M, Jones W, Lewis JL, et al: Impact of laparotomy finding of significant intra-abdominal adhesions on the surgically defined complete response rate to subsequent salvage intraperitoneal chemotherapy. J Cancer Res Clin Oncol 118:163–165, 1992. 40. Raftery AT: Regeneration of peritoneal and visceral peritoneum. A light microscopical study. Br J Surg 60:293–299, 1973. 41. Holmdahl, LThe plasmin system, a marker of the propensity to develop adhesions. In DiZerega G, DeCherney A, Diamond M, et al (eds), Peritoneal Surgery. New York, Springer, 2000, pp 117–131. 42. DiZerega GS: Peritoneum, peritoneal healing and adhesion formation. In DiZerega G, DeCherney A, Diamond M, et al (eds). Peritoneal Surgery. New York, Springer, 2000, pp 3–38. 43. Montz FJ, Shimanuki T, DiZerega GS: Postsurgical mesothelial re-epithelization. In DeCherney AH, Polan ML (eds). Reproductive Surgery. Chicago, Year Book, 1987, pp 31–47. 44. Binda MM, Molinas CR, Koninck PR: Reactive oxygen species and adhesion formation. Clinical implications in adhesion prevention. Hum Reprod 18:2503–2507, 2003.

45. Saed GM, Diamond MP: Hypoxia-induced irreversible up-regulation of type I collagen and transforming growth factor-β1 in human peritoneal fibroblasts. Fertil Steril 78: 144–147, 2002. 46. Saed GM, Diamond MP: Molecular characterization of postoperative adhesions: The adhesion phenotype. J Am Assoc Gynecol Laparosc 11:307–314, 2004. 47. Saed GM, Diamond MP: Modulation of the expression of tissue plasminogen activator and its inhibitor by hypoxia in human peritoneal and adhesion fibroblasts. Fertil Steril 79:164–168, 2003. 48. Saed GM, Zhang W, Diamond MP: Molecular characterization of fibroblasts isolated from human peritoneum and adhesions. Fertil Steril 75:763–768, 2001. 49. Saed GM, Collins KL, Diamond MP: Transforming growth factors β1, β2 and β3 and their receptors are differentially expressed in human peritoneal fibroblasts in response to hypoxia. Am J Reprod Immunol 48:387–393, 2002. 50. Saed GM, Munkarah AR, Diamond MP: Cyclooxygenase-2 is expressed in human fibroblasts isolated from intraperitoneal adhesions but not from normal peritoneal tissues. Fertil Steril 79:1404–1408, 2003. 51. Myhre-Johnson O, Larsen SB, Astrup T: Fibrinolytic activity in serosal and synovial membranes. Arch Pathol 88:623–630, 1969. 52. Diamond MP, El-Hammady E, Wang R, et al: Regulation of expression of tissue plasminogen activator and plasminogen activator inhibitor-1 by dichloroacetic acid in human fibroblasts from normal peritoneum and adhesions. Am J Obstet Gynecol 190:926–934, 2004. 53. Ivarsson ML, Diamond MP, Falk P, Holmdahl L: Plasminogen activator/ plasminogen activator inhibitor-1 and cytokine modulation by the PROACT System. Fertil Steril 79:987–992, 2003. 54. Robbins GF, Brunschwig A, Foote FW: Deperitonealization: Clinical and experimental observations. Ann Surg 130:466–479, 1949. 55. Buckman RF, Buckman PD, Hufnagel HV, Gervin AS: A physiologic basis for the adhesion-free healing of deperitonealized surfaces. J Surg Res 21:67–76, 1976. 56. Mecke H, Schunke M, Schulz S, Semm K: Incidence of adhesions following thermal tissue damage. Res Exp Med 191:405–411, 1991. 57. O’Leary DP, Coakley JB: The influence of suturing and sepsis on the development of postoperative peritoneal adhesions. Ann R Coll Surg Eng 74:134–137, 1992. 58. Holtz G: Adhesion induction by suture of varying tissue reactivity and caliber. Int J Fertil 27:134–135, 1982. 59. Morgenstern L, Hart M, Lugo D, Friedman NB: Changing aspects of radiation enteropathy. Arch Surg 120:1225–1228, 1985. 60. Soderstrom RM: Preventing adhesions: Electrosurgery—advantages and disadvantages. In diZerega GS, Malinak LR, Diamond MP, Linsky DB (eds). Treatment of Post-Surgical Adhesions. New York, Wiley-Liss, 1990 pp 841–844. 61. Ivarsson M-L, Holmdahl L, Eriksson E, et al: Expression and kinetics of fibrinolytic components in plasma and peritoneum during abdominal surgery. Fibrin Proteo 12:61–67, 1998. 62. Ellis H: The cause and prevention of postoperative intraperitoneal adhesions. Surg Gynecol Obstet 133:497–511, 1971. 63. Almdahl SM, Burhol PG: Peritoneal adhesions: Causes and prevention. Dig Dis 8:37–44, 1990. 64. Ellis H: The hazards of surgical glove dusting powders. Surg Gynecol Obstet 171:521–527, 1990. 65. Down RHL, Whitehead R, Watts JMcK: Do surgical packs cause peritoneal adhesions? Aust NZ J Surg 49:379–382, 1979. 66. Elkins TE, Stovall TG, Warren J, et al: A histologic evaluation of peritoneal injury and repair: Implications for adhesion formation. Obstet Gynecol 70:225–228, 1987. 67. Saxén L, Myllärniemi H: Foreign material and postoperative adhesions. NEJM 279:200–202, 1968. 68. Perry JF, Smith GA, Yonehiro EG: Intestinal obstruction caused by adhesions. Ann Surg 142:810–816, 1955. 69. Barnhill D, Doering D, Remmenga S, et al: Intestinal surgery performed on gynecologic cancer patients. Gynecol Oncol 40:38–41, 1991. 70. Alvarez RD: Gastrointestinal complications in gynecologic surgery: A review for the general gynecologist. Obstet Gynecol 71:533–1540, 1988.

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71. Duffy DM, diZerega GS: Is peritoneal closure necessary? Obstet Gynecol Surv 49:817–822, 1994. 72. Wilkinson C, Enkin M: Peritoneal non-closure at cesarean section. In Neilson J, Crowther C, Hodnett E, Hofmeryr G (eds). Pregnancy and Childbirth Module. Cochrane Database Syst Rev 1998; CD000163. 73. Conolly WB, Stephens FO: Factors influencing the incidence of intraperitoneal adhesions: An experimental study. Surgery 63:976–979, 1968. 74. Ellis H: The etiology of postoperative abdominal adhesions. Br J Surg 50:10–16, 1962. 75. Al-Took S, Platt R, Tulandi T: Adhesion-related small bowel obstruction after gynecologic operations. Am J Obstet Gynecol 180:313–315, 1999. 76. Tulandi T: Peritoneal closure and adhesions. Hum Reprod 17:249–250, 2002. 77. Meyer WR, Grainger DA, DeCherney AH, et al: Ovarian surgery on the rabbit: Effect of cortex closure on adhesion formation and ovarian function. J Reprod Med 36:639–643, 1991. 78. Larsson B, Perbeck L: The possible advantage of keeping the uterine and intestinal serosa irrigated with saline to prevent intra-abdominal adhesions in operations for fertility. An experimental study in rats. Acta Chir Scand Suppl 530:15–18, 1986. 79. Zamir G, Bloom AI, Reissman P: Prevention of intestinal adhesions after laparotomy in a rat model—a randomized prospective study. Res Exp Med (Berl) 197:349–353, 1998. 80. Operative Laparoscopy Study Group: Postoperative adhesion development after operative laparoscopy: Evaluation at early second look procedures. Fertil Steril 55:700–704, 1991. 81. Nagle A, Ujiki M, Denham W, et al: Laparoscopic adhesiolysis for small bowel obstruction. Am J Surg 187:464–470, 2004. 82. Ordonez JL, Dominguez J, Evrard V, Koninckx PR: The effect of training and duration of surgery on adhesion formation in the rabbit model. Hum Reprod 12:2654–2657, 1997. 83. Yesildaglar N, Ordonez JL, Laermans I, Koninckx PR: The mouse as a model to study adhesion formation following endoscopic surgery: A preliminary report. Hum Reprod 14:55–59, 1999. 84. Binda MM, Molinas CR, Mailova K, Koninckx PR: Effect of temperature upon adhesion formation in a laparoscopic mouse model. Hum Reprod 19:2626–2632, 2004. 85. Hazebroek EJ, Schreve MA, Visser P, et al: Impact of temperature and humidity of carbon dioxide pneumoperitoneum on body temperature and peritoneal morphology. J Laparoendosc Adv Surg Tech A 12:355–364, 2000. 86. Molinas CR, Koninckx PR: Hypoxaemia induced by CO2 or helium pneumoperitoneum is a co-factor in adhesion formation in rabbits. Hum Reprod 15:1758–1763, 2000. 87. Molinas CR, Mynbaev O, Pauwels A, et al: Peritoneal mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation in a laparoscopic mouse model. Fertil Steril 76:560–567, 2001. 88. West MA, Hackam DJ, Baker J, et al: Mechanism of decreased in vitro murine macrophage cytokine release after exposure to carbon dioxide: Relevance to laparoscopic surgery. Ann Surg 226:179–190, 1997. 89. Gray RI, Ott DE, Henderson AC, et al: Severe local hypothermia from laparoscopic gas evaporative jet cooling: A mechanism to explain clinical observations. JSLS 3:171–177, 1999. 90. Ott DE: Laparoscopy and tribology: The effect of laparoscopic gas on peritoneal fluid. J Am Assoc Gynecol Laparosc 8:117–123, 2001. 91. Volz J, Koster S, Spacek Z, Paweletz N: Characteristic alterations of the peritoneum after carbon dioxide pneumoperitoneum. Surg Endosc 13:611–614, 1999. 92. Martin DC, Diamond MP, Yussman MA: Laser laparoscopy for infertility surgery. In Sanfillippo J, Levine R (eds). Operative Gynecologic Endoscopy. New York, Springer-Verlag, 1989, pp 211–235. 93. Diamond MP: Assessment of results of laser surgery. In Sutton CJG (ed). Bailliere’s Clinical Obstetrics and Gynecology: Laparoscopic Surgery. London, Bailliere Tindall, 1989, 649–654. 94. Diamond MP: Assessment of results of laparoscopic laser surgery. In Sutton CJG (ed). Lasers in Gynaecology. London, Chapman & Hall Medical, 1992, pp 55–72.

95. Daly DC. Hysteroscopy and infertility. In Sciarra JJ (ed). Gynecology and Obstetrics. Philadelphia, Harper & Row, 1986. 96. Martin DC, Diamond MP: Extended laparoscopic surgery: Comparison of laser and other techniques. Curr Probl Obstet Gynecol Fertil 9, 1986. 97. Daniell JF: The role of lasers in infertility surgery. Fertil Steril 42: 815–823, 1984. 98. Dixon JA: Lasers in surgery. Curr Probl Surg 21:1–65, 1984. 99. Paloyan D: Intestinal problems in gynecologic surgery. In Schiarra JJ (ed). Gynecology and Obstetrics Philadelphia, Harper and Row, 2004. 100. Holtz G, Baker E, Tsai C. Effect of 32% dextran 70 on peritoneal adhesion formation and reformation after lysis. Fertil Steril 33:660–662, 1980. 101. Holtz G, Baker ER: Inhibition of peritoneal adhesion reformation after lysis with 32% dextran 70. Fertil Steril 34:394–395, 1980. 102. Elkins TE, Bury RJ, Ritter JL, et al: Adhesion prevention by solutions of sodium carboxymethylcellulose in the rat: I. Fertil Steril 41:926–928, 1984. 103. Elkins TE, Ling FW, Ahokas RA, et al: Adhesion prevention by solutions of sodium carboxymethylcellulose in the rat: II. Fertil Steril 41:929–932, 1984. 104. Diamond MP, DeCherney AH, Linsky CB, et al: Assessment of carboxymethylcellulose and 32% dextran 70 for prevention of adhesions in a rabbit uterine horn model. Int J Fertil 33:278–282, 1988. 105. Diamond MP, DeCherney AH, Linsky CB, et al: Adhesion reformation in the rabbit uterine horn model: I. Reduction with carboxymethylcellulose. Int J Fertil 33:372–375, 1988. 106. Diamond MP, Nezhat F: Adhesions after resection of ovarian endometriomas. Fertil Steril 59:934–935, 1993. 107. Wiseman DM, Trout JR, Franklin RR, Diamond MP: Meta-analysis of the safety and efficacy of an adhesion barrier (Interceed TC7) in laparotomy. J Reprod Med 44:325–331, 1999. 108. Tulandi T, Falcone T, Kafka I: Second-look operative laparoscopy 1 year following reproductive surgery. Fertil Steril 52:421–424, 1989. 109. Ugur M, Turan C, Mungan T, et al: Laparoscopy for adhesion prevention following myomectomy. Int J Gynaecol Obstet 53:145–149, 1996. 110. Lavy G, Diamond MP, DeCherney AH: Ectopic pregnancy: Its relationship to tubal reconstructive surgery. Fertil Steril 47:543–556, 1987. 111. Swolin K: Electromicrosurgery and salpingostomy long-term results. Am J Obstet Gynecol 1975 121:418–419. 112. Raj SC, Hulka JF: Second-look laparoscopy in infertility surgery: Therapeutic and prognostic value. Fertil Steril 38:325–329, 1982. 113. Becker JM, Dayton MT, Fazio VW, et al: Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: A prospective, randomized, double-blind multicenter study. J Am Coll Surg 183:297–306, 1996. 114. Reed KL, Fruin AB, Bishop-Bartolomei KK, et al: Neurokinin-1 receptor and substance P messenger RNA levels increase during intraabdominal adhesion formation. J Surg Res 108:165–172, 2002. 115. Diamond MP, DeCherney AH: Pathogenesis of adhesion formation/ reformation: Application to reproductive pelvic surgery. Microsurgery 8:103–107, 1987. 116. Adhesion Study Group: Reduction of postoperative pelvic adhesions with intraperitoneal 32% dextran 70: A prospective, randomized clinical trial. Fertil Steril 40:612–619, 1983. 117. Boys F: The prophylaxis of peritoneal adhesions. A review of the literature. Surgery 11:118–168, 1942. 118. Wright LT, Smith DH, Rothman M, et al: Prevention of postoperative adhesions in rabbits with streptococcal metabolites. Proc Soc Exp Biol Med 75:602–604, 1950. 119. James DCO, Ellis H, Hugh TB: The effect of streptokinase on experimental intraperitoneal adhesion formation. J Pathol Bacteriol 90:279–287, 1965. 120. Lai HS, Chen Y, Chang KJ, Chen WJ: Tissue plasminogen activator reduces intraperitoneal adhesion after intestinal resection in rats. J Formos Med Assoc 97:323–327, 1998.

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Chapter 52 Adhesion Prevention 121. Buckenmaier CC 3rd, Pusateri AE, Harris RA, Hetz SP: Comparison of antiadhesive treatments using an objective rat model. Am Surg 65:274–282, 1999. 122. Menzies D, Ellis H: The role of plasminogen activator in adhesion prevention. Surg Gynecol Obstet 172:362–366, 1991. 123. Dunn RC, Mohler M: Effect of varying days of tissue plasminogen activator therapy on the prevention of postsurgical adhesions in a rabbit model. J Surg Res 54:242–245, 1993. 124. Evans DM, McAree K, Guyton DP, et al: Dose dependency and wound healing aspects of the use of tissue plasminogen activator in the prevention of intra-abdominal adhesions. Am J Surg 165:229–232, 1993. 125. Farquhar C, Vandekerckhove P, Watson A, et al: Barrier agents for preventing adhesions after surgery for subfertility. Cochrane Database Syst Rev 2000; CD000475. 126. Sawada T, Nishizawa H, Nishio E, Kadowaki M: Postoperative adhesion prevention with an oxidized regenerated cellulose adhesion barrier in infertile women. J Reprod Med 45:387–389, 2000. 127. Hellebrekers BW, Trimbos-Kemper GC, van Blitterswijk CA, et al: Effects of five different barrier materials on postsurgical adhesion formation in the rat. Hum Reprod 15:1358–1363, 2000. 128. Johns A: Evidence-based prevention of post-operative adhesions. Hum Reprod Update 7:577–579, 2001.

129. Reijnen MM, Bleichrodt PJ, van Goor RP: Pathophysiology of intraabdominal adhesion and abscess formation, and the effect of hyaluronan. Br J Surg 90:533–541, 2003. 130. Muzii L, Bellati F, Manci N, et al: Ringer’s lactate solution remains in the peritoneal cavity after laparoscopy longer than expected. Fertil Steril 84:148–153, 2005. 131. Nagler A, Rivkind AI, Raphael J, et al: Halofuginone—an inhibitor of collagen type I synthesis—prevents postoperative formation of abdominal adhesions. Ann Surg 227:575–582, 1998. 132. Siegler AM, Kontopoulos V, Wang CF: Prevention of postoperative adhesions in rabbits with ibuprofen, a nonsteroidal anti-inflammatory agent. Fertil Steril 34:46–49, 1980. 133. Jansen RP: Failure of intraperitoneal adjuncts to improve the outcome of pelvic operations in young women. Am J Obstet Gynecol 153:363–371, 1985. 134. Larsson B: Prevention of postoperative formation, reformation of pelvic adhesions. In Treutner KH, Schumpelick V (eds). Peritoneal Adhesions. Berlin, Springer, 1997, pp 331–334. 135. Swolin K: The effect of a massive intraperitoneal dose of glucocorticoid on the formation of postoperative adhesions: Clinical studies using laparoscopy in patients operated on for extrauterine pregnancy. Acta Obstet Gynecol Scand 46:204–218, 1967.

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Surgery for Male Infertility Peter N. Kolettis

INTRODUCTION Infertility affects at least 15% of all couples, and male factor is involved in approximately half of these cases. Approximately half the men with male factor infertility will have problems that are surgically correctable: 40% of men will have a varicocele and 15% will have an obstruction, including those with a previous vasectomy.1 Treatment of surgically correctable male factors is cost-effective and can spare the female partner invasive procedures and potential complications associated with the use of assisted reproductive technologies.2–4 Detection of surgically correctable problems requires an appropriate male factor evaluation, including a history, physical examination, and at least two semen analyses. Further testing, such as endocrine or genetic testing, may be required, depending on the results of the preliminary evaluation. In addition to diagnosing correctable problems, some men may have significant underlying medical problems diagnosed during their evaluation.5,6 Fertility-related surgery on the male reproductive system is performed for three general purposes: diagnosis (procedures such as testicular biopsy and vasography), correction of anatomic abnormalities such as varicocele and obstruction, and sperm retrieval. This chapter focuses on the indications, techniques, and outcomes for these procedures.

DIAGNOSTIC PROCEDURES Transrectal Ultrasound Transrectal ultrasound is employed to detect abnormalities of the prostate, seminal vesicles, and ejaculatory ducts. Azoospermic men with low semen volume (