Treatment of the Postmenopausal Woman Basic and Clinical Aspects THIRD EDITION
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Treatment of the Postmenopausal Woman Basic and Clinical Aspects THIRD EDITION EDITOR
Rogerio A. Lobo, M.D. Department of Obstetrics and Gynecology Columbia University College of Physicians and Surgeons New York, New York
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Copyright 6) 2007, Elsevier Inc. All rights reserved. Portions of this work have been adapted from Menopause:Biology and Pathobiology by Rogerio A. Lobo, Jennifer Kelsey, and Robert Marcus (Academic Press, 2000), and Treatment of the Postmenopausal Woman:Basic and Clinical/Ispects, SecondEdition, by Rogerio A. Lobo (Lippincott Williams & Wilkins, 1999).
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Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
David F. Archer (169, 847) Department of Obstetrics and Gynecology, CONRAD Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia 23507 Cecilia Artacho (655) Department of Obstetrics/Gynecology, Columbia University, New York, New York 10032 Gloria Bachmann (263) Department of Obstetrics/Gynecology & Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901 Randall B. Barnes (767) Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60633 Kurt T. Barnhart (1) Division of Reproductive Endocrinology and Infertility, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 Yves Muscat Baron (227) Department of Obstetrics and Gynecology, St. Luke's Hospital Medical School, University of Malta, Msida MSD 06, Gwardamangia, Malta Narender N. Bhatia (693, 739) Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Torrance, California 90509 Stephanie V. Blank (593) Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York 10016 Mark Brincat (227) Department of Obstetrics and Gynecology, St. Luke's Hospital Medical School, University of Malta, Msida MSD 06, Gwardamangia, Malta
Henry G. Burger (67) Prince Henry's Institute, Clayton, Victoria 3168, Australia John E. Buster (821) Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Baylor College of Medicine, Houston, Texas 77030 R.Jeffrey Chang (49) University of California, San Diego, School of Medicine, La Jolla, California 92093 Ru-fongJ. Cheng (263) Department of Obstetrics, Gynecology, & Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901 Judi L. Chervenak (157) Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York 10461 Claus Christiansen (377, 393) Center for Clinical and Basic Research, 2750 Ballerup, Denmark Thomas B. Clarkson (509) Wake Forest University School of Medicine, Comparative Medicine Clinical Research Center, WinstonSalem, North Carolina 27157 Felicia Cosman (323, 837) Helen Hayes Hospital, West Haverstraw, New York 10993; Columbia University College of Physicians and Surgeons, New York, New York 10032 John P. Curtin (585) Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York 10016 Ivaldo da Silva (199) Gynecology Department, Federal University of S~o Paulo, Brazil 04038-031
Vi
Susan R. Davis (799) Women's Health Program, Monash University (CECS), Alfred Hospital, Prahran, Victoria 3181, Australia Lorraine Dennerstein (271) Office for Gender & Health, Department of Psychiatry, The University of Melbourne, Parkville 3010, Australia Martina DSren (813) Charitd-Universitiitsmedizin Berlin, Campus Benjamin Franklin, Clinical Research Center of Women's Health, D-12200 Berlin, Germany Paul S. Dudley (821) Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Baylor College of Medicine, Houston, Texas 77030 Richard Eastell (337) Academic Unit of Bone Metabolism, University of Sheffield, Metabolic Bone Centre, Sorby Wing, Northern General Hospital, Sheffield, United Kingdom $5 7AU Gregory F. Erickson (49) University of California, San Diego, School of Medicine, La Jolla, California 92093 David A. Fishman (593) Section of Gynecologic Oncology, New York University School of Medicine, New York, New York 10016 Ian S. Fraser (149) Department of Obstetrics and Gynaecology, University of Sydney, NSW 2006, Australia Robert R. Freedman (187) Departments of Obstetrics and Gynecology and Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan 48201 Adriane Fugh-Berman (683) Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC 20057 Ray Galea (227) Department of Obstetrics and Gynecology, St. Luke's Hospital Medical School, University of Malta, Msida MSD 06, Gwardamangia, Malta J.C. OaUagher (847) Department of Medicine, Bone Metabolism Unit, Creighton University School of Medicine, Omaha, Nebraska 68178 Margery L.S. Gass (611) Clinical Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 Radhika Gogoi (593) Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York 10016 Ellen B. Gold (77) Division of Epidemiology, Department of Public Health Sciences, University of California, Davis, California 95616
CONTRIBUTORS
Juan Gonzalez (1) University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 Eiran Zev Gorodeski (405) Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195 George I. Gorodeski (405) Department of Reproductive Biology, CASE (Case Western Reserve) University, Cleveland, Ohio 44106 Gall A. Greendale (77) Divisions of Geriatrics/General Internal Medicine, Department of Internal Medicine, David Geffen School of Medicine, University of California at Los Angeles, Torrance, California 90095 Allison R. Hagey (655) Department of Obstetrics/Gynecology, Columbia University, New York, New York 10032 Georgina E. Hale (149) Department of Obstetrics and Gynaecology, University of Sydney, NSW 2006, Australia RosemaryA. Hannon (337) Academic Unit of Bone Metabolism, University of Sheffield, Metabolic Bone Centre, Sorby Wing, Northern General Hospital, Sheffield, United Kingdom $5 7AU Victor W. Henderson (295) Departments of Health Research and Policy, and of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305 William H. Hindle (579) Department of Obstetrics and Gynecology, University of Southern California; The William Hindle, M.D. Breast Diagnostic Center, Los Angeles, California 90033 Mat H. Ho (693, 739) Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Torrance, California 90509 Howard N. Hodis (529) Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 Christian F. Holinka (863) PharmConsult | New York, New York 10468 Diane M.Jacobs (287) Consultant, San Diego, California; Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10468 Jay R. Kaplan (509) Wake Forest University School of Medicine, Comparative Medicine Clinical Research Center, Winston-Salem, North Carolina 27157
CONTRIBUTORS
Richard H. Karas (453) Molecular Cardiology Research Center, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111 Morten A. Karsdal (393) Pharmos Bioscience, 2730 Herlev, Denmark Harry Irving Katz (237) Department of Dermatology, University of Minnesota, Minneapolis, Minnesota 55455 Fergus S.J. Keating (351) Giggs Hill Surgery, Thames Ditton, Surrey, United Kingdom KT7 0EB Michael Kleerekoper (331) St. Joseph Mercy Hospital, Ann Arbor, Michigan; Department of Internal Medicine and Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan; St. Joseph Mercy Reichert Health Center, Ypsilanti, Michigan 48197 Kwang Kon Koh (471) Vascular Medicine and Atherosclerosis Unit, Division of Cardiology, Gil Medical Center, Gachon Medical School, Namdong-Gu, Incheon, Korea 405-760 Ronald M. Krauss (461) Children's Hospital & Research Center Oakland, Oakland, California 94609 Carlo La Vecchia (599) Istituto di Ricerche Farmacologiche "Mario Negri," 20157 Milano, Italy; Istituto di Statistica Medica e Biometria, Universit~ degli Studi di Milano, 20133 Milano, Italy Sulggi Lee (569) Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 Seth G. Levrant (767) Tinley Park, Illinois 60477 Robert Lindsay (323, 837) Helen Hayes Hospital, West Haverstraw, New York 10993; Columbia University College of Physicians and Surgeons, New York, New York 10032 Rogerio A. Lobo (875) Department of Obstetrics & Gynecology, Columbia University College of Physicians and Surgeons, New York, New York 10032 WendyJ. Mack (529) Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 Sten Madsbad (501) Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
vii
Pauline M. Maki (279) Departments of Psychiatry and Psychology, Center for Cognitive Medicine, University of Illinois at Chicago, Chicago, Illinois 60612 JoAnn E. Manson (619) Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215 Donald P. McDonnell (17) Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 C. Noel Bairey Merz (471) Division of Cardiology, Department of Medicine, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center; Department of Medicine, University of California School of Medicine, Los Angeles, California 90048 Karin B. Michels (619) Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 Frederick Naftolin (199) Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York 10016 Morris Notelovitz (481,855) Adult Women's Health & Medicine, Boca Raton, Florida 33496 James M. Olcese (829) Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida 32306 Annlia Paganini-Hill (627) Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 C. Leigh Pearce (569) Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 Alison C. Peck (157) The Fertility Institutes, Encino, California 91436 James H. Pickar (863) Wyeth Research, Collegeville, Pennsylvania 19426 Malcolm C. Pike (569) Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033
viii
Janet Hill Prystowsky (237) St. Luke's-Roosevelt Hospital Center, New York, New York 10021 Nancy King Reame (127) School of Nursing, Columbia University, New York, New York 10032 Robert W. Rebar (99,471) American Society for Reproductive Medicine, Birmingham, Alabama 35216 Catherine A. Roca (307) Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, Maryland 20892 Elisheva Rovner (263) Women's Health Institute, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901 David R. Rubinow (307) Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599 Ichiro Sakuma (471) Cardiovascular Medicine, Hokko Memorial Hospital, Sapporo, Japan G6ran Samsioe (251,813) Department of Obstetrics & Gynecology, Lund University Hospital, 221 85 Lund, Sweden Mary Sano (287) Alzheimer's Disease Research Center, Department of Psychiatry, Mount Sinai School of Medicine, James J. Peters VA Medical Center, Bronx, New York 10468 Nanette Santoro (157) Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology & Women's Health, Albert Einstein College of Medicine, Bronx, New York 10461 MarkV. Sauer (111) Columbia University Medical Center, New York, New York 10032 PeterJ. Schmidt (307) Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, Maryland 20892 Hermann P.G. Schneider (639) Department of Obstetrics & Gynecology, University of Muenster, 48149 Muenster, Germany Andrea B. Sherk (17) Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 Barbara B. Sherwin (217) Department of Psychology, McGi11 University, Montreal, Quebec, Canada H3A 1B1 Joe Leigh Simpson (29) Department of Obstetrics and Gynecology, Human Molecular Genetics, Florida Internal University, Miami, Florida 33199
CONTRIBUTORS
Sven O. Skouby (501) Department of Obstetrics and Gynecology,Frederiksberg Hospital, University of Copenhagen, Denmark Leon Speroff (1) Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon 97201 DarcyV. Spicer (569) Department of Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 Frank Z. Stanczyk (779) Departments of Obstetrics & Gynecology, and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 John C. Stevenson (351) National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, London, United Kingdom SW3 6NP Lfiszl6 B. Tank6 (377, 393) Center for Clinical and Basic Research, 2750 BaUerup, Denmark HelenaJ. Teede (67) Jean Hailes Research Group, Monash Institute for Health Services Research, Clayton, Victoria, 3168 Australia Prati Vardhana (111) Columbia University Medical Center, New York, New York 10032 MicheUe P. Warren (655) Department of Obstetrics/Gynecology, Columbia University, New York, New York 10032 Carolyn Westhoff (491) Columbia University Medical Center, New York, New York 10032 Anna H. Wu (569) Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 Byung-Koo Yoon (471) Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea RalfC. Zimmermann (829) Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Columbia University College of Physicians and Surgeons, New York, New York 10032
Preface
This is the third edition of Treatment of the Postmenopausal Woman."Basic and Clinical Aspects. In reality it is a merging of chapters from the second edition of this book and a book I edited together with Bob Marcus and Jennifer Kelsey, entitled Menopause, which dealt with more basic and research issues. Although these books were published almost 8 years ago, it was important for me to wait until now to update the book because of the various randomized clinical trials on hormonal therapy that were being conducted at the time of the last edition. Now that we have a great deal of new clinical information that has been synthesized and updated, it is appropriate to try to put these findings into perspective. It should be stated, however, that menopausal management is more than just hormonal therapy, and it is the aim of this edition to approach menopausal management more globally. There are now close to 50 million postmenopausal women in the United States and many more worldwide. In developed countries, once a woman reaches the age of natural menopause, her life expectancy is approximately 84 years. As life expectancy increases in women, the total population of postmenopausal women increases, and this increasing segment of the population requires comprehensive health care. Most countries around the world have established national menopause societies, lending credence to the importance and interest in this field of health care. For women in developed countries, the leading cause of death is still cardiovascular disease (coronary disease and stroke), followed by total cancer deaths; lung cancer mortality exceeds that of breast cancer. All of these concepts and findings will be discussed in this book. The book has been written with a clinical orientation and is appropriate reading for all providers of health care for women, as well as for medical professionals in training. Newer sections have been added since the last edition, and as in the previous edition, each section is preceded with a preface, in which I have attempted to orient the reader to the key issues contained therein. Once again, I hope the reader will enjoy this book. It is my desire that this book will help provide the basis and rationale for strategies that will result in better health care for the mature woman, a growing segment of the U.S. population and the world.
Rogerio A. Lobo, M.D.
ix
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Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
The Menopause" A Signal for the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leon Speroff, Kurt T. Barnhart, and Juan Gonzalez
Section I" Basics to Enhance Our Understanding 2.
Molecular Pharmacology of Estrogen and Progesterone Receptors . . . . . . . . . . . . . . . . . . . . . . Andrea B. Sherk and DonaM P McDonnell
17
3.
Genetic Programming in Ovarian Development and Oogenesis . . . . . . . . . . . . . . . . . . . . . . . Joe Leigh Simpson
29
4.
Basic Biology: Ovarian Anatomy and Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gregory E Erickson and R. Jeffrey Chang
49
5.
Endocrine Changes During the Perimenopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henry G. Burger and Helena J. Teede
67
6.
Epidemiology of Menopause: Demographics, Environmental Influences, and Ethnic and International Differences in the Menopausal Experience . . . . . . . . . . . . . . . . . . Ellen B. Gold and Gaild. Greendale
77
Section II: Ovarian Senescence and Options 0
0
Premature Ovarian Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert W. Rebar Reproductive Options for Perimenopausal and Menopausal Women . . . . . . . . . . . . . . . . . . . . . Mark V. Sauer and Prati Vardhana
99 111
Section III: The Perimenopause Neuroendocrine Regulation of the Perimenopause Transition . . . . . . . . . . . . . . . . . . . . . . . . Nancy King Reame
127
10.
Changes in the Menstrual Pattern During the Menopause Transition . . . . . . . . . . . . . . . . . . . . Georgina E. Hale and Ian S. Fraser
149
11.
Decisions Regarding Treatment During the Menopause Transition . . . . . . . . . . . . . . . . . . . . . Alison C. Peck,Judi L. Chervenak, and Nanette Santoro
157
12.
Use of Contraceptives for Older Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David E Archer
169
0
xi
xii
CONTENTS
Section IV: Changes Occurring After Menopause 13.
Menopausal Hot Flashes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
187
Robert R. Freedman 14.
Clinical Effects of Sex Steroids on the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
199
Ivaldo da Silva and Frederick Naftolin
15.
Impact of the Changing Hormonal Milieu on Psychological Functioning . . . . . . . . . . . . . . . . . .
217
Barbara B. Sherwin 16.
Connective Tissue Changes in the Menopause and with Hormone Replacement Therapy . . . . . . . . .
227
Mark Brincat, Ray Galea, and Yves Muscat Baron 17.
Menopause and the Skin . . . . . . . . .
..................................
237
Harry Irving Katz and Janet Hill Prystowsky
18.
Urogenital Symptoms around the Menopause and Beyond . . . . . . . . . . . . . . . . . . . . . . . . . .
251
GO'ran Samsioe
19.
Vulvovaginal Complaints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
263
Gloria Bachmann, Ru-fongJ. Cheng, and Elisheva Rovner 20.
Sexuality: Clinical Implications from Epidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . .
271
Lorraine Dennerstein
Section V: Brain Function 21.
Menopause and Cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
279
Pauline M. Maki 22.
Cognitive Health in the Postmenopausal Woman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
287
Diane M. Jacobs and Mary Sano 23.
The Role of Sex Steroids in Alzheimer's Disease: Prevention and Treatment . . . . . . . . . . . . . . . .
295
Victor W. Henderson 24.
Estrogens and Depression in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
307
David R. Rubinow, Catherine A. Roca, and PeterJ. Schmidt
Section VI: Bone Changes 25.
Pathogenesis of Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
323
Robert Lindsay and Felicia Cosman 26.
Assessment of Bone Density and Bone Strength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
331
Michael Kleerekoper 27.
Biochemical Markers of Bone Turnover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
337
Richard Eastell and Rosemary A. Hannon 28.
Interventions for Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
351
Fergus S.J. Keating and John C. Stevenson
29.
Treatment of Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
377
Ldszl6 B. Tank6 and Claus Christiansen
30.
Potentials of Estrogens in the Prevention of Osteoarthritis: W h a t Do We Know and W h a t Questions are Still Pending? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ldszl6 B. Tank5, Claus Christiansen, and Morten A. Karsdal
393
xiii
CONTENTS
Section VII" Cardiovascular 31.
Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women . . . . . . . . . . . Eiran Zev Gorodeski and George I. Gorodeski
405
32.
Mechanisms of Action of Estrogen on the Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . Richard H. Karas
453
33.
Lipids and Lipoproteins and Effects of Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Ronald M. Krauss
461
34.
The Effects of Hormone Therapy on Inflammatory, Hemostatic, and Fibrinolytic Markers in Postmenopausal Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kwang Kon Koh, Byung-Koo Yoon, C. Noel Bairey Merz, Icloiro Sakuma, and Robert W. Rebar
471
35.
Hormone Therapy and Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morris Notelovitz
481
36.
Risk of Pulmonary Embolism/Venous Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carolyn Westhoff
491
37.
Glucose Metabolism After Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sven O. Skouby and Sten Madsbad
501
38.
Stage of Reproductive Life, Atherosclerosis Progression and Estrogen Effects on Coronary Artery Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas B. Clarkson and Jay R. Kaplan
509
Randomized Controlled Trials and the Effects of Postmenopausal Hormone Therapy on Cardiovascular Disease: Facts, Hypotheses, and Clinical Perspective . . . . . . . . . . . . . . . . . . . . . Howard N. Hodis and WendydI. Mack
529
39.
Section VIII: Neoplasia 40.
Body Weight, Menopausal Hormone Therapy, and Risk of Breast Cancer . . . . . . . . . . . . . . . . . . Anna H. Wu, C. Leigh Pearce, Darcy V. Spicer, Sulggi Lee, and Malcolm C. Pike
569
41.
Postmenopausal Breast Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . William H. Hindle
579
42.
Endometrial Cancer and Hormonal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . John P. Curtin
585
43.
Ovarian Cancer and Its Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radhika Gogoi, Stephanie V. Blank, and Davidd. Fishman
593
Hormone Replacement Therapy in Menopause and Breast, Colorectal, and Lung Cancer: An U p d a t e . . . Carlo La Vecchia
599
4Q
Section IX: Clinical Trials and Observational Data 45.
The Women's Health Initiative~Data and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . Margery L.S. Gass
46.
Postmenopausal Hormone Therapy in the 21st Century: Reconciling Findings from Observational Studies and Randomized Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . Karin B. Michds andJodnn E. Manson
47.
Morbidity and Mortality Changes with Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . dnnlia Paganini-Hill
611
619 627
CONTENTS
xiv
Section X: Life Cycle and Q OL 48.
Issues Relating to Quality of Life in Postmenopausal Women and Their Measurement . . . . . . . . . . . Hermann P.G. Schneider
639
49.
Role of Exercise and Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michelle P. Warren, CeciliaArtacho, and Allison R. Hagey
655
50.
Herbs, Phytoestrogens, and Other CAM Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adriane Fugh-Berman
683
Section Xl: Urinary Symptoms and Pelvic Support 51.
Lower Urinary Tract Disorders in Postmenopausal Women . . . . . . . . . . . . . . . . . . . . . . . . . Mat H. Ho and Narender N. Bhatia
693
52.
Pelvic Organ Prolapse in Postmenopausal Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mat H. Ho and Narender N. Bhatia
739
Section Xll: Hormonal Therapy 53.
Pharmacology of Estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Randall B. Barnes and Seth G. Levrant
54.
Structure-Function Relationships, Pharmacokinetics, and Potency of Orally and Parenterally Administered Progestogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Frank Z. Stanczyk
767
779
55.
Intervention: Androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Susan R. Davis
799
56.
Future Strategies in Climacteric Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GOran Samsioe and Martina DO'ren
813
Section Xlll: Some Alternative Medical Therapies 57.
Alternative Therapy: Dehydroepiandrosterone for Menopausal Hormone Replacement . . . . . . . . . . . Paul S. Dudley and John E. Buster
821
58.
Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ralf C. Zimmermann and James M. Olcese
829
59.
Selective Estrogen Receptor Modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Felicia Cosman and Robert Lindsay
837
60.
Tibolone: Selective Tissue Estrogen Activity Regulator Utilization in Postmenopausal Women . . . . . . . David E Archer andJ. C. Gallagher
847
Section XIV: Women's Centers, Information Needed for Clinical Trials, and the Future 61.
Integrated Adult Women's Medicine: A Model for Women's Health Care Centers . . . . . . . . . . . . . Morris Notelovitz
853
62.
Clinical Trials in Postmenopausal Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christian E Holinka and James H. Pickar
863
63.
The Furore of Therapy and the Role of Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Rogerio d. Lobo
875
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
881
~HAPTER
_
The Menopause: A Signal for the Future LEON SPEROFF
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR 97201
K U R T T. B A R N H A R T
Division of Reproductive Endocrinology and Infertility, University of Pennsylvania Medical Center, Philadelphia, PA 19104
JUAN G O N Z A L E Z
University of Pennsylvania Medical Center, Philadelphia, PA 19104
Throughout recorded history, multiple physical and mental conditions have been attributed to the menopause. Although medical writers often wrote colorfully in the past, they were also less than accurate, unencumbered by scientific information and data. A good example of the stereotypical, inaccurate thinking promulgated over the years is the following passage, which was written in 1887 (1). The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity. The belief that behavioral disturbances are related to manifestations of the female reproductive system is an ancient one that has persisted in contemporary times. This belief regarding menopause is not totally illogical; there is reason to associate the middle years of life with negative experiences. The events that come to mind are impressive: onset of a major illness or disability (even death) in a spouse, relative, or friend; retirement from employment; financial insecurity; the need to provide care for very old parents and relatives; and separation
TREATMENT OF THE POSTMENOPAUSAL W O M A N
from children. It is therefore not surprising that a middle-age event, the menopause, shares in this negative outlook. The scientific study of all aspects of menstruation has been hampered by the overpowering influence of social and cultural beliefs and traditions. Problems arising from life events have often been erroneously attributed to the menopause. However, data, especially more reliable communitybased longitudinal data, have established that the increase of most symptoms and problems in middle-aged women reflects social and personal circumstances, not the endocrine events of the menopause (2-8). The Massachusetts Women's Health Study, a large and comprehensive prospective, longitudinal study of middleaged women, provides a powerful argument that menopause is not and should not be viewed as a negative experience by most women (3,9). The cessation of menses was perceived by these women (as by the women in other longitudinal studies) to have almost no impact on subsequent physical and mental health. Most women expressed positive or neutral feelings about menopause. An exception was the group of women who experienced surgical menopause, but the reasons for the surgical procedure usually were more important than the cessation of menses. Copyright 9 2007 by Elsevier,Inc. All rights of reproductionin any form reserved.
2
SPEROFF ET AL.
The Study of Women's Health across the Nation (SWAN), a large multiethnic cohort study, found that menopause-related symptoms exert a stronger influence on impaired functioning. Menopause in itself does not impact quality of life. Experiencing night sweats, urinary incontinence, and hot flashes is, however, associated with lower health-related quality of life. SWAN also showed that significant ethnic differences exist regarding health-related quality of life (ga). Among the ethnic groups studied, Bodily Pain and Social Functioning subscales remained significant even in adjusted analyses. Alterations in menstrual function are not symbols of some ominous "change." There are good physiologic reasons for changing menstrual function, and understanding the physiology can do much to reinforce a healthy, normal attitude. Attitude and expectations about menopause are important. Women who have been high users of health services and who expect to have difficulty do experience greater symptoms and higher levels of depression (4,9). The symptoms that women report are related to many variables within their lives, and the hormonal change at menopause cannot be held responsible for the common psychosocial and lifestyle problems we all experience. It is time to stress the normalcy of this physiologic event. Menopausal women do not suffer from a "hormone deficiency disease." Hormone therapy remains effective for treating vasomotor symptoms, vaginal atrophy, and retardation of osteoporosis in select patients (gb). The risks of hormone therapy exceed the benefits for the prevention of chronic diseases. It can be further argued that physicians have had a biased negative point of view regarding women's experience of menopause, because most women who are healthy and happy do not seek contact with physicians (10,11). Clinicians must be familiar with the facts about menopause and have an ap-
propriate attitude and philosophy regarding this period of life. Medical intervention at this point of life should be regarded as an opportunity to provide and reinforce a program of preventive health care. The issues of preventive health care for women are familiar ones. They include family planning, cessation of smoking, control of body weight and alcohol consumption, prevention of accidents and trauma, prevention of cardiovascular disease and osteoporosis, maintenance of mental well-being (including sexuality), cancer screening, and treatment of urologic problems.
I. AGE OF MENOPAUSE Menstrual irregularity is the only marker used to define and establish the perimenopausal transition. The menopause is permanent cessation of menstruation after the loss of ovarian activity. Menopause is derived from the Greek words men (month) and pausis (cessation). The years before menopause that encompass the change from abnormal ovulatory cycles to cessation of menses are known as the perimenopausal transitional years, marked by irregularity of menstrual cycles. Climacteric indicates the period when a woman passes from the reproductive stage of life through the perimenopausal transition and the menopause to the postmenopausal years. Climacteric is derived from the Greek word for ladder. In July 2001 the Stages of Reproductive Aging Workshop (STRAW) was convened to establish nomenclature and guidelines (Fig. 1.1) (lla). Designating the average age of menopause has been somewhat difficult. Based on cross-sectional studies, the median age was estimated to be between 50 and 52 (12). These studies relied on retrospective memories and the subjective vagaries of the individuals being interviewed.
FIGURE 1.1 The STRAWstaging system.SoulesMR, Sherman S, Parrott E, e t al.
Executive summary:Stagesof ReproductiveAgingWorkshop (STRAW).Fertilityand Sterility 2001;76:874-878.
3
CHAPTER 1 The Menopause: A Signal for the Future SWAN provided a cross-sectional examination of the relation of lifestyle and demographic factors to age at natural menopause in seven U.S. centers and five ethnic groups. Median age of menopause was found to be 51.4 years. Current smoking, lower educational attainment, being separated/ widow/divorced, nonemployment, and history of heart disease were all independently associated with earlier natural menopause. In the contrary parity, prior use of oral contraceptives and Japanese ethnicity were associated with later age of menopause (13). A median age of menopause means that only one-half the women have reached menopause at this age. In the classic longitudinal study by Treolar, the average age of menopause was 50.7 years, and the range that included 95% of the women was 44 to 56 years (14). In a survey in the Netherlands, the average age of menopause was 50.2 years (15). About 1% of women experience menopause before the age o f 40 (16). Clinical impression has suggested that mothers and daughters tend to experience menopause at the same age, and two studies indicate that daughters of mothers with an early menopause (before age 46) also have an early menopause (17-19). There is sufficient evidence to believe that undernourished women and vegetarians experience an earlier menopause (17,20). Because of the contribution of body fat to estrogen production, thinner women experience a slightly earlier menopause (21). Consumption of alcohol is associated with a later menopause (18). This is consistent with the reports that women who consume alcohol have higher blood and urinary levels of estrogen and greater bone density (22-26). There is no correlation between age of menarche and age of menopause (14,15,17). In most studies, race, parity, and height have no influence on the age of menopause; however, two cross-sectional studies found later menopause to be associated with increasing parity (15,17,21). Two studies have found that irregular menses among women in their forties predicts an earlier menopause (27,28). A French survey detected no influence of heavy physical work on early menopause (before age 45) (29). An earlier menopause is associated with living at high altitudes (30). Multiple studies have consistently documented that an earlier menopause (average of 1.5 years earlier) is a consequence of smoking. There is a dose response relationship with the number of cigarettes smoked and the duration of smoking (31,32). Even former smokers show evidence of an impact. There is reason to believe that premature ovarian failure can occur in women who have previously undergone abdominal hysterectomy, presumably because ovarian vasculature has been compromised (33). Unlike the decline in age of menarche that occurred with an improvement in health and living conditions, most historical investigation indicates that the age of menopause has changed little since the reports from ancient Greece (34,35). A few authorities have disagreed, concluding that the age of
menopause did undergo a change, starting with an average age of about 40 years in ancient times (36). If there has been a change, however, history indicates it has been minimal. Even in ancient writings, 50 is usually cited as the age of menopause.
II. SYMPTOMS OF MENOPAUSE During the menopausal years, some women experience multiple severe symptoms, but others have no reactions or minimal reactions that can go unnoticed. The differences in reactions to menopausal symptoms across different cultures is poorly documented, and it is difficult to do so. Individual reporting is so conditioned by sociocultural factors that it is hard to determine what is caused by biologic or cultural variability. Women often seek medical assistance for disturbances in menstrual pattern, hot flushes, atrophic conditions, and psychologic symptoms. Disturbances in the menstrual pattern include anovulation and reduced fertility, decreased or increased flow, and irregular frequency of menses. Vasomotor instability results in the hallmark symptom of menopause, the hot flush (Table 1.1). The vasomotor flush is viewed as the hallmark of the female climacteric, experienced to some degree by most postmenopausal women. The term hotflush is descriptive of a sudden onset of reddening of the skin over the head, neck, and chest, accompanied by a feeling of intense body heat and concluded by sometimes profuse perspiration. The duration varies from a few seconds to several minutes or, rarely, for an hour. They may occur rarely or recur every few minutes. Flushes are more frequent and severe at night (when a woman is often awakened from sleep) or during times of stress. In a cool environment, hot flushes are fewer, less intense, and shorter in duration compared with a warm environment (37). In a longitudinal follow-up study of a large number of women, fully 10% of the women experienced hot flushes
TABLE 1.1
Characteristics of Hot Flushes
Premenopausal Postmenopausal 9 Number of flushes: 9 Daily flushing: 9Average duration: 9 5 + years' duration: Other causes 9 Psychosomatic 9 Stress 9Thyroid disease ~ Pheochromocytoma 9 Carcinoid 9 Leukemia 9Cancer
15-25% of women 15-25% of women 15-20% of women 1-2 years 25% of women
4 before menopause, but in other studies, as many as 15% to 25% of premenopausal women reported hot flushes (38,39). In the Massachusetts Women's Health Study, the incidence of hot flushes increased from 10% during the premenopausal period to about 50% just after cessation of menses. By approximately 4 years after menopause, the rate of hot flushes declined to 20%. In a community-based Australian survey, 6% of premenopausal women, 26% of perimenopausal women, and 59% of postmenopausal women reported hot flushing (40). Although the flush can occur in the premenopause, it is a major feature of postmenopause, lasting in most women for 1 to 2 years but in as many as 25% for longer than 5 years. In cross-sectional surveys, up to 40% of premenopausal women and 85% of menopausal women report vasomotor complaints (39). In the United States, there is no difference in the prevalence of vasomotor complaints in surveys of black and white women (41,42). In a massive review of hot flushes, it was concluded that exact estimates on prevalence are hampered by inconsistencies and differences in methodologies, cultures, and definitions (43). The physiology of the hot flush is still not understood, but it apparently originates in the hypothalamus and is brought about by a decline in estrogen. However, not all hot flushes are caused by estrogen deficiency. Flushes and sweating can result from diseases, including pheochromocytoma, carcinoid, leukemias, pancreatic tumors, and thyroid abnormalities (44). Unfortunately, the hot flush is a relatively common psychosomatic symptom, and women often are unnecessarily treated with estrogen. When the clinical situation is not clear, estrogen deficiency as the cause of hot flushes should be documented by elevated levels of folliclestimulating hormone (FSH). The correlation between the onset of flushes and estrogen reduction is clinically supported by the effectiveness of estrogen therapy and the absence of flushes in hypoestrogen states, such as gonadal dysgenesis. Only after estrogen is administered and withdrawn do hypogonadal women experience the hot flush. Although the clinical impression that premenopausal surgical castrates suffer more severe vasomotor reactions is widely held, this is not borne out in objective study (45). Although the hot flush is the most common problem of the postmenopause, it presents no inherent health hazard. The flush is accompanied by a discrete and reliable pattern of physiologic changes (45a). The flush coincides with a surge of luteinizing hormone (LH), not FSH, and is preceded by a subjective prodromal awareness that a flush is beginning. This aura is followed by measurable increased heat over the entire body surface. The body surface experiences an increase in temperature, accompanied by changes in skin conductance and followed by a fall in core temperature--all of which can be objectively measured. In short, the flush is not a release of accumulated body heat but is a sudden inappropriate excitation of heat release mechanisms. Its relation to the LH surge
SPEROFF ET AL.
and temperature change within the brain is not understood. The observation that flushes occur after hypophysectomy indicates that the mechanism does not depend on LH release. The same hypothalamic event that causes flushes also stimulates gonadotropin-releasing hormone (GnRH) secretion and elevates LH. This probably results in changes in neurotransmitters that increase neuronal and autonomic activity. A strong interaction exists between estrogens and the serotonergic system. Serotonin levels fall with menopause. The 5-HT 2A receptor is postulated to underlie changes in thermoregulation. Stimulation of the receptor leads to changes in the set temperature, leading to autonomic changes that cool the body. Figure 1.2 illustrates the postulated mechanism of hot flashes (46). Premenopausal women experiencing hot flushes should be screened for thyroid disease and other illnesses. A comprehensive review of all possible causes is available (47). Clinicians should be sensitive to the possibility of an underlying emotional problem. Looking beyond the presenting symptoms into the patient's life can be an important service to the patient and her family that eventually will be appreciated. This is more difficult than prescribing estrogen, but confronting problems is the only hope of reaching some resolution. Prescribing estrogen inappropriately (i.e., in the presence of normal levels of gonadotropins) only temporarily postpones by a placebo response dealing with the underlying issues.
in, or external stimulus - i (coffee, anxiety, alcohol etc) I
eetrogen withdrawal ...........
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_
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,
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,~
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, . ;, HH I autonomic reactions to cool........i down the b..ody
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HOT FLUSH FIGURE 1.2 Possible mechanism by which a hot flush is induced. Berendsen HH. The role of serotonin in hot flushes. Maturitas 2000;36: 155-164.
CHAPTER 1 The Menopause: A Signal for the Furore A striking and consistent finding in most studies dealing with menopause and hormonal therapy is a marked placebo response in a variety of symptoms, including flushing. In an English randomized, placebo-controlled study of women being treated with estrogen implants and requesting repeat implants, there was no difference in outcome in terms of psychologic and physical symptoms comparing the women who received an active implant with those receiving a placebo (48). Hormone therapy is indicated for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. Therapy should be used at the lowest effective dose and for the appropriate duration (48a). Atrophic conditions include atrophy of the vaginal epithelium; formation of urethral caruncles; dyspareunia and pruritus from vulvar, introital, and vaginal atrophy; and urinary difficulties such as stress incontinence, urgency, and bacterial urethritis and cystitis. Psychologic symptoms include anxiety, mood depression, irritability, insomnia, and decreased libido. The view that menopause has a deleterious effect on mental health is not supported in the psychiatric literature or in surveys of the general population (38,39,49,50). The concept of a specific psychiatric disorder (i.e., involutional melancholia) has been abandoned. Depression is less common among middle-aged women than younger women, and the menopause cannot be linked to psychologic distress (2-8,51). The longitudinal study of premenopausal women indicates that hysterectomy with or without oophorectomy is not associated with a negative psychologic impact among middle-aged women. Longitudinal data from the Massachusetts Women's Health Study document that menopause is not associated with an increased risk of depression (52). Although women are more likely to experience depression compared with men, this sex difference begins in early adolescence, not at menopause (53). The U.S. National Health Examination Follow-up Study includes longitudinal and cross-sectional assessments of a nationally representative sample of women. This study found no evidence linking natural or surgical menopause to psychologic distress (54). The only longitudinal change was a slight decline in the prevalence of depression as women aged through the menopausal transition. Results in this study were the same for estrogen users and nonusers. A negative view of mental health at the time of menopause is not justified; many of the problems reported at menopause are caused by the vicissitudes of life (55,56). There are problems encountered in the early postmenopause that are seen frequently, but their causal relation with estrogen is unlikely. These problems include fatigue, nervousness, headaches, insomnia, depression, irritability, joint and muscle pain, dizziness, and palpitations. Men and women at this stage of life express a multitude of complaints that do not reveal a gender difference that could be explained by a hormonal cause (57).
5 Attempts to study the effects of estrogen on these problems have been hampered by the subjectivity of the complaints (i.e., high placebo responses) and the "domino effect" of what reduction of hot flushes does to the frequency of the symptoms. Using a double-blind, crossover, prospective study format, Campbell and Whitehead concluded many years ago that many symptomatic "improvements" ascribed to estrogen therapy result from relief of hot flushes~a domino effect (58). A study of 2001 women between the ages of 45 and 55 focused on the use of the health care system by women in the perimenopausal period of life (10). Health care users in this age group were frequent previous users of health care, less healthy, and had more psychosomatic symptoms and vasomotor reactions. These women were more likely to have had a significant previous adverse health history, including a history of premenstrual complaints. This study emphasized that perimenopausal women who seek health care help are different from those who do not seek help, and they often embrace hormone therapy in the hope it will solve their problems. This population is seen most often by clinicians, producing biased opinions regarding menopause among physicians. We must be careful not to generalize to the entire female population the behavior experienced by this relatively small group of women. Most importantly, perimenopausal women who present to clinicians often end up being treated with estrogen inappropriately and unnecessarily. Nevertheless, it is well established that a woman's quality of life is disrupted by vasomotor symptoms, and estrogen therapy provides impressive improvement (59,60). Once improvement has been reached, it is recommended that the decision to maintain estragon therapy be revisited periodically. If upon stopping estrogen therapy, vasomotor symptoms are not severe, therapy should be reinitiated based on other indications. Emotional stability during the perimenopausal period can be disrupted by poor sleep patterns. Hot flushing does have an adverse impact on the quality of sleep (61). Estrogen therapy improves the quality of sleep, decreasing the time to onset of sleep and increasing the rapid eye movement (REM) sleep time (59,62). Perhaps flushing may be insufficient to awaken a woman but sufficient to affect the quality of sleep, thereby diminishing the ability to handle the next day's problems and stresses. The overall quality of life reported by women can be improved by better sleep and alleviation of hot flushing. However, it is still uncertain whether estrogen treatment has an additional direct pharmacologic antidepressant effect or the mood response is an indirect benefit of relief from physical symptoms and, consequently, from improved sleep. Using various assessment tools for measuring depression, improvements with estrogen treatment have been recorded in oophorectomized women (63,64). In the large, prospective cohort study of the Rancho Bernardo retirement community, no
6 benefit could be detected in measures of depression in current users of postmenopausal estrogen compared with untreated women (65). Treated women had higher depressive symptom scores, presumably reflecting treatment selection bias; symptomatic and depressed women seek hormone therapy. Nevertheless, estrogen therapy is reported to have a more powerful impact on women's well-being beyond the relief of symptoms such as hot flushes (66). In elderly, depressed women, improvements in response to fluoxetine were enhanced by the addition of estrogen therapy (67). Sexuality is a lifelong behavior with evolving changes and development. It begins with birth (perhaps before) and ends with death. The notion that it ends with aging is inherently illogical. The need for closeness, caring, and companionship is lifelong. Old people today live longer, are healthier, and have more education and leisure time, and they have had their consciousness raised in regard to sexuality. Younger people, especially younger physicians, underrate the extent of sexual interest in older people. In a random sample of women between the ages of 50 and 82 in Madison, Wisconsin, nearly one-half reported an ongoing sexual relationship (68). In the Duke longitudinal study on aging, 70% of men in the 67 to 77 age group were sexually active, and 80% reported continuing sexual interest, whereas 50% of all older women were still interested in sex (69). In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, 60% of women 55 to 64 years old were sexually active (70). The decline in sexual activity with aging is influenced more by culture and attitudes than by nature and physiology (or hormones). The two most important influences on older sexual interaction are the strength of a relationship and the physical condition of each partner (70). The single most significant determinant of sexual activity for older women is the unavailability of partners because of divorce and the fact that women are outliving men. Given the availability of a partner, the same general high or low rate of sexual activity can be maintained throughout life (4,71). Longitudinal studies indicate that the level of sexual activity is more stable over time than previously suggested (72-74). Individuals who are sexually active earlier in life continue to be sexually active into old age.
III. G R O W T H O F T H E OLDER POPULATION We are experiencing a relatively new phenomenon: We can expect to become old. We are on the verge of becoming a rectangular society, one of the greatest achievements of the 20th century. This is a society in which nearly all individuals survive to advanced age and then succumb rather abruptly over a narrow age range centering on 85 years. In 1000 sc, life expectancy was only 18 years. By 100 BC, the time of Caesar, it had reached 25 years. In 1900 in the United
SPEROFF ET AL.
States, life expectancy had reached only 49 years. In 2000, the average life expectancy is 79.7 years for women and 72.9 for men (75). Today, after a man reaches 65, he can expect to reach 80.5, and a woman who reaches 54 can expect to reach the age of 84.3 years. We can anticipate that eventually about two-thirds of the population will survive to 85 years or longer, and more than 90% will live past the age of 65, producing the nearly perfect rectangular society (76,77). Sweden and Switzerland are closest to this demographic composition. A good general definition of elderly is 65 and older, although it is not until age 75 that a significant proportion of older people show the characteristic decline and health problems. The elderly population is the largest contributor to illness and human need in the United States (78). There are more old people (with their greater needs) than ever before (79). In 1900, there were approximately 3 million Americans 65 years or older (about 4% of the total population). By 2030, the elderly population will reach about 57 million (17% of the total population). Population aging will soon replace population growth as the most important social problem. Two modern phenomena have influenced the rate of change. The first was the baby boom after World War II (1946 through 1964) that temporarily postponed the aging of the population but now is causing a faster aging of the general population. The second major influence has been the modern decrease in old-age mortality. Our success in postponing death has increased the upper segment of the demographic contour. By 2050, the current developed nations will be rectangular societies. By 2050, China will contain more people older than 65 years of age (270 million) than the number of people of all ages currently living in the United States. This is a worldwide development, not limited to affluent societies (80). The population of the earth will continue to grow until the year 2100 or 2150, when it is expected to stabilize at approximately 11 billion, and 95% of this growth will occur in developing countries. The poorest countries today (in Africa and Asia) account for about one-half of the global population, and in 2000, 87% of the world's population will be living in what are now called developing countries. In most developing countries, the complications associated with pregnancy, abortion, and childbirth are the first or second most common cause of death, and almost one-half of all deaths are children younger than 5 years of age. Limiting family size to two children would cut the annual number of maternal deaths by 50% and infant and child mortality by 50% (81). It is appropriate to focus attention on population control; however, even in developing countries, this will change. In 1950, only 40% of people 60 and older lived in developing countries. By 2025, more than 70% will live in those countries (Table 1.2). In 1900, older men in the United States outnumbered women by 102 to 100. In the 1980s, there were only 68 men
7
CHAPTER 1 The Menopause: A Signal for the Future TABLE 1.2
Projected Size of the Population 60 Years of Age and Older
Year
World (millions)
Developing countries (millions)
1950 1975 2000 2025
200 350 590 1100
80 (40%) a 178 (51%) 355 (60%) 792 (72%)
aThe percentageswithin parentheses compare the populations in developing countries with the world populations. From ref. 80, with permission.
for every 100 women older than 65 years. By age 85, only 45 men are alive for every 100 women. Nearly 90% of white American women can expect to live to age 70. Vital statistics data indicate that this gender difference is similar in the black and white populations in the United States (82). Approximately 55% of girls but only 35% of boys live long enough to celebrate their 85th birthday (83). Men and women reach old age with different prospects for older age, a sex differential that in part results from the sex hormone-induced differences in the cholesterol lipoprotein profile and other cardiovascular factors, producing a greater incidence of atherosclerosis and earlier death in men (84). From a public health point of view, the greatest impact on the sex differential in mortality would be gained by concentrating on lifestyle changes designed to diminish atherosclerosis in men: low-cholesterol diet, no smoking, optimal body weight, and active exercise. The death rate is higher for men at all ages. Coronary heart disease accounts for 40% of the mortality difference between men and women. Another one-third is from lung cancer, emphysema, cirrhosis, accidents, and suicides. In our society, the mortality difference between men and women is largely a difference in lifestyle. Smoking, drinking, coronaryprone behavior, and accidents account for most of the higher male mortality rate after age 65. It has been estimated that perhaps two-thirds of the difference has been because of cigarettes alone, but this results from a greater prevalence of smoking among men. Women whose smoking patterns are
TABLE 1.3 Age 55-64 65-74 >75 Total
similar to those of men have a similar increased risk of morbidity and mortality. Perhaps because more women are smoking, drinking, and working, the mortality sex difference has begun to lessen. The U.S. Census Bureau projects that the difference in life expectancy between men and women will increase until the year 2050 and then level off (79). In 2050, life expectancy will be 82 years for women and 76.7 years for men (75). There will be 33.4 million women 65 or older, compared with 22.1 million men (Table 1.3). Unmarried women will be an increasing proportion of the elderly. By 1983, 50% of American women between the ages of 65 and 74 were unmarried (some were divorced, but most were widowed), and after age 75, 77% were unmarried (85). One-half of men 85 or older live with their wives, but only 10% of elderly women live with their husbands. Because the unmarried tend to be more disadvantaged, there will be a need for more services for this segment of the elderly population. Older unmarried people are more vulnerable, demonstrating higher mortality rates and lower life satisfaction. In addition to the growing numbers of elderly people, the older population itself is getting older (86). For example, in 1984, the 65 to 74 age group was more than seven times larger than in 1900, but the 75 to 84 group was 11 times larger, and the 85 and older group was 21 times larger. The most rapid increase is expected between 2010 and 2030, when the baby boom generation hits 65. In the next century, the only age groups in the United States expected to experience significant growth will be those past the age of 55. In this elderly age group, women outnumber men by 2.6 to 1. By the year 2040, there will be 8 million to 13 million people 85 years of age or older; the estimate varies according to pessimistic to optimistic projections regarding disease prevention and treatment.
IV. T H E RECTANGULARIZATION OF LIFE The life span is the biologic limit to life, the maximal obtainable age by a member of a species. The general impression is that the human life span is increasing, but in fact
The Older U.S. Female Population
1990 (millions)
2000 (millions)
10.8 (8.6%)a 10.1 (8.1%) 7.8 (6.2%) 28.7
12.1 (9.0%) 9.8 (7.3%) 9.3 (7.0%) 31.2
2010 (millions) 17.1 (12.1%) 11.0 (7.8%) 9.8 (6.9%) 37.9
2020
(millions) 19.3 (12.9%) 15.6 (10.4%) 11.0 (7.3%) 45.9
aThe percentageswithin parentheses compare the group populations with world populations. From ref. 79, with permission.
8
the life span is fixed, and it is a biologic constant for each species (87). Differences in species' life spans argue in favor of a species-specific genetic basis for longevity. If life span were not fixed, it would mean an unlimited increase in the number of elderly. But a correct analysis of survival reveals that death converges at the same maximal age; what has changed is life expectancy, the number of years of life expected from birth. Life expectancy cannot exceed the life span, but it can closely approximate it. The number of old people will eventually hit a fixed limit, but the percentage of a typical life spent in the older years will increase. Our society has almost eliminated premature death. Diseases of the heart and the circulation and cancers are the leading causes of death. The reason for this is not an increase or an epidemic; it is a result of our success in virtually eliminating infectious diseases. The major determinant is chronic disease, affected by genetics, lifestyle, the environment, and aging itself. The major achievement left to be accomplished is in cardiovascular diseases, but even if cancer, diabetes, and all circulatory diseases were totally eliminated, life expectancy would not exceed 90 years (76). Fries describes three eras in health and disease (88). The first era existed until sometime in the early 1900s and was characterized by acute infectious diseases. The second era, highlighted by cardiovascular diseases and cancer, is beginning to fade into the third era, marked by problems of frailty (e.g., fading eyesight and hearing, impaired memory and cognitive function, decreased strength and reserve). Much of our medical approach is still based on the first era (i.e., find the disease and cure it), but we have conditions that require a combination of medical, psychologic, and social approaches. Our focus has been on age-dependent, fatal chronic diseases. The new challenge is with the nonfatal, age-dependent conditions such as Alzheimer's disease, osteoarthritis, osteoporosis, obesity, and incontinence. It can be argued that health programs in the future should be evaluated by their impact on years free of disability, rather than on mortality.
V. SUCCESSFUL AGING: THE ROLE OF PREVENTIVE HEALTH CARE Chronic illnesses are incremental in nature. The best health strategy is to change the slope, the rate at which illness develops, postponing the clinical illness, and if it is postponed long enough, effectively preventing it. There has been a profound change in public consciousness toward disease. Disease is increasingly seen as something not necessarily best treated by medication or surgery but by prevention or, more accurately, by postponement. Postponing illness is expressed by J.E Fries as the compression of morbidity (87,89). We would live relatively healthy lives and compress our illnesses into a short period just be-
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fore death. Is this change really possible? The mean national body weight has decreased by 5 pounds despite a slight increase in the national average height. There has been a decrease in atherosclerosis in the United States. Reasons include changes in the use of saturated fat, more effective detection and treatment of hypertension, increased exercise, and decreased smoking. Smoking initiation has decreased markedly in men but unfortunately has remained essentially unchanged in women. Female smokers begin smoking at a younger age. More young women (including teenagers) smoke than young men. Smoking appears to have a greater adverse effect on women compared with men (90). Physician smokers have declined from a high of 79% to a small minority (91). The greatest decrease has been among pulmonary surgeons, and the least decrease has been among proctologists. From the mid-1970s to the early 1990s, smoking among physicians declined from 18.8% to 3.3%. Unfortunately, that still amounts to approximately 18,000 physicians who smoke. Fifteen percent of Registered Nurses smoke. That is about 388,960 of the 2.6 million Registered Nurses in the United States. Twentyeight percent of Licensed Practical Nurses smoke. Smoking is declining among Registered Nurses but is higher than the Healthy People 2010 goal of 12% for the general population (91a). In the year 2005, approximately 20.9% (45.1 million) of U.S. adults were smokers. Current smoking was higher among men (23.9%) than women (18.1%). By education level, smoking prevalence was higher among adults who had earned a General Educational Development diploma (43.2%) and those with 9 to 11 years of education (32.6%) and prevalence decreased with increasing education (91b). Cigarette smoking therefore continues to be the single most preventable cause of premature death in the United States. The use of chewing tobacco, pipe smoking, and cigars contributes significantly to morbidity and mortality. Physicians and older patients may be skeptical that quitting after decades of smoking could be beneficial. In a longitudinal study of 2674 persons between the ages of 65 and 74, the mortality rates for ex-smokers were no higher than for nonsmokers (92). The effects are at least partly reversible within 1 to 5 years after quitting. Even older patients who already have coronary artery disease have improved survival after they quit smoking (93). No matter how old a person is, if he continues to smoke, he has an increased relative risk of death, but if he quits smoking, his risk of death decreases. Since 1970, the death rate from coronary heart disease has declined by approximately 50% in the United States (90). During the 20 year period of 1970 to 1990 age-adjusted coronary heart disease mortality rates decreased 3% per year. However, during the 7-year period between 1990 and 1997 coronary heart disease mortality declined at a rate 2.7% (93a).
CHAPTER I The Menopause: A Signal for the Future
Despite our progress, we must continue to exert preventive efforts on the risk factors associated with cardiovascular disease, especially obesity, hypertension, and lack of physical activity. The effort to improve the quality of life has an important value to society; it will decrease the average number of years that people are disabled and a liability. Frailty and disability have become the major health and social problems of society. Most significantly, this is a major financial challenge for health care systems and social programs. With evolution toward a rectangular society, the ratio of beneficiaries to taxpayers grows rapidly, jeopardizing the financial support for health and social programs. Compression of morbidity is at least one attractive solution to this problem.
VI. MENOPAUSE AS AN OPPORTUNITY Clinicians who interact with women at the time of menopause have a wonderful opportunity and therefore a significant obligation. Medical intervention at this point of life offers women years of benefit from preventive health care. This represents an opportunity that should be seized. It is logical to argue that health programs should be directed to the young. It makes sense to create good lifelong health behavior. Although not underrating the importance of good health habits among the young, it can be argued that the impact of teaching preventive care is more observable and more tangible at middle age. The prospects of limited mortality and the morbidity of chronic diseases are now viewed with belief, understanding, and appreciation during these older years. The chance of illness is higher, but the impact of changes in lifestyle is greater.
VII. THE MENOPAUSE AS A SIGNAL FOR THE FUTURE The menopause should remind patients and clinicians that this is a time for education. Preventive health care education is important throughout life, but at the time of menopause, a review of the major health issues can be especially rewarding. Diseases of the heart are the leading cause of death for women in the United States, followed by malignant neoplasms, cerebrovascular disease, and motor vehicle accidents. Of the 550,000 people in the United States who die each year of heart disease, 250,000 are women (94). Nearly onethird of heart disease mortality in women occurs before the age of 65. Most cardiovascular disease results from atherosclerosis in major vessels. The risk factors are the same for men and women: high blood pressure, smoking, diabetes mellitus, and
9 obesity. When controlling for these risk factors, men have a 3.5 times greater risk of developing coronary heart disease than women. Even taking into consideration the changing lifestyle of women (e.g., employment outside the home), women still maintain their advantage in terms of risk for coronary heart disease. However, with increasing age, this advantage is gradually lost, and cardiovascular disease becomes the leading cause of death for older women and men. In the past 30 years, stroke mortality has declined by 60% and mortality from coronary heart disease by 50% in the United States (90). Improvements in medical and surgical care can account for some of this decline, but 60% to 70% of the improvement results from preventive measures. Excellent data from epidemiologic studies and clinical trials demonstrate a decline in stroke and heart disease morbidity and mortality from smoking cessation, blood pressure reduction, and lowering of cholesterol (95,96). There is a strong and growing scientific basis for preventive medicine and health promotion efforts in clinical practice. Multiple observational studies in younger postmenopausal women support the conclusion that hormone therapy has cardiovascular benefit in postmenopausal women. Data from randomized control trials of older postmenopausal women have not supported the observational data. Risk factors for cardiovascular disease, such as diabetes and subclinical arthrosclerosis, increase with age. It is possible that potential cardiovascular benefits of hormone therapy may decrease the further from the onset of menopause that estrogen therapy is initiated. However, initiation or continuation of hormone therapy should not be based on primary or secondary prevention of cardiovascular disease (96a). Osteoporosis is a major global public health problem, and it is epidemic in the United States, affecting more than 20 million individuals (97). The increase in osteoporotic fractures in the developed world is partly caused by an increase in the elderly population. A comparison of bone densities in proximal femur bones in specimens from a period of over 200 years suggested that women lose more bone today, perhaps because of less physical activity and less parity (98). Other contributing factors include a dietary decrease in calcium and an earlier and greater loss of bone because of the impact of smoking. Our Stone Age predecessors consumed a diet high in calcium, mostly from vegetable sources (99). However, the impact of the tremendous increase in the elderly population throughout the world cannot be underrated. Because of this demographic change, the number of hip fractures occurring in the world each year will increase approximately sixfold from 1990 to 2050, and the proportion occurring in Europe and North America will fall from 50% to 25% as the numbers of old people in developing countries increase (100). The onset of spinal bone loss begins in the twenties, but the overall change is small until menopause. Bone density in the femur peaks in the middle to late twenties and begins to
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decrease around age 30. In general, trabecular bone resorption and formation occur four to eight times as fast as cortical bone. Beyond age 30, trabecular resorption begins to exceed formation by about 0.7% per year. This adverse relationship accelerates after menopause, and up to 5% of trabecular bone and 1% to 1.5% of total bone mass loss per year occurs after menopause. This accelerated loss continues for 10 to 15 years, after which bone loss is considerably diminished but continues as the aging-related loss. For the first 20 years after cessation of menses, menopause-related bone loss results in a 50% reduction in trabecular bone and a 30% reduction in cortical bone (101,102). Estrogen therapy provides a 50% to 60% decrease in fractures of the arm and hip (103-105), and when estrogen is supplemented with calcium, an 80% reduction in vertebral compression fractures occurs (106). This reduction is seen primarily in patients who have taken estrogen for more than 5 years (107,108). Protection against fractures wanes with age, and long-term estrogen use is necessary to maximally reduce the risk of fracture after age 75. Because most osteoporotic fractures occur late in life, women and clinicians must understand that the short-term use of estrogen immediately after menopause cannot be expected to protect against fractures in the seventh and eighth decades of life. Some long-term protection is achieved with 7 to 10 years of estrogen therapy after menopause, but the impact is minimal after age 75 (109). In a prospective cohort study of women 65 years of age or older, in the women who had stopped using estrogen and in those who were older than 75 and had stopped using estrogen even if they had used estrogen for more than 10 years, there was no substantial effect on the risk for fractures (110). The effective impact of estrogen requires initiation within 5 years of menopause and use extending into the elderly years. The protective effect of estrogen rapidly dissipates after treatment is stopped, because estrogen withdrawal is followed by rapid bone loss. In the 3- to 5-year period after loss of estrogen, whether after menopause or after cessation of estrogen therapy, there is accelerated loss of bone (111-113). The benefits of estrogen-progestin treatment suggest that other treatment regimens should be considered as well. One indication for estrogen treatment for osteoporosis includes concomitant treatment of vasomotor symptom. Maximal protection against osteoporotic fractures therefore requires lifelong therapy, and even some long-term protection requires 10 or more years of treatment.
VIII. CONCLUSION The menopause has been overly laden with negative symbolism. Many of the behavioral complaints at the time of menopause, however, can be explained by psychologic and sociocultural influences. That is not to say that important interactions among biology, psychology, and culture do not
occur, but it is time to stress the normalcy of this life event. Menopausal women do not suffer from a hormone deficiency disease. Hormone replacement therapy should be viewed as specific treatment for symptoms in the short term. Therapy remains effective for treating women with vasomotor symptoms and vaginal atrophy and selected women with osteoporosis. The benefits and risks of hormone therapy should be balanced in each individual. Part of the reason for our negative stereotypical views of menopause is that the initial characterization of menopause was derived from women presenting with physical and psychologic difficulties. The variability in menopausal reactions makes the cross-sectional study design particularly unsuitable. More and larger longitudinal studies are needed to document what is normal and the variations around normal. It is important to educate women and clinicians about the normal events of this time. Changes in menstrual function are not symbols of some ominous change. There are good physiologic reasons for changing menstrual function, and understanding the physiology can do much to reinforce a healthy, normal attitude. The menopause serves a useful purpose. This physiologic event brings clinicians and patients together, providing the opportunity to enroll patients in a preventive health care program. Contrary to popular opinion, menopause is not a signal of impending decline, but rather a wonderful phenomenon that can signal the start of something positive, such as a good health program. Rather than being a lightning rod for social and personal problems, menopause can be a signal for the future.
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CHAPTER 1 The Menopause: A Signal for the Future 104. Ettinger B, Genant HK, Cann CE. Long-term estrogen replacement therapy prevents bone loss and fractures.Ann Intern Med 1985;102:319. 105. Kiel DP, Felson DT, Anderson JJ, Wilson PW, Moskpwitz MA. Hip fracture and the use of estrogen in postmenopausal women. The Framingham Study. N E n g l J M e d 1987; 317:1169. 106. Riggs BL, Seeman E, Hodgson SF, Taves DR, O'Fallon WM. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. N EnglJ IVied 1982; 306:446. 107. O.uigley MET, Martin PI, Burnier AM, Brooks E Estrogen therapy arrests bone loss in elderly women. Am J Obstet Gynecol 1987;156:1516. 108. Lafferty FW, Fiske ME. Postmenopausal estrogen replacement: a long-term cohort study. Am J Med 1994;97:66. 109. Felson PT, Zhang Y, Hannan MT, et al. The effect of postmenopausal estrogen therapy on bone density in elderly women. N EnglJ Med 1993;329:1141-1146. 110. Cauley JA, Seeley DG, Enbsrud K, et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995;122:9-16. 111. Lindsay R, MacLean A, Kraszewski A, Clark AC, Garwood J. Bone response to termination of estrogen treatment. Lancet 1978;1:1325. 112. Horsman A, Nordin BEC, Crilly RG. Effect on bone of withdrawal of estrogen therapy. Lancet 1979;2:33. 113. Christiansen C, Christiansen MS, Transbol IB. Bone mass in postmenopausal women after withdrawal of oestrogen/gestagen replacement therapy. Lancet 1981;1:459.
Additional References American College of Obstetricians and Gynecologists, Women's Health Care Physicians. Executive summary: hormone therapy. Obstet Gynecol 2004;104:1S-4S. Avis NE, Ory M, Matthews KA, et al. Health-related quality of life in a multiethnic sample of middle-aged women. Med Care 2003;41: 1262-1276. Berendsen HH. The role of serotonin in hot flushes. Maturitas 2000;36:155-164. Gold EB, Bromberger J, Crawford S, et al. Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am J Epidemio12001;153:865-874. Mendelsohn ME, Karas RH. The time has come to stop letting the HERS tale wag dogma. Circulation 2001;104:2256-2259. Mosca L, Collins P, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499-503. Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Ferti! Steri! 2001;76:874-878. The North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: September 2003 position statement of The North American Menopause Society. Menopause 2003;10:497-506.
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SECTION I
Basics to Enhance Our Understanding The aim of this book, and its prior editions, is to provide a comprehensive basis for the treatment and care of the postmenopausal woman. Accordingly, both basic science information and clinical data will be presented for all areas that are relevant for the health care of postmenopausal women. In this first section of the book, several chapters are devoted to basic information that will help the reader to understand the changes that occur around the time of menopause and thereafter, as the basis for choosing a treatment, if necessary. I am extremely gratified that in this section as well as in other areas of the book, the chapters are written by true experts who are highly acknowledged for their particular expertise in the areas on which they write. Chapter 2, by Sherk and McDonnell, provides an update on the mechanisms of action of estrogen and progesterone. This story has become extremely complex but has been explained in a very clear way. Particularly important concepts include nongenomic effects, receptor isoforms that affect agonist/antagonist actions, and the role of coactivators and corepressors in various tissues. The third chapter, by Simpson, describes the genetics of ovarian failure and the genes that are involved for normal function, as well as those genes that may be implicated in premature ovarian failure, which will be covered in the next section. Chapter 4, by Erickson and Chang, provides a description of the basic biology of ovarian failure. This offers us a deeper understanding of the fertility concerns of older women prior to menopause, as well as the endocrinologic changes that occur at this time. Burger and Teede next describe the endocrine changes around the perimenopause--that is, the first series of changes that occur leading up to menopause, which will set the stage for our understanding of hormonal and other changes to follow. In Chapter 6 Gold and Greendale provide a very scholarly and up-to-date review of the epidemiology of the menopause and point out areas that are still not clear, stressing the importance of the need for more longitudinal studies.
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_~HAPTER z
M ole cular P h arm acology
of Estrogen and Progesterone Receptors ANDREA
B.
SHERK
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710
DONALD P. M c D O N N E L L
Departmentof Pharmacology and Cancer Biology,Duke UniversityMedical Center, Durham, NC 27710
II. E S T R O G E N A N D P R O G E S T E R O N E RECEPTORS
I. I N T R O D U C T I O N The steroid hormones estrogen and progesterone are low-molecular weight, lipophilic hormones that, through their action as modulators of distinct signal transduction pathways, are involved in the regulation of reproductive function (1,2). These hormones have also been shown to be important regulators in bone, the cardiovascular system, and the central nervous system (3-5). Despite their different roles in these systems, however, it has become apparent that estrogens and progestins are mechanistically similar (6). Insights gleaned from the study of each hormone, therefore, have advanced our understanding of this class of molecules as a whole. This review highlights some of the recent mechanistic discoveries that have occurred in the field and explores the subsequent changes in our understanding of the pharmacology of this class of steroid hormones. TREATMENT OF THE POSTMENOPAUSAL WOMAN
Estrogen and progesterone bind to high-affinity intracellular receptors, which act as ligand-activated transcription factors. The estrogen receptor (ER) and progesterone receptor (PR) cDNAs have been cloned and used to develop specific ligand-responsive transcription systems in heterologous cells, permitting the use of reverse genetic approaches to define the functional domains within each of the receptors (Fig. 2.1) (6). The largest domain (approximately 300 amino acids) that is responsible for ligand binding is located at the carboxyl terminus of each receptor. Crystallographic analysis of the agonist-bound forms of ERs and PRs has indicated that this domain consists of 12 short o~-helical structures that fold to provide a complex ligand-binding pocket (7,8). The ligand-binding domain also contains sequences that facilitate receptor homodimerization and permit the interaction of
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Copyright 9 2007 by Elsevier,Inc. All rights of reproduction in any form reserved.
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SHERK AND McDONNELL
FIGURE 2.1 The domain structures of the estrogen and progesterone receptors are similar. AF-1, activation function 1; AF-2, activation function 2.
apo-receptors with inhibitory heat-shock proteins. An activation function (AF-2) required for receptor transcriptional activity is also contained within the ligand-binding domain (9,10). An additional activation function (AF-1) is located within the amino terminus of each receptor (11). The DNA-binding domain (DBD) is a short region (approximately 70 amino acids) located in the center of the receptor protein (12). This permits the receptor to bind as a dimer to target genes. Within the D B D there are nine cysteine residues, eight of which can chelate two zinc atoms, thereby forming two fingerlike structures that allow the receptor to interact with D N A (13). All the information required to permit target gene identification by ligandactivated ERs and PRs is contained within this region.
III. ESTABLISHED MODELS OF ESTROGEN AND PROGESTERONE ACTION The steroid hormones estrogen and progesterone are representative members of a larger family of steroid hormones, all of which appear to share a common mechanism of action. It is generally believed that steroid hormones enter cells from the bloodstream by simple passive diffusion, exhibiting activity only in cells in which they encounter a specific high-affinity receptor protein (14). These receptor proteins are transcriptionaUy inactive in the absence of ligand, sequestered in a large oligomeric heat-shock protein complex within target cells (15). On binding ligand, however, the receptors undergo an activating conformational change that promotes the dissociation of inhibitory proteins (16). This event permits the formation of receptor homodimers that are capable of interacting with specific high-affinity DNA-response elements located within the regulatory regions of target genes (17). The DNA-bound receptor can then exert a positive or negative influence on target gene transcription (Fig. 2.2).
FIGURE 2.2 Established models of estrogen and progesterone action. The classic models of estrogen and progesterone action suggested that, in the absence ofligand, the steroid receptor (SR) exists in target cells in an inactive form. On binding an agonist, the receptor would undergo an activating transformation event that displaces inhibitory heat-shock proteins (HSP) and facilitates the interaction of the receptor with specific DNA steroid response elements (SRE) within target gene promoters.The activated receptor dimer could then interact with a complex of proteins and positively or negatively regulate target gene transcription. In this model, the role of the agonist is that of a "switch"that merely converts the ER or PR from an inactive to an active form. Thus, when corrected for affinity, all agonists would be qualitatively the same and evoke the same phenotypic response. By inference, antagonists, compounds that oppose the actions of agonists, would competitivelybind to their cognate receptors and freeze them in an inactive form. As with agonists, this model predicted that all antagonists are qualitatively the same. Within the confines of this classic model it was difficult to explain the molecular pharmacology of the known ER and PR agonists and antagonists. TA, transcriptional apparatus.
CHAPTER 2 Molecular Pharmacology of Estrogen and Progesterone Receptors
In the classic models of steroid hormone action, it was proposed that progestins and estrogens function merely as switches that, on binding to their cognate receptor, permit conversion of the receptor, in an all or nothing manner, from an inactive to an active state (18). This implied that ER and PR pharmacology was very simple, and that when corrected for affinity, all progestins and estrogens were qualitatively the same. Furthermore, it suggested that antihormones (antagonists) function simply as competitive inhibitors of agonist binding, freezing the target receptor in an inactive state within the cell (see Fig. 2.2). Under most experimental conditions, this simple model was sufficient to explain the observed biology of known PR and ER agonists and antagonists. However, the results of several clinical studies of estrogens and antiestrogens suggested that the pharmacology of ER was far more complex than predicted from these classic models of hormone action. Studies probing the complex pharmacology of the antiestrogen tamoxifen, for instance, have been very informative with respect to understanding the inadequacies of the classic model. Tamoxifen is widely used as a breast cancer chemotherapeutic and as a breast cancer chemopreventive in high-risk patients (19,20). In ER-positive breast cancers, tamoxifen opposes the mitogenic action of estrogen(s) by binding to the receptor and competitively blocking agonist access. However, it has become clear that tamoxifen is not a pure antagonist, because in some target organs, it can exhibit estrogen-like actMty. This is most apparent in both the skeletal system, where tamoxifen, like estrogen, increases lumbar spine bone mineral density, and the cardiovascular system, where both tamoxifen and estradiol have been shown to decrease low-density lipoprotein (LDL) cholesterol (21,22). These in vivo properties of tamoxifen led to its being reclassified as a selective estrogen receptor modulator (SERM), rather than an antagonist. Similarly, selective progesterone receptor modulators (SPRMs), which function in a tissueselective manner, have been discovered. The most promising of these is asoprisnil, which is currently being developed for the treatment of women with uterine fibroids and dysfunctional uterine bleeding. Asoprisnil exhibits antiproliferative effects on the uterine endometrium, while maintaining ovarian estrogen production, similar to progestins, but lacks progestin-induced irregular endometrial bleeding and the mitogenic effects of progestins in the breast (23). Therefore, the ability of ligands to exert differential effects through their cognate receptors depending on the tissue environment is a common theme across the steroid receptor family. The observation that different ligand-receptor complexes were not recognized in the same manner in all cells was at odds with the established models of ER and PR action. The observed pharmacology of tamoxifen and similar compounds begged a reevaluation of the classic model of ER and PR action and initiated the search for the cellular systems that enable ER/PR-ligand complexes to manifest different biologies in different cells.
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IV. NONCLASSICAL MODELS OF ESTROGEN AND PROGESTERONE RECEPTOR ACTION It has become increasingly clear that estrogens and progestins utilize alternative pathways, in addition to the classical mode of action, to exert their biological effects. It is possible that differential activation of these pathways in various tissues might contribute to the tissue-specific activity of selective receptor modulators. As described earlier, the classical model of action of steroid hormones consists of hormone binding to its receptor and subsequent association of the receptor dimer with DNA response elements in the promoter regions of target genes (Fig. 2.3, E). However, ligand-bound ER and PR are also able to regulate genes without directly binding to their promoter regions. For example, ligand-associated ER is able to interact with and modulate the activity of the NFKB and Spl transcription factors, as well as Fos and Jun heterodimers at AP-1 binding sites (see Fig. 2.3, F and G) (24-26). Consequently, genes that lack hormone response elements can be regulated by steroid hormones due to the indirect recruitment of ligand-activated receptors to promoter regions via interactions with other transcription factors. Interestingly, tamoxifen can activate AP-1 target genes in endometrial cells but not in breast tumor cells, reflecting its growth effects on these tissues (24). Therefore, the ability of SERMs to modulate ER action at AP-1 target genes in a cell-selective manner might be a key determinant in the tissue-specific growth effects of these ligands. However, the extent to which these in vitro observations reflect activities that occur in vivo remains to be determined. Estrogens and progestins can also elicit rapid responses in cells, which occur so quickly that they are clearly not mediated by the transcriptional activity of ER and PR and are thus described as "nongenomic." For example, estrogen and progesterone can increase intracellular levels of calcium and cyclic adenosine monophosphate (cAMP), second messengers for specific signal transduction pathways, and can initiate mitogen-activated protein (MAP) kinase phosphorylation cascades (27-29). Although evidence for these rapid effects has been mounting for decades, the mechanism by which they occur is just beginning to be elucidated. It is unclear what type of receptor mediates these hormonal effects, although several models have been proposed. There is evidence that these "nongenomic" effects occur via activation of a subpopulation of the classical ER and PR or a splice variant that has been localized to the plasma membrane, either directly (through palmitoylation of the receptor) or indirectly, through interactions with other membrane-associated proteins (such as caveolin) (see Fig. 2.3, A and B) (30-32). Indeed, the classical PR and ER have both been shown to associate with the Src
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SHERK AND McDONNELL
FIGURE 2.3
Estrogen and progesterone exert their biological effects via both genomic and nongenomic mechanisms. Nongenomic effects of estrogen have been reported to occur through the classical nuclear receptor that is localized to the membrane directly through palmitoylation of the receptor (B), through interactions with other proteins, such as caveolin (A) or MNAR and c-Src (C). GPR30 is a G-protein-coupled receptor that has been reported to bind estrogen, resulting in intracellular calcium mobilization (D). There is evidence that GPR30 might be localized to the endoplasmic reticulum, rather than the plasma membrane. E: The classical mode of action of estrogen, in which the nuclear ER dimer binds to an estrogen response element (ERE) within the promoter regions of target genes. The nuclear ER can also modify transcription of target genes by being indirectly tethered to DNA through additional transcription factors, such as Fos and Jun on AP1 sites (F) or NFKB (G). Similar mechanisms are involved in progesterone action. MNAR, modulator of nongenomic activity of estrogen receptor; CoA, coactivator.
family of nonreceptor tyrosine kinases at the plasma membrane, either directly (PR) or through the interaction with the adaptor protein MNAR (ER) (see Fig. 2.3, C) (33,34). Ligand-bound ER and PR can activate Src, initiating a MAP kinase phosphorylation cascade, which ultimately influences ER and PR transcriptional activity (26,35). Therefore, although these responses are termed "nongenomic," they do eventually modulate the transcriptional activity or "genomic" response of ER and PR. Recently, a family of transmembrane G protein coupled receptors (GPCRs) that bind progesterone was identified, first in the sea trout, and then in the mouse and human
(36,37). Subsequently, another GPCR, GPR30, was shown to elicit intracellular calcium mobilization in response to estrogen binding (38,39). Surprisingly, GPR30 appears to be localized to the endoplasmic reticulum, rather than the plasma membrane (see Fig. 2.3, D) (39). It remains to be determined if these are the membrane receptors that mediate the nongenomic effects of estrogen and progesterone. The contribution of these nonclassical mechanisms of action to estrogen and progesterone physiology is yet to be determined. However, one of the most widely studied nongenomic effects of estrogen is stimulation of nitric
CHAPTER 2 Molecular Pharmacology of Estrogen and Progesterone Receptors
oxide production in endothelial cells, which may contribute to estrogen's antiatherogenic and antiatherosclerotic effects (26). It is possible that differential activation of membrane receptors and nuclear receptors is partially responsible for the tissue-specific effects of selective receptor modulators.
V. ESTROGEN AND PROGESTERONE RECEPTOR ISOFORMS AND SUBTYPES Another mechanism to explain the cell-selective action of steroid receptor ligands is the likelihood that they may activate different receptor isoforms (derived from the same gene) or subtypes (derived from similar genes). This concept has been well established for the ci- and [3-adrenergic systems, where it has been shown that different receptor subtypes have distinct ligand preferences and that selectivity can be explained by differences in the expression of these subtypes. Until recently, the parallel between this system and that of the nuclear receptors was not obvious. However, the identification and characterization of ER and PR isoforms and subtypes has shed new light on this issue (Fig. 2.4).
A. Progesterone Receptor Isoforms The progesterone receptor was the first receptor for which bona fide isoforms were shown to exist. Human PRs can exist within target cells in either of two distinct forms, hPR-A (94 kDa) or hPR-B (114 kDa) (40). These pro-
Estrogen Receptor SubtyDe~ 1
hER-a
DBo I
NH2 I
.....I............. 1
hER-I]
NH2
595
.........
.......
I
530
1
IDBD
!
I
Progesterone Receptor Isoform~ 933
1
I
769
FIGURE 2.4 At least two distinct forms of the estrogen and progesterone receptors exist in target cells. DBD, DNA-binding domain; LBD, ligand-binding domain.
21
teins, differing only in that the hPR-B isoform contains an additional 164-amino acid extension at its amino terminus, are produced from distinct mRNAs that are derived from different promoters within the same gene (9). In most progesterone-responsive tissues these two receptor isoforms are expressed in equimolar amounts. This apparent 1:1 relationship is so widespread that until about 10 years ago, the hPR-A isoform was thought to be merely an artifact derived from hPR-B by proteolysis during biochemical fractionation. It has now been established that these two proteins are produced in a deliberate manner by the cell, and that they are not functionally equivalent (40-42). The first evidence in support of this hypothesis came following the cloning and subsequent functional analysis of the chicken progesterone receptor (cPR) cDNA (43). Specifically, on expression in heterologous cells, it was found that although the A and B forms of cPRs display identical ligand-binding preferences, they activate different target genes (43). It was subsequently shown that the amino-terminal sequences, which distinguish cPR-B from cPR-A, are important in determining target gene selectivity. This concept was reaffirmed when the cloned hPR-B and hPR-A were analyzed in a similar manner (41). Studies in T47D breast cancer cells in which one or the other isoforms were overexpressed provided evidence that suggests hPR-A and hPR-B regulate a distinct subset of genes. Interestingly, the target genes identified in this manner showed very little overlap. The number of hPR-B regulated genes was far greater than those modulated by hPR-A (44). Further analysis has revealed that hPR-A functions as a ligand-dependent transdominant modulator of the transcriptional activity of hPR-B, the ability of hPR-B to activate target gene transcription being influenced by the cellular concentration of hPR-A (41,45). Surprisingly, it was also determined that ligand-activated hPR-A can inhibit the transcriptional activity of agonistactivated ERs, androgen receptors (ARs), and mineralocorticoid receptors (MRs) (41). Analysis of mice in which PR-A or PR-B was genetically disrupted has demonstrated that the two isoforms have distinct roles in progesterone biology. Mice lacking PR-A display infertility, severe endometrial hyperplasia, and anovulation but exhibit normal breast morphogenesis. On the other hand, PR-B knockout mice are fertile with a normal uterus but exhibit reduced pregnancy-induced mammary ductal morphogenesis. Collectively, these findings suggest that PR-A activation is responsible for progesterone's reproductive functions and, specifically, the "antiestrogenic" actions of progestins in the uterus, whereas PR-B is required for progesteroneinduced, pregnancy-related mammary morphogenesis (46). Thus, by virtue of having two functionally distinct receptor isoforms, a single hormone such as progesterone can have completely different functions in target cells.
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SHERK AND McDONNELL
B. Estrogen Receptor Subtypes The identification of functionally distinct PR isoforms introduced a new dimension to progesterone action, although it was not until a second estrogen receptor was cloned in 1995 that the general significance of isoforms (or subtypes) in steroid receptor signaling was established (47). Unlike the case of PRs, ERe~ and ER[3 are encoded by different genes, and although they share significant amino acid homology in their ligand-binding domains, they are not pharmacologically equivalent. Both receptors bind the endogenous estrogen, 1713-estradiol, with equivalent affinity (48). However, when binding analysis was extended to additional compounds, significant differences in ligand preferences were noted. The biological and pharmacological consequences of these differences remain to be determined. Although the discovery of ER[3 has occurred relatively recently, significant progress has been made in elucidating its role in estrogen signaling. It has been determined that the expression pattern of ER[3 does not mirror that of ERa (49,50). Expression of both isoforms is found in some tissues, whereas ER[3 alone occurs in others, such as the lung, the urogenital tract, and the colon (48). Two major approaches have been undertaken to delineate the relative contribution of these receptor subtypes to estrogen biology. The first approach involved the generation of mice whose ERos, ER[3, or both of the receptors have been genetically disrupted. The phenotype of the ER[3 knockout mice is different from that of ERa knockout mice, reflecting the distinct roles of these two receptors in the endocrinology of estrogen (51). The other approach utilized ER-subtypeselective ligands, which has corroborated observations made in the knockout mice and revealed novel functions of ER[3. Data from both these sources suggest ERc~ is responsible for the bone-protective, uterotrophic, and mammotrophic effects of estrogens. Estrogen acting through ER[3, on the other hand, has an antiproliferative, prodifferentiative effect in the breast, as well as in the prostate (51,52). Recently, work utilizing the ER[3-selective ligand, ERB-041, has uncovered a role for ER[3 in the immune system. Studies with ERB-041 in rodent models indicate that an ER[3-selective ligand might be beneficial for the treatment of chronic inflammatory diseases, such as irritable bowel syndrome and arthritis (53). In fact, ERB-041 is currently being developed for the treatment of rheumatoid arthritis and endometriosis. Therefore, estrogen can have very different, even opposing, effects by acting through two different receptor isotypes. The identification of estrogen and progesterone receptor isoforms and subtypes and the definition of specific functions that they modulate have introduced a new dimension in steroid hormone action. Understanding the regulatory
mechanisms that control the expression levels of the individual forms of each receptor is likely to provide novel targets for pharmaceutical intervention.
VI. REGULATION OF ESTROGEN AND PROGESTERONE RECEPTOR FUNCTION BY LIGANDS The finding that ERs and PRs could exist in multiple forms within target cells suggests that some of the tissueselective actions of their cognate agonists and antagonists can be explained by their ability to regulate differentially the action of one specific receptor isoform or subtype. It has become apparent, however, from the study of antiestrogens that the identical ligand operating through the same receptor can manifest different biological activities in different target cells (54). In breast tissue, for instance, where ERo~ predominates, all the known antiestrogens oppose the mitogenic actions of estrogen (55). In the endometrium, however, where ERc~ also predominates, it has been found that tamoxifen functions as a partial estrogen mimetic (56,57), whereas compounds such as raloxifene, GW5638, and ICI182,780 function as pure antiestrogens. Thus, the same compounds, acting through ERoL, manifest different biological activities in the breast and the endometrium. This finding is not in agreement with the classic models of ER action that indicate that ligands basically fall into two classes, agonists and antagonists. This paradox has been the subject of much investigation, leading to the observation that different compounds can induce different alterations in ER structure and that not all structures are functionally identical. It is implied, therefore (discussed in more detail later), that the cell possesses the cellular machinery to distinguish between these dissimilar complexes and that the identification and characterization of the specific components of these systems are the keys to the development of the next generation of tissue-selective ER and PR modulators. Much of what we know about the effect of ligands on steroid receptor structure has come from studies of different ER-ligand complexes. Initially, using differential sensitivity to proteases, it was demonstrated that the hormone-binding domain within the ER adopts different shapes on binding estradiol and tamoxifen and that these structures are dissimilar to that of the apo-receptor (54,58). Thus, receptor conformation is affected by the nature of the bound ligand. This relationship between structure and function was later confirmed by the observation that agonists and antagonists induce different alterations in PR structure (59,60). Further analysis has revealed that the majority of the structural changes that occur in the PR are located at the extreme carboxyl tail of the receptor and that removal of the
CHAPTER 2 Molecular Pharmacology of Estrogen and Progesterone Receptors carboxyl-terminal 42 amino acids of hPR-B permits the antagonist RU486 to function as an agonist (59). Interestingly, a similarly positioned domain enables the ER to discriminate between different compounds, and, not surprisingly, removal of 35 amino acids from the C-terminal tail of the ER abolishes its ability to distinguish between agonists and antagonists (61). The recent determination of the crystal structures of the ER-estradiol and ER-tamoxifen complexes confirmed the important role of the carboxyl tail in determining the pharmacology of steroid receptors (7,62,63). This new structural information has also revealed that agonist activation of the ER permits the formation of a unique surface (or pocket) on the receptor that allows it to interact with coactivator proteins. In the presence of the SERM tamoxifen, however, the carboxyl tail of the ER is positioned in such a manner that it occludes this coactivator binding pocket, preventing a productive association with coactivators that utilize this surface to interact with the receptor. In addition to tamoxifen, several additional SERMs manifest distinct activities in vivo. One of these compounds, raloxifene, has been approved as a SERM for the treatment and prevention of osteoporosis (64). This compound distinguishes itself from tamoxifen in that it does not exhibit estrogenic action in the postmenopausal endometrium (65,66). Although clearly different biologically, the crystal structures of the ER-tamoxifen and ERraloxifene complexes were shown to be virtually indistinguishable. Although these results appear to be at odds with the hypothesis that links receptor structure to function, some data from our group have reconciled these potential discrepancies. We have used phage display technology to identify small peptides, the ability of which to bind ERs is affected differentially by the nature of the ligand bound to the receptor (Fig. 2.5) (67-69). The rationale behind this approach is that because of the vast complexity of the peptides available in these libraries, it may be possible to find peptides that have the ability to distinguish between two very similar receptor-ligand complexes. This approach has led to the identification of a series of high-affinity peptide probes that, in addition to being able to distinguish between ERestradiol and ER-tamoxifen complexes, are also able to distinguish among several different E R - S E R M complexes. This approach has been extended to the study of the PR, and it was similarly observed that various PR ligands manifest different biologies in different cells, allowing the identification of peptide probes whose interaction with the receptor is influenced by the nature of the ligand bound to the PR. All these findings establish a firm relationship between the structure of a receptor-ligand complex and biological activity and suggest that novel ER and PR ligands with unique pharmaceutical properties may be developed by exploiting this observation.
23
FIGURE 2.5 Fingerprintingthe surfaces of different ER-ligand complexes using conformation-sensitivepeptide probes.A: Random peptide libraries were constructed in an M13 bacteriophage; each of the resulting bacteriophages expressed a unique random peptide on its surface pilus. Screens were subsequentlyperformed to identifyspecificpeptides (bacteriophage) whose interaction with the ER was influenced by the nature of the bound ligand. The bacteriophage identified in this manner were used to develop an enzyme-linked immunoassayto monitor changes that occur in the ER on its interaction with different ligands. Specifically, a biotinylated estrogen responseelement (ERE) was used to immobilizerecombinant ERs on streptavidin-coated plates. After incubation of this complexwith the ligand to be tested, to each well was added an aliquot of a different class of ER-interacting bacteriophage. Binding of the bacteriophage was assessed enzymatically using an anti-M13 antibody coupled to horseradish peroxidase (HRP). B: Fingerprint analysisof ER conformationin the presence of saturating concentrations of the indicated ligands; the resulting complexes were incubated with aliquots of bacteriophage expressing eight different peptides. Tam, tamoxifen; DES, diethylstilbestrol;Prog, progesterone.This figure has been publishedpreviouslyin a similarform (68) and is reproduced and presented here with permission (Copyright 1999 National Academyof Sciences, U.S.A.).
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SHERK AND McDONNELL
VII. ESTROGEN AND PROGESTERONE RECEPTOR ASSOCIATED PROTEINS The estrogen and progesterone receptors are liganddependent transcription factors that, on activation by ligands, associate with specific DNA response elements located within the regulatory regions of target genes (14). The DNA-bound receptor can then positively or negatively influence gene transcription by recruiting a complex of proteins that can modulate chromatin structure and either facilitate or prevent the interaction of RNA polymerase II with the promoter. In the past few years, it has become clear that at least two functional classes of proteins are involved in recognizing the activated receptor. One class includes components of the basic transcription machinery, the general transcription factors, whose expression levels are generally invariant from cell to cell. The second class of proteins, cofactors, is not a part of the general transcription machinery and can exert either a positive or negative influence on SR transcriptional activity (70). Those cofactors that interact with agonist-activated SRs have been called coactivators, whereas those that interact with apo-receptors or antagonistactivated receptors have been called corepressors. Interestingly, it has become apparent that differences in the relative expression levels of coactivators and corepressors can have a profound effect on the pharmacology of estrogen and progesterone receptor ligands (42,70,71).
A. Coactivator Proteins One of the most well-characterized coactivator proteins, steroid receptor coactivator 1 (SRC-1), was identified in a yeast two-hybrid screen as a protein that interacted with agonist-activated PR (73). Subsequently, this protein has been shown to also interact with estrogen, glucocorticoid, and androgen receptors. It appears that SRC-1 increases target gene transcription by linking the hormone-activated receptor with the general transcription machinery, stabilizing the transcription preinitiation complex, and nucleating a large complex of proteins that together have the ability to acetylate histones and facilitate chromatin decondensation (74,75). SRC-1 belongs to a family of p160 proteins that also includes SRC-2/GRIP1 and SRC-3/AIB1. The contribution of each of the p160 family members to the biology of estrogens and progestins has been dissected through the use of knockout mice. Although there is partial functional redundancy among the family members, the phenotypes of the three p160 single knockout strains are clearly different from one another. Mice lacking SRC-1 exhibit normal growth and fertility but demonstrate partial resistance to hormones. For example, these mice display reduced uterine
growth, uterine decidual response, mammary ductal branching and alveolar development and have an estrogen-resistant skeletal phenotype. Female SRC-3 knockout mice exhibit abnormal reproductive development and function. Estrogen levels are reduced in these mice, which might account for delayed pubertal development and reduced mammary gland growth. In addition, estrogen- and progesterone-stimulated mammary gland alveolar development is attenuated in SRC-3 knockout mice. Although both male and female SRC-2 knockout mice have impaired fertility, this is probably not due to an impairment of ER or PR signaling pathways (76). Collectively, these in vivo murine models suggest SRC-1 and SRC-3 are important for normal estrogen and progesterone biology. Interestingly, SRC-3 is overexpressed in many breast cancers, and overexpression in transgenic animals results in mammary hyperplasia and mammary tumor development, suggesting it is a potent oncogene, and implicates a role for SRC-3 overexpression in estrogenmediated carcinogenesis (77). In addition to the p160 family, more than 200 additional coactivators have been identified and characterized. These include proteins that possess enzymatic activities or recruit protein complexes that exhibit enzymatic activities (such as kinase, acetyl- or methyltransferase, ubiquitin- or SUMO-ligase activities) that modify the receptor, other associated proteins, or histones to modulate gene expression (78). Cumulatively, these studies have revealed that (1) the expression levels of these coactivators vary from cell to cell, (2) coactivators demonstrate specific receptor preferences, (3) a given receptor can interact with more than one type of coactivator, and (4) the conformation of the receptor adopted in the presence of a specific ligand can determine which coactivators are engaged. These findings strongly support the hypothesis that differential cofactor expression is the most important determinant of estrogen and progesterone receptor pharmacology. With the discovery of the nuclear receptor coactivators and the characterization of their biochemical properties has come a new understanding of the mechanism by which differently conformed receptor-ligand complexes are recognized in the cell. The studies that have been performed with ERs are the most informative. As described previously, it has been shown that ERs in the presence of estradiol undergo a conformational change that allows the presentation of surfaces on the receptors, permitting them to interact with coactivators. Because estradiol induces the same conformational change within ERs in all cells, the phenotypic consequence of the exposure of a cell to estradiol will depend on the properties of the coactivators expressed in that cell. The situation gets more complicated, however, when considering the role of coactivators in mediating the cellselective action of SERMs such as tamoxifen. It has been shown that the tamoxifen-induced conformational change within the ER does not allow the coactivator binding pocket
CHAPTER 2 Molecular Pharmacology of Estrogen and Progesterone Receptors
to form properly, preventing or hindering the interaction of those coactivators that require the coactivator binding pocket in order to interact with the ER (67). In cells in which this type of coactivator is important, therefore, tamoxifen can function as an antagonist. It is becoming clear, however, that not all coactivators rely on the coactivator binding pocket to the same degree. Thus, the relative agonist-antagonist activity of tamoxifen depends on the ability of the tamoxifen-ER complex to engage a compatible coactivator in target cells (Fig. 2.6) (54). As the repertoire of cofactors increases, we are likely to find that targeting specific cofactor-receptor complexes will yield pharmaceuticals that manifest their activities in a cell- or tissue-restricted manner. Many coactivators for ER and PR are RNA-binding proteins or proteins involved in RNA processing and maturation. The significance of this was not appreciated until recently. Previously, it was believed that transcription and RNA maturation were two separate processes. However, recent evidence suggests that transcription and RNA maturation are functionally coupled. Estrogen and progesterone can alter the alternative splicing decisions of transcripts synthesized from hormone-sensitive promoters. This coordinate control of transcription and splicing is dependent upon "coupling" coactivator proteins (79). Thus, not only can ER and PR influence the transcription rate of target genes, they can affect the exon content of the resultant
FIGURE 2.6 A molecular explanation for the tissue-selective agonist/antagonist activity of the SERM tamoxifen. The estrogen receptor undergoes different conformational changes on binding agonist, antagonist, or SERMs. The agonist-induced conformation allows the ER to interact with any coactivator protein expressed in target cells, and thus it can activate transcription. The tamoxifen-induced conformational change, on the other hand, is more restrictive and allows the interaction of the ER with only a subset of available coactivators. In those cells in which the tamoxifen-ER complex can engage a coactivator, this compound can manifest agonist activity. In other contexts, tamoxifen interacts with corepressors and functions as an antagonist. ER, estrogen receptor; ERE, estrogen response elements; CoA, coactivator; CoR, corepressor.
25
transcripts. This introduces another level of complexity into estrogen and progesterone action.
B. Corepressor Proteins Two nuclear corepressor proteins that appear to be important in ER and PR pharmacology were initially identified. These proteins, NCoR and SMRT, originally found as proteins that interact with DNA-bound thyroid hormone or retinoid X receptors, repress basal transcription in the absence of hormone (80,81). However, it has now been shown that these proteins can interact with either PR or ER, either in the absence of hormone or in the presence of antagonists (71,72). Under these conditions, the corepressors nucleate a large protein complex, which represses target gene transcription by deacetylating histones and facilitating chromatin condensation. There is little evidence suggesting that NCoR or SMRT are involved in normal estrogen or progesterone physiology, as mice that are genetically null for NCoR are embryonically lethal and there is no reported SMRT knockout mouse model (82). However, the physiological importance of corepressors in ER pharmacology was suggested by the studies of Lavinsky and coworkers, who found that passage of breast tumors in mice from a state of tamoxifen sensitivity to an insensitive state was accompanied by a decrease in the expression level of NCoR (83). A similar process, if occurring in humans, could explain how cells become resistant to the antiestrogenic actions of tamoxifen. Interestingly, tamoxifen functions as a strong agonist in cells lacking NCoR, suggesting NCoR is important for the antagonistic actions of tamoxifen and other SERMs (82). These data suggest that NCoR and perhaps SMRT are more important in the pharmacological actions of ER antagonists and SERMs, rather than normal ER physiology. Another recently described corepressor, REA (repressor of estrogen receptor activity), is able to associate with and repress the activity of both antagonist- and agonist-bound receptors, suggesting that it might act in a physiological manner to attenuate estrogen action (84). Notably, mice expressing only one copy of the REA gene exhibit an enhanced response to estrogen at the genomic level, resulting in increased uterine growth and epithelial hyperproliferation (85). This strongly suggests that REA functions as a negative regulator of estrogen-dependent signaling.
VIII. AN UPDATED MODEL OF ESTROGEN AND PROGESTERONE RECEPTOR ACTION On ligand binding, the activated receptor (ER or PR) can interact as a dimer with specific DNA response elements within target genes. It is now apparent that the conformation
SH~RK AND McDONNELL
26 of the resulting receptor is influenced by the nature of the b o u n d ligand and that the shape of the resulting receptorligand complex is a critical determinant of w h e t h e r it can activate transcription. In the presence of a full agonist, the conformation adopted by the receptor facilitates the displacement of corepressor proteins and recruitment of coactivator proteins with a concomitant increase in target gene transcription. Pure antagonists, on the other hand, drive their cognate receptor into a conformation that favors corepressor interaction. T h e activity o f mixed agonists/antagonists appears to relate to their ability to alter receptor conformation differentially and the ability of corepressor and coactivator proteins within a given target cell to recognize these complexes. Clearly, the classic models of estrogen and progesterone action need to be updated to accommodate the insights that have emerged from the study of the genetics and m o lecular pharmacology of these two receptors.
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58. Allan GF, Leng X, Tsai SY, et al. Hormone and antihormone induce distinct conformational changes which are central to steroid receptor activation. J Biol Chem 1992;267:19513-19520. 59. Vegeto E, Allan GF, Schrader WT, et al. The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell 1992;69:703-713. 60. Wagner BL, Pollio G, Leonhardt S, et al. 16 alpha-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity. Proc Natl Acad Sci USA 1996;93:8739-8744. 61. Mahfoudi A, Roulet E, Dauvois S, Parker MG, Wahli W. Specific mutations in the estrogen receptor change the properties of antiestrogens to full agonists. Proc NatlAcad Sci USA 1995;92:4206-4210. 62. Tanenbaum DM, Wang Y, Williams SP, Sigler PB. Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. Proc NatlAcad Sci USA 1998;95:5998-6003. 63. Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998;95:927-937. 64. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641-1647. 65. Sato M, Rippy MK, Bryant HU. Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEBJ 1996;10:905-912. 66. Ashby J, Odum J, Foster JR. Activity of raloxifene in immature and ovariectomized rat uterotrophic assays. Reg Toxicol Pharmacol 1997;25:226-231. 67. Norris JD, Paige LA, Christensen DJ, et al. Peptide antagonists of the human estrogen receptor. Science 1999;285:744-746. 68. Paige LA, Christensen DJ, Gron H, et al. Estrogen receptor (ER) modulators each induce distinct conformational changes in ERcx and ER[3. Proc NatlAcad Sci USA 1999;96:3999-4004. 69. Wijayaratne AL, Nagel SC, Paige LA, et al. Comparative analyses of the mechanistic differences among antiestrogens. Endocrinology 1999; 140:5828 - 5840. 70. Horwitz KB, Jackson TA, Bain DL, et al. Nuclear receptor coactivators and corepressors. Mol Endocrino11996; 10:1167 - 1177. 71. Smith CL, Nawaz Z, O'Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrino11997;11:65 7-666. 72. Wagner BL, Norris JD, Knotts TA, Weigel NL, McDonnell DR The nuclear corepressors NCoR and SMRT are key regulators of both ligandand 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor. Mol Cell Bio11998;18:1369-1378. 73. Onate SA, Tsai S, Tsai M-J, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995;270:1354-1357. 74. Spencer TE, Jenster G, Burcin MM, et al. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 1997;389:194-198. 75. Shibata H, Spencer TE, Onate SA, et al. Role of co-activators and corepressors in the mechanism of steroid/thyroid receptor action. Rec Prog Horm Res 1997;52:141-165. 76. Xu J, Li Q:. Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol Endocrino12003;17:1681 - 1692. 77. Torres-Arzayus MI, Mora JFD, Yuan J, et al. High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell 2004;6:263-274. 78. Lonard DM, O'Malley BW. Expanding functional diversity of the coactivators. Trends Biocbem Sci 2005;30:126-132. 79. AuboeufD, Dowhan DH, Dutertre M, et al. A subset of nuclear receptor coregulators act as coupling proteins during synthesis and maturation of RNA transcripts. Mol Cell Bio12005;25:5307-5316.
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~HAPTER
Genetic Programming in Ovarian Development and Oogenesis Joe L E I G H
SIMPSON
Department of Obstetrics and Gynecology, Human Molecular Genetics, Florida Internal University, Miami, FL 33199
exists even in 46,XY-phenotype females, such as in infants with XY gonadal dysgenesis (2) or the genitopalatocardiac syndrome (3). Oocyte development in the presence of a Y chromosome is also well documented in mice (4). Thus, the pathogenesis of germ cell failure in humans can be deduced to be increased germ cell attrition. If two intact X chromosomes are not present, ovarian follicles in 45,X individuals usually degenerate by birth. Genes on the second X chromosome are thus responsible for ovarian maintenance, rather than ovarian differentiation. One might expect existence of a specific gene product for primary ovarian differentiation, but this has proved elusive. Once, a popular candidate was the gene initially termed AHC (adrenal hypoplasia congenital), the gene that encodes DAX1. Following observation that duplication of X p21 resuited in 46,XY embryos differentiating into females (5), it was reasoned that this region could play a primary role in ovarian differentiation in 46,XX individuals. The region contained AHC, which includes or is identical to DAX1 (dosage-sensitive sex reversal/adrenal hypoplasia critical region X); the mouse homolog is Ahch. Ahch is upregulated in the XX mouse ovary, as predicted if Ahch (DAX1) were to play a pivotal role in primary ovarian differentiation. Transgenic XY mice overexpressing Ahch develop as females.
Failure of germ cell development is associated with complete ovarian failure, resulting in lack of secondary sexual pubertal development (primary amenorrhea). Decreased number but not total absence of germ cells is more likely associated with premature ovarian failure, presenting with infertility or secondary amenorrhea. Yet complete and premature ovarian failure may be different manifestations of the same underlying pathogenic and etiologic processes. Chromosomal abnormalities, mutations of autosomal or X-linked genes, and polygenic/multifactorial elements all play a role. In this contribution, we shall enumerate clinical disorders associated with germ cell abnormalities, deducing etiologic factors responsible for ovarian differentiation and oogenesis in normal females.
I. OVARIAN DIFFERENTIATION REQUIRES ONLY ONE X (CONSTITUTIVE) In the absence of the Y chromosome, the indifferent embryonic gonad always develops into an ovary. Germ cells exist in 45,3( human fetuses (1). Oocyte development initially TREATMENT OF THE POSTMENOPAUSAL W O M A N
29
Copyright 9 2007 by Elsevier,Inc. All rights of reproductionin any form reserved.
JoE LEIGH SIMPSON
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However, XX mice lacking Ahch (knockout) surprisingly showed normal ovarian differentiation, ovulation, and fertility (6), whereas XY mice mutant for Ahch show testicular germ cell defects. Thus, Ahch cannot be responsible for primary ovarian differentiation in mice, nor presumably could DAX1 (AHC) in humans.
II. POLYGENIC A N D STOCHASTIC C O N T R O L OVER OOCYTE NUMBER It is to be expected that oocyte number (reservoir) will be low in some women simply on statistical (stochastic) grounds. Normal distribution exists for all common anatomic traits (e.g., height), and this principle should apply to oocyte number and reservoir at birth. That a normal distribution of germ cell number exists in ostensibly normal females is well established in animals but difficult to prove in humans. Different rodent strains show characteristic breeding duration, implying genetic control over either the rate of oocyte depletion or the number of oocytes initially present. It follows that some ostensibly normal (menstruating) women may have decreased oocyte reservoir or increased oocyte attrition on a genetic basis, analogous to animal models. In humans a genetic basis for this can be presumed by analogy to the heritability of age at human menopause, a characteristic that clearly shows familiar tendencies. Assessing heritability of age of menopause is complicated because iatrogenic behavior (e.g., hysterectomy) and other confounding factors (e.g., leiomyomata or uterine cancer) must be taken into account. However, within the decade several studies have directly addressed the issue. Cramer et al. (7) performed a case control study on 10,606 U.S. women between 45 and 54 years of age. Women with an early menopause (40 to 45 years) were age-matched with control women who were either still menstruating or had experienced menopause after age 45 years. Of 129 early menopause cases (less than 46 years), 37.5% had a family history of a similarly affected mother, sister, aunt, or grandmother. Only 9% of control subjects had such relatives (odds ratio after adjustment 6.1, 95% confidence interval [CI] 3.9 to 9.4). As predicted on the basis of expectations for a polygenic condition, the odds ratio was greatest (9.1) for sisters and for when menopause occurred prior to 40 years. The frequency of galactose-l-phosphate uridylyltransferase (GALl-) variants (N314D or Q188R) did not deviate from what was expected in early menopause cases, in contrast to previous studies by some of the same authors (8). Torgerson and colleagues (9) reported that if women underwent menopause during the 5-year centile aged 45 to 49 years, the likelihood was increased that menopause would occur in a similar 5-year centile in their daughters. Twin studies have been used to estimate heritability of age at menopause. Two studies have shown similar results
(10). Snieder et al. (11) studied 27 M Z and 353 DZ twin pairs in the United States. For age at menopause, correlation (r) was 0.58 in M Z twins and 0.39 in DZ twins (heritability [h2] = 63%). Treloar et al. (10,12) performed a similar study in 1177 M Z and 711 DZ Australian twin pairs. For age at menopause, correlations (r) were 0.49 to 0.57 for M Z and 0.31 to 0.33 for DZ. Heritability was 31% to 53% (10). Differences between M Z and DZ held when iatrogenic menopause (hysterectomy for leiomyomata or endometriosis) was taken into account. More recent studies continue to show the existence of heritable factors. In the Framingham Heart Study, Murabito et al. (13) determined age of menopause in 1500 U.S. women and 932 of their offspring. Mean ages at natural menopause were 49.1 and 49.4 years, respectively. Heritability was estimated to be 0.49 for mother-daughter and 0.52 for sistersister pairs. Very similar results were reported by van Asselt et al. (14) studying 164 Dutch mother-daughter pairs. Their mean difference in age of menopause was I year; heritability was 44%. Overall, the approximately 50% heritability for age of menopause offers evidence that ovarian capacity and, hence, development is similar in relatives. Interestingly, age of menarche shows similar heritability (15), although responsible biologic mechanisms are probably different.
IIl. M O N O S O M Y X The complement most frequently associated with ovarian dysgenesis is 45,X. The proportion of 45,X individuals in a given sample will depend on the method of ascertainment. Fewer 45,X individuals will be detected if primary amenorrhea is the presenting complaint than if short stature or various somatic anomalies are the presenting complaints. Primary amenorrhea in women is more likely to be the presenting complaint ascertained by gynecologists, whereas short stature in children is likely ascertained by pediatricians. Overall, about 50% of all patients with gonadal dysgenesis have a 45,X complement; 25% have sex chromosomal mosaicism with a structural abnormality (e.g., 45,X/46,XX). Far fewer have a structurally abnormal X or Y chromosome or no detectable chromosomal abnormality (16,17). In 80% of cases the paternally derived X has been lost (18). With one possible exception to be noted, the phenotype does not differ between 45,X m and 45,XP cases (Xm,X of maternal origin; XP,X of paternal origin). That is, in general no evidence exists for imprinting (19,20). In structurally abnormal X chromosomes, it is also the paternal X that is lost (21,22).This indicates that X m and XP chromosomes are lost at random (23). Because 45,Y is lethal, the theoretical percentage of 45,X m cases would be 67%, not greatly different from the 80% actually observed.
CHAPTER 3 Genetic Programming in Ovarian Development and Oogenesis
A. Gonads In most 45,X adults with gonadal dysgenesis, the normal gonad is replaced by a white fibrous streak, 2 to 3 cm long and about 0.5 cm wide, located in the position ordinarily occupied by the ovary. A streak gonad is characterized histologically by interlacing waves of dense fibrous stroma, indistinguishable from normal ovarian stroma (Fig. 3.1). That germ cells are usually completely absent in adults but present in 45,X embryos is the basis for the belief that the pathogenesis of germ cell failure is increased atresia, not failure of germ cell formation. Speed (24,25) has shown that in monosomy X, oogenesis ceases in meiosis I at or before the pachytene meiotic stage. Degenerating pachytene oocytes are observed. A variety of pairing abnormalities and disruptions are seen at later stages of meiosis I, but oocytes in dictyotene are rare. Ogata and Matsuo (23) argue that the ovarian failure found in monosomy X is caused by generalized (nonspecific) meiotic pairing errors, the extent of ovarian failure correlating with extent of pairing failure. Ovarian rete tubules, which probably originate from either mesonephric tubules or medullary sex cords, are present in the median portion of most streak gonads. Hilar cells are usually detected in streak gonads of patients past the age of expected puberty.
FIGURE 3.1
31
That 45,X humans manifest streak gonads is not so obvious as one might expect. Relatively normal ovarian development occurs in many other monosomy X mammals (e.g., mice). These observations are, incidentally, at odds with the hypothesis I (24,25) that ovarian failure merely reflects meiotic pairing errors. If the hypothesis were true, the monosomy X mouse would not differ from the monosomy X human. The more likely explanation is that in humans not all loci on the normal heterochromatic (inactive) X are inactivated. In addition, X inactivation never exists in oocytes, because X reactivation of germ cells occurs before entry in meiotic oogenesis (26). X inactivation could also occur only after some crucial time of differentiation, beyond which only a single euchromatic (active) X is necessary for continued oogenesis.
B. S e c o n d a r y Sexual D e v e l o p m e n t Although streak gonads are usually present in 45,X individuals, about 3% of adult cases menstruate spontaneously and 5% show breast development (Table 3.1). Occasionally, the interval between menstrual periods appears normal in 45,X patients, and fertile patients have been reported. Although an undetected 46,XX cell line should always be
Streakgonad, showinglack of oocytes. From ref. 17.
JOELEIGH SIMPSON
32 suspected in menstruating 45,X patients, it is plausible that a few 45,X individuals could be fertile, inasmuch as germ cells are present in 45,X embryos. The rare offspring of 45,X women are probably not at greatly increased risk for chromosomal abnormalities (27,28), although theoretically they should be. Some authors disagree with this statement (29). Low-grade 45,X/46, XX mosaicism has been claimed to occur in women experiencing repeated abortion (30). Irrespective, menstruation and fertility occur so rarely that 45,X patients should be counseled to anticipate primary amenorrhea and sterility. After hormone therapy is initiated in such women, uterine size becomes normal. This permits 45,X women to carry pregnancies in their own uterus after receipt of donor embryos or donor oocytes mixed with their husband's sperm.
IV. X CHROMOSOMAL MOSAICISM:
45,X/46,XXAND 45,X/47,XXX If nondisjunction or anaphase lag occurs in the zygote and embryo, two or more cell lines may result (mosaicism) (Fig. 3.2). The final complement will depend on the stage at which abnormal cell division occurs and on the types of daughter ceils that survive following nondisjunction or anaphase lag. Detection of mosaicism depends on the number of cells analyzed per tissue and on the number of tissues analyzed (16,17). The most common form of mosaicism associated with gonadal dysgenesis is 45,X/46,XX. Individuals with a 45~X/ 46,XX complement predictably show fewer anomalies than do 45,X individuals. Simpson (16) tabulated that 12% of 45,X/46,XX individuals menstruate, compared with only 3% of 45,X individuals. Among 45,X/46,XX indMduals, 18% undergo breast development, compared with 5% of 45,X individuals. Mean adult height is greater with a 45,X/46,XX complement than with 45,X; more mosaic (25%) than nonmosaic (5%) patients reach adult heights greater than 152 cm (16). Somatic anomalies are less likely to occur in 45,X/46,XX than in 45,X. In Sybert's review and analysis (31), spontaneous menstruation occurred in 45% to 57% (depending on whether mode of ascertainment was in her clinic or from published reports, respectively); frequency of short stature (below the third percentile) was 45% (5/11) and 87% (7/8); fertility occurred in 14% (1/7) and 69% (9/13). Less common but phenotypically similar to 45,X/46,XX individuals is 45,X/47,XXX. 45,X/47,XXX occurs less often but is phenotypically similar to 45,X/46,XX. Individuals with 45,X/46,XY may also show bilateral streak gonads; however, more often they show a unilateral streak gonad and a contralateral dysgenetic testis (mixed gonadal dysgenesis).
TABLE 3.1 Somatic Features Associated with 45,X Chromosomal Complement Growth 9 Decreased birth weight 9 Decreased adult height (141-146 cm) 9 Intellectual function: Verbal IQ.greater than performance IQ_ Cognitive deficits (space-form-blindness) 9 Craniofacial: Premature fusion of spheno-occipital and other sutures, producing brachycephaly Abnormal pinnae Retruded mandible Epicanthal folds (25%) High-arched palate (36%) Abnormal dentition Visual anomalies, usually strabismus (22%) Auditory deficits; sensorineural or secondary to middle ear infections 9 Neck: Pterygium coli (46%) Short broad neck (74%) Low nuchal hair (71%) 9 Chest: Rectangular contour (shield chest) (53%) Apparent widely spaced nipples Tapered lateral ends of clavicle 9 Cardiovascular: Coarctation of aorta or ventricular septal defect (10-16%) 9 Renal (38%): Horseshoe kidneys Unilateral renal aplasia Duplication of ureters 9 Gastrointestinal: Telangiectasias 9 Skin and lymphatics: Pigmented nevi (63%) Lymphedema (38%) due to hypoplasia of superficial vessels 9 Nails: Hypoplasia and malformation (66%) 9 Skeletal: Cubitus valgus (54%) Radial tilt of articular surface of trochlear Clinodactyly V Short metacarpals, usually fourth (48%) Decreased carpal arch (mean angle 117 degrees) Deformities of medical tibial condyle 9 Dermatoglyphics: Increased total digital ridge count Increased distance between palmar triradii a and b Distal axial triradius in position t Modified from ref. 16.
V. PITFALLS IN LOCALIZING OVARIAN MAINTENANCE GENES TO SPECIFIC REGIONS OF THE X The first step in understanding normal ovarian differentiation and in producing gene products of therapeutic benefit is delineating the region (genes) on the X responsible
CHAPTER3 Genetic Programming in Ovarian Development and Oogenesis
NORMAL MITOSIS
33
MITOTIC NONDISJUNCTION
FIGURE 3.2 Diagrammaticrepresentation of the products of (A) normal mitosis and (B) mitosischaracterizedby nondisjunctionof a Y chromosome.If all daughtercells survived, the complementwouldbe 45,X/46,XY/47,XYY.From res 17.
for ovarian maintenance. Until the 1990s, phenotypickaryotypic correlations to deduce location of gonadal and somatic determinants relied solely on metaphase analysis. Prometaphase karyotypes allow 1200-band analysis, whereas traditional banding is 400 to 500; however, each band still contains considerable DNA. More refined analysis is possible using polymorphic DNA markers, which allow precise resolution far beyond the capacity of light microscopy. Progress has, nonetheless, been slow compared with that achieved in delineating the regions of the Y necessary for testicular differentiation (SRY) or spermatogenesis (DdZ). Several impediments are responsible for this relative lack of progress. The incidence of X deletions is low, so the ideal approach of analyzing cases ascertained by population-based methods is impractical. No individuals with X deletions were discovered among 50,000 consecutively born neonates (32). Most del(Xp) or del(Xq) individuals have been identified only because they manifested clinical abnormalities, exceptions being familial cases or cases detected in fetuses at the time of prenatal genetic diagnosis for their mother's advanced maternal age. Doubtless many less severely affected individuals escape detection. Mode of ascertainment ideally should be considered in phenotypic-karyotypic analysis, but in reality this is impractical because sample sizes are too small. Inevitably biases of selection arise. Another pitfall impeding molecular analysis of X-ovarian maintenance genes is that analysis is not always derived from individuals who are cytogenetically well studied. Mosaicism in nonhematogenous tissues has not always been excluded to the extent reasonably possible. Individuals with unstable aberrations (rings, dicentrics) should probably be excluded from phenotypic-karyotypic deductions because monosomy X and other cell lines may arise secondarily, sometimes in tissues (e.g., gonads) relatively inaccessible to
study. Utilizing X-autosome translocations for analysis may also be hazardous because of vicissitudes of X inactivation and because autosomal regions are not devoid of significance for gonadal differentiation.
VI. CYTOGENETICS OF X CHROMOSOMAL ABERRATIONS A. 46,X, del(Xp) or 45,X/46,X, del(Xp) Deletions Deletions of the short arm of the X chromosome show variable phenotypes, depending upon the amount of Xp persisting. The most common breakpoint for terminal deletions is Xp11.2611.4. In 46,X,del(X)(p11) only proximal Xp remains; the del(Xp) chromosome thus appears acrocentric or telocentric. Deletions characterized by progressively more distal breakpoints has been reported: Xp21, 22.1, 22.3. X autosomal translocations leading to Xp interstitial deletions have been reported and are analytically useful, albeit subject to caveats noted in the previous section. The standard for refined analysis is using polymorphic DNA markers to determine precise breakpoints, but relatively few cases have been subjected to refined molecular analysis. Approximately half of 46,X,del(Xp)(p11) individuals show primary amenorrhea and gonadal dysgenesis. Others menstruate and usually show breast development. In a 1989 tabulation by the author, 12 of 27 reported del(X)(p11.2) (11.4) individuals menstruated spontaneously; however, menstruation was rarely normal (33). More recent compilations have not altered these general conclusions (34-36). In another tabulation, Ogata and Matsuo (23) found that 50% of del(X)p11 cases showed primary amenorrhea, with 45% showing secondary amenorrhea. Ovarian function is thus
34 observed more often in individuals with a del(Xp11) chromosome than in 45,X individuals. Women with more distal deletions (del[X][p21.1 to p22.1.22]) menstruate more often, but many are still infertile or even have secondary amenorrhea (Fig. 3.3). Thus, Xp (X[Xpter--+p21]) retains a role in ovarian development (34-36). The distal region of importance must involve Xp21,22.1 or 22.2 because del(X) (p22.3) cases do not show primary amenorrhea. Most women with deletions of Xp are short. Thus, statural determinants--that is, regions with genes conferring stature--must exist on Xp. Because del(Xp) women may menstruate but still be short, regions on Xp responsible for ovarian and statural determinants must be distinct (34-38). Clinically it is important to realize that del(Xp) women may be short despite manifesting normal ovarian function. Both mother and daughter may show the same Xp deletions, not only in association with X autosome translocation but also in association with terminal deletions. In 1977, Fraccaro et al. (37) first called attention to familial distal Xp
FIGURE 3.3 Schematicdiagram of the X chromosomeshowing ovarian function as a function of nonmosaic terminal deletion. References initially provided by Simpson (33). Nonmosaic cases described since that report include Naguib et al. (155); Massa et al. (156); Veneman (157); Schwartz (158), which is a molecularupdate of Fitch et al. (42);Tharapel et al. (43); Zinn et al. (159); Zinn et al. (160); Ogata and Matsuo (23); Marozzi et al. (161); Davison et al. (162);James et al. (22); and Susca et al. (163). In familial aggregates, all affected cases are included because their phenotypes are not alwaysconcordant. In some case,patients are described as havingpremature ovarianfailure, but no information is provided on fertility; in the absence of explicit information it is assumed that no pregnancy has occurred. In some younger patients (e.g., older than 14 years but youngerthan 20-25 years),there has been little opportunity to demonstrate pregnancy, nor is there assurance regular menses will continue. Nonetheless, they are designated as having "regular menses/fertility."From ref. 164.
JOE LEIGH SIMPSON deletions. Among 10 del(Xp) cases studied by James et al. (22) were two mother-daughter pairs; only 6 of their 10 cases arose de n o v o . Familial cases involved deletion at X p l l as well as Xp22-12. Xp interstitial deletions involving Xp 11-22 and Xp11.422.3 (39,40) have been reported.
B. Isochromosomes for Xq (i[Xq]) Division of the centromere in the transverse rather than the longitudinal plane results in an isochromosome, a metacentric chromosome consisting of isologous arms. Both arms are structurally identical and contain the same genes. An isochromosome for the X long arm (i[Xq]) differs from a terminal deletion of Xp in that not just the terminal portion but all of the Xp is deleted. Many isochromosomes for Xq are actually isodicentrics, the clinical significance of which is that a minute portion of Xp is duplicated and retained in addition to duplication of the entire Xq. An isochromosome for the X long arm is the most common X structural abnormality, but coexisting 45,X cell lines (mosaicism) are typical. Nonmosaic cases are relatively uncommon. 46,X,i(Xq) individuals almost always have streak gonads and primary amenorrhea. Occasionally menstruation is observed, but surveys continue to agree with those published by the author (16) more than 25 years ago in showing rarity of menstruation (23). The near complete lack of gonadal development in 46,X,i(Xq) contrasts to that in 46,X, del(X)(p11) individuals, about half of whom menstruate or develop breasts. The contrast is even greater with more distal Xp deletions. Phenotypic differences could be explained if gonadal determinants were present at several different locations on Xp, one locus being deficient in i(Xq) yet retained in del(X)(p11). Alternatively, 46,XX cells may be associated with del(Xp) more often than generally appreciated. Irrespective, duplication of X q - - t h a t is, i(Xq) - - fails to compensate for deficiency of Xp. Thus, gonadal determinants on Xq and Xp have different functions. Another possibility is that all loci on i(Xq) chromosomes are completely inactivated, as indeed study of candidate genes indicates. It seems unlikely that duplication of Xq per se produces abnormalities, given that 47,XXX is often clinically normal. Almost all reported 46,X,i(Xq) patients are short. Their mean height seems to be less than in 45,X (Table 3.2). The mean height of nonmosaic 46,X,i(Xq) patients is 136 cm (16), and many somatic features of the Turner stigmata are observed (16). Somatic anomalies occur as frequently in 46,X,i(Xq) individuals as in 45,X individuals, and the spectrum of anomalies associated with the two complements is similar.
35
CHAPTER 3 Genetic Programming in Ovarian Development and Oogenesis TABLE 3.2
Ovarian Function as Tabulated on Basis of Cases Reviewed in 1995 by Ogato and Matsuo (23)* Ovarian failure (percentage) in X deletions (tabulation of Ogato and Matsuo [23]) Partial (secondary amenorrhea or Complete (primary amenorrhea or abnormal menses) streak gonads)
Monosomy X (45,X) Short arm deficiency del (X)(p11) del (X)(p21-22.2) del (X)(p22.3) i(Xq) idic(Xq) Long arm deficiency del(X)(q13-21) del(X)(q22-25) del(X)(q26-28) idic(Xp)
None (presumed normal)
88%
12%
50 13 0 91 80
45 25 0 9 20
5 65 100 0 0
69 31 8 73
31 56 67 27
0 13 25 0
0
*Ogato and Matsuo provided data in first two columns,with the assumptionbeing that remainder of cases have normal ovarian function--for example, 5% in del(X)(pl1). Publications surveyedoverlap in large part those used for analysisof Simpson (Fig. 3.4)
C. 4 6 , X . d e l ( X q ) a n d 4 5 , X / 4 6 . X , d e l ( X q ) Deletions Deletions of the X long arm are well known (33-36) and vary in composition. If the breakpoint leading to a terminal deletion originates at band Xql3, the derivative chromosome resembles number 17 or number 18; a breakpoint at band Xq21 produces a chromosome resembling number 16. Almost all deletions originating at Xq13 are associated with primary amenorrhea, lack of breast development, and complete ovarian failure (36).Xq13 thus seems to be an important region for ovarian maintenance. Key loci could lie in
proximal Xq21, but not more distal, given that del(X)(q21) to (q24) indMduals menstruate far more often (see Fig. 3.3). Menstruating del(X)(q21) women might have retained a region that contained an ovarian maintenance gene, whereas del(X)(q13 or 21) women with primary amenorrhea might have lost such a locus (36). X autosomal breakpoints associated with ovarian failure span the entire Xq21 region. This was the first indication that a single gene on Xq cannot be responsible for all cases of ovarian failure. The caveat is that balanced X autosome translocations could result not from disruption of a gene per se, but rather from generalized cytologic (meiotic) perturbation.
[BIOSYNTHETIC P.ATHWAYS]
Acetate Cholesterol Precjnenolone
Procjesterone ......
c
C
D ~.. 17 o< - OH precjnenolone ~ Dehydroepmndrosterone
17 c~ - OH progesterone ~
II - deoxycorticosterone
I I-deoxycortisol
Corticosterone
Cortlsol
Androstenedione ~ T e s t o s t e r o n e Estrone ~ E s t r a d l o l
Aldosterone
FIGURE3.4 Importantadrenal and gonadal biosyntheticpathways.Letters designate enzymesrequired for the appropriate conversions. (A) 20ot-hydroxylase,22c~-hydroxylase,and 20,22-desmolase; (B) 38fh-ol-dehydrogenase;(C) 17oL-hydroxylase; (D) 17,20-desmolase;(E) 17-ketosteroidreductase; (F) 21-hydroxylase;(G) 11-hydroxylase.Modified from ref. 17.
36
JoE LEIGH SIMPSON
In more distal Xq deletions, the more common phenotype is not primary amenorrhea but premature ovarian failure (34,35,41,42). Although distal Xq seems less important for ovarian maintenance than proximal Xq, the former must still have regions important for ovarian maintenance. Informative cases have included terminal deletions originating at various sites as well as interstitial deletions (41,43). These interstitial deletions point out hazards of interpretation without molecular studies. Although demarcation into discrete regions is not possible, it is heuristically useful to stratify terminal deletions into those occurring in these regions: Xq13--+21, Xq22--->25, Xq26-+28. Table 3.2 shows ovarian function as tabulated by Ogato and Matsuo (23) using such stratification. Figure 3.3 shows the author's tabulation using a different format. Both estimates are based on pooled cases, and both are generally consistent. Distal Xq deletions may be familial. Some familial Xq deletions are derivative of Xq autosome translocations, but familial terminal or interstitial deletions also exist (43). Familial Xp terminal or interstitial deletions have been characterized by various breakpoints between Xq25 to Xq28. Breakpoints near or in Xq27 seem most common. Some families have been ascertained for reasons other than premature ovarian failure, a case reported by our group having been ascertained following amniotic fluid analysis in a fetus (43). As will be discussed later, the locus for fragile X (FRAXA) is also in the region. About 15% of women with >55CGG repeats show premature ovarian failure. Distal Xq deletions seem to have a less deleterious effect on stature than proximal deletions. Somatic anomalies of the Turner stigmata are uncommon and perhaps no different than in the general population.
VII. OVARIAN GENES ON T H E X Although chromosomal regions on Xp (and Xq) are presumed to contain genes pivotal to ovarian germ cell function, the actual gene and gene products remain frustratingly unclear. A host of candidate genes are being studied.
A. Candidate Genes on Xp 9 USP9X (ubiquitin specific protease 9): This gene maps to Xpll.4 (44) and is expressed in multiple tissues. The Drosophila orthologue of USP9X is required for eye development and oogenesis. The role USP9X plays in human gonadal development is still unclear, but its location in the appropriate region is tantalizing. 9 Z F X (zinc finger X): Mapped to Xp22.1--+21.3, Z F X is a candidate gene for short stature and ovarian failure (45). It has attracted attention on the basis of being homologous
to ZF~, once the prime candidate gene for male sex determination. Mice null for Zfx are small, less viable, less fertile, and characterized by diminished germ cell number in ovaries and testes (46). Their external and internal genitalia are otherwise normal. 9 B M P 1 5 (bone morphogenetic protein 15): Bone morphogenetic protein 15 (BMP15) is a member of the transforming growth factor-J3 (TGF-[3) superfamily. These genes direct many developmental pathways through binding and activating transmembrane serine/threonine kinase receptors. B M P is involved in folliculogenesis and embryonic development, being expressed in gonads. The B M P 1 5 gene is located on Xpll.2 and has two exons. The gene is a member of the TGF family. Prior to human cases being reported, animal studies had suggested that perturbations of B M P 1 5 could be important in ovarian development. Heterozygous Inverdale sheep carrying a mutation in the B M P 1 5 gene show an increased ovulation rate, with twin and triplet births. Primary ovarian failure occurs in homozygotes (47). B M P 1 5 knockout mutant female mice are subfertile, showing decreased ovulation rates, reduced litter size, and decreased number of litters per lifetime (48). In humans (49), Di Pasquale et al. reported a heterozygous Y235C missense mutation in the second exon of the B M P 1 5 gene in each of two sisters having ovarian failure. The proband had streak gonads and elevated follicle-stimulating hormone (FSH 80 mlU/mL); the younger sibling had one episode of vaginal spotting but at age 18 years had an FSH level of 67 mlU/mL. The mother was homozygously normal (Y235) at this allele, and C235 was transmitted from the father. The authors presented in vitro evidence of a dominant negative mechanism. Another TGF family member, growth differentiation factor 9 (GDF9; see p. 39) has also been implicated in ovarian failure. In these cases the mutation was also heterozygous (50). Given that proteins of TGF family members (BMP15, GDF9) may form heterodimers, a single mutation could plausibly generate a dysfunctional gene product. ~ Region Localized by Q.gantitative Linkage Analysis: Genomewide linkage analysis has been applied in order to determine which genes influence age of menopause. One study has shown association between X p l l and the age of menopause. This suggests the existence of a locus of importance.
B. Candidate Genes on Xq 9 XIST" Xql3 contains the X inactivation center and XIST. Loss of germ cells may or may not be the direct result of perturbation of XIST, despite years of speculation that
CHAPTER 3 Genetic Programming in Ovarian Development and Oogenesis disturbances of X inactivation per se lead to ovarian failure. The concept of a well-defined "critical regioN' necessary for ovarian development receives less attention than in the past, but this does not exclude a region rich in pivotal genes. 9 D I d P H 2 : Human DIHPH2 is the homolog of Drosophila melanogaster diaphanous (dia). In Drosophila, dia is a member of a family of proteins that help establish cell polarity, govern cytokinesis, and reorganize the actin cytoskeleton. In both males and females, dia causes sterility in flies (51). A human Xq21 autosome translocation was found to have a disruption of the last intron o f DIHPH2 (52). Bione and Toniolo (53) and Prueitt et al. (54) found disruption of X P N P E P 2 in an Xq autosome. D I A P H 2 on X P N P E D 2 could be relevant m so-called POF2. 9 F M R 1 : On Xq27 lies the F M R 1 locus, the gene for fragile X syndrome. About 20% of females with an F M R 1 premutation (55 or more CGG repeats) develop premature ovarian failure, although paradoxically those with the full mutation do not. (Fragile X syndrome is discussed later.) This locus cannot logically correspond to that which when deleted causes ovarian failure in del(Xq) (2.7 or 2.8).
VIII. AUTOSOMAL CHROMOSOMAL ABNORMALITIES
A. Trisomy Autosomal trisomy has long been known to affect adversely ovarian development. The question remains whether this effect is mediated by nonspecific meiotic perturbation or by chromosome-specific genes, perhaps acting in double dose. Trisomies 13 and 18 are frequently associated with ovarian failure, as indicated by necropsy observations in stillborn fetuses or deceased neonates. Few longitudinal data are available in trisomy 13 or 18 because few females survive until menarche. In trisomy 21, however, ovarian function may be normal. There seems to be no objective information on age at menopause. Pregnancies occur in trisomy 21 females (55). About one third of offspring are aneuploid (fewer than the theoretically expected 50%). If nonspecific meiotic breakdown is merely secondary to an uneven number of chromosomes, the effect should be the same with chromosome 21 as with chromosomes 18 or 13. The ostensibly normal ovarian function in trisomy 21 argues for the existence of specific ovarian genes on chromosomes 13 and 18 but not on 21.
B. Translocations Chromosomal rearrangements, specifically balanced autosomal reciprocal translocations, are not infrequently observed in otherwise normal women with complete or partial
37
ovarian failure. As with autosomal trisomy, it is unclear whether this association reflects disruption of autosomal loci integral for ovarian preservation and oogenesis. That no chromosome is consistently involved suggests nonspecific meiotic perturbation. In fact, men who are azoospermic or oligospermic but otherwise normal clinically show balanced autosomal translocations far more often than expected: About 1% of men requiring intracytoplasmic sperm injection (ICSI) show a balanced autosomal rearrangement, typically a balanced translocation (56). A problem of comparable magnitude probably exists in women. The pathogenesis leading to meiotic breakdown presumably involves malalignment or failure of synapsis. Recognizing individuals with autosomal rearrangements is important because their offspring are at increased risk for gametes showing unbalanced segregation.
IX. AUTOSOMAL GENES In addition to ovarian failure resulting from monosomy X and X deletions, perturbation of a host of autosomal genes can be deduced to be pivotal because their disturbance causes ovarian dysgenesis in 46,XX indMduals. Sometimes the causative gene is known, whereas in other cases a specific phenotype merely allows us to deduce its presence. Table 3.3 shows the spectrum of genetic causes of ovarian failure in 46,XX women. The archetypal form of XX gonadal dysgenesis is that characterized by streak gonads nat associated with somatic anomalies. Inheritance is autosomal recessive (57). Affected individuals are normal in stature (58), and Turner stigmata are absent. Individuals with XX gonadal dysgenesis as defined are heterogenous and should be more precisely delineated. This may or may not be possible. Of clinical interest is that in XY gonadal dysgenesis variable expressivity occurs. In many families one sibling may show streak gonads, whereas another may show ovarian hypoplasia but not streak gonads per se. A mutant gene operative in this fashion may thus be responsible for isolated cases of premature ovarian failure (POF).
A. FSH-f3 (FSH) Mutations Coded by a gene on chromosome 11, FSH is composed of a unique [3 subunit and an (x subunit shared in common with thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and human chorionic gonadotropin (HCG). Cellular action requires an FSH receptor (FSHR), the gene for which is located on chromosome 2. Mutations in FSH-f3 are rare. Two affected females showed neither thelarche nor menarche. Matthews et al. (59) described a homozygous 2 bp deletion (GT) in exon
JOELEIGH SIMPSON
38 TABLE 3.3 Genetic Causes of Complete Ovarian Failure and Premature Ovarian Failure (POF) in 46,XX Women FSH-13 (FSH) mutations FSHR mutations Inactivating LH receptor (LHR) mutations Inhibin a (INHA) mutations Growth differentiating factor 9 (GDFg) mutations Perrault syndrome (neurosensory deafness) Cerebellar ataxia with XX gonadal dysgenesis Malformation syndromes associated with XX gonadal dysgenesis Microcephaly and arachnodactyly (94) Epibulbar dermoids (95) Short stature and metabolic acidosis (96,136) Mendelian disorders characterized predominately by somatic features (see Table 3.4) Blepharophimosis-ptosis-epicanthus (BPE) (FOXL2) 17(z-hydroxylase/17,20 desmolase deficiency (CYP17) A_romatase mutations deficiencies (CYP19) Germ cell failure in both sexes (nonsyndrome) Germ cell failure in both sexes (syndrome) Hypertension and deafness (Hamet et al. [137]) Alopecia (A1Awadi et al.) (110) Microcephaly and short stature (Mikati et al. [111]) Galactosemia Carbohydrate-deficient glycoprotein (CGD) Agonadia (46,XX cases) Dynamic mutations (triplet repeat) Fragile X Myotonic dystrophy Ovarian-specific autoimmune syndrome Polyglandular autoimmune syndrome
3 at codon 61 that resulted in a premature stop codon (Va161X). Layman et al. (60) reported a compound heterozygote: one allele was Va161X, whereas the other was Cys51Gly.
B. FSHR Mutations FSHR mutations are not uncommon in Finland but seem rare elsewhere. Aittomaki searched Finnish hospitals and cytogenetic labs to identify 75 women with 46,XX primary or secondary amenorrhea and a serum FSH of 40 mIU/mL or greater. The gene was first localized to chromosome 2p. Then, a missense mutation in the FSH receptor gene (FSHR) in exon 7 (566C---~T or Ala566Val) was found in six families (61,62). Women heterozygous for the mutation showed no decrease in fertility. Outside Finland, Ala566Val seems uncommon. No mutations in FSHR were found in North American women having either 46,XX hypergonadotropic hypogonadism (63) or premature ovarian failure (64). Similar findings were reported in 46,XX premature ovarian failure or primary amenorrhea cases from Germany (65), Brazil (66), and Mexico (67). Awaited are studies examining all
exons of the FSHR gene, rather than just the Ala566Val missense mutation. Two reports describe compound heterozygosity for FSHR mutation (68,69). Genotypes were Ile160Thr/Arg573Cys and Asp224Val/Leu602Val, respectively.
C. Inactivating LH Receptor Mutations Analogous to the FSH receptor gene, the LH receptor gene (LHR) is relatively large, 75 kD in length and consisting of 17 exons. Located on 2p near the locus for FSHR, the first 10 exons in LHR are extracellular, the l lth transmembrane, and the remaining six intracellular. Mutations have been detected only in the transmembrane domain. Most reported LHR mutations are 46,XY and have been found in individuals with XY sex reversal (70). The latter have Leydig cell hypoplasia. LHR mutations in 46,XX women cause the phenotype of XX gonadal dysgenesis or premature ovarian failure. The phenotype is oligomenorrhea or more often primary amenorrhea. Ovulation does not occur, even though gametogenesis proceeds until the preovulatory stage. This is consistent with findings using mouse knockout models (71). 46,XX cases of LHR mutation have usually been ascertained in sibships in which they have been affected 46,XY siblings. Latronico et al. (72) reported a 22-year-old woman who presented with primary amenorrhea due to an LHR mutation. In that family, three 46,XY siblings with Leydig cell hypoplasia had the same homozygous C 5 5 4 ~ X mutation, which resulted in a truncated protein consisting of five rather than seven transmembrane domains. The 46,XX sibling had breast development but only a single episode of menstrual bleeding at age 20; LH was 37 mlU/mL, FSH 9 mlU/mL. The mutation reduced signal transduction activity of the LH receptor gene. In another 46,XX case, Latronico et al. (72) observed secondary amenorrhea; LH and FSH were 10 and 9 mlU/mL, respectively. The mutation was homozygous Ala593Pro.
D. Inhibin alpha (INHA)Mutations Inhibins (INH) are heterodimeric glycoproteins. They consist of an oL subunit and one of two 13 submits (~A and 13B), producing INHd and INHB, respectively. These gene products exert negative feedback inhibition on FSH. Inhibins are opposed by activins, which enhance FSH secretion. Inhibins are synthesized by granulosa cells. In premature ovarian failure, serum inhibin is low and FSH elevated. Elevated FSH and low inhibin thus indicate reproductive aging. Perturbation of inhibins could very plausibly cause ovarian failure.
CHAPTER 3 Genetic Programming in Ovarian Development and Oogenesis Three studies have shown an association between POF and a particular I N H A missense mutation or polymorphismmG769A (50,73,74). Studying cases from New Zealand, Shelling et al. (73) found G769A in 3 of 43 POF patients (7%) versus only 1 of 150 normal control subjects (0.7%). However, the clinically normal mother of one of the three G769A cases had the same perturbation. Marozzi et al. (74) found G769A in 7 of 157 Italian POF cases, 3 of 12 primary amenorrhea cases, and 0 of 36 women with early menopause (40 to 45 years). Familial POF cases were relatively more likely to have G769A than sporadic cases. Dixit et al. (50) found G796A in 9 of 80 Indian POF cases; no mutations were found in I N H B B or INHBA. On the other hand, normal individuals have also shown the G769A transition. Individuals with G769A may also be abnormal even if another G769A family member has POF; thus, G769A itself is not necessarily paramount, but could be in linkage disequilibrium or require another perturbation in cis.
E. GDF9 Mutations GDF9 is a member of the TGFB family. Located on chromosome 5, the gene consists of 2 exons encoding a 454-amnio-acid peptide. This arrangement is similar to that of other members of the TGFB family. GDF9 is expressed in oocytes and plays an essential role both in early and late folliculogenesis. GDF9 protein promotes cumulus expansion in cumulus cell-oocyte complexes (75), whereas its suppression prevents cumulus expansion in sheep (76). Immunization against GDF9 in sheep disrupts early folliculogenesis, leading to the absence of normal follicles beyond the primary stage of development. That GDF9 perturbations can cause ovarian failure in humans is plausible given its known role in oocyte development and demonstration of lack of ovarian development in GDF9 knockout (null) mice (77). Dixit et al. (78) sought perturbations in the GDF9 coding region in 127 women with POF (FSH greater than 40 mlU/ mL), 58 with primary amenorrhea and 10 with secondary amenorrhea (cessation of menses before age 40). A total of 220 control subjects were studied. Two missense mutations were found and considered causative. A199C was found in five women, four with POF and one with secondary amenorrhea; G646A was found in two additional POF subjects. No control women showed a mutation. A variety of other sequence variants (single nucleotide polymorphisms [SNPs]) and silent mutations (no amino acid alteration) were found, but these are unlikely to be causative. Reported GDF9 mutations have been heterozygous. If pathogenesis of ovarian failure were recessive, the G646A and A199C mutations might simply connote heterozygosity of no clinical significance. That is, heterozygous status for an enzyme deficiency is not abnormal because 50% enzyme
39
level more than suffices. That GDF9 forms heterodimers with other member of the TGFB superfamily is relevant. One such member is BMP15, mutation of which also is associated with POF (79). A dominant negative interfering with dimerization is an attractive hypothesis. The proportion of Indian women with GDF9 perturbation was 2.7% (6/220) in the Dixit et al. (78) study, suggesting a not insignificant role in this population. In Japan, 2 of 53 Japanese women showed a mutation for either GDF9 or BMP15 (80). Fifteen had POF, and 38 had polycystic ovarian syndrome. In the U.S., Kovanci et al. (81) found one GDF9 mutation in 61 women with POE Although obviously not common, detection of disturbances in GDF9 in a second population confirms that this is responsible for a proportion of POF cases.
F. Perrault Syndrome XX gonadal dysgenesis with neurosensory deafness is Perrault syndrome (82). Perrault syndrome is inherited in autosomal recessive fashion (83-86). Endocrinologic features seem identical to those of XX gonadal dysgenesis without deafness. Attractive candidate genes are those in the connexin family, such as connexin 37 (Gap Junction alpha 4 or GJA4). Mutations in the connexin gene family are responsible for many forms of congenital deafness in humans, a fact of obvious relevance to Perrault syndrome. In the murine knockout model for connexin 37 (87), null mice show gonadal failure due to arrest at the antral stage of oogenesis.
G. Cerebellar Ataxia with XX Gonadal Dysgenesis Ataxia and hypergonadotropic hypogonadism were first associated by Skre et al. (88), who described cases in two families. In one family a 16-year-old girl was affected, whereas in the other family three sisters were affected. In the sporadic case and in one of the three sisters, ataxia was first observed shortly after birth; in the two other sisters age of onset of ataxia began later during childhood. Cataracts were present in all the cases reported by Skre et al. (88). Hypergonadotropic hypogonadism and ataxia was later reported by De Michele et al. (89), Linssen et al. (90), Gottschalk et al. (91), Fryns et al. (92), Nishi et al. (86), and Amor et al. (93). Ataxia differed clinically among these cases. Ataxia was not progressive in the cases of Skre et al. (88), De Michele et al. (89), Nishi et al. (86), and Amor et al. (93). Mitochondrial enzymopathy was found by De Michele et al. (89). Only Skre et al. (88) observed cataracts, whereas amelogenesis was observed only by Linssen et al. (90). Neurosensory deafness reminiscent of Perraut syndrome was reported by Amor et al. (93). Mental retardation was also variable (93).
JoE LEIGH SIMPSON
40 Overall, genetic heterogeneity exists in the hypergonadotropic hypogonadism disorders showing cerebellar ataxia. However, not every family need be unique.
H. Malformation Syndromes Associated with XX Gonadal Dysgenesis XX gonadal dysgenesis is found in three rare malformation syndromes, all presumed autosomal recessive on the basis of multiple affected siblings. These include XX gonadal dysgenesis, microcephaly, and arachnodactyly (94); XX gonadal dysgenesis and epibulbar dermoid (95); and XX gonadal dysgenesis, short stature, and metabolic acidosis (96).
I. Mendelian Disorders Characterized Predominately by Somatic Features Ovarian failure is a feature, albeit not universal, in several well-established Mendelian disorders. These are enumerated in Table 3.4.
TABLE 3.4
j. Blepharophimosis-Ptosis-Epicanthus (FOXL2) Blepharophimosis-ptosis-epicanthus syndrome (BPE) is an autosomal dominant malformation syndrome. Type II BPF is characterized not only by ocular findings but also by premature ovarian failure (POF) (97,98). The BPE gene proved to be encoded on 3q21-24, and is forkhead box L2 (FOXL2). FOXL2 consists of only one exon. The gene is expressed predominately in eyelids and ovaries (99) and like other forkhead DNA-binding proteins is crucial in signal induction. Crisponi et al. (99) showed that in four families FOXL2 mutations cosegregated with BPE and POE Mutations included stop codons as well as a 17bp duplication that resulted in a frameshift and, hence, truncated protein. In the absence of somatic features, FOXL2 mutations are rare causes of P O E De Baere et al. (100) found no FOXL2 mutations in 30 POF patients having no eyelid abnormalities. Harris et al. (101) found two mutations in 70 POF cases.
Mendelian Disorders Associated with Ovarian Failure (Hypergonadotropic Hypogonadism)* Somatic features
Cockayne syndrome (Nance and Berry [139]) Martsolf syndrome (Martsolf et al. [141]) Nijmegen syndrome (Weemaes et al. [144]) Werner syndrome (Goto et al. [147]) Rothmund-Thompson syndrome (Hall et al. [148]) Ataxia-telangiectasia
Bloom syndrome (German [152]; German et al. [153]; German [154])
Dwarfism, microcephaly, mental retardation, pigmentary retinopathy and photosensitivity, premature senility; sensitivity to ultraviolet light Short stature, microbrachycephaly, cataracts, abnormal facies with relative prognathism due to maxillary hypoplasia Chromosomal instability, immunodeficiency, hypersensitivity to ionizing radiation, malignancy Short stature, premature senility, skin changes (scleroderma) Skin abnormalities (telangiectasia, erythema, irregular pigmentation), short stature, cataracts, sparse hair, small hands and feet, mental retardation, osteosarcoma Cerebella ataxia, multiple telangiectasias (eyes, ears, flexor surface of extremities), immunodeficiency, chromosomal breakage, malignancy, x-ray hypersensitivity Dolichocephaly, growth deficiency, sunsensitive facial erythema, chromosomal instability (increased sister chromatical exchange), increased malignancy
*From ref. 138 where referencesare provided.
Ovarian anomalies
Etiology
Ovarian atrophy and fibrosis (Sugarman et al. [140])
Autosomal recessive
"Primary hypogonadism" (Harbord et al. [142]; Hennekam et al. [143])
Autosomal recessive
Ovarian failure (primary) (Conley et al. [145]; Chrzanowska et al. [146]) Ovarian failure (Goto et al. [147]) Ovarian failure (primary hypogonadism or delayed puberty) (Starr et al. [149])
Autosomal recessive (7;14 rearrangement) Autosomal recessive
"Complete absence of ovaries," "absence of primary follicles" (Zadik et al. [150]; Waldmann et al. [151]) Ovarian failure (German [154])
Autosomal recessive
Autosomal recessive
Autosomal recessive
41
CHAPTER3 Genetic Programming in Ovarian Development and Oogenesis
K. 17o~-hydroxylase/17,20 Desmolase Deficiency ( c w m 7) Deficiency of 17ci-hydroxylase/17,20 desmolase should be considered an uncommon cause of 46,XX hypergonadotropic hypogonadism. Patients with 46,XX present with primary amenorrhea or premature ovarian failure. Hypertension often coexists. Ovaries are hypoplastic and sometimes streaklike in appearance. Oocytes appear incapable of reaching diameters greater than 2.5 mm (102). Stimulation with exogenous gonadotropins can produce oocytes capable of fertilization in vitro (103).
L. Aromatase Mutations in Females (46,XX)
(C-TP19) Conversion of androgens (A 4-androstenedione) to estrogens (estrone) requires cytochrome P-450 aromatase (GYP19), an enzyme that is the gene product of a 40-kb gene located on chromosome 15q21.1 (104). The gene consists of 10 exons. Phenotypic female patients with 46,XX aromatase deficiency may present with primary amenorrhea. Ito et al. (105) reported an aromatase mutation (CYP19) in a 46,XX 18-year-old Japanese woman having primary amenorrhea and cystic ovaries. The patient was a compound heterozygote who showed two different point mutations in exon 10. No enzyme activity was evident in vitro. Conte et al. (106) also reported aromatase deficiency in a 46,XX woman presenting with primary amenorrhea, elevated gonadotropins, and ovarian cysts. Again, compound heterozygosity was found for two different exon 10 mutations. One was a C1303T transition leading to cysteine rather than arginine, whereas the other was a G1310A transition leading to tyrosine rather than cysteine. A different phenotype was reported by Mullis et al. (107). Clitoral enlargement occurred at puberty, and there was no breast development. Multiple ovarian follicular cysts were present. FSH was elevated; estrone and estradiol were decreased. Estrogen and progesterone therapy resulted in a growth spurt, decreased FSH, decreased androstenedione and testosterone, breast development, menarche, and decreased follicular cysts. Compound heterozygosity existed.
M. Germ Cell Failure in Both Sexes (Nonsyndromic) In several sibships, both males (46,XY) and females (46,XX) have shown germ cell failure. Affected females show streak gonads, whereas males show germ cell aplasia
(Sertoli-cell-only syndrome). In two families, parents were consanguineous. In neither were somatic anomalies observed (108,109). These families demonstrate that a single autosomal gene may deleteriously affect germ cell development in both sexes, presumably acting at a site common to early germ cell development.
N. Germ Cell Failure in Both Sexes (Syndromic) In contrast to families described in the previous section, in two others, coexisting patterns of somatic anomalies suggest different genes. In both, parents were consanguineous. A1 Awadi et al. (110) reported germ cell failure and an unusual form of alopecia. Scalp hair persisted in the midline, but no hair was present on sides ("mane-like"). Mikati et al. (111) reported germ cell failure, microcephaly, short stature, mental retardation; and unusual facies (synophrys, abnormal pinnae, micrognathia, loss of teeth). The siblings reported by A1 Awadi et al. (110) were Jordanian; those reported by Mikati et al. (111) were Lebanese.
O. Myotonic Dystrophy (CTG n) Myotonic dystrophy is an autosomal dominant disorder characterized by muscle wasting (head, neck, extremities), frontal balding, cataracts, and male hypogonadism (80%) attributable to testicular atrophy. Female hypogonadism is very much less common, if increased at all. Despite frequent citations in texts, ovarian failure in myotonic dystrophy is poorly documented. Pathogenesis of myotonic dystrophy involves nucleotide expansion of CTG repeats in the 3' untranslated region of the causative gene, which is located on chromosome 19. Normally, 5-27 CTG repeats are present. Heterozygotes usually have at least 50 repeats; severely affected individuals show 600 or more. As in patients with FRAXA (FMR1) (discussed later), response to ovulation induction is poor. Sermon et al. (112) report fewer embryos per cycle in these patients than in patients without FRAXA who undergo standard assisted reproductive technology (ART) treatments. More recent reports show better results (113).
P. Galactosemia Galactosemias is caused by galactose-l-phosphate uridyl transferase (GALT) deficiency. Kaufman et al. (114) reported POF in 12 of 18 galactosemic women, and Waggoner et al. (115) reported ovarian failure in 8 of 47 (17%) females with galactosemia. Pathogenesis presumably involves galactose
42
JOE LEIGH SIMPSON
toxicity after birth, given that elevated fetal levels of toxic metabolites should be cleared rapidly in utero by maternal enzymes. Consistent with this idea, a neonate with galactosemia showed normal ovarian histology (116). Once postulated, there remains little reason to believe that POF is caused by heterozygosity for galactosemia. Not even all homozygotes for human galactosemia are abnormal. Null transgenic mice in which GALT is inactivated (knockout) are normal with respect to ovarian failure (117).
Q:. Carbohydrate-Deficient Glycoprotein (CDG) In type I carbohydrate-deficient-glycoprotein (CDG) deficiency, mannose 6-phosphate cannot be converted to mannose 1-phosphate. Thus, lipid-linked mannose-containing oligosaccharides, necessary for secretory glycoproteins, cannot be synthesized. The gene is located on 16p13, and the usual molecular perturbation is a missense mutation (118). In addition to neurologic abnormalities (119), ovarian failure is common. FSH is elevated, secondary sexual development fails to occur, and ovaries lack follicular activity (120,121).
R. Fragile X Syndrome (CGG n) Fragile X syndrome is a common form of X-linked mental retardation, caused by mutation of the FMRI gene, located on Xq27. The molecular basis involves repetition of the triplet repeat CGG. If more than 200 repeats exist, transcriptional silencing of a RNA-binding protein occurs. In normal males, the normal number of CGG repeats is less than 55. Males or heterozygous females with 55 to 199 repeats are said to have a premutation (122). During female (but not male) meiosis, the number of triplet repeats may increase (expand). A phenotypicaUy normal woman with a FRAXA premutation may have an affected son if the number of CGG repeats on the oocyte of the X she transmits to her male offspring expands during meiosis to greater than 200. Affected males show mental retardation, characteristic facial features, and large testes. Expansion will not occur if there are less than approximately 55 CGG repeats, although the precise threshold remains arguable. Females may also show mental retardation, but the phenotype is less severe than in males. Of relevance here is that 20% to 25% of females with the FRAXA premutation show POF, defined as menopause prior to 40 years of age. Schwartz et al. (123) found oligomenorrhea in 38% of premutation carriers versus 6% control subjects. Analyzing 1268 control subjects, 50 familial POF cases, and 244 sporadic POF cases, Allingham-Hawkins et al. (124), reported that 63 of 395 premutation carriers (16%) underwent menopause before 40 years of age; the frequency in control subjects was 0.4%. In the U.S., Sullivan
et al. (122) found 12.9% of premutation carriers (N = 250; great than 59 repeats) to have POF, versus 1.3% (2/157) of control subjects. Surprisingly, FSH was increased in premutation carriers age 30 to 39 years, but not in carriers of other ages. The number of repeats significantly correlated with risk of POF, within a specified range. The risk slightly increased up to 79 repeats, but was much higher for 80 to 99 repeats. Yet there was no further increased risk for 100 or more repeats. The reason for the plateau is not clear. However, this observation is consistent with females with the full mutation not showing POF (124). FMRI testing is recommended in Europe as part of the evaluation for premature ovarian failure (125). If oocyte or ovarian slice cryopreservation becomes practical, population screening might be justified for fertility preservation.
S. Genes Postulated on Basis of Animal Models In many mouse mutants, knockout genes cause germ cell deficiencies, in either males and females or both. The widely varying modes of action of these genes make it clear that germ cell failure in humans will not necessarily be predicted simply on the basis of ostensible gene action. Among genes that seem promising for investigation are Folliculogenesis specific basic helix-loop-helix (FIGLA) (126); connexin 37 (CX37), also called gap junction protein, alpha 4, 37kDa (GJZI4) (87); G protein-coupled receptor 3 (GPR3) (127); and NOBOX oogenesis homeobox (NOBOX) (128), or ovarian homeobox (OBOX) (129). The only one of these genes for which a search for perturbations has been reported in human POF is NOBOX, for which Zhao et al. (130) found no mutations in 30 Japanese patients.
T. Undefined Autosomal Genes Using microarrays, Arraztoa et al. (131) found 95 genes to be expressed at high levels in primordial monkey oocytes. Each gene could be plausibly entertained as a candidate gene for ovarian failure. This citation is but a single example of the many candidate genes that can be expected to be derived from this broadly applicable approach.
X. H O W O F T E N IS PREMATURE OVARIAN FAILURE GENETIC? As already discussed individually, premature ovarian failure can result from several different genetic mechanisms. These include (1) X-chromosomal abnormalities; (2) autosomal recessive genes causing the various types of XX gonadal dysgenesis; and (3) autosomal dominant genes whose action is restricted to POE The former two topics have been
43
CHAPTER 3 Genetic Programming in Ovarian Development and Oogenesis considered in detail earlier, so we shall focus here only on the third. However, prior to doing so it is useful to recall the role the former two etiologies play in P O E
A. X - C h r o m o s o m a l
Abnormalities
Not only complete ovarian failure but premature ovarian failure occurs in X abnormalities. Many mosaic individuals are so mildly affected that they are never detected clinically. At least 10% to 15% of 45,X/46,XX indMduals menstruate, compared with fewer than 5% of45,X indMduals (16). Spontaneous menstruation occurs in about half of all 46,X, del(X)(p11) and 46,X,del(X)(p21 or 22) individuals, who often present with secondary amenorrhea and premature ovarian failure. Deletions or X autosomal translocations involving regions Xp22 and Xq26 are more likely to be associated with premature ovarian failure than complete ovarian failure. Recall also that women with the F R A X A premutation ( F M R 1 ) show an increased frequency of premature ovarian failure, a phenomenon that may or may not be the result of perturbations of the terminal Xq ovarian maintenance genes.
B. Autosomal Recessive POF In some families we have noted that the propositus may have 46,XX gonadal dysgenesis and streak gonads, but a sibling ovarian hypoplasia with some oocytes. These sibships suggest that some m u t a n t genes responsible for causing XX gonadal dysgenesis (see Table 3.3) are capable of exerting variable expressivity. Thus, these autosomal recessive mutations may be manifested as less severe ovarian pathology. In the Finnish cases of F S H R mutations ascertained by Aittomaki (61,62), P O F not infrequently coexisted in the same kindred as complete ovarian failure. Genes causing familiar XX gonadal dysgenesis genes may therefore also be responsible for familial premature ovarian failure.
C. Autosomal Dominant POF Probably distinct from conditions discussed earlier is idiopathic P O F transmitted in more than one generation (132,133). This suggests autosomal dominant inheritance. These families could also have subtle X deletions, F R A X A premutations, or any of a number of perturbations in autosomal genes listed earlier. In his 1984 study, Mattison et al. (134) examined five families. These families were probably ascertained from a very large population base, raising the concern that the familial aggregates could have been observed by chance or on the basis of polygenic factors. In none were ovarian antibodies present.
Defining POF as cessation of menses for 6 months or longer, Vegetti et al. (135) ascertained 81 Italian women under age 40. Of these, 10 were excluded on the basis of presumptive known etiology (5 abnormal karyotypes, 3 previous ovarian surgeries, 1 prior chemotherapy, 1 galactosemia). Pedigree analysis was performed. Of the remaining 71, 23 (31%) had an affected female relative. Subjects with a positive family history were an older median age (37.5 years) then those without such a history (31 years). Pattern of inheritance was autosomal dominant inheritance. Transmission occurred through both male and female members. Neither BPE nor fragile X syndromes were observed clinically.
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CHAPTER 3 Genetic Programming in Ovarian Development and Oogenesis 139. Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet 1992;42:68-84. 140. Sugarman GI, Landing BH, Reed WB. Cockayne syndrome: clinical study of two patients and neuropathologic findings in one. Clin Pediatr 1977;16:225-232. 141. Martsolf JT, Hunter AG, Haworth JC. Severe mental retardation, cataracts, short stature, and primary hypogonadism in two brothers. A m J M e d Genet 1978;1:291-299. 142. Harbord MG, Baraitser M, Wilson J. Microcephaly, mental retardation, cataracts, and hypogonadism in sibs: Martsolf's syndrome. JMed Genet 1989;26:397-400. 143. Hennekam RC, van de Meeberg AG, van Doorne JM, Dijkstra PF, Bijlsma JB. Martsolf syndrome in a brother and sister: clinical features and pattern of inheritance. EurJ Pediatr 1988;147:539- 543. 144. Weemaes CM, Hustinx TW, Scheres JM, et al. A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr &and 1981;70:557-564. 145. Conley ME, Spinner NB, Emanuel BS, Nowell PC, Nichols WW. A chromosomal breakage syndrome with profound immunodeficiency. Blood 1986;67:1251-1256. 146. Chrzanowska KH, Kleijer wJ, Krajewska-Walasek M, et al. Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. Am J Med Genet 1995;57:462-471. 147. Goto M, Tanimoto K, Horiuchi Y, Sasazuki T. Family analysis of Werner's syndrome: a survey of 42 Japanese families with a review of the literature. Clin Genet 1981;19:8-15. 148. Hall JG, Pallister PD, Clarren SK, et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly--a new syndrome? Part l: clinical, causal, and pathogenetic considerations. Am J M e d Genet 1980;7:47- 74. 149. Starr DG, McClure JP, Connor JM. Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 1985;27:102-104. 150. Zadik Z, Levin S, Prager-Lewin R, Laron Z. Gonadal dysfunction in patients with ataxia telangiectasia. Acta Paediatr Scand 1978;67: 477-479.
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151. Waldmann TA, Misiti J, Nelson DL, Kraemer KH. Ataxiatelangiectasis: a multisystem hereditary disease with immunodeficiency, impaired organ maturation, x-ray hypersensitivity, and a high incidence of neoplasia. Ann Intern Med 1983;99:367- 379. 152. German J. Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients. A m J H u m Genet 1969;21:196-227. 153. German J, Bloom D, Passarge E. Bloom's syndrome XI. Progress report for 1983. Clin Genet 1984;25:166-174. 154. German J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine 1993;72:393 - 406. 155. Naguib KK, Sundareshan TS, Bahar AM, et al. Fertility with deletion Xq25: report of three cases; possible exceptions for critical region hypothesis. Fertil Steri11988;49:917-919. 156. Massa G, Vanderschueren-Lodeweyckx M, Fryns JP. Deletion of the short arm of the X chromosome: a hereditary form of Turner syndrome. EurJ Pediatr 1992;151:893-894. 157. Veneman TF, Beverstock GC, Exalto N, Mollevanger P. Premature menopause because of an inherited deletion in the long arm of the X-chromosome. Ferti! Steri! 1991;55:631-633. 158. Schwartz C, Fitch N, Phelan MC, et al. Two sisters with a distal deletion at the Xq26/Xq27 interface: DNA studies indicate that the gene locus for factor IX is present. Hum Genet 1987;76:54-57. 159. Zinn AR, Ouyang B, Ross JL, et al. Del (X)(p21.2) in a mother and two daughters with variable ovarian function. Clin Genet 1997;52:235-239. 160. Zinn AR, Tonk VS, Chen Z, et al. Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1. AmJHum Genet 1998;63:1757-1766. 161. Marozzi A, Dalpra L, Ginelli E, Tibiletti MG, Crosignani PG. FRAXA premutations are not a cause of familial premature ovarian failure. Hum Reprod 1999;14:573-575. 162. Davison RM, Q.uilter CR, Webb J, et al. A familial case of X chromosome deletion ascertained by cytogenetic screening of women with premature ovarian failure. Hum Reprod 1998;13:3039-3041. 163. Susca F, Aoam R, Vucubim M, Louerro G, Guanti G. Xq deletion and premature ovarian failure. Hum Reprod 1999;14:236. 164. Simpson JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am JMed Genet 1999;89:186-200.
This Page Intentionally Left Blank
~HAPTER ~
Basic Biology: Ovarian Anatomy and Physiology GREGORY F. ERICKSON
Universityof California, San Diego, School of Medicine, La Jolla, CA 92093
R. JEFFREY C H A N G Universityof California, San Diego, School of Medicine, La Jolla, CA 92093
I. STATEMENT OF T H E PROBLEM
approximately 65%--that is, from approximately 25% per transfer in women 30 years of age or younger to approximately 9% per transfer in women over the age of 36 (6,7). A similar age-related decrease in female fecundity has been found using therapeutic donor insemination (8) and gamete intrafallopian tube (GIFT) transfer (9). The low fecundity rate continues through approximately 44 years, after which viable pregnancies almost never occur (9-11). These facts, together with the delay in childbearing by women in developed countries, have set the stage for an increase in reproductive problems and disorders attributable to female aging, in particular infertility. A notable consideration is that women between 36 and 44 years of age can exhibit regular menstrual cycles (12). This maintenance of ovarian cyclicity is important because it argues that the decrease in fecundity in these older women is not the result of failure of aged ovaries to produce dominant follicles. Presumably the cyclical activity reflects the ability of these dominant follicles to undergo the physiologic changes that typically occur during selection, ovulation, luteinization, and luteolysis. One of the main fines of evidence in support of this theory is that near normal quantifies of androgen (13), estrogen, and progesterone (14,15) appear to be secreted from aged dominant follicles over the menstrual cycle. These findings indicate that dominant follicles of older women in their late reproductive years are fully capable of expressing near normal
Today, the menopause occurs in most women at about 51 years of age. Demographic studies have demonstrated that the mean life expectancy of women in developed countries (1) has increased from an estimated 45 years in 1850 to 82 years in 1998 (Fig. 4.1). This is an important observation because it indicates that most women today may live up to one-third of their lives postmenopausally; that is, they will live approximately 30 years after the menopause. Clinicians can therefore expect to extend care to increasingly larger numbers of women with advanced reproductive age in whom ovarian dysfunction will be a major cause of infertility and morbidity. If one considers that the vast majority of fertility and gynecologic problems in the aging woman are a direct consequence of the age-related decrease in ovarian reserve (OR), it becomes apparent that the disappearance of primordial follicles is in one of the critical events in the life of all women. One reproductive feature most adversely affected by the age-related decrease in OR is fecundity. The basis for this age-related change is the failure of dominant follicles to release eggs that can undergo normal embryonic development (2-5). This decrease becomes particularly evident in patients older than 36 years of age undergoing in vitro fertilization (IVF), when pregnancy rates (PR) fall sharply, by T R E A T M E N T OF T H E POSTMENOPAUSAL W O M A N
49
Copyright 9 2007 by Elsevier,Inc. All rights of reproduction in any form reserved.
ERICI,:SONANn CHANG
50
FIGURE 4.1 Changesin the life expectancyand age of the menopausein women overthe past 150 years. (Reprintedfrom Nachtigall LE. The aging woman. In: SciarraJJ, ed. Gynecology and obstetrics, vol. 1. Philadelphia:J.B. Lippincott, 1995; 2, with permission.)
patterns of steroidogenic activity. By contrast, studies with oocytes from aged dominant follicles have demonstrated the existence of alterations that contribute negatively to pregnancy. For example, investigators have recently found that aneuploidy increases significantly in embryos that develop from oocytes isolated from the mature follicles of women after 35 years (16). Thus, one is led to the conclusion that (a) the endocrine and gametogenic function of dominant follicles can become dissociated in women after 36 years of age and (b) the aberrant expression of cellular responses in the egg would appear to be the basis for the age-related decrease in fecundity. Understanding how the developmental potential of the aged oocyte is altered independently of changes in granulosa and theca cell function is a fundamental question in ovary research. Although relatively little is known about this problem, an interesting role for OR has been suggested from clinical studies that indicate that basal ovarian follicle number, not oocyte age, is the main determinant predicting pregnancy in older women (17,18). That is, the likelihood of pregnancy is highest in older women with sonographic evidence of six or more ovarian follicles compared with those with less than six follicles. Given this relationship, it is not unreasonable to propose that the selective deteriorative changes that occur in the oocytes of older women are either correlated with or casually connected to a significant decrease in OR, rather than aging itself. A fundamental question is: How does this occur?
units of the ovary. Morphologically, each primordial follicle is composed of an outer single layer of squamous epithelial cells, which are termed granulosa or follicle cells, and a small (approximately 15 Ixm in diameter) immature oocyte arrested in the dictyotene stage of meiosis; both cell types are enveloped by a thin, delicate membrane called the basal lamina or basement membrane (Fig. 4.2). By virtue of the basal lamina, the granulosa and the oocyte exist in a microenvironment in which direct contact with other cells does not occur. Although small capillaries are occasionally observed in proximity to primordial follicles, these follicles do not have an independent blood supply (1). The mean diameter of a nongrowing primordial follicle is 29 lxm (19). All the primordial follicles present in a woman's ovaries are formed before birth. Developmentally, the primordial follicles are formed in the cortical cords of the fetal ovaries between the fifth and ninth months of gestation (1). During this period, all the germ cells are stimulated to initiate meiosis. Because the oocytes in the primordial follicles have entered meiosis, almost all oocytes that are capable of participating in reproduction during a woman's life are formed at birth; that is, the human ovaries acquire a lifetime quota of eggs before birth. Soon after primordial follicle formation, some are recruited (activated) to initiate growth. As successive recruitment proceeds over time, the size of the pool of primordial follicles becomes progressively smaller (Fig. 4.3). Between the times of birth and menarche the number of primordial follicles (and thus oocytes) decreases from several million to severn hundred thousand (see Fig. 4.3). As a woman ages, the number of primordial follicles (OR) continues to decline, until at menopause they are difficult to find.
II. T H E PRIMORDIAL FOLLICLE Before addressing this question, we must understand the basic biology of the primordial follicles. The primordial follicles represent a pool of nongrowing follicles from which all dominant preovulatory follicles are selected (1). Thus, primordial follicles are, in a real sense, the fundamental reproductive
FIGURE 4.2
Electronmicrographof a human primordialfollicleshowing oocyte nucleus (N), Balbiani body (*),and granulosa or follicle cells (arrowbeads). (Reprinted from ref. 1, with permission.)
CHAPTER4 Basic Biology: Ovarian Anatomy and Physiology
51 FOLLICULAR DESTINY
7.0. 2,000,000 Total Primordial Follicles
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FIGURE 4.3 Changes in the total number of oocytes in the human ovaries during aging. In the embryo at early to mid-gestation, the number of oocytes increases to almost 7 million. Shortly thereafter, the number falls sharply to about 2 million at birth. The enormous loss (approximately 70%) of oocytes in the embryo between 6 and 9 months is caused by apoptosis. The store of eggs continues to diminish with age, until no oocytes are detected in the ovaries at about 50 years of age. (Reprinted from Baker TG. Radiosensitivity of mammalian oocytes with particular reference to the human female. AmJ Obstet Gyneco11971;110:746-761, with permission.)
III. THE ADULT OVARY In this section, we deal with the anatomy and physiology of folliculogenesis as it occurs in normal women during the reproductive years. We focus our attention on the manner in which the developmental program is expressed in a recruited primordial follicle as it develops to the ovulatory stage or dies by atresia. An underlying principle of the human ovaries is that of the 2 million primordial follicles, only 400 or so will complete their development and undergo ovulation and corpus luteum formation; all others (99.9%) will die by atresia after recruitment (Fig. 4.4). Therefore, the very essence of folliculogenesis is selection.
A. Anatomy The adult human ovary is a mass of follicles, luteal tissue, blood vessels, nerves, and connective tissue elements, all of which form a relatively heterogeneous assemblance of histologic units. It is the continuous and progressive change in follicles and corpora lutea that give rise to the cyclical
FIGURE4.4 Folliculogenesis is a highly selective process. Of the 2 million primordial follicles at birth, only 4 or so are brought to ovulation and luteinization by FSH and LH. (Reprinted from Soules MR, Bremner WJ. The menopause and climacteric: endocrinologic basis and associated symptomatology. JAm Geriatr Sac 1982;30:547-561, with permission.)
changes in the menstrual cycle. During the reproductive years, the normal human ovaries are oval-shaped bodies that each measure 2.5 to 5.0 cm in length, 1.5 to 3 cm in width, and 0.6 to 1.5 cm in thickness (1). The medial edge of the ovary is attached by the mesovarium to the broad ligament, which extends from the uterus laterally to the wall of the pelvic cavity. The surface of the ovary is covered by an epithelial layer of cuboidal cells resting on a basement membrane. This layer, termed the germinal or serous epithelium, is continuous with the peritoneum. Underlying the serous epithelium is a layer of dense connective tissue termed the tunica albuginea. The ovary is organized into two principal parts: a central zone, the medulla, which is surrounded by a particularly prominent peripheral zone, the cortex (Fig. 4.5). Embedded in the connective tissue of the cortex are the follicles containing the female gametes, oocytes. The number and size of the follicles vary depending on the age and reproductive state of the female. The existence of follicles of different sizes (primordial, primary, secondary, tertiary [Graafian], and atretic) reflects specific changes associated with their growth, development, and fate. At the end of the follicular phase of the menstrual cycle, the Graafian follicle that reaches maturity distends the ovarian surface to form a stigma, which eventually ruptures with release of the ovum (see Fig. 4.5). After ovulation, the wall of the ovulating follicle develops into an endocrine structure, the corpus luteum. If implantation does not occur, the corpus luteum deteriorates and eventually becomes a nodule of dense connective
52
ERICKSON AND C H A N G
always contain a pool of small Graafian follicles from which a prospective dominant follicle can be selected. Once selected, a dominant follicle typically grows and develops to the preovulatory state. Those follicles that are not selected become committed to die by atresia. 1. ENDOCRINOLOGY OF FOLLICULOGENESI8
FIGURE 4.5 Diagram summarizing the anatomy and histology of the human ovary during the reproductive years. The development of the follicles and corpus luteum occurs within the cortex; the spiral arteries, hilus cells, and autonomic nerves are located in the medulla. (Reprinted from ref. 1, with permission.)
tissue termed the corpus albicans. At the medial border of the cortex is a mass of loose connective tissue, the medulla. This tissue contains a network of convoluted blood vessels and associated nerves that pass through the connective tissue toward the cortex (see Fig. 4.5). A distinct group of testosterone-producing cells, the hilus cells, lies in the medulla at the hilum of the ovary (20). The arterial supply to the ovary originates from two principal sources: One, the ovarian artery, arises from the abdominal aorta; the other is derived from the uterine artery (1). These two vessels, which enter the mesovarium from opposite directions, form an anastomotic trunk and become a common vessel called the ramus ovaricus artery. At frequent intervals this artery gives rise to a series of primary branches, which enter the hilum like teeth on a rake. In the hilum, numerous secondary and tertiary branches are given off to supply the medulla (see Fig. 4.5).
B. Physiology Typically, the human ovaries produce a single dominant follicle that releases a mature egg into the oviduct to be fertilized at the end of the follicular phase of the menstrual cycle. Formation of each dominant follicle begins with recruitment of several primordial follicles into a pool of growing follicles destined to participate in a subsequent ovulatory cycle. It is not known exactly how recruitment occurs, but it appears to be controlled by local ovarian regulatory factors by autocrine/paracrine mechanisms. In a broad sense, all growing follicles can be divided into two groups, healthy and atretic, according to whether or not apoptosis (programmed cell death) is present in granulosa cells (21,22). As a consequence of successive recruitments, the ovaries appear to
Regardless of age, follicle growth and development are brought about by the combined action of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on the follicle cells. FSH and LH bind to specific high-affinity receptors on the membranes of the granulosa and theca interstitial cells respectively. The interaction of these ligands with their receptors activates signal transduction pathways that stimulate mitosis and differentiation responses in the granulosa and theca cells (23,24). Physiologically, these signaling pathways act in parallel to regulate the expression of specific genes in a precise quantitative and temporal fashion. There are two major endocrine responses associated with foUiculogenesis. The first is that the actions of FSH and LH stimulate the production of large amounts of estradiol by the dominant follicle. This important gonadotropin-dependent response is called the two-gonadotropin, two-cell concept (Fig. 4.6). Because the estradiol response appears to be specific to a dominant follicle, the levels of plasma estradiol can be used as a marker for the growth and viability of the dominant follicle. The second is the marked increase in the production of inhibin B by FSH (25). With respect to aging, observations support the possibility that localized changes in inhibin B production may play a role in the accelerated loss of OR. We will return to this issue later. 2. CHRONOLOGY
In women, foUiculogenesis is a very long process (23). In each menstrual cycle, the dominant follicle that is selected to ovulate originates from a primordial follicle that was recruited to grow about 1 year earlier. Whatever the course of development or the final destiny (atresia or ovulation), all follicles undergo various progressive changes (Fig. 4.7). The very early stages of foUiculogenesis (class 1, primary and secondary; class 2, early tertiary) proceed very slowly. Consequently, it requires 300 days or more for a recruited primordial follicle to complete the preantral or hormone-independent period. The basis for the slow growth is the very long doubling time (approximately 250 hours) of the granulosa cells. When follicular fluid begins to accumulate at the class 2 stage, the Graafian follicle begins to expand relatively rapidly (see Fig. 4.7). As the antral (hormone-dependent) period proceeds, the Graafian follicle passes through the small (classes 3, 4, 5), medium (classes 6, 7), and large (class 8) stages. A dominant follicle that survives to the ovulatory stage requires about 40 to 50 days to complete the whole antral period. Selection of the
CHAPTER4 Basic Biology: Ovarian Anatomy and Physiology
53
FIGURE 4.7 The chronology offolliculogenesis in the human ovary. Folliculogenesis is divided into two major periods, preantral (gonadotropin independent) and antral (FSH dependent). In the preantral period, a recruited primordial follicle develops to the primary/secondary (class 1) and early tertiary (class 2) stage, at which time cavitation or antrum formation begins. The antral period includes the small Graafian (0.9-5 mm, class 4 and 5), medium Graafian (6-10 mm, class 6), large Graafian (10-15 mm, class 7), and preovulatory (16-20 mm, class 8) follicles. Time required for completion of preantral and antral periods is approximately 300 days and 40 days, respectively. Number of granulosa cells, go, follicle diameter, ram; percentage of atresia indicated. (Reprinted from Gougeon A. Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1986;1:81-87, with permission.) FIGURE 4.6 The two-gonadotropin, two-cell concept of follicle estrogen production. (Reprinted from Erickson GE Normal ovarian function. Clin Obstet Gyneco11978;21:31-52, with permission.)
dominant follicle is one of the last steps in the long process of foUiculogenesis. The dominant follicle, which is selected from a cohort of class 5 follicles, requires approximately 20 days to develop to the stage where it undergoes ovulation. Those follicles that are not selected become atretic. Atresia can occur at each stage of Graafian follicle development, but atresia appears most prominent in follicles at the class 5 stage (see Fig. 4.7). 3. SELECTION
The dominant follicle that will ovulate its egg in the next cycle is selected from a cohort of healthy, small Graafian follicles (4.7 + 0.7 mm in diameter) at the end of the luteal phase of the menstrual cycle (23). Morphologically, each cohort follicle contains a fully grown egg, about 1 million granulosa cells, a theca interna containing several layers of theca interstitial cells, and a band of smooth muscle cells in the theca externa (Fig. 4.8). Selection is a quintessential aspect of ovary physiology. It is characterized by a high sustained rate of granulosa mitosis. Shortly after the mid-luteal phase, the granulosa cells in all the cohort class 4 and 5 follicles show a sharp increase (approximately twofold) in the rate of granulosa mitosis (23).
FIGURE 4.8 Diagrammatic representation of a Graafian follicle. (Reprinted from Erickson GE Primary cultures of ovarian cells in serum-free medium as models of hormone-dependent differentiation. Mol Cell Endocrino11983;29:21-49, with permission from Elsevier.)
The first indication that the prospective dominant follicle has been selected is that the granulosa cells of the chosen follicle continue dividing at a fast rate while proliferation slows in the nondominant cohort follicles. Because this distinguishing event is seen at the late luteal phase, it has been concluded that selection occurs at this point in the cycle. As mitosis and follicular fluid accumulation continue (see Fig. 4.7), the dominant follicle grows rapidly during the follicular phase, reaching 6.9 + 0.5 mm at days 1 to 5, 13.7 + 1.2 mm at days 6 to 10, and 18.8 + 0.5 mm at days 11 to 14. In
54
ERICKSON AND CHANG
nondominant follicles, growth and expansion proceed more slowly, and with time, atresia becomes increasingly more evident (see Fig. 4.7). Rarely does an atretic follicle reach more than 9 mm in diameter, regardless of the stage in the cycle. FSH is obligatory for follicle selection, and no other ligand by itself can serve in this regulatory capacity. Physiologically, the mechanism of selection is causally connected to a small but significant secondary rise in plasma FSH during the early follicular phase of the menstrual cycle (the primary FSH rise being the midcycle preovulatory surge of FSH and LH). The secondary rise in plasma FSH begins a few days before the progesterone and estradiol levels reach baseline values at the end of luteal phase, and it continues through the first week of the follicular phase (Fig. 4.9). The importance of the secondary rise in FSH is demonstrated by the fact that the dominant follicle will undergo atresia if the FSH levels are decreased during this time of the menstrual cycle. Consequently, the secondary rise in FSH is obligatory for the selection of a dominant follicle that will ovulate in the next cycle. One of the major consequences of the secondary FSH rise is
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that a critical threshold level of FSH accumulates in the follicular fluid of the chosen follicle. In normal class 5 to 8 follicles, the mean concentration of follicular fluid FSH increases from approximately 1.3 mlU/mL (approximately 58 ng/mL) to approximately 3.2 mlU/mL (approximately 143 ng/mL) through the follicular phase (26). In contrast, the levels of FSH are low or undetectable in the microenvironment of the nondominant cohort follicles. Thus, the selection and continued growth of a dominant follicle involves a progressive increase in the concentration of FSH within its microenvironment. Once activated, the dominant follicle becomes dependent on FSH for its survival. The regulation of FSH levels in follicular fluid is totally obscure. The FSH triggers a marked activation of mitosis and differentiation of the granulosa cells, which in turn is reflected in a progressive increase in estradiol and inhibin B synthesis and follicular fluid accumulation (see Fig. 4.9). One of the effects of the increased estradiol and inhibin B production is that the secondary rise in FSH is suppressed (see Fig. 4.9). When this occurs, the concentration of FSH falls below threshold levels and the development of the nondominant follicles stops. It is noteworthy that mitosis in these atretic follicles can be markedly stimulated by treatment with gonadotropin during the early follicular phase. Thus, if FSH levels within the microenvironment are increased, the nondominant follicle could perhaps be rescued from atresia.
C. The Role of FSH
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The major FSH-dependent changes that occur during the development of the dominant follicle are summarized in Fig. 4.10. In women, the granulosa cells are the only cell types known to express FSH receptors. It follows, therefore, that FSH-mediated effects in the dominant follicle are at the level of the granulosa cells. In dominant follicles, the FSH-induced differentiation of the granulosa cells involves three major responses, namely increased steroidogenic potential, mitosis, and LH receptors.
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FIGURE 4.9 The endocrinology of the luteal-follicular transition in women. Data are mean + standard error (SE) of daily serum concentrations of FSH, LH, estradiol, progesterone, and immunoreactive inhibin in women with normal cycles. Note the secondary rise in plasma FSH in the late luteal phase (2 days before menses). (Reprinted from ref. 62, with permission from The Endocrine Society.)
1. STEROIDOGENIC POTENTIAL
The FSH ligand interacts with its receptor on the granulosa cells, and the binding event is transduced into an intracelMar signal via the heterodimeric G proteins (see Fig. 4.10). The FSH-bound receptor activates the ~xGstimulatory (cxGs), which activates adenylate cyclase to generate increases in cyclic adenosine 3',5'-monophosphate (c_AMP), which triggers protein kinase A (PICA) to phosphorylate cAMP-responsive element-binding protein (CREB) or other related DNAbinding proteins. After phosphorylation, these proteins bind to upstream DNA regulatory elements called cyclic-AMP response elements (CRE), where they regulate gene transcription. In this regard the FSH signal mechanisms stimulate
CHAPTER4 Basic Biology: Ovarian Anatomy and Physiology
FSH
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the expression of specific genes that control the level of estradial production by the granulosa cells (27). The major steroidogenic genes induced by FSH include the P450 aromatase (P450 arom) a~d 17[3-hydroxysteroid dehydrogenase (17 ~3-HSD) (see Fig. 4.10). The temporal pattern of expression of these genes has an important role in generating the normal pattern of estradiol production by the dominant follicle during the follicular phase of the cycle (see Fig. 4.9). FSH also acts on the granulosa cells to increase its potential for luteinization as reflected by in vitro experiments with cultured granulosa cells from human follicles at different stages of development (28). The mechanisms by which this progesterone potential remains suppressed during folliculogenesis in viva remains unknown, but a putative FSH-dependent luteinizing inhibitor has been proposed (28). Recent studies suggest that bone morphogenetic proteins (BMPs) may be physiologic mediators of endogenous progesterone production (29). Within the rat ovary, BMP messenger RNA (mRNA) is expressed in granulosa cells (BMP-2 and -6), theca cells (BMP3b,-4, and -7), and the oocyte (BMP-6 and -15 and GDF-9). In addition, BMP receptor mRNAs have been demonstrated in these tissues as well (30). In cultured rat granulosa cells, BMPs inhibit FSH-induced increases in progesterone production. As such, BMPs are considered to be luteinizing inhibitors. This concept is supported by in viva data demonstrating that the expression of BMP ligands and receptors is low or absent in the corpus luteum during luteinization. Additionally, with the onset of luteolysis the BMP system reexpresses itself as BMP receptor, ALK-6, mRNA, which was
increased in the corpus luteum (31). These findings raise the possibility that BMP signaling pathways may act as paracrine or autocrine regulators of progesterone production and, at least in part, have a functional role in preventing premature luteinization. 2. MITOSIS
The granulosa cells in the dominant follicle have the ability to divide at a relatively rapid rate throughout the follicular phase of the cycle, increasing from about 1 • 106 cells at selection to more than 50 x 106 cells at ovulation (23,24). Despite its overall importance to ovarian physiology, it remains unclear how granulosa proliferation is controlled. There is evidence in humans that FSH stimulates the rate ofgranulosa cell division in viva and in vitro (see Fig. 4.10), but the mechanism by which FSH stimulates mitosis is not understood. 3. INDUCTION OF LH RECEPTOR
The ability of LH/human chorionic gonadotropin (hCG) to activate the ovulatory cascade in the dominant follicle is dependent upon the expression of a large number of LH receptors on the granulosa cells (1). Studies have clearly demonstrated an obligatory role of FSH in the induction of LH receptor (see Fig. 4.10). A key feature of LH receptor expression in the granulosa layer is that it is suppressed throughout most of folliculogenesis. That is, the number of LH receptors remains low in
56
ERICKSONAND CHANG
interstitial cells (TIC), theca lutein cells (TLC), and hilus cells (HC). The TIC and TLC are related to each other by a developmental sequence occurring during folliculogenesis and luteogenesis, a process called the cogenesis (35). The formation of the TIC and TLC involves a developmental process that encompasses both proliferation and differentiation (32,36). Because the cogenesis is accompanied by mitosis, it contributes to total interstitial mass and therefore total androgen potential. LH promotes androgen synthesis through activation of the LH/hCG receptor/cAMP-dependent protein kinase A (PKA) signal transduction pathway (see Fig. 4.11). The heterotrimeric guanine-nucleotide proteins (G proteins) act as transducers that couple LH/hCG bound receptors to adenylate cyclase, which forms the second messenger, cAME cAMP activates PKA, which in turn phosphorylates specific serine and threonine residues on substrate proteins. The phosphorylated proteins generate cytoplasmic and nuclear responses that can lead to increased steroidogenesis. Androstenedione is the principal steroid produced by TIC, and treatment with LH increases its production in a time- and dose-dependent manner (32). This concept explains in part the regulated production of androstenedione in normal women and its overexpression in women with chronically elevated levels of plasma LH. At the molecular level, activation of the LH signaling cascade leads to the stimulation of gene transcription, most notably P450c22 and P450c17 (37). The fact that the level of transcription and translation of these genes increases during folliculogenesis argues that LH-induced differential gene expression plays a physiologic role in androstenedione production by human TIC over the menstrual cycle.
granulosa cells during the early and intermediate stages of dominant follicle growth, but then increases sharply to very high levels at the preovulatory stage. The acquisition of LH receptors implies that when the LH ligand enters the microenvironment of the dominant follicle in the late follicular phase, it can act on the granulosa cells to regulate their function, perhaps even replacing FSH as the principal regulator of granulosa cytodifferentiation.
D. The Role of L H Two hormones, LH and insulin, regulate steroidogenesis in the theca interstitial tissue, and both function as stimulators of androgen production (32). Each hormone interacts with a transmembrane receptor, and the binding event is transduced into an intracellular signal that stimulates transcription and translation of specific steroidal genes (Fig. 4.11). Throughout the life of a woman, LH acts as a critical positive regulator of ovary androgen biosynthesis (32). The LH-receptor interactions in the interstitial cells are critically important in estradiol production by virtue of their ability to promote the production of androstenedione, the P450AROM substrate (see Fig. 4.6). The activation of the LH-receptor signaling pathway in the ovary interstitial cells results in the expression of a battery of genes leading to increased androgen synthesis (see Fig. 4.11). The role of LH in stimulating androgen production has been intensively studied in women because of its involvement in infertility and hyperandrogenism, such as in polycystic ovarian syndrome (PCOS) (33,34). There are three families of interstitial cells in the human ovaries (see Fig. 4.5), the theca
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en
FIGURE4.11 Diagramofthe LH and insulinsignaltransductionpathways in ovarianinterstitialcellsleadingto increasedandrostenedioneproduction.
57
CHAPTER4 Basic Biology: Ovarian Anatomy and Physiology It has been known for many years that the rate-limiting step in steroidogenesis involves the translocation of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane where it metabolizes to pregnenolone by P450c22. This process is regulated by steroidogenic acute regulatory protein (STAR) (38). An important concept is that StAR is obligatory for LH-induced steroidogenesis. In the human ovary StAR is expressed in the interstitial cells, including the TIC (39). In addition to LH, there is convincing evidence that insulin signaling has a significant role in regulating TIC function in women (32). Insulin receptors with protein tyrosine kinase (PTK) activity have been demonstrated in normal human ovaries. In situ hybridization and immunohistochemical studies have revealed that insulin receptors are expressed in TIC of Graafian follicles (both dominant and cohort) (40). Insulin stimulates androgen production by isolated TIC, and the stimulation is believed to be mediated by the insulin receptor (41). Subsequent co-incubation with an insulin antibody was associated with a markedly subdued androgen response. Thus, activation of the insulin receptor signaling pathway can function alone to increase TIC androgen production, and importantly, the pathway can interact with the LH receptor pathway to further enhance the signals evoked by each receptor (see Fig. 4.11). The cross-talk between the insulin and LH receptor pathways appears to be clinically relevant because of the development of hyperandrogenism in women with insulin resistance and compensatory hyperinsulinemia. The link between insulin resistance and hyperandrogenemia may also involve serine phosphorylation of the insulin receptor as well as that of cytochrome P450c17, which is a microsomal enzyme normally expressed in ovaries and adrenal tissue (42,43). Serine phosphorylation of the insulin receptor occurs at the expense of tyrosine phosphorylation and causes impaired insulin action, thereby accounting for insulin resistance. By comparison, serine phosphorylation ofP450c17 upregulates 17-hydroxylase and 17-20 lyase activity in the ovary, which may explain the enhanced 17-hydroxyprogesterone response to gonadotropin stimulation in women with PCOS compared with normal women (44).
FIGURE 4.12 Comparison of the autocrine-paracrine and endocrine concepts. H, hormone. (Reprinted from Erickson GF. Nongonadotropic regulation of ovarian function: Growth hormone and IGFs. In: Filicori M, Flanigni C, eds, Ovulation induction: basic science and clinical advances, Excerpta Medica International Congress Series. Philadelphia: Elsevier, 1994; 73-84, with permission.)
act in an autocrine/paracrine manner to regulate the timing and degree of hormone-dependent folliculogenesis. This is the autocrine/paracrine or growth factor concept (Fig. 4.12). There are five different classes of growth factors (insulinlike growth factor [IGF], transforming growth factor-f3 [TGF13], TGF-o~, fibroblast growth factor [FGF], and cytokines); all five classes have been described within follicles of human ovaries (45). The principle that arises from all the evidence is that growth factors act by autocrine and paracrine mechanisms to cause plus and minus changes that determine whether a follicle lives or dies. The current challenges are to understand how specific families of growth factors exert control of ovarian functions and how these modulations are integrated into the overall pattern of physiology and pathophysiology during the life of the female.
IV. OVARY RESERVE As discussed earlier, the number of ovarian primordial follicles decreases with age from birth through the menopause (see Fig. 4.3). Importantly, recent studies (46,47) with human ovaries have established the concept that the rate of loss of OR (primordial follicles) is not constant during aging, with a significant accelerated decrease in OR occurring at about 37 years in most women (Fig. 4.13).
E. Intraovarian Control As discussed, the development of the dominant follicle is directed by the endocrine hormones FSH and LH. These ligands bind to receptors that are coupled to the cyclic AMP/PKA signal transduction pathways, which in turn are coupled to differential gene activity in a quantitative and temporal fashion. An important concept to emerge in the past decade is that growth factors, which are themselves products of the ovary, modulate (either amplify or attenuate) FSH and LH action. All growth factors are ligands that can
A. Regulation Morphometric analysis of normal ovaries has demonstrated that the rate of recruitment (initiation of primordial follicle growth) accelerates sharply in women at approximately 38 years of age. Consequently, there is a biexponential decrease in OR in women (46,47). It can be seen (Fig. 4.14) that the number of primordial follicles falls steadily for more than three decades, but when the pool of
ERICKSON AND CHANG
58
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4.13 Major events that occur in a women's life that impact on fertility and fecundity. (Reprinted from Erickson GE Basic biology: ovarian anatomy and physiology.In: Lobo R, KelseyJ, Marcus R, eds., Menopause: biology andpathobiology. San Diego: Academic Press, 2000; 13-31, with permission.)
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primordial follicles reaches a critical number of approximately 25,000 at 37.5 +_ 1.2 years, the rate of loss of primordial follicles accelerates approximately twofold. Consequently, the OR is reduced to 1000 primordial follicles at approximately 51 years of age (46,47), which corresponds to the median age at natural menopause (48). If the earlier rate of decrease in primordial follicles persisted, menopause would not be expected until the female reached 71 years of age. Notably, in this natural process the number of primordial follicles within the ovaries of any given woman who reaches 38 years of age is variable; that is, important individual differences in OR exist. As seen in Fig. 4.14, some women reach the critical threshold of 25,000 primordial follicles in their late twenties, whereas others do not reach this threshold until their forties. It seems, therefore, that age alone has limited predictive value for accurately determining a woman's OR. The significance of this variability is demonstrated by the fact that women who continue to menstruate regularly after the age of 45 have 10 times more primordial follicles than do those with irregular menses (49). Further, a greater number of primordial follicles is functionally coupled with a higher pregnancy rate in older women (6,13,17,18). It can be argued, therefore, that OR determines the number of maturing Graafian follicles, which in turn determines menstrual activity, which in turn determines fecundity. In a real sense, OR may be of greater importance than a woman's chronologic age in predicting fertility. If we accept this argument, then OR, not age, would be the fundamental factor in determining the decrease in fecundity at approximately 38 years. Hence the question: W h a t is the underlying mechanism for the accelerated recruitment at approximately 38 years of age? Although the answer to this question is not known, it is reasonable to assume that regulatory molecules are involved. In this regard, there are two possibilities: the decrease of one or more necessary inhibitors and the increase in one or more stimulators. Despite its physiologic importance, very little is known about the mechanisms of recruitment in any species. Evidence from animal studies indicates that the rate of re-
-
§247247
AGE IN YEARS FIGURE
m§
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o
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Age (years)
FIGURE 4.14. The age-related decrease in the total number of primordial follicles (PF) within both human ovaries from birth to the menopause. As a result of recruitment (initiation of PF growth), the number of PF decreases progressivelyfrom approximately1,000,000 at birth to 25,000 at 37 years. At 37, the rate of recruitment increases sharply and the number of PF declines to 1000 at menopause, at about 51 years. (Reprinted from ref. 46, with permission.)
cruitment of primordial follicles can be influenced by several regulatory factors (Table 4.1). One particularly interesting result with aging rats is that the rise in plasma FSH following unilateral ovariectomy is associated with a significant reduction in the number of primordial follicles within the ovaries; the most striking feature is that the effect was observed only in old rats (50). These studies support the potentially important concept that increased levels of FSH might function to accelerate the rate of recruitment during aging. Hence the question: To what extent is the accelerated loss of OR in aging women a consequence of increased circulating FSH? This is an important question because we know that a significant elevation of plasma F S H is observed in women when the loss of O R is accelerated at approximately 38 years (11,17,18), and the increased plasma F S H corresponds to the time that fecundity drops. Nonetheless, the question of whether the age-related increase in FSH in women is casually connected to the stimulation of recruitment remains unanswered. TABLE 4.1
Known Modulators of Primordial Follicle Number in Laboratory Animals
Regulator FSH Thymus removal Starvation GH/PRL Morphine sulfate Epidermal growth factor
Effect on OR
Reference
Decrease Decrease Increase Increase Increase Increase
42 43 44 45 46 47
59
CHAPTER4 Basic Biology: Ovarian Anatomy and Physiology Experiments in mice show that the rate of recruitment can be modulated by several factors, including the thymus, restricted food intake, prolactin (PRL) and growth hormone (GH), opiates, and epidermal growth factor (EGF) (see Table 4.1). Experiments with neonatal mice indicate that thymectomy leads to a dramatic loss of primordial follicles by apoptosis (51). Because apoptotic primordial follicles are rarely seen in aging women (46,47), it seems unlikely that a thymus factor plays an important role in the accelerated loss of OR at 38 years. In another study, a 50% reduction in food intake was found to increase the number of primordial follicles, suggesting starvation may increase OR (52). This could be potentially important in humans, but the question of whether starvation elicits a similar effect in women needs to be carefixUy examined. Studies using the sterile Snell dwarf mouse indicate that their ovaries contain significantly more primordial follicles than those of the wild type. Precisely how this occurs is uncertain, but it has been theorized that the endocrine state resulting from chronically low GH and/or PRL might be involved (53). Finally, experiments done in mature mice have shown that the administration of either morphine sulfate (54) or EGF (55) leads to a sustained reduction in the rate of primordial follicle recruitment, followed by an increase in OR. These studies, albeit limited, support the concept that the rate of recruitment can be modulated, either increased or decreased, by regulatory elements. Although the clinical significance of these animal data is unknown, they raise the intriguing idea that it may be possible to slow down the rate of recruitment. If true, these data could have important implications for increasing OR, which in turn could have important implications for fecundity in older women.
the mechanisms underlying accelerated recruitment and decreased fecundity in women after 36 years of age. Therefore, to understand the physiologic mechanism underlying the agerelated increase in FSH, one needs to understand the structure of inhibin and age-related changes in inhibin production in women. Inhibin is a member of the TGF-[3 superfamily (56). Inhibin molecules are composed of two heterodimeric proteins, a common cx subunit and one of two distinct [3 subunits termed [3A and [3B (Fig. 4.15). The two subunits (ci and [3A or [3B) are held together by disulfide bonds producing two different inhibins, termed inhibin A and inhibin B, respectively. By contrast, the activins are built of two types of the [3 subunits generating dimeric proteins called activin A ([3A, [3A), AB ([3A, [3B), or B ([3B, [3B). It should be mentioned here that the differential regulation of cx subunit expression might be expected to have profound effects on the levels of inhibin and activin produced by the ovary; that is, a high and low level of o~ subunit expression would be expected to result in relatively high and low levels ofinhibin and activin production, respectively (see Fig. 4.15). It is now clear that a monotropic rise in FSH occurs in women during aging (12). The rise in FSH, which precedes that of LH by almost 10 years, becomes detectable after 36 years of age (14). A detailed examination of the FSH and LH levels in young and old women over the cycle (57) revealed that serum FSH, but not LH, is significantly elevated in older women throughout the menstrual cycle (Fig. 4.16). It is certainly of interest that the increase in plasma FSH coincides with the accelerated loss in OR. Presumably, some alteration has occurred in the negative feedback mechanism of FSH production in aging women, which is reflected in an increase in plasma FSH levels. The most likely explanation for this observation is that aging in women leads to a significant decrease in inhibin production. Direct evidence that the changing FSH profiles in aging women are accompanied by a concomitant decrease in plasma inhibin during the follicular phase of the cycle has been reported (58). The strong evidence that inhibin exerts a negative
B. Endocrine Parameters At the present time, there is considerable interest in the hypothesis that increased plasma FSH levels causal to decreased ovary inhibin A and B production may be involved in Inhibin A
Inhibins
s
Activin A
Activins
Inhibin B
$ s
s s
Activin AB s $
Activin B $ s
FIGURE 4.15 A model of the inhibin and activin molecules.(Reprinted from Erickson GE Basic biology: ovarian anatomy and physiology.In: Lobo R, KelseyJ, Marcus R, eds., Menopause:biology andpathobiology. San Diego: AcademicPress,2000; 13-31, with permission.)
60
ERICKSON AND CHANG 40.
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10 pack-years Adjusted for number of symptoms, occupation, estradiol at late perimenopause
Hot flashes/sweats bothersome or interfered with quality of life Yes vs. no
Nonsmoking, -< 14 cigs/ day, -> 15 cigs/day
Ever hot flashes and severity and frequency Moderate or severe vs. not and daily vs. not
Ages smoked and average amount smoked Current, former, amount currently smoked, and pack-years of smoking
Number of days in past 2 weeks reporting hot flashes, cold sweats, night sweats Summed any vs. none for each of 3 symptoms for possible 0, 1, 2, or 3 symptoms
Current and former smoking in packs per day Passive smoke exposure in total person-hours/ week at home, at work, or in other public/social settings
Frequency of bothersome hot flashes in previous 2 weeks 83% of women in cohort reported bothersome hot flashes Hot flushes or flashes and night sweats 18% at baseline, 50% at 9 years
Current smoking (yes/no)
OR = 1.55, 95% CI 0.95, 2.54 for -> 15 cigs/day in postmenopausal women adjusted for age, education, menopausal status, employment, oophorectomy, alcohol consumption, increased weight, history of cancer OR = 1.9, 95% CI, 1.3, 2.9 for moderate/severe hot flashes; OR = 2.2, 95% CI 1.4, 3.7 for daily hot flashes Adjusted for age, BMI, race, menopausal status, hormone therapy use, herbal supplement use, nulliparity, tubal ligation OR = 1.0, 95% CI 0.8, 1.4 for In (no. cigs + 1); OR = 1.2, 95% CI 1.0, 1.3 for in (no. hours of passive smoke exposure + 1) Adjusted for age, ethnicity, in BMI, menopause status, In alcohol intake, education, in fat intake, In dietary fiber intake, genistein intake, In calories, history of premenstrual symptoms, use of over-the-counter pain medication, physical activity, comorbidities, stress Adjusted OR = 1.65, p = 0.005 for current smoking Adjusted for age, menopausal status, in estradiol, In FSH, exercising every day
Current, former, never
Adjusted OR = 2.8 (95% CI 1.5, 5.3) for current smokers Adjusted for age, logBMI, IogFSH, testosterone, logestradiol, smoking, menopausal status, use of oral contraceptives, use of hormone therapy, marital status, parity continued
86
GOLD AND GREENDALE
TABLE 6.1 Publication year and first author (citation) 2006 Gold (30)
Observational Studies of Smoking (Active and Passive) and Vasomotor Symptoms - - cont'd
Sampleand design characteristics
VMS: how measured and frequency
Longitudinal Age 42-52 years and pre- or early perimenopausal at baseline Community-based sample of 2784: 930 African American; 1543 Caucasian; 284 Hispanic; 250 Chinese; 281 Japanese
Number of days in past 2 weeks reporting hot flashes, cold sweats, night sweats Any vs. no VMS Any VMS - 6 days in past 2 weeks vs. no or any VMS < 6 days 23-43% any VMS among premenopausal to 58-82% any VMS in late perimenopause
higher circulating estrogen levels in heavier postmenopausal women due to peripheral production of estrone in adipose tissue. However, most recent studies have not confirmed this in perimenopausal women (Table 6.2). One study showed no relation of body mass index (BMI) to reporting of hot flashes in nonsmokers (86). Another study reported that women with more lower body fat reported more hot flashes (192). However, several studies have recently reported significantly higher BMI in women reporting hot flashes, pins and needles, backaches, aches/stiffness in joints, shortness of breath, and fluid retention (21,26,29,30,186,193-195). Additionally, two populationbased studies have reported no significant increase in weight at the menopause (196,197), and one large study reported no increase in waist-to-hip ratio with menopause (150), although a larger, more recent study has shown increased body mass index with the menopausal transition (198). 3. PHYSICALACTIVITY
Serum concentrations of estradiol, progesterone, prolactin, LH and FSH all tend to increase during and after intense exercise (153-155), whereas resting values tend to be lower in athletes (154,156). The findings from various studies regarding the effect of physical activity on reporting of symptoms, particularly vasomotor symptoms, have been inconsistent (Table 6.3), perhaps due to differences in techniques in assessing physical activity and in sample sizes. Midlife women who participate in an exercise program have been reported in some studies to experience less frequent and less severe vasomotor symptoms, despite the fact that lower estrogen concentrations are associated with higher levels of physical activity (199,200). However, this has not been consistent in other cross-sectional, case-control, or longitudinal cohort studies and in some intervention studies, some of which have found no association of
Smoking: how measured
Results
Current and former smoking in packs per day Passive smoke exposure in total person-hours/ week at home, at work, or in other public/social settings
Adjusted OR = 1.63 (95% CI 1.25, 2.12) for current smoking in overall cohort; ORs ranged from 1.14 to 3.09 by race/ethnicity Adjusted for menopausal stares, age, body mass index, education, history of premenstrual symptoms, site, symptom sensitivity, baseline anxiety, baseline depressive symptoms
physical activity with symptoms (85,201-207); others have found a protective effect (29,185,208). Because the onset of hot flashes is accompanied by lower circulating levels of plasma [3-endorphins (209) and physical actMty increases secretion of endogenous opioid peptides, particularly ~-endorphins (210), exercise may prevent symptoms. Exercise also appears to have antidepressant effects (211,212) and thus may also be associated with increased well-being and with fewer midlife psychologic symptoms, including negative mood and change in sexual desire (85). 4. DIET
A number of dietary factors are considered to play a role in production, metabolism, and excretion of estrogen; in phases of the menstrual cycle; and in severity of menopausal symptoms. Vegetarian women have been shown to have lower plasma estrone and estradiol concentrations, perhaps due to lower saturated fat intake (213). Further, Asian women, who consume less fat, excrete two to four times as much estrogen and have substantially lower plasma estrone and estradiol concentrations than Caucasian women (122,125). The relation of fat, alcohol, protein, or other nutrient (such as antioxidant) intake to risk of experiencing menopausal symptoms has not been well studied. Nonetheless, some reports have indicated that alcohol may be estrogenic and may contain phytoestrogens (214) and that alcohol intake is inversely associated with levels of SHBG (149,215,216). However, at least one case-control (86) and one longitudinal study (30) found no association of alcohol consumption with vasomotor symptom reporting, although amounts consumed were relatively low (Table 6.4). One cross-sectional study (194) did report a significant positive association of hot flashes with number of alcoholic drinks consumed per week.
87
CHAPTER 6 Epidemiology of Menopause TABLE 6.2
Observational Studies of Body Mass Index and Vasomotor Symptoms BMI: how measured and BMI of study participants
Publication year and first author (citation)
Sample and design characteristics
VMS: how measured and frequency
1994 Schwingl (86)
Control group from population-based study of reproductive cancers 344 postmenopausal women Mean age 58 years,--- 9 years postmenopausal Subsample from population-based breast cancer screening project in Netherlands N = 3273 age 40-44 years N = 601 age 54-69 years
Recalled HF when menses stopped Outcome: any vs. no VMS
Not specified
Thin (BMI < 24) smokers, higher odds of VMS OR = 1.9 (p = 0.03)
Self-reported Yes/no, preceding year Prevalence VMS: 18% of younger group 32% of older group Self-reported Any vs. none, time frame not specified
Measured height and weight BMI groups: < 22 (low) 22-25 (medium) > 25 (high)
Medium vs. low OR 1.3 (1 - 1.7) High vs. low OR 1.7 (1.3-2.2) Adjusted for age, menopause status, and waist/hip ratio Prevalence VMS: Low: 50% Medium: 70% High: 74% Unadjusted OR = 1.09 per BMI unit Adjusted for age, professional status, FSH, estradiol
1996 den Tonkelaar (193)
1997 Chiechi (195)
Convenience sample from outpatient menopause clinic N = 181 (age not reported)
1998 Wilbur (21)
24-cell randomly selected quota sample (professional status, race, age) Postmenopausal
Self-reported Any vs. none, past 2 weeks
2001 Freeman (194)
Community-based sample 218 Caucasian; 218 African-American women with cycles 22- 35 days Mean age 41 years Community-based sample 750 African American; 1148 Caucasian; 218 Chinese; 239 Hispanic; 198 Japanese; 2823 total Pre- and early perimenopausal mean age 46 years
Structured interview HF past month Frequency Outcome: any vs. no VMS Prevalence VMS: 27% Self-report questionnaire Hot flashes, cold sweats in past 2 weeks Any vs. none of each, summed (range
2004 Gold (26)
Measured height and weight BMI groups: < 24 (low) 24-27 (medium) > 27 (high) Measured height and weight Mean BMI = 28 Mean BMI by VMS: VMS present = 34 V-MS absent = 21 Measured height and weight Analyses per unit BMI
Measured height and weight Overall sample Median BMI = 28.5
0-3)
V-MS,vasomotor symptoms; BMI, body mass index (kg/squared meters); OR, odds ratio; CI, confidence interval. aNote that because controlled covariates differ among all studies, adjusted point estimates are not directly comparable.
Results a
OR = 1.04 per BMI unit Adjusted for menopause symptoms, FSH, anxiety, cycle day
OR = 1.2 (p < 0.05) log BMI 75th percentile compared to 25th percentile Adjusted for ethnicity, menopause stage, education, smoking (active and passive), alcohol, comorbidity, perceived stress, physical activity continued
GOLD AND GREENDALE
88
TABLE 6.2
Observational Studies of Body Mass Index and Vasomotor Symptoms - - cont'd
Publication year and first author (citation)
Sample and design characteristics
VMS: how measured and frequency
BMI: how measured and BMI of study participants
2005 Ford (186)
Longitudinal Ages 24-44 years at baseline 660 communitybased Caucasian women
Hot flushes or flashes and night sweats 18% at baseline, 50% at 9 years
Measured height and weight Mean 26.8 (+_ 6.1) at baseline
2006 Gold (30)
Longitudinal Ages 42-52 years and preor early perimenopausal at baseline Community-based sample of 2784:930 African American; 1543 Caucasian; 284 Hispanic; 250 Chinese; 281 Japanese
Number of days in past 2 weeks reporting hot flashes, cold sweats, night sweats Any vs. no VMS Any VMS -> 6 days in past 2 weeks vs. no or any VMS < 6 days 23-43% any VMS among premenopausal to 58-82% any VMS in late perimenopause
Measured height and weight Overall sample median BMI = 28.5 at baseline
Plant sterols have also been under study in recent research with regard to their effects on circulating hormones, menstrual cycles, and menopausal symptoms. Pbytoestrogen is a term that includes classes of compounds that are nonsteroidal and either of plant origin or derived from metabolism of precursors in plants eaten by humans (217). The main classes of compounds are isoflavones and lignans. They structurally resemble estradiol and have been shown to have weak estrogenic actMty, to compete with estradiol for binding to estrogen receptors in tissues (218,219), and when ingested to have estrogenic and antiestrogenic effects, depending on the concentrations of circulating endogenous estrogens and estrogen receptors (220,221). In rats, the most potent of these, coumestrol, suppressed estrous cycles but did not behave as a typical antiestrogen (222). Soy products are rich in phytoestrogens, which have been detected in high concentrations in the plasma or urine of indMduals who consumed soy or other phytoestrogens (223). Other less concentrated dietary sources of phytoestrogens include rice, corn, alcohol, cereal bran, whole wheat, and beans (224). In Japanese women, phytoestrogen excretion is 100 times higher and endogenous estrogen excretion is 100 to 1000 times higher than in American and Finnish women (225). Differences in phytoestrogen intake may be a (partial)
Results Adjusted OR per unit logBMI = 6.5 (95% CI 1.9, 21.6) Adjusted for age, logFSH, testosterone, logEstradiol, smoking, menopausal status, use of oral contraceptives, use of hormone therapy, marital status, parity Adjusted OR = 1.03 (95% CI 1.01, 1.04) per unit increase in BMI in overall cohort; adjusted ORs ranged from 1.02 to 1.05 by race/ethnicity Adjusted for menopausal status, age, smoking, education, history of premenstrual symptoms, site, symptom sensitivity, baseline anxiety, baseline depressive symptoms
explanation for the differences in frequencies of menopausal symptoms observed in Asian and Caucasian women, although this is not currently known and has not been confirmed in one cross-sectional (26) and one longitudinal (30) study. Urinary excretion of phytoestrogens and the concentration of plasma SHBG have been positively associated with dietary intake of fiber, which has been inversely related to plasma percentage of free estradiol (226). In postmenopausal women whose diets were supplemented with soy or wheat flour (which contain less potent enterolactones), statistically signific a n t - 4 0 % and 25%, respectivelymreductions in hot flashes were observed, while vaginal cell maturation was unchanged and FSH decreased (227). In addition, in a small randomized trial of a 12-week phytoestrogen-rich diet, postmenopausal women on the diet showed significantly increased SHBG, significant reduction in hot flashes and vaginal dryness, and significant increases in serum concentrations of phytoestrogens, though no significant change in estradiol (217). Other observational and intervention studies, examining different types of phytoestrogens and different dosages, have found a protective effect on vasomotor symptoms (228-233), but other studies have found no protective effect (234-238). In summary, environmental factors do influence the menopausal transition. Active smoking has been consistently
89
CHAPTER 6 Epidemiology of Menopause
TABLE 6.3
Observational and Interventional Studies of Physical Activity and Vasomotor Symptoms
Publication year and first author (citation)
Sample and design characteristics
VMS: how measured and frequency
1998 Ivarsson (208)
Population-based cohort Cross-sectional analyses 739 postmenopausal No oophorectomy 35% were HT users
1990 Wilbur (204)
Volunteer sample of 386 women from a bone health study Cross-sectional Pre-, peri-, and postmenopausal No HT No oophorectomy Subsample of 214 women from a community-based survey Cross-sectional Perimenopausal No HT use No oophorectomy 90% Caucasian Randomly selected peri- and postmenopausal women from large HMO case control (N = 171) No HT use No oophorectomy All Caucasian
Light discomfort from flashes, moderate hot flashes, severe hot flashes 33.7% light, 37.5% moderate, 13.5% severe Self-reported over "past few months" Prevalence of VMS 30% on overall sample
1999 Li (205)
1999 Sternfeld (201)
PA: how ascertained
Results
Intensity-based sport and recreational PA Strenuous compared to sedentary
RR = 0.26 (0.10, 0.71) Only unadjusted analyses reported
Usual PA in multiple domains during prior year Ergometer measured fitness
No association between self-reported PA or measured fitness and VMS
Self-reported VMS in past year Prevalence of VMS low; mean score of 0.8 corresponds to rare on scale
Usual current and long-term PA, recreational
No association between current or prior PA and VMS
Self-reported VMS Cases had at least 1 VMS/day in 3 months following FMP Controls had VMS less than 1x/week in 3 mos after FMP
Self-reported habitual PA in multiple domains, in prior year
Usual current and long-term PA, three domains Vigorous exercise for greater than 3 hours/week Exercise every day
No association between vigorous recreational PA and VMS: OR = 1.03 (0.97, 1.1) for 50-unit increment in PA No association between PA in any domain and VMS No independent effect of PA on VMS PA + HT was not related to lower VMS than HT alone Adjusted OR = 0.94, ? = 0.01 Adjusted for age, menopausal status, In estradiol, In FSH, current smoking
2003 Li (189)
Substudy of 239 women from community survey Cross-sectional All postmenopausal HT permitted
Self-reported VMS in past year
2005 Guthrie (185)
Longitudinal Age 45-55 years at baseline 350 community-based women
Frequency of bothersome hot flashes in previous 2 weeks 83% of women in cohort reported bothersome hot flashes
HT, hormone therapy; VMS, vasomotor symptoms; PA, physical activity; RR, relative risk; OR, odds ratio.
associated with a 1- to 2-year earlier menopause (26,63,66,69, 70, 76,132-136), in a dose response relationship, although the role of passive smoke exposure, shown in one study to be associated with vasomotor symptoms (26), is uncertain. Findings regarding the relations of body weight and body composition to age at menopause have been inconsistent. However, a number of recent studies have found a significant positive association of body mass index to vasomotor symptom reporting, contrary to the expectation based on early
observations in menopausal women of reduced symptom reporting due to increased estrone levels in heavier women as a result of conversion from androstenedione in peripheral fat. The relations of diet, physical activity, and occupational or other environmental factors to age at menopause largely have not been investigated. Active smoking has been associated in numerous studies with increased symptom reporting during the menopause transition (29,30,44,84,85,87,181,183,187189). The findings regarding a relation of physical activity to
G O L D AND GREENDALE
90
TABLE 6.4 Publication year and first author (Citation)
Observational Studies of Alcohol Use and Vasomotor Symptoms
Sample and design characteristics
VMS: how measured and frequency
Alcohol: how ascertained
Results
Control group from populationbased study of reproductive cancers 344 postmenopausal women Mean age 58 years -~ 9 years postmenopausal Community-based sample 218 Caucasian; 218 AfricanAmerican women with cycles 22-35 days Mean age 41 years
Recalled HF when menses stopped Outcome: any vs. no HF
Ever (any) vs. never use
OR = 1.3 (/5 = 0.13) Adjusted for age, BMI, smoking
Structured interview HF past month Outcome: any vs. no HF Prevalence of HF: 27%
Number of drinks per
OR = ~.~ (p =
2004 Gold (26)
Community-based sample 750 African-American; 1148 Caucasian; 218 Chinese; 239 Hispanic; 198 Japanese; 2823 total Pre- and early perimenopausal Mean age 46 years
Self-report questionnaire Hot flashes, cold sweats in past 2 weeks Any vs. none of each, summed (range 0 - 3)
Food frequency questionnaire % of calories from alcohol (converted to grams) Median intake 6 grams of alcohol
2006 Gold (30)
Longitudinal Age 42-52 years and pre- or early perimenopausal at baseline Community-based sample of 2784:930 African American; 1543 Caucasian; 284 Hispanic; 250 Chinese; 281 Japanese
Number of days in past 2 weeks reporting hot flashes, cold sweats, night sweats Any vs. no VMS Any VMS >- 6 days in past 2 weeks vs. no or any VMS < 6 days 23-43% any VMS among premenopausal to 58-82% any VMS in late perimenopause
Food frequency questionnaire % of calories from alcohol (converted to grams) Median intake 6 grams of alcohol
1994 Schwingl
(86)
2001 Freeman (194)
week
Average drinks per week: HF group = 3; no HF group = 1.5
0.0002) adjusted for age, race, other symptoms, FSH, anxiety, BMI cycle day No effect of alcohol (median of nonzero alcohol use vs. no alcohol use) Adjusted for age, BMI, smoking, comorbidity, menopause stage No effect of alcohol Adjusted for menopausal status, age, education, smoking, body mass index, history of premenstrual symptoms, site, symptom sensitivity, baseline anxiety, baseline depressive symptoms
VMS, vasomotorsymptoms;HF, hot flushes; OR, odds ratio; BMI, body mass index. symptom reporting have been inconsistent, but the best designed studies suggest no effect. Phytoestrogen intake has been related to reduced frequency or severity of hot flashes in some studies (217,227-233), but this result has not been consistent (26,30,234-238), quite possibly due to the different types and dosages of phytoestrogens that have been examined. The role of alcohol consumption in relation to vasomotor symptoms has been inconsistent across the few studies that have examined it, and the role of other dietary factors is only beginning to be explored.
V.
CONCLUSIONS
Despite important methodologic differences and the limitations in the study designs used and the populations studied in the accumulating literature on the menopausal experience, an interesting and complex picture is emerging. A number of
demographic (e.g., education, employment, race/ethnicity), menstrual and reproductive, and lifestyle (e.g., smoking and diet) factors appear to be important determinants of the age at which natural menopause occurs and to have meaningful relationships to the varied symptom experiences of women. African American and Latina race/ethnicity, smoking, lower parity, vegetarian diet and undernutrition, and lower socioeconomic status have been found fairly consistently to be associated with earlier menopause, an indicator of reduced longevity. Symptom reporting varies by race/ethnicity, with less reporting of vasomotor symptoms in most Asian populations and increased reporting of vasomotor symptoms and vaginal dryness in African-American and Hispanic women. History of premenstrual tension or symptoms, smoking, and lower socioeconomic status have been associated with increased symptom reporting. However, a number of the relationships are inconsistent (e.g., the role of body mass and composition, diet, and physical
91
C~taVTER 6 Epidemiology of Menopause activity), possibly due to varying methodologic approaches and limitations, and others remain largely unexplored (e.g., passive smoke exposure and occupational and other environmental exposures). Therefore, much remains to be learned about how these factors affect hormones at the physiologic level and thus determine the onset of the perimenopause, the timing of the final menstrual period, and the occurrence of the constellation of symptoms that are associated with the menopause transition. Furthermore, increased understanding of the underlying physiologic bases of these influences needs to include potential racial/ethnic differences in physiologic responses to lifestyle factors and other environmental exposures, as well as increased understanding of the cultural contexts, cultural differences, and cultural sensitivities that affect the presentation and experience of the menopausal transition. Increasing knowledge about these relationships ultimately offers w o m e n and their health care providers enhanced choices and alternatives, based on deeper understanding, to deal with the individual presentations of menopause.
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CHAPTER 6 Epidemiology of Menopause 187. Whiteman MK, Staropoli C, Langenberg P, et al. Smoking, body mass, and hot flashes in mid-fife women. Obstet Gyneco12003;101:264. 188. Staropoli CA, Flaws JA, Bush TL, Mouton AW. Predictors of menopausal hot flashes. J WomensHealth 1998;7:1149-1155. 189. Li C, Samsioe G, Borgfeldt J, et al. Menopause-related symptoms: what are the background factors? A prospective population-based cohort study of Swedish women (the Women's Health in Lund area study). Am J Obstet Gyneco12003;189:1646-1653. 190. Campagnoli C, Morra G, Belforte P, et al. Climacteric symptoms according to body weight in women of different socio-economic groups. Maturitas 1981;3:279-287. 191. Erlik Y, Meldstrum DR, Judd HL. Estrogen levels ofpostmenopausal women with hot flushes. Obstet Gyneco11981;59:403-407. 192. Morton K, Moore M. Predictors of hot flash severity. Ann NYAcad &i 1976;592:457-458. 193. den Tonkelaar I, Seidell JC, van Noord PAH. Obesity and fat distribution in relation to hot flashes in Dutch women from the DOMproject. Maturitas 1996;23:301 - 305. 194. Freeman EW, Sammel MD, Grisos JA, et al. Hot flashes in the late reproductive years: risk factors for Africa American and Caucasian women. J WomensHealth Gend Based Med 2001;10:67- 76. 195. Chiechi LM, Ferreri R, Granieri M, et al. Climacteric syndrome and body-weight. Clin Exp Obstet Gyneco11997;24:163-166. 196. Hjortland M, McNamara P, Kannel WB. Some atherogenic concomitants of menopause: the Framingham study. Am J Epidemiol 1976;103:304-311. 197. Wing R, Matthews K, Kuller LH, et al. Weight gain at the time of menopause. Ann Intern Med 1991;151:97-102. 198. Matthews KA, Abrams B, Crawford S, et al. Body mass index in midlife women: relative influence of menopause, hormone use, and ethnicity. IntJ Obes Relat Metab Disord 2001;25:863-873. 199. Wallace JP, Lovell S, Talano C, et al. Changes in menstrual function, climacteric syndrome, and serum concentrations of sex hormones in pre- and post-menopausal women following a moderate intensity conditioning program. Med Sci Sports Exer 1982;14:154. 200. Hammar M, Berg G, Lindgren R. Does physical exercise influence the frequency of postmenopausal hot flushes? Acta Obstet Gynecol &and 1990;69:409-412. 201. Sternfeld B, Quesenberry Jr CP, Husson G. Habitual physical activity and menopausal symptoms: a case-control study. J Womens Health 1999;8:115-123. 202. Slaven L, Lee C. Mood and symptom reporting among middle-aged women: the relationship between menopausal status, hormone replacement therapy, and exercise participation. Health Psycho11997;16: 203-208. 203. Guthrie JR, Smith AMA, Dennerstein L, Morse C. Physical activity and the menopause experience: a cross-sectional study. Maturitas 1995;20:71-80. 204. Wilbur J, Dan A, Hedricks C, Holm K. The relationship among menopausal status, menopausal symptoms, and physical activity in midlife women. Faro Community Health 1990;13:67-78. 205. Li S, Holm K, Gulanick M, et al. The relationship between physical activity and perimenopause. Health Care Women Int 1999;20: 163-178. 206. Li S, Holm K. Physical activity alone and in combination with hormone replacement therapy on vasomotor symptoms in postmenopausal women. WestJNurs Res 2003;25:274-288. 207. Aiello EJ, Yswi Y, Tworoger SS, et al. Effect of a year-long moderate intensity exercise intervention on the occurrence and severity of menopause symptom in postmenopausal women. Menopause 2004;11: 382-388. 208. Ivarsson T, Spetz A-C, Hammar M. Physical exercise and vasomotor symptoms in postmenopausal women. Maturitas 1998;29:139-146. 209. Tepper R, Neri A, Kaufman H, Schoenfeld A, Ovadia J. Menopausal hot flushes and plasma beta-endorphins. Obstet Gynecol 1987;70: 150-152.
95 210. Harber VJ, Sutton JR. Endorphins and exercise. Sports Med 1984;1: 154-171. 211. Wilbur J, Holm K, Dan A. The relationship of energy expenditure to physical and psychologic symptoms in women at midlife. Nurs Outlook 1992;40:269-276. 212. Dunn AL, Dishman RK. Exercise and the neurobiology of depression. Exer Sports Sci Rev 1991;19:41-98. 213. Armstrong BK, Brown JB, Clarke HT, et al. Diet and reproductive hormones: a study of vegetarian and nonvegetarian post-menopausal women. JNatl CancerInst 1981;67:761-767. 214. Gavaler JS, Rosenblum ER, Deal SR, Bowie BT. The phytoestrogen congeners of alcoholic beverages: current status. Proc Soc Exp BiolMed 1985;208:98-102. 215. Katsouyanni K, Boyle P, Trichopoulos D. Diet and urine estrogens among postmenopausal women. Oncology 1991;48:490-494. 216. Reichman ME, Judd JT, Longcope C, et al. Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women.JNatl CancerInst 1993;85:722-727. 217. Brzezinski A, Adlercreutz H, Shaoul R, et al. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause 1997;4:89-94. 218. Shutt DA, Cox ILl. Steroid and phyto-estrogen binding to sheep uterine receptors in vitro. J Endocrino11972;52:299 - 310. 219. Martin PM, Horwitz KB, Ryan DS, McGuire WL. Phytoestrogen interaction with estrogen receptors in human breast cancer ceils. Endocrinology 1978;103:1860-1867. 220. Cassidy A, Bingham S, Carlson J, Setcheil KDR. Biological effects of plant estrogens in premenopausal women. FASEBJ 1993;A866. 221. Cassidy A, Bingham S, Setchell KDR. Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994;60:33 - 40. 222. Whitten PL, Lewis C, Russell E, Naftolin E Potential adverse effects of phytoestrogens. J Nutr 1995;125:771S- 776S. 223. Axelson M, Kirk DN, Farrant RD, et al. The identification of the weak estrogen equol in human urine. BiochemJ 1982;210:353-357. 224. Coward L, Barnes NC, Setchell KDR, Barnes S. The isoflavones genistein and diadzein in soybean foods from American and Asian diets. JAgric Food Chem 1993;41:1961-1967. 225. Adlercreutz H, Fotsis T, Bannwart C, et al. Determination of urinary lignans and phytoestrogen metabolites, potential anti-estrogens and anticarcinogens, in urine of women on various habitual diets.J Steroid Biochem 1986;25:791-797. 226. Adlercreutz H, Hockerstedt K, Bannwart C. Effect of dietary components, including lignans and phytoestrogens, on enterohepatic circulation and liver metabolism of estrogens and on sex hormone binding globulin (SHBG). J Steroid Biochem 1987;27:1135-1144. 227. Murkies AL, Lombard C, Strauss BJ, et al. Dietary flour supplementation decreases post-menopausal hot flushes: effect of soy and wheat. Maturitas 1995;21:189-195. 228. Albertazzi P, Pansini F, Bonaccorsi G, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gyneco11998;91:6-11. 229. Harding C, Morton M, Gould V, et al. Dietary soy supplementation is estrogenic in menopausal women. Am J Clin Nutr 1998;68:1532S. 230. Washburn S, Burke GL, Morgan T, Anthony M. Effect of soy protein supplementation on serum lipoproteins, blood pressure and menopausal symptoms in perimenopausal women. Menopause 1999;6: 7-13. 231. Scambia G, Mango D, Signorile PG, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause 2000;7:105-111. 232. Upmalis DH, Lobo R, Bradley L, et al. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized placebo controlled study. Menopause 2000;7:236-242.
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236. Woods MN, Swine R, Kronenberg G. Effects of a dietary soy bar on menopausal symptoms. Am J Clin Nutr 1999;68(suppl):1533S. 237. Burke GL, Legault C, Anthony M, et al. Soy protein and isoflavone effects on vasomotor symptoms in peri- and post-menopausal women: the Soy Estrogen Alternative Study. Menopause2003;10:147-153. 238. Verhoeven MO, van der Mooren MJ, van de Weijer PHM, et al. Effect of a combination of isoflavones and Actaea racemosa Linnaeus on climacteric symptoms in healthy symptomatic perimenopausal women: a 12-week randomized, placebo-controlled, double-blind study. Menopause2005;12:412-426.
SECTION 11
Ovarian Senescence and Options In the rodent, there is good evidence that the brain (hypothalamus) contributes to the decline in reproductive function. In the human, however, the process is almost entirely that of ovarian failure, with loss of oocytes through atresia until the point of depletion around the time of menopause. This was reviewed in the previous section by Erickson and Chang. The clinical issues that result from ovarian failure in younger women are the focus of this section. Ovarian failure, which occurs in women prior to age 40, is termed premature ovarian failure. Robert W. Rebar discusses this entity in terms of diagnosis, etiology, and treatment. In terms of treatment, providing hormonal support for these young women can really be seen as "replacement therapy," which is a term we no longer use for hormonal therapy after the menopause. Substantial bone loss and increased cardiovascular morbidity has been documented in women with premature ovarian failure who have not received any hormonal "replacement." How these women may be able to conceive is also discussed here and is the subject of Chapter 8 by Mark V. Sauer and Prati Vardhana. Fertility problems due to an "egg factor" are among the most difficult to treat. This often includes chronologically young women, often in their 30s, who have poor ovarian reserve and cannot produce adequate, healthy, and mature oocytes even with maximal gonadotropic stimulation and in vitro fertilization. Many of these women consider egg donation. With the ovarian aging process and accelerated atresia come problems with the egg cytoplasm, including waning mitochondrial function. Although some enthusiasm has been garnered with using donor cytoplasm (cytoplasmic transfer) or nuclei transfer (transfer of the nucleus from an "older" egg into a donor enucleated egg), these techniques are not available and may not be advisable. Also, although in the rodent there is evidence that ovarian stem cells exist that could potentially lead to regeneration of the oocyte pool, this probably does not occur in the human. Thus, egg donation remains the most practical alternative for chronologically young women, many prior to the age of natural menopause, who wish to bear their own biological children. Remarkably, the success of this process (egg donation), as reviewed by Mark Sauer, is the most successful of all our treatments for fertility, with pregnancy rates in the range of 50% to 60% per initiated cycle.
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tAPTEf
Premature Ovarian Failure ROBERT W. REBAR
American Society for Reproductive Medicine, Birmingham, AL 35216
I. I N T R O D U C T I O N
is true even if 4 or more months of amenorrhea and menopausal symptoms are added to criteria for establishing the diagnosis (3,4). Thus, the term premature ovarian failure is medically inaccurate and misleading to patients and their caregivers as well.
Premature ovarian failure (POF) remains an enigmatic condition. It is even known by several different names. Although most commonly called premature ovarianfailure, it is sometimes referred to as premature menopause, hypergonado-
tropic hypogonadism, hypergonadotropic amenorrhea, primary ovarianfailure, andprimary ovarian insufficiency.We shall use the term premature ovarianfailure throughout this chapter.
II. CLINICAL FEATURES OF PREMATURE OVARIAN FAILURE
P O F generally describes a syndrome consisting of (a) primary or secondary amenorrhea; (b) hypoestrogenism; (c) hypergonadotropinism (with circulating levels of folliclestimulating hormone [FSH] typically greater than 30 mlU/ mL and consistent with ovarian failure); and (d) age under 40 years at the time of onset. Menopause is generally defined as the permanent cessation of menses and normally occurs at about the age of 51 years (1); thus, by definition P O F is distinct from normal menopause. Moreover, at one time it was believed that circulating levels of FSH in the menopausal range provided prima facie evidence for ovarian follicle depletion and thus permanent cessation of ovarian function (2); however, it is now clear that such is not the case (3). Individuals with P O F may ovulate and even conceive spontaneously years after the diagnosis is established (4). More problematic is the fact that definitive criteria for diagnosis have not even been established. However, an operational definition in common use states that affected women should have an interval of at least 4 months of amenorrhea in association with menopausal levels of serum FSH on at least two occasions (4-6). The fallacy of using elevated FSH levels alone to establish a diagnosis of irreversible ovarian failure has already been noted, and the same
To define the clinical spectrum of women with POF, we compiled data from 115 sequential affected women seen between 1978 and 1988 (4). These data have been confirmed by the more than 300 additional women we have seen with this disorder since that report (unpublished). A number of interesting differences and similarities between those with primary and those with secondary amenorrhea were noted in the published series (Table 7.1). In more than 75% of the patients, symptoms of estrogen deficiency, most commonly estrogen deficiency or dyspareunia due to vaginal dryness, were evident, but these symptoms were far more common in women with secondary amenorrhea. Failure to develop mature secondary sex characteristics and chromosomal abnormalities were far more common in those with primary amenorrhea. Chromosomal abnormalities were present in more than half the women with primary amenorrhea, who tended to have deletions of all or part of one X chromosome, whereas those with secondary amenorrhea more commonly had an additional X chromosome. In contrast, chromosomal abnormalities were present in only about 13% of those with secondary amenorrhea who were tested.
TREATMENT OF THE POSTMENOPAUSAL W O M A N
99
Copyright 9 2007 by Elsevier,Inc. All rights of reproductionin any form reserved.
ROBERT W. REBAR
100 TABLE 7.1
Features of Women with Primary and Secondary Amenorrhea
Description
Primary amenorrheaa
Symptoms of estrogen deficiency Incomplete sexual development Karyotypic abnormalities Immune abnormalities Decreased spinal bone densityb Progestin-induced withdrawal bleeding Pregnancies before diagnosis Evidence of ovulation after diagnosis Pregnancies after diagnosis
20 90 55 20 50 20 0 0 0
Secondary amenorrheaa 85 8 13 20 60 50 35 25 8
aApproximatepercentagesbased on data from Rebar and Connolly(4). UComparedwith age-matched normal controls. Four of the women with secondary amenorrhea and normal karyotypes in our series reported a family history of early menopause prior to the age of 40. Since publication of this series, other investigators have documented the importance of family history. Premutations in the FMR1 gene, now recognized as sometimes associated with a neurodegenerative disorder (7,8), are present in 14% of women with familial POF, as well as in about 2% of women with isolated POF (9). Easily detected immune disturbances were present in approximately 20% of the patients. Thyroid abnormalities were most common, with five women having Hashimoto's thyroiditis, two developing primary hypothyroidism, one developing subacute thyroiditis, and one having Graves' disease. Three asymptomatic patients had high titers of antimicrosomal antibodies. One of the women had vitiligo and hypoparathyroidism; one had Addison's disease; and one additional woman had insulin-dependent diabetes mellitus. Because there is no control population with which to compare the affected women and because autoimmune disturbances are so common in women, it is impossible to conclude with assurance that immune disorders are more common in women with POE Although numerous investigators have suggested the possibility, it would be irresponsible to conclude that immune disturbances and POF are causally linked. The association of POF with adrenal insufficiency (Addison's disease) has been recognized for several years (10,11), and lymphocytic oophoritis has been documented in a handful of patients with this complex. More recently, testing for adrenal antibodies using an indirect immunofluorescence assay (which is commercially available) revealed that 4% of those with normal karyotypes and spontaneous POF had steroidogenic cell autoimmunity (12,13). A relatively small number of the women in our series, all with secondary amenorrhea, had received chemotherapy with alkylating agents, and in some cases radiation therapy as well, before developing hypergonadotropic amenorrhea. The effects of alkylating agents and radiation therapy on ovarian function have been recognized for several years (14,15), and
it is now recognized that the incidence of permanent ovarian failure increases as the age of the woman at the time of therapy increases. The number of women presenting with POF after curative treatment for any of a variety of malignancies is increasing; in this population, too, the POF is not always permanent. Spinal bone density, as evaluated by dual photon absorptiometry, was less than 90% (range 62% to 105%, mean 85.7%) of the mean value observed in age-matched controls in 16 of the 26 women who underwent such testing. The association of POF with osteopenia is now well recognized (16). Progestin-induced withdrawal bleeding occurred in just less than 50% of the women tested in this series. Withdrawal bleeding even occurred in two of the nine individuals with primary amenorrhea who were challenged. Moreover, there was no correlation between the response to exogenous progestin and subsequent ovulation. None of the women with primary amenorrhea ever ovulated or conceived with her own oocytes. In contrast, more than one-third of the women with secondary amenorrhea were pregnant at least once before developing hypergonadotropic amenorrhea, and almost one-quarter had evidence of ovulation after the diagnosis of POF was established. Yet only one-ninth (8.2%) of those with secondary amenorrhea later conceived spontaneously. Twenty-five of the patients with secondary amenorrhea were treated with clomiphene citrate in an effort to induce ovulation, but only four (16%) ovulated as determined by serial ultrasound and serum progesterone levels. Because each of the four who ovulated had evidence of spontaneous episodic ovulation before therapy, it is unclear if the clomiphene actually induced ovulation or if ovulation occurred in association with clomiphene by chance alone. Nineteen women had gonadotropin secretion suppressed either with exogenous estrogen and progestin (n = 14) or with gonadotropinreleasing hormone agonist (n = 5) for 1 to 3 months. Ovulation induction was then attempted with exogenous gonadotropins. Only two of the patients (among those suppressed with agonist) ovulated, and only one conceived. These data
CHAPTER 7 Premature Ovarian Failure are consistent with a later controlled trial documenting that ovulation induction is unlikely to be successful (5). Twelve women with secondary amenorrhea underwent ovarian biopsies, with apparent viable oocytes noted in seven of the specimens. Yet two of the eight subsequent pregnancies occurred in women with no follicles found in the biopsy specimens. Fully seven of these eight pregnancies occurred while the patients were taking exogenous estrogen; the remaining pregnancy in this series occurred following administration of clomiphene. Five of the eight pregnancies ended in normal-term live births, two ended in spontaneous abortion, and one ended in elective abortion. Only three patients with primary amenorrhea underwent biopsy of gonadal tissue: The two with 46,XY karyotypes had dysgerminoma. The one additional patient had fibrous streaks. These observations confirm that POF is a heterogeneous disorder. Moreover, they stress the importance of measuring circulating levels of FSH in all women who present with amenorrhea. Progestin-induced withdrawal bleeding is now an outmoded and inappropriate tool in the evaluation of women with amenorrhea.
III. PREVALENCE OF PREMATURE OVARIAN FAILURE Estimation of the prevalence of POF in the general population is difficult. In one study, 7% of 300 consecutive women presenting with amenorrhea had POF (17). An estimate based on several studies concluded that 0.3% of reproductiveage women (approximately 130,000) have POF (18). Still another study suggested that 5% to 10% of women with secondary amenorrhea have POF (19). Based on 1950 data, the risk of experiencing menopause prior to the age of 40 was calculated as 0.9% in Rochester, Minnesota (20). Perhaps the major point of these estimates is that POF is sufficiently common that most clinicians will see individuals who present with this disorder.
IV. ETIOLOGY OF PREMATURE OVARIAN FAILURE De Moraes-Ruehsen and Jones (17) suggested three possible explanations for the early completion of atresia that they believed existed in women with hypergonadotropic amenorrhea and premature ovarian failure: (a) decreased germ cell endowment, (b) accelerated loss of oocytes (atresia), and (c) postnatal germ cell destruction. Because none of these possibilities can be true in individuals in whom many follicles still remain, some block to gonadotropin action in ovarian follicles must exist in such affected women. Given older data that even postmenopausal women may have a few remaining ovarian follicles (21,22) and evidence
101 that follicle number decreases rapidly in the last several months before the menopause (23,24), occasional ovulations and rare pregnancies may occur in women with this disorder who are just experiencing an "early" but "normal" menopausal transition (1). Among the various causes of POF that have now been identified, it is clear that some are present only in those who have no oocytes, whereas others may include the potential for ovulation and spontaneous pregnancy. Given current knowledge, it is impossible to develop a classification scheme for POF that does not include some overlap, but a suggested classification is presented in Table 7.2.
A. Cytogenetic Abnormalities Involving the X Chromosome 1. STRUCTURALALTERATIONS OR ABSENCE OF AN X CHROMOSOME Individuals with the various forms of gonadal dysgenesis, with or without the stigmata of Turner syndrome, typically present with hypergonadotropic amenorrhea, regardless of the extent of pubertal development and the presence or absence of associated anomalies or stigmata. It is well recognized that cytogenetic abnormalities of the X chromosome can impair TABLE 7.2
Tentative Classification of Premature Ovarian Failure
I. Cytogenic abnormalities involving the X chromosome A. Structural alterations or absence of an X chromosome B. Fragile X premutations C. Trisomy X with or without mosaicism II. Enzymatic defects A. Steroidogenic enzyme defects 1. 17ot-hydroxylasedeficiency 2. 17,20-desmolase deficiency 3. 20,22-desmolase deficiency 4. Aromatase deficiency B. Galactosemia III. Other genetic alterations IV. Defective gonadotropin secretion or action A. Receptor or postreceptor defects 1. FSH receptor mutations 2. LH receptor mutations B. Secretion of biologically inactive gonadotropin V. Environmental insults A. Chemotherapeutic agents B. Ionizing radiation C. Viral infection D. Surgical injury or extirpation VI. Immune disturbances A. In association with other autoimmune disturbances (15-20% of cases) B. Isolated C. In association with congenital thymic aplasia VII. Idiopathic LH, luteinizinghormone.
102
ROBERT W. REBAR
ovarian development and function. Studies of 46,,3( individuals and those with various X chromosomal deletions have confirmed that two intact X chromosomes are necessary for maintenance of oocytes (25). The gonads of 45,X fetuses contain the normal complement of oocytes at 20 to 24 weeks of fetal age, but these rapidly undergo atresia so that essentially none are present at birth (26). Primary or secondary amenorrhea typically occurs in women with deletions in either the short or the long arm of one X chromosome (25). Structural abnormalities of the X chromosome also can have a negative impact on ovarian function and are present in some women with POF (25,27). The association of submicroscopic deletions of Xq26-27 indicates that even subtle molecular defects in the X chromosome can impact on ovarian function and be associated with POF (28). Although women with stigmata of Turner syndrome are evident on physical examination, individuals with many forms of gonadal dysgenesis may not have any such stigmata. Women with pure gonadal dysgenesis, who generally present with primary amenorrhea and sexual infantilism, are of normal height and do not have the somatic abnormalities associated with Turner syndrome (25,29). Such individuals have either a 46,XX or 46,XY karyotype. In the extremely rare disorder of mixed gonadal dysgenesis, a germ cell tumor or a testis accounts for one gonad, with an undifferentiated streak, rudimentary, or no gonad accounting for the other (30). Such individuals are generally mosaic, with the 45,X/46,XY karyotype reported most commonly. Almost all affected individuals are raised as females, with mild to moderate masculinization occurring at puberty. Abnormal genitalia may be noted at puberty. Because of the malignant potential of intraabdominal gonads with a Y chromosomal component (31-33), the gonads should be removed. 2. TRISOMY X WITH OR WITHOUT MOSAICISM
An excess of X chromosomes also may be found in some women who develop POF (34). Affected individuals typicaUy develop normal secondary sex characteristics and only later develop POE Reports of the triple-X syndrome associated with immunoglobulin deficiency (35) and Marfan syndrome (36), together with the observation that control of T-cell function may be related to the X chromosome (37), suggest a possible association between immunologic abnormalities and triple-X females with POE
B. Enzymatic Defects 1. 170s
DEFICIENCY
The rare women with deficiency of the 17cx-hydroxylase enzyme are identified easily because of the associated findings of primary amenorrhea, sexual infantilism, hypergonadotropinism, hypertension, hypokalemic alkalosis, and
increased circulating concentrations of deoxycorticosterone and progesterone (38-41). Ovarian biopsies have revealed numerous large follicular cysts with complete failure of orderly follicular maturation (40). 2. GALACTOSEMIA
Women with galactosemia may develop amenorrhea with elevated gonadotropin levels even when treatment with a galactose-restricted diet begins at an early age (42-44). The etiology of the ovarian failure in this disorder is unresolved, but pregnant rats fed a 50% galactose diet deliver pups with significantly reduced numbers of oocytes, apparently because of decreased germ cell migration to the genital ridges (45). There is also evidence that excess galactose inhibits follicular development in the rat ovary (46). 3. AROMATASE DEFICIENCY
Several case reports of individuals with documented mutations in the CYP19 (aromatase P450) gene have been described in detail (47-52). Estrogen biosynthesis was virtually absent in all these patients and associated with a number of anticipated and unanticipated findings. It is clear that aromatase deficiency is an autosomal recessive condition manifested in 46,XX individuals by female pseudohermaphroditism with clitoromegaly and posterior labioscrotal fusion at birth; enlarged cystic ovaries in association with elevated FSH levels during childhood; lack of pubertal development in association with further enlargement of the clitoris, normal development of pubic and axillary hair, and continued existence of enlarged multicystic ovaries during the teenage years; and severe estrogen deficiency, virilization, and enlarged multicystic ovaries in association with markedly elevated levels of gonadotropins in adulthood. Administration of exogenous estrogen results in prompt lowering of circulating gonadotropin levels. Consistent with the diagnosis of POF is the observation that many closely packed primordial follicles were present in an ovarian biopsy specimen obtained from an affected 17 month old (51), but a biopsy specimen from a 13 year old showed excessive atresia (52). Affected 46,XY individuals are normal at birth and during childhood but develop eunuchoid proportions and osteoporosis as they continue to grow during adulthood. It has become clear that estrogen is essential for epiphyseal closure. Because of the absence of aromatase enzyme in the placenta, mothers of affected children develop reversible virilization during the second half of pregnancy.
C. Other Genetic Alterations It is becoming clear that mutations to any of several different genes can result in POE As noted previously, perhaps the most important mutations identified thus far involve the
CHAPTER 7 Premature Ovarian Failure FMR1 gene; mutations result in the fragile X syndrome
(characterized by impaired intellectual functioning, certain mild physical changes, social anxiety, language difficulties, and problems with balance), and premutations can result in POF and a neurodegenerative disorder (7,8). Other rare genetic causes of familial POF for which routine genetic testing in sporadic cases is not now clinically warranted include mutations involving FSHR (the FSH receptor), FOXL2 (a forkhead transcription factor associated with the blepharophimosis/ptosis/epicanthus inversus syndrome), I N H A (inhibin alpha gene), EIF2B (a family of genes associated with central nervous system leukodystrophy and ovarian failure), BMP15 (bone morphogenetic protein 15), PMM2 (phosphomannomutase 2), and AIRE (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome) (53-61). It is likely that other genetic mutations that lead to POF will be identified in the future.
D. Defective Gonadotropin Secretion or Action Data from a variety of sources now indicate that abnormal structure, secretion, metabolism, or action of gonadotropins forms the basis for early ovarian failure in some women. We have reported altered forms of immunoreactive luteinizing hormone (LH) and FSH in urinary extracts from women with POF compared to those from oophorectomized and postmenopausal women (62), suggesting that metabolism or excretion of gonadotropins is altered in some cases. As already noted, genetic mutations in receptor structure manifest in altered FSH action and POF (53,54). Also reported are individuals with POF and evidence of intermittent follicular activity who appear to have low-molecular-weight FSH receptor-binding activity that antagonizes normal FSH binding (63).
E. Environmental Insults Destruction of oocytes by any of several environmental insults, including ionizing radiation, various chemotherapeutic agents, certain viral infections, and even cigarette smoking, may accelerate follicular atresia (64). 1. RADIATION Approximately 50% of individuals who receive 400 to 500 rads to the ovaries over 4 to 6 weeks, as commonly occurs in treatment for Hodgkin's disease, will develop permanent ovarian failure (15,65). For any given dose of radiation, the older the woman, the greater the likelihood of her developing hypergonadotropic amenorrhea. It appears that 800 rads is sufficient to result in permanent sterility in all women (65).
103 That the amenorrhea following radiation therapy is not always permanent was reported as long ago as 1939 (66). The transient nature of the hypergonadotropic amenorrhea in some women suggests that some follicles may be damaged but not destroyed by relatively low doses of radiation. This information has led to the practice of transposing the ovaries to the pelvic sidewalls, today often by laparoscopy, to minimize the dose of radiation to which they are exposed; one review has concluded that transposition in women under age 40 results in preservation of ovarian function in 88.6% of cases (67,68). 2. CHEMOTHERAPEUTICAGENTS
It is clear that chemotherapeutic agents, particularly alkylating agents, may produce either temporary or permanent ovarian failure (14,15,69-72). In general, the younger the woman at the time of therapy, the more likely it is that ovarian function will not be compromised by chemotherapy. It appears that the greater the number of oocytes present in the ovaries at the time of therapy, the more likely it is that normal ovarian function will persist. The frequency of congenital anomalies does not appear to be increased in the children of women previously treated with chemotherapeutic agents (73). There is the suggestion, however, that one agent, dactinomycin, may be associated with an increased risk of congenital heart disease, and further studies in this area are clearly needed. 3. VIRALAND OTHER AGENTS
Although several viruses are believed to have the potential to cause ovarian failure, confirming that this is the case in women is difficult. The best documented series includes three presumptive cases of"mump oophoritis" that preceded ovarian failure, including cases in a mother and her daughter in which the mother had documented mumps parotiditis and abdominal pain during pregnancy just prior to the delivery of a daughter who later suffered from hypergonadotropic amenorrhea (74). Although there is no evidence that cigarette smoking will lead to premature menopause, data do exist documenting that cigarette smokers experience menopause several months before nonsmokers (75).
F. I m m u n e D i s t u r b a n c e s Several autoimmune abnormalities are known to be associated with hypergonadotropic amenorrhea (Table 7.3). As is characteristic for other autoimmune disturbances, the ovarian "failure" may wax and wane, and pregnancies may occur, at least early in the disease process. We reviewed 380 cases of premature ovarian failure in the literature and noted that 17.5% had an autoimmune disorder present in addition to the ovarian failure. Unfortunately,
104 TABLE 7.3
ROBERT W. REBAR
Possible Autoimmune Disorders Associated with Premature Ovarian Failurea Percentage of women with POF affected
Thyroid Polyendocrinopathy type I Polyendocrinopathy type II Unspecified Other (misceUaneous)b Myasthenia gravis Adrenal Multiple endocrinopathy (unclassified) Diabetes mellitus Pernicious anemia Systemic lupus erythematosus
6.8 5.3 5.0 3.9 2.9 2.4 2.1 1.6 0.8 0.5 0.5
aBased on data from reic. 89:119 out of 380 patients (31.3%) surveyed had autoimmune disease. bIncluding one case each with asthma, Crohn's disease, glomerulonephritis, idiopathic thrombocytopenia, purpura, and vitiligo.
autoimmune dysfunction is also common in women without ovarian failure, and it is not clear that the incidence is actually increased in women with POE However, additional evidence that some cases of POF may have an autoimmune etiology is provided by sporadic case reports documenting return of ovarian function following either immunosuppressire therapy or recovery from an associated autoimmune disease (76-79). In a few cases, lymphocytic infiltrates suggesting autoimmune dysfunction have been observed in ovarian biopsy specimens (79). In fact, autoimmune lymphocytic oophoritis was originally reported in association with adrenal insufficiency (Addison's disease) (10,11). It is now clear that the women with POF who have steroidogenic cell autoimmunity have lymphocytic oophoritis as the mechanism for the ovarian failure. One review reported that all patients with histologically confirmed lymphocytic autoimmune oophoritis had adrenal antibodies when tested using an indirect immunofluorescence assay (10). There is now evidence that antibodies to the 21-hydroxylase enzyme measured by a commercially available immunoprecipitation assay are generally in good agreement with results testing for adrenal cortex antibodies by indirect immunofluorescence, although a variety of antibodies to steroidogenic enzymes can be detected in patients with steroidogenic cell autoimmunity (80). Testing for adrenal antibodies by indirect immunofluorescence will identify the 4% of women with spontaneous POF who have steroidogenic cell autoimmunity and are at risk for adrenal insufficiency, a potentially fatal disorder (12,13). When POF occurs in association with adrenal insufficiency, the ovarian failure presents first about 90% of the time (81). It appears that a few women presenting with POF
will have asymptomatic adrenal insufficiency; these individuals are at risk of developing adrenal crisis. Adrenal antibodies will identify women who may have occult adrenal insufficiency at the time of initial presentation as well as those who should be followed closely for the subsequent development of adrenal insufficiency (82,83). Still other immune abnormalities have been identified in some patients with POE Enhanced release of leukocyte migration inhibition factor (MIF) by peripheral lymphocytes has been observed following exposure of the lymphocytes to crude ovarian proteins (84,85). A significant association of early ovarian failure with HLA-DR3 has been noted (86), perhaps suggesting a genetic susceptibility in some individuals. Several years ago, complement-dependent cytotoxic effects, as documented by inhibition of progesterone production and cell lysis, were observed when sera from 9 of 23 patients were added to cultured granulosa cells (87). Indirect immunofluorescence of ovarian biopsy specimens from some patients has revealed antibodies reacting with various ovarian components (88). Circulating immunoglobulins to ovarian proteins have been detected by immunochemical techniques by several investigators (89). Utilizing a solid-phase, enzyme-linked immunosorbent assay, we have detected antibodies to ovarian tissue in 22% ofkaryotypically normal women with POF (90). The most welldocumented evidence of autoantibodies to ovarian tissue comes from a study of two patients with POF and myasthenia gravis who had circulating immunoglobulin G that blocked binding of FSH to ovarian cell surface receptors (91). However, presently there is no test to detect ovarian specific antibodies that has proven clinical utility (90,92,93). It has become clear that there are links between the immune and reproductive systems. It has been known for several years that congenitally athymic girls dying before puberty have ovaries devoid of oocytes on autopsy (94). We have shown that congenitally athymic mice, well known to have premature ovarian failure, have lower gonadotropin concentrations prepubertally than do their normal heterozygous littermates (95). These hormonal alterations, as well as the accelerated loss of oocytes, can be prevented by thymic transplantation at birth (96). It is essential to recognize that ovarian development occurring during the first few weeks of life in the mouse occurs in utero in women and in nonhuman primates. Thus, thymic ablation in fetal rhesus monkeys in late gestation is associated with a marked reduction in oocyte number at birth (97). One possible explanation for the association of thymic aplasia and ovarian failure may be found in our observation that peptides produced by the thymus gland can stimulate release of gonadotropin-releasing hormone (GnRH) and consequently LH (98). That gonadotropins are required for normal ovarian development is supported by the observation that fetal hypophysectomy in rhesus monkeys leads to newborns having no oocytes in their ovaries (99).
CHAPTER 7 Premature Ovarian Failure
From a theoretical point of view, identifying women with an autoimmune etiology for their POF is important because affected patients might be treated effectively early in the disease process, before all viable oocytes are destroyed.
G. Idiopathic Premature Ovarian Failure Although the diagnosis of "idiopathic" causes of POF should be a diagnosis of exclusion, presently no definitive etiology is identified in most patients with POE It is likely that additional causes of POF will be recognized as investigation of the human genome continues.
H. Resistant Ovary Syndrome"
An Outdated Term As originally defined, the resistant ovary or "Savage" syndrome was found in young amenorrheic women with (a) elevated peripheral gonadotropin levels, (b) normal but immature follicles in the ovaries, (c) a 46,XX karyotype, (d) mature secondary sex characteristics, and (e) decreased sensitivity to stimulation with exogenous gonadotropin (100). It is clear from this consideration of the causes of POF, however, that these criteria might easily be the result of several different etiologies. Moreover, regardless of the etiology, these features may be common to the vast majority of individuals who present with hypergonadotropic amenorrhea at some time during the disease process prior to the final loss of all oocytes. Thus, the term resistant ovary is outdated and should no longer be used.
V. EVALUATION OF INDIVIDUALS WITH HYPERGONADOTROPIC AMENORRHEA Young women with hypergonadotropic amenorrhea should be evaluated to identify (a) specific, potentially treatable causes and (b) other potentially dangerous associated disorders. It is important to make the diagnosis in a timely manner. One report found that more than one-half of patients who presented with secondary amenorrhea saw three or more clinicians before laboratory testing established the diagnosis (101). In general, young women who experience loss of regular menses for 3 or more consecutive months merit appropriate evaluation. A thorough history and physical examination are warranted. Clinical evaluation of the vaginal mucosa and cervical mucus may help determine if any endogenous estrogen is present. In general, laboratory evaluation should include measurement of basal levels ofprolactin, FSH, and thyroid-stimulating hormone (TSH) after pregnancy is ruled out.
105 FSH levels are generally greater than 30 mlU/mL in women who do not have functioning gonads. If the FSH level is greater than 20 mIU/mL in the initial measurement and the patient is less than 40 years old, then the measurement of FSH should be repeated and serum estradiol should be measured as well to confirm hypogonadism. In addition, the measurement of basal LH levels may help determine if any functional follicles are present. In general, if the estradiol concentration is greater than 50 pg/mL or if the LH concentration (in terms of milli-International Units per milliliter) is greater than the FSH concentration on any occasion, then at least a few viable oocytes still must be present. Irregular uterine bleeding, indicative of continuing estrogen production, also suggests the presence of remaining functional oocytes. The presence of identifiable follicles on transvaginal ultrasonography also can be used to identify women with remaining oocytes. Because about one-half the women with POF will experience withdrawal bleeding in response to a progestin challenge (4), this test should not be used as a substitute for measuring basal FSH levels. When ovarian failure presents as primary amenorrhea, approximately 50% of individuals will have an abnormal karyotype (4). However, most cases of spontaneous POF present as secondary amenorrhea. In our series, we found an abnormal karyotype in only 13% of women 30 years of age or younger who developed secondary amenorrhea. Still it would seem prudent to obtain a karyotype in women with onset of hypergonadotropic amenorrhea prior to age 30 to identify those with various forms of gonadal dysgenesis, individuals with mosaicism, those with trisomy X, and those with a portion of a Y chromosome. If a Y chromosome is present, gonadal extirpation is warranted because of the increased risk of malignancy (31-33). Chromosomal evaluation also may be warranted to rule out familial transmission in women who develop hypergonadotropic amenorrhea after the birth of daughters. Approximately 6% of women with 46,XX spontaneous POF have premutations of the FMR1 gene, the gene responsible for the fragile X syndrome, the most common cause of familial mental retardation, with the risk being greater if there is a family history of POF (9). Thus, a good argument can be made for screening for this abnormality. In addition, testing for adrenal antibodies by indirect immunofluorescence is warranted. If antibodies are detected, a corticotropin stimulation test is warranted to identify women with adrenal insufficiency. Because of the frequency of autoimmune thyroid disease in women with POF, it is also reasonable to measure TSH and thyroid-stimulating immunoglobulins in women with POE Ovarian biopsy is not justified in women with hypergonadotropic amenorrhea and a normal karyotype. It is not clear how the results would alter therapy. In one series, one of the two patients who eventually conceived had no oocytes present on biopsy (18). Similarly, we reported that two of
106 eight subsequent pregnancies among 97 women with secondary hypergonadotropic amenorrhea occurred in women with no follicles present in ovarian tissue obtained at laparotomy (4). As noted (19), if five sections of an ovarian biopsy are examined and each is 6 Ixm thick, then the presence of follicles is sought from a sample representing less than 0.15% of a 2 • 3 x 4 cm ovary. Thus, the absence of follicles on biopsy may not be representative of the remainder of the ovary. Evaluation of bone density appears warranted in women with POF because of the high incidence of osteopenia (4). Periodic assessment may be warranted, regardless of therapy, to assess the rate of bone loss. Similarly, monitoring patients for the development of autoimmune endocrinopathies may be warranted even if all the tests are normal when the patient is first evaluated. Development of other disorders after diagnosis of POF does occur (4), and there is little knowledge about the natural history of the development of associated autoimmune disorders.
VI. TREATMENT Perhaps the first challenge in providing appropriate treatment to women with POF is informing the patient of the diagnosis in a sensitive manner. The manner in which the diagnosis is delivered can affect the degree of emotional trauma experienced, especially if the woman already sought assistance because of infertility or anticipates having children in the future. It may be best to schedule a separate visit to review the findings and discuss treatment options when the diagnosis is suspected. It is important to explain that remissions and spontaneous pregnancies can occur, and that POF differs from the normal menopause in important ways. Because the diagnosis can be emotionally devastating, it may be important to provide ongoing psychologic support. Referral to an organization such as the POF Support Group (www.pofsupport.org) should also be considered. It is reasonable to treat all young women with POF with exogenous estrogen whether they are interested in childbearing or not. The accelerated bone loss often accompanying this disorder may well be prevented by the administration of exogenous estrogens (16). In addition, spontaneous pregnancies can occur in patients with this disorder when they are taking exogenous estrogen--even in the form of combined oral contraceptive agents (4,102). However, the possibility of spontaneous pregnancy after the diagnosis is established appears to be less than 10%. The pregnancy rate is low despite the fact that about one-fourth of women ovulate after the diagnosis of hypergonadotropic amenorrhea is made (4). Because of the possibility of pregnancy, women who do not desire pregnancy and are sexually active should be advised to use barrier contraception, even if they are taking oral contraceptives. Women should be advised to contact
ROBERT W. REBAR
their physician if they develop any signs or symptoms consistent with pregnancy or if they do not have withdrawal bleeding while taking exogenous estrogen and progestin. Why it is that these women can ovulate and conceive while taking oral contraceptives has not been determined. Although exogenous estrogen may be provided in the form of either estrogen-progestin therapy or oral contraceptives, therapy with exogenous estrogen and progestin is more physiologic. It is important to remember that these young women may require twice as much estrogen as do postmenopausal women to alleviate signs and symptoms of hypoestrogenism. Findings documenting significant risks of exogenous estrogen when administered to postmenopausal women do not apply to these patients, for whom estrogen therapy is truly replacement. At present there just are no data assessing the risks in young women. There is controversy as to how best to provide progestin. Although many clinicians now provide progestin continuously along with the estrogen, this is less physiologic than utilizing the progestin sequentially. Some clinicians administer the progestin for 12 to 14 days each month, whereas others administer it less frequently. Because many patients prefer having fewer menses, I typically administer progestin every other month and commonly use micronized progesterone. I prefer administering estradiol-17[3 by patch in an effort to provide therapy that is as physiologic as possible. There is no evidence, however, that any one form of estrogen replacement therapy is safer or more efficacious than any other. Several isolated case reports suggested that ovarian suppression with estrogen or a GnRH agonist followed by stimulation with human menopausal gonadotropin might be efficacious in inducing ovulation and allowing pregnancy (103-106). Most of these reports originated from patients treated by just one group of physicians. Larger series suggest that the possibility of successful ovulation induction and pregnancy is small indeed and appears no greater than what occurs spontaneously in these patients (4,5,107). The majority of the data indicate that there is little point in attempting to induce ovulation in women with POE In vitro fertilization involving oocyte donation clearly provides individuals with hypergonadotropic amenorrhea with the greatest likelihood of bearing children. The first successful case of oocyte donation in humans was reported in 1984. A young woman with ovarian failure was given oral estradiol valerate and progesterone pessaries to prepare the endometrium for transfer of a single donated oocyte following fertilization with her husband's sperm (108). Following several series documenting success with oocyte donation (109-111), use of oocyte donation has become widespread, and success rates are generally greater than those observed with traditional in vitro fertilization. Thus, oocyte donation offers the possibility of pregnancy to all women with POF as long as a normal uterus is present. One cautionary note, however, is warranted: Recent data indicate that the risk of
CI-IAeTER 7 Premature Ovarian Failure
aortic rupture is increased during pregnancy in women with Turner syndrome (112,113). An echocardiogram to exclude dilation of the aortic root is indicated in women with Turner syndrome who are contemplating pregnancy. However, even if the findings are normal, the risk of aortic rupture may be increased because the structure of the aortic wall is abnormal. Thus, such women must be counseled carefully before oocyte donation is contemplated. If the patient does become pregnant, careful cardiac monitoring is warranted throughout the course of the pregnancy. A strong case exists for recommending adoption for such women, as well as for those unwilling to undergo the laborious procedures involved in oocyte donation.
References 1. Soules MR, Sherman S, Parrott E, et al. Executive summary: stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001;76: 874-878. 2. Goldenberg RL, Grodin JM, Rodbard D, Ross GT. Gonadotropins in women with amenorrhea. The use of plasma follicle-stimulating hormone to differentiate women with and without ovarian follicles. Am J Obstet Gyneco11973;116:1003-1012. 3. Rebar RW, Erickson GF, Yen SS. Idiopathic premature ovarian failure: clinical and endocrine characteristics. Fertil Steri11982;37:35-41. 4. Rebar RW, Connolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Fertil Steri11990;53:804-810. 5. Nelson LM, Kimzey LM, White BJ, Merriam GR. Gonadotropin suppression for the treatment of karyotypically normal spontaneous premature ovarian failure: a controlled trial. Fertil Steri11992;57:50-55. 6. Anasti JN. Premature ovarian failure: an update. Fertil Steri11998;70: 1-15. 7. Hagerman RJ, Hagerman PJ. The fragile X premutation: into the phenotypic fold. Curr @in Genet Dev 2002;12:278-283. 8. Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am JHum Genet 2004;74:1051-1056. 9. Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet 2000;97:189-194. 10. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev 1997;18:107-134. 11. Irvine WJ, Chan MM, Scarth L, et al. Immunological aspects of premature ovarian failure associated with idiopathic Addison's disease. Lancet 1968;2:883 - 887. 12. Bakalov VK, Vanderhoof VII, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Re])rod 2002; 17:2096 - 2100. 13. Falorni A, Laureti S, Candeloro P, et al. Steroid-cell autoantibodies are preferentially expressed in women with premature ovarian failure who have adrenal autoimmunity. Fertil Steri12002;78:270-279. 14. Siris ES, Leventhal BG, Vaitukaitis JL. Effects of childhood leukemia and chemotherapy on puberty and reproductive function in girls. NEnglJMed 1976;294:1143-1146. 15. Damewood MD, Grochow LB. Prospects for fertility after chemotherapy or radiation for neoplastic disease. Fertil Steri11986;45(4):443-459. 16. Metka M, Holzer G, Heytmanek G, Huber J. Hypergonadotropic hypogonadic amenorrhea (World Health Organization III) and osteoporosis. Fertil Steri11992;57:37-41.
107 17. De Moraes-Ruehsen M, Jones GS. Premature ovarian failure. Fertil Steri11967;18:440-461. 18. Aiman J, Smentek C. Premature ovarian failure. Obstet Gyneco11985;66: 9-14. 19. Alper MM, Garner PR, Seibel MM. Premature ovarian failure. Current concepts. J Reprod Med 1986;31:699-708. 20. Coulam CB, Adamson SC, Annegers JE Incidence of premature ovarian failure. Obstet Gyneco11986;67:604-606. 21. CostoffA, Mahesh VB. Primordial follicles with normal oocytes in the ovaries of postmenopausal women. J Am Geriatr Soc 1975;23: 193-196. 22. Hertig AT. The aging ovary-preliminary note. J Clin EndocrinolMetab 1944;4:581. 23. Richardson SJ, Nelson JE Follicular depletion during the menopausal transition. Ann N YAcad Sci 1990;592:13 - 20; discussion 44- 51. 24. Richardson SJ, Senikas V, Nelson JE Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231-1237. 25. Simpson JL, Rajkovic A. Ovarian differentiation and gonadal failure. AmJMed Genet 1999;89:186-200. 26. Singh RP, Cart DH. The anatomy and histology of XO human embryos and fetuses. Anat Rec 1966;155:369-383. 27. Rebar RW, Erickson GF, Coulam CB. Premature ovarian failure. In: Gondos B, Riddick D, eds. Pathology of infertility. New York: Thieme Medical Publishers, 1987. 28. Krauss CM, Turksoy RN, Atkins L, et al. Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N EnglJ Med 1987;317:125 - 131. 29. Espiner EA, Veale AM, Sands VE, Fitzgerald PH. Familial syndrome of streak gonads and normal male karyotype in five phenotypic females. N EnglJ Med 1970;283:6-11. 30. Davidoff F, Federman DD. Mixed gonadal dysgenesis. Pediatrics 1973;52:725-742. 31. Manuel M, Katayama PK, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. A m J Obstet Gyneco11976;124:293- 300. 32. Schellhas HE Malignant potential of the dysgenetic gonad. I. Obstet Gynecol 1974;44:289- 309. 33. Schellhas HE Malignant potential of the dysgenetic gonad. II. Obstet Gyneco11974;44:455-462. 34. Villanueva AL, Rebar RW. Triple-X syndrome and premature ovarian failure. Obstet Gyneco11983;62(3 Suppl):70S-73S. 35. SillsJA, Brown JK, Grace E, et al. XXX syndrome associated with immunoglobulin deficiency and epilepsy.J Pediatr 1978;93:469-471. 36. Smith TF, Engel E. Marfan's syndrome with 47,XXX genotype and possible immunologic abnormality. South MedJ 1981;74:630-632. 37. Purtilo DT, DeFlorio D Jr, Hutt LM, et al. Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome. NEnglJMed 1977;297:1077-1080. 38. Biglieri EG, Herron MA, Brust N. 17-hydroxylation deficiency in man.J Clin Invest 1966;45:1946-1954. 39. Goldsmith O, Solomon DH, Horton R. Hypogonadism and mineralocorticoid excess. The 17-hydroxylase deficiency syndrome. N EnglJ Med 1967;277:673-677. 40. Mallin SR. Congenital adrenal hyperplasia secondary to 17-hydroxylase deficiency. Two sisters with amenorrhea, hypokalemia, hypertension, and cystic ovaries.Ann Intern Med 1969;70:69-75. 41. Miller WL. Steroid 17alpha-hydroxylase deficiency--not rare everywhere. J Clin EndocrinolMetab 2004;89:40-42. 42. Hoefnagel D, Wurster-Hill D, Child EL. Ovarian failure in galactosaemia. Lancet 1979;2:1197. 43. Kaufman FR, Kogut MD, Donnell GN, et al. Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med 1981;304:994-998.
108 44. Guerrero NV, Singh RH, Manatunga A, et al. Risk factors for premature ovarian failure in females with galactosemia. J Pediatr 2000;137: 833-841. 45. Chen YT, Mattison DR, Feigenbaum L, Fukui H, Schulman JD. Reduction in oocyte number following prenatal exposure to a diet high in galactose. Science 1981;214:1145-1147. 46. Liu G, Shi F, Blas-Machado U, et al. Dietary galactose inhibits GDF-9 mediated follicular development in the rat ovary. Reprod Toxicol 2006;21:26-33. 47. Shozu M, Akasofu K, Harada T, Kubota Y. A new cause of female pseudohermaphroditism: placental aromatase deficiency. J Clin Endocrinol Metab 1991;72:560-566. 48. Portrat-Doyen S, Forest MG, Nicolino M, Morel Y, Chatelain PC. Female pseudohermaphroditism (FHP) resulting from aromastase (P450arom) deficiency associated with a novel mutation (R457) in the CYP19 gene. Horm Res 1996;46(suppl):14-20. 49. Ludwig M, Beck A, Wickert L, et al. Female pseudohermaphroditism associated with a novel homozygous G-to-A (V370-to-M) substitution in the P-450 aromatase gene. J Pediatr Endocrinol Metab 1998;11: 657-664. 50. Mullis PE, Yoshimura N, Kuhlmann B, et al. Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. J Clin Endocrinol Metab 1997;82:1739-1745. 51. Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 1994;78:1287-1292. 52. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689-3698. 53. Aittomaki K, Lucena JL, Pakarinen P, et al. Mutation in the folliclestimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 1995;82:959-968. 54. Aittomaki K, Herva R, Stenman UH, et al. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene.J Clin Endocrinol Metab 1996;81:3722-3726. 55. Crisponi L, Deiana M, Loi A, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 2001;27:159-166. 56. Bodega B, Porta C, Crosignani PG, Ginelli E, Marozzi A. Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure. Mol Hum Reprod 2004;10:555-557. 57. De Baere E, Dixon MJ, Small KW, et al. Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation. Hum Mol Genet 2001;10:1591-1600. 58. Fogli A, Rodriguez D, Eymard-Pierre E, et al. Ovarian failure related to eukaryotic initiation factor 2B mutations.Am J Hum Genet 2003;72: 1544-1550. 59. Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet 2004;75: 106-111. 60. Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322: 1829-1836. 61. Nagamine K, Peterson P, Scott HS, et al. Positional cloning of the APECED gene. Nat Genet 1997;17:393-398.
ROBERT W. REBAR 62. Silva de Sa MF, Matthews MJ, Rebar RW. Altered forms of immunoreactive urinary FSH and LH in premature ovarian failure. Infertility 1988;11:1-11. 63. Sluss PM, Schneyer AL. Low molecular weight follicle-stimulating hormone receptor binding inhibitor in sera from premature ovarian failure patients. J Clin Endocrinol Metab 1992;74:1242-1246. 64. Verp M. Environmental causes of ovarian failure. Semin ReprodEndocrinol 1983;1:101-111. 65. Ash P. The influence of radiation on fertility in man. Br J Radiol 1980;53:271-278. 66. Jacox H. Recovery following human ovarian irradiation. Radiology 1939;32:538-545. 67. Tulandi T, Al-Took S. Laparoscopic ovarian suspension before irradiation. Fertil Steri11998;70(2):381-383. 68. Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an underused procedure. Am J Obstet Gyneco12003;188:367- 370. 69. Homing SJ, Hoppe RT, Kaplan HS, Rosenberg SA. Female reproductive potential after treatment for Hodgkin's disease. N Engl J Med 1981;304:1377-1382. 70. Koyama H, Wada T, Nishizawa Y, Iwanaga T, Aoki Y. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer 1977;39:1403-1409. 71. Stillman RJ, Schiff I, Schinfeld J. Reproductive and gonadal function in the female after therapy for childhood malignancy. Obstet Gynecol Surv 1982;37:385-393. 72. Whitehead E, Shalet SM, Blackledge G, et al. The effect of combination chemotherapy on ovarian function in women treated for Hodgkin's disease. Cancer 1983;52:988-993. 73. Green DM, Zevon MA, Lowrie G, Seigelstein N, Hall B. Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. N EnglJ Med 1991;325:141-146. 74. Morrison JC, Givens JR, Wiser WL, Fish SA. Mumps oophoritis: a cause of premature menopause. Fertil Steri11975;26:655-659. 75. Jick H, Porter J. Relation between smoking and age of natural menopause. Report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. Lancet 1977;1:1354-1355. 76. Bateman BG, Nunley WC Jr, Kitchin JD 3rd. Reversal of apparent premature ovarian failure in a patient with myasthenia gravis. Fertil Steri11983;39:108-110. 77. Coulam CB, Kempers RD, Randall RV. Premature ovarian failure: evidence for the autoimmune mechanism. Fertil Steri11981;36:238-240. 78. Lucky AW, Rebar RW, Blizzard RM, Goren EM. Pubertal progression in the presence of elevated serum gonadotropins in girls with mukiple endocrine deficiencies.J Clin Endocrinol Metab 1977;45:673 -678. 79. Rabinowe SL, Berger MJ, Welch WR, Dluhy RG. Lymphocyte dysfunction in autoimmune oophoritis. Resumption of menses with corticosteroids. Am J Med 1986;81:347- 350. 80. Chen S, Sawicka J, Betterle C, et al. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison's disease, and premature ovarian failure.J Clin EndocrinolMetab 1996;81:1871-1876. 81. Turkington RW, Lebovitz HE. Extra-adrenal endocrine deficiencies in Addison's disease. Am JMed 1967;43:499-507. 82. Betterle C, Volpato M, Rees Smith B, et al. I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison's disease. J Clin Endocrinol Metab 1997;82:932-938. 83. Betterle C, Volpato M, Pedini B, et al. Adrenal-cortex autoantibodies and steroid-producing cells autoantibodies in patients with Addison's disease: comparison of immunofluorescence and immunoprecipitation assays. J Clin Endocrinol Metab 1999;84:618-622. 84. Edmonds M, Lamki L, Killinger DW, Volpe R. Autoimmune thyroiditis, adrenalitis and oophoritis. Am J Med 1973;54:782- 787.
CHAPTER 7 Premature Ovarian Failure 85. Pekonen F, Siegberg R, Makinen T, Miettinen A, Yli-Korkala O. Immunological disturbances in patients with premature ovarian failure. Clin Endocrinol (Oxf) 1986;25:1-6. 86. Walfish PG, Gottesman IS, Shewchuk AB, et al. Association of premature ovarian failure with HLA antigens. Tissue Antigens 1983;21: 168-169. 87. McNatty KP, Short RV, Barnes EW, Irvine WJ. The cytotoxic effect of serum from patients with Addison's disease and autoimmune ovarian failure on human granulosa cells in culture. Clin Exp Immunol 1975;22:378-384. 88. Muechler EK, Huang KE, Schenk E. Autoimmunity in premature ovarian failure. IntJ Ferti11991;36:99-103. 89. LaBarbera AR, Miller MM, Ober C, Rebar RW. Autoimmune etiology in premature ovarian failure. Am J Reprod Immunol Microbiol 1988;16:115-122. 90. Kim JG, Anderson BE, Rebar RW, LaBarbera AR. A biotinstreptavidin enzyme immunoassay for detection of antibodies to porcine granulosa cell antigens. J Immunoassay 1991;12:447-464. 91. Chiauzzi V, Cigorraga S, Escobar ME, Rivarola MA, Charreau EH. Inhibition of follicle-stimulating hormone receptor binding by circulating immunoglobulins. J Clin Endocrinol Metab 1982;54:1221 - 1228. 92. Wheatcroft NJ, Salt C, Milford-Ward A, Cooke ID, Weetman AR Identification of ovarian antibodies by immunofluorescence, enzymelinked immunosorbent assay or immunoblotting in premature ovarian failure. Hum Reprod 1997;12:2617- 2622. 93. Novosad JA, Kalantaridou SN, Tong ZB, Nelson LM. Ovarian antibodies as detected by indirect immunofluorescence are unreliable in the diagnosis of autoimmune premature ovarian failure: a controlled evaluation. BMC Womens Health 2003;3:2. 94. Miller ME, Chatten J. Ovarian changes in ataxia telangiectasia. Acta Paediatr &and 1967;56:559-561. 95. Rebar RW, Morandini IC, Erickson GF, Petze JE. The hormonal basis of reproductive defects in athymic mice: diminished gonadotropin concentrations in prepubertal females. Endocrinology 1981;108:120-126. 96. Rebar RW, Morandini IC, Benirschke K, Petze JE. Reduced gonadotropins in athymic mice: prevention by thymic transplantation. Endocrinology 1980;107(6):2130-2132. 97. Healy DL, Bacher J, Hodgen GD. Thymic regulation of primate fetal ovarian-adrenal differentiation. Bid Reprod 1985;32:1127-1133. 98. Rebar RW, Miyake A, Low TL, Goldstein AL. Thymosin stimulates secretion of luteinizing hormone-releasing factor. Science 1981;214: 669-671. 99. Gulyas BJ, Hodgen GD, Tullner WW, Ross GT. Effects of fetal or maternal hypophysectomy on endocrine organs and body weight in infant rhesus monkeys (Macaca mulatta): with particular emphasis on oogenesis. Biol Reprod 1977;16:216-227.
109 100. Jones GS, De Moraes-Ruehsen M. A new syndrome of amenorrhea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am J Obstet Gyneco11969;104:597-600. 101. Alzubaidi NH, Chapin HL, Vanderhoof VH, Calls KA, Nelson LM. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure. Obstet Gynecol 2002;99:720-725. 102. Alper MM, Jolly EE, Garner PR. Pregnancies after premature ovarian failure. Obstet Gyneco11986;67(3 suppl):59S-62S. 103. Check JH, Chase JS. Ovulation induction in hypergonadotropic amenorrhea with estrogen and human menopausal gonadotropin therapy. Fertil Steri11984;42:919-922. 104. Check JH, Chase JS, Spence M. Pregnancy in premature ovarian failure after therapy with oral contraceptives despite resistance to previous human menopausal gonadotropin therapy. Am J Obstet Gynecol 1989;160:114-115. 105. CheckJH, Chase JS, Wu CH, Adelson HG. Ovulation induction and pregnancy with an estrogen-gonadotropin stimulation technique in a menopausal woman with marked hypoplastic ovaries. Am J Obstet Gyneco11989;160: 405 - 406. 106. Check JH, Wu CH, Check ML. The effect of leuprolide acetate in aiding induction of ovulation in hypergonadotropic hypogonadism: a case report. Fertil Steri11988;49:542-543. 107. Ledger WL, Thomas EJ, Browning D, Lenton EA, Cooke ID. Suppression of gonadotrophin secretion does not reverse premature ovarian failure. BrJ Obstet Gynaeco11989;96:196-199. 108. Lutjen P, Trounson A, Leeton J, et al. The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature 1984;307:174-175. 109. Chan CL, Cameron IT, Findlay JK, et al. Oocyte donation and in vitro fertilization for hypergonadotropic hypogonadism: clinical state of the art. Obstet Gynecol Surv 1987;42:350-362. 110. Sauer MV, Paulson R. Oocyte donation for women who have ovarian failure. Contemp Obstet Gyneco11989:125-135. 111. Rebar RW, Cedars MI. Hypergonadotropic forms of amenorrhea in young women. Endocrinol Metab Clin North Am 1992;21:173-191. 112. Karnis ME Zimon AE, Lalwani SI, et al. Risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Fertil Steri12003;80:498-501. 113. Practice Committee of the American Society for Reproductive Medicine. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril 2005;83:1074-1075.
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2HAPTER
Reproductive Options for Perimenopausal and Menopausal Women M A R K V. S A U E R PRATI
VARDHANA
Columbia University Medical Center, New York, NY 10032 Columbia University Medical Center, New York, NY 10032
Since 1990, there has been a substantial increase in the number of perimenopausal and menopausal women interested in fertility care. This rise followed the publication of successful pregnancies in frankly menopausal women undergoing oocyte donation, which focused international attention on the reproductive problems of women in their 40s and 50s (1). Presently, more than 9000 cases of oocyte donation are performed in the United States, mostly for women of advanced reproductive age. In 2003, of the 122,872 assisted reproductive technology (ART) cycles performed, 12%, or approximately 14,000 cycles, utilized donated eggs or embryos, a percentage that has been steadily increasing since 1995 (Fig. 8.1). Similarly, more than 12,000 cases of in vitro fertilization are initiated annually in women older than 40 years of age, as reported by the Society for Assisted Reproductive Technology (SART) and the Centers for Disease Control and Prevention (CDC) (2). Twenty percent of women undergoing ART cycles in 2003 were over the age of 40 (Fig. 8.2). However, despite the rising enthusiasm for fertility care, success rates in older women using their own oocytes have not significantly improved and remain very low compared with pregnancy rates observed in younger patients (Fig. 8.3). Poor TREATMENT OF THE POSTMENOPAUSAL WOMAN
outcomes are a result of natural ovarian senescence, which directly contributes to reduced fertility and pregnancy wastage in this population. Consequently, a woman's age is the most important factor affecting the chances of a live birth when her own eggs are used. Unless the aging oocyte is replaced, most efforts at assisted reproduction are destined to fail once perimenopausal signs and symptoms are present. The term fecundity refers to a woman's normal ability to reproduce. A fecundability rate is often used to describe the monthly conceptions that occur among sexually active couples within a population. Fecundability rates have been calculated for many different populations and vary slightly according to cultural, religious, and sexual practices. However, a feature common to all groups is the inevitable decline in fecundity that accompanies aging. Women most often conceive and deliver their children while in their twenties. Typically, fertility rates decline during the fourth decade of life, reaching a nadir by the time women enter their early forties. The inevitable loss of fertility is readily apparent when reviewing the birth rates of "natural populations." Natural populations are composed of individuals who do not practice contraception. Within 111
Copyright 9 2007 by Elsevier,Inc. All rights of reproduction in any form reserved.
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FIGURE 8.1 Types of ART procedures in the United States, 2003. (Data from www.cdc.gov/ART/ART2003.)
natural populations, fertility remains relatively stable until women reach approximately 30 years of age, when a significant fall occurs (Fig. 8.4) (3). By age 35, delivery rates are reduced by one-half, and by age 45, live births are diminished by 95% from values seen in the same population at age 25 (4). Comparing figures from natural populations to delivery rates in the U.S. population at large, similar trends are apparent (5). Less than 2% of all live births occur in women older than 40 years. By age 47, this is further reduced to a mere 0.01% of deliveries (6). Although the lay press has focused on sensational births occurring in menopausal women, few individuals are actually able to successfully deliver a healthy baby beyond the age of 45 without assistance from oocyte donation.
consistency, all
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FIGURE 8.3 Pregnancy rates, live birth rates, and singleton live birth rates for women of different ages who had ART procedures using fresh nondonor eggs or embryos in 2003. (Data from www.cdc.gov/ART/ ART2003.)
Further complicating the decreasing fertility rate of older women is the exponential rise in the incidence of aneuploidy noted in the embryos of conception cycles. This phenomenon leads to an elevated rate of miscarriage and an increase in the number of observed anomalies in the delivered offspring. For example, at age 25, only 10% of clinically diagnosed pregnancies end in spontaneous abortion (7). By age 45, the spontaneous abortion incidence is 40% to 50%. Increased rates of spontaneous abortion occurring with advancing maternal age is further demonstrated by reviewing studies of women undergoing artificial 600
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FIGURE 8.2 Age distribution of women who had ART cycles using fresh nondonor eggs or embryos, 2003. (Data from www.cdc.gov/ART/ ART2003.)
FIGURE 8.4 Fertility rates in natural populations, and recent United States populations, note a dramatic fall beginning approximately at age 30 years to almost negligible levels at age 45 years. [black four pointed star], Hutterites (United States 20th Century); ", Burgeoisie Geneva 17th Century; [white circle], Burgeoisie Geneva 16th Century; [black small square], French Village 17th Century; [white square], Iranian Village 20th Century; [white up pointing small triangle], United States (1955); [black up pointing small triangle], United States (1981). Maroulis GB. Affect of aging on fertility and pregnancy. Semin ReprodEndocrino11991;9:165-175.
CHAPTER 8 Reproductive Options for Perimenopausal and Menopausal Women insemination using donor sperm (8). Even in ART cycles, miscarriage rates approach almost 30% in women using their own eggs at the age of 40 (Fig. 8.5). Pregnancy wastage is thought to result principally from random mutations within resting oocytes. Throughout life, human eggs are suspended in development at the diplotene stage of meiosis I. The oocytes residing in the ovaries during the perimenopause have been present since before birth. The protracted process of oocyte aging seems to exert its deleterious effects primarily on the cell nucleus, as evidenced by the positive correlation of maternal age with chromosomal aberrations. As a result, trisomy is witnessed in only 0.1% of newborns of 25-year-old mothers, rising to 10% as maternal age reaches 45 years (9). The meiotic competence of in vitro matured human oocytes is influenced adversely by age, with an increased frequency of errors in chromosome segregation at the first meiotic division (Table 8.1) (10). Studies performing preimplantation genetic diagnosis (PGD) using fluorescence in situ hybridization (FISH) in IVF embryos have documented the increase in chromosomal aneuploidies with advancing maternal age (Fig. 8.6) (11). These findings agree with observations that a high percentage of abortuses in women of advanced reproductive age are chromosomally abnormal (12). In a teleologic sense, preimplantation and postimplantation losses protect the species from unwanted genetic mutations while simultaneously minimizing the health risks posed by pregnancy in the older individual. Although less well defined, adverse reproductive events also occur in men older than 55 years of age. Advanced paternal age has been associated with trisomies and the iso-X syndrome (13,14). Other reproductive hazards include an increased incidence of chronic genitourinary ailments, particularly prostatitis and epididymitis, which affect fertilization in vivo and in vitro. Chronic infections are difficult or impossible to eradicate using antibiotic therapy. Even when infections are successfully treated, lingering inflammation in the genitourinary tract may produce leukocytospermia, 70 60 50 =
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Miscarriagerates amongwomenwho had ART cyclesusing flesh nondonoreggs or embryos,by age of woman, 2003.
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FIGURE 8.5
Adapted from reir 10.
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The prevalence of childlessness and infertility in older couples is difficult to ascertain. However, a progressive increase in the number of childless couples has been described. It is estimated that only 5% of childless couples in their early 20s wish to begin a family, compared with more than 60% of couples in their 40s (2). Biologically, women may be best suited to reproduce while in their 20s. However, psychosocially, many young individuals are neither in a position to raise a child nor desirous to begin a family. Demographic data from the United States indicates that the majority of women utilizing ART procedures to achieve pregnancy are over the age of 30, and oftentimes, over 40 years (5). Reasons given for this delay include the pursuit of educational and vocational goals, later marriages, an increased prevalence of divorce, and the widespread availability of effective birth control. Many women are electing to begin a family later in life as a result of second marriages. Unfortunately, many individuals are unaware of the change in fecundity status that naturally occurs with advanced age and suddenly find themselves unable to conceive despite having had little or no problem in the past. In one survey, among women older than 40 interested in oocyte donation two-thirds had never delivered a baby and 51% were recently divorced (19). In general, women seeking fertility care who are older than 40 have poor reproductive outcomes (20-24) (Fig. 8.7). Registries that track and tally success rates for assisted reproduction have reported similar findings from various parts of the world (25-27). The pregnancy rates logged in the medical literature actually overestimate the likelihood of achieving pregnancy, since manywomen entering treatment are dropped from therapy because of poor responses to controlled ovarian hyperstimulation and are not included in tallies. In essence, evolution has precluded many modern women from having children after the age of 40 and certainly by age 50, when most individuals experience complete cessation of ovulatory function. Unlike other mammals, the human ovaries have largely exhausted their supply of oocytes by the time menopause occurs (28). This diminution inevitably occurs despite the fact that less than 0.001% of the ovary's original number of oocytes are actually ovulated. Histologic studies reveal that, regardless of chronologic age, only a few thousand eggs remain by menopause (29). The compensatory rise in stimulating pituitary gonadotropin that normally accompanies ovarian failure is unable to recruit eggs from this surviving cohort. Cadaver studies indicate a decline in follicular mass with advancing age, with accelerated rates of follicular atresia occurring during the last decade of reproductive life. Similarly, ovaries removed from healthy women of various ages and analyzed for the presence of gametes demonstrate an accelerated depletion of oocytes as menopause approaches. Curiously, the largest turnover of eggs occurs before birth, with a steady decline in number noted, from approximately 7 million oocytes at 20 weeks' gestation to about 2 million at the time of delivery (30). At the time
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of menarche there are approximately 300,000 eggs, and by menopause, few primordial follicles remain (28) (Fig. 8.8).
I. NATURAL FERTILITY IN THE PERIMENOPAUSE Despite the low incidence of pregnancy in women of advanced reproductive age, spontaneous conceptions do occur even in the face of elevated gonadotropins. However, reports of healthy older women undergoing artificial insemination demonstrate reduced fecundity, with cumulative pregnancy rates approximating 40% (31,32). Spontaneous abortions are common and occur in as many as one-half of the clinical pregnancies reported for these women. A high percentage of losses result from aneuploidy. Anomalies in live births are also increased. For instance, Down syndrome occurs in 0.5 to 0.7 per thousand live births in 25-year-old mothers, but the number rises to 75.8 to 152.7 per thousand live births by age 49 (33). Of 2404 amniocenteses performed
CHAPTER 8 Reproductive Options for Perimenopausal and Menopausal Women
FIGURE 8.8 Decline in oocytes from birth to menopause. Faddy MJ, Gosden RG, Gougeon A, et al. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992;7:1342-1346; Erickson GF. Ovarian anatomy and physiology. In: Lobo RA, KelseyJ, Marcus R. Menopause."biology and pathobiology. San Diego, CA: Academic Press, 2000:13-32.
because of advanced maternal age, 2.4% were discovered to be aneuploid, and 50% of these were trisomy (34). As menopause approaches, menstrual cycles rhythm generally decreases in length as a result of oocyte loss, earlier follicular recruitment and shortening of the follicular phase (35-37). As a measure of reproductive reserve, serum follicle-stimulating hormone (FSH) levels drawn on the third day of the menstrual cycle have been used as prognostic indicators before in vitro fertilization (38). Levels above 15 mIU/mL are associated with decreased success rates, and when greater than 25 mIU/mL, pregnancy rarely occurs. Elevated values are observed with increasing frequency when evaluating women older than 40 years of age and are common in most women older than 45. An increase in early follicular phase FSH coincides with the period in which diminished fecundity rates are witnessed. The elevated gonadotropins represent compensatory stimulation resulting from a progressively dwindling number of functioning follicles. This rise in FSH is caused in part by a decreased secretion of ovarian inhibin B, a glycoprotein heterodimer produced by the granulosa cells of the developing antral follicles and a decrease in inhibin A, secreted by the corpus luteum (39-43). The loss of negative feedback inhibition triggers the rise in FSH levels (39,40,44). It appears that a state of
115
"reproductive menopause" exists up to 10 years before the cessation of menses heralds the onset of the "endocrine menopause" (Fig. 8.9) (45). Traditional therapies designed to enhance fertility during this transition period are likely to fail, and live births occur in fewer than 5% of treatment cycles (46,47). The identification and accurate measurement of inhibin has provided further insight into the effect of age on follictdogenesis. Inhibin correlates with follicular function and granulosa cell competence and is decreased with age (41,48). Inhibin measured in the follicular fluid of hyperstimulated ovaries aspirated for purposes of in vitro fertilization reflects correlations among the number of recruited follicles, oocytes retrieved, and embryos produced. Not surprisingly, inhibin was reduced in women experiencing a poor response to ovarian hyperstimulation (49). As a serum marker, it may be a more sensitive prognostic indicator of ovarian reproductive competence than levels of serum FSH. After menopause, inhibin is undetectable in serum samples. In vitro studies of cultured luteinized granulosa cells have shown that in patients with low basal FSH values (< 6 IU/L), inhibin secretion is twofold higher than patients with high basal FSH levels (> 10 IU/L) (50). In recent years, new promising markers for assessing reproductive potential have emerged. Another method used to measure ovarian reserve involves ultrasound determination of the number of antral follicles, or developing oocytes, in the early follicular phase. A detectable decline in follicle count precedes the decrease in ovarian steroid hormones and rise in gonadotropins. Sonographic studies confirm that the antral follicle count declines with chronologic age, likely a result of a diminution in the primordial follicle reserve (51). Antral follicles in the ovary can be visualized by transvaginal ultrasound at a size of 2 to 10 mm. Measurements are taken in the early follicular phase (cycle days 2, 3, or 4) (51). Below the age
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of 30, the number of antral follicles is much greater than after 40, with women over age 40, usually revealing less than 10 total antral follicles (51,52). The rate of decline of antral follicle counts rapidly increases after the age of 37, reflecting the diminution of the remaining primordial follicle pool (51). Antral follicle counts have been shown to be reproducible over multiple cycles and correlate with age and response to ovarian stimulation during IVF (Fig. 8.10). Therefore, some consider it to be the best marker of ovarian reserve (53,54). Recently, serum antimfillerian hormone (AMH) levels have been introduced as a novel measure of ovarian reserve. Anti-Mfillerian hormone, also called Mfillerian inhibitory substance (MIS), is a product of the granulosa cells within the preantral and antral follicles. Serum MIS levels on cycle day 3 decrease progressively with age and become undetectable after menopause (55). In addition, MIS is related to the number of antral follicles and to the ovarian response to controlled ovarian hyperstimulation. During IVF cycles, higher day 3 serum MIS values are associated with a greater number of retrieved oocytes (56). In a study at one center of 56 women with normal day 3 FSH levels, patients with a poor response to IVF (less than six oocytes retrieved) had significantly lower follicular and luteal phase MIS compared with high responders (20 or more oocytes retrieved) (57). Because MIS levels represent the primordial pool of nongrowing FSH-independent follicles that may respond to exogenous gonadotropins, measuring MIS levels could help to predict ovarian response in assisted reproduction cycles, especially in older women with early follicular FSH levels within the normal range (56). Numerous studies have shown that serum MIS concentrations show the best correlation with diminished
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ovarian reserve. When women are studied prospectively over time by assessing their ovarian reserve, MIS has been shown to best reflect the process of reproductive aging and the continuous decline of the oocyte/follicle pool as compared with FSH, inhibin B, and antral follicle count (58). As such, serum MIS is becoming a standard test performed in many fertility centers prior to the starting controlled ovarian hyperstimulation. The diminished capacity to conceive and carry babies to term typically has been blamed on the ovaries and uterus. A large drop in available oocytes for recruitment and ovulation accompanies senescence in the ovary. Higher rates of chromosomally abnormal eggs are present in the remaining pool for selection. However, in laboratory animals, the uterus also undergoes age-related changes responsible for diminished implantation and pregnancy rates. As a result, older animals eventually are unable to achieve pregnancy despite the transfer of embryos produced by younger donors. The number of implantations per animal and the proportion of mice found to have any implantation a week postconception declined significantly by 9 months of age (59). Similarly, older mice were observed to have fewer implantations sites and subsequently were noted to be twice as likely to resorb an early pregnancy compared with younger animals (60). Correlates using other laboratory animals also exist and include a reduction in litter size with age observed in the hamster (61). In younger animals, 31% of the losses resulted from preimplantation death, and 69% were postimplantation events. However, in senescent hamsters, a reversed scenario was observed, with preimplantation death occurring in 64% and postimplantation losses seen in 36% of cases. The higher overall loss rates of older animals were thought to be a consequence of less viable ova. When older hamsters received ovarian grafts from younger animals, they were better able to support transferred blastocysts, implying the aging corpus luteum also plays a role in the early establishment and maintenance of pregnancy (62). Although the number of implants is significantly reduced in mated female hamsters, the number of decidual reactions per uterine horn is the same in older animals and younger females (63). This may reflect delayed or abnormal patterns of embryonic development in the blastocysts of older individuals. Abnormal concepti may be secondary to impaired oocyte quality or may perhaps be secondary to effects of the oviductal environment that alters early preimplantation development. Many possible factors influence the relationship between the conceptus and the endometrial environment. These include the rate and normal pattern of development of ova within the older female reproductive tract, delayed uterine receptivity to blastocyst implantation secondary to a decreased capacity of older uterine tissues to take up steroids, and the less efficient uterine response to a decidualizing stimulus as seen in aging mice, rats, and hamsters (64). Similarly, the age-related decline in human fertility may partly be caused by uterine factors (65). Uterine receptivity
CHAPTER 8 Reproductive Options for Perimenopausal and Menopausal Women is best measured by comparing individual embryo implantation rates in humans of various ages undergoing in vitro fertilization and embryo transfer. Women younger than 30 years of age approach rates as favorable as 20% per embryo transferred, decreasing to 9% for women 36 years of age and older (66). After age 40, individual embryo implantation rates are less than 5% (67). Alterations in uterine blood flow also occur with declining levels of estradiol, which may adversely affect the local endometrial environment (68). The identification of estrogen receptors in the wall of human uterine arteries supports this hypothesis (69). Fibrotic changes found in the muscularis of the uterine artery further underscore important physiologic changes accounting for decreases in local blood flow (70). Approximately one-half of spontaneously aborted pregnancies are chromosomally normal, implying that a local endomyometrial factor may be responsible for the loss. Whether this is a primary target organ event or secondary to the inability of the aging corpus luteum to support the pregnancy remains conjectural. Unfortunately, it is not possible to dissociate the oocyte from the influence of the local environment when studying normal postfertilization development and implantation. Oocyte and embryo donation to older women, using gametes obtained from younger individuals, provides an ideal opportunity to ascertain the contribution of each of these two variables independently from each other. When prescribed hormone replacement, the endometria of menopausal women between 40 and 60 years of age exhibit normal histologic and steroid receptor response (70). Likewise, biopsied endometria of younger women with ovarian failure are indistinguishable from older women on similar replacement regimens. When adequate doses of exogenous estrogen and progesterone are delivered, most uteri respond appropriately and demonstrate normal endometrial morphology, regardless of the patient's age or diagnosis. The high rate of implantation and delivered pregnancies reported in women of advanced reproductive age undergoing oocyte donation is testimony to the receptivity of a uterine environment supplemented with hormone replacement. Success rates with oocyte donation are three to five times higher than those in older women using their own eggs who are undergoing standard in vitro fertilization (Fig. 8.11) (67).
II. DEVELOPMENT OF OOCYTE AND EMBRYO D O N A T I O N AND ITS APPLICATION IN OLDER W O M E N The ability to transfer preimplantation embryos conceived in vitro or in viva from one female to another has been performed in more than a dozen different mammals
117
FIGURE 8.11 Live birth rates for ART cycles using flesh embryos from donor eggs versus ART cycles using a woman's own eggs among women of different ages. (Data from www.cdc.gov/ART/ART2003.)
(71). First demonstrated in the rabbit, this method was popularized by the animal husbandry business and revolutionized the cattle breeding industry (72). More than 100,000 calves are born annually as a result of refinements in this technique. Transfer of zygotes to recipient animals, synchronized to the menstrual cycle of donors, results in the establishment of pregnancy in 25% to 50% of transfer cycles. Modification of these techniques led to the establishment of the first embryo donation pregnancy in humans in 1983 (73). Early attempts focused on the nonsurgical obtainment of embryos conceived in viva from spontaneously ovulating cycles using uterine lavage. However, natural cycles produced morphologically normal embryos in only 25% of attempts, and as a result, pregnancies in recipients occurred in only 10% to 12% of initiated cycles (74). In addition, the use of uterine lavage of embryos risked the transmission of infectious agents, causing this method to fall out of favor. Unlike the experience in cattle, efforts to maximize the yield of embryos per lavage by superovulating human donors were unsuccessful and resulted in a high rate of complications (75,76). Controlled ovarian hyperstimulation of oocyte donors followed by in vitro fertilization and embryo transfer to women with premature ovarian failure was reported in 1983 and resulted in a successful pregnancy in one of seven women undergoing treatment (77). During the next 10 years, with the advent of transvaginal oocyte aspiration and advances in laboratory techniques, increasing numbers of studies employing a variety of transfer techniques were published showing high rates of successful implantation and pregnancy (78-82).
118
Surprisingly, in women with hypergonadotropic hypogonadism receiving sex steroid replacement and donated oocytes fertilized in vitro, clinical pregnancy rates and individual embryo implantation rates are significantly increased over values normally seen in women attempting in vitro fertilization using their own oocytes (47). This is attributed to the provision of large numbers of high-quality oocytes for in vitro fertilization produced by young, fertile donors, combined with the enhanced endometrial environment provided by the orderly deliverance of controlled doses of estrogen and progesterone. In this manner, embryo quality is maximized and endometrial receptivity simultaneously enhanced (83). By 1990, reports of successful pregnancies in menopausal women beyond the age normally considered to be "premature" appeared (67,84). Reluctance to transfer embryos to women older than 40 was based on the general belief that a uterine factor precluded implantation and pregnancy in aging animals. However, preliminary trials of oocyte donation in menopausal women demonstrated similar success rates for implantation and pregnancy as younger recipients. Obstetric outcomes were favorable, and miscarriage rates were reduced below that normally seen in older mothers (47). As mentioned earlier, donor eggs or embryos were used in approximately 12% of all ART cycles carried out in 2003. The majority of these cycles were performed in women over the age of 39 (2) (Fig. 8.12). Oocyte donation from young donors overcomes the problems of diminished ovarian reserve and increased aneuploidy risk that accompanies advancing age and results in significantly higher pregnancy rates than standard IVF regimens. Women over 45 years of age, even as old as 55, may achieve pregnancy rates on par with young women using their own eggs (18,85,86). Recipient age does not adversely affect cycle outcome when donor
FIGURE 8.12 Percentageof ART cycles using donor eggs, by ART patient's age, 2003.
SAUER AND VARDHANA
oocytes are used, with fertilization rates, embryo implantation rates, and ongoing pregnancy rates similar to younger cohorts (87). Donor egg and embryo transfer provides the most reasonable reproductive option for older women who are either perimenopausal or menopausal and remains the most successful fertility treatment for patients of advanced reproductive age.
III. CHILDBEARING BY THE PERIMENOPAUSAL A N D MENOPAUSAL W O M A N Most women interested in oocyte donation appear to be perimenopausal, usually between the ages of 40 and 50 years (1,2). Older patients traditionally have the worst prognosis for fertility using natural or assisted reproductive techniques with their own eggs (Fig. 8.13). Poor response to ovarian hyperstimulation and IVF has been well documented in older women. Numerous studies have demonstrated a decline in IVF success with advancing age, especially above age 40 (88). With advancing age, the number of oocytes retrieved and embryos obtained, implantation, and viable pregnancy rates rapidly decline. The response to ovarian stimulation is diminished, requiring large dosages of gonadotropins and yielding high cycle cancellation rates (89). Often, poor response to stimulation with gonadotropins is the earliest sign of ovarian aging and is seen prior to any hormonal alterations or menstrual cycle changes (90-92). However, using oocyte donation, women of advanced reproductive age have pregnancy rates similar to younger women.
Demographic differences are apparent in older recipients seeking fertility care compared with women with premature ovarian failure (19). They are commonly employed in fulltime vocational pursuits and in many cases are highly educated. A large percentage of patients have delayed childbearing in order to achieve professional goals. In addition, these women have often remarried, are likely to have undergone an elective termination of pregnancy, and usually have been a recipient of extensive infertility care prior to attempts at oocyte donation (93). Oocyte donation remains one of the most efficient and safe assisted reproductive techniques (1). Endometrial biopsies of recipients age 50 to 60 years suggests that the uterus maintains its ability to respond normally if given pharmacologic doses of sex steroid (18,70). Analysis of egg donation cycles shows no significant differences in rates of implantation or ongoing pregnancy in older women as compared with younger women receiving donated embryos. These rates, however, are significantly higher than the rates in infertile women of similar age undergoing standard in vitro fertilization using their own eggs. This suggests that the
CHAPTER 8 Reproductive Options for Perimenopausal and Menopausal Women
*For consistency, all rates are based on cycles started.
FIGURE 8.13 Pregnancyrates, live birth rates, and singleton live birth rates for ART cyclesusing fresh nondonor eggsor embryosamongwomen aged 40 and older,2003. (Data from www.cdc.gov/ART/ART2003.)
endometrium retains its ability to respond to gonadal steroids and provides a receptive environment for embryo implantation and gestation even in older women (67,94,95). Despite the success of oocyte donation in perimenopausal and postmenopausal women, there is still some debate as to what the upper age limit for donor IVF should be (96). Concerns include the unknown risks to the elderly gravidarum, issues of longevity in the delivering parents, and the "unnatural" method inherent to the process of establishing the gestation (97,98). The recommendation to extend therapy to women over the age of 45 has been made with cautious reservation by the American Society for Reproductive Medicine and with the proviso that recipients be adequately screened medically and psychologically (99). As many as 20% to 30% of potential recipients of advanced reproductive age may fail the screening process and ultimately be precluded from treatment (47). However, after comprehensive medical screening, women found to be emotionally and physically fit have performed well in their attempts at pregnancy, and outcomes have been good.
IV. SCREENING AND PREPARATION OF POTENTIAL RECIPIENTS Screening potential candidates for oocyte donations has centered on testing their overall health. Although the probabilities for establishing pregnancy in recipients may be dramatically altered using oocyte donation, obstetric risks are age related and therefore significantly increased in the older population. Testing cardiovascular health is important,
119
because the stress of pregnancy on the heart is significant. For this reason, baseline assessments to uncover diabetes, hyperlipidemia, and exercise intolerance are also indicated. A generalized search for occult malignancies has uncovered several cancers, including breast, uterine, and cervical carcinomas; lymphoma; and melanoma. Table 8.2 lists the surveillance tests most often used in screening older recipients. Donors and recipients follow a standard synchronization regimen with donors undergoing ovarian downregulation using leuprolide acetate followed by gonadotropins. In many perimenopausal patients, ovarian function is typically still intact, because ovulatory cycles usually continue throughout the 5- to 10-year transition period that defines the perimenopause. Therefore, for purposes of donor synchronization and to avoid an untimely premature ovulation in perimenopausal recipients, which would create a progestational endometrium, it is preferable to downregulate the pituitary of cycling women with a gonadotropin-releasing hormone (GnRH) agonist before prescribing standard hormone replacement. Women undergoing donor IVF have successfully used a variety of hormone replacement regimens. Recipients are treated with oral micronized estradiol (E2) for several days before donor-initiated gonadotropin
TABLE 8.2
Screening Examination Required of Couples of Advanced Reproductive Age Requesting Oocyte Donation
If over 40:
Electrocardiogram Mammogram Chest roentgenogram 2-hour glucose tolerance test If over 45:
Treadmill test If over 50 or premature ovarian failure:
Bone densitometry All women of advanced reproductive age: Blood chemistry panel Sensitive thyroid-stimulating hormone (TSH) Complete blood count with platelets Papanicolaou examination Cervical cultures (gonorrhea/Chlamydia) Rubella Urinalysis and culture Blood type and Rh Hemoglobin electrophoresis Genetic testing (if applicable for certain ethnic groups) Infectious disease, both spouses
Human immunodeficiency virus (HIV- 1/2) Syphilis (RPR) Hepatitis A, B, C screen Human lymphotrophic virus (HTLV-1/2) Reproductive
Transvaginal ultrasound of pelvis Hysterosalpingogram or saline hysterosonogram Semen analysis
120 therapy. Most commonly, oral estradiol, micronized or in the valerate form, has been prescribed. Estrogen has also been delivered transdermally with good results. Advantages of this method include maintenance of physiologic sex steroid levels and lessened hepatic effects (100). However, many patients develop rashes and irritation at the patch sites, and multiple patches must be worn simultaneously to achieve adequate levels of estradiol. Delivery may be accomplished in a sequential step-up fashion to mimic the normal fluctuations in serum estradiol levels (101) or delivered as a fixed continuous dose (102). Pregnancy rates are similar using either approach. When following the step-up approach, synchronization with the donor undertaking ovarian hyperstimulation requires the recipient begin medication 4 to 5 days in advance of the donor's injecting gonadotropins. Pharmacologic levels of circulating sex steroid result from prolonged use of medicinal estrogen, and despite claims of "physiologic" replacement, serum values of estrone, estrone sulfate, and estrone glucuronide are known to be grossly elevated (103). Progesterone is needed to decidualize the endometria in preparation for embryo implantation. Recipients begin taking progesterone on the morning of the day before the donor's egg retrieval and continue progesterone until after the pregnancy is established. A variety of formulations have been used successfully (104,105). Most commonly, intramuscular progesterone given twice daily or daily vaginal progesterone has been recommended. The need to maintain replacement steroids throughout the first trimester commonly leads to local irritation and inflammation at the injection sites. Mternate regimens include suppositories and gel-based or encapsulated micronized progesterone. Embryo transfers occurs 72 hours after retrieval, or 5 days after retrieval in the case of a blastocyst transfer. E2 and progesterone are continued until either a negative pregnancy test results or until 10 to 14 weeks of gestational age (program dependent) in women achieving pregnancy (106) (Fig. 8.14). Morphologic analyses of endometrial biopsy specimens taken from women using hormone replacement therapy have uncovered certain unique characteristics. Although histologically close to normal, mid-luteal samples typically demonstrate a delayed pattern of glandular maturation, exhibited in up to 25% of samples (70). When endometria are resampled later in the cycle (day 26 to 28), biopsy results are usually normal, implying a catch-up phenomenon. Transvaginal ultrasound images denote a homogeneous echodense pattern, with a thickness approaching 8 to 10 mm. However, pregnancies have occurred with measures as thin as 4 mm and as thick as 23 mm (107). Sex steroid receptors for progesterone and estrogen are within normal limits for luteal endometria. In many cases, women might not have been taking hormone replacement therapy and therefore require a priming cycle to develop a full endometrial response. This occurs in
SAUERAND VARDHANA
FIGURE8.14 Schematicof cyclesynchronizationusing a GnRH agonist in both donor and recipient. GnRH agonists are used to down-regulatethe pituitary of recipients with evidence of ovarian activityprior to beginning oral estradiol. Oral estradiol is prescribed to the recipient 4-5 days in advanceof the donor startinggonadotropin injections.Progesteroneis administered starting the day after hCG injection in the donor, and I day prior to aspirating oocytes. Embryo transfer is performed 3 days following oocyte retrieval. Serum pregnancytesting occurs 12 days post-transfer. Pregnant patients are maintained on estradiol and progesterone through 12 weeksof gestational age. SauerMV, Cohen MA. Egg/embryodonation. In: Gardner D, WeissmanA, Howles C, Shohan Z, eds. Textbook of assisted reproductive techniques laboratory and clinicalperspectives, 2nd ed. London: Taylor and Francis, 2001:843-853.
approximately 5% of new cases, regardless of the recipient's age. A mock cycle enables the discovery of such indMduals and permits adjusting for a hyperplastic glandular pattern of response that occasionally occurs (2%) (108). A practice transfer using an embryo transfer catheter is performed at the time of biopsy to measure the length and contour of the cavity and to ensure that a transcervical embryo transfer can easily be accomplished.
V. OBSTETRIC MANAGEMENT AND DELIVERY CONSIDERATIONS Pregnancies resulting from oocyte donation are considered high risk by obstetricians. Although several studies have concluded that the outcomes of pregnancies following oocyte donation are favorable, there are potential obstetric risks such as gestational hypertension, which can be more complicated in older women. Furthermore, the occurrence of multiple gestations is common and is seen in 20% to 40% of live births (Fig. 8.15). Pregnancies initially are documented using serum beta human chorionic gonadotropin ([3hCG) measurements and transvaginal ultrasound. Ultrasound examinations performed early in the gestation document the number of implantation sites and delineate normal embryonic growth. Commonly, supernumerary implantations occur and often fail to develop normally. In many cases, abnormal implantation sites are absorbed without incident. Other times, their collapse results in vaginal bleeding. Ultrasound is useful for identifying patients at risk. Visualizing the early pregnancy appears to facilitate the patient's acceptance of the pregnancy, many of whom initially express difficulty in believing the pregnancy
121
CHAPTER 8 Reproductive Options for Perimenopausal and Menopausal Women
*Number of fetuses not known because the pregnancy ended in early miscarriage.
FIGURE 8.15 Risk of having multiple-fetus pregnancy and multipleinfant live birth from ART cyclesusing fresh donor eggs. (Data from www. cdc.gov/ART/ART2003.) actually occurred. Serial measures of estradiol and progesterone are neither helpful nor indicated, because pharmacologic doses of hormone are delivered daily and serum levels do not reflect the tissue response (103,109). Referral to specialists in maternal and fetal medicine is appropriate given the age of patients. Regardless of their prior health, pregnant women older than 40 should be considered high-risk patients. Reports describe a tendency for hypertensive complications in women after oocyte donation (110). Monitoring for diabetes and early signs of hypertension is important. Serial growth assessment provides early evidence of fetal growth retardation. Late-occurring events that complicate pregnancies in the older women, particularly stillbirth, may best be avoided by an aggressive approach to delivery (111). With full knowledge of the gestational age of these mothers, attempts to induce labor near term (38 to 39 weeks) should be considered iudicious.
lative bodies in the United States will enact restrictive measures to preclude this application of the method. Increasing numbers of women in their 40s are seeking fertility care. Most of these patients fail to become pregnant using their own eggs, and many elect a trial of oocyte donation. For older patients, oocyte donation may actually represent the only viable option for parenting, because adoption services are also difficult to secure for couples of advanced reproductive age. Vigilant surveillance is imperative in the screening of these individuals. To maximize success, a thorough health assessment is mandatory. Oocyte donation was not intended to be used indiscriminately (118). Many abnormalities are discovered, some of which do not preclude treatment, but others may dictate exclusion. This necessitates a more primary care approach by the fertility specialist and requires the development of more discriminatory criteria from that usually practiced when dealing with younger patients. Concerns have been raised regarding the potential harm to the "fabric of society" brought on by allowing older individuals the chance to become parents. However, precedent already exists in that many children have been reared by grandparents, and the grandparents take on most of the parenting role in many cultures. Society has been accepting of older men and younger wives starting families. Typically, in countries where restrictions on oocyte donation exist, no laws preclude males from using donated sperm or older men from procreating with their younger wives. Precluding healthy women from granting themselves a successful alternative for reproduction while allowing their male counterparts access to such opportunity should be considered sexist and prejudicial. As in most cases of social evolution, as increasing numbers of cases accumulate, it is likely that acceptance will follow.
VI. FUTURE APPLICATIONS References Interest has focused on the means for rejuvenating the oocytes of older women using cytoplasm infused from younger donor oocytes (112). Similarly, nuclear transplantation techniques may allow enucleated donor oocytes to be reconstituted with the genetic material of older recipients (113), allowing women an opportunity to perpetuate their genetic lineage. It has also been suggested that women should store or bank their oocytes (oocyte cryopreservation), similar to men and their sperm, to avoid age-related infertility later in life (114). However, given the low rate of success in using cryopreserved oocytes (115), promoting this approach for routine clinical use remains highly controversial. The widespread use of oocyte donation for increasing numbers of women of advanced reproductive age was inevitable. Despite attempts in several countries to limit or prohibit oocyte donation (116,117), it is unlikely that legis-
1. SauerMV. Treatingwomen of advancedreproductiveage.In: Principlesof oocyteand embryodonation. New York: Springer-Verlag,1998;271-292. 2. Assisted reproductive technology in the United States and Canada: 2003 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Register. www.cdc.gov/ART/ART2003, 2005;389. 3. Maroulis G. Effects of aging on fertility and pregnancy. Semin Reprod Endocrino11991;9:165.
4. Henry L. Some data on natural fertility. Eugenics 1961;8:81. 5. Center for Disease Control and Prevention. 2003 Assisted Reproductive Technology (ART) Report. www.cdc.gov/ART/ART2003. 6. HansenJR Older maternal age and pregnancyoutcome: a reviewof the literature. Obstet GynecolSurv 1986;41:726-742. 7. Stein ZA. A woman's age: childbearing and child rearing.Am J Epidemio11985;121:327-342.
8. Virro MR, Shewchuk AB. Pregnancy outcome in 242 conceptions after artificial insemination with donor sperm and effects of maternal age on the prognosis for successful pregnancy. Am J Obstet Gynecol 1984;148:518-524.
122 9. Leveno KJ. Pregnancy after 35. In: Cunningham FG, MacDonald PC, Gant NF: Williams obstetrics, 18th ed., vol suppl 2. Norwalk, CT: Appleton-Century-Crofts, 1989:1-12. 10. Volarcik K, Sheean L, Goldfarb J, et al. The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum Reprod 1998;13:154-160. 11. Benadiva CA, Kligman I, Munne S. Aneuploidy 16 in human embryos increases significantly with maternal age. Fertil Steril 1996;2: 248-255. 12. Lauritsen JG. Aetiology of spontaneous abortion. A cytogenetic and epidemiological study of 288 abortuses and their parents. Acta Obstet Gynecol Scand Supp11976;52:1-29. 13. Magenis RE, Chamberlin J, Cruz FF, Gerald SG. Trisomy 21 clown's syndrome. NICHD Mental Retardation Research Center Series. Baltimore: University Park Press, 1981. 14. Lenz W. Epidemiology of congenital malformations.Ann NYAcad Sci 1965;123:228-236. 15. Hellstrom WJG, Neal DE. Diagnosis and therapy of male genital tract infections. Infertil Reprod Med Clin North Am 1992;3:399. 16. Cnattingius S, Forman MR, Berendes HW, et al. Delayed childbearing and risk of adverse perinatal outcome. A population-based study. JAMA 1992;268:886- 890. 17. Public Health Statistics 1978-84. Wisconsin Department of Health and Human Services, 1985. 18. Sauer MV, Paulson RJ, Lobo RA. Pregnancy after age 50: application of oocyte donation to women after natural menopause. Lancet 1993;34 1(8841):321-323. 19. Sauer MV, Paulson RJ. Demographic differences between younger and older recipients seeking oocyte donation. J Assist Reprod Genet 1992;9: 400-404. 20. Medical Research International. In vitro fertilization/embryo transfer in the United States: 1985 and 1986 results from the National IVF/ET Registry. Fertil Steri11988;49:212-215. 21. Medical Research International and the Society of Assisted Reproductive Technology. In vitro fertilization/embryo transfer in the United States: 1987 results from the National IVF-ET Registry. Fertil Steril 1989;51:13-19. 22. Medical Research International and the Society for Assisted Reproductive Technology. In vitro fertilization-embryo transfer in the United States: 1988 results from the IVF-ET Registry. Fertil Steril 1990;53: 13-20. 23. Medical Research International and the Society for Assisted Reproductive Technology. In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1989 results from the IVF-ET Registry. Fertil Steri11991;55:14-22. 24. Medical Research International and the Society for Assisted Reproductive Technology. In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1990 results from the IVF-ET Registry. Fertil Steri11992;57:15-24. 25. Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 1998; 339:573-577. 26. Dicker D, Goldman JA, Burton AH, Dicker RC. Age and pregnancy rates in in vitro fertilization. J In Vitro Fert Embryo Transf 1991;8: 141-144. 27. Piette C, de Mouzon J, Bachelot A, Spira A. In vitro fertilization: influence of women's age on pregnancy rates. Hum Reprod 1990;5: 56-59. 28. Richardson SJ, Senikas V, Nelson JE Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65(6):1231-1237. 29. Block E. Q.uantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat (Basel) 1952;14: 108-123.
SAUER AND VARDHANA 30. Baker TG. A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond B Bid Sci 1963;158:417-433. 31. Stovall DW, Toma SK, Hammond MG, Talbert LM. The effect of age on female fecundity. Obstet Gyneco11991;77:33- 36. 32. Schwartz D, Mayaux MJ. Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS. NEnglJ Med 1982;306:404-406. 33. Huck E. Rates of chromosomal abnormalities at different maternal ages. Obstet Gyneco11981;58:282. 34. Golbus MS, Loughman WD, Epstein CJ, et al. Prenatal genetic diagnosis in 3000 amniocenteses. N EnglJ Med 1979;300:157-163. 35. Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 1996;81:1495-1501. 36. Klein NA, Soules MR. Endocrine changes of the perimenopause. Clin Obstet Gyneco11998;41:912-920. 37. Macklon NS, Fauser BC. Ovarian reserve. Semin Reprod Med 2005;23:248-256. 38. Scott RT, Toner JP, Muasher SJ, et al. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steri11989;51:651-654. 39. Klein NA, Illingworth PJ, Groome NP, et al. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab 1996;81:2742- 2745. 40. Klein NA, Battaglia DE, Fujimoto VY, et al. Reproductive aging: accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women. J Clin Endocrinol Metab 1996;81:1038-1045. 41. Danforth DR, Arbogast LK, Mroueh J, et al. Dimeric inhibin: a direct marker of ovarian aging. Fertil Steri11998;70:119-123. 42. Groome NP, Illingworth PJ, O'Brien M, et al. Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab 1996;81:1401-1405. 43. Santoro N, Adel T, Skurnick JH. Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women. Fertil Steri11999;71:658-662. 44. Soules MR, Battaglia DE, Klein NA. Inhibin and reproductive aging in women. Maturitas 1998;30:193-204. 45. Natchtigall R. Assessing fecundity after age 40. Contemp Obstet Gynecol 1991;36:11. 46. Wood C, Calderon I, Crombie A. Age and fertility: results of assisted reproductive technology in women over 40 years. JAssist Reprod Genet 1992;9:482-484. 47. Sauer MV, Paulson RJ, Lobo RA. Reversing the natural decline in human fertility. An extended clinical trial of oocyte donation to women of advanced reproductive age. JAMA 1992;268:1275-1279. 48. Hughes EG, Robertson DM, Handelsman DJ, et al. Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome. J Clin Endocrinol Metab 1990;70:358-364. 49. Jacobs SL, Metzger DA, Dodson WC, Haney AE Effect of age on response to human menopausal gonadotropin stimulation.J Clin Endocrinol Metab 1990;71:1525-1530. 50. Seifer DB, Gardiner AC, Lambert-Messerlian G, Schneyer AL. Differential secretion of dimeric inhibin in cultured luteinized granulosa cells as a function of ovarian reserve.J Clin Endocrinol Metab 1996;81: 736-739. 51. Scheffer GJ, Broekmans FJ, Dorland M, et al. Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility. Fertil Steri11999;72:845- 851. 52. Kline J, Kinney A, Kelly A, Reuss ML, Levin B. Predictors of antral follicle count during the reproductive years. Hum Reprod 2005;20: 2179-2189.
CHAPTER 8 Reproductive Options for Perimenopausal and Menopausal W o m e n 53. Vladimirov IK, Tacheva DM, Kalinov KB, Ivanova AV, Blagoeva VD. Prognostic value of some ovarian reserve tests in poor responders. Arch Gynecol Obstet 2005;272:74- 79. 54. Ng EH, Chan CC, Tang OS, Ho PC. Antral follicle count and FSH concentration after clomiphene citrate challenge test in the prediction of ovarian response during IVF treatment. Hum Reprod 2005;20: 1647-1654. 55. Fanchin R, Schonauer LM, Righini C, et al. Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003;18: 323-327. 56. Seifer DB, MacLaughlin DT, Christian BP, et al. Early follicular serum mullerian-inhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. Fertil Steril 2002;77:468-471. 57. Eldar-Geva T, Ben-Chetrit A, Spitz IM, et al. Dynamic assays of inhibin B, anti-Mullerian hormone and estradiol following FSH stimulation and ovarian ultrasonography as predictors of IVF outcome. Hum Reprod 2005;20:3178-3183. 58. van Rooij IA, Broekmans FJ, te Velde ER, et al. Serum anti-Mullerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002; 17:3065 - 3071. 59. Harman SM, Talbert GB. The effect of maternal age on ovulation, corpora lutea of pregnancy, and implantation failure in mice. J Reprod Ferti11970;23:33- 39. 60. Holinka CF, Tseng YC, Finch CE. Reproductive aging in C57BL/6J mice: plasma progesterone, viable embryos and resorption frequency throughout pregnancy. Biol Reprod 1979;20:1201 - 1211. 61. Thorneycroft IH, Soderwall AL. The nature of the litter size loss in senescent hamsters. Anat Rec 1969; 165:343 - 348. 62. Blaha GC. The influence of ovarian grafts from young donors on the development of transferred ova in aged golden hamsters. Fertil Steril 1970;21:268-273. 63. Maibenco HC, Krehbiel RH. Reproductive decline in aged female rats. J Reprod Ferti11973;32:121-123. 64. Wener MA, BJ, Gordon JW. The effects of aging on sperm and oocytes. Semin ReprodEndocrino11991;9:231. 65. Levran D, Ben-Shlomo I, Dor J, et al. Aging of endometrium and oocytes: observations on conception and abortion rates in an egg donation model. Fertil Steri11991;56:1091-1094. 66. Sauer MV, Paulson RJ. Oocyte donation to women with ovarian failure. Contemp Obstet Gyneco11989;34:125. 67. Sauer MV, Paulson RJ, Lobo RA. A preliminary report on oocyte donation extending reproductive potential to women over 40. N EnglJ Med 1990;323:1157-1160. 68. de Ziegler D, Bessis R, Frydman R. Vascular resistance of uterine arteries: physiological effects of estradiol and progesterone. Fertil Steril 1991;55:775-779. 69. Perrot-Applanat M, Groyer-Picard MT, Garcia E, Lorenzo F, Milgrom E. Immunocytochemical demonstration of estrogen and progesterone receptors in muscle cells of uterine arteries in rabbits and humans. Endocrinology 1988;123:1511-1519. 70. Sauer MV, Miles RA, Dahmoush L, et al. Evaluating the effect of age on endometrial responsiveness to hormone replacement therapy: a histologic ultrasonographic, and tissue receptor analysis. JAssist Reprod Genet 1993;10:47-52. 71. Buster JE, Sauer MV. Nonsurgical donor ovum transfer: new option for infertile couples. Contemp Obstet Gyneco11986;28:39. 72. Seidel G E Jr. Superovulation and embryo transfer in cattle. Science 1981;211:351-358. 73. Bustillo M, Buster JE, Freeman AG, et al. Nonsurgical ovum transfer as a treatment in infertile women. Preliminary experience. JAMA 1984;251:1171-1173. 74. Sauer MV, Bustillo M, Gorrill MJ, et al. An instrument for the recovery of preimplantation uterine ova. Obstet Gyneco11988;71:804-806.
123
75. Sauer MV, Anderson RE, Paulson RJ. A trial of superovulation in ovum donors undergoing uterine lavage. Fertil Steri11989;51:131-134. 76. Carson SA, Smith AL, Scoggan JL, Buster JE. Superovulation fails to increase human blastocyst yield after uterine lavage. Prenat Diagn 1991;11:513-522. 77. Lutjen P, Trounson A, Leeton J, et al. The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature 1984;307:174-175. 78. Sauer MV, Paulson RJ, Macaso TM, Francis MM, Lobo RA. Oocyte and pre-embryo donation to women with ovarian failure: an extended clinical trial. Fertil Steri11991;55:39-43. 79. Rosenwaks Z. Donor eggs: their application in modern reproductive technologies. Fertil Steri11987;47:895- 909. 80. Navot D, Laufer N, Kopolovic J, et al. Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N EnglJ Med 1986;314:806-811. 81. Abdulla HI, Baber R, Kirkland A, et al. A report on 100 cycles ofoocyte donation: factors affecting the outcome. Hum Reprod 1990;5:1018. 82. Asch RH, Balmaceda JP, Ord T, et al. Oocyte donation and gamete intrafallopian transfer in premature ovarian failure. Fertil Steril 1988;49:263-267. 83. Paulson RJ, Sauer MV, Lobo RA. Factors affecting embryo implantation after human in vitro fertilization: a hypothesis. AmJ Obstet Gynecol 1990; 163:2020- 2023. 84. Serhal PF, Craft IL. Oocyte donation in 61 patients. Lancet 1989;1: 1185-1187. 85. Sauer MV, Paulson RJ, Ary BA, Lobo RA. Three hundred cycles of oocyte donation at the University of Southern California: assessing the effect of age and infertility diagnosis on pregnancy and implantation rates. JAssist Reprod Genet 1994;11:92-96. 86. Yaron Y, Amit A, Brenner SM, et al. In vitro fertilization and oocyte donation in women 45 years of age and older. Fertil Steril 1995;63: 71-76. 87. Legro RS, Wong IL, Paulson RJ, Lobo RA, Sauer MV. Recipient's age does not adversely affect pregnancy outcome after oocyte donation. Am J Obstet Gyneco11995;172:96-100. 88. Elizur SE, Lerner-Geva L, Levron J, et al. Factors predicting IVF treatment outcome: a multivariate analysis of 5310 cycles. Reprod Biomed Online 2005;10:645-649. 89. Lass A, Croucher C, Dully S, et al. One thousand initiated cycles of in vitro fertilization in women > or = 40 years of age. Fertil Steri11998; 70:1030-1034. 90. Lashen H, Ledger W, Lopez-Bernal A, Barlow D. Poor responders to ovulation induction: is proceeding to in-vitro fertilization worthwhile? Hum Reprod 1999;14:964-969. 91. Kailasam C, Keay SD, Wilson P, Ford WC, Jenkins JM. Defining poor ovarian response during IVF cycles, in women aged 7 days different from normal) Elevated in early follicular phase
Long cycles with episode of amenorrhea (> 60 days) Elevated (at any stage)
Continuing amenorrhea Markedly elevated
CHAPTER 10 Changes in the Menstrual Pattern During the Menopause Transition
151
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reached menopause. On the other hand, she also has a 54.5% chance of having one or more additional menses before menopause supervenes. Others have found that 70% of women experienced significant oligomenorrhea before menopause, whereas 18% experienced heavy or frequent, irregular bleeding, and only 12% had fairly regular cycles up to the onset of postmenopausal amenorrhea (10). The important message is that the actual time of occurrence of menopause is difficult to predict ahead of this event in individual women. The increasingly erratic nature of the menstrual cycle as menopause approaches is associated with an increasing incidence of shortened follicular phases, lengthened follicular phases, defective luteal function, and anovulation (7,11-13). Data from a large cross-sectional basal body temperature chart study demonstrated that the incidence of defective luteal function increases from 8% of cycles at 31 to 35 years to 36% at 40 to 50 years of age (10). This study also demonstrated that anovulation increases from 8% at 31 to 35 years up to 16% of cycles at 45 to 50 years, and the increase is mainly noticeable in the late menopausal transition. This information is mirrored by the demonstration of a marked increase in the incidence of anovulation associated with cystic glandular hyperplasia of
the endometrium in older women, peaking at the age of around 50 years (14,15). This condition could be regarded as one end of the spectrum of anovulatory dysfunctional uterine bleeding, and up until recently, it was graced with the specific name of m e t r o p a t h i a hemorrhagica. A dramatic decline in fertility precedes menopause by about 10 years but this does not correlate directly with any changes in the menstrual pattern (13). Individuals may still be fertile during periods of considerable irregularity, and spontaneous pregnancies, albeit rare, can occur after the age of 50. Indeed, the longstanding substantiated record of the oldest mother to give birth after a spontaneous conception is Ruth Ellen Kistler at 57 years and 129 days, but the oldest reported mother so far is Rossanna Dalla Corta from Italy, who gave birth in 1994 at the age of 63. It is likely that further births to women in their late 50s and 60s will now occur because of the application of assisted reproductive technologies using donor oocytes (16). The incidence of natural quinquagenarian births varies widely from culture to culture, with the highest known rate in the mid 1970s being in Albania (at 55 per 10,000 births). In these days of assisted reproductive technologies, the majority of births occurring to women in their 50s and 60s
152
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are now due to the use of donated oocytes from younger women. Nevertheless, flesh corpora lutea have been found at laparotomy even up to 3 years after the age of apparent spontaneous menopause (17). It is clear from the data of WaUace et al. (9) that return of menses may occur after prolonged periods of perimenopausal amenorrhea, and that these cycles may occasionally be ovulatory (12). TABLE 10.2 Percentage Probability of Menopause Having Already Occurred According to Age and to Duration of First Episode of Amenorrhea Age (years) Duration of first amenorrheic episode (days)
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B. Postmenopausal Bleeding Episodes The Treloar data demonstrate that even in women over the age of 52 with 1 year of amenorrhea, 4.5% will have at least one more episode of menstruation (9). Vaginal bleeding occurring more than 1 year after the menopause is conventionally defined as postmenopausal bleeding and must be investigated because of an incidence of 10% to 20% of underlying genital tract malignancy. Nevertheless, a majority of such episodes of bleeding occur in the absence of pathology and are probably associated with growth and atresia of an evanescent ovarian follicle and rarely even ovulation.
C. Menstrual Blood Loss The volume of menstrual blood loss is unrealistic to objectively measure in clinical practice, and there are no published longitudinal studies of menstrual blood loss through the perimenopause. Our preliminary data indicate that measured menstrual blood loss does not increase
CHAPTER 10 Changes in the Menstrual Pattern During the Menopause Transition
through the menopause transition when the woman experiences normal ovulatory cycle endocrine patterns. However, bleeding may become heavier when the woman experiences distorted ovarian follicular patterns of increased estradiol secretion. Cross-sectional data are fragmentary but suggest an overall tendency toward an increase in the volume of blood loss as menopause approaches. These cross-sectional studies have demonstrated a trend towards increasing volumes of objectively measured blood loss as women grow older (18,19). In the Swedish study from Gothenburg, the mean monthly volume rose from 28.4 mL at 15 years of age to 62.4 mL at 50 years (18). Although this mean rise could have been accounted for by substantial increases in a small proportion of the total group, Rybo and colleagues demonstrated a highly significant and progressive rise in menstrual blood loss in 33 individual women from 36 mL to 68 mL at intervals over 12 years between the ages of 38 and 50 years (20) (Fig. 10.3). Perception and tolerance play a major role in the reporting of"heaviness" of menstrual bleeding (18,21). A major proportion (more than 50%) of the volume of the menstrual flow is made up of an endometrial transudate rather than whole blood (22).
FIGURE 10.3 Objective measurements of menstrual blood loss in 33 Swedish women studied on three occasions over a 12-year period between the ages of 38 and 50 years. (Modified from ref. 20.)
153
This proportion does not appear to change with age and probably greatly influences women's perception of the absolute volume of their flow. An increasing proportion of women develop excessively heavy menstrual bleeding as they move into the late reproductive years (14,18). The incidence of ovulatory and anovulatory disturbances of bleeding patterns increase during this phase, and heavy bleeding due to pelvic pathology is also more common. Few women with heavy bleeding due to disturbances of endometrial or ovulatory function in this age group are consistently anoxatlatory as implied by American definitions (23), and most have ovulatory cycles from time to time (24). Some women also experience genuinely excessive bleeding, with measured menstrual blood loss in excess of 80 mL per month, when they are placed on treatment with standard regimens of hormone replacement therapy following the menopause (25,26) (Table 10.3).
D. Causes of Menstrual Changes in the Menopause Transition The main physiologic explanation for changes in the regularity of menstrual cycles during the menopause transition is loss of ovarian follicle numbers (27,28). As the follicle pool decreases, the levels of inhibin B produced by the preantral and antral follicle decreases (29,30). This in turn causes an increase in FSH secretion, particularly during the follicle phase of the cycle. High FSH levels cause a disturbance in normal cyclical follicle growth and high and often erratic levels of estradiol (31). As the number of follicles deplete, the less ovarian follicles will be able to respond to high FSH levels, and the more elongated the cycles will become (28). The irregularities in estradiol levels and the inconsistent cyclical progesterone levels contribute to irregularities in bleeding, and there is some evidence that high and prolonged unopposed estradiol secretion is associated with increased menstrual blood loss (32,33). Alternating ovulatory and anovulatory cycles are also likely to contribute to increased menstrual blood loss through increasing the likelihood of disordered endometrial proliferation and altered hemostats mechanisms during menstrual flow (34). Various genital tract pathologies are common in this age group, and the likelihood of finding particular pathology will depend on the nature of the bleeding disturbance (Table 10.4). In one study of 500 perimenopausal women attending a single clinic, 20% gave a history of menorrhagia, metrorrhagia or intermenstrual bleeding; 9% of these had a genital tract malignancy, and 14% had endometrial hyperplasia (10). Q.ginn et al. have reported that 38% of women found to have a premenopausal endometrial carcinoma presented with regular menorrhagia, whereas 29% presented with irregular bleeding and 33% with both irregular and very heavy
154
HALE AND FRASER
TABLE 10.3 Measured Menstrual Blood Loss During Programmed Withdrawal Bleeds in Postmenopausal Women Treated with Three Different Regimens of Combined Sequential Hormone Replacement Therapy Range ofMBL (mL)
Median MBL (mL) Number of women Rees" Sporrong 1a Sporrong 2a
50 23 23
3 mo
6 mo
12 mo
3 mo
6 mo
12 mo
% with MBL > 80 mL
26
23
17 ~ ~
1-313 0-582 0-346
2-256 ~ --
1-106 ~ ~
13 13 13
22
16
~
From refs. 25 and 26. apreparations used: Rees: estradiol valerate 2 mg, levonorgestrel 75 Ixg; Sporrong 1: estradiol valerate 2 mg, levonorgestre150 Ixg; Sporrong 2: estradiol valerate 2 mg, medroxyprogesterone 10 mg.
bleeding (35). Benign pelvic causes of these menstrual symptoms are also very common, with uterine myomata, adenomyosis, endometriosis, and endometrial polyps accounting for at least 50% of cases of menorrhagia. The remainder are due to ovulatory and anovulatory dysfunctional uterine bleeding. The need for precision in diagnosis and evaluation has become increasingly important in recent years with the development of a widening range of options for medical and surgical management (36,37).
E. N e e d for Investigation a n d T r e a t m e n t The key requirement here is to determine when an alteration in the pattern of bleeding in a woman who is the perimenopausal age group is the result of serious pelvic TABLE 10.4 Patterns and Causes of Menstrual Disturbance in the Menopause Transition
Oligomenorrhea, amenorrhea, short cycles, hypomenorrhea: Can be part of the natural changes in pattern and volume of menstruation that occur with declining ovarian function Range of pathologic causes occasionally may be found with these symptoms at this stage of life Intermenstrual Needing (with or without postcoital bleeding): Usually associated with recognizable pelvic pathology (predominantly surface lesions of the genital tract): Endometrial disease--polyps, leiomyomata, endometrifis, carcinoma Adenomyosis or endometriosis Cervical diseasempolyps, cervicitis, ectropion, carcinoma
Abnormally heavy bleeding: Pelvic diseasemleiomyomata, adenomyosis, endometriosis, endometrial polyps, endometrial adenocarcinoma, myometrial hypertrophy, atriovenous malformations, and other rarities Systemic diseasemdisorders of hemostasis, hypothyroidism, systemic lupus erythematosus, rarities Dysfunctional uterine bleeding--anovulatory, ovulatory (acute or chronic) Irregular bleeding: Hypothalamicmpituitary anovulatory disturbances Endometrial or cervical carcinoma
pathology, the most serious, of course, being genital tract cancer. Table 10.4 summarizes the situations where genital tract cancer is a possibilitymthat is to say, almost every type of menstrual bleeding disturbance apart from the typical patterns seen before and during the menopause transition (where shortening of cycles occurs through the late reproductive age, followed by increasingly erratic short and long cycles and ultimately oligomenorrhea). This means that a high index of suspicion needs to be exercised when the bleeding pattern is frequent, prolonged, intermenstrual, or excessively heavy. The following approaches to investigation need to be considered: 9 Good quality transvaginal ultrasound scanning (sometimes with sonohysterography) to define pelvic pathologies involving the endometrium, myometrium, or ovaries (see Table 10.4). 9 Hysteroscopy and dilation and curettage (or endometrial biopsy) to assess endometrial and endocervical surface lesions 9 Full blood count to exclude significant anemia; other blood tests are only infrequently helpful (there is considerable controversy about the value of a rise in serum follicle-stimulating hormone [FSH] in predicting menopausal transition; if a serum FSH level is to be of any help, it probably needs to be timed on day 2 to 3 of menses) 9 Prospective menstrual charting (may help to define the nature of the menstrual disturbance) Treatment is basically aimed at management of the cause of the menstrual disturbance. Modern techniques have allowed an unprecedented degree of precision in diagnosis, and this continues to improve with ongoing research. This precision should help to ensure that treatment is guided reasonably precisely to the options appropriate for the defined cause. If underlying pathology is confirmed, then active therapy should clearly be directed to the specific cause. This will generally require surgery of some type, but certain pathologies can be managed satisfactorily by
CHAPTER 10 Changes in the Menstrual Pattern During the Menopause Transition medical therapy. This topic is too large for comprehensive review in this chapter. The remaining group of conditions includes those where no specific underlying cause has been detected. These conditions are often poorly defined, and the terminologies vary greatly from one country to another. They generally come under the ambit of terms such as anovulatory dysfunctional uterine bleeding and ovulatory dysfunctional uterine bleeding(38).
The broad approaches to treatment are threefold: 9 Observation. One approach is to keep the patient under
observation but institute no initial active therapy.
155
pattern of flow. Increasing volume of flow is common as women grow older, and this may be perceived by the woman as being abnormal. This symptom commonly causes social distress and concern about cancer and is relatively infrequently associated with progressive development of iron deficiency and anemia. It is a critically important clinical skill to know when to investigate the unpredictable menstrual changes of women during the menopausal transition in order to determine the possible presence of serious underlying pathology. The physician must remain alert to ensure early detection of the 40% to 50% of endometrial adenocarcinomas that manifest before menopause is reached.
9 Medical management. There is limited good-quality evi-
dence concerning management of dysfunctional uterine bleeding in the menopause transition, but much anecdote. Hormonal therapies are used most widely, with the combined oral contraceptive pill being the most popular (in spite of limited good-quality evidence of efficacy [39]). There is increasing evidence for the benefits of the levonorgestrel intrauterine system (Mirena, Schering) in this situation, and this may indeed be the hormonal therapy of choice for many women encountering problems with dysfunctional uterine bleeding through the menopause transition (40). An alternative effective medical therapy for those women with excessively heavy menstrual bleeding through the menopause transition is tranexamic acid (Cyklokapron, Pharmacia), an oral antifibrinolytic preparation (41). 9 Surgical management. This has been the traditional approach to the management of bleeding disturbances in the menopause transition, and hysterectomy carried out by any one of a variety of different routes has been the most widely recommended procedure (42). The issue of conservation or simultaneous removal of the ovaries needs consideration in this situation, and this usually needs to be individualized by discussion with the patient. Alternative surgical approaches may include one of the effective endometrial ablation techniques (43). The general public possesses an increasing awareness of alternative treatments for menstrual disturbances among this age group, and many women are now choosing the L N G - I U S or endometrial ablation in preference to hysterectomy (44,45).
II. C O N C L U S I O N During the menopausal transition, menstrual intervals generally tend to increase, but many cycles show shortened follicular phases or anovulation, especially in the late transition. The most striking feature of the menstrual cycle in women during the menopausal transition is its unpredictability, with erratic and major variations in menstrual intervals, volume, and
References 1. Fraser IS, Petrucco OM. The management ofintermenstrual and postcoital bleeding and an appreciation of the issues arising out of the recent medico-legal case of O'Shea v Sullivan and Macquarie Pathology. ANZJOG 1996;36:67- 73. 2. Richardson SJ, Senikas V, Nelson JE Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231-1237. 3. SoulesMR, Sherman S, Parrott E, et al. Stages of Reproductive Aging Workshop (STRAW). Fertil Steri12001;76:874-878. 4. TreloarAE, Boynton RE, Behn BG, Brown BW. Variationof the human menstrual cyclethrough reproductive life. IntJFerti11967;12:77-126. 5. Treloar AE. Menarche, menopause and intervening fecundity. Hum Bid 1974;46:89-107. 6. Treloar AE. Menstrual cyclicityand the premenopause. Maturitas 1981; 3:49-64. 7. Vollman RE The menstrual cycle. Philadelphia: WB Saunders, 1977. 8. Jeyaseelan L, Antonisamy B, Rao PS. Pattern of menstrual cycle length in South Indian women: a prospective study. Soc Bid 1992;39: 306-309. 9. Wallace RB, Sherman BM, BeauJA, Treloar AE, Schlabaugh L. Probability of menopause with increasing duration of amenorrhoea in middle-aged women. Arn J Obstet Gyneco11979;135:1021-1024. 10. Seltzer VL, Benjamin F, Deutsch S. Perimenopausal bleeding patterns and pathologic findings.JAm WornAssoc 1990;45:132-134. 11. Doring GK. The incidence ofanovular cycles in women.JReprod Fertil 1969; 6(suppl):77- 81. 12. Sherman BM, Korenman SG. Hormonal characteristics of the menstrual cycle throughout reproductive life.J Clin Invest 1975;55:699-706. 13. Burger HG, Robertson DM, Baksheev L, et al. The relationship between the endocrine characteristics and the regularityof the menopause transition. Menopause 2005;12:267-274. 14. Schr6der R. Endometrial hyperplasia in relation to genital function. Arn J Obstet Gyneco11954;68:294-309.
15. Fraser IS, Baird DT. Endometrial cystic glandular hyperplasia in adolescent girls. J Obstet Gynaecol Brit Cwlth 1972;79:1009-1015. 16. Matthews P, ed. The Guinness book of records. Dublin: Guinness Publishing, 1996;57. 17. Novak ER. Ovulation after fifty. Obstet Gyneco] 1970;36:903-910. 18. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss--a population study.Acta Obstet Gynecol &and 1966;45:320-351. 19. Cole SK, BillewiczWZ, Thomson AM. Sources of variation in menstrual blood loss.J Obstet GynaecolBrit Cwlth 1971;78:933-939. 20. Rybo G, Leman J, Tibblin E. Epidemiology of menstrual blood loss. In: Baird DT, Michie EA, eds. Mechanism of menstrual bleeding. New York: Raven Press, 1983:181-193.
156 21. Fraser IS, McCarron G, Markham R. A preliminary study of factors influencing perception of menstrual blood loss volume. Am J Obstet Gyneco11984;149:788- 793. 22. Fraser IS, McCarron G, Markham R, Resta T. Blood and total fluid content of menstrual discharge. Obstet Gyneco11985;65:194-198. 23. Cowan BD. Dysfunctional uterine bleeding: clues to efficacious approaches. In: Alexander NJ, d'Arcangues C, eds. Steroid hormones and uterine bleeding. Washington: AAAS Press, 1992:9-15. 24. Fraser IS, Baird DT. Blood production and ovarian secretion rates of oestradiol-17[3 and estrone in women with dysfunctional uterine bleeding. J Clin Endocrinol Metab 1974;39:564- 570. 25. Rees MCP, Barlow DH. Q.uantitation of hormone replacement-induced withdrawal bleeds. BrJ Obstet Gynaeco11991;98:106-107. 26. Sporrong T, Rybo G, Vilbergson G, Crona N, Mattson LA. An objective and subjective assessment of uterine blood loss in postmenopausal women on hormone replacement therapy. Br J Obstet Gynaecol 1992; 99:399-401. 27. Van Zonneveld P, Scheffer GJ, Broekmans FJ, et al. Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women. Hum Reprod 2003;18:495-501. 28. O'Connor KA, Holman DJ, Wood JW. Menstrual cycle variability and the perimenopause. Am J Hum Bid 2001;13:465-478. 29. Welt CK, McNicholl DJ, Taylor AE, HallJE. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 1999;84:105-111. 30. Burger HG, Cahir N, Robertson DM, et al. Serum inhibins A and B fall differentially as FSH rises in perimenopausal women. [erratum appears in Clin Endocrinol (Oxf) 1998, Oct;49:550]. Clin Endocrinol 1998;47:809-813. 31. Miro F, Parker SW, AspinaU LJ, et al. Origins and consequences of the elongation of the human menstrual cycle during the menopausal transition: the FREEDOM Study.J Clin Endocrin Metab 2004;89:4910-4915. 32. Brown JB, Kellar R, Matthews GD. Preliminary observations on urinary oestrogen excretion in certain gynaecological disorders. J Obstet Gynaecol Brit Empire 1959;66:177-211. 33. Balfinger CB, Browning MC, Smith AH. Hormone profiles and psychological symptoms in perimenopausal women. Maturitas 1987;9:235-251. 34. Ferenczy A. Pathophysiology of endometrial bleeding. Maturitas 2003;45:1-14.
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35. Q.uinn M, Neale BJ, Fortune DW. Endometrial carcinoma in premenopausal women: a clinico-pathological study. Gynaecol Oncol 1985;20: 298-306. 36. Hickey M, Fraser IS. Mechanisms and management of dysfunctional uterine bleeding. In: Fraser IS, Jansen RPS, Lobo R, Whitehead MI, eds. Estrogens and progestogens in clinicalpractice. London: Churchill Livingstone, 1998;419-436. 37. Cameron IT, Fraser IS, Smith SK, eds. Clinical disorders of the endometrium and menstruation. Oxford: Oxford University Press 1998. 38. Fraser IS, Inceboz US. Defining disturbances of the menstrual cycle. In: O'Brien PMS, Cameron IT, MacLean AB, eds. Disorders of the menstrual cycle. London: RCOG Press 2000:141-152. 39. Fraser IS, McCarron G. Randomised trial of two hormonal and two prostaglandin-inhibiting agents in women with a complaint of menorrhagia. Aust N Z J Obstet Gynaeco11991;31:66-72. 40. Andersson K, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. BrJ Obstet Gynaeco11991;97:690-704. 41. Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gyneco11991;164:879-883. 42. Clarke A, Black N, Rowe P, Mott S, Howie K. Indications for and outcomes of total abdominal hysterectomy for benign disease: a prospective cohort study. Br J Obstet Gynaeco11995 ;102:611- 620. 43. Lethaby A, Hickey M. Endometrial destruction techniques for heavy menstrual bleeding: a Cochrane review. Hum Reprod 2003;17: 2795-2806. 44. Hurskainen R, Teperi J, Aalto AM. Q.uality of life and cost effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised controlled trial. Lancet 2001; 357:273-277. 45. Bourdiez P, Bongers MY, Mol BWJ. Treatment of dysfunctional uterine bleeding: patient preferences for endometrial ablation, a levonorgestrel releasing intrauterine device or hysterectomy. Fertil Steril 2004;82:160-166.
-IAPTER 1~
Decisions Regarding
Tre atme nt D uring the Menopause Transition ALISON C . PECK The Fertility Institutes, Encino, CA 91436 JUDI
L. CHERVENAK Department of Obstetrics and Gynecology,DMsion of Reproductive Endocrinology and Infertility, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY 10461
N A N E T T E SANTORO
Divisionof Reproductive Endocrinology, Department of Obstetrics, Gynecology& Women's Health, Albert Einstein College of Medicine, Bronx, NY 10461
The U.S. population is aging. We are seeing an increase in the number of elderly people and an improvement in survival at advanced ages (1). As the post-World War II baby boom generation reaches age 65, which will occur between the years 2010 and 2030, the most rapid increase in the elderly population in history is expected to occur. As life expectancy increases, women will spend more of their lives in the postmenopausal period. It is therefore critical to identify and correct risk factors that could adversely affect health and quality of life. The menopausal transition is a stage in a woman's life during which she has an opportunity to reduce her risk factors in order to maximize the quality of the rest of her life. Natural menopause is traditionally defined as 12 consecutive months of amenorrhea. A variety of terms and definitions have been used in medical literature to define the period before menopause when a woman's hormonal milieu is associated with irregular menstrual cycles and increased episodes of amenorrhea. Commonly accepted terminology TREATMENT OF THE POSTMENOPAUSAL W O M A N
for this time has included premenopause, perimenopause, menopausal transition, and climacteric. In July 2001, the Stages of Reproductive Aging Workshop (STRAW) assembled to standardize the staging system for reproductive aging and develop a consensus on the nomenclature for the premenopause (2). With the final menstrual period (FMP) as the anchor point, the staging system encompasses five stages before the FMP and two stages after. Stages - 5 to - 3 are the reproductive interval; stages - 2 to - 1 represent the menopausal transition; and stages + 1 to +2 encompass the postmenopause (2). The revised nomenclature is as follows (Fig. 11.1): 9 Menopause." The anchor point that is defined after 12 months of amenorrhea following the FMP, which reflects a near complete but natural decrease in ovarian hormone secretion. 9 Menopausal transition: Stages - 2 (early) and - 1 (late) encompass the menopausal transition and are defined 157
Copyright 9 2007 by Elsevier,Inc. All rights of reproduction in any form reserved.
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PECK E T
by menstrual cycle and endocrine changes. The menopausal transition begins with variation in menstrual cycle length in a woman who has a monotropic folliclestimulating hormone (FSH) rise and ends with the FMP, recognized only after 12 months of amenorrhea. 9 Postmenopause: Stages + 1 (early) and +2 (late) encompass the postmenopause. The early postmenopause is defined as 5 years since the FMP. (The participants agreed that this interval is relevant because it encompasses a further dampening of ovarian hormone function to a permanent level, as well as a phase of 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. 9 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 used synonymously with perimenopause. Generally speaking, the term menopausal transition is preferred over perimenopause and climacteric. Smoking is the greatest independent risk factor for earlier menstrual irregularity and earlier menopause. Smoking causes an earlier menopause by about 1 to 2 years (3,4). Another strong indicator for an earlier age at menopause is a maternal history of early menopause (5). The likelihood of a premature menopause has also recently been shown to vary by ethnicity (6). Premature (before age 40) and early (before age 45) menopause are more common in African-American (1.4%), Hispanic (1.4%), and Caucasian (1%) women and much less common in Chinese (0.5%) and Japanese (0.1%) women. Once a woman older than 45 has had 1 year of amenorrhea, she has less than a 10% likelihood of ever menstruating
AL.
again (7). However, there is no clear-cut transition period from the premenopausal to the postmenopausal state. Cessation of menstrual cyclicity occurs spontaneously at some point during this transition. Regarding the hormonal milieu of women traversing the menopause, Metcalf et al. (8) could not identify any hormonal differences between the irregular cycles of the perimenopausal woman and the immediately postmenopausal woman, except that no detectable progesterone was ever produced after a woman's FMR The preponderance of evidence now suggests that significant changes are occurring in a woman's hormonal environment during the menopausal transition. During the menopausal transition, there is an increase in the proportion of anovulatory cycles. However, the mechanisms responsible for the menopausal transition's anovulation remain unclear. The anovulatory cycles occurring during the menopausal transition appear similar to those occurring in adolescence and may reflect an inability to produce a luteinizing hormone (LH) surge after exposure to estrogen (9). Central changes in the hypothalamicpituitary axis may affect gonadotropin secretion. In the Study of Women's Health across the Nation (SWAN), Weiss and colleagues found a relative hypothalamic-pituitary insensitivity to estrogen in aging women that was manifested by positive and negative feedback mechanisms. Anovulatory cycles with estrogen peaks similar to those that result in LH surges in younger women did not result in LH surges in older reproductive-age women, indicating a lack of estrogen-positive feedback on LH secretion in this older population. In addition, levels of follicular-phase estrogen that cause negative feedback of LH in normal ovulatory women fail to suppress LH secretion in some older women (10). A lack of response to an estradiol challenge with an LH surge in perimenopausal women with dysfunctional uterine bleeding has also been described
FIGURE 11.1 Stages/Nomenclature of Normal Reproductive Aging in Women.
Recommendations of Stages of Reproductive Aging Workshop (STRAW), Park City, UT, July 2001. (Adapted from ref. 2.)
159
CHAPTER 11 Decisions Regarding Treatment During the Menopause Transition (9,11,12). However, abnormalities in ovarian steroid or peptide secretion may also play a role. During the menopausal transition, ovarian function is highly variable. Length and quality of menses varies as anovulatory cycles become more common. In women approaching menopause, Landgren et al. have reported an increasing proportion of cycles with prolonged follicular phases that are either due to delayed ovulation or anovulation (13). Hormone levels may fluctuate widely during this time, and as estrogen levels decrease, the inherent protective effects of estrogen on bone may also decrease. Thus, these hormonal changes associated with aging may have detrimental effects that must be recognized, addressed, and ameliorated whenever possible.
I. C H A N G E S A S S O C I A T E D WITH AGIN G Many of the physiologic changes associated with menopause occur or begin before the last menstrual period (14) and may be associated with somatic aging. Somatic aging is reflected by decreases in somatotropic axis function, adrenal androgen production, and loss of bone mineral density after peak bone mass has been attained. Several hormonal systems have age-related changes that may interact with reproductive aging (9). The most important factor regulating the pace of the menopausal transition is ovarian function. Ovarian follicular depletion is the ultimate causative factor for menopausal transition and menopause. However, the commencement of the menopausal transition may also result from aging-associated changes in other systems, such as the hypothalamus, pituitary, and uterus. Because none of these systems has been fully examined in the human, their contribution to the onset of menopause remains unclear.
II. C H A N G E S IN T H E H O R M O N A L ENVIRONMENT
A. Progestogenic Changes Normal (15-18) and decreased (19,20) corpus luteum production of progesterone has been observed in the menopausal transition. In the Daily Hormone Study, a substudy of SWAN, older women (49 years or older) had lower totalcycle integrated progesterone compared with younger women (ages 18 to 32) (21). Clinically, it would be very helpful to have further clarification regarding progesterone levels in the menopausal transition. If decreased progesterone levels are associated with increased estradiol, then this may predispose women to dysfunctional uterine bleeding and endometrial hyperplasia.
B. Estrogenic Changes Although progesterone is no longer produced after a woman's final menstrual period, there exists a brief time when small amounts of estrogen may still be produced. Metcalf et al. (8) observed that although elevations in FSH and LH are common before the final menses, episodes of significant estrogen production are not uncommon in the first year after the final menstruation. Midcycle estrogen concentrations in the menopausal transition have been shown to be normal or increased (15,19,20,22), whereas androgens have been observed to be normal or decreased, independent of major changes in sex hormone-binding globulin (23,24). Hyperestrogenemia may be a feature of the early menopausal transition, but cycles in the late menopausal transition may have decreased levels of estrogen (9,19). During the menopausal transition, estradiol levels do not gradually decrease but instead fluctuate greatly around the normal range until menopause, when no more responsive follicles are present (25). Thus, as a woman ages, there is not a downward spiral in the estrogenic milieu, but instead, a "roller coaster" in estrogen production (9). This important feature of the menopausal transition is clinically frustrating, because patients may complain of waxing and waning symptoms for which therapy must be customized. It is important to seriously consider a patient's complaints of irregular bleeding because the fluctuations in estrogen levels, associated with periods of hyperestrogenemia, may predispose a woman to endometrial hyperplasia with its potential sequelae. Ultrasound monitoring and biopsy may be necessary in these patients. Finally, fluctuations in estradiol during the menopausal transition may be due to a decrease in the aging ovary's ability to regulate FSH secretion. It has been suggested that decreasing negative feedback of estrogen on the hypothalamic-pituitary axis, reflecting a decrease in the number of ovarian follicles with age, leads to a rise in FSH. However, increases in FSH in normally cycling older reproductive age women are not accompanied by a decrease in estradiol. For this reason, attention has been directed to the concurrent fall in inhibin during this reproductive stage (26).
C. Changes in Inhibin It has been suggested that a cycle day 3 serum FSH is an indirect bioassay of dimeric inhibin production at the level of the granulosa cell (27). Because inhibins are products of granulosa cells, they have been proposed to be menopausal markers and have been used to measure ovarian reserve. Different patterns of circulating inhibins A and B observed during the human menstrual cycle suggest that they may
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have different physiologic roles. Inhibin A is believed to be a product of the dominant follicle and corpus luteum. Inhibin B is a product of smaller, preovulatory follicles and is the dominant inhibin in the follicular phase of the cycle. Decreased production of both these peptides has been reported in women during the menopausal transition, leading to decreased "restraint" of FSH secretion (28). More recent data by Burger et al. imply that falling follicle numbers with consequent falls in the levels of inhibin B are the primary trigger for the rising FSH level observed in the early menopausal transition. It is not until late in the menopausal transition that inhibin A and estrogen levels fall in relation to the decrease in the number of ovarian follicles (29). Women approaching menopause, studied during the follicular phase of their menstrual cycle, had elevated FSH levels and low inhibin/FSH ratios, providing further evidence supporting the basis for the early increase in serum FSH and decrease in inhibins (13). Furthermore, women with low cycle day 3 serum concentrations of inhibin B have been shown to demonstrate a poorer response to ovulation induction than women with high day 3 inhibin B (28). It also appears that greater circulating amounts of FSH are needed to initiate folliculogenesis in reproductively aged women with "decreased follicular reserve." When all these mechanisms are active, enhanced FSH secretion may cause an "overshoot" of estradiol production and the process of folliculogenesis that results in hyperestrogenemia (9,19). In support of this concept, it appears that women in their 40s are more likely to have naturally occurring twin pregnancies than are younger women, implying that multiple folliculogenesis may be more common in this age group (30). Thus, although reproductive efficiency is markedly decreased in the menopausal transition, hormonal secretion patterns may be occasionally exuberant. The early menopausal transition is therefore conceptualized as an endocrine state of compensated failure.
D. Androgenic Changes The three major sources for circulating androgens during the reproductive period are the ovary, the adrenal cortex, and peripheral conversion of circulating androstenedione and dehydroepiandrosterone (DHEA) to testosterone. The premenopausal ovary produces 25% of circulating testosterone, 60% of circulating androstenedione, and about 20% of circulating DHEA. The adrenal cortex produces 40% of circulating androstenedione, 25% of testosterone, and almost all D H E A and D H E A sulfate (DHEAS). In the postmenopausal period, 50% of circulating testosterone levels result from peripheral conversion of androstenedione (31). Androgen production from the postmenopausal ovary is controversial. In the study of Laughlin et al. plasma
testosterone and androstenedione levels were 40% and 10% lower, respectively, in oophorectomized women than in intact postmenopausal women (32). Although Laughlin et al. and others (32-34) have reported on the ovaries being a critical source of androgens throughout the lifespan of older women, Couzinet and colleagues concluded that the climacteric ovary is not a major androgen-producing gland (35). They observed similar plasma androgen levels in naturally postmenopausal and oophorectomized women. In addition, they performed immunohistochemistry in steroidogenicaUy active cells in postmenopausal and premenopausal ovaries. They found that steroidogenic enzymes mandatory for androgen biosynthesis, P-450 SCC, 3 [3-HSD, P-450 C17, and aromatase, were absent in the cells of postmenopausal ovaries compared with more than 20% in cells of younger control subjects. It is interesting that cross-sectional studies of oophorectomized women in more than one worldwide sample indicate lower androgens, but direct examination of the ovary suggests that the source of these circulating androgens may well not be ovarian. Further research is needed to clarify this apparent discrepancy. Both adrenal and ovarian androgen levels decline after age 20. By age 40, serum androgen levels are approximately half those found at age 20 (36). Most of the marked decrease in circulating C19 steroids and the resulting androgen metabolites occurs between ages 20 to 30 and 50 to 60 years. Smaller changes are seen after age 60 years (37). However, changes in the androgenic environment can be affected by other factors associated with aging. For example, insulin and insulin-like growth factor 1 (IGF-1) can both act as stimulants of androgens by the ovarian stroma and theca tissues. In normally menstruating women, there is a preovulatory increase in intrafollicular and peripheral androgens. At midcycle, peripheral androstenedione and testosterone increase by 15% to 20% (38). Several speculations exist regarding the role of the midcycle rise in androgens. It may help accelerate follicular atresia so that at ovulation, there is a single dominant follicle (39). Alternatively, it may be involved in the stimulation of libido: It has been shown that femaleinitiated sexual activity occurs most often at midcycle (40). If androgens are important in the production of a single dominant follicle and in stimulating libido, then the agerelated decrease in androgens may be associated with the increased incidence of multiple pregnancy and decreased libido that has been reported in older reproductive-aged women. If this association holds true, then androgen replacement may be useful for restoring libido in symptomatic older women. Among the adrenal androgens, DHEAS is most abundant hormone in the body. However, DHEAS is not biologically active unless it is converted to testosterone or estradiol. In the early 20s, D H E A production is maximal. With increasing age, its secretion is greatly decreased. The decrease is accelerated after menopause (25). In the elderly,
CHAPTER 11 Decisions Regarding Treatment During the Menopause Transition concentrations of DHEAS are only about 10% of those in younger persons (41). The age-associated decrease in DHEAS is independent ofcortisol (42). Decreased DHEAS also appears to be independent of reproductive aging and instead represents a somatic aging event. Studies to support this belief still need to be performed (9). Because the adrenal cortex androgens, D H E A and DHEAS, have such low intrinsic biologic activity unless converted to more active androgens, they only recently have been considered to be potentially important in immunocompetence and general well-being (43). Their role in the menopause transition has yet to be fully established. Lasley et al. have noted an increase in D H E A S associated with the late menopausal transition (44). Relationships between DHEAS levels and cardiovascular morbidity and mortality that have been reported for men are not true for women. In women, although higher levels of DHEAS were associated with several major cardiovascular disease risk factors, they were not related to risk of fatal cardiovascular disease (45,46). The role of DHEAS and a rationale for its supplementation in the menopausal transition remains to be elucidated.
E. S o m a t o t r o p i c Axis C h a n g e s Growth hormone (GH), under hypothalamic regulation by growth hormone-releasing hormone (GHRH), is a pulsatile hormone released from the anterior pituitary. Somatostatin, on the other hand, inhibits GH secretion. With aging, there is a decrease in GH secretion. It remains to be elucidated whether the decrease in GH results from increased release of somatostatin, decreased levels of GHRH, decreased sensitivity to GHRH, or a combination of these factors (9). Significant gender differences exist in GH secretion. In women, estrogen appears to play an important role in GH secretion. There is a positive association between estrogen status and GH concentrations. Thus, in a decreased estrogenic environment, such as that found in menopause, there is decreased GH secretion (47). Age itself may be a more important factor affecting concentrations of GH than estrogen alone. Recent studies have shown that decreased somatotropic axis activity is detectable before any changes occur in menstrual cyclicity or evidence of ovarian failure is present. Older, regularly cycling women (ages 42 to 46) secrete less GH in the daytime than do younger, regularly cycling controls (ages 19 to 34). This was found to occur in the older women despite higher estradiol levels on the day of sampling (when compared with their younger control subjects ). Older reproductive-age women had twice the early follicular phase concentration of estradiol as their younger controls (48).
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Lower IGF-1 levels have been observed to be associated with elevated estradiol and decreased G H levels in older reproductive-age women (48). The mechanism by which changes in IGF-1 and G H affect perimenopausal physiology is not fully understood. Whether or not functional changes in the somatotropic axis and hormonal environment affect sensitivity to insulin remains to be shown.
F. M e t a b o l i c C h a n g e s In many women, emergence of the metabolic syndrome presents concurrent with estrogen deficiency. The metabolic syndrome encompasses insulin resistance, central adiposity, dyslipidemia, hypertension, hypercoagulability, and a proinflammatory state (49). It is not considered one disease entity but rather a constellation of related risk factors that together increase the risk of cardiovascular disease (50). Postmenopausal women have a 60% increased risk of the metabolic syndrome (51), and approximately half of cardiovascular events in women are related to the metabolic syndrome (52). Although the etiology is unknown, many believe the underlying pathophysiology is related to increased visceral obesity and insulin resistance (53). During the menopausal transition, insulin sensitivity decreases, especially when there is weight gain (54-56). Wing et al. noted a direct association between weight gain and insulin resistance in women during the menopausal transition (55). A prospective study of 485 middle-aged women aged 42 to 50 years showed that after 3 years, the average weight gain was 2.25 to 4.19 kg. However, there were no significant differences between the amounts of weight gain in premenopausal versus postmenopausal women (2.07 vs. 1.35 kg, respectively) (55). Although it is commonly believed that women gain weight with menopause, studies have shown that increases in body mass index (BMI) are not independent of normal aging (57). Even so, body fat composition does change across the menopause transition. Estrogen promotes the accumulation of gluteofemoral fat (58), whereas the loss of estrogen with menopause is associated with an increase in central fat (59). In the Melbourne Women's Midlife Health Project, 102 middleaged women were evaluated during the menopausal transition to find that the free testosterone index was the major hormonal change associated with central adiposity (60). Finally, in SWAN, the authors confirmed that changes in menopausal status were not associated with weight gain or increases in weight circumference and found that maintaining or participating in regular exercise can help prevent or diminish these gains (61). Thus, aging has been associated with decreased GH and IGF-1 levels, decreased insulin sensitivity, increased insulin resistance (62), and weight gain (43). It is important for
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women, especially during the menopausal transition and postmenopausal period, to control their weight to minimize their already age-associated increased risk for diseases such as cardiovascular disease.
G. G o n a d o t r o p i n Level C h a n g e s During the menopausal transition, there is an increase in FSH that has been attributed to a loss of ovarian inhibin. This relationship appears to be supported by available immunoassay data (15,17,63). Although serum levels of FSH progressively increase with age, much overlap exists regarding the level and its association with the timing of menopause. Therefore, although measuring FSH may be useful in an infertility setting, it is a poor predictor of the timing of menopause for any individual woman (23,24). Longitudinal studies have shown that the increase in FSH occurs as early as the early 40s in normal women (64). Along with the elevation in FSH, there is a lesser, but still significant, rise in perimenstrual levels of LH (64). Because the age at which the rise in FSH first appears may not necessarily correlate with onset of the menopausal transition or menopause, monitoring of serum FSH or LH for menopause status has limited usefulness. Gonadotropin receptor level changes have also been noted to occur during the menopausal transition. A Finnish study (65) investigated FSH, LH, and 17[3-estradiol levels in women during the menopausal transition before elective abdominal hysterectomy and salpingo-oophorectomy and measured ovarian FSH and LH receptor content. Higher serum gonadotropin levels were found in women with fewer gonadotropin receptors. Postmenopausal women had no detectable FSH or LH receptor levels. High serum gonadotropin levels in women during the menopausal transition suggest the presence of low or undetectable levels of ovarian gonadotropin receptors. The authors proposed that measurement of gonadotropin receptor levels might be a useful indicator of ovarian status during the menopause transition. No absolute predictors of ovarian function exist to date. The marked variations in excreted FSH and LH during a typical ovulatory cycle indicate that there is no simple measure of the effect of age on ovarian function. As mentioned earlier in the chapter, the inhibins have been used to measure ovarian reserve, but inhibin B does not appear to surpass FSH (66). Attention has recently focused on available, stable markers of ovarian follicular development. Antral follicles and follicles in earlier stages produce mtillerian-inhibiting substance (MIS) or antimtillerian hormone (AMH). van Rooij et al. measured MIS, FSH, inhibin B, and estradiol in 81 women ages 25 to 46, who
were cycling at the first of two time points approximately 4 years apart (67). Fourteen of the 81 women developed irregular menses by the second blood draw, indicating the onset of the menopausal transition. MIS was the hormone most closely associated with the onset of the transition. Thus, although it is difficult to recognize early ovarian failure in the clinical setting (64), MIS may be more reflective of the primordial follicle pool than other previously studied markers of ovarian reserve (68) and a promising predictor for the occurrence of the menopausal transition (67).
H. Cycle L e n g t h C h a n g e s As age increases, there is a significant decrease in length of the follicular phase. Although average follicular phase length in women ages 18 to 24 is 15 ___2 days, the average in women 40 to 44 years is 10 ___4 days (16). This follicular phase shortening appears to result from accelerated folliculogenesis during the menopausal transition. This subsequently causes a 3-day decrease in the intermenstrual interval in most women (19). However, this change in length of the follicular phase is not necessarily continuous. Before the menopausal transition, with increasing age there is a decrease in mean menstrual cycle length. During the menopausal transition, cycle length becomes highly variable (69). Menstrual cycles during the menopausal transition are unpredictably irregular or "irregularly irregular," and there is no apparent orderly progression between the extremes of short and long cycles (69,70). The average follicular phase decrease by 3 to 4 days is clinically useful because it precedes obvious, clinically detectable endocrine changes (16). Patients with very frequent cycles or very heavy bleeding often present as a diagnostic and therapeutic challenge. For many such women, hormonal therapy with low-dose oral contraceptives may be useful. SWAN was the first study to evaluate daily menstrual cycle characteristics of a community-based cohort of women in the early stages of the menopausal transition. Santoro et al. noted important differences in cycle characteristics related to age, body mass index, and ethnicity. As reported previously, older age was associated with greater cycle variability, such as longer and more irregular cycles (71). Interestingly, women from all ethnic groups with BMIs greater than 25 kg/m 2 were less likely to have cycles with evidence of luteal activity and more likely to have longer total cycle lengths, a longer follicular phase length, and a shorter luteal phase length (71). Furthermore, after adjusting for BMI, Chinese and Japanese women had lower whole-cycle estradiol excretion compared with African-American, Caucasian, and Hispanic women, possibly indicating that Chinese and Japanese women are approaching menopause more slowly than other ethnic groups (71).
CHAPTER 11 Decisions Regarding Treatment During the Menopause Transition
III. C O M M O N COMPLAINTS AND HEALTH RISKS ASSOCIATED WITH THE MENOPAUSAL TRANSITION A. Hot Flushes The incidence of hot flushes is about 10% before the menopausal transition. However, during the menopausal transition, the incidence greatly increases, reaching a peak at menopause of about 50%. By about 4 years postmenopause, the incidence decreases to about 20% (72). A populationbased study of subjective hot flush reporting in pre-, peri-, and postmenopausal women revealed that 13% of premenopausal, 37% of perimenopausal, and 62% of postmenopausal women (as well as 15% of women on hormonal therapy) complained of at least one hot flush in the 2 weeks prior to the study. Although FSH levels were higher in the women with at least one hot flush per day, estradiol levels were higher in women with one or no hot flushes per week. These investigators concluded that hot flush frequency was associated with increasing FSH and decreasing estradiol levels (73). In the Melbourne Women's Midlife Health Project, Dennerstein et al. reported that vasomotor symptoms, vaginal dryness, and breast tenderness appeared to be specifically related to hormonal changes in women as they progressed through the menopausal transition (73). Patients often present with a primary complaint of vasomotor symptoms. For these patients, hormonal therapy may ameliorate their symptoms. Choice of hormonal therapy should be customized for each patient. Low-dose oral contraceptives in nonsmoking candidates or standard or lowdose estrogen therapy (pill or patch) are potential choices. Of note, a twofold increase in the overall estimated risk of myocardial infarction is associated with low-dose oral contraceptive use (74). Tanis et al. found that oral contraceptive use in women with co-morbidities, including hypertension, smoking, diabetes, and hypercholesterolemia, are at considerable risk of myocardial infarction (75), and therefore careful selection of appropriate candidates is crucial when initiating therapy.
B. Cardiovascular Changes During the menopausal transition, as women age, their risk for cardiovascular disease increases. In fact, the leading cause of death for women in the United States, beginning at age 40, is cardiovascular disease. After age 50, women have the same rate of cardiovascular disease as 40-year-old men, and eventually they have the same or higher rates as men in older age. After age 50, women have greater rates of hypertension than do men (76,77). The possible sequelae of changes in weight and IGF-1 levels may have great clinical
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impact because they are predictive of cardiovascular disease (55,56). The menopausal transition presents an opportunity for a woman to mitigate her risk factors for cardiovascular disease (through weight control, diet, and exercise). After menopause, the incidence of coronary heart disease increases, probably secondary to multiple mechanisms. Risk factors for cardiovascular disease include high cholesterol and other alterations in the lipid profile, abnormal glucose tolerance, hypertension, insulin resistance, smoking, and obesity. After the menopause, higher cholesterol, triglycerides, total/high-density lipoprotein cholesterol, insulin levels, and body weight are present (55,56,78,79). Risk factors for cardiovascular disease can be affected by hormonal fluctuations. Estrogen may have cardioprotective effects independent of its effects on lipids, including improved pulsatility index, vasodilation, improved blood flow, and inhibition of atheromatous plaque formation (80-83). Guthrie et al. investigated hormone levels at menopause in the Melbourne Women's Midlife Health Project. In this longitudinal observational study of middle-aged Australianborn women, high BMI, an increase in BMI, low estradiol levels, a decrease in estradiol levels, and high free testosterone levels were associated with increased risk of a coronary event, whereas frequent exercise lowered the risk (84). Lifestyle changes can vastly ameliorate cardiovascular risk factors. These changes include exercise, weight loss, careful diet, blood pressure monitoring, stress reduction, and cessation of smoking. The menopausal transition presents an ideal time for modification of risk factors so that a woman will maximize not only her years during the menopausal transition but also her postmenopausal years.
C. Bone Mineral Density Changes In the menopausal transition, decreased ovarian function is associated with altered calcium metabolism and decreased trabecular bone mass (85). Perimenopausal and postmenopausal women have significant bone loss in all skeletal sites, especially trabecular bone. Sex steroids appear to play an important role in maintaining integrity of the skeleton throughout a woman's life (86). During the menopausal transition, changes in bone mineral density (BMD) are influenced by endogenous estradiol levels. Mean estradiol levels of 69 pg/mL at the femoral neck and 89 pg/mL at the lumbar spine on dual-energy x-ray absorptiometry (DEXA) are the optimal levels for preventing postmenopausal bone loss. Slemenda and colleagues (86) found that premenopausal and postmenopausal bone loss are significantly associated with decreased concentrations of androgens. Hence, the literature supports the use of androgens with estrogen therapy in postmenopausal women to stimulate bone formation and prevent bone loss (87,88). However, recent data show that the absolute level of androgens and changes in
164 these levels have no influence on bone loss in middle-aged women (89). Bone mass measurements, such as those used to predict postmenopausal fracture risk, may also be predictive of traumatic fractures in the menopausal transition. Fractures in women approaching menopause can be weakly but significantly predicted by bone mass quantification (especially of the lumbar spine) using DEXA of the spine and hip. One study involving 1000 perimenopausal women who had screening DEXA noted a 2% incidence of stress fractures in women in the 2 years before screening (90). Traditionally it has been shown that women of different ethnicities have varying degrees of fracture rates and BMD. Caucasian women have been reported to have lower BMD than African Americans (91,92) and higher BMD than Asian women (93). Recent data from SWAN have challenged this belief. In SWAN, after adjusting for ethnic differences in bone size and lifestyle variables, lumbar spine and femoral neck BMD were highest in African Americans, and there were no significant differences among Caucasian, Japanese and Chinese women (94). In women weighing less than 70 kg, lumbar spine BMD was similar in AfricanAmerican, Chinese, and Japanese women and was lowest in Caucasian women, which may explain why Caucasian women have higher fracture rates than other groups (94). The use of urinary bone markers, such as urine C- and N-telopeptides (NTX), hydroxyproline, free deoxypyridinoline, calcium and pyridinium cross-link excretion, and serum bone markers, such as osteocalcin (OC) and bone-specific alkaline-phosphatase, to assess bone turnover is appealing because of its ease of use and noninvasiveness. However, there is no consensus regarding the optimal biochemical markers of bone turnover, and different markers of either osteoblast activity or bone resorption can give qualitatively different results (95). Nevertheless, serum OC and urinary NTX are among the most widely used assays and are more responsive to changes in estrogen status than other markers (96). SWAN evaluated the ethnic variation in bone turnover, employing these markers, in 2313 premenopausal or early perimenopausal women of varying ethnicities. Finkelstein et al. reported serum osteocalcin levels 11% to 24% higher in Caucasians compared with African-American, Chinese, and Japanese women (97). Urinary NTX levels were significantly higher in African Americans and Caucasians than in Chinese women, which is consistent with the findings of other investigators (98,99). Interestingly, SWAN showed that ethnic patterns of adult bone turnover do not parallel ethnic patterns of BMD. Finally, there is significant variation in bone turnover in postmenopausal women in different geographic areas (100), and regional variation in bone turnover independent from ethnicity was documented in SWAN, with higher levels of serum OC and urinary NTX in women from the Midwest and Northeast than in women from California (97). Further
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studies are necessary to establish the role of urinary bone markers in the clinical diagnosis of osteopenia and in the care of women approaching menopause. Prevention of bone loss should be encouraged early in all women. Weight-bearing exercise, calcium and vitamin D supplementation, and hormone therapy should be discussed with all women during and after the menopausal transition. If a patient has not already considered ways to reduce her risk for bone loss, the menopausal transition can serve as an "alarm" so that she can take action to maximize her bone density.
IV. H O R M O N E THERAPY IN THE MENOPAUSAL TRANSITION During the menopause transition, hormone therapy (HT) may reduce symptoms such as hot flushes and difficulty sleeping. One study of 32 women ages 42 to 47 years, with irregular anovulatory cycles and symptoms associated with menopause, involved administration of a 6-month course of transdermal estradiol patches (0.05 mg/day for 21 days) and oral progestogens (10 mg/day for 10 days) (10l). Menopausal symptoms were relieved during therapy; there were decreases in serum levels of FSH and LH and an increase in serum estradiol. After 6 months of therapy, FSH and LH concentrations were significantly lower than they were before HT. If a patient reports hot flushes, difficulty sleeping, or other complaints associated with the menopause transition, H T is a viable option. H T will alleviate symptoms such as hot flushes and thus immediately improve her quality of life and will also reduce her risk factors for osteoporosis and cardiovascular disease, two major causes of morbidity and mortality in the older woman. On the other hand, it is important to advise the patient that standard H T regimens are not adequate for contraception. If a sexually active woman has less than 1 year of amenorrhea before beginning HT, she is at a low but real risk for a possibly unwanted pregnancy. She should be advised and encouraged to consider using other forms of contraception such as barrier methods. Alternatively, very-low-dose (20 tag) ethinyl estradiol-containing oral contraceptives are often appealing and well tolerated, with an excellent safety profile in a nonsmoking, older, reproductive-aged woman. Low-dose oral contraceptives may be safely continued up to menopause in women without co-morbidities that increase their risk for myocardial infarction, as long as they are aware of the risks. When to switch a patient from oral contraceptives to hormone therapy presents a clinical dilemma. At present, there does not exist a simple biochemical test that definitively predicts the onset of menopause. Without conclusive clinical data, it is our policy to prospectively establish a date
CHAPTER 11 Decisions Regarding Treatment During the Menopause Transition
at which oral contraceptive use will be stopped and H T use begun. For most women, age 5 1 - the average age at natural menopause m i s a comfortable age at which to make this transition. This transition should be done in partnership with the patient and must take into account the fact that hormone therapy is not an adequate contraceptive.
V. SUMMARY During the menopausal transition, a woman may present with "irregularly irregular" menses, hot flushes, dysfunctional uterine bleeding, difficulty sleeping, mood changes, and osteoporosis/osteopenia. These and other complaints may result from periods of hyperestrogenemia, normal or hypoestrogenemia, decreased androgen levels, and decreased levels of GH and IGF-1 seen in the menopausal transition. The treatment of women in the menopausal transition may present a clinical challenge secondary to the lack of a neatly organized transition period and to the variation that exists among women and within each woman. Therefore, it is important that we become familiar with the woman in the menopausal transition and her needs. The menopausal transition presents an ideal time for reduction of risk factors that may affect quality of life, not just during the menopausal transition but also for her postmenopausal years.
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54. Wing RR, Matthews KA, Kuller LH, et al. Environmental and familial contributions to insulin levels in middle-aged women. JAMA 1992;268:1890. 55. Wing RR, Matthews KA, Kuller LH, et al. Weight gain at the time of menopause. Arch Intern Med 1991;151:97. 56. Wing RR, Kuller LH, Bunker C, et al. Obesity, obesity-related behaviors and coronary heart disease risk factors in black and white premenopausal women. IntJ Obesity 1994;13:511. 57. Crawford SL, Casey VA, Avis NE, McKinlay SM. A longitudinal study of weight and the menopause transition: results from the Massachusetts Women's Health Study. Menopause 2000;7:96-104. 58. Krotkiewski M, Bjorntorp P, Sjostrom L, Smith U. Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution.J Clin Invest 1983;72:1150-1162. 59. Poehlaman ET, Toth MJ, Gardner AW. Changes in energy balance and body composition at menopause: a controlled longitudinal study. Ann Intern Med 1997;123:673-675. 60. Guthrie JR, Dennerstein L, Taffe JR, et al. Central abdominal fat and endogenous hormones during the menopausal transition. Fertil Steril 2003;79:1335-1340. 61. Sternfeld B, Wang H, Quesenberry CP Jr, et al. Physical activity and changes in weight and waist circumference in midlife women: findings from the Study of Women's Health Across the Nation. Am JEpidemiol 2004;160:912- 922. 62. Proudler AJ, Felton CV, Stevenson JC. Aging and the response of plasma insulin, glucose and C-peptide concentrations to intravenous glucose in postmenopausal women. ClinJ Sci 1992;83:489. 63. Buckler HM, Evans CA, Mantora H, et al. Gonadotropin, steroid and inhibin levels in women with incipient ovarian failure during anovulatory and ovulatory rebound cycles. J Clin Endocrinol Metab 1991; 72:116. 64. Metcalf MG, Livesey JH. Gonadotropin excretion in fertile women: effect of age and the onset of the menopausal transition. J Endocrinol 1985;105:357. 65. Vihko KK, Kujansuu E, Morsky P, et al. Gonadotropins and gonadotropin receptors during the perimenopause. Eur J Endocrinol 1996; 134:357. 66. Hall JE, Welt CK, Cramer DW. Inhibin A and inhibin B reflect ovarian function in assisted reproduction but are less useful at predicting outcome. Hum Reprod 1999:14:409-415. 67. van Rooij IAJ, den Tonkelaar I, Broekmans FJM, et al. Anti-mullerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause 2004;11:601-606. 68. Santoro N. Can a blood test predict the onset of menopause? Menopause 2004;11:585-586. 69. Treloar A, Bounton A, Benn R, et al. Variation of the human menstrual cycle through reproductive life. lntJ Ferti11967;12:77. 70. MetcalfMG. The approach of menopause: a New Zealand study. N Z MedJ 1988;101:103. 71. Santoro N, Lasley B, McConnell D, et al. Body size and ethnicity are associated with menstrual cycle alterations in women in the early menopausal transition: the Study of Women's Health across the Nation (SWAN) Daily Hormone Study. J Clin Endocrinol Metab 2004;89: 2622-2631. 72. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Am J Hum Bio11992;4:37. 73. Guthrie JR, Dennerstein L, Hopper JL, et al. Hot flushes, menstrual status and hormone levels in a population-based sample of midlife women. Obstet Gyneco11996;88:437-430. 74. Tanis BC, Rosendall FR. Venous and arterial thromboembolism during oral contraceptive use: risk and risk factors. Semin VascMed 2003; 3:69-84.
CHAPTER 11 Decisions Regarding Treatment During the Menopause Transition 75. Tanis BC, van den Bosch MA, Kemmeren JM, et al. Oral contraceptives and the risk of myocardial infarction. N Engl J Med 2001;345: 1787-1793. 76. Castelli WP. Menopause and cardiovascular disease. In: Eskin BA, ed. The menopause-comprehensive management. New York: McGraw-Hill, 1994:117-136. 77. Kannel WB. Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study. Am HeartJ 1987;114: 413-419. 78. Razay G, Heaton KW, Bolton CR. Coronary heart disease risk factors in relation to the menopause. N Z J M e d 1992;85:889. 79. Matthews K, Meilahn E, Kuller LH, et al. Menopause and risk factors for coronary heart disease. NEnglJMed 1989;321:641. 80. Steinleitner A, Stanczyk FZ, Levin JN. Decreased in vitro production of 6 keto-prostaglandin F1 by uterine arteries from postmenopausal women. Am J Obstet Gyneco11989;161:1677. 81. Wren BG. Hypertension and thrombosis with postmenopauaal estrogen therapy. In: Studd JW , Whitehead MI, eds. The menopause. Oxford: Blackwell Scientific, 1989;181-189. 82. Hussman F. Long-term metabolic effects of estrogen therapy. In: Greenblatt RB, Heithecker R, eds. A modern approach to the perimenopausal years." nero developments in bioscience. New York: W de Gruyter, 1986:163-175. 83. Adams MR, Clarkson TB, Koritnik DR, et al. Contraceptive steroids and coronary artery atherosclerosis in cynomolgus macaques. Fertil Steri11987;144:41. 84. Guthrie JR, Taffe JR, Lehert P, Burger HG, Dennerstein L. Association between hormonal changes at menopause and the risk of coronary event; a longitudinal study. Menopause 2004;11:315-322. 85. Garton M, Martin J, New S, et al. Bone mass and metabolism in women aged 45-55. Clin Endocrino11996;44:536. 86. Slemenda C, Longcope C, Peacock M, et al. Sex steroids, body mass, and bone loss. A prospective study of pre, peri and postmenopausal women.J Clin Invest 1996;97:14. 87. Barrett-Connor E, Young R, Notelovitz M, et al. A two-year, doubleblind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women: effects on bone mineral density, symptoms and lipid profiles. J Reprod Med 1999;44:1012-1020. 88. Davis SR, McCloud P, Strauss BJG, et al. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas 1995;21:227-236. 89. Guthrie JR, Lehert P, Dennerstein L, et al. The relative effect of endogenous estradiol and androgens on menopausal bone loss: a longitudinal study. OsteoporosInt 2004;15:881-886.
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90. Stewart A, Torgeson DJ, Reid DM. Prediction of fractures in perimenopausal women: A comparison of DEXA and broadband ultrasound attenuation. Ann Rheum Dis 1996;55:140. 91. Trotter M, Broman GE, Peterson RR. Densities of bone of White and Negro skeletons. J BoneJoint Surg 1960;42A:50-58. 92. Kleerekoper M, Nelson DA, Peterson EL, et al. Reference data for bone mass, calciotropic hormones, and biochemical markers of bone remodeling in older (55-75) postmenopausal white and black women. J Bone Miner Res 1994;9:1267-1276. 93. Russell-Aulet M, Wang J, Thornton JC, Colt EWD, Pierson RN. Bone mineral density and mass in a cross-sectional study of white and Asian women. J Bone Miner Res 1993;8:575-582. 94. Finkelstein JS, Mei-Ling TL, Sowers M, et al. Ethnic variation in bone density in premenopausal and early perimenopausal women: effects of anthropometric and lifestyle factors. J Clin EndocrinolMetab 2002;87:3057- 3067. 95. Rosen CJ, Chesnut CH, Mallinak NJS. The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation. J Clin Endocrinol Metab 1997;83:1904-1910. 96. Prestwood KM, Pillbeam CC, Burleson JA. The short term effects of conjugated estrogen on bone turnover in older women. J Clin Endocrinol Metab 1994;79:366-371. 97. Finkelstein JS, Sowers M, Greendale GA, et al. Ethnic variation in bone turnover in pre- and early perimenopausal women: effects of anthropometric and lifestyle factors. J Clin Endocrinol Metab 2002;87:3051 - 3056. 98. Henry YM, Eastell R. Ethnic and gender differences in bone mineral density and bone turnover in young adults; effect of bone size. Osteoporos Int 2000;11:512-517. 99. Bell NH, Williamson BT, Hollis BW, Riggs BL. Effects of race on diurnal patterns of renal conservation of calcium and bone resorption in premenopausal women. OsteoporosInt 2001;12:43-48. 100. Cohen FJ, Eckert S, Mitlak B H. Geographic differences in bone turnover: data from a multinational study in healthy postmenopausal women. Calcif Tissue Int 1998;63:277-282. 101. DeLeo V, Lanzetta D, D'Antona D, et al. Transdermal estrogen replacement therapy in normal perimenopausal women: effects on pituitary ovarian function. Contraception 1996;10:49.
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2HAPTER
11
Use of Contraceptives
for Older Women DAVID E A R C H E R
Department of Obstetrics and Gynecology, CONRAD Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA 23507
Despite an age-related decline in fecundity, women over the age of 35 have a fertility rate of 335 per 1000 age 35 to 39 and 25 per 1000 age 45 plus (1) (Fig. 12.1). Sexually active women over the age of 35 require an acceptable, effective contraceptive (1). The perimenopausal transition is marked by irregular ovulation and clinically is apparent with changes in the woman's menstrual cycle. Despite this reduced incidence of ovulation, these women are still at risk for pregnancy. The use of hormonal steroids in combination oral contraceptives can provide contraception and menstrual cycle control for these women (2). Menopausal symptoms, which frequently occur in the perimenopause, can be improved with the use of oral contraceptives (3,4). Older women have a variety of contraceptive options available to them based on their lifestyle and individual preferences. The final decision on which contraceptive method to recommend and utilize should be based on the patient's history and physical findings, current frequency of coital activity, and prior contraceptive experiences. The information obtained by the physician or health care provider concerning these three parameters will allow for a frank discussion of the risks and benefits of each contraceptive option. This dialogue will allow the patient to reach a decision on the best method for her. Currently available contraceptive options are listed in Table 12.1. TREATMENT OF THE POSTMENOPAUSAL W O M A N
This review will discuss each of these methods with the intent that they will be used for women over the age of 35 years. Combination oral contraceptives (COCs, containing both an estrogen and a progestin) should be considered for those individuals over 35 years of age who do not smoke. The use of oral contraceptives in women who smoke cigarettes and are over the age of 35 is not recommended because of the reported increase in cardiovascular disease. The incidence is reported to be 400 cases per 100,000 women who smoke and are over the age of 35 (5-7). The use of COCs in women with controlled hypertension or diabetes mellitus should be individualized. These medical conditions are felt to represent relative contraindications to the use of COCs. Women with cardiovascular risks (Table 12.2) should be individually evaluated. Controlled dyslipidemia is not a contraindication to the use of COC. Women with diabetes who have retinopathy or nephropathy should not use COC (8). A progestin-only contraceptive is recommended for women with coronary artery disease, cerebrovascular disease, and congestive heart failure (9).
I. ORAL CONTRACEPTIVES Combination oral contraceptives are one of the best options because of their ease of administration and known benefits for reduction in the incidence of functional ovarian 169
Copyright 9 2007 by Elsevier,Inc. All rights of reproductionin any form reserved.
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Risk Factors for Cardiovascular Disease
Hypertension Smoking cigarettes Diabetes mellitus Pregnancy-induced hypertension Dyslipidemias Family history of early onset of cardiovascular disease Obesity Androgen excess states
FIGURE 12.1
Fertility rates for women as a function of age. (From res 1.)
cysts, pelvic inflammatory disease, ovarian cancer, and endometrial cancer (2,10). The reluctance to use them in older women has in part been due to the perception that they increase the risk of cardiovascular events in older women. As described later, this is not the case, making COCs a first choice for these women. COCs have been available since 1960. They consist of an orally active estrogen, usually ethinyl estradiol (EE), and a synthetic progestin. All the formulations on the U.S. market
TABLE 12.1
Available Contraceptive Options for Older Women
Combination estrogen plus progestin steroidal contraceptives Oral Vaginal Transdermal Progestin-only methods Subcutaneous implants (not available in the United States at the time of writing) Injectable 3-month interval Oral progestin-only pills Intrauterine devices Copper containing Levonorgestrel releasing Barrier devices Condoms: male and female Spermicides Diaphragms Other Diaphragm-like devices Symptothermal or rhythm methods
have undergone clinical trials or are generic versions of the original compound. All marketed products have been found to be effective in preventing pregnancy. There has been a steady reduction in the concentration of estrogen and progestin in COCs since their introduction. This has been driven by the concern that some of the adverse side effects are related to the dose of the estrogen. Secondly, the philosophy of using the least amount of a medication that can be proven to be effective is an important consideration. At the present time there are several COC formulations on the U.S. market that contain low doses of ethinyl estradiol (20 ~g) (Table 12.3). All these formulations have pregnancy rates (Pearl Indices) of less than 2 pregnancies per 100 women per year (Pearl Index). Associated with the reduction in the estrogen dose has been the development of new progestational compounds. The first progestins marketed in the United States were 19-nor steroids derived from testosterone. Although ethynodid diacetate was the first marketed progestin, it is converted to norethindrone after ingestion, which appears to be the biologically active form (11) (Fig. 12.2). Norethindrone has been further modified to create what are called gonane progestins, with a methyl group at position 18 of the molecule. Norgestrel or its active isomer levonorgestrel is the principal gonane progestin. The last 15 years have seen further modification in the steroidal configuration of levonorgestrel to yield three progestins known as norgestimate, desogestrel, and gestodene. Figure 12.2 has drawings of the steroid configuration of these orally active progestational agents.
TABLE 12.3 Combination Oral Contraceptives Containing 20 Izg of Ethinyl Estradiol Progestin concentration Name Loestrin Mircette Alesse YAZ
Progestin
(~g)
Norethindrone Acetate Desogestrel Levonorgestrel Drospirenone
1.000 0.150 0.100 3.0
CHAPTER 12 Use of Contraceptives for Older Women
171
Chemical Derivatives of Testosterone OH
T
Norethindmne
0
"
~
(~H CinCH
v
OH
Ethi
.
CinCH
H
N
ICH
"
Chemical Derivatives of
Levonorgestrel Levonorgestre! \ OH
C CH
Desogestrel
\
OH ...CinCH
Norgestimate ~
OAcetate CnCH
HEN"" ~
V
FIGURE 12.2 Orally active progestational agents derived from testosterone. Estranes are derivatives of norethindrone, while gonanes are related to levonorgestrel.
A recent introduction is the progestin drospirenone (DRSP), which is derived from spironolactone. This compound has a different molecular configuration than the classical 19-nor steroids used in COCs (Fig. 12.3) (see color insert).
A. Efficacy Oral combination contraceptives are designed to prevent pregnancy. Efficacy is assessed using the Pearl Index, which measures the number of pregnancies that occur in a known number of women during 1 year of use of a contraceptive agent (12). It is calculated by dividing the number of unintended
pregnancies by the number of months of use of the particular method whose efficacy is being measured, and multiplying the result by 1200. The current method uses the number of cycles of use (rather than months), and the result is multiplied by 1300 (on the basis that the average cycle length is 28 days). The contraceptive effectiveness of COCs can also be calculated using a life table analysis (13). Women over the age of 35 have been shown to have a decreasing fecundity (1,14). It is obvious that this reduction does not reach zero, and these women are at risk for pregnancy. According to data from the CDC, unintended pregnancies are a major problem in older women, where the use of therapeutic abortion is 400 per 1000 live births (Fig. 12.4).
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Spironolactone and Drospirenone
FIGURE 12.3
Drospirenonea progestational agent derived from spironolactone.
is the inhibition of ovulation; second is alteration in the receptivity of the cervical mucus for sperm penetration; and third is a change in the endometrium that may alter or inhibit implantation (16-18).
2. REDUCED INCIDENCE OF ECTOPIC PREGNANCY
FIGURE 12.4 Abortion rates by age groups in the United States by year. (From http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5212al.htm#tab4/)
These data underscore the need for contraceptive methods for the older woman.
B. Benefits of Oral Contraceptives in Women over 35 1. CONTRACEPTION
The principal benefit of COCs is the ability to allow a couple to determine when they want a pregnancy to occur. The utilization of oral contraceptives has been limited in older women because of the risk of cardiovascular events (discussed later). Current evidence indicates that for women with no cardiovascular risk, COCs are a highly effective and safe method (15). A low-dose estrogen-containing (35, 30, or 20 txg) COC should be the principal method used. Contraception is achieved in several ways. The principal method
Associated with the reduction in the occurrence of pregnancy is a concomitant reduction in ectopic pregnancy (10,19,20). This is obvious because inhibition of ovulation is one of the major mechanisms of action of COCs. Thus, the reduction in intrauterine pregnancies should be mirrored with a similar decline in ectopic pregnancies. COCs have been shown to reduce the incidence of functional ovarian cysts (10,12,20,21). In fact, COCs are indicated for the treatment of functional ovarian cysts, although one to two cycles may be required before the ovarian cyst regresses.
3. PELVIC INFLAMMATORY DISEASE
Use of COCs has been reported to decrease the incidence of pelvic inflammatory disease (PID) (10,12,20,21). The occurrence and incidence of cervical colonization with Neisseriagonorrhea and Cblamydiatracbomatisis not reduced, but the rates of clinical PID have been found to be decreased in women using COCs (20).
4. ENDOMETRIAL AND OVARIAN NEOPLASIA COCs have been found to reduce the incidence of endometrial cancer by at least 40% (22-25). This protective effect is apparent after 1 year of use. The reduced incidence
CHAPTER 12 Use of Contraceptives for Older Women lasts for 15 years. This duration is the length of the followup studies reported to date. The mechanism of action is thought to be due to the progestin altering the endometrium. In support of this hypothesis is the finding of an enhanced reduction in the incidence of endometrial adenocarcinoma in women who have used a low-dose estrogen with a potent progestin. COC reduce the incidence of ovarian neoplasia by 40% (20,26). The duration of this effect is also 15 years following 1 or more years of use of COCs. Recent data indicate that reduction in the incidence of ovarian cancer is also applicable to women who have a strong history of inheritable breast and ovarian cancer (27). These women often have BRCA1 or BRCA2 present on genotyping. The inhibition of ovulation is felt to be the principal mechanism whereby ovarian neoplasia is interdicted by COCs.
5. IRREGULAROR EXCESSIVEUTERINE BLEEDING
COCs have been used for the treatment of irregular or heavy uterine bleeding associated with anovulation, uterine fibroids, and women presenting with dysfunctional uterine bleeding (28). Clinical evidence of the COC efficacy for each of these clinical conditions is sparse. COCs have been shown to reduce the amount of bleeding in normal women. Menorrhagia and irregular menstrual intervals are also amenable to intervention with COCs (21). The data on the efficacy of COC as a treatment menorrhagia is scant (29).
6. BONE MINERAL DENSITY
COCs have been reported to enhance bone mineral density (BMD) in older women (30-34). This attribute would make them a logical choice for perimenopausal women who need to have a "bone bank" of increased bone mineral density prior to menopause.
C. A d v e r s e E v e n t s A s s o c i a t e d with Oral Contraceptives 1. MYOCARDIALINFARCTION
Myocardial infarction has been reported to be increased in women over the age of 35 who use a COC and who smoke (7,8). Recent epidemiologic studies have indicated that in healthy women who do not smoke, there is no increased risk of myocardial infarction (8,35,36). The Transnational study at one time showed that desogestrel-containing COCs would actually reduce the incidence of myocardial infarction in women compared with other progestins (37,38). In women over the age of 35 who do not have any cardiovascular risk, COCs are indicated as an effective means of contra-
173 ception (see Table 12.2). This author would recommend that the 20-1xg preparations be used if starting women on COCs at this age. The risk of myocardial infarction related to smoking and oral contraceptive use decreases after stopping smoking. Several studies have found that the risk is diminished 1 or more years after smoking cessation (39,40). Women who have successfully stopped smoking for more than 1 year do not appear to have an increased risk of myocardial infraction, and COCs can be used in these women.
2. CEREBROVASCULARDISEASE Cerebrovascular disease, or stroke, has been suggested to be increased in women who use COCs (41). This increase in the incidence has been linked to the dose of estrogen, with a reduction in the incidence of stroke associated with a decrease in estrogen dose. The overall incidence of stroke is rare in women under the age of 45 (42,43). A significant increase in stroke is associated with advancing age. Smoking is a risk factor for stroke in both premenopausal and postmenopausal women. Recent data have found an increased incidence of both thrombotic and hemorrhagic stroke in women who smoke (43). In women without risk factors, the current or past use of COCs was not associated with an increase in the incidence of either thrombotic or hemorrhagic stroke (41,43). The World Health Organization ( W H O ) has reported an increased risk of ischemic stroke in nonsmokers with normal blood pressure using oral contraceptives (44). There was no significant increase in hemorrhagic stroke in this population (45). Women receiving treatment for diabetes mellitus or hypertension were found to have a significant increase in the relative risk for stroke (43,45). These data indicate that other disease states may contribute significantly to the cause of stroke in women and not specifically the hormones in COCs.
3. VENOUSTHROMBOEMBOLISM COCs have been linked with the occurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) (46,47). The incidence of venous thrombosis increases with age (48). The occurrence of DVT has been linked to the dosage of EE in the COCs (49,50). Reductions in the ethinyl estradiol dose from more than 50 Ixg to the current formulations containing 20 to 35 Ixg have reduced the incidence and relative risk from venous thromboembolism (VTE). The reports from three recent studies indicate that the relative risk for DVT is approximately 2.0 for COCs with less than 35 Ixg of ethinyl estradiol (46,47,51). These results translate into an actual incidence of 2 to 4 cases of DVT per 10,000 women at risk per year. Controversy has arisen from these papers in regard to an increased incidence of VTE in women using third-generation COCs, such as norgestimate, desogestrel,
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and gestodene. Compared with second-generation COCs, such as levonorgestrel, the epidemiologic studies have found a relative risk of 1.5 or 2.0 for VTE in young women using third-generation COCs compared with second-generation COCs (levonorgestrel). Recent publications have discussed the potential biases in each of these studies in order to explain the increased relative risk with the newer progestational COCs (47,52-54). One of the biases identified is the healthy user effect (55,56). Physicians will not or do not change COC formulations in women without problems. A second bias is the attrition of susceptibles. This hypothesis states that there is a pool of women who are more likely to develop VTE when placed on COCs. This group of women could develop a DVT or PE after having a VTE diagnosed. The patient who develops a DVT on COCs is no longer a candidate for COCs. New starters on COCs can include a pool of susceptible women within the larger cohort of women who are not susceptible to VTE. Therefore, use of newer formulations of COCs can have a larger at-risk group of women than the older formulations because of their inclusion as new starters. These findings could result in the apparent increased incidence of DVT in current users of desogestrel- or gestodenecontaining products. These points have been extensively debated in the literature. At present, the most important point that has been made is that there is no biologic plausibility for the results of an increase in VTE incidence in women on third-generation progestational agents. Estrogens have always been implicated in the etiology of VTE. The low-dose 20-1~g ethinyl estradiol products available have an even lowered incidence of VTE (49,50). 4. BREAST CANCER
The role of hormonal agents in the development of breast cancer has been debated for some time. The use of COCs in North America has been estimated to have involved 85% of the female population at some time in their life. The most recent review by the Centers for Disease Control and Prevention (CDC) has not shown a significant increase in the incidence of breast cancer in current or past users of COCs (57). The incidence of breast cancer was the same in both white and black women, and the age at initiation of COC was not associated with an increased incidence (57).
5. WEIGHT GAIN
One of the principal reasons for discontinuation of COCs is the real or perceived weight gain. Clinical trials that are performed for the introduction or licensing of COCs have failed to show any significant weight gain in participants during the clinical trial (58,59). A recent Cochrane review found equivocal evidence for COCs' effect
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on weight but concluded that if weight gain occurred, no large effect was apparent (60). Despite this, there remains a strong feeling that COCs will cause weight gain. The most common reasons for weight gain are lack of exercise and overeating. Counseling on diet and exercise is required to interdict weight gain, but its effectiveness in modifying behavior is limited.
6. HEADACHES
Headache is a ubiquitous symptom and is reported in about 10% of women participating in clinical trials of COCs (61). This figure always seems high, but this is due to the lack of an appropriate control group. Menstrual-related headaches and other symptoms are those that are associated with the onset of menstruation and are cyclic and repetitive in nature (62). The management of these headaches can be a problem. Recently, the extended use of COC for 42 days or longer in a continuous fashion has been described (63). This may be used for the management of menstrual migraines, and other menstrual symptoms (64,65). The consumer and health care practitioner should be aware that continuous use of COC can result in breakthrough bleeding in these women (64,66-68). When breakthrough bleeding occurs, the COC should be stopped for 3 to 5 days. After this, continuous COC can be reinitiated, and this may enhance compliance. There are no known successful interventions for the irregular bleeding that occurs with continuous-use COCs. A second option is to use a transdermal delivery system of estradio1-17b (E2) as a bridge during the placebo or pill free days of the COC cycle. This will theoretically prevent the fall in serum E2 levels, which are thought to be the stimulus for the headache. Efficacy data are limited for this approach which has largely been driven by anecdotal reporting (69). The recent introduction of COCs with a reduced pill-free interval (Mircette [Organon, Inc, West Orange, NJ] and Loestrin-24 [Warner Chilcott, Rockaway, NJ]) may be useful in this instance, but there are no data indicating efficacy for menstrual migraine with this addition of several more days of hormonal steroids. Migraine headache is also associated with the withdrawal of the estrogen in the COC preparation. The significance of migraine headaches is their association with stroke, and the effect of COCs has been debated (70,71). The migraine literature indicates that there is an increased incidence of migraine headache in COC users. The COC literature is sparse in this regard, but a recent review indicates that migraine headache sufferers do not have an increased incidence of occurrence of headaches while using COCs (72). A trial of COC is indicated in women with a history of migraine headaches. This can be viewed as a therapeutic trial. In women with no increase in frequency or intensity of their migraine headaches, continued use of COCs is indicated. The use of progestin-only contraceptives, either oral, injec-
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CHAPTER 12 Use of Contraceptives for Older Women
tion, or implantation, may be indicated in women who continue to have frequent or severe migraine headaches.
There are two different IUDs on the U.S. market--the copper-containing IUD, known as Paraguard (Ortho Pharmaceutical, Raritan, NJ) and the medicated device containing levonorgestrel, Mirena (Berlex, Montville, NJ).
II. INTRAUTERINE DEVICES Intrauterine devices offer a significant alternative for older women. They are a highly effective means of contraception and have few systemic side effects. Intrauterine devices (IUDs) have been linked to an increased incidence of peMc inflammatory disease (PID) (73-75). The early articles from the C D C implied that there was an increased risk of PID in users of IUDs (73). The more recent review of the CDC data does not support an increase in the incidence of PID in monogamous couples (76). The increased incidence is found in divorced or unmarried women and is strongly linked to the number of sexual partners. A large multicenter, multinational trial reported by the World Health Organization also indicated that there is no increase in the incidence of PID in women using IUDs. There is evidence for an increase in what appears to be PID in the first 3 to 4 weeks following insertion of the IUD (77). These data have led to published reports indicating that prophylactic antibiotics could or should be used at the time of insertion of the IUDs. There is no consensus on the use of antibiotics at the time of IUD insertion. At the present time in the United States there is no compelling evidence that concurrent antibiotics with insertion of the IUD prevent the occurrence of infection immediately following the insertion of the IUDs. Intrauterine devices do not have a systemic contraceptive action. They appear to exert their effects locally, either by altering gamete function or changing the endometrial receptivity. The bulk of the data support an effect on gametes with either no or few sperm cells detected in the fallopian tubes of women using IUDs (78,79). This finding is also reflected in the lack of fertilized oocytes or embryos present in the fallopian tubes of women using an IUD. At one time it was hypothesized that one of the mechanisms of action of the IUD was to inhibit implantation or to be an abortifacient. There is no evidence that there is any abortifacient activity associated with IUDs. Published reports have failed to find any evidence of an increased occurrence of either early clinical miscarriages or evidence of human chorionic gonadotropin (hCG) in serum or urine as an indicator of pregnancy (78). Recently we have shown that the administration of pentoxifylline (Trental) to rats bearing an IUD can reverse the contraceptive effect of the IUDs (80). We believe that this effect is due to the action of pentoxifylline altering the function of the endometrial leukocytes that are present in the intrauterine lumen and the endometrial stroma of women and animals bearing an IUD. Our current hypothesis is that intrauterine cytokines are involved as part of the mechanism of IUD action.
A. Copper-Containing IUDs The copper-containing (Cu) IUD is a highly effective contraceptive with a Pearl Index of between 1.0 and 2.5 pregnancies per 100 women per year of use. The variability of the Pearl Index is related to the population under investigation. The mechanism of action of the Cu IUDs is both a foreign body reaction of the IUD's frame (silicone) and the release of elemental copper, which is a known spermicide. The load or amount of copper on the devices has been variable, but the Paraguard has 380 square millimeters of surface area of copper wound on the arms and the stem of the IUD. This system has an effective duration of action of 10 years (81- 84). Side effects include uterine cramping and, in some instances, expulsion of the device. Another side effect is an increase in the amount and duration of menstrual flow. Nonsteroidal anti-inflammatory agents have been shown to be effective in decreasing the amount of bleeding associated with IUDs (76). The studied doses are ibuprofen 800 mg three times a day and Anaprox 500 mg three to four times a day.
B. Levonorgestrel-Releasing Intrauterine Device The release of levonorgestrel from the stem of the IUD (Mirena [Berlex laboratories, Montville, NJ]) is designed to enhance its contraceptive efficacy. The Mirena has been described as a levonorgestrel intrauterine system (LNG-IUS) delivering levonorgestrel to the endometrium. Levonorgestrel concentrations are high in the endometrium, which shows progestationaX dominance on endometrial histology (85,86). The use effectiveness of the LNG-IUS is very high, with a Pearl Index of 0.2. The duration of efficacy is currently 5 years, which makes this a cost-effective method. Clinical trials have found that there is a decrease in the amount of menstrual blood loss in women using the intrauterine system (87). Menstrual cramps are also decreased with this system.
III. INJECTABLE CONTRACEPTION Injectable preparations of a progestin have been available for 30 years. The prototype is Depo-Provera, a crystalline suspension of medroxyprogesterone acetate. A long-acting form of norethindrone enanthate (Noristerate [Schering AG]) is marketed outside the United States. Noristerate is
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administered on an every 2-month basis. Depot medroxyprogesterone acetate (DMPA) is administered at 11- to 12-week intervals. The advantage of DMPA is the fact that it only contains a progestational steroid and has no estrogen component. The contraceptive efficacy is high, on the order of less than 1 pregnancy per 100 women per year of use (Pearl Index) (88). The advantages for older women are the lack of estrogenic side effects. Progestin-only methods may be used in women at risk for cardiovascular problems. Women who have liver dysfunction may be candidates for DMPA, but this decision should be individualized. Limited data suggest that progestin-only contraception should or could be used in women with migraine headaches. Conclusive medical evidence in this regard is lacking. One significant drawback is the pharmacokinetic profile of DMPA. In some women, medroxyprogesterone acetate has been found to remain in the circulation for more than 18 months (76). This extended duration of action has resulted in a delay in the return of ovulation and, of course, fertility. This potential problem should be discussed with women who may want to become pregnant in the future. The overall return of fertility (fecundity) is comparable to that of women stopping other forms of reversible contraception based on the cumulative pregnancy rate. There is a delay of between 3 to 6 months in pregnancy rates immediately following DMPA use, but by the end of 24 months, pregnancy rates are comparable between women who used D P M A and users of other forms of reversible contraceptives. The disadvantages for older women are the increased risk of irregular bleeding that occurs in the first year of use. A decrease in bone mineral density has been observed in current users, which appears to improve after discontinuation of the method (89,90). Irregular bleeding is common in all progestin-only methods of contraception. The cause of the irregular bleeding is unknown. The pattern of bleeding is irregular spotting and staining without premenstrual or prodromal symptoms (91). The bleeding usually consists mainly of spotting; rarely is there an associated anemia. This irregular bleeding does not imply that there is endometrial pathology. Endometrial biopsies have demonstrated only an atrophic or progestationally suppressed endometrium. Treatment usually consists of simple reassurance and observation. In some cases where there is concern, the use of an oral estrogen has been reported. There appears to be some efficacy in the use of ethinyl estradiol or estrone sulfate to stop the bleeding or spotting, but the improvement is minimal (92). By the end of the first year of use of DMPA, more than 50% of the women are not bleeding (93). A decrease in bone mineral density in women using DMPA has been reported (94). Peripheral serum estradiol levels were lower than those found in the early follicular phase. This study was small and requires further follow up. Extensive follow up of users of DMPA has been performed
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by the W H O because of concerns over potential breast cancer. The report of a multinational, multicenter trial has shown only an increase in breast cancer in the first 3 months of use, and there is no increase in breast cancer with longterm (over 10 years) use of DMPA (95,96). There appears to be a significant reduction in the incidence of endometrial cancer in DMPA users (97,98). This latter fact may enhance the utility of DMPA for older women. There is always concern about changes in mood in older women using medroxyprogesterone acetate orally. Reports of these changes are for the most part anecdotal. The same effect on mood or depression has been sought in younger women using DMPA. No significant change in depression scores was found in a prospective study of DMPA users (99,100). Overall, DMPA is a reasonable alternative for contraception in older women. It has the advantage of limited motivation for the consumer. The need to return for repeat injections on a regular basis may be a significant issue for some individuals, making this a less desirable alternative for contraception in women over the age of 35 years.
IV. IMPLANTABLE CONTRACEPTIVES There were no implantable contraceptive devices marketed in the United States at the end of 2006.
A. Levonorgestrel Implants Levonorgestrel implants (Norplant [Wyeth-Ayerst, Philadelphia]) are a six-capsule system with each capsule containing 30 mg of levonorgestrel. A newer two-rod device, known as Jadelle, also contains levonorgestrel. The contraceptive efficacy is due to increasing the length of the rods to enhance delivery of the steroid (101,102). Levonorgestrel implants were developed by the Population Council beginning in 1968 to 1970. Several different progestational agents were evaluated for efficacy at that time, but levonorgestrel was selected due to its release rate through silastic membrane (103). Clinical trials have indicated that levonorgestrel implants have a very low contraceptive failure rate, with a Pearl Index of less than 0.5 pregnancies per 100 women per year (104). Levonorgestrel implants can be used in older women because it contains no estrogen, as mentioned earlier for DMPA. The advantages of the Norplant contraceptive devices are the fact that the consumer requires little motivation after the insertion, and the duration of contraceptive efficacy is up to 5 years. As with all progestin-only contraceptives, side effects include irregular uterine bleeding (101,105). This is principally light bleeding and spotting and is similar to that described for DMPA. Thirty percent of women will experience
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irregular bleeding and spotting within the first 3 months after the insertion of Norplant and Jadelle (105 - 107). With continued use of levonorgestrel implants, occurrences of menstrual bleeding decrease (101). Other side effects that have been associated with the levonorgestrel system include weight gain, depression, acne, and loss of scalp hair (101,108-110). No one has reported alopecia, although a heavy loss of hair has been anecdotally reported. The principal contraindications to levonorgestrel implants are active liver disease and undiagnosed uterine bleeding. Both these conditions should be evaluated prior to insertion, along with any other laboratory evaluation that is indicated. Overall, the levonorgestrel implant systems have a very positive safety profile. They have not been linked to any risk of cardiovascular disease (101,107,110). There is no evidence of an increased risk of venous thromboembolism with progestin-only contraceptive methods (107).
B. Etonorgestrel Implant Etonorgestrel, the metabolite of desogestrel (3-keto desogestrel) or etonogestrel, has been used in a ethylene vinyl acetate delivery system. This product is a single-rod implant with a duration of action of 3 years (111,112). The contraceptive efficacy was found to be high during clinical trials (113-115). Endometrial bleeding that is irregular in occurrence and duration was a common side effect. Recent attempts to control the endometrial bleeding and spotting using short-term therapeutic interventions resulted in only minimal improvements (116).
V. TRANSDERMAL CONTRACEPTION The ability to deliver ethinyl estradiol and norgestimate through the skin using enhancers has resulted in the development of a once-a-week transdermal contraceptive, OrthoEvra (Ortho-McNeil Pharmaceutical, Raritan, NJ) (117). The efficacy of the transdermal contraceptive is comparable to oral contraceptives (118). The compliance with a oncea-week administration was higher in younger women compared with COCs, resulting in an increased efficacy in the 18-to-25-year-old population (119). There is a need for reliability of the adhesive characteristics of the transdermal system. Patch adherence was maintained under various degrees of heat and wetness (120). Concerns have been raised over the risk of venous thrombosis with transdermal contraception. There was no evidence of an increased adverse event profile in the clinical trials (121). According to data from the manufacturer, there is an increase of 60% in the area under the curve for ethinyl estradiol compared with a 35-~g COC preparation.
Peak blood levels of ethinyl estradiol were less than that found with a COC (122). A recent nested case-controlled study found that both COC and transdermal contraceptive systems had a similar incidence of venous thromboembolism (123). An increased risk of venous thrombosis is present with all estrogen-containing hormonal preparations.
VI. STEROIDAL VAGINAL CONTRACEPTIVE Vaginal rings delivering steroids have been investigated for many years as a different route of delivery for contraceptive steroids (124). The first development was of progestinonly vaginal rings that were associated with a high incidence of irregular bleeding (125). Combination rings using ethinyl estradiol and a progestin were effective and had a better bleeding profile (126). The ethinyl estradiol and etonorgestrel vaginal contraceptive ring (NuvaRing [Organon, Inc, Roseland, NJ]) found inhibition of ovulation with good cycle control in clinical trials (127-129). A significant advantage for compliance is the ability to leave the vaginal ring in place for 21 days, removing it only to have a withdrawal bleeding episode (127). There does not appear to be a significant local reaction to the vaginal contraceptive ring (130).
VII. BARRIER CONTRACEPTIVES A variety of barrier-type contraceptives are available on the U.S. market. Physical barriers include the diaphragm, other diaphragm-like devices (Lea's contraceptive, Femcap), and male and female condoms. Listed under barriers, although not truly a physical barrier, are spermicides, usually containing nonoxynol-9 (N-9), that are available in a variety of forms, including films, suppositories, and tablets. In general, barrier contraceptives have been associated with a higher pregnancy rate than hormonal contraceptive methods. The use effectiveness rates range from 7 to 15 pregnancies per 100 women per year with a variety of barrier contraceptives (12,131). With highly motivated couples who consistently use barrier contraceptives in a reliable fashion, pregnancy rates as low as 4 to 5 pregnancies per 100 women per year have been reported. Overall, barriers offer an advantage to older women from several standpoints. They are coitally related, and from this standpoint they only require use at the time of intercourse. In a couple with declining frequency of coital activity, this may be something that is attractive to them. Secondly, they do not involve hormonal medication, an intrauterine device, or an implant. From this standpoint, they are totally consumer controlled
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and consumer driven. The appropriate use of the barrier contraceptive is dependent on the motivation of the consumer and her partner. Barrier contraceptives depend on the utilization of an associated spermicide to enhance their efficacy. This is true for the diaphragm, the cervical cap, and, in some instances, male and female condoms. Male and female condoms have been impregnated with N-9 as an additional means of reducing pregnancy rates. The spermicidal product nonoxynol-9 is a surface-active detergent that has been shown to lyse cell membranes, resulting in spermicidal immobilization or death (132). The concentrations of N-9 in spermicide vary between preparations. Marketed preparations and their spermicidal content and concentration are shown in the accompanying table (Table 12.4). Barrier contraceptives, in order to be effective, should be inserted prior to penile penetration of the vagina. In general, for spermicides, an interval of between 5 and 15 minutes has been recommended between application and vaginal penetration. Clinical trials to confirm the efficacy of this time interval have not been reported. Some spermicides on the U.S. market have never been tested in clinical trials. Our experience using a variety of marketed spermicidal preparations has shown that the spermicide effectively reduces the number of motile sperm seen in the postcoital test of normal couples to less than one sperm per high-powered microscopic field (HPF) (133,134). There is no good correlation between the postcoital test results and the reduction in fecundity at this juncture. However, the postcoital test has been used along with in vitro spermicidal function as surrogates to indicate a high level of contraceptive efficacy.
A. Diaphragms Diaphragms have been available for many years on the U.S. market and have principally been made out of latex. A coil spring is present in the outer margin as a means of holding the diaphragm in place. All diaphragms require fitting by a health care provider, and fitting changes should be performed after vaginal delivery. The fitting is done best by using a ringlike device to measure the normal dimensions of the upper vagina. Diaphragm sizes are in millimeters, such that a number 70 diaphragm is a 70 mm in transverse diameter. All marketed diaphragms, whether they are spring or arc-spring types, rely on the application of the spermicide within the concavity and around the edges of the diaphragm to enhance their contraceptive efficacy. There are no studies that this author is aware of indicating that the diaphragm alone without a spermicidal product has any contraceptive efficacy. Recent clinical trials of two new barrier devices, the Lea's contraceptive and the Femcap, have been performed with and
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TABLE 12.4 Firms Manufacturing or Distributing Contraceptives Worldwide, 1993 and 1994 Company Aladan Ansell Berlex
Boehringer Ingelheim Bristol-Myers Squibb Carter-Wallace CCC (Canada)" Cervical Cap Ltd. Chartex (United Kingdom) Cilar (UK)a Dongkuk Trading (Korea)a Finishing Enterprisesa Gedeon Richter (Hungary) Gruenenthal Hyosung (Korea)a Jenapharm (Germany) Kinsho Mataichi (Japan) a Leiras Oy Pharmaceuticals Lexis London Rubber Magnafarma Mayer Mead Johnson Medimpex a (Hungary and USA) Menarini Milex Products Inc.
National Sanitary Okamoto, USA
Product manufactured or distributed Condoms Condoms (including one with nonoxynol-9) Oral contraceptives (Tri-Levlen, Levlen) Intrauterine system (Mirena) Oral contraceptives Oral contraceptives Condoms (including one spermicidally lubricated) IUDs Cervical cap (Prentif; manufactured by Lamberts/Dalston England) Female condom (Femidom) Oral contraceptives Condoms IUDs Emergency postcoital contraceptive (Postinor) Oral contraceptives Condoms Oral contraceptives Spermicides Progestin-releasing IUD (Mirena) Norplant (manufacture) Oral contraceptives (NEE) Condoms Diaphragms Oral contraceptives Condoms Oral contraceptives (Ovcon) Oral contraceptives/raw materials Oral contraceptives Diaphragms (Omniflex, Wide-seal) Jellies and creams (Shur Seal Jel has nonoxynol-9) Condoms Condoms
aFirm supplies to UNFPA procurement.Where the firm is listed with more than one product line and is a UNFPA source,the product supplied is also markedwith an ~. SOURCES: Frost and Sullivan.U.S. contraceptive and fertility product markets.New York, 1993. United Nations PopulationFund (UNFPA). 1993 procurement statistics. New York, 1993.
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CHAPTER 12 Use of Contraceptives for Older Women TABLE 12.4 Firms Manufacturing or Distributing Contraceptives Worldwide, 1993 and 1994--cont'd Company Organon
(Akzo) (Netherlands) a Ortho Pharmaceuticala
Parke-Davis (Warner-Lambert) Polifarma Reddy Health Care RFSU of Sweden Roberts Rugby Labs Safetex Schering AG (Germany)a Schering Plough (USA) Schmid
Searle (Monsanto) Seohung (Korea)a Syntex Thompson Medical Upjohn a (Upjohn Belgium)a Warner-Chilcott Whitehall Wisconsin Pharmacal Wyeth-Ayerst (American Home Products) Wyeth-Pharma (Germany)a Wyeth (France)a
Product manufactured or distributed Oral contraceptives (Marvelon, Desogen, Jenest) Implant (IMplanon) Vaginal Ring (NuvaRing) IUD (Multiload) (manufacturing subsidiary, Bangladesh) Oral contraceptives (Loestrin; Ortho-Cept, Ortho-Cyclen, Other Tri-Cyclen, Ortho-Novum, Modicon) Diaphragms (Allflex, Ortho Diaphragm) Spermicidesa (Gynol [octoxynol]) IUDs Oral contraceptives Oral contraceptives Condoms Condoms Oral contraceptives Oral contraceptives (Genora) Condoms Oral contraceptivesa Injectablesa Spermicides Condoms (including spermicidal condoms) Spermicides Diaphragms (distributed by GynoPharma) Oral contraceptives (Demulen) Condoms Oral contraceptives (TriNorinyll, Devcon, Norinyl, Brevicon) Spermicides Injectable (Depo-Provera/
DMPA) Oral contraceptives (Nelova) Sponge (Today)b Female condom (Reality) Oral contraceptives (Lo-Ovral, Nordette, Triphasil) (joint venture, Egypt, production) Norplant (marketing, distribution) Oral contraceptives Oral contraceptives
bWhitehall decided to discontinuethe Todaysponge because of the costs of bringing the plant up to U.S. Food and Drug Administration specifications.
without spermicide. The postcoital test was used as the measure with the Femcap, which was tested with and without spermicide, and compared with the diaphragm with spermicide (133). There was no difference in the number of sperm in the cervical mucus (average 0.1 sperm per HPF) in each treatment arm. Similar results were found in a phase I trial of the Lea's contraceptive when it was compared with and without spermicide to a diaphragm with spermicide (135). No sperm were present in the cervical mucus of the women with a diaphragm or Lea's contraceptive with spermicide. Only two sperm were found in one woman in the group using the Lea's contraceptive alone without spermicide. The contraceptive efficacy of the Lea's contraceptive was evaluated further in a clinical trial with and without spermicide. There were more pregnancies in the nonspermicide group, but the difference was not statistically different. The overall pregnancy rate was not different from the historical pregnancy rate of diaphragm users (136). Neither of these barrier devices is available on the U.S. market as of this time.
B. Condoms Both male and female condoms are available on the U.S. market. In the past, male condoms were made of latex, but recently they have been made of a polyurethane material that is designed to increase strength, reduce breakage, and enhance heat transmission and therefore increase sensation with coital activity (137-139). A variety of condom designs and colors have been used in order to enhance consumer utilization in both developing and developed countries. The addition of a spermicide to the male condom should enhance its contraceptive efficacy, but there are no identified studies that address this issue. It should be pointed out that nonoxynol-9, as well as latex, can result in allergic reactions in consumers. This reaction can take the form of a local irritation, or burning, and in rare instances an anaphylactoid reaction has been reported. Female condoms, on the other hand, are available and are made out of a polyurethane material (140). This device has a baglike structure with an inner ring that is designed to anchor in the upper portion of the vagina, and an outer ring that protrudes outside the vaginal introital area. This was designed to protect the perineum. The objective of the female condom is to allow a woman-controlled method that will prevent pregnancy and reduce the heterosexual transmission of sexually transmitted diseases, such as gonorrhea, chlamydia, syphilis, and possibly human immunodeficiency virus (HIV) (141). The female condom has as its major advantage this protective effect. Its major disadvantage is its price and the fact that it is only utilized for one time and then is disposed of.
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C. S p e r m i c i d e s Spermicides are principally nonoxynol-9 products in the United States. They come in a variety of formulations and packaging as shown in Table 12.4. Other agents that have been used as spermicides are octoxynol-9, menfegol, and benzalkonium chloride. At the present time, spermicides, like condoms, are available over the counter, but many couples are unaware of their availability, effectiveness, and utility. Use effectiveness with spermicides are on the order of condoms and diaphragms, with a wide range of reported pregnancy rates (131). Many spermicides are packaged in such a manner that they can be carried in the purse or in a small wallet without contributing undue bulk. At the present time, the U.S. Food and Drug Administration is undertaking a review of currently marketed spermicides to document their efficacy. In general, spermicides are to be utilized prior to the insertion of the penis. They are only effective for a one-time use, and a second episode of coital activity requires a second application of the product. Side effects associated with spermicide use have been an increased incidence of vaginitis and an increase in urethritis (142-147). Benefits have been a reduction in the transmission of sexually transmitted diseases and the fact that it is a local product without systemic effects (148-150).
VIII. S U M M A R Y The contraceptive products that are available for young women are also available for women over the age of 35. However, the physician or health care provider should take into consideration the woman's medical history, physical findings, and past contraceptive utilization before recommending or prescribing any of the contraceptive options as listed in this chapter. Overall, in highly motivated individuals, even barrier contraceptives can reduce the pregnancy rate down to below 5 to 6 pregnancies per 100 women per year. The health care provider should be aware of the fact that women over the age of 35 still have a pregnancy potential and require contraception.
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5. W H O scientific group meeting on cardiovascular disease and steroid hormone contraceptives. Wkly E.pidemiolRec 1997;72(48):361-363. 6. Petitti DB, Sidney S, Q.gesenberry CP. Oral contraceptive use and myocardial infarction. Contraception 1998;57:143-155. 7. Farley TM, Collins J, Schlesselman JJ. Hormonal contraception and risk of cardiovascular disease, an international perspective. Contraception 1998;57:211-230. 8. ACOG Committee on Practice Bulletins--Gynecology. ACOG practice bulletin no. 73. Use of hormonal contraception in women with coexisting medical conditions. Obstet Gyneco12006;107:1453-1472. 9. Cardiovascular disease and steroid hormone contraception. Report of a W H O scientific group. World Health Organ Tech Re.p Ser 1998; 877:1-89. 10. Burkman RT. Noncontraceptive clinical benefits of oral contraceptives. Int J Ferti11989;34(suppl):50- 55. 11. Thorneycroft IH. Cycle control with oral contraceptives: a review of the literature.Am J Obstet Gyneco11999;180(2 Pt 2):280-287. 12. Hatcher R, Trussell J, Stewart F, et al. Contraceptive technology, 16th rev ed. Manchester, NH: Irvington Publishers, 1994. 13. Farley TM. Life-table methods for contraceptive research. Star IVied 1986;5:475-489. 14. Schwartz D, Mayaux MJ. Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS. N EnglJ Med 1982;306:404-406. 15. Thorneycroft IH. Update on androgenicity. Am J Obstet Gynecol 1999;180(2 Pt 2):288-294. 16. Grimes DA, Godwin AJ, Rubin A, Smith JA, Lacarra M. Ovulation and follicular development associated with three low-dose oral contraceptives: a randomized controlled trial. Obstet Gyneco11994;83:29-34. 17. Killick SR, Fitzgerald C, Davis A. Ovarian activity in women taking an oral contraceptive containing 20 microg ethinyl estradiol and 150 microg desogestrel: effects of low estrogen doses during the hormonefree interval. Am J Obstet Gynecol1998;179: S18- $24. 18. Lete I, Morales E Inhibition of follicular growth by two different oral contraceptives (monophasic and triphasic) containing ethinylestradiol and gestodene. EurJ Contrace.ptRe.prodHealth Care 1997;2:187-191. 19. Drife J. Benefits and risks of oral contraceptives. Adv Contrace.pt 1990;6 (suppl): 15 - 25. 20. Mishell DR Jr. Noncontraceptive benefits of oral contraceptives. J Reprod Med 1993;38(12 suppl):1021-1029. 21. The ESHRE Capri Workshop Group: noncontraceptive health benefits of combined oral contraception. Hum Reprod Update2005;11:513-525. 22. La Vecchia C, Tavani A, Franceschi S, Parazzini F. Oral contraceptives and cancer. A review of the evidence. Drug Saf1996;14:260-272. 23. Schlesselman JJ. Risk of endometrial cancer in relation to use of combined oral contraceptives. A practitioner's guide to meta-analysis. Hum Re.prod 1997;12:1851-1863. 24. Vessey MP, Painter R. Endometrial and ovarian cancer and oral contraceptives--findings in a large cohort study. BrJ Cancer 1995;71: 1340-1342. 25. Jick SS, Walker AM, Jick H. Oral contraceptives and endometrial cancer. Obstet Gyneco11993;82:931-935. 26. Grimes DA, Economy KE. Primary prevention of gynecologic cancers. d m J Obstet Gyneco11995;172(1 Pt 1):227-235. 27. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. NEnglJMed 1998;339(7):424-428. 28. Shaw RW. Assessment of medical treatments for menorrhagia. Br J Obstet Gynaeco11994;101(suppl 11):15-18. 29. Iyer V, Farquhar C, Jepson R. Oral contraceptive pills for heavy menstrual bleeding. CochraneDatabase Syst Rev 2000:CD000154. 30. Gambacciani M, Spinetti A, Cappagli B, et al. Hormone replacement therapy in perimenopausal women with a low dose oral contraceptive preparation: effects on bone mineral density and metabolism. Maturitas 1994;19:125-131.
CHAPTER 12 Use of Contraceptives for Older W o m e n 31. Liu SL, Lebrun CM. Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review. BrJ Sports Med 2006;40: 11-24. 32. Gambacciani M, Ciaponi M, Cappagli B, et al. Effects of low-dose, continuous combined hormone replacement therapy on sleep in symptomatic postmenopausal women. Maturitas 2005;50(2):91-97. 33. Kleerekoper M, Brienza RS, Schultz LR, Johnson CC. Oral contraceptive use may protect against low bone mass. Henry Ford Hospital Osteoporosis Cooperative Research Group. Arch Intern Med 1991;151: 1971-1976. 34. Tuppurainen M, Kroger H, Saarikoski S, Honkanen R, Alhava E. The effect of previous oral contraceptive use on bone mineral density in perimenopausal women. OsteoporosInt 1994;4:93-98. 35. Rosenberg L, Palmer JR, Sands MI, et al. Modern oral contraceptives and cardiovascular disease. Am J Obstet Gyneco11997;177:707- 715. 36. Sidney S, Petitti DB, Q.uesenberry CP Jr, et al. Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynecol 1996;88: 939-944. 37. Lewis MA, Heinemann LA, Spitzer WO, MacRae KD, Bruppacher R. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Contraception 1997;56:129-140. 38. Lewis MA, Spitzer WO, Heinemann LA, et al. Third generation oral contraceptives and risk of myocardial infarction: an international casecontrol study. Transnational Research Group on Oral Contraceptives and the Health of Young Women. Brit MedJ 1996;312:88-90. 39. Rosenberg L, Palmer JR, Shapiro S. Decline in the risk of myocardial infarction among women who stop smoking. N EnglJ Med 1990;322: 213-217. 40. McElduff P, Dobson A, Beaglehole R, Jackson R. Rapid reduction in coronary risk for those who quit cigarette smoking. Aust N Z J Public Health 1998;22:787- 791. 41. Lidegaard O, Kreiner S. Cerebral thrombosis and oral contraceptives. A case-control study. Contraception 1998;57:303 - 314. 42. Petitti DB, Sidney S, Q.uesenberry CP Jr, Bernstein A. Incidence of stroke and myocardial infarction in women of reproductive age. Stroke
1997;28:280-283. 43. Petitti DB, Sidney S, Bernstein A, et al. Stroke in users of low-dose oral contraceptives. N EnglJ Med 1996;335:8-15. 44. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. W H O Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1996;348:498-505. 45. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results of an international, multicentre, case-control study. W H O Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1996;348:505-510. 46. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995;346:1575-1582. 47. Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women. Brit MedJ 1996;312:83 - 88. 48. Walker AM. Newer oral contraceptives and the risk of venous thromboembolism. Contraception 1998;57:169-181. 49. Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism: a five-year national case-control study. Contraception 2002;65:187-196. 50. Lidegaard O, Kreiner S. Contraceptives and cerebral thrombosis: a five-year national case-control study. Contraception 2002;65:197-205.
181 51. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589-1593. 52. Lewis MA, Heinemann LA, MacRae KD, Bruppacher R, Spitzer WO. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. The Transnational Research Group on Oral Contraceptives and the Health of Young Women. Contraception 1996;54:5-13. 53. Lewis MA. The epidemiology of oral contraceptive use: a critical review of the studies on oral contraceptives and the health of young women. Am J Obstet Gyneco11998;179:1086-1097. 54. Suissa S, Blais L, Spitzer WO, et al. First-time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception 1997;56:141-146. 55. Spitzer WO. The 1995 pill scare revisited: anatomy of a non-epidemic. Hum Reprod 1997;12:2347-2357. 56. Spitzer WO. Bias versus causality: interpreting recent evidence of oral contraceptive studies, d m J Obstet Gyneco11998;179(3 Pt 2):$43-50. 57. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. NEnglJMed 2002;346:2025-2032. 58. Rosenberg M. Weight change with oral contraceptive use and during the menstrual cycle. Results of daily measurements. Contraception 1998;58:345-349. 59. Reubinoff BE, Grubstein A, Meirow D, et al. Effects of low-dose estrogen oral contraceptives on weight, body composition, and fat distribution in young women. Fertil Steri11995;63:516-521. 60. Gallo MF, Grimes DA, Schulz KF, Helmerhorst FM. Combination estrogen-progestin contraceptives and body weight: systematic review of randomized controlled trials. Obstet Gyneco12004;103(2):359-373. 61. Archer DF, Maheux R, DelConte A, O'Brien FB. A new low-dose monophasic combination oral contraceptive (Alesse) with levonorgestrel 100 micrograms and ethinyl estradiol 20 micrograms. North American Levonorgestrel Study Group (NALSG). Contraception 1997;55:139-144. 62. Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gyneco12000;95: 261-266. 63. Sulak PJ, Cressman BE, Waldrop E, Holleman S, Kuehl TJ. Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms. Obstet Gyneco11997;89:179-183. 64. Edelman A, Gallo ME Nichols MD, et al. Continuous versus cyclic use of combined oral contraceptives for contraception: systematic Cochrane review of randomized controlled trials. Hum Reprod 2006;21: 573-578. 65. Edelman AB, Gallo MF, Jensen JT, et al. Continuous or extended cycle vs. cyclic use of combined oral contraceptives for contraception. Cochrane Database Syst Rev 2005;3:CD004695. 66. Kwiecien M, Edelman A, Nichols MD, Jensen JT. Bleeding patterns and patient acceptabifity of standard or continuous dosing regimens of a lowdose oral contraceptive: a randomized trial. Contraception2003;67:9-13. 67. Anderson FD, Halt H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception 2003;68:89-96. 68. Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial. Obstet Gynecol 2003;101:653-661. 69. Macgregor EA, Hackshaw A. Prevention of migraine in the pill-free interval of combined oral contraceptives: a double-blind, placebocontrolled pilot study using natural oestrogen supplements, y Fam Plann Reprod Health Care 2002;28:27-31. 70. Curtis KM, Mohllajee AP, Peterson HB. Use of combined oral contraceptives among women with migraine and nonmigrainous headaches: a systematic review. Contraception 2006;73:189-194. 71. Mohllajee AP, Curtis KM, Martins SL, Peterson HB. Does use of hormonal contraceptives among women with thrombogenic mutations increase their risk of venous thromboembolism? A systematic review. Contraception 2006;73:166-178.
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72. Mattson RH, Rebar RW. Contraceptive methods for women with neurologic disorders. Am J Obstet Gyneco11993;168(6 Pt 2):2027-2032. 73. Lee NC, Rubin GL, Borucki R. The intrauterine device and pelvic inflammatory disease revisited: new results from the Women's Health Study. Obstet Gyneco11988;72:1-6. 74. Kronmal RA, Whitney CW, Mumford SD. The intrauterine device and pelvic inflammatory disease: the Women's Health Study reanalyzed. J Clin Epidemio11991;44:109-122. 75. Grodstein F, Rothman KJ. Epidemiology of pelvic inflammatory disease. Epidemiology 1994;5:234-242. 76. Archer DE Reversible contraception for the woman over 35 years of age. Curr Opin Obstet Gyneco11992;4:891- 896. 77. Farley TM, Rosenberg MJ, Rowe PJ, Chen JH, Meirik O. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992;339:785- 788. 78. Ortiz ME, Croxatto HB, Bardin CW. Mechanisms of action of intrauterine devices. Obstet GynecolSurv 1996;51(12 suppl):S42-51. 79. Spinnato JA 2nd. Mechanism of action of intrauterine contraceptive devices and its relation to informed consent. Am J Obstet Gyneco11997;176: 503-506. 80. Ramey JW, Starke ME, Gibbons WE, Archer DE The influence of pentoxifyUine (Trental) on the antifertility effect of intrauterine devices in rats. Fertil Steri11994;62:181-185. 81. Chi IC. The multiload I U D - - a U.S. researcher's evaluation of a European device. Contraception 1992;46:407-425. 82. Kimmerle R, Weiss R, Berger M, Kurz KH. Effectiveness, safety, and acceptability of a copper intrauterine device (CU Safe 300) in type I diabetic women. Diabetes Care 1993;16:1227-1230. 83. Rosenberg MJ, Foldesy R, Mishell DR Jr, et al. Performance of the TCu380A and Cu-Fix IUDs in an international randomized trail. Contraception 1996;53:197-203. 84. Sivin I, Shaaban M, Odlind V, et al. A randomized trial of the Gyne T 380 and Gyne T 380 Slimline Intrauterine Copper devices. Contraception 1990;42:379-389. 85. Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin Endocrinol (Oxf) 1982;17:529-536. 86. Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrelreleasing intrauterine devices. IntJ GynecolPatho11986;5:235-241. 87. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. CochraneDatabase Syst Rev 2005:CD002126. 88. Kaunitz AM. Long-acting contraceptive options. Int J Fertil Menopausal Stud 1996;41:69- 76. 89. Cundy T, Ames R, Home A, et al. A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. J Clin EndocrinolMetab 2003;88:78- 81. 90. Tang OS, Tang G, Yip P, Li B, Fan S. Long-term depot-medroxyprogesterone acetate and bone mineral density. Contraception 1999;59: 25-29. 91. Fraser IS, Jansen RE Why do inadvertent pregnancies occur in oral contraceptive users? Effectiveness of oral contraceptive regimens and interfering factors. Contraception 1983;27:531 - 551. 92. Said S, Sadek W, Rocca M, et al. Clinical evaluation of the therapeutic effectiveness of ethinyl oestradiol and oestrone sulphate on prolonged bleeding in women using depot medroxyprogesterone acetate for contraception. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Long-acting Systemic Agents for Fertility Regulation. Hum Reprod 1996;ll(suppl 2):1-13. 93. Fraser IS. A survey of different approaches to management of menstrual disturbances in women using injectable contraceptives. Contraception 1983;28:385-397.
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94. Cromer BA, Blair JM, Mahan JD, Zibners L, Naumovski Z. A prospective comparison of bone density in adolescent girls receiving depot medroxyprogesterone acetate (Depo-Provera), levonorgestrel (Norplant), or oral contraceptives.J Pediatr 1996;129:671-676. 95. Skegg DC, Noonan EA, Paul C, et al. Depot medroxyprogesterone acetate and breast cancer. A pooled analysis of the World Health Organization and New Zealand studies. JWMA 1995;273:799-804. 96. Long-term use of hormonal contraceptive DMPA not linked to breast cancer. Prog Hum Reprod Res 1995:5. 97. Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 1991;49:186-190. 98. Kaunitz AM. Depot medroxyprogesterone acetate contraception and the risk of breast and gynecologic cancer. J Reprod Med 1996;41 (5 suppl):419-427. 99. Westhoff C, Wieland D, Tiezzi L. Depression in users of depomedroxyprogesterone acetate. Contraception 1995;51:351 - 354. 100. Westhoff C, Truman C, Kalmuss D, et al. Depressive symptoms and Depo-Provera. Contraception 1998;57:237-240. 101. Sivin I, Alvarez F, Mishell DR Jr, et al. Contraception with two levonorgestrel rod implants. A 5-year study in the United States and Dominican Republic. Contraception 1998;58:275-282. 102. Sivin I, Wan L, Ranta S, et al. Levonorgestrel concentrations during 7 years of continuous use of Jadelle contraceptive implants. Contraception 2001;64:43-49. 103. Lifchez AS, Scommegna A. Diffusion of progestogens through Silastic rubber implants. Fertil Steri11970;21:426-430. 104. Sivin I, Viegas O, Campodonico I, et al. Clinical performance of a new two-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls. Contraception 1997;55:73-80. 105. Archer DF, Philput CA, Weber ME. Management of irregular uterine bleeding and spotting associated with Norplant. Hum Reprod 1996;ll(suppl 2):24-30. 106. Diaz J, Faundes A, Olmos P, Diaz M. Bleeding complaints during the first year of norplant implants use and their impact on removal rate. Contraception 1996;53:91-95. 107. Sivin I. Risks and benefits, advantages and disadvantages oflevonorgestrel-releasing contraceptive implants. Drug Saf2003;26:303- 335. 108. DugoffL, Jones OW 3rd, Allen-Davis J, Hurst BS, SchlaffWD. Assessing the acceptability of Norplant contraceptive in four patient populations. Contraception 1995;52:45-49. 109. Tang GW, Lo SS. Levonorgestrel intrauterine device in the treatment of menorrhagia in Chinese women: efficacy versus acceptability. Contraception 1995;51:231-235. 110. Sivin I, Mishell DR Jr, Darney P, Wan L, Christ M. Levonorgestrel capsule implants in the United States: a 5-year study. Obstet Gynecol 1998;92:337-344. 111. Bennink HJ. The pharmacokinetics and pharmacodynamics of Implanon, a single-rod etonogestrel contraceptive implant. EurJ Contracept Reprod Health Care 2000;5(suppl 2):12-20. 112. Makarainen L, van Beek A, Tuomivaara L, Asplund B, Coelingh Bennink H. Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant. Fertil Steril 1998;69: 714-721. 113. Funk S, Miller MM, Mishell DR Jr, et al. Safety and efficacy oflmplanon, a single-rod implantable contraceptive containing etonogestrel. Contraception 2005;71:319-326. 114. Le J, Tsourounis C. Implanon: a critical review..~Inn Pbarmacotber 2001;35:329-336. 115. Zheng SR, Zheng HM, Qian SZ, Sang GW, Kaper RF. A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant. Contraception 1999;60:1-8.
CHAPTER 12 Use of Contraceptives for Older Women 116. Weisberg E, Hickey M, Palmer D, et al. A pilot study to assess the effect of three short-term treatments on frequent and/or prolonged bleeding compared to placebo in women using Implanon. Hum Reprod 2006;21:295- 302. 117. Abrams LS, Skee DM, Natarajan J, Wong FA, Lasseter KC. Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception 2001;64:287-294. 118. Zieman M, Guillebaud J, Weisberg E, et al. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steri12002;77(2 suppl 2):$13-18. 119. Archer DF, Bigrigg A, Smallwood GH, et al. Assessment of compliance with a weekly contraceptive patch (Ortho Evra/Evra) among North American women. Fertil Steri12002;77(2 suppl 2):$27-31. 120. Zacur HA, Hedon B, Mansour D, et al. Integrated summary of Ortho Evra/Evra contraceptive patch adhesion in varied climates and conditions. Fertil Steri12002;77(2 suppl 2):$32-35. 121. Sibai BM, Odlind V, Meador ML, et al. A comparative and pooled analysis of the safety and tolerability of the contraceptive patch (Ortho Evra/Evra). Fertil Steri12002;77(2 suppl 2):$19-26. 122. Abrams LS, Skee D, Natarajan J, Wong FA. Pharmacokinetic overview of Ortho Evra/Evra. Fertil Steri12002;77(2 suppl 2):$3-12. 123. Jick SS, KayeJA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception 2006;73:223-228. 124. Ballagh SA. Vaginal ring hormone delivery systems in contraception and menopause. Clin Obstet Gyneco12001;44:106-113. 125. Mishell DR Jr, Lumkin M, Jackanicz T. Initial clinical studies of intravaginal rings containing norethindrone and norgestrel. Contraception 1975;12(3):253-260. 126. Alvarez-Sanchez F, Brache V, Jackanicz T, Faundes A. Evaluation of four different contraceptive vaginal rings: steroid serum levels, luteal activity, bleeding control and lipid profiles. Contraception 1992;46(4): 387-398. 127. Roumen E Contraceptive efficacy and tolerability with a novel combined contraceptive vaginal ring, NuvaRing. Eur J Contracept Reprod Health Care 2002;7 (suppl 2):19-24; discussion 37-39. 128. Roumen FJ, Apter D, Mulders TM, Dieben TO. Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol. Hum Reprod 2001;16:469-475. 129. Mulders TM, Dieben TO. Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition. Fertil Steril 2001; 75:865 - 870. 130. Veres S, Miller L, Burington B. A comparison between the vaginal ring and oral contraceptives. Obstet Gyneco12004;104:555-563. 131. TrusseUJ. Efficacy of barrier contraceptives. In: Mauck CK, Cordero M, Gabelnick HL, Spieler JM, Rivera R, eds. Barrier contraceptives, current status andfuture prospects. New York: Wiley-Liss;1994:22. 132. Doncel GE Chemical vaginal contraceptives: preclinical evaluation. In: Mauck CK, Cordero M, Gabelnick HL, Spieler JM, Rivera R, eds. Barrier contraceptives, current status andfuture prospects. New York: Wiley-Liss;1994:147-162.
183 133. Mauck CK, Baker JM, Barr SP, Johanson W, Archer DE A phase I study of Femcap used with and without spermicide. Postcoital testing. Contraception 1997;56:111-115. 134. Mauck CK, Baker JM, Barr SP, Johanson WM, Archer DE A phase I comparative study of three contraceptive vaginal films containing nonoxynol-9. Postcoital testing and colposcopy. Contraception 1997;56: 97-102. 135. Archer DF, Mauck CK, Viniegra-Sibal A, Anderson FD. Lea's Shield: a phase I postcoital study of a new contraceptive barrier device. Contraception 1995;52:167-173. 136. Mauck C, Glover LH, Miller E, et al. Lea's Shield: a study of the safety and efficacy of a new vaginal barrier contraceptive used with and without spermicide. Contraception 1996;53:329-335. 137. Farr G, Katz V, Spivey SK, et al. Safety, functionality and acceptability of a prototype polyurethane condom. Adv Contracept 1997;13: 439-451. 138. Frezieres RG, Walsh TL, Nelson AL, Clark VA, Coulson AH. Breakage and acceptability of a polyurethane condom: a randomized, controlled study. Faro Plann Perspect 1998;30:73-78. 139. Rosenberg MJ, Waugh MS, Solomon HM, Lyszkowski AD. The male polyurethane condom: a review of current knowledge. Contraception 1996;53:141-146. 140. Farr G, Gabelnick H, Sturgen K, Dorflinger L. Contraceptive efficacy and acceptability of the female condom. Am J Public Health 1994;84: 1960-1964. 141. Elias CJ, Coggins C. Female-controlled methods to prevent sexual transmission of HIV. Aids 1996;10(suppl 3):$43-51. 142. Berer M. Adverse effects of nonoxynol-9. Lancet 1992;340:615-616. 143. Feldblum PJ. Self-reported discomfort associated with use of different nonoxynol-9 spermicides. Genitourin Med 1996;72:451-452. 144. McGroarty JA, Reid G, Bruce AW. The influence of nonoxynol9-containing spermicides on urogenital infection. J Urol 1994;152: 831-833. 145. Roddy RE, Cordero M, Cordero C, Fortney JA. A dosing study of nonoxynol-9 and genital irritation. Int J STD AIDS 1993;4: 165-170. 146. Stafford MK, Ward H, Flanagan A, et al. Safety study of nonoxynol-9 as a vaginal microbicide: evidence of adverse effects. JAcquir Immune Defic Syndr Hum Retroviro11998;17:327- 331. 147. Steiner MJ, Cates W Jr. Condoms and urinary tract infections: is nonoxynol-9 the problem or the solution? Epidemiology 1997;8: 612-614. 148. Howett MK, Neely EB, Christensen ND, et al. A broad-spectrum microbicide with virucidal activity against sexually transmitted viruses. Antimicrob Agents Chemother 1999;43:314-321. 149. Roddy RE, Zekeng L, Ryan KA, et al. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N EnglJ IVied 1998;339:504- 510. 150. Cook RL, Rosenberg MJ. Do spermicides containing nonoxynol-9 prevent sexually transmitted infections? A meta-analysis. Sex Transm Dis 1998;25:144-150.
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SECTION IV
Changes OccurringAfter Menopause In this section on changes occurring after menopause, the intent is to provide a review of some of the major changes affecting women after the perimenopausal period described in the previous section. Missing here, but of sufficient importance to warrant separate dedicated sections, are the concerns for cardiovascular health, cancer, and osteoporosis. An in-depth understanding of many of the physiologic changes that occur will be valuable for clinicians in counseling women and offering possible treatments. Robert R. Freedman begins with an in-depth discussion of hot flushes, the classic symptom of postmenopausal women. Next, Frederick Naftolin and colleagues review the effects of sex steroids on the brain and how changes in these levels may affect brain chemistry and symptomatology. This theme is continued with Barbara B. Sherwin's discussion of psychologic functioning, which should be paired with David R. Rubinow's discussion of such changes in perimenopausal women in Chapter 24. Mark Brincat discusses collagen in Chapter 16 and describes the importance of collagen content for the skin and skeleton and how menopause and sex steroids may influence collagen content. In the next chapter, H. Irving Katz describes skin changes after menopause and differentiates between normal aging and the influence of hormones. G6ran Samsioe next describes the importance of changes in the urinary system after menopause and how this affects quality of life. In this edition a new section has been created that will delve more deeply into female urology and pelvic support, which are of great importance to older women. Next Gloria Bachmann describes vulvovaginal complaints after menopause and atrophic changes that accompany the changes in the hormonal milieu after menopause. On a related but different topic, Lorraine Dennerstein describes sexuality around the time of menopause and the possible influence of hormones.
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~ H A P T E R 1;
Menopausal Hot Flashes ROBERT R.
FREEDMAN
Departments of Obstetrics and Gynecology and Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201
I. EPIDEMIOLOGY OF H O T FLASHES
answers to these questions are unknown and represent important avenues for further research.
Hot flashes are the most common symptom of the menopause and occur in the vast majority of postmenopausal women. Their prevalence among naturally menopausal women has been reported to be 68% (1) to 82% (2) in the United States, 60% in Sweden (3), and 62% in Australia (4), with a median age of onset of approximately 51 years (5). Among ovariectomized women, the prevalence of hot flashes is approximately 90% (2,6). In one study, Feldman et al. (2) found that 64% of women experienced hot flashes for 1 to 5 years, and Kronenberg reported the median length of the symptomatic period to be 4 years. Studies of risk factors for menopausal hot flashes have found few strong effects. There is some evidence that heavier women are more likely to report hot flashes because increased body fat raises core body temperature (7). No significant association has been found between the report of hot flashes and socioeconomic status, age, race, parity, age at menarche, age at menopause, or number of pregnancies (5). Cultural factors do affect the reporting of hot flashes. Compared with Western women, women from Indonesia report hot flashes at rates of only 10% to 20% (8,9), Chinese women at rates of 10% to 25% (10), and Mexican Mayan women not at all (11). Reasons for these findings are not known. Perhaps women from rural and non-Western cultures demonstrate physiologically defined hot flashes as frequently as Western women but are acculturated in some way to not report them. Or they may actually have fewer physiologically defined flashes. This could be due to factors such as diet, because some foods such as yams and soy products contain substantial amount of phytoestrogens, which may help ameliorate hot flashes (12). The TREATMENT OF THE POSTMENOPAUSAL WOMAN
II. DESCRIPTIVE PHYSIOLOGY A. Self-Reported Data Kronenberg (5) conducted an extensive questionnaire study of hot flashes in 506 women ranging in age from 29 to 82. Of those reporting current symptoms, 87% had daily hot flashes, and one-third of these reported more than 10 per day. Hot flashes generally lasted 1 to 5 minutes, with about 6% lasting more than 6 minutes. About 40% of the women recognized a premonition that a hot flash was about to begin. The experience of a hot flash was most often described as sensations of heat, sweating, flushing, chills, clamminess, and anxiety. Sweating was reported most often in the face, head, neck, and chest, but rarely in the lower body.
B. Physiologic Data 1. SKINTEMPERATURE AND BLooD FLow Peripheral vasodilation, as evidenced by increased skin temperature, occurs during hot flashes in all areas that have been measured. These areas include the fingers, toes, cheek, forehead, forearm, upper arm, chest, abdomen, back, calf, and thigh (13-16). Finger blood flow (14) and hand, calf, and forearm blood flow (17) also increase during hot flashes. Thermographic measurements during hot flashes yielded data similar to those obtained with skin temperature (18).
187
Copyright 9 2007 by Elsevier,Inc. M1 rights of reproductionin any form reserved.
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2. SWEATINGAND SKIN CONDUCTANCE
Sweating and skin conductance, an electrical measure of sweating, also increase during hot flashes (Fig. 13.1). Molnar (13) obtained sweat prints with iodized paper during hot flashes and reported profuse sweating on the forehead and nose, moderate sweating on the sternum and adjacent areas, and little or none on the cheek and leg. The total body sweat rate was estimated to be about 1.3 g/min. In our laboratory, we measured sweat rate and skin conductance simultaneously from the sternum (16). Sweat rate was recorded by capacitance hygrometry using a 3.5 cm diameter plastic chamber attached over the sternum. Compressed air, regulated at 200 mL/min, was dried over CaCO2 and passed through the chamber. Skin conductance level was also recorded from the sternum using a 0.5-volt constant voltage circuit and disposable Ag/AgC1 electrodes. Both measures increased significantly during 29 hot flashes recorded in 14 women (Fig. 13.2). Measur-
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able sweating occurred during 90% of the flashes, and there was a close time correspondence between both measures. 3. CORE BODYTEMPERATURE
Homeotherms regulate core body temperature between upper thresholds, where sweating and peripheral vasodilation occur, and a lower threshold, where shivering occurs. If core body temperature were elevated in women with hot flashes, their symptoms of sweating and peripheral vasodilation could be explained. However, measurements of esophageal (13), rectal (13), and tympanic (15) temperatures were not elevated prior to hot flashes. These studies all found declines of about 0.3~ following hot flashes, probably due to increased heat loss (peripheral vasodilation) and evaporative cooling (sweating). However, esophageal and rectal temperatures have long thermal lag times and might respond too slowly to appear along with the rapid peripheral events of the hot flash (19). Addi-
FIGURE 13.1 Peripheralphysiologice v e n t s of the hot flash. (Data from ref. 16. Drawingby Jeri Pajor.)
CHAPTER 13 Menopausal Hot Flashes
189
FIGURE 13.3
Radiotelemetry pill.
had not significantly changed. These results were replicated during a daytime study in the laboratory (16).
4. METABOLIC RATE
FIGURE 13.2 Time course of skin conductance and sweating in 29 hot flashes. (From res 16.)
tionaUy, it has been shown that tympanic temperature does not reliably measure core body temperature because it is affected by peripheral vasodilation and sweating (20). We therefore conducted several studies in which we measured core body temperature using an ingested radiotelemetry pill, which has a faster response time than the esophageal and rectal methods (Fig. 13.3). The pill is swallowed 90 minutes before an experiment, to allow its egress from the stomach, and the signals are detected and stored in a small digital recorder. The typical transit time through the gut is about 24 to 72 hours, during which the recorder samples the data every 30 seconds. Hot flashes are recorded on a separate device, using sternal skin conductance level as the marker. In the first study, 10 symptomatic women were recorded using ambulatory monitoring for 24 hours (21). Of 77 hot flashes recorded, 46 (60%) were preceded by small but significant increases in core body temperature. In a second study, conducted during sleep in a temperature-controlled laboratory, 37 hot flashes occurred in 8 postmenopausal women (22). Significant core temperature elevations preceded 24 of the flashes (65%), whereas rectal temperature
Elevations in core body temperature can be caused by increased metabolic rate (heat production) and by peripheral vasoconstriction (decreased heat loss). In the last study (16) we sought to determine if either of these factors accounted for the core body temperature elevations preceding hot flashes. Twenty-nine flashes were recorded in 14 postmenopausal women. Significant elevations in metabolic rate (about 15%) occurred but were simultaneous with sweating and peripheral vasodilation and did not precede the core temperature elevations. Peripheral vasoconstriction did not occur. Thus, increased metabolic rate and peripheral vasoconstriction did not account for the core body temperature elevations in these women. 5. HEART RATE
Modest increases in heart rate, about 7 to 15 beats/min (13,23,24), occur at approximately the same time as the peripheral vasodilation and sweating.
III. OBJECTIVE MEASUREMENT OF HOT FLASHES
A. In the Laboratory 1. FINGER TEMPERATURE
Temperature from the dorsum of one finger was proposed as the first physiologic marker for menopausal hot flashes (25). In 7 symptomatic women, 41 skin temperature elevations greater than 1~ occurred within approximately
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1 minute of the subjective hot flash. However, the duration of the temperature elevations averaged 31 minutes, whereas the duration of subjective flushing was 2.3 minutes. Also, precise definitions of the onset and offset of the temperature elevations were not reported. 2. SKIN CONDUCTANCE
Subsequently, skin conductance recorded from the sternum was investigated as a hot flash marker. Tataryn et al. (26) found that 98% of 128 subjective flashes in 8 postmenopausal women were accompanied by elevations in sternal skin conductance, compared with 82% for finger temperature and 81% for decreased tympanic temperature. All these changes were significantly reduced by estrogen administration in 4 of the women. However, the precise characteristics of the skin conductance responses were not defined. Our laboratory subsequently sought to determine these characteristics (24). Sternal skin conductance level, finger temperature, and heart rate were recorded for 4 hours in 11 postmenopausal and 8 premenopausal women. Twentynine subjective hot flashes were indicated by pushbutton in the first group. All these were accompanied by an increase in sternal skin conductance >-2 gmho/30 sec. One skin conductance elevation occurred without a button press. All skin conductance elevations occurred within 66 seconds of the button press. No skin conductance elevations occurred in the premenopausal women. Thus, there was a concordance of 95% between the skin conductance criterion and the subjects' reports. Significant elevations in skin temperature and heart rate occurred during the flashes but were not as sensitive or specific as the skin conductance elevations. We replicated these findings in 18 symptomatic and 8 asymptomatic postmenopausal women (27). There was a concordance of 80% between the sternal skin conductance criterion (2 }amho/30 sec) and the subjective reports (button press) in 15 flashes recorded in the symptomatic women. No events occurred in the asymptomatic women. Our findings were then independently replicated by another laboratory (28). In two separate studies of 20 symptomatic women, a concordance of 90% was obtained between the sternal skin conductance criterion and subjective reports. Measurements of finger temperature and blood flow were less predictive and did not improve the concordance rate when added to the skin conductance measure.
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24 hours. Using the same basic circuit and electrodes, we found a concordance of 86% between the skin conductance criterion and button presses in 43 flashes recorded in seven symptomatic women (24). No such changes occurred in the eight premenopausal women. We replicated these findings in a second study (27). A concordance of 77% was obtained in 149 flashes recorded in 10 symptomatic women. Twelve skin conductance responses occurred in 8 putative asymptomatic women, representing a false response rate of about 8%. These ambulatory monitoring procedures were then successfully used to demonstrate the efficacy of a behavioral treatment for hot flashes in two subsequent studies (29,30). More recently, a smaller solid-state recorder has become available (UFI Biolog) that will continuously record hot flashes for up to 7 days. However, the skin conductance level (SCL) electrodes must be replaced every 1 or 2 days. Use of this device in symptomatic breast cancer survivors resulted in a concordance rate of 70% between SCLdetected hot flashes and event marks (31).
C. Provocation Techniques For laboratory investigations, it would be useful to reliably provoke hot flashes as opposed to waiting for them to occur during extended recording periods. Sturdee (23) observed that peripheral warming provoked objective and subjective hot flashes in seven of eight symptomatic women. We therefore sought to operationally define this procedure. Two 40- • circulating water pads maintained at 42~ were placed on the torso of 11 supine symptomatic women in a 23~ room (24). Eight hot flashes occurred within 30 minutes. A concordance of 73% was obtained between the skin conductance criterion (2 btmho/30 sec) and subjective report (button press). These findings were replicated in a subsequent study in 14 symptomatic women with a concordance of 84%. In this study, 25 hot flashes occurred during a 45-minute heating period. No objective or subjective responses occurred in eight asymptomatic women.
IV. ENDOCRINOLOGY A. Estrogens
B. Ambulatory Monitoring To evaluate treatment studies it would be useful to have a method that could be used outside the laboratory over longer periods. We therefore developed methods for recording sternal skin conductance on ambulatory monitors for
Because hot flashes accompany the decline of estrogens in the vast majority of naturally and surgically menopausal women, there is little doubt that estrogens play a role in the genesis of hot flashes. However, estrogens alone do not appear responsible for hot flashes because there is no correlation between the presence of this symptom and plasma (32),
CHAPTER 13 Menopausal Hot Flashes urinary (33), or vaginal (33) concentrations. No differences in unconjugated plasma estrogen concentrations were found in symptomatic versus asymptomatic women (34). AdditionaUy, clonidine significantly reduces hot flash frequency without altering circulating estrogen values (35). Prepubertal girls have low estrogen production without hot flashes, and hot flashes occur in the last trimester of pregnancy when estrogen production is high. Nevertheless, estrogen administration in hormone replacement therapy virtually eliminates hot flashes (36,37).
B. Gonadotropins Because gonadotropins become elevated at menopause, their possible role in the initiation of hot flashes has been investigated. Although no differences in leuteinizing hormone (LH) concentrations were found between women with and without hot flashes (38), a temporal association was found between LH pulses and hot flash occurrence (39,40). However, subsequent investigation revealed that women with a defect of gonadotropin-releasing hormone (GnRH) secretion (isolated gonadotropin deficiency) had hot flashes but no LH pulses and women with abnormal input to GnRH neurons (hypothalamic amenorrhea) had some LH pulses but no hot flashes (41). Additionally, hot flashes occur in hypophysectomized women, who have no LH release (42); in women with pituitary insufficiency and hypoestrogenism (43); and in women with LH release suppressed by GnRH analog treatment (44,45). Thus, LH cannot be the basis for hot flashes.
C. Opiates It was observed that alcohol-induced flushing in subjects taking chlorpropamide, a drug that stimulates insulin release and lowers blood glucose, was related to opiate receptor activation (46). Lightman et al. (47) subsequently found that naloxone infusion significantly reduced hot flash and LH pulse frequencies in six postmenopausal women. However, DeFazio et al. (48) attempted to replicate this study and found no effects. Tepper et al. (49) found that plasma [3endorphin concentrations decreased significantly before menopausal hot flashes, whereas Genazzani et al. (50) found significantly increased values preceding hot flashes. Thus, there is no consistent evidence of the involvement of an opioidergic system in menopausal hot flashes.
D. Catecholamines There is considerable evidence that norepinephrine plays an important role in thermoregulation mediated, in part through ot2-adrenergic receptors (51). Injection of norepi-
191 nephrine into the preoptic hypothalamus causes peripheral vasodilation, heat loss, and a subsequent decline in core body temperature (51). Additionally, there is considerable evidence that gonadal steroids modulate central noradrenergic activity (52). Studies of plasma norepinephrine have not found increased concentrations prior to or during hot flashes (14,39). However, brain norepinephrine content cannot be measured in plasma, due to the large amounts derived from peripheral organs (53). We therefore measured plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), the main metabolite of brain norepinephrine, to determine if central norepinephrine concentrations were elevated during hot flashes (29). We studied 13 symptomatic and 6 asymptomatic postmenopausal women who were supine, with an intravenous (IV) line in place, in a 23~ room. Blood samples were drawn at the beginning and end of a 60-minute period and during a hot flash, if one occurred. The same procedures were followed during a 45-minute heating period. Basal M H P G levels were significantly higher in the symptomatic women (p < 0.0001) and increased significantly during resting and heat-induced flashes. There were no hot flashes or significant M H P G changes in the asymptomatic women, whose blood drawing times were yoked to those of six symptomatic women. However, approximately 50% of the free M H P G that enters the blood is metabolized peripherally to vanillylmandelic acid (VMA), and VMA formation can compete with M H P G production (54). Thus, fluctuations in peripheral VMA formation could potentially distort measurements of plasma MHPG. Therefore, we measured both compounds simultaneously before and after hot flashes in 14 symptomatic women (16). Plasma M H P G concentrations increased significantly (p < 0.02) between the preflash (3.7 ng/mL _+ 1.4) and postflash (5.1 _+ 2.3) blood samples, whereas VMA levels did not significantly change (6.2 + 1.8 ng/mL versus 6.1 + 2.5). However, more recent research (53) has shown that only a minority of plasma M H P G is derived from brain, with the majority coming from skeletal muscle. Therefore, the measurement of plasma MHPG, in and of itself, cannot be used to indicate central nervous system (CNS) activation but does represent whole-body sympathetic activation. Clonidine, an ot2-adrenergic agonist, reduces central noradrenergic activation and hot flashes (55-57). Yohimbine, an cx2-adrenergic antagonist, increases central noradrenergic activation. We sought to determine if clonidine would ameliorate hot flashes and if yohimbine would provoke them in controlled laboratory conditions (58). Nine symptomatic postmenopausal women, ages 43 to 63 years, served as subjects. Six asymptomatic women, ages 46 to 61 years, served as a comparison group. All women were in good health and had been amenorrheic for 2 years or more. In two blind laboratory sessions, subjects received either intravenous clonidine HC1 (l~tg/kg) or placebo followed by a 60-minute waiting period and then by 45 minutes of
192
FIGURE 13.4 A hot flash, indicated by a sternal skin conductance response, occurred after intravenous infusion of 0.032 mg/kg yohimbine in a menopausal women with hot flashes. No responses occurred in the matched placebo session or in an asymptomatic woman given higher doses. (From ref. 58.) peripheral heating. In two additional blind sessions, subjects received yohimbine HC1 (0.032 to 0.128 mg/kg IV) or placebo. Clonidine significantly (p = 0.01) increased the length of heating time needed to provoke a hot flash compared with placebo (40.6 ___ 3.0 minutes versus 33.6 ___ 3.6) and reduced the number of hot flashes that did occur (2 versus 8) (Fig. 13.4). In the symptomatic women, six hot flashes occurred during the yohimbine sessions and none during the corresponding placebo sessions, a statistically significant difference (p < 0.015). No hot flashes occurred in the asymptomatic women during either session (Fig. 13.5). These data support the hypothesis that oL2_adrenergic receptors within the central noradrenergic system are involved in the initiation of hot flashes and are consistent with the idea that brain norepinephrine is elevated in this process. Animal studies have shown that yohimbine increases norepinephrine release by blocking inhibitory presynaptic oL2-adrenergic receptors (59). These autoreceptors mediate the turnover of norepinephrine through a feedback mechanism, and a reduction in their number or sensitivity would result in increased norepinephrine release (60). This mechanism is consistent with human studies showing that yohimbine elevates and clonidine reduces plasma levels of M H P G (61). Therefore, the yohimbine provocation and clonidine inhibition of hot flashes in symptomatic women may reflect a deficit in inhibitory o~2-adrenergic receptors not seen in asymptomatic women. Additionally, the injection of clonidine into the hypothalamus reduces body temperature and activates heat conservation mechanisms, effects that are blocked by yohimbine (62). Thus, oL2-adrenoceptors in the hypothalamus may be responsible for the events of the hot flash that are characteristic of a heat dissipation response. There is considerable evidence demonstrating that estrogens modulate adrenergic receptors in many tissues (52). It is possible, therefore, that hypothalamic oL2-adrenergic
ROBERT R. FREEDMAN
FIGURE 13.5 The occurrence of a hot flash during body heating was delayed after l~lg/kg clonidine, compared with placebo. No hot flashes occurred in an asymptomaticwoman. (From ref. 58.)
receptors are affected by the estrogen withdrawal associated with the menopause. As noted earlier, a decline in inhibitory presynaptic cx2 receptors would lead to increased central norepinephrine levels, and this is consistent with evidence from animal studies.
V. THERMOREGULATION AND H O T FLASHES Increased thermosensitivity at menopause has been noted in the literature for many years and is reflected in reports of increased hot flash frequency and duration during warm weather (63,64). Peripheral heating has been demonstrated to provoke hot flashes in most of our symptomatic subjects (24), and this has been found by others as well (23). As noted earlier, core body temperature (Tc) in homeotherms is regulated by hypothalamic centers between the thresholds of Tc for sweating and peripheral vasodilation and shivering (Fig. 13.6). According to this mechanism, the heat dissipation responses of hot flashes (sweating, peripheral vasodilation) would be triggered if body temperature were elevated or the sweating threshold lowered. We previously demonstrated that peripheral heating induced hot flashes in symptomatic but not asymptomatic postmenopausal women nor in premenopausal women (24,27). These data suggested that the sweating threshold was reduced in symptomatic postmenopausal women. Considerable research in humans and animals has shown that conditions that alter the sweating threshold tend to alter the shivering threshold in the same direction (51). We therefore tested to see if the Tc shivering threshold was reduced in symptomatic women, similar to their reduction in sweating threshold. We found that the shivering threshold was elevated rather than reduced in symptomatic compared with
193
CHAPTER 13 Menopausal Hot Flashes Small core body temperature (T~) elevations acting within a reduced thermoneutral zone trigger HFs in symptomatic postmenopausal women.
~sYMPT_ _.O_~_T.~ HF) _ , i ~ ' - - " ~ . _ . . . . / Sweating Threshold ~.~ ~, ThermoneutralZone
ASYMFr_O_MA_TIC= Sweating Threshold
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FIGURE 13.6 We have shown that the thermoneutral zone is narrowed in symptomaticwomen. Elevated brain norepinephrine (NE) in animals reduces this zone. Yohimbine (YOH) elevatesbrain norepinephrine and should reduce this zone. Conversely, clonidine (CLON) should widen it.
....
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Shivering Threshold
asymptomatic women (65). This result implies that the thermoneutral zone is narrowed in postmenopausal women with hot flashes. This hypothesis would explain the ability of small Tc elevations, as we found with the telemetry pill, to trigger the heat loss mechanisms of the hot flash (sweating, cutaneous vasodilation) and would also explain the shivering observed following many of them. We therefore measured the thermoneutral zone in symptomatic and asymptomatic postmenopausal women, hypothesizing a reduction in the former group. We studied 12 symptomatic and 8 asymptomatic postmenopausal women (66). We measured body temperature using a rectal probe, the ingested telemetry pill, and a weighted average of rectal and skin temperatures and determined the sweating and shivering thresholds for each. In a subsequent session, we raised body temperature to the sweating threshold using exercise. The symptomatic women had significantly smaller interthreshold zones than the asymptomatic women on all three measures of body temperature (Table 13.1). Sweat rates were significantly higher in the former group. During exercise, all the
symptomatic and none of the asymptomatic women demonstrated hot flashes. We subsequently studied the effects of clonidine and estrogen on the Tc sweating threshold. In the first study, 12 symptomatic postmenopausal women and 7 asymptomatic women received IV clonidine (2btg/kg) or placebo during separate laboratory sessions in which the Tc sweating threshold was determined. Clonidine significantly raised this threshold in the symptomatic women but lowered it in the asymptomatic women (67). In the second study, 24 symptomatic women were randomly assigned to receive 1 mg/day of 17 ~3-estradiol (E2) orally or a placebo, double-blind, for 90 days. E2 significantly raised the sweating threshold and reduced laboratory-recorded hot flashes, whereas placebo had the opposite effects. Neither group demonstrated changes in plasma M H P G , basal body temperature, or Tc elevations (68). Animal studies have shown that increased brain norepinephrine narrows the width of the interthreshold zone (51). Conversely, clonidine reduces norepinephrine release, raises the sweating threshold and lowers the shivering threshold in
TABLE 13.1 Sweating Thresholds, Shivering Thresholds, and Interthreshold Zones for Rectal Temperature, Telemetry Pill Temperature, and Mean Body Temperature (means + S.E.) Sweating Symptomatic Asymptomatic Pvalue
37.4 + 0.06 37.7 + 0.05 0.001
Symptomatic Asymptomatic P value
37.2 _+ 0.09 37.5 _+ 0.14 0.008
Symptomatic Asymptomatic P value
37.2 +_ 0.07 37.6 _+ 0.04 0.0003
P values for group differences, unpaired T-tests.
Rectal temperature (~ Shivering 37.4 _+ 0.06 37.3 __ 0.16 NS Telemetry pill temperature (~ 37.2 _+ 0.15 37.1 ___0.09 NS Mean body temperature (~ 36.4 _+ 0.06 36.1 + 0.18 0.02
Interthreshold 0.0 + 0.06 0.4 _+ 0.18 0.005 0.0 ___0.11 0.4 _+ 0.18 0.005 0.8 _+ 0.09 1.5 _+ 0.20 0.0006
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human studies (69). Thus, we suggest that elevated brain norepinephrine narrows the thermoregulatory interthreshold zone in symptomatic postmenopausal women (see Fig. 13.6). This zone was so small as to be virtually zero using our methods. We propose that small elevations in core body temperature trigger hot flashes when the sweating threshold is crossed. Core body temperature falls following hot flashes, and patients often report shivering at this time. This likely represents the point where the shivering threshold is crossed, although this has not been directly measured.
VI. CIRCADIAN R H ~ H M S The circadian rhythm of Tc is well known, and similar variations in other thermoregulatory parameters, such as heat conductance and sweating, have also been shown. These patterns suggest that the thermoregulatory effector responses of hot flashes might also demonstrate temporal variations. A previous study showed circadian rhythmicity of self-reported hot flashes in some menopausal women, but no physiologic data were collected (70). We recruited and screened 10 symptomatic and 6 asymptomatic postmenopausal women (21). Each received 24-hour ambulatory monitoring of sternal skin conductance level to detect hot flashes as well as ambient temperature, skin temperature, and Tc. The last measure was recorded using the ingested radiotelemetry pill. Cosinor analysis demonstrated a circadian rhythm ~ < 0.02) of hot flashes with a peak around 1825 hours (Fig. 13.7). This rhythm lagged the circadian rhythm of Tc in symptomatic women by about 3 hours. Tc values of the symptomatic women were lower than those of the asymptomatic women (p < 0.05) from 0000 to 0400 and at 1500 and 2200 hours. The majority of hot
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FIGURE 13.7 Hot flash frequency and core body temperature over 24 hours. Hot flash frequency in 10 symptomatic women, shown as bars. Best-fit cosine curve for hot flash frequency is shown as a dashed line ( . . . . ). A solid line ( O - - O ) with best-fit cosine curve ( ) represents 24-hour core temperature data for 10 symptomatic women. A dotted line (~1.......•) with best-fit cosine curve ( ..... ) represents 24-hour core temperature data in six asymptomatic women. (From ref. 21.)
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flashes were preceded by elevations in To, a statistically significant effect (p < 0.05). Hot flashes began at significantly (p < 0.02) higher levels of Tc (36.82 ___0.04~ compared with all nonflash periods (36.70 ___0.005~ These data are consistent with the hypothesis that elevated Tc serves as part of the hot flash triggering mechanism.
VII. H O T FLASHES AND SLEEP Many epidemiologic studies have found increased reports of sleep disturbance during the menopausal transition (71-74). It is generally believed that hot flashes produce arousals and awakenings from sleep, leading to fatigue and, possibly, impaired performance. However, this notion is challenged by two recent laboratory investigations (75,76). In one stu@ symptomatic and asymptomatic postmenopausal women and premenopausal women of similar ages were recorded under controlled laboratory conditions (75). They were screened to eliminate those with any drug use; sleep, physical, or mental disorder; or BMI greater than 30. There were no group differences whatsoever on any sleep stage measure, sleep or fatigue questionnaires, or performance test. When hot flashes occurred (mean - 5.2 ___ 2.9 SD/night), they tended to follow, rather than precede, arousals and awakenings. These data provide no evidence that hot flashes produce sleep disturbance in symptomatic postmenopausal women. These findings are strongly supported by those of a large, recent epidemiologic investigation (76). The Wisconsin Sleep Cohort Study measured sleep quality by complete laboratory polysomnography and by self-reports in a probability sample of 589 pre-, peri-, and postmenopausal women. Sleep quality was not worse in perimenopausal or postmenopausal women nor in symptomatic versus asymptomatic women on any measure. Thus, whereas the majority of epidemiologic studies find increased reports of sleep disturbance during menopause, this is not supported by laboratory investigations. This apparent contradiction may be partially resolved by a recent study conducted in our laboratory. Eighteen symptomatic and 6 asymptomatic postmenopausal women and 12 eumenorrheic women of similar ages were recorded on warm (30~ ambient), neutral (23~ and cold (18~ nights. When data were examined for the entire night, the same findings reported above were obtained: There were no significant differences among the groups and no evidence of hot flash-induced sleep disturbance. However, when data were examined by halves of the night, a different picture emerged. We divided the data because most rapid eye movement (REM) sleep occurs in the second half of the night, and it has been previously reported that thermoregulatory effector responses (e.g., hot flashes) are suppressed during REM. These analyses showed that, during the first half of the night, the women
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CHAPTER 13 Menopausal Hot Flashes
with hot flashes had significantly more arousals and awakenings than the other two groups and the 18~ ambient temperature significantly reduced the number of hot flashes. These effects did not occur in the second half of the night. In the first half of the night most hot flashes preceded arousals and awakenings. In the second half this pattern was reversed. Because the previous laboratory studies did not analyze data by halves of the night, the discrepancy with the epidemiologic studies may be partially explained. Further research on the role of menopause and hot flashes in sleep disturbance is needed.
VIII. TREATMENT OF H O T FLASHES
A. Hormone Therapy Until recently, hormone therapy was the gold standard of treatment for hot flashes. However, recent studies from the Women's Health Initiative have shown increased risks for breast cancer, coronary heart disease (CHD), thromboembolism, stroke, and dementia for estrogen plus progesterone treatment (77) and an increased risk of stroke with no reduction of C H D risk for estrogen alone (78). In light of the altered risk/benefit ratios for these treatments, they are now being given at lower doses. These issues are discussed elsewhere in this volume.
B. Lifestyle Modifications Because hot flashes are triggered by Tc elevations (66,79) and are more frequent in warm environments (64), procedures to reduce Tc and ambient temperature are recommended. Dressing in layers, drinking cold drinks, and using fans and air conditioning should be attempted. Weight loss may be helpful through reduction of insulation from body fat (7). Smoking cessation may also be beneficial (80-82).
C. Behavioral Treatments Because the thermoneutral zone may be narrowed due to elevated sympathetic activity, relaxation procedures to reduce this activation have been employed. Paced respiration (slow, deep, abdominal breathing) has been shown to reduce hot flash frequency by about 50% from baseline, when implemented to symptom onset. In the first study, women given this procedure plus muscle relaxation exercises showed significant amelioration of objective, laboratory-recorded hot flashes relative to the control procedure (alpha wave electroencephalography [EEG] biofeedback) (83). In the second study, women received paced respiration, muscle re-
laxation, or alpha EEG biofeedback (29). Only the women in the paced respiration group showed significant declines in hot flash frequency, measured by 24-hour ambulatory monitoring of sternal skin conductance. These results were replicated in a third study (30), which did not find declines in measures of sympathetic activation: plasma catecholamines, M H P G , and platelet ci2-receptors. Therefore, the mechanism of action of paced respiration upon hot flashes is not yet known. Two subsequent studies also found significant amelioration of subjective hot flashes using relaxation procedures (84,85).
D. Exercise Physical exercise has also been used as a potential treatment for hot flashes. There have been three randomized clinical trials (RCT) and three other studies. The largest RCT (n = 173) (86) compared a moderate-intensity exercise intervention with a stretching control group over I year. Exercise significantly increased the severity of hot flashes with no change in their occurrence. A Japanese study (87) compared 20 women in a 12-week education and exercise program with 15 no-treatment controls. There were no significant effects on hot flashes. A Swedish study (88) compared 15 women in a three-times-per-week exercise program with 15 women receiving oral estradiol. There was no change in hot flash frequency in the exercise group but a 90% decline in the estradiol group. A large (n = 1323), population-based, retrospective study in Linkoping, Sweden (89) found no significant effect of moderate exercise (1 to 2 hours a week) on hot flash occurrence. A case-control study (n = 171) (90) at a health maintenance organization (HMO) in California also found no effects of exercise on hot flashes. A retrospective, population-based study in Lund, Sweden (n = 6917) (91) found that vigorous exercise (more than 3 hours a week) was associated with significant reductions in hot flash frequency and intensity in a small number of women (4%), but this was confounded by other factors. Taken together, these studies do not demonstrate significant, positive effects of physical exercise on menopausal hot flashes. Our finding that exercise triggers hot flashes in the laboratory may, in part, explain these results (66).
E. Phytoestrogens Isoflavones or phytoestrogens possess estrogenic properties and are found in soy products and red clover. Black cohosh is another plant-derived substance used to treat hot flashes (Remifemin). A recent review of 22 controlled studies (92), 12 on soy and 10 on other botanical compounds, found no consistent improvement of hot flashes relative to placebo.
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F. Antidepressants Several recent studies have found efficacy for certain antidepressants in the treatment of hot flashes. Paroxetine (93), a selective serotonin reuptake inhibitor (SSRI), was shown to decrease hot flash composite scores by 62% (12.5 mg/day) and 65% (25.0 mg/day)in 165 women reporting two to three hot flashes a day. The placebo response rate was 37.8%. Fluoxetine is another SSRI used to treat hot flashes. In a study of 81 breast cancer survivors (94), a crossover analysis showed a reduction in hot flash frequency of about 20% over the placebo condition. Venlafaxine, a serotonin/norepinephrine reuptake inhibitor (SNRI), has also shown efficacy in treating hot flashes. In a study of 229 women (95), venlafaxine reduced hot flash scores by 60% from baseline at 75 and 150 mg/day and 37% at 37.5 mg/day compared with 27% for placebo. Side effects of these antidepressants include nausea, dry mouth, somnolence, decreased appetite, and insomnia. As noted earlier, clonidine ameliorates hot flashes by raising the Tc sweating threshold. Two small placebocontrolled studies found that oral clonidine reduced hot flash frequency by 46% (66) and transdermal clonidine reduced it by 80% (96). Two larger studies of breast cancer survivors on tamoxifen showed smaller, but significant reductions in hot flash frequency for oral (97) and transdermal clonidine (98) compared with placebo. Side effects of clonidine include hypotension, dry mouth, and sedation.
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ingested telemetry pill. We then found that the thermoneutral zone, within which sweating, peripheral vasodilation, and shivering do not occur, is virtually nonexistent in symptomatic women but normal (about 0.4~ in asymptomatic women. Thus, we believe that small temperature elevations preceding hot flashes acting within a reduced thermoneutral zone constitute the triggering mechanism. We also demonstrated that central sympathetic activation is elevated in symptomatic women, which, in animal studies, reduces the thermoneutral zone. Clonidine reduces central sympathetic activation, widens the thermoneutral zone, and ameliorates hot flashes. Estrogen virtually eliminates hot flashes and widens the thermoneutral zone, but the pathway through which this occurs is not known. Behavioral relaxation procedures reduce hot flash frequency to the same extent as clonidine (about 50%), but their mechanism of action is also not understood. The role of hot flashes and menopause in sleep disturbance is currently unresolved.
References 1. Neugarten BL, Kraines RJ. "Menopausal symptoms" in women of various ages. PsychosomMed 1965;27:266-273. 2. Feldman BM, Voda A, Gronseth E. The prevalence of hot flash and associated variables among perimenopausal women. Res Nurs Hlth 1985;8:261-268. 3. Hagstad A, Janson PO. The epidemiologyof climacteric symptoms. dcta Obstet Gynecol&and Supp11986;134:59-65.
G. Gabapentin Finally, gabapentin is an anticonvulsant of unknown mechanism, which was fortuitously found to ameliorate hot flashes in some patients. A controlled study of 59 women (99) found a reduction of hot flash frequency of 45% versus 29% for placebo. Side effects of this compound include dizziness and peripheral edema.
IX. SUMMARY Hot flashes are the most common symptom associated with menopause, although prevalence estimates are lower in some rural and non-Western areas. The symptoms are characteristic of a heat-dissipation response and consist of sweating on the face, neck, and chest, as well as peripheral vasodilation. Although hot flashes clearly accompany the estrogen withdrawal at menopause, estrogen alone is not responsible because levels do not differ between symptomatic and asymptomatic women. Until recently it was thought that hot flashes were triggered by a sudden, downward resetting of the hypothalamic set point, because there was no evidence of increased core body temperature. However, we recently obtained such evidence, using a rapidly responding
4. Gutherie JR, Dennerstein L, Hopper JL, Burger HG. Hot flushes, menstrual status, and hormone levels in a population-based sample of midlife women. Obstet Gyneco11996;88:437-442. 5. KronenbergE Hot flashes:epidemiologyand physiology.~Inn NY/Icad Sci 1990;592:52-86. 6. Chakravarti S, Collins WP, Newton JR, Oram DH, Studd JWW. Endocrine changes and symptomatologyafter oophorectomyin premenopausal women. BrJ Obstet Gyneco11977;84:769-775. 7. Freedman RR. Hot flash trends and mechanisms. Menopause 2002;9: 151-152. 8. Van Keep PA, HumphreyM. Psycho-socialaspects of the climacteric. In: Van Keep PA, Greenblatt RB, A1-Beaux-FernetM, eds. Consensus on menopause research. Lancaster, England: MTP Press, 1976;5-8. 9. Flint M, Samil RS. Cultural and subcultural meanings of the menopause. /Inn N Y/Icad &i 1990;592:134-148. 10. Tang G. Menopause: the situation in Hong Kong Chinese women. In: Berg G, Hammar M, eds. The modern management of the menopause, ed 8. New York: Parthenon Press, 1993;47-55. 11. Beyene Y. Cultural significance and physiological manifestations of menopause a biocultural analysis. Cult Med Psychiatry 1986;10:47-71. 12. Murkies AL, Wilcox G, Davis SR. Phytoestrogens.J Clin Endocrinol Metab 1998;83:297-303. 13. Molnar GW. Body temperature during menopausalhot flashes.Jdppl Physiol Resp Environ Ex Physio11975;38:499-503.
14. KronenbergF, Cote LJ, Linkie DM, Dyrenfurth I, DowneyJA. Menopausal hot flashes: thermoregulatory, cardiovascular, and circulating catecholamine and LH changes.Maturitas 1984;6:31-43. 15. Tataryn IV, Lomax P, BajorekJG, et al. Postmenopausalhot flushes: a disorder of thermoregulation.Maturitas 1980;2:101-107. 16. Freedman RR. Biochemical, metabolic, and vascular mechanisms in menopausal hot flushes. Fertil Steri11998;70:1-6.
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197 41. Gambone J, Meldrum DR, Laufer L, et al. Further delineation ofhypothalamic dysfunction responsible for menopausal hot flashes. J Clin Endocrinol Metab 1984;59:1092-1102. 42. Mulley G, Mitchell RA, Tattersall RB. Hot flushes after hypophysectomy. Br MedJ 1977;2:1062. 43. Meldrum DR, Erlik Y, Lu JKH, Judd HL. Objectively recorded hot flushes in patients with pituitary insufficiency.J Clin Endocrinol Metab 1981;52:684-687. 44. Casper RF, Yen SSC. Menopausal flushes: effect of pituitary gonadotropin desensitization by a potent luteinizing hormone releasing factor agonist. J Clin Endocrinol Metab 1981;53:1056-1058. 45. DeFazio J, Meldrum DR, Laufer L, et al. Induction of hot flashes in premenopausal women treated with a long-acting GnRH agonist. J Clin Endocrinol Metab 1983;56:445-448. 46. Leslie RDG, Pyke DA, Stubbs WA. Sensitivity to enkephalin as a cause of non-insulin dependent diabetes. Lancet 1979;1:341-343. 47. Lightman SL, Jacobs HS, Maguire AK, McGarrick G, Jeffcoate SL. Climacteric flushing: clinical and endocrine response to infusion of naloxone. BrJ Obstet Gynaeco11981;88:919-924. 48. DeFazio J, Verheugen C, Chetkowski R, et al. The effects of naloxone on hot flashes and gonadotropin secretion in postmenopausal women. J Clin EndocrinolMetab 1984;58:578-581. 49. Tepper R, Neri A, Kaufman H, Schoenfield A, Ovadia J. Menopausal hot flushes and plasma g-endorphins. Obstet Gyneco11987;70:150--152. 50. Genazzani AR, Petraglia F, Facchinetti F, et al. Increase of proopiomelanocortin-related peptides during subjective menopausal flushes. Am J Obstet Gyneco11984;149:775-779. 51. Brfick K, Zeisberger E. Adaptive changes in thermoregulation and their neuropharmacological basis. In: Sch6nbaum E, Lomax P, eds. Thermoregulation:physiology and biochemistry. New York: Pergamon Press, 1990; 255-307. 52. Insel PA, Motulskey HJ. Physiologic and pharmacologic regulation of adrenergic receptors. In: Insel PA, ed. Adrenergic receptors in man. New York: Marcel Dekker, 1987;201-236. 53. Lambert GW, Kaye DM, Vaz M, et al. Regional origins of 3-methoxy-4-hydroxyphenylglycol in plasma: effects of chronic sympathetic nervous activation and devervation, and acute reflex sympathetic stimulation. Jgluto Nerv Sys 1995;55:169-178. 54. Kopin IJ, Blombery P, Ebert MH, et al. Disposition and metabolism of MHPG-CD3 in humans: plasma MHPG as the principal pathway of norepinephrine metabolism and as an important determinant of CSF levels of MHPG. In: Usdin E, ed. Frontiers in biochemicalandpharmacological research in depression. New York: Raven Press, 1984;57-68. 55. Clayden JR, Bell JW, Pollard E Menopausal flushing: double blind trial of a non-hormonal medication. Br MedJ 1974;1:409-412. 56. Laufer LR, Erlik Y, Meldrum DR, Judd HL. Effect of clonidine on hot flushes in postmenopausal women. Obstet Gynecol 1982;60: 583-589. 57. Schmitt H. The pharmacology of clonidine and related products. In: Gross F, ed. Handbook ofexperimentalpharmacology, vo139: Antihypertensive agents. New York: Springer-Verlag, 1977;299-396. 58. Freedman RR, Woodward S, Sabharwal SC. e~2-Adrenergic mechanism in menopausal hot flushes. Obstet Gyneco11990;76:573-578. 59. Golberg M, Robertson D. Yohimbine: A pharmacological probe for study of the e~2-adrenoceptor.Pharmacol Rev 1983;35:143-180. 60. Starke K, Gothert M, Kilbringer H. Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev 1989;69:864-989. 61. Chamey DS, Heninger GR, Sternberg DE. Assessment of c~2-adrenergic autoreceptor function in humans: Effects of oral yohimbine. L ~ Sci 1982; 30:2033-2041. 62. Zacny E. The role of ot2-adrenoceptors in the hypothermic effect of clonidine in the rat.J Pharm Pharmaco11982;34:455-456. 63. Molnar GW. Menopausal hot flashes: their cycles and relation to air temperature. Obstet Gyneco11981;57(suppl):52-55. 64. Kronenberg F, Barnard RM. Modulation of menopausal hot flashes by ambient temperature. J Therm Bio11992;17:43-49.
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65. Freedman RR, Woodward S. Altered shivering threshold in postmenopausal women with hot flashes. Menopause 1995;2:163-168. 66. Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol 1999;181: 66-70. 67. Freedman RR, Dinsay, R. Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women. Fertil Steri12000; 74:20-23. 68. Freedman RR, Blacker CM. Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steri12002;77:487-490. 69. Delaunay L, Bonnet F, Liu N, et al. Clonidine comparably decreases the thermoregulatory thresholds for vasoconstriction and shivering in humans. Anesthesiology 1993;79:470-474. 70. Albright DL, Voda AM, Smolensky MH, Hsi B, Decker M. Circadian rhythms in hot flashes in natural and surgically induced menopause. ChronobiolInternat 1989;6:279-284. 71. Baker A, Simpson S, Dawson D. Sleep disruption and mood changes associated with menopause.J Psychosom Res 1997;43:359-369. 72. Kuh DL, Wadsworth M, Hardy R. Women's health in midlife: the influence of the menopause, social factors and health in earlier life. BrJ Obstet Gynaeco11997;104:923-933. 73. Owen JF, Matthews KA. Sleep disturbance in healthy middle-aged women. Maturitas 1998;30:41-50. 74. Kravitz HM, Ganz PA, Bromberger J, et al. Sleep difficulty in women in midlife: a community survey of sleep and the menopause transition. Menopause 2003;10:19-28. 75. Freedman RR, Roehrs TA. Lack of sleep disturbance from menopausal hot flashes. Fertil Steri12004;82:138-144. 76. Young T, Rabago D, Zgierska A, Austin D, Finn L. Objective and subjective sleep quality in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin cohort study. Sleep 2003;26: 667-672. 77. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestins in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. J_//MA 2002;288:321-333. 78. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. J_dMA 2004;291:1701-1712. 79. Freedman RR. Core body temperature variation in symptomatic and asymptomatic postmenopausal women: brief report. Menopause 2002;3: 399-401. 80. Gold EB, Sternfield B, KelseyJL, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemio12000;152:463-473. 81. Whiteman MK, Staropoli CA, Lengenberg PW, et al. Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol 2003;101: 264-272. 82. Jessen AB, Toubro S, Astrup A. Effect of chewing gum containing nicotine and caffeine on energy expenditure and substrate utilization in men. Am J Clin Nutr 2002;77:1442-1447. 83. Germaine LM, Freedman RR. Behavioral treatment of menopausal hot flashes: evaluation by objective methods. J Consult Clin Psychol 1984;52:1072-1079.
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84. Irvin JH, Domar AD, Clark C, Zuttermeister PC, Friedman R. The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gyneco11996;17:202-207. 85. Wijima K, Melin A, Nedstrand E, Hammar M. Treatment of menopausal symptoms with applied relaxation: a pilot study.J Behavior Tber Exper Psychiatr 1997;28:251-261. 86. Aiello EJ, Yasui Y, Tworoger SS, et al. Effects of a year-long, moderateintensity exercise intervention on the occurrence and severity of menopause symptoms in postmenopausal women. Menopause 2004;11: 382-388, 2004. 87. Ueda M. A 12-week structured education and exercise program improved climacteric symptoms in middle-aged women. J Physiol AnthropolAppl Human Sci 2004;23:143-148. 88. Lindh-Astrand L, Nestrand E, Wyon Y, Hammar M. Vasomotor symptoms and quality of life in previously sedentary postmenopausal women randomized to physical activity or estrogen therapy. Maturitas 2004;48:97-105. 89. Ivarsson T, Spetz A-C, Hammar M. Physical exercise and vasomotor symptoms in postmenopausal women. Maturitas 1998;29:139-146. 90. Sternfield B, Q.uesenberry CP, Husson G. Habitual physical activity and menopausal symptoms: a case-control study. J Womens Health 1999;8:115-123. 91. Li C, Samsioe G, Borgfeldt C, et al. Menopause-related symptoms: what are the background factors? A prospective population-based cohort study of Swedish women (The Women's Health in Lund Area Study). Am J Obstet Gyneco12003;189:1646-1653. 92. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med 2002;137:805-813. 93. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMff 2003;289:2827-2834. 94. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes.J Clin Onco12002;20:1578-1583. 95. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet 2000;356:2059-2063. 96. Nagamani M, Kelver ME, Smith ER. Treatment of menopausal hot flashes with transdermal administration of clonidine. Am J Obstet Gyneco11987;156:561-565. 97. Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000;132: 788-793. 98. Goldberg RM, Loprinzi CL, O'Fallon JR, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Onco11994;12: 155-158. 99. Guttuso T Jr, Kurlan R, McDermott MP, Keiburtz K. Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gyneco12003;101:337-345.
~HAPTER 1 ~
Clinical Effects of Sex Steroids on the Brain IVALDO DA SILVA Gynecology Department, Federal University of $5o Paulo, Brazil 04038-031 FREDERICK NAFTOLIN
Department of Obstetrics and Gynecology, NewYork University School of Medicine, New York, NY 10016
early symptoms of menopause are hot flushes (vasomotor episodes [VMEs]), mood/cognition changes, and sleep disorders. Although the occurrence of hot flushes is usually transient (3 to 5 years), they are important in two ways: First, hot flushes are often intense and debilitating (2). Second, they indicate the presence of uncompensated, clinically relevant estrogen deficiency that may herald the development of other complications of estrogen deficiency, such as vascular disease, bone loss, and metabolic syndromes, as noted elsewhere in this book. The central and peripheral nervous systems, which are estrogen target tissues, undergo anatomic and biochemical remodeling throughout life. These changes may be subtle; but the brain's responses to sex hormones ~ estrogen, progesterone, and androgen ~ have important roles in the modulation of brain function (3). These hormones affect neurons, glia, and microglia (i.e., brain macrophages) in many areas in the brain, not just in the portions of the hypothalamus and preoptic area involved solely with autonomic function. The decline of sex steroids, particularly estrogen, during the postreproductive decades is accompanied by changes in eating, metabolism, and sleep; behavior; mood; sexuality; locomotor activity; immune response; memory; and cognitive function (4). The list continues to grow and now includes ischemic vascular and dystrophic brain problems (5).
I. CLINICAL EFFECTS OF SEX STEROIDS O N T H E BRAIN Over the past century, better medical, economic, and sociocultural conditions in our society have doubled life expectancy for women. Symptomatology, mental health, and degenerative brain diseases, especially stroke and dementia due to vascular conditions or Alzheimer's disease, are part of aging and of menopause. They have become increasingly important with the rise in the aging population. This importance will only grow during the coming years, so that a better understanding and proactive stance become more important in the 21st century. Menopause is an important period of transition to dependence on locally formed estrogen. During the reproductive period, the chief source of estrogen is the ovary. Although extra gonadal estrogen formation furnishes estrogen in most tissues, including the brain and blood vessels (1), this is a relatively small source of estradiol in the woman's economy. At menopause, the loss of ovarian estrogen and continued secretion of androgens by the ovary and adrenal gland make extra gonadal estrogen the chief source of estrogen. This is tissue dependent and insufficient to block the appearance of menopausal symptoms in the great majority of women. The most common TREATMENT OF THE POSTMENOPAUSAL WOMAN
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Although these brain changes originate in the central nervous system (CNS), there are reports that hormonal changes also influence peripheral nervous system (PNS) functions such as sensory function, fine-touch perception, two-point discrimination, hearing, smell, and vision (6). These are less well documented and do not exclude primary effects of sex steroids on the tissues and organs in which the PNS is embedded and from which it derives its blood supply. For completeness, we have listed major groups of brain functions that may deteriorate during the menopause (Table 14.1). This table gives a powerful demonstration of the brain's integrative function and estrogen's role. Because of space limitations, the remainder of this chapter concentrates on brain functions in which sex steroids are best known to play a role and that may be preserved by hormone treatment. An overview of the brain, its functional construction, and the mechanism of sex steroid actions on the brain precedes these considerations.
FIGURE 14.1 Brain development along the neural tube results in functional and anatomic mini-organs linked by tracts. The adult brain is the result of folding the neural tube and its derivatives to fit the cranium.
II. THE BRAIN A N D SEX STEROIDS A. Anatomic-Functional Correlations The brain is a linear ensemble of structures that develop along the neural tube and that are roughly proportional in size to the functional requirements of individual species (Fig. 14.1). Humans have a large prefrontal cortical area, which serves to serve cognition, memory, and mood. This area and the central, sensory cortical areas are linked with other regions through axonal connections running along the area beneath the original neural tube (i.e., adult ventricular system). These axons form "tracts" that connect distant areas of the brain, allowing signals to be processed between brain areas and eventually stored, used, or discarded (Fig. 14.2). The hippocampus, which primarily processes incoming
TABLE 14.1
Brain Functions Affected During Menopause
Autonomic Gonadotrophins Sleep Vasomotor episodes Libido Mood Metabolic regulation Cognition Sensory perception Memory Voluntary motor function Immunologic function Sexually dimorphic function and dysfunction (presumed to be sex steroid related)
information from the environment, body sensors, and other brain areas and stores short-term memory, is located in, and connected to, the temporal cortex. There are also major reciprocal connections with the hypothalamus and cortical areas in which long-term memory is stored and other cognitive functions occur. Memory and cognitive centers along the visual pathway contribute to the final inflow path to the hippocampus. The interaction of all these structures results in optimal function of the brain. Evidence for this arrangement shows that age-related dystrophy affecting the hippocampal neurons first results in a deficit of short-term memory and then is generalized to most brain functions (7). Because the brain is an active metabolic tissue, it requires a massive blood flow, which is also hormone-sensitive (8). Although most attention has focused on its neurons, the brain is mainly composed of glial cells, particularly astroglia. Therefore, reported discordance in size and in areas of the brain most likely reflects glial differences; neurons are interspersed in the mass of glial cells, usually clustering into groups called nuclei. However, closeness is not critical, as the neurons interact through arborization of their axonal (afferent) processes, which connect to the dendritic (efferent) tree of target neurons via cell specializations known as synapses. The information then passes to the neuronal cell body, or soma. The cellular actions are similar to the general metabolism that goes on in nonneural cells; the main difference is in the arborization of communicating axons and dendrites that allows both local and long distance communication. The astroglia, like the neurons, are sex steroid sensitive. They can form metabolites through the steroid degradation process. Generally, it is accepted that androgens are aromatized by neurons (9) and ring-A reduced by astroglia (10).
CHAPTER 14 Clinical Effects of Sex Steroids on the Brain
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FIGURE 14.2 Each region of the brain has an important role in specific brain functions. Optimal brain activity is maintained by means of the integration of different areas by neural tracts. ARC, arcuate nucleus; POA, preoptic area; SO, supraoptic nucleus; PVN, paraventricular nucleus; VMN, ventromedial nucleus.
Evidence has been presented indicating that astroglia can be activated to aromatize androgens (11). The astroglia are becoming better understood as a second communication system in the brain, but the regulation of this calciumdriven communication is not well understood, nor are the roles of aging and steroids resolved (12). Neuronal processes connect through myriad synapses, cellcell interfaces that perform the specialized function of furnishing neurotransmitters to the synaptic cleft and passing them back and forth (uptake and reuptake). Neurotransmitter expression is regulated by many substances, including sex steroids (13). The formation and maintenance of synapses is estrogen regulated (14), especially in the areas where there are estrogen receptors (ERs). Sex steroids also regulate the number and function of the neurotransmitter receptors that translate the messages carried into the synapses by the neurotransmitters. As mentioned earlier, with aging, there is a shift in the regulatory balance between circulating steroids and locally formed steroids. During menopause, the follicular estrogen decreases, leaving a greater burden of steroid supply to peripheral conversion by brain and other issues. Generally, estradiol is synaptogenic and promotes communication between neurons. This is best recognized in animal studies that have shown that estradiol induces the growth of specialized outpouchings called spines along the afferent dendrites of neurons. This has been especially studied in the information processing part of the brain, the bilateral hippocampuses (15). The addition/lengthening of spines on the dendrites furnishes "space" for the axons to place more boutons and form information-carrying synapses. Thus, the effect of estrogen is largely to bring more information into the brain and speed processing, especially in the hippocampus. This
may be the mechanism for estrogen's effect on memory (16-19). The glial cells have a major role in all these activities. The astroglia are the embedment of the neurons. Synapses must penetrate sheets ofglial processes to make their connections. The astroglia respond to neurotransmitters and other products in the area of the neuronal cell bodies and along the neurites (neural processes) and synapses (10). The glia buffer the leakage of neural products (e.g., neurotransmitters, cytokines, free radicals). In this way, the glia cells form a protective or reparative barrier between neurons. We and others have shown that the astroglia are extremely physically active, slinging out processes and shuttering the space vacated by changing synapses (20). This is regulated by estradiol (14). A specialized form of glia, the oligodendroglia, is present in CNS and PNS. These glial cells wrap axons with myelin, ensuring rapid, efficient neurotransmission. In animals, the oligodendroglia have also been shown to metabolize cholesterol and other B-ring unsaturated steroids, such as pregnenolone and cognate progestins (21). The major metabolic products are allopregnanolone and alloprogesterone, which are presently being studied as sedative, anxiolytic neuroactive compounds (21,22). The role of these compounds in menopausal mood changes is only now being explored (23). Another type of glia, the microglia, constitutes the brain's macrophages. The microglia express ER(x, make estrogen, and produce cytoldnes, growth factors (molecules that regulate cellular responses to insult), and immune-checkpoint proteins in response to estrogen. We have proposed that in this way the microglia form the (estrogen-sensitive) immunologic brain barrier to maintain homeostasis and avoid inflammation that could damage nearby neurons and other cells. Maintaining homeostasis could avoid brain dystrophy
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(10,24). We also proposed that this "immune brain barrier" (IBB) (12) helps to maintain the brain as an immunologically privileged organ. The IBB is mediated by the expression of the activational response to antigens (25) and the production of the immune-checkpoint proteins, Fas ligand (FasL), and CD40 in microglia, astrocytes, and neurons (24). As activated T cells enter the brain, they may contact processes of the glia limitans or perivascular microglia (26), thereby receiving an estrogen-regulated Fas/FasL-mediated death signal (25,27,28). These actions of estrogen that limit the inflammatory response in the brain may keep harmful inflammation in check during the postreproductive period, but this would require the presence of estrogen or androgenic precursors. The outcome of repeated inflammation is dystrophy, so there are implications for the advent and course of dementia in aging. Finally, there are direct interactions with the proteins found in Alzheimer's dementia (AD). Estrogen has been associated with regulation of the presence of insoluble amyloid [3 in the brain. This is the inflammatory form of a commonly circulating protein (29). In addition, estradiol has been shown to inhibit the hyperphosphorylation of tau, a microtubule associated protein (MAP) that is bound up in the tangles that escape degenerated cells in AD (30).
B. Estrogen and General Brain Function Estrogen appears to affect all brain cells via direct cellular effects and indirect effects (estrogen-sensitive cells regulating connected non-ER-bearing cells). Estrogen affects neurons and glia and also regulates the brain's blood vessels. Estrogen has been shown to influence most brain functions by regulating biochemical and anatomic conditions and modulating the uptake and turnover of neurotransmitters, neuronal enzyme activity, and the expression of steroid receptors on the brain. Most estrogen actions on brain cells are ER mediated.
C. Estrogen, Estrogen Receptors, and the Brain Because Doisy and Butenandt identified and determined the formula for estrogen (31), the term estrogen has many times been redefined because of the discovery of many classes of compounds that are estrogenic and also for the broadening description of specific biochemical actions of estrogenic compounds. After the development of the primary steroidal estrogens (e.g., estradiol, estrone, estriol), the first nonsteroidal, synthetic estrogen, diethylstilbestrol (DES), was produced. Description of the estrogenic effects of plant estrogen (i.e., phytoestrogen) soon followed, and a large group of nonsteroidal compounds were also found to have estrogenic actions. Shortly thereafter,
TABLE 14.2 Clinical Effects of Estradiol (E2), Raloxifene (RLX), Tamoxifen (TMX), and Genistein (GEN) E2 Vasomotor events
Sexuality Cognitive
effects SSRI synergy Brain fMRI
TMX
GEN
t -~?
t-~?
t
lr- t
Gonadotrophins Sleep regulation
RLX
1[~
t- t t- t t- t t- t
t- t t- t?
It-,?
t , strong evidence; ) , weak evidence.
primary estrogens and DES became clinically available. The next step was the commercial development: steroidal estrogens, nonsteroidal estrogens, estrogen agonists or antagonists, and antiestrogens were drawn from the previously described compounds or their congeners. Researchers became interested in studying differences in mechanism of action of these classes of compounds. The development of compounds with new agonist or antagonist properties was accompanied by descriptive terms that appear to add little to the fundamental understanding of estrogen action: phytoestrogen, xenoestrogens, estrogen-like endocrine disrupters, and selective estrogen receptor modulators (SERMs) (32). A composite of the known clinical effects of the prototypical SERMs in clinical practice follows. Note the large gaps in knowledge (Table 14.2). With increased knowledge of estrogen actions on the brain, quantitative and qualitative inconsistencies were apparent in clinical situations. This may be resolved by the discovery of a second, specific ER, ER-[3, (33,34), which has a regional distribution and specificity of action in the brain that differs from ER-oL, although ER-ci and ER-13 may be found together in specific brain areas (Fig. 14.3). Estrogen regulates the neural activity through genomic effects that are regulated by ERs. DNA binding regulates transcription of RNA for new protein synthesis and expression. Because the ligand ERs dimerize before DNA binding, and there are two individual ERs (ER-ci and ER-[3), the formation of homodimers or heterodimers is possible (35). The resulting transcripts can be agonistic or antagonistic to transcription depending on the ligands (36), the receptor type (37), co-transcription factors, and possible effects of homodimer or heterodimer formation (Fig. 14.4) (37). Although receptors mediate the bulk of steroid actions in the brain, some actions appear to not require receptors. These have been shown experimentally to include changes in cell membrane channel permeability (38). Other, rapid actions of sex steroids may be cause by direct effects through several possibilities, such as early-intermediate gene activation (e.g., cFOS) or neurotrophin-driven actions (38).
CHAPTER 14 Clinical Effects of Sex Steroids on the Brain
203
FIGURE 14.3 Distributionof estrogen receptors ER-cxand ER-f3 mRNA in the rat brain.
Studies mapping estrogen and progestin receptors (PRs) in the brain have shown that ERs and PRs are co-localized in many areas, including the hypothalamus, hippocampus, amygdala, and limbic forebrain system (39,40). Studies showing that ER is present in areas previously thought to be devoid of ER, such as the cortex, are especially promising for explaining effects of estrogen (41,42). In fact, the distribution of steroid receptors is regionalized in a manner similar to the regionalization of function in the brain (see Figs. 14.2 and 14.3). For example, ER levels are high in the hypothalamus, where estrogen-dependent actions regulate neuroendocrine functions such as gonadotropin-releasing hormone (GnRH) control, sexual behavior, feeding behavior, and vasomotor stability. Because of diverse axon pathways and the synapses that these axons form with distant neurons, effects of small numbers of neurons often have disproportionate effects on brain function. For example, a small number of estrogen-sensitive acetylcholine neurons send axons throughout the brain, allowing indirect effects of estrogen on distant neurons. Because of the possibility of connections between ER-positive and ER-negative neurons, very few of the brain's neural networks could be insensitive to estrogen. This is shown in a diagrammatic manner in Fig. 14.4 (43). It also follows that cell death or dystrophy among relatively distant neurons can have widely felt consequences.
D. Sex Steroids and Brain Phenotype The presence of morphologic or functional sexual dimorphism in brain areas could give clues to estrogen action on the brain. In animals, hormonal effects during early prenatal and postnatal development induce sexual differentiation of many organ systems, including the brain (44). These sex differences carry over into adulthood, when estrogen affects
FIGURE 14.4 Possibilities for dimerization ofliganded receptors as they regulate DNA transcription.
females and males differently. In addition to classic signs of menopause in women (e.g., hot flushes), the incidence of depression and Alzheimer's dementia are higher among women (45-47), supporting the hypothesis that gender or hormonal balance is involved. In monkey models, neurite formation and synaptogenesis have been proven to be targets of estrogen in developing and adult subjects (48,49).
1. BIOCHEMICAL EFFECTS OF ESTROGEN IN THE BRAIN
Neurons are responsive to estrogen. Regulation of fiber growth and branching; synaptic plasticity; dendritic spines; synaptogenesis; glial cell function; blood flow; regulation of neurotransmitters/neuropeptides, neurotransmitter receptors, and neurotrophic factors; and clearance of proteins (e.g., [3-amyloid) have all been traced to estrogen. The enzyme aromatase (i.e., estrogen synthetase) is present in many brain areas (49). During the normal reproductive cycle, physiologically important levels of estrogen enter the circulation and reach the brain, thereby being the important regulator as
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opposed to locally formed estrogen. In the postreproductive years, the circulating estrogen falls and androgens are relatively maintained. This emphasizes local estrogen formation in specific brain areas as having functional importance.
III. HORMONES AND BRAIN FUNCTIONS OF CLINICAL IMPORTANCE TO THE MENOPAUSE A. V a s o m o t o r E p i s o d e s a n d O t h e r Brain D y s f u n c t i o n at the Start o f the C l i m a c t e r i c Vasomotor episodes (VMEs), usually referred to as hot flushes or hot flashes, are the most common symptom reported by climacteric women and are the primary cause for seeking medical advice during this period. The rate of reporting of VMEs is not constant throughout the world; for example, 50% to 85% of women in North America and Europe report VMEs at the time of cessation of ovarian function. The basis for this discrepancy is not understood, but evolutionary and cultural aspects appear to play important roles (50,51). The regular and dose-related diminution of VMEs in symptomatic women described elsewhere in this book attest to the role of estrogen in the occurrence of VMEs. Thermoregulatory centers in the hypothalamus are largely responsible for the control of vasomotor tone and VMEs (see Fig. 14.2). This is discussed in detail elsewhere in this book. VMEs are only one of many estrogen-dependent signs and symptoms of brain dysfunction that are prominent during the climacteric. Interestingly, these manifestations are generally not conceived as "brain symptoms." Rather, they are usually lumped in the category of "menopausal symptoms," thereby losing their significance as harbingers of brain dysfunction and perhaps permanent brain disease. This is a massively underdocumented area in need of much research.
FIGURE 14.5 Illustrationof the widespreadinfluenceof few acetylcholineand estrogen-receptor-containingneuronson the brain.
VMEs can have marked effects on personal and professional performance, especially when they are associated with other estrogen-deficiency brain dysfunction, such as sleep cycle disintegration (52), cognitive disorders (53), and neuroendocrine dysfunction (54,55). Most women have VMEs only for a limited time, 3 to 5 years, although estrogen levels remain low. Some compensatory changes in the brain or elsewhere must underlie the recession of symptoms. To explore this link, we studied VMEs in postpartum women and found that suckling-related VMEs continued past the reestablishment of ovarian cycles, indicating the presence of an intermediary neuronal network such as oxytocin in the chain of VME-related events (56). In any case, the role of estrogen cannot be doubted, because any time women (or men) undergo estrogen withdrawal, they have VMEs and they respond to estrogen replacement (57,58). The therapy for VMEs is estrogen. Although other approaches have been tried, they are largely unsuccessful and do not act to avoid other long-term consequences of ovarian failure. Although phytoestrogens or other forms of estrogen have been used, their efficacy and usefulness against longterm estrogen deficiency remains to be proven (59). As discussed elsewhere, numerous other treatments may substitute for estrogen, but they are secondary treatments.
B. Sleep D i s o r d e r s a n d the C l i m a c t e r i c The hypothalamus contains nuclei involved in sleep regulation (see Fig. 14.5). This hypothalamic area is associated with the circadian clock located in the suprachiasmatic nucleus. The periaqueductal gray matter is near and is involved in sleep regulation. In addition to ERs, the periaqueductal gray matter has a high PR content. Sleep is a reparative brain function. Sleep architecture is influenced by internal and external signals, including estrogen and progesterone. Loss of these hormones results in disintegrating sleep patterns, as measured clinically by
CHAPTER 14 Clinical Effects of Sex Steroids on the Brain electroencephalogram recordings (60). Sleep is clinically divided into two major states: rapid eye movement, (REM) sleep and non-rapid eye movement (NREM) sleep. During sleep, NREM and REM alternate or cycle. The average individual falls asleep within 10 minutes. The first part of sleep normally is an NREM phase, which is followed after 70 to 90 minutes by REM. The onset of sleep and the first REM period is defined as REM latency. Sleep can be disturbed by many external and internal factors. For example, sleep disturbances may be associated with VMEs in menopausal women (52). Associated complaints include sleeplessness, sweating to the point of needing to change clothes during the night, and impairment of one's daily life because of a lack of rest. Our group has shown that another cause of failed sleep, sleep apnea, occurs in menopausal women and responds to hormone therapy (HT). Sleep apnea is important because, in addition to lost sleep, it is thought to be a precursor to nocturnal cardiac arrhythmias and myocardial infarction (61). REM latency is increased and sleep efficiency decreased in menopausal women experiencing VMEs compared with those without VMEs (62,63). Because VMEs and sleep disorders go hand in hand, estrogen is the first-line pharmacologic approach for both disorders (52), and earlier studies showed that estrogen was effective in reducing sleep disorders and hot flushes in menopausal women (68). A pilot study investigated the effects of estrogen replacement therapy (ERT) on the rates of cycling alternate patterns of sleep (CAPS) and nocturnal hot flushes in postmenopausal women. It confirmed the previously described findings. Estrogen decreases the hot flushes and sleeps disturbances, reducing the rate of CAPS (65). Moreover, estrogen treatment of hypogonadal women decreased sleep latency, reduced waking episodes, and prolonged REM sleep (66). Others investigators' analyses of hot flushes and night sweats as the cause of psychosocial, behavioral, and health factors have suggested nonpharmacologic therapy (63), but this should only be tried in cases of failed HT. The key issues are the long-term effects of estrogen deficiency.
C. M o o d a n d the C l i m a c t e r i c Mood is a generic term with many aspects, such as feeling of worth, aggression, and psychomotor activity. Many brain regions are involved in establishing and maintaining mood. The highlighted brain areas in Fig. 14.2 are most directly associated with mood. Many of the same areas are simultaneously involved in the development and level of mood and cognition. Both the climacteric and premenstrual syndrome (PMS) are associated with symptoms such as irritability, anxiety, fatigue, depression, and sleep disturbances, which raises the consideration of hormonal causes. Depression also is more
205 prevalent among women (67), a discordance that could be related to developmental sex differences but more likely reflects the neurotransmitter and hormonal environment. Cyclic affective disorders seem to be more often expressed by females (68); after puberty the rate increases rapidly in girls compared with boys (69). Despite these variations, there is no evidence that depression in women is related only to abnormalities of gonadal function. Women are subject to changes in mood and to hormonal shifts. It is therefore not surprising that the two have been associated, and many therapeutic attempts have been made at connecting them. However, the results of these treatments are equivocal and appear to be specific to the individual being treated. Moreover, these patients often receive mood-altering drugs and HT.
1. ANATOMIC BASIS FOR SEX STEROIDS AND MOOD
Our understanding of the anatomic basis of CNS function is an amalgam of animal studies and clinical observations. The main anatomic areas related to the regulation of mood are limbic brain structures, including the amygdala, hippocampus, parahippocampal gyrus (part of the temporal lobe), thalamus, mamillary body, septum pellucidum, cingulate cortex, and cingulum. The hypothalamus has many connections to these areas and is considered by some to be part of the limbic system. However, because of its neuroendocrine activity, we prefer to consider it a distinct region that contributes to limbic function. All these structures interact by neural networks, together affecting brain functions related to emotion and mood. Similarly, areas of the temporal cortex, including the amygdala, have been related to specific emotions such as joy, fear, and anger. Sex steroids directly affect all these areas. Estrogen receptors are very dense in regions of the limbic system and hypothalamus. ER-ci and ER-[3 have been localized in these regions and may be involved in estrogen's regulation of mood (41,42). 2. FUNCTIONAL BASIS FOR MOOD
The problem of composing a mechanistic description or even a solution for mood changes based on anatomic or neuroendocrine differences in clinical subjects or patients is extraordinarily complex. Animal models are very poor substitutes for human mood or behavior. Most studies have required grossly (i.e., clinically diagnosable) abnormal mood to even show effects of hormone treatment. Less disturbed mood is often identified after its correction, when H T is employed for some other reason. Because of the inability to find endocrine changes that predict or even explain mood disorders (70), we have considered that there is a "substrate" of brain function (the totality of neuronal and nonneuronal cells, connections, and milieu interior) on which is laid the effects of many neurotransmitter and neuroregulatory substances, including sex steroids. Although the complex equation that is represented by
206 "mood" may well respond to hormone replacement (71), especially when the hormone deficiency is direct and abrupt (72-74), numerous psychotropic agents, especially the selective serotonin reuptake inhibitors (SSRIs), may have effects on the same substrate. These effects may be direct or indirect. For example, the SSRIs have been shown to cause rapid changes in serotonin metabolism but only gradual improvement in dysphoria. Some intermediate shift in the substrate seems likely; in such cases, catecholamines may be the final pathway of positive results. In a similar manner, sex steroids may shift the substrate, improving dysphoria and other moods.
3. EFFECTS OF SEX STEROIDS ON MOOD
Hormonal fluctuations have been associated with mood changes and perhaps mood disorders. The effects of changing estrogen levels are likely through changes in neurotransmitter systems. For example, when an estrogen deficit is evident, changes have been reported in the cholinergic, catecholaminergic, and serotoninergic systems (75). Variations in serotonin function are related to mood and depression. Antiserotonin drugs have been shown to induce depression in some humans (76). Estrogen has been shown to influence the midbrain serotoninergic system. Serotonin activity and serotonin receptors are increased by estrogen, while monoamine oxidase (MAO) levels are decreased. Menopause may be accompanied by a decrease in serotonin levels, which is reversed by H T (77). Other neurotransmitter systems may be involved in estrogen's effect on SSRI efficacy. For example, estrogen has also been shown to have a dose-dependent effect the dopamine system. Estrogen increases dopamine transmission and D2 dopamine receptors. Estrogen acts on the neurotransmitters' receptors and synapses involving in all these systems is fast. In contradistinction to the proposed secondary effect of SSRIs, above, estrogens affects on dopamine levels and receptors are very rapid (78). The role of individual sex steroids in mood is of great interest and is still a mystery. Extreme deficiencies of androgen or estrogens respond well to replacement therapy. Less clear are the effects of progesterone or the 19-nor progestins, both of which are employed in H T for their antiestrogenic actions on the endometrium. Despite the perceived clinical wisdom that they cause mood changes, blinded, cross-over studies employing controls have not confirmed a connection between depression and the use of progestins (79,80). Placebo-controlled clinical studies have tested the effects of ERT on mood symptoms in women during the postpartum period and in natural and surgical menopause. Generally, women treated with high-dose estrogen therapy have reported improved symptoms, particularly an improved sense of well-being (71). On the other hand, contradicting studies have reported no effects of hormone replacement on
DA SILVAAND NAFTOLIN
women's mood (69,81). These studies evaluated various estrogen regimens: estrogen alone and combined sequentially with progestin. Negative moods and psychologic symptoms were expressed by women in therapy with low-dose estrogen plus progestin compared with estrogen and placebo (82). Studies in hysterectomized women also reported a decrease in depressive symptoms after treatment with estrogen therapy (72,73,83- 85). ' Mood is a complex term that includes clinical mania, depression, and other disorders. The basis of mood disorders is not clear, but they are often related to or affected by hormone status. However, the long-term effect of repeated progestin administration on such chronic conditions as the neural dystrophies is not well known. Considerations for treatment should follow these guidelines: 1. Treatment should only be for indications. 2. All drugs have side effects, and patients should be accordingly monitored. 3. All efforts made to minimize dosage have thus far been rewarded. 4. Because the basis for success and failure of sex steroids in affecting mood is unclear, other possible underlying causes may appear during treatment. 4. DEPRESSION AND THE CLIMACTERIC Although mood disorders may be troublesome, clinical depression is recognized because of its disabling nature. Severely disordered sleep, psychomotor retardation, and feelings of worthlessness characterize depression and may be associated with suicidal ideation. Clinical depression is a severe dysphoria and requires a rigorous evaluation, followup, and a treatment plan. Considerable evaluation of the possible relationship between thyroid status and adrenocorticoid status and depression has occurred; however, less attention has been given to sex steroids and clinical depression. Despite dropping the diagnosis of"involutional melancholia," longitudinal studies continue to report increased rates of clinical depression during the perimenopause (86-89). Mood changes are influenced by various factors, such as a history of depression or PMS. However, it is hard to evaluate the role of the clinical history, and the literature is ambiguous (90). In any case, it seems that severe psychiatric illnesses commonly recur (91,92). Because of reported improvement in clinically depressed postmenopausal women on treatment with conjugated equine estrogen (93), many attempts at hormonal treatment of depressive symptoms have been undertaken. Most of the studies showed positive results in patients with depressed mood or mild depressive symptoms but did not provide new information about the effect of H T on major depression (71). A
CHAPTER 14 Clinical Effects of Sex Steroids on the Brain report appeared regarding women previously affected by "postpartum depression," a clinical depression marked by psychomotor retardation and sleep disorder. High doses of transdermal estradiol were administered. In this preliminary study, a striking improvement in depression was reported compared with those receiving placebo. During the first month of therapy, about 50% of women reported beneficial effect on depressive symptoms. Those are encouraging results because one-half of the patients reported a rapid effect on mood symptoms in contradistinction to the usual 2-week delay seen with SSRIs (94). Unfortunately, the researchers did not disclose the previous treatment status of their patients. Further and better described studies are needed. Patient selection and the test instruments play important roles in the outcomes and interpretation of studies on depression. Because improvement of depression with psychotropic agents, especially the SSRIs, has been dramatic, it is likely that hormones will remain an adjunct therapy. The first diagnostic measures must distinguish between mood disorders and major depressive illnesses. A dysphoric mood can be treated with estrogens at the outset. Psychotropic agents may then be added. It is important to add tricyclics or SSRIs slowly.Their effects may take some time to be fully felt. Possible synergistic actions between ERT and psychotropic drugs must be kept in mind (95). Estrogen may synergize with antidepressants. In the case of major depression, because ERT has not been shown to regularly or sufficiently improve the symptoms, we consider ERT as second-line adjunctive therapy. In all cases of major depression, a psychiatric consultation must be attained. No evidence supports a role for progestins or androgens in the treatment of major depression.
D. Cognitive F u n c t i o n and the Climacteric Many brain regions are involved in the cognitive process. Although this section focuses on memory and the limbic system, other cognitive functions may bypass the limbic system (see Fig. 14.2). For example, the visual cognitive system apparently has multiple memory and cognitive way-stations that contribute to the complete cognitive process. Cognition is the mental process by which knowledge is acquired or used, and it depends on several elements of the brain functioning harmoniously. These include the intake of information, processing, and distribution of action (including autonomic function) and memory.
ON
1. ANATOMIC BASIS FOR SEX STEROIDS' EFFECTS COGNITION
The areas of the brain involved in cognition are mainly the cerebral cortex, the temporal lobes, and the limbic system. New information enters the brain through the sensory
207 system (i.e., peripheral and cranial nerves) and is processed through the sensory cortex. Each of these areas has been shown to contain ERs (ER-[3 > ER-ot) (41,42) and therefore can be expected to be estrogen-sensitive. Study results have supported the effect of estrogen on cognition (96); however, because ER distribution is selective, it is reasonable to expect that estrogens can affect cells in specific regions of cortex. This high degree of selectivity results in a multitude of cognitive functions that may respond to estrogen. It also complicates evolution of estrogen effects on cognition (Fig. 14.9). More than just the estrogenic environment plays a role in cognitive decline related to aging. For example, from the endocrine side, neuronal loss has been associated with stress, possibly through adrenocorticosteroids (97). Much work remains to complete the understanding of the process, and derailment of memory and estrogen replacement represents a disproportionately large clinical therapeutic area that will shrink as more information appears. 2. EFFECT OF SEX STEROIDS ON COGNITION AND MEMORY
Verbal memory has also been positively correlated with endogenous estrogen levels during the luteal phase of the ovarian cycle and in hormone treated menopausal women (98). Menopausal women undergoing estrogen treatment often remark on the beneficial effects on memory and cognitive functions, even though they did not initially complain of deficits. Several studies have evaluated the effects of estrogen replacement therapy on cognitive function in menopausal women. Although these studies are heterogeneous in their experimental designs and evaluations, in general they support a role for HT, specifically ERT, in maintaining several types of short-term memory and cognition (96,99,100). Other investigators have evaluated treatments using estrogen or estrogen plus androgen versus placebo in women who had undergone total abdominal hysterectomy (TAH) and bilateral salpingooophorectomy (BSO), showing beneficial effects of the drugs on memory (53,101). Similarly, using GnRH analog to induce artificial menopause produced a decline in verbal memory score during the GnRH treatment that was reversed by treatment with conjugated equine estrogen (98). In our own double-blind study, we have shown (unpublished data) that ERT improves verbal and cognitive reading skills (102). Evaluating cognition and memory is a complex task in the usual clinical situation. Most often, the improvement is noticed in retrospect. Although the picture of estrogen's effect on memory is promising, further studies comparing like aspects of memory and excluding confounding side effects of estrogen, such as improved sleep, are needed.
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3. DEMENTIA AND THE CLIMACTERIC
Severe loss of intellectual function and short-term memory in aging subjects are the hallmarks of dementia. AD and vascular dementia are the most frequent diagnoses; the former is more common in the United States. Dementia is estimated to increase approximately 5% per year in women older than 65 years of age, reaching 50% in women older than 85 (103). Alzheimer's dementia is a neurodegenerative disease associated with neuronal cell loss and with development of degenerative lesions called amyloid plaques and neurofibrillary tangles. These lesions are present in relatively larger numbers than seen in normal aging. It is critical to distinguish AD from vascular dementia. The two conditions may coexist, and failure to establish the diagnosis is among the problems surrounding the evaluation of such studies as the subset analysis in the Woman's Health Initiative (104). As in AD, the occurrence of repeated small strokes results in short-term memory loss. On the other hand, long-term memory is more durable and continues to function when not required for storage or retrieval of impaired of shortterm memory and cognition loss. The dementia is progressive and distinguished mainly by a decline in memory followed by a gradual disintegration of intellectual function and orientation, language, judgment, and problem solving.
Ultimately, other vital functions begin to fail, leaving the patient unable to care for herself or himself and subject to terminal wasting or intercurrent illness. All treatment should aim to avoid late progress of AD. Prevention of early AD can also accomplish the same objective (105). It is critical to understand this end point's importance; anything that delays the transition from self-sufficiency is of greater importance than improvement of individual brain activities such as cognitive skill scores. This is the therapeutic goal in AD cases, not complete rehabilitation. Vascular dementia is caused by multiple small infarctions and may occur without a major stroke. Preliminary results indicate a vasodilation effect of estrogen and a vasoconstrictive effect of progestins on cerebral vessels (106).
4. ESTROGEN AND DEMENTIA
Several factors support a protective role of estrogen in dementia, and there is evidence that diminished estrogen, as found in menopausal women, may contribute to the neurodegenerative process associated with dementia (Fig. 14.6). AD has been shown to have an age-corrected rate between 1.4 to 3 times higher in women than in men (45-47). Women with AD have a lower body mass index, which is consistent with estrogen production in adipose tissue weigh less than those without AD, and obese women have a
FIGURE 14.6 Thisillustrates the manner bywhich decreased estrogen could allow activation ofmicroglia to progress past homeostatic killing of the occasional inflammatory cell that enters the area before it causes a snowball of inflammation and self-propelling pathology and neuronal damage/loss. (Modified from ref. 24.)
209
CHAPTER 14 Clinical Effects of Sex Steroids on the Brain higher production rate of estrogen from endogenous androgen in adipose tissue (107). Estrogen may have specific effects on AD, for example, we have shown that estradiol diminishes tau hyperphosphorylation, the apparent basis of the role of tau in the development of microtubule tangles in AD lesions (30). Animal studies also support a protective role for estrogen. In 1998, evidence regarding a possible mechanism through which estrogen exerts an antineurodegenerative role in the brain was reported in a multicenter study. It showed that the metabolism of the Alzheimer's [3-amyloid precursor protein may be regulated by 1713-estradiol in neuroblastoma cells and in primary cell cultures derived from human and rat neocortexes (108). These data emphasize the possible role that estrogen replacement therapy could play in the prevention and delay of the onset of AD. Table 14.3 reviews a group of commonly quoted epidemiologic studies (105,107,109-111), largely supporting lower dementia (AD) incidence in women taking estrogen. Among these, the prospective study by Tang et al. is the most interesting. This group of about 1200 women received neurologic examinations before beginning the study. Although their estrogen usage was not controlled and the case-control method was being used, the study strongly supports a delay by H T of AD diagnosis, which may be dose-related. In the Tang study of ERT patients, the diagnosis of AD was delayed by about 2 years. However, once
TaBLe 14.3
diagnosed, the progression of AD was similar to the progress of the control subjects (105). We have already pointed out the importance of even a short delay of the onset and course of dementia in this elderly population. The apparent similarity in disease progress between H T users and control subjects is consistent with a collateral protective effect by estrogen. Similar implications may be drawn from the only other longitudinal prospective study that tested the neurologic status before hormones were started (112). Not all researchers agree that estrogen delays the incidence of AD. Brenner et al. reported that several oral estrogen preparations were not related to the risk of AD. A negative correlation between ERT and cognitive function was evaluated. They compared women who never used estrogen with women currently under treatment or treated in the past, showing no evident difference on cognitive performance (113). We have mentioned the W H I subgroup analysis earlier, and reintroduce it only to indicate that the results are not valuable due to the age of the subjects at the start of hormone treatment, the lack of minimal cognitive deficit preceding the diagnosis of dementia, and the lack of determination of the role of vascular dementia in the study (114). Although studies using animal models support estrogen's reduction of degenerative processes of aging in the CNS, further clinical prospective evaluation of the role played by estrogen in the onset of AD-like lesions must be accomplished.
Epidemiologic Studies on Estrogen Use and Dementia
Type of study
Number of patients
Case-control study of community elderly women Case-control study of retirement community
143 with AD; 7% taking ERT 92 controls; 18% taking ERT 138 with AD or other dementia; 38% taking ERT 550 controls; 46% taking estrogens 93 with AD; 12% taking ERT 65 with V-D; 11% taking ERT 148 controls whom 20 taking ERT 167 women developed AD from 1124 women, 13% taking estrogens
Study
Year
Henderson et al.
1994
Paganini-Hill et al.
1994
Mortel et al.
1995
Case-control study of friends and relatives
Tang et al.
1996
Prospectivecohort study of community-based study of aging northern Manhattan, New York
Kawas et al.
1997
Prospective cohort of community-dwelling women
Follow-up No report
9 years
14 years
1 - 5 years
34 women developed AD from 16 years 472 post/perimenopause women, 34% taking ERT
AD, Alzheimer's disease; ERT, estrogen replacementtherapy;VD, vascular dementia.
Outcome Postmenopausal ERT may be associated with decreased risk of AD. Increase incidence of AD in elderly women may correlate with estrogen deficiency. Lack of ERT is associated with increased risk of dementia.
AD onset was later in women who had taken estrogen compared with women who never used it. Reduced risk of AD for women who had reported the use of estrogen.
210
DA SILVAAND NAFTOLIN
5. EFFECTS OF SEX STEROIDS ON DEMENTIA
Only a few limited studies exist regarding the treatment of AD with estrogen. In the main, these reports encourage the use of estrogen to improve cognitive functions in AD patients. Honjo et al. showed that six of seven women treated for 6 weeks with ERT, after which ERT was stopped (ERT was stopped after 3 weeks for two women), reported an improvement in cognitive functions compared with nontreated women (115). Later, these results were supported by the only placebo-controlled study reported, but this was also a very limited study (116). Based on the promise of these studies, a large prospective trial of I year of treatment of well-diagnosed women with AD has now been reported that failed to show any improvement of cognition or other measures (117). The combination of the lack of an effect in this large randomized, controlled clinical trial plus the induction of thrombotic disease in elderly women (118) contraindicates the use of estrogen in these cases.
E. Effects o f P r o g e s t e r o n e a n d Progestins on the Brain Progesterone is a 21-carbon steroid normally formed during the metabolic transformation of cholesterol to androgens and estrogens. Because of pharmacodynamic problems, the clinical formulations often use progesterone substitutes (i.e., progestins), which are 19-nor androgens. Progesterone and progestins interact with the androgen, progesterone, and adrenocorticoid receptors. It is not surprising that progestins affect the brain, however, the exact outcomes and their causes are presently under examination. Our review of this topic is abbreviated because it is in a state of flux and new reports often disagree. This may be due to the great differences in available progestin compounds. These include progesterone, androgenic progestins, such as hydroxyprogesterone and 19-nor progestins, and drospirenone, which is an aldosteronederived compound that has no androgenic action. It is important to focus prospective studies on cognitive effects rather than making them subsets of studies designed to test antiestrogenic actions. It is important to understand that the main reason to use progesterone or progestins is because of their antiestrogen qualities (119), although increasing evidence documents direct effects on neurons by progesterone or progestins. The onset of menopause is characterized by a marked reduction of estrogen accompanied by the lack of the luteal (progesterone) phase. As a result, most postmenopausal progesterone comes from the adrenal cortex. The balance of its effect is to antagonize estrogen action. The use of progesterone or progestins may be a disadvantage if the (beneficial) effects of estrogen are opposed throughout
the bo@ However, because estrogen treatment has been associated with an increased rate of endometrial cancer and breast tenderness, progesterone or progestins are prescribed to downregulate the ER-mediated actions. Receptor-mediated and non-receptor-mediated progesterone effects are not confined to the reproductive organs (120). For example, progesterone crosses the blood-brain barrier. Robel and Baulieu indicated that progesterone and its metabolites may also be formed in the brain (121), but in the case of women, this remains a work in progress. 5ot-reductase of progestins occurs in the brain. Tetrahydroprogestin (THP) has been shown to interact with ~/-aminobutyric acid (GABA) receptors in animal brain studies (22). Specific gila cells (i.e., oligodendroglia) perform this metabolism. Astrocytes and some neurons contain 5ot-reductase, which may contribute to T H P formation and action (122). Regional differences in brain steroid concentrations have been shown in women postmortem, emphasizing the local role that may be played by progesterone, its metabolites, and T H P in brain function. Brain T H P variations have been found during autopsies on fertile women during the luteal phase compared with postmenopausal control women (123). Moreover, high plasma levels of progesterone and THP have been correlated with increased fatigue and confusion in healthy women taking an oral dose of micronized progesterone (124). Additional mechanisms by which progesterone and its metabolites can act on the brain have been proposed, largely on the basis of studies in rats. Neuroendocrine and behavioral function can be mediated by progesterone receptors and protein synthesis (125). This action of progesterone may also downregulate ER (119). However, progesterone and its ring-A-reduced metabolites may also affect areas of the CNS where PR expression is low or absent, indicating non-receptor-mediated progesterone actions. Rapid alterations of CNS excitability, producing behavioral effects not attributable to intracellular receptors, have been reported seconds after the parenteral introduction of many steroids (38). This emphasizes the possible sedative roles played by these steroids in physiologic conditions such as pregnancy and stress (126), perhaps through increased GABA-inhibitory synaptic neurotransmission in the brain. This effect is mediated by the interaction between reduced progesterone and the GABA-A receptor complex through activation of receptor-gated C1- channels. In humans, progesterone has been reported to have sedative and anesthetic effects (127). In this regard, administered progesterone had anxiolytic and hypnotic properties (124). These actions are similar to those of the benzodiazepines and barbiturates that are known to interact with GABA-A receptors (128). Although progesterone and progestins have been reported to have similar effects on mood when used in contraception (129-131), such effects remain less documented in postmenopausal women during HT.
CHAPTER 14 Clinical Effects of Sex Steroids on the Brain Despite widely-held beliefs, contradictory findings have been reported in the assessment of the effects of progesterone/ progestins during HT. Two double-blind, placebo-controlled, cross-over trials with postmenopausal women reported no psychologic effects of medroxyprogesterone administered alone (89) or sequentially with transdermal estrogen (79). Absence of negative effects in anxiety and depression has also been reported by other studies employing sequential and combined H T (132). When synthetic progestins were used in sequentially combined transdermal therapeutic systems, no adverse affects were reported regarding mood (133). Despite these studies, the popular anecdotal gynecologists' bias remains that mood changes are often associated with progestins during HT. This is often one of the major causes of poor compliance and is a serious problem because it obstructs the use of liT. It is important to develop objective findings of negative effects of progesterone or progestins on mood. Some studies have confirmed negative effects of progestin added sequentially to estrogen during H T (82,134). However, because negative psychologic changes are not reported by all women, a relation between the dose of progesterone or progestin preparations and rate of mood disturbances has been suggested as an explanation (133). Despite a growing body of evidence indicating that circulating or locally formed progestins may act through the GABA receptor system to affect mood or alertness, the picture remains unclear in HT. In practice we employ minimum systemic progestin treatment, favoring local progestins for protection of reproductive tissue hyperplasia. Although women continue to have a bias against progestins, more evidence is required before this is justified. The recent availability of effective very-low-dose, estrogenonly therapy (monotherapy), plus the evidence that estrogen alone may not affect the incidence of papilloserous endometrial cancer (135) or breast cancer (104), is supportive of monotherapy (136). Moreover, the clinical availability of micronized progesterone and the spironolactone derivative drospirenone (137) are both promising and will have to be carefully evaluated before the final word is written regarding the role of progestins in HT.
E Effects o f A n d r o g e n o n the B r a i n Although there is much data on the role of androgens in behavioral studies on laboratory animals, the clinical literature remains unclear in this area. However, because the removal of the ovaries results in the loss of the only major source of directly secreted testosterone in the body, the case for the use of androgens, particularly methyl testosterone in the United States and tibolone in other countries, remains substantial (138-140). Overall, numerous reports indicate that feelings of well-being and sexual desire are improved in
211 postovariectomy (73) subjects who receive ERT plus androgens. This is the subject of Chapter 55 in this book. Although the ovaries continue to secrete testosterone following menopause, it has recently become of interest to evaluate the use of testosterone and similar compounds in physiologically menopausal women. At this point, the published data are not sufficient to determine the value of this practice. The main indications have been minimal sexual dysfunction and quality-of-life issues. This remains a vexing area, mainly due to the lack of well-accepted diagnostic tools. This area will continue to be of interest, however, and future research will determine the place for androgen treatment in normally menopausal women. Attention has turned toward the possible benefits of dehydroepiandrosterone ( D H E A ) a n d dehydroepiandrosterone sulfate (DHEAS), which are the major 19-carbon secretions from the adrenal gland. Although animal data indicate that D H E A and DHEAS may also play a role in the brain (141), this remains to be shown in humans. Many experiments using animal models support roles for D H E A and its metabolites and congener acting in the brain and tissues (141,142), but these await confirmation in clinical situations (143). These compounds are not overtly androgenic, however, they may be peripherally converted into androstenedione and then into the potent androgens testosterone and dihydrotestosterone. DHEA-derived androstenedione and testosterone may also be converted into estrogen. D H E A and DHEAS decrease gradually in men and women after a peak at early adulthood (144). Beneficial effects on energy longevity, cardiovascular diseases, cancer, and immune response have been reported (145). The absence of proven D H E A receptor in humans, along with pharmacologic regimens that have excluded transformation to active androgens and estrogens, may cause difficulty in considering D H E A or DHEAS as primary preventive or therapeutic agents in hormone replacement and brain function.
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214 95. Schneider LS, Small GW, Hamilton SH, Bystritsky A, Nemeroff CB, Meyers B S. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine collaborative study group. Am J Geriatr Psychiatry 1997;5:97-106. 96. Wickelgren I. Estrogen stakes claim to cognition. Science 1997;276: 675-678. 97. Lupien SJ, McEwen BS. The acute effects of corticosteroids on cognition: integration of animal and human studies. Brain Res Rev 1997; 24:1-27. 98. Davis SR. 'Tkdd back" estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. J Clin EndocrinolMetab 1997;82:702- 703. 99. Haskell SG, Richardson ED, Horwitz RI. The effects of estrogen replacement therapy on cognitive function in women: a critical review of the literature. J Clin Epidemio11997;50:1249-1264. 100. Sherwin BB. Estrogen and cognitive functioning in women. Proc Soc Exp Bid Med 1998;217:17-22. 101. Sherwin B. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988;13:345-355. 102. Shaywitz SE, Naftolin F, Zelterman D, et al. Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen. Menopause 2003;10:420-426. 103. Bechman DL, Wolf PA, Linn R, et al. Prevalence of dementia and probable senile dementia of Alzheimer type in the Framingham study. Neurology 1992;42:115-119. 104. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295: 1647-1657. 105. Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk age at onset of Alzheimer's disease. Lancet 1996; 348:429-432. 106. Schneck MJ, Sarrel PI, Albakri E, et al. Oral progesterone therapy impairs cerebrovascular reactivity. Stroke 1995;26:724. 107. Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG. Estrogen replacement therapy in older women. Arch Neurol 1994;51:896- 900. 108. Yamamoto KR. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 1985;19:209-252. 109. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer's disease in women. Am JEpidemio11994;140:256-261. 110. Mortel KF, Meyers JS. Lack of postmenopausal estrogen replacement therapy and the risk of dementia. J Neuropsychiatry Clin Neurosci 1995;7:334-337. 111. Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, Bacal C, Lingle DD et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 1997;48:1517-1521. 112. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAM_d 2002;288:2123-2129. 113. Brenner DE, Kukull WA, Stergachis A, et al. Postmenopausal estrogen replacement therapy and risk of Alzheimer's disease: a population based case-control study. Am J Epidemio11994;140:262-267. 114. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004;291:2947-2958. 115. Honjo H, Ogino Y, Naitoh K, et al. In vivo effects by estrone sulfate on the central nervous system-senile dementia (Alzheimer's type). J Steroid Biochem 1989;34:521-525.
IDA SILVA AND NAFTOLIN 116. Honjo H, Ogino Y, Naftolin F, et al. An effect of conjugated estrogen to cognitive impairment in women with senile dementia Alzheimer's type: a placebo-controlled double blind study. Inter Menopause Soc 1993;1:167-171. 117. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA 2000;283:1007-1015. Erratum in: JAMA 2000;284:2597. 118. Langer RD, Pradhan AD, Lewis CE, et al. Baseline associations between postmenopausal hormone therapy and inflammatory, haemostatic, and lipid biomarkers of coronary heart disease. The Women's Health Initiative Observational Study. Thromb Haemost 2005;93:1108-1116. 119. Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev 1990;11:266-301. 120. Graham J, Clarke C. Physiological action of progesterone in target tissues. Endocr Rev 1997:18:502-519. 121. Robel P, Baulieu EE. Neurosteroids: biosynthesis and function. Crit Rev Neurobio11995;9:383- 394. 122. Poletti A, Rabuffetti M, Celotti F. The 5a-reductase in the rat brain. In: Genazzani A, Petraglia P, Purdy R, eds. The brain sourceand target ofsex steroids hormones. London: The Parthenon Publishing Group, 1996. 123. Bixo M, Andersson A, Winblad B, Purdy RH, Backstrom T. Progesterone, 5alpha-pregnane-3,20-dione and 3alpha-hydroxy-5alphapregnane-20-one in specific regions of the human female brain in different endocrine states. Brain Res 1997;764:173-178. 124. Freeman EW, Purdy RH, Coutifaris C, Rickets K, Paul SM. Anxiolyric metabolites of progesterone: correlation with mood and performance measures following oral progesterone administration to healthy female volunteers. Neuroendocrinology 1993;58:478-484. 125. Yamamoto KR. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 1985;19:209-252. 126. Purdy RH, Morrow AL, Moore PH Jr, Paul SM. Stress-induced elevations of aminobutyric acid type A receptor-active steroids in the rat brain. ProcNatlAcad Sci USA 1991;88:4553-4557. 127. Selye H. The anesthetic effect of steroid hormones. Proc Soc Eur Bid 1941;46:116-121. 128. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroids hormone metabolites are barbiturate-like modulators of GABA receptor. Science 1986;232:1004-1007. 129. Kane FJ Jr. Evaluation of emotional reactions to oral contraceptive uses. Am J Obstret Gyneco11976;126:968-972. 130. Wagner KD. Major depression and anxiety disorder associated with Norplant.J Clin Psychiatry 1996;57:152-157. 131. Jensvold M. Nonpregnant reproductive-age women. Part II. Exogenous sex steroid hormones and psychopharmacology. In: Jenseold M, Halbreich L, Hamilton J, eds. Sex, gender and hormones. Washington, DC: American Psychiatric Press, 1996. 132. Siddle NC, Fraser D, Whitehead MI, et al. Endometrial, physical and psychological effects ofpostmenopausal oestrogen therapy with added dydrogesterone. Br J Obstet Gynaeco11990;97 :1101-1107. 133. Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gyneco11990;75:$59- $76. 134. Holst J, Backstrom T, Hammarback S, von Schoultz B. Progesteron addition during estrogen replacement therapy-effects on vasomotor symptoms and mood. Maturitas 1989;11:13-20. 135. Naftolin F, Silver D. Is progestogen supplementation of ERT really necessary? Menopause 2002;9:1 - 2. 136. Richman S, Edusa V, Fadiel A, Naftolin F. Low-dose estrogen therapy for prevention of osteoporosis: working our way back to monotherapy. Menopause 2006;13:148-155.
CHAPTER 14 Clinical Effects of Sex Steroids on the Brain 137. Stevenson JC. A new hormone replacement therapy containing a progestogen with anti-mineralocorticoid activity. J Br Menopause Soc 2006;12(suppl 1):8-10. 138. Warnock JK, Swanson SG, Borel RW, et al. Combined esterified estrogens and methyltestosterone versus esterified estrogens alone in the treatment of loss of sexual interest in surgically menopausal women. Menopause 2005;12:374- 384. 139. Somboonporn W, Davis S, Seif MW, Bell R. Testosterone for periand postmenopausal women. Cochrane Database Syst Rev 2005;19: CD004509 140. Liu JH. Therapeutic effects of progestins, androgens, and tibolone for menopausal symptoms. Am J Med 2005;118(suppl 2):88- 92. 141. Ren X, Noda Y, Mamiya T, Nagai T, Nabeshima T. A neuroactive steroid, dehydroepiandrosterone sulfate, prevents the development of morphine dependence and tolerance via c-los expression linked to the extracellular signal-regulated protein kinase. Behav Brain Res 2004;152:243-250.
215 142. Ma]ewska MD. Neuronal actions of dehydroepiandrosterone. Possible role in brain development aging, memory and affect.Ann NYAcad Sci 1995;774:111-120. 143. Morales AJ, Nolan JJ, Nelson JC, Yen SS. Effect of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1995;80:2799. 144. Ravaglia G, Forti P, Maioli F, et al. Dehydroepiandrosterone-sulfate serum levels and common age-related diseases: results from a crosssectional Italian study of a general elderly population. Exp Gerontol 2002;37:701-712. 145. Dayal M, Sammel MD, Zhao J, et al. Supplementation with DHEA: effect on muscle size, strength, quality of life, and lipids. J Womens Health (Larchrnt) 2005;14:391-400.
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~ H A P T E R 1_
Impact of the Changing Hormonal Milieu on Psychological Functioning BARBARA
B.
SHERWIN
Department of Psychology, McGill University, Montreal, Q.uebec, Canada H3A 1B1
The steady increase in female life expectancy over the past century means that women now live one-third of their lives beyond cessation of their ovarian functioning. Therefore, quality-of-life issues related to aging in women have assumed increasing importance in the minds of health professionals and of women themselves. Prominent among the complaints of perimenopausal and postmenopausal women are changes in behavior. More specifically, changes in mood, in memory, and in sexual functioning are frequently reported around the time of menopause. Although it must be acknowledged that sociocultural factors, individual factors, and environmental factors likely converge to influence the experience of the menopause for each individual woman, there is also accumulating evidence that changes in the hormonal milieu may underlie some of the psychological symptoms reported at this time. Moreover, to the extent that specific sex hormones may enhance specific aspects of psychological functioning, it follows that their administration, after the menopause, may serve to maintain these functions, thereby preserving the quality of
ACKNOWLEDGMENT: The preparation of the manuscript for this chapter was supported by research funds associated with the CIHR Distinguished Scientist Award to B. B. Sherwin. TREATMENT OF THE POSTMENOPAUSAL W O M A N
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life in aging women. This chapter reviews the mechanisms of action of the sex steroids on the central nervous system and the clinical literature that bears on the relationship between sex hormones and behavior with the goal of providing a clearer understanding of the role of hormones in psychological functioning in menopausal women.
I. E P I D E M I O L O G Y OF PSYCHOLOGICAL SYMPTOMS Prior to the attempt to explain the manner in which changes in the endocrine milieu may precipitate psychological symptoms at menopause, it is important to establish that these symptoms do indeed occur in a considerable number of women. Several epidemiologic studies undertaken on random samples of the population in the United States (1-2) as well as in Sweden (3) and England (4) have failed to document an increase in depressive symptoms around the time of menopause compared with other times during the lifespan. Inconsistent with these reports are the results of other studies of nonclinical populations that have found increased incidences of depressive symptoms in perimenopausal and postmenopausal women (5-8). Interestingly, in a longitudinal survey of 2500 middle-aged women in Copyright 9 2007 by Elsevier,Inc. All rights of reproductionin any form reserved.
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Massachusetts, those who had undergone a surgical menopause had high and clinically significant depression scores, whereas the naturally menopausal women did not (9). Evidence from studies undertaken in menopause clinics tells yet a different story. Of 100 menopausal women who sought medical care in one clinic, 79% had physical symptoms such as hot flushes and 65% had varying degrees of depression (10). Similarly, in a British study, 89% of all women who attended a menopause clinic had depressive symptoms (11). Thus, it would seem that whereas the occurrence of depressive symptoms is far from a ubiquitous phenomenon at the time of menopause, many women do, in fact, develop these symptoms, particularly during the perimenopause. Moreover, there is some evidence that vulnerability toward the development of depressive symptoms may be greater in women who undergo a surgical menopause and those who had experienced prior episodes of depression. Complaints of memory and concentration difficulties are frequently voiced around the time of menopause. Indeed, the inclusion of items to assess memory and concentration abilities in one of the earliest menopausal symptom checklists (1) serves as acknowledgment that subjective complaints of changes in cognitive functioning have long been associated with the menopause. Unfortunately, no epidemiologic studies are available to shed light on the frequency and severity of these changes around the time of menopause. Survey data point out the considerable frequency of a variety of sexual problems in menopausal women. In a nonclinical sample, Kinsey et al. (12) documented a 53% and a 48% decrease in the frequencies of coitus and orgasm respectively in the postmenopause. Longitudinal studies of menopausal women in Sweden that found a 52% decrease in sexual interest and a 20% decrease in orgasm frequency also established statistically that these decrements in sexual functioning were related to menopause and not to aging per se (13). Numerous survey studies of menopausal women have confirmed decreases in sexual interest of 33% (14), 85% (15), and 39% (16). These epidemiologic data serve to point out that between one-third and one-half of menopausal women recruited from the general population complain of a problem in one or more aspects of sexual functioning.
II. NEUROBIOLOGIC EFFECTS OF ESTROGEN, ANDROGEN, AND PRO GESTIN In order to account for changes in sex hormone production as determinants of psychological symptoms in menopausal women, it is necessary to review briefly some of the known effects of these hormones on the brain. Estrogen has both direct and inductive effects on neurons. Direct effects of estrogen on the brain take place fairly rapidly. For
BARBARAB. SHERWIN
example, estrogens alter the electrical activity of the hypothalamus (17). On the other hand, inductive effects of estrogen are both delayed in onset and prolonged in duration. Its mode of action here is assumed to occur via its induction of ribonucleic acid (RNA) and protein synthesis by means of genomic mechanisms, which, in turn, cause changes in levels of specific gene products such as neurotransmitter synthesizing enzymes (18). In rats, autoradiographic studies have demonstrated that neurons that contain specific nuclear receptors for estrogen are found in specific areas of the brain, predominantly in the pituitary, hypothalamus, limbic forebrain (including the amygdala and lateral septum), and cerebral cortex (19). Specific cytosolic receptors for testosterone are found mainly in the preoptic area of the hypothalamus, with smaller concentrations in the limbic system and in the cerebral cortex (19). Within the past 15 years, the direct modulation of neural development and neural circuit formation by estrogen has been demonstrated in both the neonatal and adult brain. Specifically, estrogen has a facilitatory effect on synapse formation in the hypothalamus in both adult and aged female rats (20). Estrogen can also exert a stimulatory influence on synaptogenesis in the ventromedial nucleus, in the lateral septum, and in the midbrain central gray area of adult rats (21). Moreover, androgen plays a significant role in regulating synaptic remodeling in the androgen-sensitive spinal motoneuron pools (22). Thus, the sex steroids seem to play a critical role in the organization and reorganization of neural circuitry, driving neuroendocrine and behavioral functions both during development and in adulthood. The idea that estrogen interacts with genomic mechanisms to regulate levels of specific gene products led to discoveries of numerous neurochemical effects of this sex steroid. Among the most relevant of its mechanisms of action with respect to the development of depression at the time of menopause is that estrogen increases the rate of degradation of monoamine oxidase (MAO), the enzyme that catabolizes the neurotransmitter serotonin (23), whose deficiency is thought to be one causal factor in depression. One action of potential importance for memory functions is the induction by estrogen of choline acetyltransferase (CAT), the enzyme that is needed to synthesize acetylcholine (24) and whose deficiency is a hallmark of Alzheimer's disease (25). Moreover, estrogen positively effects neuronal architecture by increasing spine density in the CA 1 pyramidal cells in the hippocampus (26) and it has been suggested that estrogen's trophic and plastic effects may be caused, in part, by neurotrophic factors (27). Estrogen also may act as an antioxidant (28). Finally, estrogen enhances adrenergic function, which has also been linked to cognitive abilities. In one study, the administration of clonidine, an ~-adrenergic agonist, was associated with dosedependent decreases in plasma norepinephrine levels and with reduced mental performance scores (29).
CHAPTER 15 Impact of the Changing Hormonal Milieu on Psychological Functioning Functional imaging techniques have also been used to examine estrogenic effects on brain areas involved in cognitive functioning. For example, in a magnetic resonance imaging (MRI) study, estrogen-induced changes in brain activation patterns occurred during the administration of both verbal and nonverbal memory tests (30). In a positron emission tomography (PET) study that examined alterations in regional cerebral blood flow (rCBF), estrogen use was associated with increased rCBF in the right hippocampus, parahippocampal gyms, and middle left temporal gyms, all regions implicated in learning and memory (31). In summary, neurophysiologic studies undertaken to localize function of estrogen and testosterone provide evidence that both sex steroids are found in areas of the brain that are thought to subserve emotion, cognition, and sexuality. Moreover, findings from basic neuroscience show that estrogen can profoundly affect the concentration of neurotransmitter synthesizing and catabolizing enzymes, which, in turn, influence the brain concentrations and synaptic availability of certain neurotransmitters. These mechanisms of estrogenic action on brain chemistry provide possible explanations for the purported influence of this hormone on mood and memory. In contradistinction to the stimulatory effects of estrogen on various brain mechanisms, progestins have potent anesthetic properties (32). Indeed, the administration of large doses of progestins to humans induces dizziness, drowsiness, and even deep sleep (33). Moreover, whereas estrogen decreases MAO activity in the amygdala and hypothalamus (24), progestins increase it (34), thereby resulting in lower concentrations of brain serotonin, which may predispose to dysphoric moods. These neurochemical effects of progestins may explain why some women on estrogen-progestin replacement regimens experience unpleasant behavioral side effects, as will be discussed in a subsequent section.
III. SEX S T E R O I D S A N D M O O D The most common strategy for investigating possible effects of estrogen on mood is to test menopausal women before and after a trial of hormone replacement therapy. The findings of many early studies are difficult to interpret because of their methodologic shortcomings: Some studies were not blinded (35) or contained women who had malignant disease (36) or concurrent psychiatric illness (37). Moreover, none of these studies measured circulating levels of the sex hormones coincident with psychological testing. Several investigations undertaken in nonpsychiatric populations of postmenopausal women have reported changes in affect as a function of circulating sex hormone levels. In a prospective randomized controlled trial (RCT) (38), premenopausal women who were scheduled for total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy
219
(BSO) for benign disease were tested 1 month before surgery. Following TAH and BSO, these women received estrogen, androgen, an estrogen-androgen combined preparation, or placebo administered intramuscularly once a month for 3 months. During the fourth postoperative month, all women received placebo and, 1 month later, were crossed over to another treatment they had not already received for an additional 3 months. In addition to the placebo group, another group of women who required TAH only were included in order to control for the surgical procedure itself. Blood was sampled at each test time for assay of circulating levels of the sex hormones. In both treatment phases, women who received placebo had higher depression scores when compared with those treated with any of the active hormone preparations and compared also with the ovary-intact group (Fig. 15.1). Furthermore, depression scores of the hormonetreated women increased during the placebo month between the two treatment phases coincident with their significant decrease in plasma estradiol and testosterone levels at that time, indicating that they had more positive moods while they were receiving hormone therapy. In a cross-sectional study, Sherwin (39) investigated otherwise healthy women who had undergone TAH and BSO for benign disease approximately 4 years earlier. Women who had been receiving estrogen or an estrogentestosterone combined drug intramuscularly once a month for the previous 2 years had more positive moods than a matched control group of women who had remained untreated since their TAH and BSO 4 years earlier. In an RCT of asymptomatic surgically menopausal women, depression scores decreased in those given either 0.625 mg or
A_J U ,
5 years No change in SC hydration (early menopause) No short-term (7-week) change in SC hydration with topical estradiol gel 1" Water-holding capacity (p < 0.01) 1" SC hydration (p < 0.05) depending on the site Clinical improvement but changes in SC hydration were not significant for topical estrogen creams 1" Epidermal thickness (p < 0.05) and keratinocyte proliferation with topical estradiol preparation
Dermis--collagen content, skin thickness, and elastic tissue studies (i.e., atrophy, sagging, wrinkling, or wound healing) Primary author Brincat (50-52,58,64) Brincat (65) Callens (36) Castelo-Branco (53) Chen (62) Creidi (59) Dunn (23) Fuchs (123) Haapasaari (67) Henry (75) Jemec (33) Maheux (60) Meschia (61) Pierard (72) Pierard-Franchimont (73) Sator (63) Sauerbronn (57) Sawas (54) Schmidt (34,35) Smeets (77) Son (15) Sumino (79) Varila (55) Wolff (71)
Effect of estrogen or combined HRT in postmenopausal women Several studies showing ]" skin collagen content or 1" skin thickness 1" Skin collagen content of abdominal skin biopsy specimens (p < 0.001) with estrogen cream 1" Skin thickness over breast (p -< 0.01) and forearm (p -< 0.05) 1" Skin collagen content (p < 0.05) 1" Skin thickness in HRT group (p < 0.01) 1" Skin thickness (p = 0.013) and $ fine wrinkling (p = 0.012) of the face with an estrogen cream $ Odds of wrinkles from a cross-sectional analysis of a national probability sample-based study in multiple U.S. community sites 1" Epidermal thickness with topical estradiol cream (p = 0.0046) No changes in collagen or elastic fiber content (early menopause) Slows facial aging process but does not prevent wrinkling No short-term (--- 7 week) improvement of elasticity with topical estradiol gel 1" Skin thickness (p = 0.01) and 1" dermal thickness (p < 0.05) from greater trochanter areas but not subumbilical or thyroid sites ]" Skin thickness (p < 0.001) Slows facial sagging or slackness but does not prevent wrinkling Mitigates facial distensibility and elasticity in those subjects most compliant after 5 years $ Skin thickness (p -< 0.05) and 1" elasticity (f < 0.05) ]" Collagen content (p < 0.05) but no changes in elastic tissue 1" Collagen type III content (p < 0.01) ,l, Facial wrinkles for topical estrogen creams (p < 0.002) No significant correlation in skin thickness and bone mineral density 1" Procollagen (p < 0.01) and elastic tissue precursors (p < 0.05) with enhanced transforming growth factor-J3 levels using topical estradiol preparation 1" Skin elasticity (p < 0.05) ]" Procollagen I (p < 0.03) surrogate for collagen synthesis and collagen content (p < 0.02) with topical estradiol gel ,], Skin rigidity and $ average wrinkle scores of face (p < 0.05)
ing daughter keratinocytes provide cornified cells and other ingredients (i.e., keratohyalin granules, lamellar body lipids, keratin filament bundles, amino acids, cytokines, and enzymes) for the constantly renewing, nonviable but enzymatic active stratum corneum (5,27). The SC is composed of a selectively permeable "brick and mortar" barrier-like structure having overlapping layers of tightly compacted, protein-
enriched cornified cells called corneocytes ("the bricks") held to each other by cell-to-cell attachments called corneodesmosomes and hydrophobic lipids extraceUular domains ("the mortar") (5,27,28).
The SC forms a tough protective impediment against exogenous exposures (e.g., chemicals, toxins, microbes, etc.) (3,24,25,29). Under normal circumstances, the SC is
240 almost completely impermeable to endogenous water loss and maintains a water vapor gradient against excessive insensible water loss or transepidermal water loss (TEWL) (3,26,27). The integrity of the SC is determined experimentally by use of a noninvasive instrument known as an evaporimeter that measures T E W L from the skin surface. An intact SC barrier has low T E W L values (approximately 0.5 L per day), whereas a perturbed SC, which can be found in many inflammatory skin diseases, has T E W L levels that are 2 to 10 times higher than normal. Maintenance of the SC water balance is accomplished by virtue of matured corneodesmosomes-bound corneocytes and the physical conformation of long, tight, tortuous intercellular lamellar hydrophobic lipid (mostly ceramide) domains (5,27). Additionally, the presence of a sufficient amount of an innate "natural moisturizing factor" (NMF) to maintain proper hydration is important for homeostasis of the SC. N M F is formed by hydrolysis of filaggrin (derived from keratinocyte keratohyalin granules) within corneocytes. N M F is a mixture of amino acids, lactate, urea, and other ingredients that are hygroscopic (i.e., have the ability to absorb water from exogenous and endogenous sources). Evolutionarily, N M F at the SC surface allows for the storage of sufficient amounts of water (optimally at 30% to 50%) to maintain flexibility (plasticity) and a hydrated milieu for orderly enzyme-mediated desquamation with imperceptible corneocyte cleavage leaving a visibly smooth skin surface appearance (3,24,25,27). Ambient humidity is an important influence on the degree of SC hydration (5). Low-humidity environments stimulate keratinocyte proliferation (i.e., more NMF) to promote greater SC hydration. Determination of the actual SC water content is technically difficult to measure. However, hydration of the SC can be estimated by use of a noninvasive instrument that measures electrical capacitance. Electrical capacitance is dependent on the dielectric constant of SC constituents. Proportionally, water has a much higher dielectric constant than the other SC components. Electrical capacitance is measured in arbitrary units and is used as an indirect measure of SC hydration. Additional functions of the epidermis are also noted in Table 17.1. With dry skin, the SC less pliable and corneocytes are shed in visible clumps or flakes, especially if the water content is less than 10% (27). Severe dry skin can cause intense pruritus, compromise barrier function, and lead to secondary microbial invasion or inflammation. It is believed that N M F is lower or functionally deficient in aged skin (27,30). A National Health and Nutrition Examination Survey that included 3875 postmenopausal women from multiple USA communities found that the odds of having dry skin are less if women have been on HRT compared with those women who have not been on HRT (23). In addition, a small pilot biophysical measurement study
KATZ AND PRYSTOWSKY
evaluated the skin water-holding capacity in menopausal women (n = 30) to determine whether transdermal estrogen (n = 15) had an effect on water-holding capacity of the skin (31). Skin capacitance and transepidermal water losses were measured on normal-looking skin and at plastic occlusive stress test sites. Investigators demonstrated that the water-holding capacity of the stratum corneum was significantly increased at the plastic occlusion stress test site in those women receiving transdermal estrogen compared with menopausal women not receiving transdermal estrogen (31). Also recently, an SC hydration study was conducted in 106 Caucasian menopausal women, with otherwise healthy facial skin, who took HRT for less than 1 year, 1 to 5 years, more than 5 years, or who had never taken HRT. Electrical capacitance measurements reflecting SC hydration were significantly higher in those on HRT (especially for those who had been on H R T more than 5 years) compared with those never on H R T (32). However, other authors (33-36) have noted no significant change in epidermal hydration and dry skin, as is summarized in Table 17.3. Regardless of whether or not postmenopausal women are on HRT, more practical adjuncts are useful to prevent dry skin, which include precautions regarding the use of skin-care items that paradoxically might predispose the SC to dry out (37,38). The use of harsh soaps, astringents or other dehydrating skin-care products or exposure to ultraviolet light can lower the N M F and may compromise SC barrier function (25). Postmenopausal patients will typically have fewer dry skin symptoms if they use less soap and bath less frequently to compensate for the agerelated decrease in N M F from their skin. Cleansers with mild synthetic surfactants with added moisturizing ingredients known as syndets cause minimal barrier perturbation and may be used instead of regular soap (38). Treatment with moisturizing topical agents that contain hygroscopic ingredients such as glycerin, lactic acid, lactate or urea will tend to help the stratum corneum retain water (39). Furthermore, agents with alpha hydroxy acids (i.e., lactic acid or ammonium lactate) or products with urea may aid in the exfoliation or shedding corneocytes, promoting smoother appearing skin. Emollients containing glycol stearate or glyceryl stearate provide partial SC occlusion that helps hydration to improve the appearance of the skin surface (39). Other occlusive moisturizers such as petrolatum or lanolin are helpful because they leave a thin film of oil on the surface of the skin that decreases evaporation of water from the underlying epidermis. Avoiding excessive ultraviolet light exposure during the hours of 10 AM to 4 PM, wearing protective apparel to shade exposed skin, and frequent application of broad-spectrum UVA/UVB sunscreen agents can help to prevent photodamage.
CHAPTER 17 Menopause and the Skin
III. SWEATING Widespread cutaneous sweating is usually evoked by elevation of body temperature (e.g., secondary to fever or exercise) mediated predominantly through the thermoregulatory sympathetic nervous system's elaboration ofacetylcholine (see Table 17.1). Cutaneous vasodilation with attendant increased blood flow and evaporative sweating helps to dissipate heat (6,40,41). Eccrine sweat glands and dermal blood vessels are hormonally responsive (2). In contrast, decreased body temperature causes a noradrenergic medicated vasoconstriction with reduction in cutaneous blood flow that conserves body heat. Episodic, unpredictable, recurrent, transient day or night precipitous sweating (hyperhidrosis) is one component of the unpleasant physical manifestation of the menopausal hot flush syndrome (42,43). Hot flushes are a common hallmark of perimenopause and menopause. Abnormal sweating is preceded or accompanied by the skin sensation of warmth or intense heat and a flushed appearance. Menopausal sweating usually lasts for only minutes, but if it occurs frequently or is intense, it can be embarrassing and may even soil clothing. The incidence of hot flushes is variable from one country to another, but it has been estimated to occur in more than 50% of perimenopausal and menopausal women in the United States (43). The exact mechanism underlying menopausal hot flushes is unknown. However, recent data suggest that hot flushes are a multifactorial syndrome that involves deficiency of neuroendocrine factors involved in thermoregulation (44). Endogenous estrogen levels alone are not predictive of hot flush frequency or severity (43). The hypothalamus is considered an important focal point in the evolution of hot flushes (44). The hypothalamic thermoregulatory system acts like a thermostat located within the brain. Hypothalamic thermoregulatory pathways initiate core body temperature (To), peripheral vascular, neuromuscular, and sudoriferous responses. An increase in Tc can cause vasodilation and sweating. In contrast, a decrease in T~ can cause vasoconstriction and shivering. A neuroendocrine agent such as estrogen is thought to modulate hypothalamic thermoregulatory control within a normal homeostatic thermoneutral temperature range (45). Data suggest that perimenopausal and menopausal women who experience hot flushes have a narrow thermoneutral temperature range. Hence, a small elevation in core body temperature (i.e., a few tenths of a degree) can result in sweating that would not elicit such a response in otherwise nonclimacteric women (7). Therefore, lower sweating thresholds and high sweat rates characterize postmenopausal women with hot flushes (7). Exogenous estrogen therapy can raise sweating thresholds by expanding narrow thermoneutral zones to a more normal temperature range but does not affect core body temperature fluctuations
241 (7,44). Menopausal hyperhidrosis may be mild in intensity or occur infrequently and require no therapy other than lifestyle changes such as a cool environment. However, many other women do have considerable discomfort and require treatment interventions (46). As is well known, systemic estrogen-based hormone replacement therapy is a very effective treatment for menopausal vasomotor and sudoriferous instability. Although topical antisweat remedies such as antiperspirants and aluminum chloride preparation may be useful for localized sweating, they are impractical if sweating is widespread. Alternatively, serotonin reuptake inhibitors and clonidine have been used systemically for menopausal hot flushes (43,46-48).
IV. ATROPHY The dermis provides the structural support and the microvasculature repository supplying nourishment for the epidermis, as is summarized in Table 17.1. The fibroblast is the key cell for the dermis. Fibroblasts synthesize proteins such as collagen and elastic tissues along with hyaluronic acidcontaining glycosaminoglycans that are the major constituents for the dermal extracellular matrix (ECM). Transforming growth factor-~3 (TGF- f3) is emerging as a very important cytokine for homeostasis of the dermal E C M (49). TGF-I3 is part of a multifunctional cytokine isoform family that upregulates fibroblast synthesis of the extracellular matrix proteins and downregulates the expression of matrix metalloproteinases that can degrade matrix proteins (15). Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes such as collagenase and elastase that can degrade collagen and elastic tissue, respectively. Tissue matrix metalloproteinase inhibitor (TMMPI) dampens the proteolytic activity of MMR Collagen is formed from procollagen that is secreted by fibroblasts into the extracellular matrix. In skin collagen content experiments, hydroxyproline measurements are used as a surrogate for collagen content of the dermis. Collagen tissue (the majority as type I and a minority as type III) makes up the bulk of the fibrous protein elements (approximately 95%) of the dermis, providing the main mass and tensile strength for the skin. Sparse but especially organized elastic tissue along with collagen provides the venue for stretched skin to rebound to its original form (i.e., elasticity). Glycosaminoglycans, primarily through the presence of the hyaluronic acid, imbibe endogenous water that accounts for skin turgor (firmness). An altered balance of TGF-~3 levels, fibroblast synthetic activity, M M P enzyme activation, or presence of T M M P I can affect the support function of dermal ECM, leading to attendant wrinkling or sagging that are hallmark of aged skin. Examples of intrinsically aged skin can be found over the buttock or another cutaneous surface that has received
242
KATZ AND PRYSTOWSKY
minimal sun exposure. Intrinsic atrophy is clinically noted by the "cigarette paper" crinkling of the skin surface as is depicted in Fig. 17.1, A (see color insert) in an elderly woman's arm. Dermal atrophy results principally from a loss of collagen (50-57), which accounts for the bulk of the decrease in overall skin thickness (36,51,52,58-63) in estrogen-deficient postmenopausal women. Brincat et al. (51) found that the collagen content in untreated postmenopausal women declined as much as 30% during the first 5 years after onset of menopause. This was reflected by increased urinary hydroxyproline excretion. Furthermore, the decline in collagen in the untreated women was related to the cohort's menopausal age and not their chronologic age. In another study, Brincat et al. (52) examined skin collagen content and skin thickness in postmenopausal women. The skin collagen content and skin thickness showed similar declines between 1% to 2% per year after the menopause. Additional series of studies by Brincat and associates (50,52,58,64,65) found that decreased skin collagen con-
FIGURE 17.1
tent levels in postmenopausal women were incrementally increased by estrogen alone or estrogen plus testosterone supplementation. Other studies that are summarized in Table 17.3 (23,53-55,63) have confirmed that collagen loss and the attendant decreased skin thickness occurring in postmenopausal women is responsive (but not overresponsive) to estrogen alone or estrogen plus progesterone supplementation. Furthermore, hormonal increases in collagen content are proportional to the amount of collagen present when the supplementation is started (52,66). However, if the postmenopausal cohort chosen to be studied has been estrogen deficient only a short time (i.e., less than 1 year), then the relative changes may not be apparent or reach statistical significance, as noted in the negative studies by Haapasaari (33,67) and summarized in Table 17.3. Therefore, hormonal supplementation can be considered as a potential preventative therapy for skin atrophy in postmenopausal women who have adequate dermal collagen or as a therapy for those with decreased dermal collagen (14).
(a) Skin tear due to fragilityof forearm skin in an 87-year-old female without hormone replacement therapy. (b) Lesion taped closed to increase rate of healing by approximatingthe epidermal edges of the full-thicknesswound. (c) Wound healed, with linear scar.
CHAPTER 17 Menopause and the Skin In the real world, most postmenopausal women may not be overtly aware of the consequences of skin atrophy, as noted in Fig. 17.1 (see color insert), but they are concerned about wrinkles, which are an early sign of dermal atrophy (23). Wrinkles are foldlike surface contour depressions indicating underlying structural atrophic alterations within the dermis (68-70). Fine wrinkles are superficial and disappear by stretching the skin but deeper wrinkles do not disappear with clinical technique. Contet-Audonneau, Jeanmaire, and Pauly (69) biopsied 157 wrinkles taken from exposed facial and sun-protected areas of abdominal skin in 46 subjects of elderly men and women. Biopsy specimens underwent histochemistry, immunohistochemistry, electron microscopy, and quantification by image analysis in addition to classic standard staining techniques. The results confirmed that beneath a wrinkle there are more pronounced atrophic changes than the nonwrinkled adjacent surrounding skin. These changes were present in both the covered and exposed skin wrinkles but to a greater degree in the photodamaged facial skin biopsies (69). Dunn et al. (23) performed a cross-sectional analysis in a National Health and Nutrition Examination Survey that included 3875 postmenopausal women from multiple U.S. communities and found that the odds of having wrinkles are less if women have been on HRT compared with those women who have not been on HRT. Table 17.3 summarizes results of several studies of the effects of hormonal replacement therapy on facial wrinkles. Schmidt and associates found that topical estrogen-containing creams significantly improved wrinkles (34,35). In a very small recent study by Wolff and associates (71) it was found that the aggregate total clinical wrinkle score (but not individual scores) from 11 selected facial areas of 9 postmenopausal women treated with HRT was significantly better than that of 11 postmenopausal women not treated with HRT. Sagging and loss of elasticity also indicate further deterioration occurring in the extracellular matrix of the dermis (72,73). Evidence for the causal role of menopause in elastic fiber changes was also found by a light and electronmicroscopic study of biopsy specimens from sun-protected buttock skin from three women who had premature menopause (ages 30 to 37) (74). The authors found that elastic fibers had degenerative changes comparable to that seen in postmenopausal women two decades older. The results suggested that premature estrogen deprivation might be the cause of alterations in skin elastic fibers (74). The results of several biophysical studies on skin extensibility and elasticity in postmenopausal women treated with topical or systemic HRT are summarized in Table 17.3. Separate studies by Pierard et al. (72), Pierard-Franchimont et al. (73), and Henry et al. (75) have demonstrated that skin biophysical changes (i.e., increased laxity, increased extensibility, and decreased elasticity) occur in postmenopausal women and that oral estrogen with sequential progestin therapy can mitigate or slow facial skin aging progression but not prevent wrinkling per se.
243 Decreased skin collagen content and skin thickness parallel decreases of bone density in postmenopausal women. Both bone and skin have abundant type I collagen that declines during menopause. In support of these findings, a group of investigators found that skin-fold thickness of the back of the hand correlated with the presence of osteoporosis. Thus, the lower the skin fold thickness, the greater the probability of underlying osteoporosis (76). The anecdotal clinical observation of"thin skin and weak bones" is generally but not universally supported by many reports in the literature, as summarized in Table 17.3 (22,52,66,77). A further relationship of the loss of dermal extracellular matrix (elastic tissue and collagen) to a bone is supported Sumino and associates (78), who tested the potential association between skin elasticity of the right forearm using a suction device linked to a computer and x-ray absorptiometry for bone mineral density (BMD) of the lumbar spine in 38 otherwise healthy Japanese postmenopausal women. Their results demonstrated a positive correlation between the loss of skin elasticity and decreased BMD in these postmenopausal women (78). Furthermore, in another similar skin elasticity study by Sumino and associates (79) that was performed in 176 postmenopausal women and in 45 matched premenopausal cohorts, they found a significant negative correlation existed between skin elasticity and years in menopause. After menopause, there was a 0.55% decline per year in skin elasticity. In a subset of this study, the authors treated 12 subjects prospectively with HRT and demonstrated a 5% increase in skin elasticity after 1 year of treatment. Hence, the hypoestrogenic effects on skin thickness (i.e., collagen content and elastic tissue) have been demonstrated to increase by small but important increments in women treated with hormone replacement therapy compared with women who were not treated. These adjunctive benefits may be helpful in preventing or slowing the progression of hormone deficiency-related skin changes contributing to skin atrophy, wrinkles, and skin fragility in postmenopausal women. Furthermore, menopausal changes in skin and bone appear to be temporally and physiologically correlated.
V. W O U N D HEALING Aged skin is reported not to heal as speedily as more youthful skin, but generally the final result is qualitatively akin to that in younger subjects (80-84). However, wound healing in an elderly person occurs in a milieu tempered by confounding factors other than age that may, albeit temporarily, slow the process (85). In clinical practice, it is usually the chronic rather than the acute wound that presents a therapeutic challenge (83,85). Although many chronic wounds occur in elderly individuals, it does not necessarily mean that the failure to heal is purely related to age alone but more likely to underlying comorbid conditions such as vas-
244 cular insufficiency, diabetes mellims, sustained localized skin pressure, or debilitation (85). In contrast, a commonly occurring acute wound in elderly individuals is the result of shear trauma involving age-related collagen-deficient thinned skin with a flattened dermal-epidermal junction, as is summarized in Table 17.2 and depicted in Fig. 17.1, A (see color insert), that can be repaired with paper strips (Fig. 17.1, B) (see color insert) because sutures frequently tear the skin further. When these acute wounds heal, they form linear scars on the forearms and legs of women (Fig. 17.1, C) (see color insert). Skin wounds undergo orchestrated healing phases consisting of inflammation, vascular proliferation, cellular proliferation, and remodeling that can be influenced by the local milieu, systemic encumbrances, and hormonal factors (83,85). The cellular elements of wound repair include macrophages, inflammatory cells, vascular endothelial cells, fibroblasts, and keratinocytes. As noted in Table 17.2, aged skin may have an impaired blood supply (83) and fluid drainage (86-88) and lowered innate immune defenses (88-90) as compared with more youthful skin. In addition, aged individuals tend to have elevated levels of proinflammatory cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-or (TNF-o~) that stimulate an influx of active acute and chronic inflammatory cells with their inherent collection of degrading proteolytic enzymes to a wound that may already be deficient in components of the extracellular matrix (84,91,92). If extensive, cytokine overproduction may paradoxicaUy provoke immunosuppression that may also complicate the complex healing process (84). Hypoestrogenemia in aged menopausal females may account in part for the cytokine-induced hyperinflammation, abundant proteolytic milieu, and impaired dermal EMC content that may adversely slow wound healing (14,16,84,93). A case-cohort study of elderly (->65 years old) patients (n = 44,195) in a United Kingdom General Practice Research Database that provides retrospectively gathered information suggests that HRT usage in elderly women may reduce their susceptibility for chronic wounds (94). Elderly postmenopausal women (n = 4944) who had taken HRT were less likely to develop venous leg ulcers (age-adjusted relative risk 0.65 [95% CI 0.61-0.69]) or pressure ulcers (0.68 [0.62-0.76]) than those who did not use HRT. Ashcroft and associates (12,80,93) have performed wound healing investigations that provide more direct insight on the molecular and enzymatic role of estrogen in human wound healing. In a small skin biopsy wound study of healthy postmenopausal females, they found a reduced rate of healing associated with low levels of TGF-[3 (80). As mentioned earlier, TGF-~ is a multifunctional cytokine family that upregulates fibroblast synthesis of the extraceUular matrix proteins (collagen and elastic fibers) (15) and downregulates the expression of matrix metaUoproteinases that degrade matrix proteins (15). A second, larger randomized, double-blind study by Ashcroft and associates (93) consisted of performing
KATZANDPRYSTOWSKY 4 mm punch biopsies of upper arm sites through either estrogen or placebo patches (applied just before wounding and left on for 24 hours) in 36 elderly (mean age > 70) healthy men (n = 18) and women (n = 18). After 7 and 80 days postwounding, the healing or healed sites were excised to determine the degree of macroscopic wound area (image analysis) and microscopic cross-section wound sizes, collagen contents, inflammation, relative wound strengths, and enzymatic responses during healing. The results revealed that the estrogen patch sites were more healed at day 7 and were stronger at day 80 than the placebo patch sites in both men and women. There were fewer neutrophils, decreased elastase levels, and less fibronectin degradation in the estrogen patch wound sites than the placebo sites. Additional study by Ashcroft and associates (12) involving the wounding of ovariectomized mice suggest that macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is upregulated during hypoestrogenemia and contributes to excessive wound inflammation with delayed healing. In the presence of estrogen, MIF is downregulated with less inflammation and more prompt healing. Further human confirmation on the role of estrogen, inflammation, and wound healing actMty in aging skin comes from recent work by Son and associates (15). These authors biopsied buttock target areas of 16 elderly (68 to 82 years) Korean men (n = 8) and women (n = 8) following the application of topical 1713-estradiol or vehicle under occlusion three times per week for 2 weeks. Skin biopsy specimens were analyzed using immunohistochemistry staining, Western blotting, reverse transcriptase polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA). Topical 1713-estradiol significantly increased the synthesis and content of dermal collagen along with reducing the expression of matrix metalloproteinases in aged skin. Additional in vitro cellular and molecular studies on this topic also suggest that estrogen facilitates keratinocyte proliferation for reepithelization (15,95,96) and dampens excess inflammation with its attendant proteolytic degradation of the wound's newly formed extracellular matrix (4,97). Therefore, even though human studies are admittedly relatively few in number, estrogen alone or in combination with a progestin appears to be beneficial in regards to either the prevention of wounds (maintenance of collagen and skin thickness) or promotion of a dermal extracellular matrix environment that is more conducive to healing than is usually found with untreated hypoestrogenemia (14).
A. Vitamin D Although vitamin D is not usually directly considered estrogen dependent per se, its endogenous production is dependent on a well-functioning epidermis that could be compromised in postmenopausal women, as is noted in Tables 17.1 and 17.2. Vitamin D is essential for regulation
245
CHAPTER 17 Menopause and the Skin and important for cellular proliferation and differentiation functions in many organ systems, including bones and the skin (9). Aging and, in particular, menopause can place stress on the ability of climacteric women to maintain healthy skin that can be exacerbated by vitamin D deficiency (98-100). It turns out that the skin is a major source of the precursors for vitamin D generation. This takes on further significance because of the public health pronouncements regarding the use of sunscreens and other methods to avoid the hazards of excessive chronic ultraviolet skin exposure (101). However, it is equally true that the epidermis is involved in a photochemical reaction that initiates endogenous production of vitamin D production within the confines of the skin (8,9). Ultraviolet light B (UVB; approximately 297 nm) exposure generates the photochemical conversion of 7-dehydrocholesterol to previtamin D3 within keratinocytes. Previtamin D3 ultimately undergoes further transformation by the liver and kidney, resulting in hormonally active calcitriol (lcx, 25-dihydroxyvitamin D3). Calcitriol has many important functions, including regulation of calcium metabolism and immunomodulatory activity, along with modulation of cellular activities in the epidermis and bones (8,102). It is estimated that more than 90% of vitamin D requirement is formed through sunlight exposure (103). However, a high prevalence of significant seasonal hypovitaminosis D3 has been documented to occur in otherwise healthy postmenopausal women who have had low UVB exposure (99). Inadequate vitamin D due to insufficient UVB may be a contributing cause of osteoporosis (99). Hypovitaminosis D3 can also affect the differentiation of the epidermis, resulting in perturbations of stratum corneum barrier function, delays in wound healing, or exacerbation of other inflammatory dermatoses (9). Therefore, short bursts (5 to 10 minutes) of limited UVB exposure three times a week and increased dietary or supplemental vitamin D3 are recommended to prevent hypovitaminosis (9,100).
VI. P S Y C H O L O G I C E F F E C T S OF MENOPAUSAL CHANGES RELATED T O SKIN A P P E A R A N C E ~ S E L F - I M A G E Hypoestrogenemia occurs during perimenopause. The phenotypic effects of estrogen deficiency may affect psychosocial behavior, such as how others judge a perimenopausal woman's age (10,104). In such a study, Wildt and Sir-Petermann (104) made age estimates for each of 100 women within 1 minute of initially entering a women's clinic. Subsequently, these women had serum estradiol determination performed. The results of the study suggested that the accuracy of age estimation strongly correlated with estradiol levels. Women with high estradiol levels
appeared younger while women with low levels appeared older than their actual chronologic age. The effects of perimenopause and menopause occur within the overall background of progressive inexorable intrinsic alterations (i.e., chronologic aging that occurs in everyone with the passage of time) of the covered integument that underlies additional extrinsic changes, principally due to cumulative chronic ultraviolet light irradiation (i.e., photoaging) over exposed skin (26,105,106). Therefore, the impact of skin aging in postmenopausal women includes not only the limitations in skin homeostatic physiologic functions mentioned earlier, but also the overt changes in physical appearance due to the cumulative effects of chronologic, environmental, ultraviolet light, and hormonal deficiency factors on the integument, as are summarized in Table 17.2 (14). All these are important issues because women may survive one-third of their lives in the postmenopausal state (107). Preserving physical appearance is a multibillion-dollar business. Among older women, attractiveness promotes a better self-image that benefits their mental, physical, and social well-being (11). Last but not the least, women with aging facial skin frequently expresses concern because these changes are a visible and frequent reminder that they are getting older every time they look at themselves in the mirror (11). Referral to a knowledgeable dermatologist or cosmetic surgeon can assist patients with the problems associated with the changes in their skin appearance and, at the same time, screen for precancerous and cancerous lesions. Sunscreens, cosmetics, topical retinoids, cx- and [3-hydroxy acids, chemical peels, dermabrasion, botulinum toxin injections, soft-tissue fillers, laser resurfacing, and cosmetic surgery are among the many approaches to rejuvenating aging skin for women in the postmenopausal phase of their life (105,106,108-114). These agents and procedures principally help ameliorate the cumulative aging changes that accompany menopause.
VIII. T O P I C A L H O R M O N E REPLACEMENT THERAPY In recent years the role of HRT in menopausal and postmenopausal women has been assessed. Systemic HRT therapy is no longer recommended for the prevention of chronic conditions per se (115). Therefore, systemic HRT use solely for postmenopausal skin aging changes noted in this presentation is n o t recommended (13,71,116,116a). Skin benefits, at present, will only be available to those menopausal women who have other climacteric medical needs requiring systemic HRT. This is a conundrum for most women because estrogen is a relatively small molecule that can easily be incorporated into an acceptable cream or gel topical delivery vehicle (117). In fact, as noted in Table 17.3, investigational low-dose topical estrogen products (creams or gels) have
246 generally, but not always, demonstrated increases in dermal collagen, skin thickness, and rates of wound healing and reduction of facial wrinkles (see studies by Brincat [52], Jemec [33], Creidi [59], Callens [36], Schmidt [34], Schmidt [35], Varila [55], Fuchs [123], and Son [15]). Unfortunately, for apparent safety reasons, there is no approved prescription topical estrogen product for use for hypoestrogenic skin. However, it would be highly desirable to have a safe and effective topical estrogenic preparation that has been robusily tested and can be delivered to a limited skin area in such a way as to provide local but not systemic effects. This would necessitate double-blind, randomized, rigorous scientific studies to support all claims of safety and efficacy. Liability concerns and governmental regulatory requirements (117) would be considerable, and it would take many years to achieve; however, the reward of a safe and effective topical estrogen for use on estrogen-deficient skin might be worth the effort by obviating the need for systemic HRT.
VII. SUMMARY Human skin is a three-tiered hormonally responsive integrated organ system to maintain homeostasis through preservation of a constantly renewing, intact, functioning stratum corneum barrier. Epidermal keratinocytes, dermal fibroblasts, blood vessels, and skin appendages have estrogen receptors. Menopausal skin effects occur within the overall background of progressive inexorable intrinsic alterations (i.e., chronologic aging) that are superimposed changes over extrinsic changes, principally due to cumulative ultraviolet exposure. The principal way to discern skin alterations related to hypoestrogenemia occurring in menopausal women is through study of the amelioration that occurs after estrogen-based hormonal replacement. HRT studies have not generally been scientifically vigorous but indicate mixed clinical effects regarding improvements in dry skin, SC hydration, and barrier preservation, as shown in Table 17.3. Dry skin complaints are common and generally can easily be treated with small alterations in personal lifestyle habits. Significant menopausal-associated sweating can be managed with HRT or other systemic therapies. The scientific data regarding the role of HRT for menopausal changes in the dermis (ECM) are in the direction of being possibly beneficial. Incremental increases of the dermal extracellular matrix and a wound microenvironment are statistically significant in small scale studies. HRT helps to maintain or restore collagen and skin thickness, possibly dampening of the pace of development of fine wrinkles, increasing skin strength, improving acute wound healing rates, and perhaps preventing skin breakdown in elderly postmenopausal women. On the molecular level, HRT limits proteolytic effects of excessive inflammation by generating TGF-[3 to promote a wound environment that is favorable to healing.
KATZ AND PRYSTOWSKY
Oral vitamin D3 supplementation can help to augment deficiency that may occur due to decreased photochemical conversion of 7-dehydrocholesterol to previtamin D3 in the aged epidermis. The maintenance of skin function and appearance is important and plays an influential role in the quality of life for women who can spend up to one-third of their lives in a hypoestrogenic state. Ideally, a safe and effective topical hormone replacement preparation without systemic adverse effects would be a highly desirable treatment for hypoestrogenic skin (124).
References 1. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermato12001;45:$116- $124. 2. Thornton MJ. The biological actions of estrogens on skin. Exp Dermatol 2002;11:487- 502. 3. Chuong CM, Nickoloff BJ, Elias PM, et al. What is the 'true' function of skin? Exp Dermato12002;11:159-187. 4. Kanda N, Watanabe S. Regulatory roles of sex hormones in cutaneous biology and immunology. J Dermatol Sci 2005;38:1-7. 5. Elias PM. Stratum corneum defensive functions: an integrated view. J Invest Dermato12005;125:183-200. 6. DiPasquale DM, Buono MJ, Kolkhorst FW. Effect of skin temperature on the cholinergic sensitivity of the human eccrine sweat gland. Jpn J Physio12003;53;427-430. 7. Freedman RR, Subramanian M. Effects of symptomatic status and the menstrual cycle on hot flash-related thermoregulatory parameters. Menopause 2005;12:156-159. 8. Lehmann B, Querings K, Reichrath J. Vitamin D and skin: new aspects for dermatology. Exp Dermato12004;13(suppl)4:11-15. 9. Holick ME Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. AmJ Clin Nutr 2004;80:1678S- 1688S. 10. Kligman AM, Koblenzer C. Demographics and psychological implications for the aging population. Dermatol Clin 1997;15:549-553. 11. Koblenzer CS. Psychosocial aspects of beauty: how and why to look good. Clin Dermato121:473-475. 12. Ashcroft GS, Mills SJ, Lei K, et al. Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. J Clin Invest 2003;111:1309-1318. 13. Sator PG, Schmidt JB, Rabe T, Zouboulis CC. Skin aging and sex hormones in women--clinical perspectives for intervention by hormone replacement therapy. Exp Dermato12004;13(suppl)4:36-40. 14. Brincat M, Baron YM, Galea R. Estrogens and the skin. Climacteric 2005;8:110-123. 15. Son ED, Lee JY, Lee S, et al. Topical application of 17beta-estradiol increases extracellular matrix protein synthesis by stimulating TGFbeta signaling in aged human skin in vivo. J Invest Dermatol 2005;124:1149-1161. 15a. Hall G, Phillips TJ. Estrogen and skin: the effects of estrogen, menopause, and hormone replacement therapy on the skin. JAm Acad Dermato12005;53:555-568. 15b. Ohnemus U, Uenalan M, Inzunza J, Gustafsson JA, Paus R. The hair follicle as an estrogen target and source. EndocrRev 2006;27:677-706. 16. Ashcroft GS, Ashworth JJ. Potential role of estrogens in wound healing. d m J Clin Dermato12003;4:737-743. 17. Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Bid Med (Maywood) 2004;229:1127-1135. 18. Hall GK, Phillips TJ. Skin and hormone therapy. Clin Obstet Gynecol 2004;47:437-449.
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247 46. Bachmann GA. Menopausal vasomotor symptoms: a review of causes, effects and evidence-based treatment options. J Reprod Med 2005;50: 155-165. 47. Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med 2005;23:117-125. 48. Anonymous. Treatment of menopausal vasomotor symptoms. Obstet Gyneco12005;105:1137-1139. 49. Ignotz RA, Endo T, Massague J. Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta. JBio! Chem 1987;262:6443 -6446. 50. Brincat M, Moniz CF, Studd JVV, et al. Sex hormones and skin collagen content in postmenopausal women. Br Meat J (Clin Res Ed) 1983;287:1337-1338. 51. Brincat M, Moniz CJ, Studd, JW, et al. Long-term effects of the menopause and sex hormones on skin thickness. Br J Obstet Gynaecol 1985;92:256-259. 52. Brincat M, Versi E, Moniz CF, et al. Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy. Obstet Gyneco11987;70:123-127. 53. Castelo-Branco C, Duran M, Gonzalez-Merlo J. Skin collagen changes related to age and hormone replacement therapy. Maturitas 1992;15: 113-119. 54. Savvas M, Bishop J, Laurent G, Watson N, Studd J. Type III collagen content in the skin of postmenopausal women receiving oestradiol and testosterone implants. BrJ Obstet Gynaeco11993;100:154-156. 55. Varila E, Rantala I, Oikarinen A, et al. The effect of topical oestradiol on skin collagen of postmenopausal women. Br J Obstet Gynaecol 1995;102:985-989. 56. Affinito P, Palomba S, Sorrentino C, et al. Effects of postmenopausal hypoestrogenism on skin collagen. Maturitas 1999;33:239-247. 57. Sauerbronn AV, Fonseca AM, Bagnoli VR, Saldiva PH, Pinotti JA. The effects of systemic hormonal replacement therapy on the skin of postmenopausal women. IntJ Gynaeco! Obstet 2000;68:35-41. 58. Brincat M, Yuen AW, Studd JVV, et al. Response of skin thickness and metacarpal index to estradiol therapy in postmenopausal women. Obstet Gyneco11987;70:538-541. 59. Creidi P, Faivre B, Agache P, et al. Effect of a conjugated oestrogen (Premarin) cream on ageing facial skin. A comparative study with a placebo cream. Maturitas 1994;19:211 - 223. 60. Maheux R, Naud F, Rioux M, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gyneco11994;170:642-649. 61. Meschia M, Brusch F, Amicarelli FEA. Transdermal hormone replacement therapy and skin in postmenopausal women: A placebo controlled study. Menopause 1994;1:79- 82. 62. Chen L, Dyson M, Rymer J, Bolton PA, Young SR. The use of highfrequency diagnostic ultrasound to investigate the effect of hormone replacement therapy on skin thickness. Skin Res Techno! 2001;7: 95-97. 63. Sator PG, Schmidt JB, Sator MO, Huber JC, Honigsmann H. The influence of hormone replacement therapy on skin ageing: a pilot study. Maturitas 2001;39:43- 55. 64. Brincat M, Moniz CF, Kabalan S, et al. Decline in skin collagen content and metacarpal index after the menopause and its prevention with sex hormone replacement. BrJ Obstet Gynaeco11987;94:126-129. 65. Brincat M, Versi E, O'Dowd T, et al. Skin collagen changes in postmenopausal women receiving oestradiol gel. Maturitas 1987;9:1-5. 66. Castelo-Branco C, Pons F, Gratacos E, et al. Relationship between skin collagen and bone changes during aging. Maturitas 1994;18: 199-206. 67. Haapasaari KM, Raudaskoski T, Kallioinen M, et al. Systemic therapy with estrogen or estrogen with progestin has no effect on skin collagen in postmenopausal women. Maturitas 1997;27:153-162. 68. Lapiere CM. The ageing dermis: the main cause for the appearance of 'old' skin. BrJ Dermato11990;122 (suppl 35):5-11.
248 69. Contet-Audonneau JL, Jeanmaire C, Pauly G. A histological study of human wrinkle structures: comparison between sun-exposed areas of the face, with or without wrinkles, and sun-protected areas. Br J Dermatol 1999;140:1038-1047. 70. Bosset S, Barre P, Chalon A, et al. Skin ageing: clinical and histopathologic study of permanent and reducible wrinkles. EurJ Dermatol 2002;12:247-252. 71. Wolff EF, Narayan D, Taylor HS. Long-term effects of hormone therapy on skin rigidity and wrinkles. Fertil Steri12005;84:285-288. 72. Pierard GE, Letawe C, Dowlati A, Pierard-Franchimont C. Effect of hormone replacement therapy for menopause on the mechanical properties of skin. JAm Geriatr Soc 1995;43:662-665. 73. Pierard-Franchimont C, Cornil F, Dehavay J, et al. Climacteric skin ageing of the face--a prospective longitudinal comparative trial on the effect of oral hormone replacement therapy. Maturitas 1999;32:87-93. 74. Bolognia JL, Braverman IM, Rousseau ME, Sarrel PM. Skin changes in menopause. Maturitas 1989; 11:295- 304. 75. Henry F, Pierard-Franchimont C, Cauwenbergh G, Pierard GE. Agerelated changes in facial skin contours and rheology. JAm Geriatr Soc 1997;45:220-222. 76. Orme SM, Belchetz PE. Is a low skinfold thickness an indicator of osteoporosis? Clin Endocrinol (Oxf) 1994;41:283-287. 77. Smeets AJ, Kuiper JW, van Kuijk C, Berning B, Zwamborn AW. Skin thickness does not reflect bone mineral density in postmenopausal women. OsteoporosInt 1994;4:32-35. 78. Sumino H, Ichikawa S, Abe M, et al. Effects of aging and postmenopausal hypoestrogenism on skin elasticity and bone mineral density in Japanese women. EndocrJ 2004;51:159-164. 79. Sumino H, Ichikawa S, Abe M, et al. Effects of aging, menopause, and hormone replacement therapy on forearm skin elasticity in women. JAm Geriatr Soc 2004;52:945-949. 80. Ashcroft GS, Dodsworth J, van Boxtel E, et al. Estrogen accelerates cutaneous wound heating associated with an increase in TGF-betal levels. Nat Meal 1997;3:1209-1215. 81. Ashcroft GS, Horan MA, Herrick SE. Age-related differences in the temporal and spatial regulation of matrix metaUoproteinases (MMPs) in normal skin and acute cutaneous wounds of healthy humans. Cell Tissue Res 1997;290:581-591. 82. Ashcroft GS, Horan MA, Ferguson MW. Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Lab Invest 1998;78:47-58. 83. Gosain A, DiPietro LA. Aging and wound healing. WorldJ Surg 2004;28:321-326. 84. Kovacs EJ. Aging, traumatic injury, and estrogen treatment. Exp Geronto12005;40:549- 555. 85. Thomas DR. Age-related changes in wound healing. Drugs Aging 2001;18:607-620. 86. Gniadecka M, Serup J, Sondergaard J. Age-related diurnal changes of dermal oedema: evaluation by high-frequency ultrasound. BrJDermato11994;131:849-855. 87. Ryan T. The ageing of the blood supply and the lymphatic drainage of the skin. Micron 2004;35:161-171. 88. Reed MJ, Ferara NS, Vernon RB. Impaired migration, integrin function, and actin cytoskeletal organization in dermal fibroblasts from a subset of aged human donors. Mech Ageing Dev 2001;122:1203-1220. 89. Horan MA, Ashcroft GS. Ageing, defence mechanisms and the immune system. Age Ageing 1997;26(suppl 4):15-19. 90. Ogrin R, Darzins P, Khalil Z. Age-related changes in microvascular blood flow and transcutaneous oxygen tension under basal and stimulated conditions. J GerontolA Bid Sci Med Sci 2005;60:200-206. 91. Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev 2002;23:90-119. 92. Menger MD, Vollmar B. Surgical trauma: hyperinflammation versus immunosuppression? Langenbecks Arch Surg 2004;389:475-484.
KATZ AND PRYSTOWSKY 93. Ashcroft GS, Greenwell-Wild T, Horan MA, Wahl SM, Ferguson MW. Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Patho11999;155:1137-1146. 94. Margolis DJ, Knauss J, Bilker W. Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers. Lancet 2002;359: 675-677. 95. Verdier-Sevrain S, Yaar M, Cantatore J, Traish A, Gilchrest BA. Estradiol induces proliferation of keratinocytes via a receptor mediated mechanism. FASEBJ 2004;18:1252-1254. 96. Kanda N, Watanabe S. 17 [3-estradiol enhances heparin-binding epidermal growth factor-like growth factor production in human keratinocytes. Am J Physiol Cell Physio12005;288:C813- C823. 97. Kanda N, Watanabe S. 17 [3-estradiol inhibits MCP-1 production in human keratinocytes. J Invest Dermato12003 ;120:105 8 -1066. 98. MacLaughlin J, Holick ME Aging decreases the capacity of human skin to produce vitamin D3.J Clin Invest 1985;76:1536-1538. 99. Bhattoa HP, Bettembuk P, Ganacharya S, Balogh A. Prevalence and seasonal variation of hypovitaminosis D and its relationship to bone metabolism in community dwelling postmenopausal Hungarian women. OsteoporosInt 2004;15:447-451. 100. Reginster JY. The high prevalence of inadequate serum vitamin D levels and implications for bone health. Curr Med Res Opin 2005;21: 579-586. 101. Nola I, Kotrulja L. Skin photodamage and lifetime photoprotection. Acta Dermatovenerol Croat 2003;11:32-40. 102. Kira M, KobayashiT, Yoshikawa K. Vitamin D and the skin.JDermatd 2003;30:429-437. 103. Reichrath J, Girndt M, Tilgen W, Q.uerings K. UV-exposition and vitamin D: how much sunlight do we need? Exp Dermato12005;14:153 (abstract). 104. Wildt L, Sir-Petermann T. Oestrogen and age estimations of perimenopausal women. Lancet 1999;354:224. 105. Lockman A, Lockman D. Skin changes in the maturing woman. Clin Fam Pract 2002;4:113-134. 106. Stratigos AJ, Katsambas AD. The role of topical retinoids in the treatment of photoaging. Drugs 2005;65:1061-1072. 107. Wines N, Willsteed E. Menopause and the skin. AustralasJDermatol 2001;42:149-148. 108. Said S, Meshkinpour A, Carruthers A, Carruthers J. Botulinum toxin A: its expanding role in dermatology and esthetics. AmJ Clin Dermatol 2003;4:609-616. 109. Obagi S. Correction of surface deformities: Botox, soft-tissue fillers, lasers and intense pulsed fight, and radiofrequency.Atlas OralMaxillofac Surg Clin North Am 2004;12:271-297. 110. Friedman O. Changes associated with the aging face. FacialHast Surg Clin North Am 2005;13:371-380. 111. DiBernardo BE, Cacciarelli A. Cutaneous lasers. Clin Plast Surg 2005;32:141-150. 112. Weiss J. A review of clinical experience and recommendations for improving patient care. Cutis 2005;75:32-38. 113. Samuel M, Brooke PC, Hollis S, Griffiths, CE. Interventions for photodamaged skin. CochraneDatabase Syst Rev 2005;CD001782. 114. Thornfeldt CR. Cosmeceuticals: separating fact from voodoo science. Skinmed 2005;4:214-220. 115. Anonymous. Summaries for patients. Hormone therapy to prevent chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med 2005; 142:159. 116. Schmidt JB. Perspectives of estrogen treatment in skin aging. Exp Dermato12005;14:156. 116a. Verdier-Sevrain S, Bonte F, Gilchrest B. Biology of estrogens in skin: implications for skin aging. Exp Dermato12006;15:83-94.
CHAPTER 17 Menopause and the Skin 117. Draelos ZD. Topical and oral estrogens revisited for antiaging purposes. Fertil Steri12005;84:291-292. 118. Kanitakis J. Anatomy, histology and immunohistochemistry of normal human skin. EurJ Dermato12002;12:390-399. 119. Rodriguez AM, Elabd C, Amri EZ, Ailhaud G, Dani C. The human adipose tissue is a source of multipotent stem cells. Biochimie 2005;87:125-128. 120. Fruhbeck G. The adipose tissue as a source of vasoactive factors. Curr Med Chem CardiovascHematolAgents 2004;2:197-208. 121. Montagna W, Carlisle K. Structural changes in ageing skin. Br J Dermato11990;122(suppl 35):61- 70.
249 122. Rossi AB, Vergnanini AL. Cellulite: a review. J Eur Acad Dermatol Venereo12000;14:251- 262. 123. Fuchs KO, Solis O, Tapawan R, Paranjpe J. The effects of an estrogen and glycolic acid cream on the facial skin of postmenopausal women: a randomized histologic study. Cutis 2003;71:481-488. 124. Naunton M, A1 Hadithy AF, Brouwers JR, Archer DE Estradiol gel: review of the pharmacology, pharmacokinetics, efficacy, and safety in menopausal women. Menopause 2006;13:517-527.
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;HAPTER 1
Urogenital Symptoms around the Menopause and Beyond GORAN SAMSIOE
Departmentof Obstetrics & Gynecology,Lund University Hospital, 221 85 Lund, Sweden
I. I N T R O D U C T I O N
with age, typically 20% to 30% in young adults, peaking around middle age (prevalence 30% to 40%), and rising steadily in old age (30% to 50%) (3,4). Female urinary incontinence leads to significant morbidity, resulting in impaired quality of life and social and occupational life and adversely affecting women's physical, psychologic, sexual, and domestic well-being. Not surprisingly, symptoms of depression and anxiety increase in patients with U-I; such symptoms complicate medical illnesses and management and have major economic consequences. Despite the burden of UI symptoms, only some 25% of affected women consult a doctor (5-7), often because of their misconception that the condition is a normal consequence of childbirth and aging, their lack of knowledge about possible therapy (6,8), or shame and embarrassment about discussing incontinence (6,9). Several questionnaire-based surveys have been carried out to delineate the nature and occurrence of urogenital problems in women, especially after the age of 50 years (1-8) (Fig. 18.1). Results are variable due mainly to different definitions of incontinence and sometimes to a selection among women that were studied. From observational studies it can be inferred that urinary incontinence is two to three times more prevalent in women than in men and that prevalence increases with age. If data from various population-based studies are pooled, incontinence in women
Advancing age is associated with a decline in a large number of physiologic processes. The urogenital system is no exception. Symptoms and signs from urologic structures and the female sex organs often parallel each other as they originate from a common fetal structure, the urogenital sinus. Symptoms and signs of lost urogenital integrity increase with age but could be modulated by hormonal status as well as lifestyle and environmental factors (Table 18.1). By introducing measures that have an impact on lifestyle, environment, and the hormonal situation, it is possible to influence the urogenital aging process and thereby reduce disabling symptoms and signs in elderly women. The aging process as well as hormonal insufficiency will ultimately occur in all women. Lifestyle changes often accompany these two processes. There is a huge inter-individual as well as intra-individual sensitivity to these changes and symptoms and signs of urogenital aging are therefore highly variable within an individual as well as between individuals. Urinary incontinence is defined by the International Continence Society (ICS) as "any involuntary leakage of urine" (1). Urinary incontinence (UI) is currently an underdiagnosed and underreported condition (2) that is especially common in women. Estimates of the prevalence of UI vary and increase T R E A T M E N T OF T H E POSTMENOPAUSAL W O M A N
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252
G6RANSAMSIOE TABLE 18.1
Some Common Symptoms of Urogenital Aging
Urologic symptoms Frequent micturition Recurrent cystitis Urethritis Dysuria Urge incontinence Stress incontinence Mixed type of incontinence
Vaginal symptoms Vaginal dryness Loss of lubrication Dyspareunia Vaginitis Vaginal discharge Vulvar itching and burning
seems to increase from 3% to 5% at age 20, to 8% to 9% at age 30, to 12% to 15% at age 50. We published one study in women under 65 years, with a detailed questionnaire on urogenital problems concomitant with a personal interview of each subject (9). Among these 3000 women we can confirm that the overall prevalence of poor control of micturition occurred in about one-third of the cases. However, it should be pointed out that some women complained of this only in specific social situations, such as concomitantly with coughing due to bronchitis. Incontinence was associated with increased parity, overweight, and hysterectomy, confirming previous data, but the condition was also associated with a family history of diabetes. As can be expected, there is a difference between the prevalence and incidence of various symptoms related to urogenital ageing, depending on the design of a given study. In comparison with osteoporosis and cardiovascular disease, much less attention has been paid to problems incurred by urogenital aging. Given the present composition of the population in modern Western countries, 8% of the total population experiences urogenital problems (8). In the United States alone, 20 million women suffer from
these socially disabling symptoms. The prevalence figures obtained by questionnaire surveys are often higher than the clinical experience suggests. Many women feel embarrassed and do not readily address problems related to lost of urogenital integrity, unless specifically asked. Methodologically sound studies are needed to document the economic and personal impact of UI in order to develop better guidelines for the allocation of health care resources and research funding to this major public health problem. Furthermore, although there are several examples of randomized clinical trials and epidemiologic studies that provide evidence about the prevalence of UI, the efficacy and safety of UI treatments, the direct costs of treatment, the characteristics of the patients seeking treatment for UI, and the impact of UI on health-related quality of life (HRQoL), the results cannot be compared or combined across the different studies, countries, and patient populations because the studies have used different methodologies, and were carried out in different settings, using different definitions. The economic costs for incontinence have been estimated to be $8 to $10 billion per annum, corresponding to 2% to 3% of the total costs of the health care system. There can be little doubt that incontinence is the major urogenital problem encountered by women. Consequently this chapter will concentrate on the pathophysiology and treatment of this disabling disorder. Other problems will be mentioned in brief.
A. Paraurethral Collagen and the Menopause Menopause seems to induce a paraurethral connective tissue which is enriched with collagen which has different mechanical properties due to a higher degree of cross-linking (10). A concomitant decrease in the proteoglycan/coUagen ratio suggests that this tissue has some increase in load-bearing ability but has decreased in elasticity (10).
B. Paraurethral Collagen and Stress Urinary Incontinence in Women of Reproductive Age
FIGURE 18.1 Prevalenceofvarious types of femaleurinaryincontinence by age from a community-basedsurvey
A higher collagen concentration in combination with higher cross-linking has been demonstrated in women with stress-incontinence compared with continent control subjects (11). These biochemical changes are accompanied by ultrastructural differences in terms of significantly larger collagen fibril diameters. These alterations focus on a possible disturbance in the fibrilization process (11). It is possible that the pathophysiology of stress urinary incontinence in women is different between women of reproductive age and women after menopause (11). In women of reproductive age with severe stress incontinence, significant changes in the extracellular matrix of the paraurethral
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CHAPTER 18 Urogenital Symptoms around the Menopause and Beyond connective tissue have been shown (11). These changes result in a stiffer, less supportive paraurethral tissue with no major changes in biochemistry or ultrastructure.
III. MECHANISMS OF C O N T I N E N C E A. Urine Storage and Micturition
II. INNERVATI ON
A. Parasympathetic Pathways The parasympathetic innervation to the bladder is derived from the sacral parasympathetic nucleus located at $2-$4, which in turn receives input from the pontine micturition center in the central nervous system (CNS). Preganglionic axons travel in the pelvic nerve to ganglia located within the pelvic plexus, to vesical ganglia (located on the serosal surface of the bladder), or to intramural ganglia in the bladder wall. Postganglionic axons leave the ganglia to supply the smooth muscle of the lower urinary tract. Activation of parasympathetic postganglionic nerves contracts the smooth muscle of the detrusor during micturition. The role of the parasympathetic nervous system in urethral function remains uncertain (12).
B. Sympathetic Pathways The preganglionic sympathetic axons are derived from T 1 0 - 1 2 and leave the spinal cord via the splanchnic nerves. The fibers are conveyed to the inferior mesenteric ganglion, where they either synapse with postganglionic cell bodies or pass directing through without synaptic contact. They pass via the pelvic plexus or directly to the bladder and urethra via the hypogastric nerve. Some preganglionic axons pass down the sympathetic chain to the lumbosacral level of the spinal cord, where they either synapse with cell bodies of the sympathetic chain ganglia or pass directly in the pelvic nerve (12). A substantial part of urethral tone, an important factor for maintenance of intraurethral pressure, is mediated through the stimulation of c~-adrenoreceptors by released noradrenaline (13).
C. SensoryAfferent Innervation The hypogastric pathway is implicated in sensations associated with bladder filling and bladder pain. The pudendal pathway is involved with the sensation that micturition is imminent. The sensory fibers traveling along the hypogastric nerve are responsible for a feeling of bladder filling and bladder pain. Axons located in the pudendal nerve are implicated in a sensation that micturition is imminent. Sensory afferents travel in the pelvic nerve to the dorsal horn of the sacral spinal cord (14) (Fig. 18.2).
The function of the bladder and urethra is to store urine and, when appropriate, for the evacuation of urine. The bladder forms a reservoir and accommodates to increasing volumes of urine, by the outlet region increasing its resistance. Several factors contribute to the ability of the outlet region to maintain continence. The proximal portion of the urethra lies within the abdominal cavity, and this position allows the pressure to rise along with any rise in intraabdominal pressure by passive transmission. The periurethral striated muscle seems to play an important role in maintaining continence during coughing and sneezing (15), but the rhabdosphincter and the properties of the smooth muscle of the urethra also contribute to maintaining continence. The lamina propria is also believed to "seal" the female urethra, thereby contributing to urethral closure (16). The previously described meshwork of detrusor muscle is ideally suited for emptying the spherical bladder. Urethral opening is not only a consequence of bladder contractions, but it is also facilitated by a drop in urethral pressure which proceeds the contraction (15). The factors contributing to this drop in pressure are still largely unknown. All pelvic floor muscles connected to the urogenital system are intimately involved in the mechanisms of urinary continence. Disturbance of any part of this delicate system may contribute to the development of incontinence. However, when one element is abnormal, other mechanisms may be able to compensate and maintain continence (17,18). The micturition cycle can be separated into three phases: bladder filling, activation of the micturition reflex, and bladder emptying (Fig. 18.3). During filling (stretch), passive bladder wall properties are activated and build up intramural tension, which in turn triggers bladder afferent nerves, leading to a desire to void. Activation of the micturition reflex, in the meaning of initiation of voiding, is a condition of nervous control. Emptying (contractility) is a neuromuscular activity. When the micturition reflex has been activated, pressure falls in the urethra and the pelvic floor becomes silent, as evidenced by the electromyelogram (EMG) pattern. The detrusor muscle contracts, the bladder neck opens, and urine is passed. The bladder emptying is related to the various morphologic and functional aspects of detrusor contractility, including also intramural changes. Stress urinary incontinence (SUI) is caused by a deficiency of the closure pressure in the urethra concomitant, with an increase in intraabdominal pressure in the absence of detrusor activity (17). There are probably several types of stress incontinence. Each type of stress incontinence reflects the malfunction of one or a battery of anatomic components of the supportive and the sphincteric system.
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Nerves, neurotransmitters and receptors involved in continence/voiding
FIGURE 18.2 This diagram showswhich neurotransmitters and receptors are involvedin the peripheral motor innervation of the lower urinary tract (LUT). During bladder filling, noradrenaline (NA) release from the sympathetic hypogastric nerve results in bladder relaxationby stimulating f32/f33-adrenoceptorsin the detrusorsmooth muscleand in closureof the bladder neck by stimulating cxl-adrenoceptors.The urethral striated muscle remains closedby release of acetylcholine (ACb) from the somaticpudendal nerve,which results in stimulationof nicotinic receptors (Nic) in the urethral striated muscle and subsequent contraction.The pelvicfloor striated muscles contract due to release of ACh from the somatic sacral nerve. During voiding, the release of NA and ACh from these nerves is inhibited, which leads to relaxation of the bladder neck, urethral striated muscle, and pelvic floor muscles.At the same time, the parasympatheticpelvic nerve releases ACh. This stimulates M2/M3 muscarinic/cholinergic receptors in the detrusor smooth muscle,which results in bladder contraction and emptying.
Until recently the predominating theory behind the occurrence of stress incontinence has been the so-called pressure transmission theory (17). In stress-incontinent women, this theory suggests that the intraabdominal pressure increase (caused by coughs, jumps, etc.)will not be properly transmitted from the intraabdominal pressure compartment (in which the bladder is located) down to the urethra and therefore the bladder pressure will exceed the urethra pressure during a short period, allowing urine to leak. The "integral theory" suggests that continence is maintained by a complicated interplay between specific urogenital structures, aiming to stop the flow of urine at the level of the mid-urethra during situations of increased intra-abdominal pressure. Consequently, a surgical procedure should aim at creating a functional pubourethral ligament supporting the mid-urethra and reinforcing the suburethral vaginal wall (19). Another theory emphasizes a strong anatomic support of the urethra from below, implying that the urethra may be closed by forces acting from above, such as the abdominal pressure transmitted at stress situations (18,19). Accumulating evidence indicates that a more integrated, comprehensive view regarding the different structures, both
inside and outside the urethra, is needed to explain the mechanisms of continence (18,19). In addition, biochemical changes inclusive of enzyme activities may well be different in continent and incontinent patients. This is an area that is only recently being exploited. Defects in the supporting tissues that both actively and passively stabilize the urethra lead to poor control of micturition. In addition, the neuromuscular function is of pivotal importance, and impaired secretion, uptake, or synthesis of neurotransmitters such as noradrenaline and serotonin may also contribute to the pathophysiology.
IV. TREATMENT MODALITIES FOR FEMALE URINARY INCONTINENCE From a clinical standpoint it is often wise to differentiate between stress and urge incontinence, as treatments may be quite different. However, a huge overlap between the two conditions occurs, and therefore it is sometimes difficult to treat them separately. Some types of treatments could be regarded as common to both stress and urge
CHAPTER 18 Urogenital Symptoms around the Menopause and Beyond
255 TABLE 18.2
Scandinavian Guidelines for Assessment of Female Incontinence
Patient history
Type and severity of incontinence Effect on quality of life Other diseases/drug affecting the lower urinary tract Drinking and voiding habits Pelvic mass Mucosal atrophy Genital descensus Blood, glucose, protein Infection Clarifies patient history Basis for behavioral advice Objective incontinence Q.uantification of incontinence
Pelvic examination Urine test Frequency/Volume chart Stress test Pad test FIGURE 18.3 The innervation of the LUT by several afferent sensory and efferent peripheral autonomic and somatic nerves is controlled by the central nervous system. The coordinated alternated activity of the bladder, urethra, and pelvic floor during urine storage and voiding is regulated by afferent sensory and efferent autonomic and somatic peripheral nerves. These involve different neurotransmitters that act on different receptors in the target organs (bladder, urethra, and pelvic floor). The activity of the peripheral nerves is coordinated by the pontine micturition center (PMC) in the brainstem of the central nervous system (CNS). The PMC itself is under conscious control of the cerebral cortex. During bladder filling, the sympathetic fibers of the hypogastric nerve ensure relaxation of the detrusor and closure of the bladder neck. The urethral striated muscle remains closed due to somatic pudendal nerve activity. The somatic sacral nerve ensures that the pelvic floor muscles are also contracted and as such support the compression of the urethra and prevention of leakage. During voiding, the activity of the hypogastric, pudendal, and sacral nerves is inhibited, whereas the parasympathetic pelvic nerve is stimulated. This results in relaxation of the bladder neck, urethral striated muscle, and pelvic floor muscle and contraction of the detrusor and, therefore, bladder emptying.
incontinence, such as pelvic floor exercise, (local) estrogen administration, or electrostimulation. Table 18.2 summarizes recommendations for the clinical evaluation of women with incontinence. Multiple surgical techniques have been devised, perhaps suggesting the difficult nature of this disorder and the less than satisfactory success of treatment (20). Details will be described in Chapter 51.
A. Pharmacologic Treatment of Stress Incontinence In urodynamic investigations, it has been found that the intraurethral pressure is low in women with stress incontinence. Accordingly, data suggest that at least two (x-adrenergic receptor agonists, norephedrine and midodrine, increase intraurethral pressure and were effective also in clinical trials. It should be pointed out that the lowered intraurethral pressure is only a minor contributor to the overall clinical picture,
Adapted from Mouritsen L, Lose G, Ulmsten U, et al. Consensus of basic assessment of female incontinence, dcta Obstet Gyneco! &and 1997;(suppl 166):59-60.
which limits the use of any pharmacologic agent only to milder cases.
B. Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) Preparations One strategy for improving urinary continence is to augment the function of the urethral rhabdosphincter through neuropharmacology. Targeting serotonin and norepinephrine (or noradrenaline) receptors in Onuf's nucleus has been shown to augment the function of the urethral rhabdosphincter by increasing pudendal nerve efferent activity. It is proposed that the ability of serotonin and norepinephrine to enhance the effects of glutamate (the primary excitatory neurotransmitter for pudendal sphincter motor neurons), while having no direct effects of their own, allows facilitation of rhabdosphincter activity during urine storage while allowing complete relaxation during micturition. Indeed duloxetine, a dual serotonin (5-HT)-norepinephrine reuptake inhibitor (SNRI), potentiates these physiologic effects of endogenous serotonin and norepinephrine (by inhibiting the reuptake of these neurotransmitters in the presynaptic element) and thereby enhances the central nervous system's natural continence control mechanisms. Duloxetine, 80 mg per day (40 mg twice daily), decreased the incontinence episode frequency (IEF) and improved incontinence-related quality of life (I-QOL) independent of baseline incontinence severity and also in patients awaiting surgery. In the trial in patients awaiting surgery, onset of action was closely monitored and all
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patients who responded to duloxetine did so within 1 to 2 weeks. The decrease in IEF and improvement in I-Q_OL were not due to more frequent voiding, as the mean time between voids increased. Nausea was the most common treatment adverse event. This was mostly experienced early after the start of duloxetine (usually within the first few days) and was usually mild or moderate and nonprogressive in severity. The majority of patients reporting nausea continued treatment with duloxetine, and in most of these patients the nausea resolved within 1 to 4 weeks. It can therefore be concluded that duloxetine 40 mg twice daily is a new and promising pharmacologic treatment approach for women with SUI (21).
C. Urge I n c o n t i n e n c e Drug treatment for female urinary incontinence requires a thorough knowledge of the differential diagnosis and pathophysiology of incontinence, as well as of the pharmacologic agents employed. Pharmacotherapy has to be tailored to suit the incontinence subtype and should be carefully balanced according to efficacy and side effects of the drug. Pharmacologic treatments of incontinence due to detrusot overactivity (urge incontinence) include anticholinergic agents such as tertiary amines. Tricyclic agents such as imipramine have been shown to be effective in decreasing incontinence frequency (22). Strategies in pharmacologic treatment of incontinence due to urethral sphincter insufficiency are designed to increase bladder output resistance. Drugs include those with direct oL-adrenergic agonist activity, which may be enhanced by concomitant estrogen treatment. Also [3-adrenergic blocking drugs, which might allow unopposed stimulation of o~-receptor-mediated contracted muscle responses, are of theoretical interest (23). Antimuscarinic drugs have a long-standing tradition in the treatment of urge incontinence (24). Atropine and related substances are tertiary amines easily absorbed from the gastrointestinal (GI) tract. However, these substances also readily penetrate into the CNS, and central nervous side effects are therefore a limiting factor in clinical usage. The quartery amines such as propantheline, emepronium, and tolterodine display less of these effects. However, oral bioavailability is variable and fairly low (5% to 10%). Mouth dryness, the most common of these side effects, limits the use of these drugs. Tolterodine and metabolites seems to have some selectivity for the bladder compared with the salivary glands (24). Calcium channel blockers such as nifedipine are theoreticaUy interesting. However, peripheral vasodilation is often pronounced and effects on the bladder are still debatable. Hence these drugs are at present not a viable alternative for the clinician (25).
Oxybutynin displays mainly antimuscarinic effects, although a direct relaxing effect on muscular tissues has been demonstrated. Again low oral bioavailability and a fairly high percentage of typically antimuscarinic side effects, such as mouth dryness, constipation, and visual disturbances, limits its use. Side effects are dose dependent, and lower than recommended oral doses may render side effects which are minimal (26). Recently a transdermal patch was introduced that seemed to widen the therapeutic window and increase compliance. 13-receptor agonists have also been used because such agents can relax human bladder muscle cells and increase bladder capacity.Therapeutic effects in patients have been obtained by terbutaline but often at the expense oftachycardia. It can be concluded that the therapeutic effect is less distinct than with anticholinergics, and the specific indications, if any, of this family of drugs needs to be established (27). Overactive bladder (OAB) is the term used to describe the symptom complex of urinary frequency and urgency, with or without urge incontinence. Although antimuscarinic drug therapy has proven to be effective in the management of patients with symptoms of the OAB syndrome, compliance with medication is often affected by the bothersome antimuscarinic adverse effects of dry mouth, constipation, somulence, and blurred vision. The development of bladder selective M(3)-specific antagonists offers the possibility of increasing efficacy while minimizing adverse effects. At present, there are but a few M(3)-specific antagonists available, such as solifenacin and darifenacin. Darifenacin is a novel muscarinic M(3) selective receptor antagonist developed for the once-daily treatment of overactive bladder, a chronic, debilitating, and highly prevalent condition affecting adults of all ages. Preclinical research has confirmed the pharmacologic profile of darifenacin as a potent antimuscarinic agent with up to 59-fold higher affinity for M(3) receptors than other muscarinic receptor subtypes and selectivity for the bladder over other tissues expressing these receptors. Extensive research in large, randomized, placebo-controlled trials have demonstrated that darifenacin, at doses of 7.5 and 15 mg once daily, is efficacious in the treatment of overactive bladder, improving the core symptoms of urinary urgency, urge incontinence, increased micturition frequency, and bladder capacity. In addition, post hoc analyses have shown that many patients can achieve clinically meaningful continence levels, such as 90% or greater reduction in incontinence episodes or 7 or more consecutive dry days. These results are supported by significant improvements in quality of life, which have paralleled the overactive bladder symptom reductions. Both fixed and flexible darifenacin dosing regimens produce these beneficial effects, which extend to the more vulnerable population of older patients. Hence, in conjunction with data showing that this agent has a good safety and tolerability profile, these findings indicate that darifenacin may provide an effective
CHAPTER 18 Urogenital Symptoms around the Menopause and Beyond alternative pharmacotherapy for the treatment of patients with overactive bladder. Solifenacin, with a flexible dosing regimen, showed greater efficacy to tolterodine in decreasing urgency episodes, incontinence, urge incontinence, and pad usage and increasing the volume voided per micturition. More solifenacin-treated patients became continent and reported improvements in perception of bladder condition assessments. The majority of side effects were mild to moderate in nature, and discontinuations were comparable and low in both groups. Another novel and intriguing approach is the use ofbotulinum toxin type A. This regimen should be saved for patients with otherwise refractory idiopathic detrusor overactMty. Preliminary results (28) are encouraging, with subjective marked improvements but also improvements in objectively measured variables.
D. Estrogen Loss of estrogen leads to atrophy of the urethral mucosa, which in turn results in a widening of the urethra and thereby a decrease in resistance to flow. Control of micturition calls for increased muscular activity that is hard to achieve, as estrogen deficiency reduces blood flow through the urogenital tissues, thereby impeding muscular function. With a decline in blood flow, important functions of the immune system may also be affected and, in combination with the wide urethra, facilitate microbial migration into the urinary bladder. This, together with the vaginal reservoir of urinary pathogenic microorganisms, makes it understandable that there is a high frequency of symptomatic and asymptotic bacteriuria, as well as recurrent cystitis (29). In stress incontinence, anatomic changes are the main player and consequently a surgical approach remains the first-line treatment of this condition even if estrogens improve the condition somewhat. Albeit limited, data support the notion that estrogen effects in stress incontinence may be mediated via an influence on collagen and neuromuscular metabolism, which are of importance for the supportive function of the pelvic floor. This may well include an effect on intraurethral pressure. However, use of hormone therapy does not seem to prevent urinary incontinence. In fact, observational studies (30,31) as well as randomized controlled trials suggest the opposite, inclusive of the estrogen-only arm of the W H I study (32). Consequently, neither hormone therapy nor estrogen monotherapy could be used as prophylaxis for urinary incontinence in postmenopausal women. Whether there is a place for hormones in the treatment of incontinence is still open. In elderly women, incontinence is a major reason for a permanent admission to nursing homes. The use of
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estrogen replacement therapy, especially low-dose topical applications, may substantially reduce both incontinence and recurrent urinary tract infections, thereby making it possible to live outside an institution. This is a major aspect, which affects both quality of life and the costs of caring for those with incontinence. In addition, the use of sanitary protection may be limited. Women with incontinence often suffer socially, as they are afraid of situations in which they cannot reach a toilet almost immediately. That is why many elderly women avoid long travel on buses and visits to the theater or other cultural events and often remain confined to their own homes, which has a serious impact on their quality of life (33). As mentioned earlier, urogenital atrophy does not begin until endogenously produced estrogens are markedly lower than those required for endometrial proliferation. This observation opens a therapeutic window (see Fig. 18.1). It is possible to target urogenital atrophy while minimizing the risk of endometrial proliferation. Estrogen aimed at controlling urogenital symptoms therefore could and should be given at much lower doses than is common when treating other climacteric complaints. Vaginal estrogens can also be given without a progestogen. For estradiol, daily doses of 50 to 100 b~g are recommended in systemic patches to ensure relief of vasomotor symptoms, whereas 8 to 10 btg of vaginally delivered estradiol seems sufficient to combat urogenital symptoms and signs. In other words, only 10% to 15% of the dose required to alleviate hot flushes is needed to achieve clinical improvement of urogenital estrogen deficiency symptoms. Instead of using ultra-low-dose estradiol, it is also possible to administer estriol, which is a short-acting estrogen. Estriol is available in tablet, cream, and vaginal pessary forms. Vaginal administration is preferred, as the therapeutic window with tablets is fairly narrow and may lead to endometrial proliferation and possibly an increased risk of cancer (34). A number of clinical trials have shown the clinical efficacy of estriol as well as of ultralow doses of estradiol in treating lower urinary tract infections (35,36), various forms of incontinence (37,38), and vaginal problems (39). Marked changes may occur within the lower urogenital tract with little or no influence on endocrine parameters such as sex steroid hormone levels, Sex Hormone Binding Globulin (SHBG), or gonadotropin levels. Even lipid metabolic parameters, such as triglycerides, are not influenced (40). Systemic absorption via the vaginal route is negligible after 3 to 4 weeks of treatment. Hence, low-dose estrogen treatment offers no protection for osteoporosis or cardiovascular disease but also carries no increased risk for breast cancer or any other side effect. Consequently, neither absolute nor relative contraindication exists for low-dose estrogen therapy via the vaginal route. However, in the old elderly, long-standing low-dose estrogen therapy may have some systemic effect (34,41).
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In 1991, well-established vaginal delivery systems of estrogens aimed at the treatment of urogenital estrogen deficiency symptoms were made available as over-the-counter (OTC) preparations in Sweden. Experience with vaginal estrogens as OTC preparations have been positive; no negative effects have been encountered. With low-dose OTC vaginal estrogens, the costs of treatment and prevention of estrogen deficiency symptoms of the urogenital tract can be limited to the cost of the medication itself. There is no need for compulsory follow-up programs. Trained nurses may give counseling and answer questions about low-dose estrogen treatment by vaginal administration in elderly women. As in the vagina, estrogen stimulates maturation of the urethral mucosa, as evidenced by an increase in superficial cells and a decrease in parabasal cells (42-45). Furthermore, several studies have shown a correlation between cell maturation index in the urethra, with subjective improvement of urinary stress incontinence during estrogen therapy (46-49). However, these two events may well be coincidental, and further studies are needed to suggest a functional relationship. General recommendations may be found in Figure 18.4
E. Genital Symptoms In terms of genital symptoms of menopause, the symptom which occurs first is a feeling of dryness, dependent on atrophy of the mucus-producing glands of the vaginal wall.
In the vagina, atrophy yields a thin mucosa susceptible not only to infections but also to stress through intercourse. Petechial bleedings are not uncommon and will lead to vaginal obliteration, which is most pronounced in the fundal region of the vagina. Itching and a feeling of burning are well-known symptoms in the vulva and vagina as a result of atrophic vaginitis. Also, atrophy of the minor lips can lead to burning sensations and itching in the xatlva, but it should be remembered that several dermatologic conditions such as lichen tuber, psoriasis, eczema, and lichen sclerosus yield similar vulvar symptoms, and differential diagnosis must always be considered. Infections such as candidosis may be superimposed and should also be considered in this context. Vaginal symptoms are especially overt in women who have a male partner capable of and interested in sexual activity. There is a general belief that sexual activity is elderly women is low, but in the study by Barlow et al. in women ages 55 to 74, about half reported being sexually active. Among these, 23% of women in general and 14% of women between 70 and 74 reported frequent intercourse--that is, once per week or more. There was a difference between countries, which may reflect cultural differences, as intercourse was relatively less common in the United Kingdom and Germany and higher in Italy and Denmark. Of those women who were sexually active in the past year, 22% reported a loss of interest. However, the most common cause for lost sexual activity (66%) was loss of partner. Male factors inclusive of impotence were reported by 10% of women. In this report by the women there was also a striking geographic difference in lost male capacity, as 13% of Danish women reported this problem but only 6% of women in Italy and the United Kingdom. Sexual activity is dependent not only on the vaginal function but also on libido.
E Libido
FIGURE 18.4 The definition of the three main types ofUI (SUI, UUI,
and MUI) were developedby the International Continence Society(ICS) and adopted by the International Consultation on Incontinence (ICI). They differentiate three main types/symptomsof UI: Stressurinaryincontinence (SUI) is defined as the involuntaryleakage (of urine) on effort or exertion, or on sneezing or coughing.Urge urinary incontinence (UUI) is defined as the involuntaryleakage (of urine) accompaniedby or immediately precededby urgency.Mixed urinaryincontinence (MUI) is defined as the involuntaryleakage (of urine) associatedwith urgency and also with exertion, effort, sneezing and coughing.
There can be little doubt that sex steroids contribute to brain dimorphism and to neuroplasticity as well as psychoplasticity. Estrogen is a prudent activator of sexual attraction, as the hormone causes and maintains secondary sex characteristics and is included in nocturnal activation of the neurovegetative pathways that lead to vaginal and clitoral congestion during rapid eye movement (REM) phases of sleep (50,51). Estrogens have been shown to activate pheromone secretion in sweat and sebaceous glands that contributes to the scent of women, which is of great importance in sexual attraction (52). For women with an active sex life, the loss of lubrication and glandular functions severely impairs sexual desire. Treatment of this condition improves quality of life, not only for the woman but also for her partner.
CHAPTER 18 Urogenital Symptoms around the Menopause and Beyond Human sexuality is rooted in three main dimensions: biologic, motivational-affective, and cognitive. Human sexunity is mainly relational. Couple satisfaction and premenopausal quality of sexuality are strong predictors also for the quality (and quantity) of postmenopausal sex life (53). Hormonal influence is of importance for the level of sexual arousal and the quality of physical and physiologic response. However, hormones cannot influence the direction of sexual arousal. Optimal estrogenic influence could be considered a very important factor for female sexuality, but it is the androgenic influence that enhances vital energy, libido, and sexual activity both in men and women (54). It should be remembered in this context that peak concentrations of androgens during the menstrual cycle coincides with the estradiol peak at ovulation (55). Administration of combined oral contraceptives but also hormone replacement therapy (HRT) may increase prolactin. Prolactin may inhibit libido via the dopaminergic system in the central nervous system. Progesterone and most progestogens seem to have a mild inhibiting effect. Oxytocin is also of importance. It peaks in plasma at orgasm, and in animals it is responsible for sexual satiety after extended mating. Loss of sexual desire is often a symptom of depression, and it may accompany several chronic diseases both psychiatric and somatic (56). The relation of estrogen treatment to libido is again complex. The vasointestinal peptide (VIP) is a neurotransmitter that is closely linked to variations in sex steroids, and estrogens are a potent stimulator. VIP in turn translates sexual desire into a vascular response that leads to liquid transudation in the vagina (50). By increasing number of glands as well as glandular function, estrogen contributes further to the lubrication of the vagina, thereby rendering dyspareunia less common. On the other hand, systemic estrogen treatment may increase the level of SHBG and thereby decrease the free androgen fraction, which may have a negative impact on libido. But estrogen also has a positive effect on general well-being and mood swings, as well as sleep disturbances. By doing so, a general interest in sex is conceivably increased, but this should be regarded as an indirect effect of the estrogens. Local estrogen treatment in the forms of a vaginal ring, a vaginal tablet, pessaries, or cream improves a local function only. Hence, no effects could be encountered on general well-being or mood. The vaginal lamina propria contains a plexus of large but thin veins. One of the important physiologic response factors for sexual arousal is vasocongestion of the vaginal wall. Normal function of this plexus could well be of importance for vaginal physiology (50). It is also well known that sexually active women have fewer vaginal problems than those who do not have a partner (57). Local stimulatory factors, directly or indirectly, contribute to vaginal integrity.
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Sexual activity is dependent on the psychologic and physiologic integrity of both the male and the female counterpart. Impotence in men gradually increases with age, and erectile dysfunction is a common problem. Unfortunately, men are less prone than women to consult doctors for sexual dysfunction. Chronic prostatitis can often be treated, and other measures to help or ameliorate erectile dysfunction are available today. In order to have a good sex life, a couple must be able to communicate their problems to one another. Understanding of a problem of the counterpart is of great importance to the success of other modalities of treatment of sexual dysfunction both in men and in women. Using the McCoy Sex Scale, Nathorst B66s and Hammar recently reported (58) that a continuous combined regimen containing 2 mg of estradiol and 1 mg of norethisterone acetate significantly improved several parameters of importance for sexual function. The same was true for the preparation tibolone, which is a steroid with weak estrogenic and progestogenic but also androgenic properties. The difference in effect of the two preparations was small. The result of this study conceivably suggests that androgen treatment could be used for improving sexual function in women. Similar results have been obtained also by Sherwin et al. in combination with estrogens and androgens (59). Also tibolone could be used in women with endogenously deprived androgen influence. This not uncommon in oophorectomized women, as the postmenopausal ovary is responsible for a substantial part of female androgen production throughout life. Embarrassing increase of libido is a side effect sometimes encountered in H R T with androgenic progestogens, especially with advancing age. Of interest is also the fact that the stimulatory effect of oxytocin on libido, which has been well documented in animals, also seems to be true for humans. Indeed H R T influences oxytocin; estrogens stimulate and progestogens attenuate estrogen effects (56).
References 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the international continence society. Urology 2003;61:37-49. 2. Culligan pJ, Heit M. Urinary incontinence in women: evaluation and management. Am Faro Physician 2000;62:2433-2444, 2447, 2452. 3. Hunskaar S, Burgio K, Diokno AC, et al. Epidemiology and natural history of urinary incontinence (UI). In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 2nd International consultation on incontinence, 2nd ed. Plymouth: Health Publication Ltd, 2002:165-201. 4. Hannestad YS, Rortveit G, Sandvik H, Hunskaar S. A communitybased epidemiological survey of female urinary incontinence: the Norwegian EPINCONT study.J Clin Epidemio12000;53:1150-1157. 5. Hannestad YS, Rortveit G, Hunskaar S. Help-seeking and associated factors in female urinary incontinence. &and J Prim Health Care 2002;20:102-107.
260 6. Shaw C, Tansey R, Jackson C, Hyde C, Allan R. Barriers to help seeking in people with urinary symptoms. Family Practice 2001;18:48-52. 7. Kinchen KS, Burgio K, Diokno AC, Fultz NH, Bump R, Obenchain R. Factors associated with women's decisions to seek treatment for urinary incontinence. J Women'sHealth 2003;12:687-698. 8. Norton PA, MacDonald LD, Sedgwick PM, Stanton SL. Distress and delay associated with urinary incontinence, frequency, and urgency in women. BMJ 1988;297:1187-1189. 9. Margalith I, Gillon G, Gordon D. Urinary incontinence in women under 65: quality of life, stress related to incontinence and patterns of seeking health care. Quality of Life Research 2004;13:1381-1390. 10. Hu TW. Impact of urinary incontinence on health care costs. J A m Geriatr Soc 1990;38:292-295. 11. Ekelund P, Grimby A, Milsom I. Urinary incontinence: social and financial costs high. Br MedJ 1993;306:1344-1346. 12. Falconer C, Ekman-Ordeberg G, Ulmsten C, et al. Changes in paraurethral connective tissue at menopause are counteracted by estrogen. Maturitas 1996;24:197-204. 13. Falconer C. Metabolic and functional aspects of collagen in stress urinary incontinence. Menopause Rev 1998;3:17- 23. 14. Lincoln J, Burnstock G. Autonomic innervation of the urinary bladder and urethra. In: Maggi CA, ed. Nervous control of the urogenital system. Chur, UK: Harwood Academic Press, 1993:33-68. 15. Andersson KE. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993;45:253- 308. 16. Morrison JBE Sensations arising from the lower urinary tract. In: Torrens M, Morrison JBF, eds.: The physiology of the lower urinary tract. Berlin, Germany: Springer-Verlag, 1987:89-131. 17. DeLancey JO. Structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. Am J Obstet Gynecol 1994;170:1713 - 1720. 18. Tanagho EA, Miller ER. Initiation of voiding. Br J Urol 1970;42: 175-183. 19. Rud T, Andersson KE, Asmussen H, et al. Factors maintaining the intraurethral pressure in women. Invest Uro11980;17:343-347. 20. Petros PE, Ulmsten U. An integral theory of female urinary incontinence. Acta Obstet Gynecol &and 1990;69(suppl):153. 21. Cammu H,Van Nylen M, Blockeel C, Kaufman L, Amy JJ. Who will benefit from pelvic floor muscle training for stress urinary incontinence. Am J Obstet Gyneco12004;191:1152 - 1157. 22. Vierhout ME, Lose G. Preventive vaginal and intra-urethral devices in the treatment of female urinary stress incontinence. Curr Opin Obstet Gynecol 1997;9:325- 328. 23. Thyssen H, Lose G. New disposable vaginal device (continence guard) in the treatment of female stress incontinence. Acta Obstet Gynecol Scand 1996;75:170-173. 24. Grodstein F, Lifford K, Resnick NM, Curhan GC. Postmenopausal hormone therapy and risk of developing urinary incontinence. Obstet Gyneco12004;103:254-260. 25. Moghaddas F, Lidfeldt J, Nerbrand C, Jemstr6m H, Samsioe G. Prevalence of urinary incontinence in relation to self-reported depression, intake of serotonergic antidepressants and hormone therapy in middle-aged women: a report from the Women's Health in the Lund Area Study. Menopause 2005;12:318-324. 26. Hen&ix SL, Cochrane BB, Nygaard IE, et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005;293: 935-948. 27. Samsioe G. Urogenital ageing--a hidden problem. Am J Obstet Gynecol 1998;178:S245- $249. 28. Weiderpass E, Baron JA, Adami HO, et al. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet 1999;353: 1824-1828. 29. Brandberg A, Mellstr6m D, Samsioe G. Low dose oral estriol treatment in elderly women with urogenital infections. Acta Obstet Gynecol &and 1987;33(suppl 140):33-38.
G6RAN SAMSIOE 30. Raz R, Stamm W. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Eng!J Med 1993;329:753-756. 31. Samsioe G, Jansson I, Mellstr6m D, Svenborg A. The occurrence, nature and treatment of urinary incontinence in a 70 year old population. Maturitas 1985;7:335-343. 32. Fantl JA, Cardozo L, McClish DK. Estrogen therapy in the management of urinary incontinence in postmenopausal women: a metaanalysis. First report of the Hormones and Urogenital Therapy Committee. Obstet Gyneco! 1994;1:12-18. 33. Barentsen R, van de Weijer PHM, Schram JHN. Continuous low dose estradiol released from a vaginal ring versus estriol vaginal cream for urogenital atrophy. EurJ Obstet Gyneco11997;71:73-80. 34. Sindberg Eriksen P, Rasmussen H. Low-dose 17 [3-ostradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study. EurJ Obstet GynecolReprod Bio! 1992;44:137-144. 35. Mettler L, Olsen PG. Long-term treatment of atrophic vaginitis with low-dose oestradiol vaginal tab lets. Maturitas 1991; 14:23 - 31. 36. Crona N, Samsioe G, Svanborg C. A double-blind, cross-over study of the effects of orally administered estriol (Triovex) and placebo on lipid and lipoprotein metabolism in postmenopausal women. J Clin Exp Geronto! 1982;4:137-150. 37. Naessen T, Berglund L, Ulmsten U. Bone loss in elderly women prevented by ultralow doses of parenteral 17 beta-estradiol. Am J Obstet Gyneco11997;177:115-119. 38. Klutke JJ, Bergman JA. Hormonal influence on the urinary tract. Uro! Clin North Am 1995;22:629-639. 39. Bhatia NN, Bergman A, Karram MM. Effects of oestrogens on urethral function in women with urinary incontinence. Am J Obstet Gynecol 1989;260:176-181. 40. Iosif CS, Batra SW, Astedt B. Estrogen receptors in the human female lower urinary tract. A m J Obstet Gyneco11981;141:817- 820. 41. Griebling TL, Nygaard IE. The role of estrogen replacement therapy in the management of urinary incontinence and urinary tract infection in postmenopausal women. Endocrinol Metab Clin North Am 1997;26: 347-360. 42. Smith E Estrogens and the urogenital tract. Studies on steroid hormone receptors and a clinical study on a new estradiol releasing vaginal ring. dcta Obstet Gynecol &and Supp11993;157:1-26. 43. Sundberg A, Rosen J, Gustafsson A, Carlstrom K. Cytosol estrogen receptors in the urogenital tissues in stress incontinent women. Acta Obstet Gynecol &and 1981;60:585-586. 44. Ahlstrom K, Sandahl B, Sjoberg B, et al. Effect of combined treatment with phenyl propanolamine and estriol, compared with estriol treatment alone, in postmenopausal women with stress urinary incontinence. Gynecol Obstet Invest 1990;30:37-43. 45. Fantl JA, Cardozo L, McClish DK, Estrogen therapy in the management of urinary incontinence in postmenopausal women: a metaanalysis. First report of the Hormones and Urogenital Therapy Committee. Obstet Gyneco11994;83:12-18. 46. Baldessarini KJ. Drugs in the treatment of psychiatric disorders. In: Gilman et al, eds. The pharmacological basis of therapeutics, 7th ed. New York: McMillan, 1985;387-445. 47. Cardozo LD, Stanton SL. An objective comparison of the effects of parenterally administered drugs in patients suffering from detrusor instability. J Uro11979;122:58-59. 48. Stahl MMS, Ekstr6m B, Sparf B, Mattiasson A, Andersson KE. Urodynamic and other effects of tolterodine: a novel antimuscarinic drug, for treatment of detrusor overactivity. Neurouro! Urodyn 1995;14: 647-655. 49. Forman A, et al. Effects of nifedipine on the smooth muscle of the human urinary tract in vitro and in vivo. Acta PharmacolToxico11978;43:11 - 118. 50. Yarker YE, Goa KL, Fitton A. Oxybutynin: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drug Aging 1995;6:243-262.
CHAPTER 18 Urogenital Symptoms around the Menopause and Beyond 51. Lindholm P, Lose G. Terbutaline (Bricanyl) in the treatment of female urge incontinence. UrolInt 1986;41:158-160. 52. Ghonheim GM, Van Leeuwen JS, Elser DM. A randomized controlled trial of duloxetine alone, pelvic floor muscle training alone, combined treatment and no active treatment in women with stress urinary incontinence. J Uro12005;173:1647-1653. 53. Graziottin A. Sexuality and libido. In: Studd JWW, ed. The year book oft be Royal College of Obstetricians and Gynecologists. London: RCOG Press, 1966:235-244. 54. Levin RJ. The mechanisms of human female sexual arousal. Ann Rev Sex Res 1992;3:1-48. 55. Arimondi C, Vannelli GB, Balboni GC. Importance of olfaction in sexual life: morphofunctional and psychological studies in man. Biorned Res (India) 1993;4:43-52.
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56. MacPhee DC, Johnson SM, Van der Veer MM. Low sexual desire in women: the effect of marital therapy. J Sex Marital Tber 1995;21: 159-182. 57. McCoy NL. Menopause and sexuality. In: Beard MK, ed. Optimizing hormone replacement therapy. Minneapolis: McGraw-Hill, 1995: 32-36. 58. Nathorst-B66s J, Hammar H. Effect on sexual fife: a comparison between tibolone and a continuous estradiol-norethisterone acetate regimen. Maturitas 1997;26:15-20. 59. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. PsychosomMed 1985;47:339-351.
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-~ ( ~ H A P T E R 1~
VulvovaginalComplaints GLORIA BACHMANN
RU-FONG
j.
CHENG
Department of Obstetrics/Gynecology & Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901
Departmentof Obstetrics, Gynecology,& Reproductive Sciences,UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901
ELISHEVA ROVNER Women's Health Institute, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901
I. I N T R O D U C T I O N Estrogen loss from follicular depletion in the menopausal ovary is the major cause of vulvovaginal dysfunction in the older woman, as it accounts for most of the anatomic, cytologic, physiologic, and bacteriologic genital changes that occur. As the overall life expectancy of women increases, so does the amount of time that women will spend in the postmenopausal state of their lives. Although hot flushes and night sweats can dramatically herald the loss of estrogen production by the ovaries, these symptoms usually abate over time regardless of whether or not an acute intervention was utilized. Vulvovaginal symptoms, in contrast to vasomotor disturbances, are usually progressive in nature and do not ameliorate with time from the menopausal transition. Women may start to experience subtle signs of changing estrogen levels, such as vaginal dryness, early in the perimenopausal years. Although atrophic changes of the vagina and vulva are unlikely to resolve spontaneously, they are reversed when estrogen therapy is initiated. Data also suggest that continued sexual exchange may help to maintain vaginal integrity as well. Atrophic changes of the vagina and vulva are the most frequent causes of genital complaints in the menopausal woman, but other causes should be considered. Similar symptoms can be experienced TREATMENT OF THE POSTMENOPAUSAL WOMAN
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by postmenopausal women suffering from infection, trauma, foreign body, inflammatory conditions, and benign and malignant tumors.
II. VULVOVAGINAL C O M P L A I N T S Numerous studies have investigated the prevalence of vulvovaginal symptoms. In an interview study of 500 postmenopausal women attending health centers in Istanbul, Turkey, Oskay et al. found that the most common complaints were urinary incontinence (68.8%), vaginal dryness (43.2%), vaginal itching and infection (36.2%), and difficulty voiding (11.6%). For women who were sexually active, 83.6% reported decrease in sexual desire and 68.8% reported difficulty in sexual arousal (1). Pastore et al., using data from the Women's Health Initiative, a U.S.-based study of postmenopausal women, found the most prevalent urogenital symptoms were vaginal dryness (27%), vaginal irritation or itching (18.6%), vaginal discharge (11.1%), and dysuria (5.2%) (2). In a study of noninstitutionalized Dutch women ages 50 to 75 years, Van Geelen et al. found a 27% overall prevalence of vaginal symptoms. However, only one out of every three women sought help for these symptoms (3). Table 19.1 summarizes the common presentations of vulvovaginal complaints. Copyright 9 2007 by Elsevier,Inc. All rights of reproduction in any form reserved.
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BACHMANNET AL. TABLE 19.1
Common Presentations
Vaginal dryness and irritation Vulvovaginal pruritus Vaginal pressure Malodorous vaginal discharge Dyspareunia Postcoital bleeding Dysuria Urinary frequency and urgency Frequent urinary tract infections Urinary stress incontinence
During the perimenopausal and early menopausal years, vulvovaginal symptoms may be attributed to infectious/ inflammatory, vulvodynia, or psychologic causes. Women may go through several treatment regimens with various antifungal agents, antibiotics, steroids, vitamins, and antidepressants without significant relief of symptoms. Many older women self-medicate with home remedies for relief of symptoms and seek medical assistance only at the point where the vulva is excoriated from chronic scratching. Inflammatory conditions of the vulva, such as contact dermatitis, squamous hyperplasia, or lichen sclerosis, should be ruled out before a hormonal etiology is diagnosed, as these conditions also produce symptoms of severe pruritus, soreness, pain, and dyspareunia like atrophic vaginitis does. Vaginal pressure in the older woman may result from atrophic changes in the genital region alone or in conjunction with uterine prolapse, cystocele, or rectocele. Although vaginal dryness can be bothersome to sexually abstinent women, it is most often voiced as a significant problem in sexually active women who find coital activity uncomfortable because of inadequate lubrication. As the atrophic symptoms worsen over time, pelvic changes due to loss of estrogen become more pronounced, and the symptom complex is referred to as atrophic vaginitis. In addition to vulvar dystrophies, vulvovaginal complaints in postmenopausal women not related directly to estrogen loss also include a variety of systemic and chronic conditions such as diabetes, autoimmune diseases, and urinary incontinence. Table 19.2 summarizes the differential diagnosis for vulvovaginal complaints. An in-depth discussion of vulvar intraepithelial neoplasia (VIN), which can be an important cause of vulvovaginal complaints, can be found elsewhere.
III. E S T R O G E N LOSS Estrogen plays an important role in genital health, especially vulvovaginal health. Estrogen stimulates the maturation of the vaginal epithelium. The mature epithelium produces glycogen, which breaks down to glucose in the vagina. Lactobacilli metabolize this glucose and produce lactic acid, which some data suggest is responsible for the acidic pH of the vagina (4). Lactobacilli have been shown
TABLE 19.2
Differential Diagnosis
Acute: Bacterial vaginosis Candidiasis Pudendal nerve injury Trauma Foreign body Intermediate: Ulcers: Cicatricial pemphigoid Pyoderma gangrenosum Decubitus ulcer Apthous ulcer Papule/nodule/tumor: Bartholin's gland Hidradenoma Apocrine gland Genital wart Pustule/abscess: Bartholin's gland Scabies/pediculosis Chronic: Vulvodynia Dermatoses: Squamous cell hyperplasia Lichen sclerosis Lichen simplex chronicus Lichen planus Chronic eczema Other: Seborrheic dermatitis Psoriasis Contact dermatitis Tinea cruris Medical disorders Psychiatric disorder
to control the growth of vaginal pathogens through the production of hydrogen peroxide (5-6). As the amount of estrogen decreases, the quantity of lactobacilli decrease as well. This in turn leads to a shift of vaginal pH toward alkalinity, which allows for colonization of the vagina by fecal flora and other pathogens. Estrogen loss also leads to a change in both quality and quantity of vaginal secretions. Other changes that occur with estrogen loss include the following (7-11): 9 Vulva loses collagen, adipose, and water-retaining ability. 9 Vagina shortens and narrows. 9 Vaginal walls become thinner and less elastic, lose rogation, and become pale. 9 Vaginal surface becomes friable with petechiae, ulcerations, and bleeding often occurring after minimal trauma. (As this cycle is repeated, adhesions develop between touching surfaces.) 9 Prepuce of clitoris atrophies; the clitoris loses its protective covering and is more easily irritated. 9 Vaginal secretions change in quality and quantity.
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CHAPTER 19 Vulvovaginal Complaints
IV. SEXUAL COMPLAINTS Although the incidence of sexual problems in the general population is high and increases with age, older women and men are often reluctant to seek medical services for their sexual difficulties because they may consider these dysfunctions a natural part of aging (12-14). Although psychologic and sociocultural factors play a role in the cause of sexual problems, in the older population anatomic and physiologic causes of sexual dysfunctions are more common as compared with younger individuals. Dyspareunia, a common sexual problem in the postmenopausal female, is usually related to estrogen loss to the genitalia, with the most common symptom initially being lack of adequate vaginal lubrication with sexual arousal. Over time, dyspareunia, and postcoital bleeding may also result from estrogen loss to the vagina. Loss of sexual desire also becomes an issue for older women, especially those who are surgically menopausal, because of loss of gonadal production of androgens. Women without significant testosterone level changes may also report loss of libido and be reluctant to pursue their sexual desire because of fear of coital pain from local atrophic changes of the vagina (15). In addition, because the postmenopausal vagina has decreased basal levels of vaginal capillary blood flow and oxygen, it does not reach the level of engorgement that the estrogen-primed vagina does during sexual arousal. Estrogen therapy results in an increase in vaginal lubrication, blood flow, and oxygen levels (16-17). In aging women, dyspareunia is usually of the insertional type rather than the thrusting-induced type seen in younger women with pelvic pathology. Hallstrom (18) reported coital pain in 8% of 231 postmenopausal women he studied and Eskin noted that dyspareunia was the second most frequent complaint of postmenopausal women requesting gynecologic services (19). Bachmann et al. (20) found that 30% of postmenopausal women not on hormone therapy experience dyspareunia. Menopausal patients should be given supportive guidance and factual information about changes in sexual function. Even when urogenital factors have been reversed by estrogen therapy, the loss of sexual desire and arousal may persist. Some women, especially those who have been oophorectomized, may benefit from the addition of an androgen to improve sexual desire (21-24). The level of sexual function for many older women will be determined by the activity of their partner. Vulvovaginal changes and associated symptoms in the woman may affect the sexual performance of the man as well. Medical problems and cancer become more prevalent during the later years and the impact of these diseases on sexual function should be addressed by the clinician. When couples experience problems that are chronic and not improved by nonhormonal or hormonal therapy, more extensive counseling and education should be offered. If information on alter-
native sexual activities and practices still do not alleviate the problem, a sex specialist should be considered (25).
V. EVALUATION Although many urogenital complaints in the postmenopausal woman can be attributed to estrogen loss, all complaints should be evaluated with a pelvic examination to rule out other causes. Medical history should include questions about exogenous agents such as soaps, perfumes, powders, deodorants, use of panty liners or perineal pads, spermicides, and lubricants, all of which may cause or exacerbate symptoms. Inquiries should be made into gynecologic history, especially sexual dysfunction during the reproductive years. A review of systems should focus on recurrent urinary tract infections and urinary incontinence, and social history should screen for any handicap that would interfere with sexual activity, as well as a history of domestic violence and substance abuse.
A. Physical Examination A pelvic examination should be performed, which may include diagnostic testing as dictated by findings. Inspection of the vulva may reveal obvious lesions, dermatoses, erythema, lacerations, or inflammation. More subtle findings on the vulva are changes in connective tissue support and turgor, elasticity, dryness, and loss of pubic hair (26). The labia may show shrinkage or fusion of the labia minora, and there may be a change in caliber of the introital opening or stenosis. Vulvar biopsy with a 3- to 5-mm Keyes punch or shave or excisional biopsy should be performed whenever there is an abnormal-appearing lesion or mass (27). Examination should also include inspection of the urethra for a polyp, urethral caruncle, eversion of the urethral mucosa, and ecchymoses. On vaginal examination, the epithelial rugae, color, and moisture can be noted. If there is discharge, the color and odor should be evaluated. Any lesions such as fissures, ecchymoses, telangiectasias, and ulcerations should be documented and evaluated properly, and the total depth of the vagina can be noted. And finally, one should evaluate for any evidence of organ prolapse, such as cystocele, rectocele, and enterocele. An example of atrophic vaginitis is seen in Fig. 19.1 (see color insert). Cervical cancer screening with a Pap test is recommended every 1 to 3 years depending on prior screening results and indMdual risk (28). A wet mount for infection can reliably diagnose bacterial vaginosis, Candida, and Tricbomonas.
B. Evaluation The problem inherent with evaluation of vulvovaginal symptoms is that they are largely subjective and descriptive. Laboratory markers provide some objective measure for
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FIGURE 19.1 This photo demonstrates classic changes in an atrophic vulva, with narrowing of the introitus and inflamed mucosal surfaces.There is also loss of labial and vulvar fullness.
Vulva No Lesions or Discharge Diffuse Changes
Trial of Hormone Therapy
Perineal Hygiene Remove Irritants NonNormonal
3
14 IU/L for the perimenopause. Although estradiol levels 60 pg/ml may nonetheless appear in the presence of markedly elevated FSH levels that suggest ovarian insensitivty. The therapy selected for a major depressive disorder during the perimenopause will depend on the nature and severity of the somatic symptoms and the type of hormone replacement therapy (if present). In perimenopausal women presenting with depression, the presence of distressing signs of estro-
CHAPTER 24 Estrogens and Depression in Women gen deficiency, such as vaginal dryness or hot flushes, should lead to consideration of a trial of hormone replacement as the first approach, unless relative contraindications to estrogen replacement exist. Alternatively, if perimenopausal somatic symptoms are minimal despite laboratory evidence of hypoestrogenism and mood symptoms are moderate to severe, then the choice of hormone replacement versus antidepressant therapy may best be informed by such factors as past personal history of depression, family history of affective disorder, severity of affective symptoms, or the presence of contraindications to estrogen replacement. Finally, clinicians should appreciate that perimenopausal depression may present in the absence of typical perimenopause-related somatic symptoms, such as hot flushes or vaginal dryness. Thus, somatic symptoms are neither necessary nor sufficient for the production of depression during the perimenopause. Moreover, as demonstrated previously, the absence of hot flushes in depressed women who are endocrinologically confirmed to be perimenopausal does not predict the lack of efficacy of estrogen in the treatment of depression. The relationship between the onset of mood symptoms and the initiation of hormone replacement therapy should be determined for at least two reasons. First, mood and behavioral symptoms may appear with inadequate estrogen replacement and can remit with appropriate dosage adjustments or with a change to an alternative form of estrogen replacement. Adjustment of hormone replacement therapy is therefore recommended before adjunctive psychopharmacotherapy is considered. Second, mood and behavioral symptoms may directly result from the hormone replacement therapy. Specifically, cyclic mood and behavioral symptoms have been reported in association with sequential hormone replacement in some (177-179) but not all (180,181) studies and may remit with a change in the replacement regimen from sequential to continuous combination therapy. Alternatively, if addition of progesterone consistently precipitates adverse mood changes, estrogen replacement alone may be attempted if accompanied by appropriate monitoring of the endometrium. Symptoms of depression and loss of libido consequent to ovarian failure may nonetheless be responsive to antidepressant therapy, and this option should be considered (particularly in patients with more severe or disabling symptoms) regardless of the strength of the association between ovarian dysfunction and affective disorder.
IX. FUTURE DIRECTIONS Several new methodologic issues have been identified that may predict a differential response to changes in ovarian hormones (either endogenous or exogenous), including phase of reproductive aging (i.e., late perimenopause or early menopause versus 5 to 10 years postmenopause), presence of
315 menopausal symptoms, the duration of hypogonadism prior to receiving estrogen therapy, and genetic polymorphisms that underlie differences in steroid responsivity. A differential response to estradiol was originally reported by Appleby (182), with depressive symptoms in perimenopausal but not postmenopausal women responding to estradiol therapy under randomized, placebo-controlled conditions (observations confirmed by several recent randomized, controlled trials employing standardized psychiatric diagnostic interviews to establish the presence of depression [170-172]). Similarly, literature reviews and meta-analyses by Yaffe et al. (183) and LeBlanc et al. (184) concluded that the benefits of ovarian hormone therapy on cognitive function were limited to perimenopausal women compared with postmenopausal women and suggested that the beneficial effects of hormone therapy were secondary to the concurrent improvement in perimenopausal symptoms. Similarly, studies in both animals and humans suggest that a short duration of hypogonadism prior to initiation of estrogen therapy is associated with beneficial effects on measures of both cognition (185-187) and atherosclerotic plaque formation and cardiac function (188,189). These findings are consistent with the observed differences in treatment response in perimenopausal or recently menopausal versus older postmenopausal women (the former are more likely to be symptomatic) (128,129). Additionally, these findings introduce the concept of the critical window for the efficacy of estrogen therapy. For example, nonhuman primate studies have shown that initiation of estrogen is associated with cardioprotection when administered immediately after oophorectomy but not after 30 months (approximately 6 human years) (188). This critical window construct has been proposed as an explanation for some of the discrepant findings between the observational studies (many of which included younger, more symptomatic women) and the recent randomized controlled trials in the Women's Health Initiative (WHI) (190,191), which principally included older asymptomatic women (187,192). Finally, independent of stage of reproductive life or duration of hypogonadism, several studies employing both plasma lipid levels and cognitive outcome measures suggest that the effects of sex steroids may be influenced by the presence of polymorphisms in specific steroid receptors (193,194). Pursuit and refinement of these predictors of response to hormone therapy should define the optimal parameters for the use of hormone therapy in the treatment of perimenopausal mood disorders.
References 1. SavageGH. Some mental disorders associatedwith the menopause. Lancet 1893;ii:1128. 2. SavageGH. Some neuroses of the climacteric and summaryof climacteric cases at Bethlem, from July 1, 1888, to June 30, 1893. Tr Med Soc Lond 1893;xvii:31-47.
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319 159. Montgomery JC, Brincat M, Tapp A, et al. Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lancet 1987;1:297-299. 160. Strickler RC, Borth R, Cecutti A, et al. The role ofoestrogen replacement in the climacteric syndrome. PsycholMed 1977;7:631-639. 161. Coope J. Is oestrogen therapy effective in the treatment of menopausal depression? J R Coll Gen Pract 1981;31:134-140. 162. Sherwin BB, Gelfand MM. Sex steroids and affect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology 1985;10:325-335. 163. Sherwin BB. The impact of different doses of estrogen and progestin on mood and sexual behavior in postmenopausal women. J Clin EndocrinolMetab 1991;72:336-343. 164. Sherwin BB. Affective changes with estrogen and androgen replacement therapy in surgically menopausal women. J Affective Disord 1988;14:177-187. 165. Ditkoff EC, Crary WG, Cristo M, et al. Estrogen improves psychological function in asymptomatic postmenopausal women. Obstet Gyneco11991;78:991-995. 166. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry 2001;9:393-399. 167. Schneider LS, Small GW, Hamilton SH, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. AmJ Geriatr Psychiatry 1997;5:97-106. 168. Small GW, Schneider LS, Holman S, et al. Estrogen plus fluoxetine for geriatric depression. AbstrAPA 147th Ann Meeting 1994:203. 169. Amsterdam J, Garcia-Espana F, Fawcett J, et al. Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affective Disord 1999;55:11-17. 170. Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gyneco12000;183:414-420. 171. Soares CD, Almeida OP, Joffe H, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a doubleblind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58:529-534. 172. Morrison MF, Kallan MJ, Ten Have T, et al. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry 2004;55:406-412. 173. Zweifel JE, O'Brien WH. A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology 1997;22:189-212. 174. Nass R, Baker S. Androgen effects on cognition: congenital adrenal hyperplasia. Psychoneuroendocrinology1991; 16:189-201. 175. Saletu B, Brandstatter N, Metka M, et al. Double-blind, placebocontrolled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression. Psychopharmacology 1995;122:321-329. 176. Butler RN, Lewis MI. Late-life depression: when and how to intervene. Geriatrics 1995;50:44-55. 177. Smith RNJ, Holland EFN, Studd JWW. The symptomatology of progestogen intolerance. Maturitas 1994;18:87-91. 178. Hammarback S, Backstrom T, Holst J, et al. Cyclical mood changes as in the premenstrual tension syndrome during sequential estrogenprogestagen postmenopausal replacement therapy. Acta Obstet Gynecol &and 1985;64:393-397. 179. Magos AL, Brewster E, Singh R, et al. The effects of norethisterone in postmenopausal women on oestrogen replacement therapy: a model for the premenstrual syndrome. BrJ Obstet Gynaeco11986;93: 1290-1296. 180. Kirkham C, Hahn PM, VanVugt DA, et al. A randomized, doubleblind, placebo-controlled, cross-over trial to assess the side effects of medroxyprogesterone acetate in hormone replacement therapy. Obstet Gyneco11991;78:93-97.
320 181. Prior JC, Alojado N, McKay DW, et al. No adverse effects of medroxyprogesterone treatment without estrogen in postmenopausal women: double-blind, placebo-controlled, crossover trial. Obstet Gyneco11994;83:24-28. 182. Appleby L, Montgomery J, Studd J. Oestrogens and affective disorders. In: Studd J, ed. Progressin obstetricsandgynaecology. Edinburgh: Churchill Livingstone, 1981. 183. Yaffe K, Sawaya G, Lieberburg I, et al. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998;279:688-695. 184. LeBlanc ES, Janowsky J, Chan BKS, et al. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 2001 ;285:1489-1499. 185. Gibbs RB. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. NeurobiolAging 2000;21:107-116. 186. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County study. JAMA 2002;288:2123-2129. 187. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA 2002;288:2170-2172. 188. Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. CardiovascRes 2002;53:605-619.
RUBINOW ET AL. 189. Brownley KA, Hinderliter AL, West SG, et al. Cardiovascular effects of 6 months of hormone replacement therapy versus placebo: differences associated with years since menopause. Am J Obstet Gynecol 2004; 190:1052-1058. 190. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333. 191. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-2662. 192. Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N EnglJ Med 2003;348: 645-650. 193. Herrington DM, Howard TD, Hawkins GA, et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. NEnglJ Med 2002;346:967-974. 194. Yaffe K, Lui LY, Grady D, et al. Estrogen receptor 1 polymorphism and risk of cognitive impairment in older women. Bid Psychiatry 2002;51:677-682.
SECTION VI
Bone Changes One of the major concerns after menopause is the development of osteoporosis and its sequelae, namely fractures and ensuing disability. Since the last Edition of this text, more options have become available, although some discourage the use of hormonal therapy, which remains an excellent choice in terms of efficacy, for the treatment of osteoporosis because of concerns of various risks. This section aims to cover the major areas of importance for the preservation of bone mass in postmenopausal women. There is clear overlap between chapters, but this may be useful, allowing each chapter to stand alone. First, Robert Lindsay and Felicia Cosman discuss the pathophysiology of bone loss as it occurs throughout life and particularly after menopause. An important new concept is that of bone strength, which is different from bone density per se. Bone mass, which primarily determines bone mineral density, is not a good predictor of fracture risk, while it is envisioned that bone strength may better reflect fracture risk along with other traditional risk factors. This topic will be introduced and discussed by Michael Kleerekoper. Biochemical markers of bone tumors (resorption and formation) have become popular. What is their role, and which markers should be measured? What follows is a discussion of prevention and treatment of osteoporosis in two separate chapters by John C. Stevenson and colleagues and Claus Christiansen and colleagues. While there is clear overlap here, the intent is for the first chapter to focus on prevention and the second on treatment. Finally, because of the importance and high prevalence of osteoarthritis after menopause, the chapter by Tank6 and colleagues attempts to put this in perspective for the reader. This section should also be read with the chapter on collagen by M. Brincat and colleagues, as this relates closely to the issue of bone health.
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.~HAPTER 2.
Pathogenesis of Osteoporosis ROBE R T
LINDSAY
Helen Hayes Hospital, West Haverstraw, NY 10993; Columbia University College of Physicians and Surgeons, New York, NY 10032
FELICIA COSMAN
HelenHayes Hospital, West Haverstraw,NY 10993; ColumbiaUniversityCollege of Physicians and Surgeons, New York, NY 10032
II. PEAK BONE MASS A N D ITS DETERMINANTS
I. I N T R O D U C T I O N Osteoporosis is a disease characterized by reduced bone strength and increased susceptibility to fractures. Loss of bone strength encompasses both reduced bone mass and abnormal bone quality, which includes changes in bone microarchitecture, bone turnover, damage accumulation, and mineralization. Osteoporosis is generally asymptomatic until the clinical sequelae (fractures) occur. These fractures and their consequences cause pain, disability, deformity, and sometimes premature death. At any given level of trauma, an individual with the skeletal changes of osteoporosis is more likely to fracture than an individual with normal skeletal structure. The ability to measure bone mass noninvasively has allowed greater understanding of the pathogenesis of osteoporosis. We know now that the pathophysiology of osteoporosis is multifactorial and includes genetic, endocrine, and lifestyle influences. This chapter briefly reviews the role of these factors in the earlier gain and later loss of bone mass, as well as the cellular mechanisms responsible for the latter. The amount of tissue in the skeleton (bone mass) is the integral of the amount of bone accrued during growth and consolidation (peak bone mass) and the inevitable loss of bone tissue with aging and menopause in women. Therefore both peak bone mass and the rate and duration of bone loss determine fracture risk. Most clinicians consider the process of loss of mass and its accompanying architectural changes to be a prerequisite to the relationship between bone mass and fracture risk in older individuals. TREATMENT OF THE POSTMENOPAUSAL WOMAN
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A. Genetic Factors Bone mass peaks sometime between the late teenage years and early 30s. Peak bone mass (PBM) is primarily determined by genetic factors, although lifestyle and environmental factors also influence the growth of the skeleton. At skeletal maturity, men have approximately 5% to 10% higher bone mass (measured by dual energy x-ray absorptiometry [DXA]) than do women (1). This difference appears around the time of puberty and is due to sexual dimorphism in periosteal bone apposition at puberty. This likely is stimulated by increased androgen production leading to greater periosteal apposition in males, whereas estrogen inhibits this process in females (2). There are also significant racial differences in PBM, with African Americans having 5% to 10% greater bone mass than Caucasians. Numerous genes regulate growth, including skeletal growth and thus peak bone mass and body size. Other genes control skeletal structure and perhaps density. Twin studies suggest heritability estimates for PBM of 50% to 80% for different skeletal sites (3). Many candidate genes have been identified, including those encoding collagen type 1-alpha; the estrogen (ER alpha) and vitamin D receptors; transforming growth factor beta; insulin-like growth factor; apolipoprotein E; interleukins (IL) including IL-1, IL-6, and IL-11; and bone morphogenetic protein. However, there is little consistency regarding the magnitude of importance of each of these genes Copyright 9 2007 by Elsevier,Inc. All rights of reproductionin any form reserved.
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and the extent to which their contribution can be generalized to all populations (4). Recently, a so-called "high bone mass" gene has been identified as a mutation in the lowdensity lipoprotein receptor-related protein (LRP-5) (5). The extent to which this gene contributes to bone density in the general population is not known, although the importance of the pathway has become clear since the description of the relationship in this single family (5). During growth, the effect of genes is modulated by hormonal factors, which in themselves may be genetically mediated. For example, it has been suggested that 33% of the variance in PBM can be explained by variations in endogenous growth hormone production, even when adjusted for height (6).
B. Nutrition When Charles Dent said, "Senile osteoporosis is a pediatric disease," he meant that failure to achieve adequate PBM increases the risk of osteoporosis in later life. Nutrition is an important, modifiable factor that determines PBM. Several nutrients play key roles in skeletal development, including protein (calories), calcium, phosphorus, and vitamin D. Calcium is perhaps the nutrient that is commonly deficient in the diet of children and adolescents in the United States. Higher lifetime calcium intakes are inversely correlated with hip fracture rates, and milk consumption in youth is related to bone density in young adult women and men (7).
C. Exercise Bone adapts to the loads that are applied to it (Wolff's Law), and higher mechanical loads lead to increased bone density. This is particularly true during childhood and growth (8). High-impact forces applied to the skeleton appear to confer the greatest benefit. Weight-bearing exercise is associated with higher PBM in both genders. Gymnasts have greater bone density than runners, whereas swimmers and cyclists have lower bone density (9). In a recent study (10), which avoided the usual bias introduced by recruiting volunteers, a general, school-based exercise program for 2 years increased bone density and bone size in 7- to 9-yearold girls.
D. Menstrual Function Achieving maximal PBM requires a normal transition through puberty, and inadequate pituitary-ovarian function in teenage years adversely affects attainment of PBM. Reduced bone mass has repeatedly been demonstrated in women with amenorrhea due to different primary condi-
tions, including anorexia nervosa and hyperprolactinemia. This deficit is partially reversible if normal ovarian function is resumed, but the longer the amenorrhea, the less likely that bone mass can be completely regained (11). Excessive exercise with amenorrhea is also associated with lower bone mass than in eumenorrheic athletes. Depo medroxyprogesterone acetate (MPA), a commonly used birth control method that suppresses endogenous estrogen production, appears to be associated with a decrease in bone mass, which in some situations may be reversible (12).
III. THE PATHOGENESIS OF BONE LOSS Age-related bone loss is a universal phenomenon and occurs at almost all skeletal sites (except the skull, for example) in all races and in both genders. However, the cellular mechanism underlying bone loss differs between the sexes. The rate of age-related bone loss is influenced by factors similar to those modifying skeletal growth: genetic, endocrine, and environmental factors. The effects of each factor are mediated through modulation of the bone remodeling cycle.
A. Bone Remodeling and the Cellular Basis of Bone Loss Bone remodeling describes the process whereby old bone is continuously replaced by new tissue. The balance between the amount of bone removed and the amount that replaces it, when integrated over a number of remodeling cycles, determines whether there is net loss or gain of bone tissue. Bone remodeling is accomplished primarily by osteoclasts and osteoblasts, which together with other accessory cell types are called bone remodeling units (BRUs) (13). The three-dimensional geometry of the completed units of bone, called osteons or packets, is somewhat different in cortical and cancellous bone (Figs. 25.1 to 25.3) but the cellular processes are essentially the same. The first event to occur in the remodeling process is activation. During activation (occurring about 6 times per minute in the skeleton), mononuclear osteoclast precursors, which are derived from circulating monocytes, are attracted to the surface of bone and fuse to form multinucleated osteoclasts. Remodeling may be both a random and a targeted event. One enduring hypothesis argues that osteocytes act as mechanosensor cells that detect changes in the mechanical and perhaps chemical properties of the surrounding bone matrix and communicate them to the lining cells on the surface (14). Lining cells then appear to retract, leaving denuded bone surface that chemo-attracts osteoclast precursors. The differentiated osteoclasts degrade both the organic and inorganic components of the matrix. In
CHAPTER 25 Pathogenesis of Osteoporosis
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FIGURE 25.1 Cross-sectionaldiagrams of evolving BRU in cancellous bone (upper) and cortical bone (lower).The arrowindicates the direction of movement through space. Note that the cancellous BRU is essentially one-half of the cortical BRU. (Reproduced with permission from Dempster DW. New concepts in bone remodeling. In: Seibel MJ, Robins SP, Bilezikian JP, eds. Dynamics of bone and cartilage metabolism. San Diego: Academic Press, 1999:261-273.)
FIGURE25.2 An intact bone packet in human cancellous bone and an intact Haversian systemin human cortical bone. Note the osteons that have been partially replaced by prior remodelingevents. (Reproducedwith permissionfrom Dempster DW. Bone remodeling.In: Coe FL, FavusMJ, eds. Disorders of bone and mineral metabolism, ed 2. Philadelphia, Lippincott,Williams & Wilkins, 2002:315-343.)
cancellous bone and on the endosteal and periosteal surfaces of cortical bone, osteoclasts move along the bone surface, leaving a trench behind them. In cortical bone, osteoclasts tunnel through the bone, creating a cylindric hole. Formation, activation, and activity of osteoclasts are regulated by local cytokines such as receptor activator of nuclear factorkappa beta ligand (RANKL), IL-1 and IL-6, and colonystimulating factors (CSFs), as well as by systemic hormones such as estrogens, parathyroid hormone, 1,25-dihydroxyvitamin D3, and calcitonin (15). The final common pathway for osteoclast activation is through RANK, the cognate receptor for RANKL, which is a member of the tumor necrosis factor (TNF) family. RANKL is secreted by osteoblasts and mononuclear cells and interacts with RANK, its recep-
tor, expressed on osteoclast precursor cells and other marrow stromal cells. The R A N K L / R A N K interaction promotes the differentiation, activation, and prolonged survival of osteoclasts. Osteoprotegerin (OPG), a member of the superfamily of T N F receptors, is a decoy receptor for RANKL and is also secreted by osteoblasts. The binding of RANKL to O P G results in inhibition of the differentiation and activity of osteoclasts. The rate of bone remodeling is ultimately controlled by the relative amounts of RANKL and O P G secreted close to the surface of bone. The resorption phase is followed by the reversal phase. The osteoclasts and mononucleated resorbing cells die by apoptosis and are replaced by osteoblasts as the cycle progresses into the formation phase (16). Teams of osteoblasts
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FIGURE 25.3 Scanningelectron micrograph of a trabecular plate in hu-
man iliac cancellous bone. Osteoclasts have perforated the plate from the top and, a few millimeters to the left, from underneath. (Reproducedwith permission from Dempster DW. Bone remodeling.In: Coe FL, FavusMJ, eds. Disorders of bone and mineral metabolism, ed 2. Philadelphia, Lippincott, Williams & Wilkins, 2002:315-343.) follow osteoclasts as they traverse the bone surface or tunnel through the cortex. On the bone surfaces, they refill the trench with a new unit of lamellar bone, which is referred to as a hemi-osteon or, more commonly, a packet (see Fig. 25.2). Within the cortex, the osteoblasts refill the tunnel dug by osteoclasts and deposit concentric lamellae, starting on the outer wall and working inward. As a result, cross-sections of cortical osteons, or Haversian systems, are reminiscent of a cross-section of the trunk of a tree. Women experience slight but gradual trabecular thinning from the time of PBM until menopause, when an abrupt acceleration in the rate of bone loss occurs. This accelerated loss persists for about 5 to 10 years (Fig. 25.4) and is accompanied by a dramatic increase in bone turnover rate (17). The rapid bone loss experienced after menopause is due to
FIGURE 25.4 The relationship between cancellous bone volume and age in the human ileum in men (open circles) and women (closed circles, stippled). (Reproduced with permission.)
LINDSAY AND COSMAN
enhanced osteoclast activity and an overall increase in the rate of remodeling. An increased number of resorption sites are active per unit time, and the osteoclasts dig farther into the trabeculae and often perforate and ultimately remove them (Fig. 25.5). In contrast, in men aging results in a gradual decrease in the efficiency with which the osteoblasts refill the resorption cavities. Consequently, the thickness of the cancellous bone packets gradually decreases, which in turn leads to trabecular thinning with a linear reduction in cancellous bone volume with age (see Fig. 25.4). Although the individual trabeculae are thinner, trabecular connectivity is generally preserved (18). The consequence is a greater age-related loss of trabecular number and connectivity with age in women compared with men. The reason why osteoclasts gain the ability to perforate trabecular plates after menopause is thought to be due to an increase in their life span as a result of decreased estrogen levels and an accompanying increase in RANKL production, with perhaps a concomitant reduction in O P G production (19). Estrogen inhibits osteoclast production and promotes osteoclast apoptosis, whereas RANKL stimulates osteoclast recruitment and prolongs osteoclast life span. Bone loss by trabecular elimination is considerably more harmful to bone strength than loss of an equivalent amount of bone tissue through trabecular thinning (20). A significant increase in resorption cavity depth has been observed in early postmenopausal women, which together with simultaneous osteoclastic attack from both sides may contribute to complete trabecular perforation and elimination. Alternatively, particularly destructive onesided resorption can also perforate trabecula (see Figs. 25.5 and 25.6). At weight-bearing sites, including the vertebral bodies and the hip, trabeculae have a clear orientation with the weight-bearing struts aligned in the direction of the primary axis of loading. These trabeculae are in turn supported by trabeculae oriented perpendicular to the load axis, serving as
CHAPTER 25 Pathogenesis of Osteoporosis
FIGURE 25.5
OP
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Scanningelectron micrographs of human cancellous bone.
Rx
/
FIGURE25.6 Theoreticexplanationfor the bone fragilityassociatedwith enhanced remodeling and why treatment with an agent that reduces bone turnover may be beneficial without changing bone mass significantly.In a normal subject (N), the two resorption cavities do not represent a threat to the stability of the trabecula because it is stabilized by the two horizontal trabeculae. In an osteoporotic individual (OP), the same two cavities significantly increase the chance of failure at these stress-concentrating loci. Reducing the number of resorption cavitiesby treatment (Rx) decreasesthe risk of failure.
cross-ties. Several studies have shown that preferential loss of these cross-ties occurs with aging (21), with consequent serious penalties for strength. According to Euler's theorem, the buckling load of a weight-bearing trabecula decreases inversely with the square power of its unsupported length. The loss of two cross-ties will triple the effective length of the trabecula but will decrease the load that the trabecula can support by a factor of nine. Thus, small changes in tissue mass can have devastating consequences for strength when the losses are strategically placed. In support of this concept, Ciarelli et al. (22) showed that trabecular bone in the proximal femur of women with hip fracture has significantly greater anisotropic (oriented) structure than controls, even
when the samples were matched for the total cancellous bone mass. The greater anisotropy was thought to be the result of preferential loss of cross-ties. Several studies have confirmed compromised cancellous bone microarchitecture in both men and women with osteoporosis-related fractures when compared with controls with the same bone mass (23). The loss of horizontal trabeculae leaves the load-bearing struts vulnerable to failure of a process that is compounded by the increased bone turnover that occurs after menopause. Each resorption cavity acts to concentrate stress at that trabecular site, creating a weak point and increasing the probability of failure at that site (24). This is analogous to filing a tiny scratch on a glass rod prior to breaking it. The mass of the rod barely changes, but when force is applied, the rod dutifully breaks exactly at the location of the scratch. The rapid reduction in the number of stress-concentrating resorption cavities by antiresorptive agents may be the explanation for the early decrease in fracture risk that is disproportionately greater than that predicted by the improvements in bone density. With aging, long bones increase in diameter, but the cortices become thinner. This is the end product of small differences in the amount of bone removed and formed in each remodeling cycle. This remodeling balance is negative on the inner endosteal surface but positive on the outer periosteal surface. Furthermore, more bone is lost at the endosteal surface than is gained at the periosteal surface. Although these differences may be quite small within each remodeling unit, the effects accumulate with age. Consequently, the endosteal surface drifts outward at a greater rate than the periosteal surface and, as a result, the cortex gets thinner. With age, women lose more bone from the endosteal surface than do men (25), and men may compensate for endosteal loss by laying down more bone on the periosteal surface (2). The result is a greater decline in the cross-sectional moment of inertia of long bones with age in women and consequently a
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greater increase in fracture risk. Within the cortex, other agerelated changes magnify the effect of this cortical drift phenomenon, including a decline in the area occupied by circumferential lamellar bone, an increase in the number of Haversian systems and their fragments, a decrease in the radial closure rate of osteons, an increase in the diameter of the Haversian canals, a decrease in osteon wall thickness, and an increase in the number of resorption cavities that are aborted in the reversal phase and remain unfilled. Each of these contributes to an increase in cortical porosity that occurs to a greater extent in women than men (26). As with trabecular thinning in cancellous bone, this occurs mostly through an age-related decline in osteoblast recruitment and/or activity.
IV. E S T R O G E N DEFICIENCY Driving the changes that occur in remodeling is the transition from the estrogen-replete premenopausal state to the relatively estrogen-deficient postmenopausal state. Bone loss accelerates after a natural or surgical menopause. Some studies have shown that the rate of loss is dependent on the remaining estrogen supply. Rapid bone loss may continue for some years in most postmenopausal women but eventually slows as surfaces are lost. Bone remains sensitive to estrogen until old age, and estrogen intervention slows bone loss and reduces fracture risk. It appears as though the estrogen effect is mediated through modulation of RANKL and OPG, with evidence that estrogen downregulates RANKL and upregulates OPG.
protein has been found to reduce complications following hip fracture (30). Some elderly individuals may be deficient in intake of phosphate, which may also contribute to bone loss (31). In people who are elderly or chronically ill or who have malabsorption, low magnesium levels may accelerate bone loss (32). Several studies show a positive association between vitamin C and bone mass (33), and vitamin K intakes may be related to bone density levels and fracture risk (34). Excess vitamin A may cause bone loss, and high intakes have been associated with a twofold increase in the risk of hip fracture in some studies (35). Elevated serum homocysteine, perhaps associated with vitamin B deficiencies, may be associated with bone loss and increased fracture risk (36).
C. Alcohol and Smoking Excessive alcohol consumption increases the risk of osteoporosis by inhibiting bone formation and results in an increased risk of hip fracture (37). Nutritional deprivation in alcoholics contributes to the toxic effects of alcohol on bone and other organ systems. Alcohol abuse also increases the risk of falling. Smoking exerts a toxic effect on osteoblasts, leads to premature menopause, and reduces the production while accelerating the degradation of estrogen. As a result, smokers often have low bone mass (38). Smokers also generally weigh less than nonsmokers and are generally less physically active, further increasing the risk of fracture.
D. Physical Activity A. Nutrition: Calcium and Vitamin D It is clear that an adequate calcium intake throughout life is important for skeletal health. Some studies have shown that calcium plus vitamin supplementation reduces fracture risk among older individuals, and maintaining total calcium intake between 1000 and 1500 mg/day is prudent (27). Vitamin D deficiency or insufficiency (25-hydroxyvitamin D levels less than 20 ng/mL) is believed to play a role in fracture pathogenesis as a result of increasing rates of bone loss and possibly contributing to muscle weakness, impaired balance, and thereby increased risk of falling (28). A recent study suggested that approximately 50% of patients receiving therapy for osteoporosis had suboptimal circulating levels of 25-hydroxyvitamin D (29).
B. Other Nutritional Factors Low-protein intake can have deleterious effects in the elderly. Hip fracture patients are frequently malnourished with inadequate protein intake, and supplementation with
Immobilization results in rapid and profound bone loss. In contrast, weight-bearing and resistance exercise are associated with increased bone mass or slowed rate of bone loss (39). Lifetime physical activity is associated with reduced risk of fracture (40).
E. Chronic Diseases and Medications Many chronic diseases or conditions are associated with enhanced bone loss and increased risk ofosteoporosis (41,42). These include endocrine diseases (e.g., hyperthyroidism and hyperparathyroidism), rheumatologic conditions (e.g., rheumatoid arthritis and systemic lupus), chronic lung disease, gastrointestinal conditions associated with malabsorption (e.g., celiac disease or inflammatory bowel disease), eating disorders, neurologic diseases (e.g., Parkinson's disease, multiple sclerosis, and spinal cord injury), hematologic/oncologic diseases (most notably multiple myeloma), and organ transplantation. Bone loss associated with these diseases is due to a variety of reasons, including medication use, nutritional factors, diminished ability to perform physical activity, and
CHAPTER 25 Pathogenesis of Osteoporosis factors that directly affect bone remodeling. In addition, certain medications are known to alter bone metabolism and have detrimental effects on the skeleton. Glucocorticoids, for example, profoundly inhibit bone formation by p r o m o t i n g osteoblast apoptosis. T h e y also reduce calcium absorption, increase renal calcium excretion, and have multiple other adverse effects on bone and mineral metabolism. O t h e r medications that adversely affect the skeleton include antiepileptics, excessive thyroid hormone, chemotherapy, and gonadotropin-releasing h o r m o n e antagonists.
E Falling T h e majority of osteoporosis-related fractures are secondary to a fall (43,44). Approximately 30% of free-living (i.e., noninstitutionalized) elderly individuals fall at least once per year, and this n u m b e r is even higher in institutionalized individuals. T h e incidence of falls increases with age and, prior to age 70, is greater in w o m e n than men. A history o f falling greatly increases the risk o f subsequent falls. Risk factors for falling can be separated into intrinsic and extrinsic factors. Intrinsic factors include underlying disorders that impair balance and ambulation and may be associated with the clinical syndrome o f frailty. External factors include the use of medications such as anxiolytics, narcotics, antipsychotics, and hypoglycemic, hypotensive, and diuretic agents; alcohol abuse; and environmental hazards. T h e r e is also a strong association between inadequate vitamin D intake/production and fall risk (45).
References 1. Looker AC, Wahner HW, Dunn WL, et al. Proximal femur bone mineral levels of U.S. adults. OsteoDorosInt 1995;5:389-400. 2. Seeman E. Periosteal bone formation--a neglected determinant of bone strength. N EnglJ Med 2003;349:320-323. 3. Arden NK, Baker J, Hogg C, et al. The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res 1996;11:530-534. 4. Eisman JA. Genetics of osteoporosis. Endocr Rev 1999;20:788-804. 5. Little RD, Recker RR, Johnson ML. High bone density due to a mutation in LDL-receptor-related protein 5. N EnglJ Med 2002;347:943944. 6. Rissell-Aulet M, Shapiro B, Jaffe CA, et al. Peak bone mass in young healthy men is correlated with the magnitude of endogenous growth hormone secretion. J Clin Endcrinol Metab 1998;83:3463-3468. 7. Welten DC, Kemper HCG, Post GB, Van Staveren WA. A metaanalysis of the effect of calcium intake on bone mass in young and middle aged females and males. J Nutr 1995;125:2802-2813. 8. Wallace BA, Cumming RG. Systematic review of randomized trials of the effect of exercise on bone mass in pre- and postmenopausal women. Calcif Tissue Int 2000;67:10-18. 9. Jaffe DR, Snow-Hatter C, Connolly DA, et al. Differential effects of swimming versus weight-bearing activity on bone mineral status of eumenorrheic athletes. J Bone Miner Res 1995;10:586-593.
329 10. Linden C, Ahlborg H G, Besjakov J, Gardsell P, Karlsson MK. A school curriculum-based exercise program increases bone mineral accrual and bone size in prepubertal girls: two year data from the pediatric osteoporosis prevention (POP) study. J Bone Miner Res 2006;21: 829-835. 11. Rencken ML, Chesnut CHIII, Drinkwater BL. Bone density at multiple skeletal sites in amenorrheic athletes. JABdA 1996;276:238-240. 12. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med 2005 159:139-144. 13. Dempster DW. Bone remodeling. In: Coe FL, Favus MJ, eds. Disorders of bone and mineral metabolism, ed 2. Philadelphia: Lippincott, Williams & Wilkins, 2002:315-343. 14. Rubin J, Rubin C, Jacobs CR. Molecular pathways mediating mechanical signaling in bone. Gene 2006;367:1-16. 15. Blair HC, Athanasou NA. Recent advances in osteoclast biology and pathological bone resorption. Histol Histopatbo12004;19:189-199. 16. Parfitt AM. Bone forming cells in clinical conditions. In: Hall BK, ed. Bone, vol 1: The osteoblast and osteocyte, Caldwell, NJ: Telford Press, 1990:351-429. 17. Recker R, Lappe J, Davies KM, Heaney R. Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients. J Bone Miner Res 2004;19:1628-1633. 18. Weinstein RS, Hutson MS. Decreased trabecular width and increased trabecular spacing contribute to bone loss with aging. Bone 1987;8: 137-142. 19. Eghbali-Fatourechi G, Khosla S, Sanyal A, et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003;111:1221-1230. 20. Guo XE, Kim CH. Mechanical consequence of trabecular bone loss and its treatment: a three-dimensional model simulation. Bone 2002;30:404-411. 21. Thomsen JS, Ebbesen EN, Mosekilde LI. Age-related differences between thinning of horizontal and vertical trabeculae in human lumbar bone as assessed by a new computerized method. Bone 2002;31: 136-142. 22. Ciarelli TE, Fyhrie DP, Schaffler MB, Goldstein SA. Variations in three-dimensional cancellous bone architecture of the proximal femur in female hip fractures and controls. J Bone Miner Res 2000;15:32-40. 23. Dempster DW. Bone microarchitecture and strength. Osteoporos Int 2003;14:54-56. 24. Parfitt AM. Use ofbisphosphonates in the prevention of bone loss and fractures. Am J Med 1999;91:42S-46S. 25. Riggs BL, Melton LJ III, Robb RA, et al. Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites.J Bone Miner Res 2004;19:1945-1954. 26. Bousson V, Peyrin F, Bergot C, et al. Cortical bone in the human femoral neck: three-dimensional appearance and porosity using synchrotron radiation. J Bone Miner Res 2004;19:794-801. 27. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N EnglJ Med 1992;327: 1637-1642. 28. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005;293:2257-2264. 29. Holick MF, Siris ES, Binldey N, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005;90:3215-3224. 30. Munger RG, Cerhan JR, Chiu BC. Prospective study of dietary protein intake and risk of hip fracture in postmenopausal women. Am J Clin Nutr 1999;69:147-152. 31. Heaney RP. Phosphorus nutrition and the treatment of osteoporosis. Mayo Clin Proc 2004;79:91-97.
330 32. Durlach J, Bac P, Durlach V, et al. Magnesium status and aging: an update. Magnes Res 1998;11:25-42. 33. Hall SL, Greendale GA. The relationship of dietary vitamin C intake to bone mineral density. Results from the PEPI study. CalcifTissue Int 1998;63:183-189. 34. Booth SI, Tucker KI, Chen H, et al. Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr 2000;71:1201-1208. 35. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287: 47-54. 36. McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004;350: 2042-2049. 37. Felson DT, Kiel DP, Anderson JJ, Kannel WB. Alcohol consumption and hip fractures. The Framingham Study. Am J Epidemio11998;128: 1102-1110. 38. Bainbridge KE, Sowers M, Lin X, Harlow SD. Risk factors for low bone mineral density and the 6-year rate of bone loss among premenopausal and perimenopausal women. OsteoporosInt 2004;15:439-446.
LINDSAY AND COSMAN 39. Gregg EW, Pereira MA, Caspersen CJ. Physical activity, falls, and fractures among older adults: a review of the epidemiologic evidence. JAm Geriatr Sac 2000;48:883-893. 40. Jaglal SB, Kreiger N, Darlington G. Past and recent physical activity and risk of hip fracture. Am J Epidemiol 1993;138:107-118. 41. Kelman A, Lane NE. The management of secondary osteoporosis. Best Pract Res Clin R&umato12005;19:1021-1037. 42. Boling EP. Secondary osteoporosis: underlying disease and the risk for glucocorticoid-induced osteoporosis. Clin Ther 2004;26:1-14. 43. Close JC, Lord SL, Menz HB, Sherrington C. What is the role of falls? Best Pract Res Clin Rbeumato12005;19:913-935. 44. Gregg EW, Pereira MA, Caspersen CJ. Physical activity, falls, and fractures among older adults: a review of the epidemiologic evidence. JAm Geriatr Soc 2000;48:883-893. 45. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. JAMA 2004;291:1999-2006.
2HAPTER 2(
Assessment of Bone Density and B one S trength MICHAEL
KLEEREKOPER
St. Joseph Mercy Hospital, Ann Arbor, MI; Department of Internal Medicine and Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; St. Joseph Mercy Reichert Health Center, Ypsilanti, MI 48197
I. I N T R O D U C T I O N
the body (5). From attainment of this peak bone mass until menopause, BMC is constant, although some studies suggest a very slight decrease in BMC during the few years prior to menopause (6,7). At menopause there is a marked loss of BMC, which continues for approximately 5 to 7 years. At that time the rate of loss slows down to a rate known as age-related bone loss, a phenomenon that appears to be universal in all primates, both male and female. As BMC decreases, bone strength diminishes and risk of fracture increases. Fractures resulting from this low BMC are termed oste@orosis-relatedfractures. In general these are low- or minimal-trauma fractures, which are defined as fractures occurring after trauma equal to or less than a fall from a standing height. Although a decrease in BMC is the root cause of osteoporosis and osteoporosis-related fractures, it has become accepted practice in clinical medicine to report bone mineral density (BMD). Only Q C T can measure BMD directly because it is a three-dimensional (3D) technology. However, access to Q C T is limited, and few epidemiologic studies or clinical trials have been performed using Q C T (8-10). DXA is a two-dimensional (2D) technology such that only "areal" BMD can be measured. To obtain this areal BMD, the area of the skeleton through which the x-ray beams are passed is computed and BMC is divided by area results in areal BMD. While not strictly a physiologic measurement because density is by definition a 3D phenomenon, DXA is more widely available and has been the preferred method for epidemiologic studies, controlled clinical trials, and the everyday practice of medicine. Q CT is re-
Each day in the United States, 2500 to 3500 women become menopausal. Unless treated with estrogen (with or without progestin) for control of menopausal symptoms, each of these women will experience accelerated bone loss for about 5 to 7 years. After that time, the bone loss continues but at a slower rate. The consequence of this bone loss, if left unrecognized or untreated, is that 50% of these women are likely to develop one or more osteoporosisrelated fractures before the end of life (1). These fractures result directly from progressive loss of bone mass and bone density and loss of bone strength due to the microarchitectural changes that accompany the bone loss. This chapter details the approaches to assessing bone density and bone strength.
II. B O N E MASS A N D B O N E M I N E R A L DENSITY Bone mass, or more precisely, bone mineral content (BMC) can be measured directly with radiographic techniques, the most common methods being quantitative computerized tomography (QCT) and dual-energy x-ray absorptiometry (DXA). BMC measured by these methods has been shown to correlate well with directly measured bone ash weight (2-4). BMC increases with age until about age 25, although there are minor differences in the age at which this peak bone mass is reached at different skeletal sites in TREATMENT OF THE POSTMENOPAUSAL WOMAN
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332 stricted to radiology suites, whereas DXA is most often placed in physicians' offices. Despite the physical shortcomings of DXA, this method of assessing BMD has been demonstrated to correlate extremely well with fracture risk in untreated populations, with fracture risk doubling for each standard deviation decrease in BMD, no matter which skeletal site is measured (11,12). DXA-measured BMD varies markedly from site to site in the skeleton (13-16). The most common sites measured are the forearm (both radial midshaft, which is predominantly cortical bone, and the ultradistal radius, which is predominantly cancellous bone and a common site of fracture), the lumber spine from the first to the fourth lumbar vertebrae (L1-L4), and the proximal femur. Within the proximal femur, precise measurements can be made at the femoral neck (a very common site of hip fracture), the intertrochanteric region (another common site of fracture), and the total proximal femur. At each of these sites, BMD is normally distributed around a mean value. The distribution around the mean value at the radial midshaft is quite narrow, whereas it is quite broad at the femoral neck. To obviate these site-to-site differences in BMD and the range of BMD in healthy young premenopausal women (ages 25 to 49 in general), it has become common practice to report DXA BMD results in terms of standard deviations around the mean. By convention, these standard deviations are expressed as a T-score. In groups of women, T-scores at the different measurement sites are more closely correlated with each other than the raw BMD score. In the early 1990s a committee of experts convened by the World Health Organization (WHO) reviewed all the (then) available data and determined that the prevalence of a Tscore of-2.5 or lower closely approximated the prevalence of osteoporosis-related fractures in the community (17). They concluded that a T-score at -2.5 or below should be defined as osteoforosis (in much the same way that cut-points are used to define hypertension or hyperlipidemia). For reasons that are less clear, normal BMD was defined as a T-score of-1.0 or above. Women with a T-score between -1.0 and -2.5 were considered to have low bone mass. It is equally unclear why they chose to provide an alternative term, osteofenia, for this low bone mass group. In practice, osteofenia has become the more commonly used of these two terms. Because of site-to-site differences in BMD and T-scores, an individual subject may be found to have normal BMD at one site, low bone mass at another site, and osteoporosis at still another site. This is almost an inevitable consequence of skeletal anatomy and the indirect method of measuring BMD using DXA. Regrettably this has resulted in considerable confusion, such that many (probably most) bone density reports provide the patient with more than one diagnosis. This is an incorrect use of the technology, as a patient can only have one diagnosis, which should be based on the
MICHAEL KLEEREKOPER
lowest T-score obtained during the DXA study. It is this information that provides the most reliable DXA-based prediction of fracture risk. For older women (65 +) there is good epidemiologic data to develop a site-specific fracture risk (18). For women in the early menopausal years, this is not yet possible. The average age of menopause is close to 50, and the average age at which clinicians begin to see an increase in hip fracture rates is close to 75--an interval of 20 to 25 years between menopause and hip fracture. As the technology for hip DXA has been available for less than 20 years, it is simply not yet possible to have any confidence about site-specific fracture risk in younger postmenopausal women. As BMD decreases with advancing age, so do osteoporosisrelated fracture rates. However, the actual population of women over age 70 is substantially less than the population of women ages 50 to 70, and the incidence of osteoporosisrelated fractures is in fact greater in this younger group of women. In the first 10 years postmenopause, fracture of the distal forearm (CoUes' fracture) is most common; during the next decade, vertebral fracture is most common.
A. In Whom Should BMD Be Measured? Most professional organizations dealing with either osteoporosis as a disease or postmenopausal women as a group have developed clinical guidelines to address this question. The reader is advised to use the guidelines prepared by his or her professional organization. In general, the differences between these guidelines are small. In the United States, both Medicare and the United States Preventive Services Task Force (USPSTF) have determined that it is practical and cost effective to measure BMD in all women aged 65 or older and to obtain repeat measurements at 2-year intervals (19). The USPSTF recognizes that many risk factors accelerate bone loss in women under age 65, and each of the professional organizations that have developed guidelines has a similar approach. Although the selected risk factors vary among guidelines, the philosophy is that the more risk factors that are present, the earlier should the first BMD study be performed. The most compelling risk factor is a history of a previous fracture as an adult. Intellectually, this would seem to apply only to those who sustained a minimal trauma fracture, but in actuality this dictum seems to apply even to traumatic fractures. Other commonly applied risk factors include a family history of osteoporosis with fracture, premature menopause or a premenopausal history of prolonged amenorrhea, use of glucocorticosteroids, and cigarette smoking. A number of diseases associated with malnutrition or malabsorption are also important risk factors for fracture and indications for a BMD study (1). BMD change at menopause is rapid, but fracture risk is low such that if a decision is made to measure BMD at
CHAPTER 26 Assessment of Bone Density and Bone Strength menopause, a repeat study should not be performed for 2 to 3 years (20). As women age, the rate of bone loss slows but the risk of fracture increases. Here too the combination of rate of loss and risk of fracture is such that an interval of 2 years between serial studies is recommended (20). It is appropriate to make a strong comment about how serial studies should be performed. There are three manufacturers of DXA in the United States, and each has developed a different approach to optimizing B M D measurement on its system. Accordingly, the same person measured on the same day on each of these three DXA instruments is very likely to have minor differences in B M D and T-score. Because changes in B M D over time can be quite small, even in the treated state, considerable confusion and both patient and physician distress is the likely outcome if serial studies are performed at different facilities. This is true, albeit to a lesser extent, if the two studies were performed on exactly the same DXA make and model but at two different locations. Given the movement of people around the country and the changing locations dictated by health insurers, this will be a persistent problem, and at present, there is no recommended or accepted solution. It remains important for the physician (who may have no control over where the serial study is performed) to be aware of this issue and take it into consideration when discussing results with the patient. Another pitfall to consider when interpreting a DXA result is that it is a 2D technique that tends to "shortchange" slender women. Although it has been demonstrated in epidemiologic studies that "thinness" is indeed a risk factor for fracture, this generally refers to thinness that is disproportionate to the woman's height. Short, slender women will most likely have a low BMD, but that value will overestimate their risk of fracture. One more consideration is that the W H O criteria for "diagnostic" labeling based on B M D does not match most standard "laboratory" criteria. It is usual to label all values within 2 standard deviations of the mean value as being a normal result. The W H O opted to label values between -1.0 and-2.5 as abnormal. This ignores the statistics in that 16% of all normal subjects will be between 1 and 2 standard deviations below the mean. If the W H O criteria are strictly applied, 16% of normal woman would be categorized as having low bone mass or "osteopenia" (20). Caution is advised when applying this term to patients, many of whom regard osteopenia as a frightening condition with imminent risk of fracture.
B. How to Best Use DXA in Clinical Practice The simplest approach is to regard B M D as a risk factor for an adverse health outcome (fracture), just as a lipid profile is regarded as a risk factor for acute myocardial infarction and blood pressure as a risk factor for stroke. (It is worth
333 noting that B M D predicts fracture as well as blood pressure predicts the risk of stroke, and considerably better than total cholesterol predicts acute myocardial infarction.) Diagnostic labels should be used with caution, as should intervention decisions. Identified correctable risk factors should be corrected before more specific therapy is initiated. Nutritional and lifestyle advice should also be given. Once a decision to begin disease-specific therapy has been made, it is important to discuss expected outcomes. In particular, with those drugs that act by inhibiting bone loss (estrogen, calcitonin, raloxifene, and the bisphosphonates), antifracture protection may be provided even though serial B M D studies do not demonstrate any significant increase in BMD. The patient should be made aware of this before the second DXA study. The only time there should be concern that the therapy is not effective is when a significant decrease in B M D occurs between one study and the next. Even a fracture occurring on therapy is not an indication of treatment failure in the individual patient.
C. Bone Strength The most recent National Institutes of Health (NIH) consensus definition of osteoporosis is that it is "a systemic disease characterized by low bone mass and diminished bone quality" (21). Bone quality is a nebulous term including each of the many factors that can contribute to bone strength above and beyond bone mass. In practical terms there are only two parameters that are or are nearly ready for use in clinical practice: bone turnover and bone microarchitecture.
D. Bone Turnover Bone is a structural tissue and, in common with all structural materials, is subject to fatigue damage. Unique to the skeleton is the ability to self-repair and minimize the risk of fatigue damage. The process is known as either bone turnover or bone remodeling. Once peak adult bone mass has been attained, maintenance is achieved by removal of old bone (bone resorption) and replacement at the same site with new bone (bone formation). Resorption results from the action of osteoclasts and resorption from the action of osteoblasts. Resorption is rapid, with old bone being removed in about 10 days, but the repair process takes place over approximately 90 days. At menopause, estrogen deficiency unleashes a number of local cytokines that stimulate the recruitment and action of osteoclasts to an extent that osteoblast-mediated repair cannot keep up with resultant rapid bone loss. After 5 to 7 years, the intense osteoclastic activity slows down and the osteoblast-mediated repair begins to catch up, but never to a point where all bone loss is restored. After this 5- to 7-year period, when age-related bone loss takes control of
334
MICHAEL KLEEREKOPER
TABLE 26.1 Bone Turnover Markers (Available as Serum Based Assays) A. Resorption Cross-linked C-telopeptide of type I collagen (ICTP) Tartrate-resistant acid phosphatase 5b (TRACPSb) Amino-terminal telopeptide of collagen cross-links (NTx) Carboxy-terminal telopeptide of collagen cross-links (CTx) B. Formation Bone specific alkaline phosphatase (BSAP) Osteocalcin (OC) Carboxy-terminal propeptide of type I collagen (PICP) Amino-terminal propeptide of type I collagen (PINP)
the system, the osteoblast repair always lags behind the osteoclast-mediated bone loss, with a slow rate of bone loss continuing. Clearly, at some point a situation close to bone remodeling balance must occur or total loss of bone mass would result. This never happens, even in those conditions with the most rapid bone loss. The absolute and relative action of osteoclasts and osteoblasts can be measured by dynamic histomorphometry on bone biopsy specimens, but this invasive procedure is impractical for the many millions of women experiencing postmenopausal and age-related bone loss. A number of biochemical markers of bone resorption and bone formation have been developed and applied in clinical use (Table 26.1). There has been a great deal of reluctance to widely apply these biochemical tools to clinical practice because of a belief that these markers have too much variability to be applied to individual patients. To some extent this is true, but the techniques have evolved to a point where analytic variability has been minimized to closely match the analytic variability of many specialized biochemical tests. The biologic variability is a real phenomenon, but this too is not unique to the clinical biochemistry of the skeleton. These biochemical markers cannot be used to diagnose osteoporosis but are an important adjunct to BMD in "predicting" rates of future bone loss and in monitoring the responses to therapy. At menopause there is a marked increase
FIGURE 26.1 BMD change: healthypostmenopausal women with low and high bone turnover. BMD, bone mineral density; BAP,bone alkaline phosphatase; PICP, C-terminal propeptide of type 1 collagen; PINP, N-terminal propeptide of type 1 collagen; NTX, N-telopeptide breakdownproducts; CTX, C-telopeptide breakdownproducts;high turnover, bone marker levels abovethe upper limit of the premenopausal range. (From res 22, with permission.)
in markers of resorption and formation in many, but not all, women. A prospective 4-year study ofpostmenopausal women measured bone loss in those women in whom the markers were still within 2 standard deviations of the mean values in premenopausal women and compared the results with those women in whom the markers were already above the premenopausal reference interval (22). Those women with premenopausal levels for the markers had a BMD decrease of 1% or less over the 4 years. Those women with elevated markers had a 3% to 5% decrease in BMD during that same follow-up period. With each marker studied (there were seven in all), these differences were highly statistically significant and almost certainly of biologic significance as well (Fig. 26.1). In practical terms, for a woman in whom the DXA data does not clearly demonstrate that therapeutic intervention is immediately necessary, biochemical markers can be of considerable help in decision making. If the markers are still within the premenopausal reference interval, the anticipated loss in BMD over 2 years is low, and little irreversible skeletal harm is likely to ensue if the patient is followed without specific therapy. In contrast, a high value for the markers would seem to justify the use of specific therapy to prevent bone loss. The difficulties of using DXA to follow patients on therapy have already been addressed. Biochemical markers of bone turnover can be a very useful adjunct to monitoring the therapeutic response. In each of the published controlled clinical trials, there has been a decrease of 50% or more in the resorption markers within 3 months of initiation of therapy, after which time they remain at this lower level as long as effective therapy is continued (23-25). The nadir in formation markers is not seen until after 6 months of therapy. In an individual patient, if the expected decrease in markers are not seen, it is important to ensure that the patient is taking the therapy regularly and correctly. If so, then it is appropriate to look for causes for ongoing bone loss that is not halted by effective antiresorptive drugs. It is also worth noting that the early change in markers in clinical trials has generally been a better predictor of antifracture effectiveness of the therapy than changes in BMD.
CHAPTER 26 Assessment of Bone Density and Bone Strength
E. Bone Microarchitecture The process of menopause- and age-related bone loss results in the loss of connectivity of the elements of cancellous bone and in thinning of the cortical shell. This can be crudely assessed by plane radiographs but not to an extent that it is widely clinically applicable. Abnormal bone microarchitecture can also be assessed by 2D and 3D analysis of bone biopsy specimens. As noted, this is impractical in most clinical situations. Modalities for noninvasive in vivo assessment of bone microarchitecture are in various stages of development and clinical application. High-resolution peripheral Q CT (pQ_CT) has been developed for measurement of bone microarchitecture at the distal radius and distal tibia (Fig. 26.2, A) (see color insert), and preliminary data show that it has potential to predict future fracture occurrence (26). Highresolution MRI, termed virtual bone biopsy (VBB), has also been developed for assessment of microarchitecture at the distal radius and distal tibia (Figs. 26.2, B [see color insert], 26.3, and 26.4) (27,28). Short-term studies in postmenopausal women randomized to estrogen or placebo have demonstrated that within 1 year, microarchitectural disruption is seen in those women on placebo, with preservation of microarchitecture in those receiving estrogen (data only available as an abstract). Similar data have been punished for hypogonadal men receiving testosterone or placebo (29), and very recent data indicate the relationship between abnormal microarchitecture determined by VBB and the presence or absence of osteoporosis-related fractures (data only available as an abstract). These data are very encouraging but quite pre-
335 liminary because the technology for high-resolution p Q C T and VBB is not yet widely deployed. Nonetheless the available data demonstrate that microarchitectural changes can be seen earlier than changes seen with DXA and that smaller numbers of subjects are needed for serial studies than are needed for studies employing DXA. Although not directly clinically applicable, this latter finding will likely improve the ability to perform side-by-side comparison of available os-
FIGURE 26.3 Reproducibilityof VBB images.A: Repeat tibial scans in the patient with the highest Trabecular Volume/Bone Volume (TWBV). B: Repeat radius scans in the patient with the highest TWBV. (From ref. 28, with permission.)
FIGURE 26.2 High-resolution pQ.CT images of the distal radius. A: Radiograph showingthe site of imaging at the distal radius. The white line indicates the beginning of the joint space, and the two smaller lines to the left indicate the section of bone over which images are acquired. B: Representative cross-sectional images from the stack of CT slices from proximal (top left) to distal (bottom right). C: Representative 3D image. (From ref. 26, with permission.)
FIGURE 26.4 High-resolutionin vivo microscopyof the distal radius in a eugonadal man (left) and a hypogonadalman (right). (From ref. 29, with permission.)
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MICHAEL KLEEREKOPER
teoporosis therapies and may make it more cost effective to conduct clinical trials of potential new therapies. It must be emphasized that, as with the biochemical markers, knowledge of bone microarchitecture is several years away from becoming a diagnostic tool for osteoporosis and risk of fracture, and a long-term prospective study in a large number of at-risk patients will be required for confirmation.
III. C O N C L U S I O N Q CT is the only technology that directly measures true volumetric BMD, but its availability is limited and there are few prospective studies of its true capabilities. DXA measures "areal" BMD, which is not a true physiologic measurement. However, despite this shortcoming, DXA has proven to be an invaluable clinical tool in the evaluation of osteoporosis. DXA has several shortcomings with respect to monitoring the progression or regression of osteoporosis. The technologies of biochemical markers of bone remodeling are now mature enough to be applied more routinely in clinical practice as an adjunct to DXA. Methods for detecting disruption in bone microarchitecture have been developed and refined, but the clinical data to determine their true clinical utility are not yet complete.
References 1. National Osteoporosis Foundation. Accessed March 23, 2007, from http://www.nof.org/osteoporosis/diseasefacts.htm. 2. Louis O, Van den Vinkel P, Covens P, Schoutens A, Osteaux M. Dualenergy x-ray absorptiometry of lumbar vertebra: relative contribution of body and posterior elements and accuracy in relation with neutron activation analysis. Bone 1992;13:317-320. 3. Hotchkiss CE. Use of peripheral quantitative tomography for densitometry of the femoral neck and spine in cynomolgus monkeys (Macaca fascicularis). Bone 1999;24:101-107. 4. Korver DR, Saunders-Blades JL, Nadeau KL. Assessing bone mineral density in vivo: quantitative computed tomography. Poult Sci 2004; 83:222-229. 5. Lorentzon M, Mellstrom D, Ohlsson C. Age of attainment of peak bone mass is site specific in Swedish men. J Bone Miner Res 2005; 20:1123-1227. 6. Toledo VA, Jergas M. Age-related changes in cortical bone mass: data from a German female cohort. Eur Radio12005;8:1-7. 7. Khan AA, Syed Z. Bone densitometry in premenopausal women: synthesis and review.J Clin Densitom 2004;7:85-92. 8. Kleerekoper M, Nelson DA, Flynn MJ, et al. Comparison of radiographic absorptiometry with dual-energy x-ray absorptiometry and quantitative computed tomography in normal older white and black women. J Bone Miner Res 1994;9:1745-1749. 9. Duboeuf F, Jergas M, Schott AM, et al. A comparison of bone densitometry measurements of the central skeleton in post-menopausal women with and without vertebral fracture. Br J Radiol 1995;68: 747-753. 10. Genant HK, Lang T, Fuerst T, et al. Treatment with raloxifene for 2 years increases vertebral bone mineral density as measured by volumetric quantitative computed tomography. Bone 2004;35:1164-1168.
11. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254-1259. 12. Schuit SC, Van der Klift M, Weel A, et al. Fracture incidence and association with bone mineral density in men and women: the Rotterdam study. Bone 2004;34:195-202. 13. K_rallEA, Dawson-Hughes B, Hirst K, et al. Bone mineral density and biochemical markers of bone turnover in healthy elderly men and women. J Gerontol Bid Sci Med Sci 1997;52:M61-M67. 14. Jorgensen HL, Warming L, Bjarnason NH, Andersen PB, Hassager C. How does quantitative ultrasound compare to dual x-ray absorptiometry at various skeletal sites in relation to the W H O diagnosis categories? Clin Physio12001;21:51-59. 15. Sahota O, Pearson D, Cawte SW, San P, Hosking DJ. Site-specific variation in the classification of osteoporosis, and the diagnostic reclassification using the lowest individual lumbar vertebra T-score compared with the L1-L4 mean, in early postmenopausal women. Osteoporos Int 2000;11:852-857. 16. Melton LJ III. The prevalence of osteoporosis: gender and racial comparison. Cakif Tissue Int 2001;69:179-181. 17. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser 1994;843:1-129. 18. Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res 2005;20:1185-1194. 19. U.S. Preventive Services Task Force. Screening for osteoporosis in postmenopausal women: recommendations and rationale. Ann Intern Med 2002;137:526-528. 20. Kleerekoper M, Nelson DA. Is BMD testing appropriate for all menopausal women? IntJ Fertil Womens Med 2005;50:61-66. 21. http://www.nlm.nih.gov/pubs/cbm/osteoporosis/html. 22. Garnero P, Sornay-Rendu E, DuboeufF, Delmas PD. Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: the OFELY study. J Bone Miner Res 1999;14:1614-1621. 23. Chestnut CH, Ettinger MB, Miller PD, et al. Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE. Curr Med Res Opin 2005;21:391-401. 24. Johnell O, Scheele WH, Lu Y, et al. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteporosis. J Clin Endocrinol Metab 2002;87:985-992. 25. Rosen CJ, Hochberg MC, Bonnick SL, et al. Treatment with onceweekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized doubleblind study. J Bone Miner Res 2005;20:141-151. 26. Khosla S, Riggs BL, Atkinson EJ, et al. Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment. J Bone Miner Res 2006;21:124-131. 27. Gomberg BR, Saha PK, Wehrli FW. Topology-based orientation analysis of trabecular bone networks. Med Phys 2003;30:158-168. 28. Gomberg B R, Wehrli FW, Vasilic B, et al. Reproducibility and error sources of micro-MRI-based trabecular bone structural parameters of the distal radius and tibia. Bone 2004;35:266-276. 29. Benito M, Gomberg B, Wehrli FW, et al. Deterioration of trabecular architecture in hypogonadal men. J Clin Endocrinol Metab 2003;88: 1497-1502. 30. Benito M, Vasilic B, Wehrli FW, et al. Effect of testosterone replacement on trabecular architecture in hypogonadal men. J Bone Miner Res 2005 ;20:1785-1791.
2HAPTER 2,
Biochemical Markers of Bone Turnover RICHARD EASTELL AcademicUnit of Bone Metabolism, University of Sheffield, Metabolic Bone Centre, Sorby Wing, Northern General Hospital, Sheffield, UK $5 7AU
ROSEMARYA.
HANNON
AcademicUnit of Bone Metabolism, University of Sheffield, Metabolic Bone Centre, Sorby Wing, Northern General Hospital, Sheffield, UK $5 7AU
The past few years have seen an expansion of the use of biochemical markers of bone turnover in the care of postmenopausal women. Several new markers have become available and automated methods for measuring the markers have been developed, which means that most hospital clinical chemistry laboratories have the facilities to make these measurements. Measurement of markers of bone turnover is noninvasive and relatively inexpensive, and these markers can be measured repeatedly in the same subject. The major benefit of using bone turnover markers is that significant changes in response to treatment are observed within a few months, whereas significant changes in bone mineral density (BMD) are not observed for at least 12 months. In this chapter we review the most commonly used markers of bone turnover and discuss the use of these markers in the care of the postmenopausal woman.
I. MARKERS OF B O N E T U R N O V E R Biochemical markers of bone turnover are generally classified as markers of bone formation or markers of bone resorption (Table 27.1), reflecting osteoblast and osteoclast activity, respectively. The ideal marker is bone specific and reflects either bone formation or bone resorption, but not both. However, it must be kept in mind that bone formation and bone resorption are "coupled" events in most circumstances, such that any marker of bone formation or bone resorption can be used to characterize both the high turnT R E A T M E N T OF T H E POSTMENOPAUSAL W O M A N
337
over state after the menopause and the decrease in bone turnover in response to antiresorptive treatment.
A. Markers of Bone Formation 1. PROCOLLAGEN PROPEPTIDES
The procollagen propeptides, procollagen type I carboxyterminal propeptide (PICP) and procollagen type I aminoterminal propeptide (PINP), are released into the circulation during the extracellular conversion of procollagen to collagen. Type I collagen is a trimer comprising two identical oq (I) polypeptide chains and one o~2(I)polypeptide chain and is the major protein of bone matrix (90%) (1). It is synthesized by osteoblasts as a precursor, procollagen, and secreted into the extracellular space, where it undergoes a series of post-translational modifications including the cleavage of the propeptides by specific proteases (Fig. 27.1). The propeptides are released into the circulation, and the newly formed collagen molecules assemble as fibrils. PICP is a globular polypeptide with a molecular weight of 100 kDa, which contains both intrachain and interchain disulphide bridges. PINP is a smaller polypeptide with a molecular weight 35 kDa, with intrachain disulphide bridges but no interchain disulphide bridges. It is primarily a globular peptide but contains small amount of helix. Intact PINP appears to be a more sensitive marker of bone formation than PICP: the increases in PINP during the pubertal growth spurt, at the menopause and in Paget's Copyright 9 2007 by Elsevier,Inc. All rights of reproduction in any form reserved.
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EASTELL
disease, are significantly greater than those for PICP (2). Likewise, the percentage decrease in PINP after one year of HRT was ~40% compared with ~20% in PICP in 47 postmenopausal women (1). There are several possible reasons for this difference in sensitivity. Although the contribution to circulating levels of the propeptides from nonosseous sources is thought to be small (2), differences in the patterns of cleavage of the propeptides from procollagen in different tissues may be responsible for intact PINP being more bone specific than PICP. PICP is completely cleaved and released in amounts equimolar to the amount of collagen synthesized in any tissue, whereas PINP is completely cleaved in collagen found in mineralized tissues but in soft tissues may be retained in fibers and released during fiber growth or collagen degradation in a degraded form (3) that is not detected by the intact PINP assay but is detected by the total PINP assay, which detects the intact molecule and other smaller fragments of the molecule. Differences in the clearance mechanisms of the two propeptides may also account for some of the differences in sensitivity. PICP is cleared by the mannose receptor of the liver endothelial cells, which are sensitive to hormones including estrogen, whereas PINP is cleared by the scavenger receptor of liver endothelial cells, which are not thought to be sensitive to circulating hormones (3-5). The greater sensitivity of PINP has meant that it is measured in preference to PICP in most studies.
TABLE 27.1 Bone Turnover Markers Specimen
Marker Bone resorption markers Cross-linked N-telopeptide of type I collagen (NTX) Cross-linked C-telopeptide of type I collagen (CTX)
Urine, serum Urine (cxotand [313 forms) Serum ([3[3 form) Serum
MMP-generated telopeptide of type I collagen (ICTP or CTX-MMP) Deoxypyridinoline, free and peptide bound (fDPD, DPD) Pyridinoline, free and peptide bound (fPYD, PYD) Hydroxyproline (OHP) Glycosyl hydroxylysine (GylHyl) Helical peptide (HelP) Tartrate resistant acid phosphatase 5b isoform specific for osteoclasts (TRACP 5b) Cathepsin K (Cath K) Osteocalcin fragments (uOC) Bone formation markers Osteocalcin (OC) Procollagen type I C-terminal propeptide (PICP) Procollagen type I N-terminal propeptide (PINP) Bone-specific alkaline phosphatase (bone ALP)
Urine, serum Urine serum Urine Urine, serum Urine Serum, plasma Urine, serum Urine Serum Serum Serum Serum
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CHAPTER 27 Biochemical Markers of Bone Turnover 2.
OSTEOCALCIN
Osteocalcin (bone Gla protein) is the most abundant noncollagenous bone matrix protein, also found in dentin. It is a small protein of 49 amino acid residue and molecular weight 58 kDa, which is synthesized almost exclusively by highly differentiated osteoblasts and is therefore bone specific, an important property for a marker of bone formation (6). The majority of newly synthesized osteocalcin is incorporated into the bone matrix, but about 10% to 30% is released into the circulation. Osteocalcin is cleared by the kidneys and to a lesser extent by the liver. In renal failure, levels of osteocalcin and particularly its fragments are elevated (7). The function of osteocalcin is not fully understood. It has been suggested that it is involved in the regulation of coupling of bone resorption and bone formation (8). In a study of osteocalcin knockout mice, bone formation was increased but bone resorption was unaffected, which suggests that osteocalcin may be a limiting factor for bone formation (9). A major feature of the primary structure of osteocalcin is the y-carboxylated glutamic acid residues at positions 17, 21, and 24. The post-translational y-carboxylation of these residues is vitamin K dependent. Osteocalcin in bone is not completely carboxylated, and serum levels of the undercarboxylated form increase with age, especially in elderly women (10). The degree of carboxylation appears to be related to bone strength, since Vergnaud et al. (11) have shown that increased serum levels of undercarboxylated osteocalcin predict hip fracture risk independently of femoral neck BMD. Elderly women with hip fracture have lower levels of vitamin K1 and menquinone 7 and 8, two major components of vitamin I(2 (12). Although numerous immunoassays are available for the measurement of serum or plasma osteocalcin, comparability of the different assays is poor (13). This is probably due to the heterogeneity of the circulating fragments of osteocalcin and differences in the immunorecognition of these fragments by different assays. Intact osteocalcin is degraded in the circulation and in vitro (14). Only about 36% of circulating immunoreactive osteocalcin is the intact protein, 30% is a large N-mid-molecule fragment (residues 1-43), and the remainder consists of smaller fragments. The apparent stability (15) of immunoreactive osteocalcin is significantly greater when assays designed to measure the intact molecule and Nmid-molecule fragment are used than when assays designed to measure only the intact molecule are used. Assays that measure both the intact and N-mid-molecule fragment are therefore recommended, particularly in clinical practice. Recently, small fragments of osteocalcin have been isolated in urine (16), which are thought to be degradation products of bone matrix rather than byproducts of bone formation. This suggests that osteocalcin may also be a marker of bone resorption. Indeed it is now possibly best to regard osteocalcin as a marker of bone turnover rather than a specific marker of bone formation.
339 3. ALKALINE PHOSPHATASE
Total serum alkaline phosphatase has been used for many years as a marker of bone formation. Alkaline phosphatase is a membrane-bound orthophosphoric mono-ester phospho2-hydrolase with optimal activity at alkaline pH. Several different isoenzymes of alkaline phosphatase exist, coded for by four different genes: tissue nonspecific, intestinal, placental, and germ cell line. The tissue nonspecific gene codes for bone, liver, and kidney isoforms; the differences in these isoforms result from differences in the patterns of posttranslational glycosylation (17). In healthy adults, circulating alkaline phosphatase consists primarily of the bone isoform (~50%) and liver isoform (~50%). Only trace amounts of the intestinal and placental isoenzymes are found in normal adult serum. The precise function of the bone isoform remains unclear, but it is thought to be associated with mineralization. Total alkaline phosphatase is a useful marker of bone formation in diagnosis and monitoring of treatment in diseases characterized by major disturbances in bone turnover, such as Paget's disease, and some would argue that in most clinical situations, measurement of total alkaline phosphatase provides sufficient information (18). However, there is evidence to support the contrary argument that the bone alkaline phosphatase (bone ALP) is a more sensitive and more clinically useful marker in the measurement of more subtle changes in bone turnover, such as occur at the menopause (19,20). Garnero et al. (19) found a 77% increase in bone alkaline phosphatase after the menopause compared with a 24% increase in total alkaline phosphatase. Manual and automated immunoassays are available that are specific for the bone isoform. There is some crossreactivity with the liver isoform in most of these assays, but this is small (between 7% and 16%) and should only be a problem in patients with liver disease (19,21).
B. Markers of Bone Resorption 1. DEGRADATION PRODUCTS OF THE TELOPEPTIDE REGION OF TYPE I COLLAGEN
The majority of the markers of bone resorption are the degradation products of type I collagen. The most widely used of these are the peptide bound cross-links of type I collagen, the cross-linked carboxy and amino telopeptides of type I collagen (NTX and CTX), which are released into the circulation during bone resorption (22). A proportion of these are excreted into the urine, and the rest are degraded in the kidneys and eventually excreted in urine as free cross-links. Fig. 27.2 shows the origins of these markers in collagen. The pyridinium cross-links, pyridinoline and deoxypyridinoline, are nonreducible cross-links found in mature collagen, formed by the condensation of lysine and hydroxylysine residues in the telopeptide regions and specific lysine or hydroxylysine
340
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residues in the helical regions of adjacent collagen molecules. Free and peptide-bound forms of cross-finks are detectable in both serum and urine (23). In adult urine, 40% to 50% are free and 50% to 60% are bound (24), but the ratio of free to bound in both serum and urine may depend on the level of bone turnover; the higher the rate of bone turnover, the smaller the ratio of free to bound crosslinks (23,25). NTX can be measured in both urine and serum. The assay measures crosslinked N terminal telopeptides fragments of type I collagen which contain a specific 8 amino acid sequence from the ot2(I) N telopeptides o~2(26,27). The peptide component of CTX is an 8-amino acid sequence containing an aspartic acid, glycine peptide, which is highly susceptible to isomerization and racemization. This yields 4 isoforms of the telopeptide, the otL, [3L, otD, and [3D forms. The native L isoform is found in newly formed bone, whereas the other forms are found in increasing amounts as bone matures (28). Therefore a heterogeneous mix of the different isoforms of CTX molecules is found in urine and serum. Several assays have been developed to measure these different forms in urine (29). There is a radioimmunoassay that measures cio~ and cx[3 cross-linked molecules and also the single-chain, noncross-linked o~ forms of the peptide in urine, and an enzymelinked immunoassay (EHSA) that measures [3[3 and o~[3 and the single-chain, non-cross-linked [3 in urine. Recently two more specific EHSAs have been developed to specifically measure the cross-linked cici forms and the cross-linked [3[3 forms of CTX in urine. Neither assay measures single chain fragments of the Type I collagen telopeptides. The serum assay for CTX is probably currently the most widely used of the CTX assays is specific for the cross-linked [3[3 form. The free cross-links, pyridinoline and deoxypyridinoline, can be measured by immunoassay. Both the free and peptidebound cross-links can also be measured by High Performance Liquid Chromatography (HPLC), although this method has been used less since the development of immunoassays and automated methods.
Another C-terminal telopeptide of type I collagen that can be used as a marker of bone resorption is CTX M M P or ICTP (30). It has a longer peptide sequence than CTX and is released during the degradation of type I collagen by matrix metallopeptidases. It is a poor marker in osteoporosis, but may be useful in oncology as several studies have found highly elevated levels of ICTP in patients with metastatic bone disease (31). 2. COLLAGEN DEGRADATION PRODUCTS FROM THE HELICAL REClON OF TYPE I COLLACEN Hydroxyproline, possibly one of the longest-established markers of bone resorption, is a product of the degradation of the helical region of type I collagen. It represents about 13% of the amino acid content of collagen and is released into the circulation during bone resorption but is not reincorporated into new collagen (32). It circulates in either the free form (90%) or in peptide-bound forms. Most of the free hydroxyproline is filtered and reabsorbed by the kidney. The remainder is excreted in the urine together with the dialyzable and non-dialyzable peptide-bound forms. However, urinary hydroxyproline suffers from three major disadvantages as a marker of bone resorption: (1) a significant fraction of it is derived from nonosseous sources (33); (2) hydroxyproline is absorbed from dietary sources and diet must be restricted for 24 hours before samples are collected (34); and (3) most hydroxyproline is metabolized in the liver. It has now been largely superseded by the telopeptides. The other markers derived from the helical region are the galactosyl and glucosylgalactosyl hydroxylysines, which are products of the post-translational glycosylation of type I collagen. They are technically demanding to measure and are not widely used (35). However, an immunoassay has recently been developed that measures the so-called helical peptide, which is the 620-633 peptide of the (xI chain of type I collagen (36).
CHAPTER 27 Biochemical Markers of Bone Turnover 3. OSTEOCLASTICENZYMES
The other resorption markers are osteoclast enzymes.
a. Tartrate Resistant Acid Phosphatase Tartrate resistant acid phosphatase (TRAcP) 5b is an osteoclast enzyme. Serum TRAcP has been used for many years as a marker of bone resorption. However, until recently the kinetic methods used to measure TRAcP were not specific for the 5b isoform and detected TRAcP from other sources such as platelets, erythrocyte, and possibly osteoblasts (37). In the past few years, immunoassays have been developed that are specific for the 5b isoform (38). Using these 5b-specific assays, it has been shown that serum levels of TRAcP 5b reflect osteoclast number rather than osteoclast activity. b. Cathepsin K and Matrix Metalloproteinases Two newer markers of bone resorption are also osteoclast enzymes: cathepsin K and matrix metalloproteinase (MMP). Cathepsin K is a cysteine protease expressed by osteoclasts, which is essential for bone resorption (39). Preliminary evaluation has shown that serum levels are elevated in postmenopausal osteoporosis and in women with a history of fracture (40).
C. Summary There is now a large range of markers of bone turnover available, most of which can be measured reliably by simple ELISAs. Some may also be measured on automated analyzers. Different markers reflect different aspects of bone formation or resorption, and this must be considered when choosing markers for a particular study or clinical situation. In clinical research we usually recommend measuring two markers of bone formation and two markers of bone resorption, and in clinical practice, one marker of bone formation and one marker of bone resorption. PINP and bone alkaline phosphatase (ALP) are generally the most useful markers of bone formation in large clinical studies and clinical practice, and urinary NTX and serum CTX are the most useful markers of bone resorption. These markers tend to be more stable than some of the others, which is an important consideration, particularly in clinical practice.
II. VARIABILITY OF MARKERS Although biochemical markers are useful noninvasive tools that can be used repeatedly in the same patient to assess bone turnover, one of the major confounding factors for their use is their variability. The main components of overall intraindividual variability are analytical and biological. Analytical variability is small compared with biological variability for most assays (41,42). There are numerous
341 sources of variability such as age, gender, pubertal stage, menopausal status, diseases, drugs, fractures, menstrual, seasonal, day to day, and circadian. These sources of variability may be divided into two categories, the first being those that can be controlled by collecting samples under the appropriate conditions (43). These controllable sources of variability include circadian, menopausal, seasonal, or effect of exercise. The second category of sources of variability comprises the uncontrollable sources such as age, gender, diseases, drugs, and fractures. The effect of these uncontrollable sources of variability must be taken into account in the interpretation of results by the use of appropriate references ranges and a knowledge of the effects of diseases, drugs, and fractures on bone turnover. The intraindividual variability is greater for the urinary markers than for the serum markers. The intraindividual variability for serum markers is in the order of 10%, whereas for urinary markers it may be as much as 35% (41,44). This difference may be due to difficulties in timing and completeness of urine collections or to day-to-day changes in renal clearance or the renal conversion of peptide bound to free cross-links. Variability may also be affected by osteoporosis and tends to be higher for all markers in women with postmenopausal osteoporosis than in normal postmenopausal women (45). Intraindividual variability has considerable effect on the use of markers in research and in clinical practice. A useful concept that accounts for the intraindividual variability when deciding whether a true biologic change in a marker has occurred is the "least significant change." The least significant change is calculated from the intraindividual variation and represents a cut-off point. Any change between two measurements must be greater than this cut-off point to be biologically significant. Circadian rhythms can have a major effect on variability of the markers. Both markers of bone resorption and bone formation exhibit circadian rhythms, reaching a peak between 23:00 and 08:00 hours and falling to a nadir between 12:00 and 17:00 hours. The greatest circadian changes are seen in the markers of bone resorption. In young women the amplitude of the variation (i.e., the difference from peak to trough) is 70% of the mean value for 24 hours for total DPD (Fig. 27.3) and 63% for NTX (46). The amplitude of circadian rhythm free of free cross-links tends to be smaller than that of the telopepetides. Serum CTX, for example, exhibits a circadian rhythm with an amplitude of 80% of the 24 hour mean (47). The amplitude of the variation for bone formation markers range from 5% to 30% (48-52). These circadian rhythms are maintained into old age (55). In late postmenopausal women with osteopenia or osteoporosis, the circadian rhythm of some biochemical markers of bone turnover appears to be disturbed. The
342
FmURE 27.3 Circadian variation in excretion of DPD in 18 healthy premenopausal women. Results are shown as percentages of the 24-hour mean excretion in each subject. Each thin line represents one individual. The solid lines represent the mean _+ standard error of the mean (SEM) of the normalized values. Data are plotted at the midpoint of each 4-hour collection period. Subjects were recumbent with the lights off during the period indicated by the shaded bar. (Modified from ref. 46, with permission.)
peak in total DPD excretion is extended into the morning in women with osteoporosis compared with healthy agedmatched women (53). However, in women with osteopenia (forearm bone mineral content [BMC] more than 2 SDs below premenopausal mean BMC), the circadian rhythm in total DPD is the same as that for age-matched women (54). The nocturnal peak in PICP, but not in osteocalcin or bone alkaline phosphatase, is higher and extended in the osteopenic women (49). The implications of these circadian rhythms are considerable, both in investigative studies and in clinical practice. For example, if NTX is measured in a urine sample collected in the early morning (07:00) and in a second sample collected in the afternoon (15:00), there could be a difference in the measurements of 50%, which is comparable to the change in NTX expected after 6 months of hormone replacement therapy (HRT). Several recent studies have shown that much of the circadian rhythm, particularly that of CTX, is due to the effect of feeding (55,56). Menstrual and seasonal variations in markers are much weaker than the circadian variations. Markers of bone formation have been shown to be 15% higher in the luteal phase than in the follicular phase (57). Urinary levels of markers of resorption, NTX and total pyridinium cross-links, are somewhat higher during the earlier parts of follicular and luteal phases than in the later parts of these phases (58). ICTP, a serum marker of bone resorption, is 17% higher in the luteal phase than in these follicular phase (59).
EASTELL AND HANNON
Seasonal variation in markers of bone turnover has been observed in several but not all studies (60-65). In most studies that have demonstrated a significant seasonal rhythm, bone turnover tends to be lower in the summer than in the winter (61,62) and be related to seasonal changes in the vitamin D-parathyroid hormone (PTH) axis. However, in a recent multicenter European study of premenopausal and postmenopausal women, no wintertime increase in bone turnover was observed despite a significant seasonal decrease in vitamin D levels (64). The impact of fractures and drugs on intraindividual variability of markers is particularly important for postmenopausal women as they have an increased risk of fracture. Biochemical markers of bone formation and bone resorption increase up to 30% during the healing of a Colles' fracture, a characteristic osteoporotic fracture (66). Furthermore, the markers can remain elevated for up to 1 year after the fracture (67). In addition to drugs such as HRT and bisphosphonates taken to prevent bone loss, other drugs can affect levels of biochemical markers. Corticosteroids suppress bone formation without having a direct effect on bone resorption. Consequently, markers of bone formation, in particular osteocalcin, are reduced during corticosteroid treatment. There may be a small increase in markers of bone resorption, resulting from a secondary hyperparathyroidism induced by the effect of the corticosteroid on calcium absorption. Thiazide diuretics reduce bone turnover (68). Conversely, treatment with anticonvulsant drugs results in threefold increases in markers of bone resorption (69) and increases of up to 33% in markers of bone formation in women (70).
A. Summary A number of strategies can be followed to minimize variability: (1) samples, particularly for resorption markers, should be collected at a fixed time of day after an overnight fast; (2) two or more samples can be collected on different days within a given period and the mean level of the marker reported; and (3) patients should be asked about previous fractures and use of drugs.
III. CHANGES IN MARKERS AT MENOPAUSE, IN OSTEOPOROSIS, AND IN RESPONSE TO THERAPY A. Menopause Estrogen deficiency caused by ovariectomy or drug therapy, such as gonadotropin-releasing hormone (GnRH) agonist therapy, result in a rapid increase in the levels of
CXaVTER 27 Biochemical Markers of Bone Turnover
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markers of bone turnover (71). Similarly the menopause is marked by an increase in levels of markers. The magnitude of the increase varies for the different markers, probably reflecting their specificity for bone or differences in their metabolism in low and high turnover states. The markers probably start to increase in the perimenopausal period before menstruation has ceased. Premenopausal women over the age of 40 years have higher levels of CTX and osteocalcin than younger women (72), which may be weakly associated with lower BMD. In women with altered menstrual patterns, where follicle-stimulating hormone (FSH) is elevated but estradiol is still at premenopausal levels, N T X is increased by 20% but formation markers are unchanged, compared with premenopausal levels (73) (Fig. 27.4). Perrien et al. have shown that the changes in bone turnover in premenopausal and perimenopausal women may be regulated by inhibins, particularly inhibin A, independently of FSH and estrogen levels (74). Once the estradiol levels decrease, markers of bone resorption and formation increase (75). In the first years of the menopause, mean levels of pyridinium cross-link excretion significantly increase and may even be doubled (26,76,77), but there is still considerable overlap with levels in premenopausal women. The increases in the telopeptides or total cross-links are greater than the increase in the free pyridinolines, possibly for reasons discussed previously (73,78). Garnero et al. (79)
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found increases of 80% to 100% in total cross-links measured by HPLC, 100% to 130% in telopeptides, and 50% in free deoxypyridinoline in a comparative study of 14 premenopausal women ages 33 to 44 years and 29 postmenopausal women ages 46 to 53 years who were within 3 years of the menopause. There is a considerably smaller increase in the serum markers of bone resorption, T R A C P and ICTP, of the order of 20% to 25% (80). Interestingly, cathepsin K appears to be lower in older women compared with premenopausal women (81). The differences in the increases in markers of bone formation in postmenopausal women may be related to the different aspects of bone formation that each marker reflects. It may also reflect a difference in tissue specificities of the markers. The increases in bone alkaline phosphatase and osteocalcin are in the order of 50% to 100% but may be as high as 150%. The increase in PICP is considerably less, around 20%. PINP, which may be the more bone-specific propeptide, shows a greater increase at the menopause (82). Whether the increase in bone turnover that occurs at the menopause is maintained into old age has been questioned (83), but we have found elevated levels of bone turnover in women into their eighth decade (84). Garnero et al. have shown that N T X and CTX and markers of bone formation remain elevated in women for 40 years after the menopause (85).
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B. Osteoporosis Markers of bone resorption are significantly elevated in osteoporotic postmenopausal women as compared with normal postmenopausal women, but the markers of bone formation are much less elevated and may indeed be decreased (86,87). This pattern of changes suggests that a degree of imbalance of bone resorption and bone formation occurs in osteoporosis. We found a mean increase of 40% in the level of total deoxypyridinoline in a group of 63 women with postmenopausal osteoporosis compared with a group of 67 normal postmenopausal women (88). However, there was a considerable overlap of individual levels in the two groups. The heterogeneity of bone resorption in the osteoporotic group probably indicates different causes of the disease or may represent differences in the stage of the disease observed in the individuals in the study. Single measurements of total and free cross-links are unlikely to be useful in identifying osteoporosis in an individual postmenopausal woman. However, a recent study suggests that NTX can discriminate between normal postmenopausal, osteopenic, and osteoporotic women, as defined by the World Health Organization ( W H O ) criteria (89). Recently, Meier et al. have shown that the new marker of resorption, cathepsin K, is significantly increased in postmenopausal women with osteoporosis compared with healthy women (11.3 versus 3.1 nmol/L) (90).
In contrast to the antiresorptive drugs that suppresses bone turnover, the new anabolic treatment for osteoporosis, teriparatide, stimulates bone turnover, which when combined with a positive remodelling balance leads to an increase in bone mass (96). Both bone formation and bone resorption markers are increased in response to teriparatide (97). The procoUagen propetides peak 6 months after initiation of treatment: PINP is increased by 200% (98) and PICP by 60% (99), after which they return towards pretreatment levels. However, bone ALP remains elevated throughout treatment, as do markers of bone resorption, such as urinary NTX, which may be elevated by 200% after 12 months of treatment (99). Strontium ranelate has yet another mode of action, which is not fully understood; it results in small increases in bone formation and a small decrease in bone resorption. However, the changes in bone turnover markers in response to sodium ranelate are smaller than those seen in response to other treatments: serum CTX decreases by 12% and bone ALP increases by 8% (100).
IV. PREDICTION OF BONE LOSS, FRACTURE, AND RESPONSE TO THERAPY A. Bone Loss
C. Response to Therapy Currently bisphosphonates are the treatment of choice in postmenopausal osteoporosis. Bisphosphonates are antiresorptive agents that suppress osteoclast activity. Markers of bone resorption decrease rapidly in response to treatment. Typically there is a decrease of 50% to 70% in the telopeptides within the first 12 weeks of treatment (91,92). We have shown that there is a significant decrease in urinary NTX within the first 8 weeks of treatment with alendronate. The changes in other markers of bone resorption are somewhat smaller. Serum levels of TRACP5b are reduced just under 20% (93). The markers of bone formation are also significantly reduced in response to bisphosphonates. PINP is reduced by as much as 60% and bone ALP more modestly by about 40% (91). Although the efficacy of alendronate and risedronate in reducing fractures is similar, the decrease in bone turnover appears to be greater in patients treated with alendronate. Treatment with selective estrogen receptor modulators (SERMs) such as raloxifene have a smaller effect on markers of bone turnover than do bisphosphonates. Serum CTX decreases by 30% to 40% and TRACP 5b by only 10%. The response of the markers of bone formation is also smaller: PINP is decreased by 30% and bone ALP by 15% to 20% (94,95).
BMD in the postmenopausal woman is determined by peak bone mass and the amount of bone loss since the menopause. With increasing age, the contribution of bone loss to the resultant BMD becomes more significant (101). Furthermore, increased bone turnover becomes an increasingly important determinant of BMD as women grow older (86). In several studies, bone loss has been shown to correlate with markers of bone turnover, although this is not a universal finding. We have shown that in early postmenopausal women there is an inverse relationship between markers of bone turnover and bone loss (102). In other studies of women in the first 7 years after the menopause, a combination of resorption and formation markers or a combination ofpyridinoline with estradiol glucuronide and body mass index can predict up to 59% of the variance of bone loss at the forearm (103,104). Change in BMD at the spine and hip, the clinically relevant sites, can only be poorly predicted, if at all (105-107). At the forearm, high levels of PINP, osteocalcin, urinary NTX, and serum CTX are associated with rapid bone loss (108). In women over age 70, the correlation between baseline levels of biochemical markers and annual rate of change of BMD over a 3-year period at the total hip was moderate at best (106). Although most of these studies indicate that a relationship exists between high levels of bone turnover markers and increased bone loss, they
CHAPTER27 Biochemical Markers of Bone Turnover are not sufficiently sensitive to be used to predict bone loss in an indMdual postmenopausal woman.
B. Fracture Although biochemical markers of bone turnover may be able to predict bone loss and hence fracture risk, they may also predict fracture risk independently of BMD. High bone turnover per se can disrupt the trabecular architecture by increasing the incidence of trabecular perforation and buckling, thus reducing bone strength, without necessarily affecting BMD significantly. In retrospective and prospective studies, fracture risk may be associated with increased levels of markers of bone resorption but not bone formation (109). In a short prospective study of elderly French women, a 1SD increase in CTX and free deoxypyridinoline, adjusted for femoral neck BMD and gait, above the upper limit for premenopausal women, resulted in 2- and 1.7-fold increases, respectively, in risk of hip fracture over a 22-month followup period (110). Increased pyridinolines have also been shown to predict a history of fracture independent of BMD, age, and other markers of bone turnover (111). However, there is little convincing evidence to indicate that a single measurement of a biochemical marker of bone turnover can predict fracture risk in an individual woman, even over a short period of time. The combination of a biochemical marker and BMD may be a much more powerful predictor of fracture than BMD alone (112). Women with a low hip BMD (2 SD above premenopasusal mean) have a considerably higher risk of hip fracture than those who have only one of these independant risk factors (109). Biochemical markers of bone turnover cannot substitute for serial BMD measurements but may be useful when considered in conjunction with BMD measurement.
C. Response to Therapy Early changes in bone turnover markers in response to treatment may be predictive of change in BMD and fracture risk. A number of studies have shown that changes in CTX and NTX after the start of treatment predict changes in lumbar spine BMD obtained 2.5 to 4 years later in elderly women treated with alendronate (113). Early change markers of bone turnover may predict change in hip BMD in elderly women treated with alendronate or HRT (114). Similar results have also been reported in the Danish cohort of the Early Postmenopausal Intervention Cohort (EPIC) Study for younger postmenopausal women treated with alendronate for the prevention of osteoporosis (115). Chen et al. have shown that increase in PICP at 1 month and PINP at 3 months was predictive of change at lumbar
345 spine BMD at 18 months in osteoporotic women treated with teriparatide (97). In addition, baseline levels of markers were also weakly predictive of response to treatment. Bauer et al. have recently published similar findings (116). In addition to predicting change in BMD, early changes in bone turnover markers may predict change in fracture risk. We have shown that magnitude of changes in urinary NTX and CTX 3 to 6 months after the start of risedronate treatment is related to the decrease in vertebral fractures in women with at least one previous vertebral deformity (117). In the Multiple Outcomes of Raloxifene Evaluation (MORE), a randomized, placebo-controlled trial of 7705 osteoporotic women treated with raloxifene for 3 years, change in serum osteocalcin was predictive of change in vertebral fracture risk and was a better predictor than change in femoral neck BMD in the women treated with raloxifene (118).
V. M O N I T O R I N G THERAPY For the individual woman, the change in BMD in the first year of antiresorptive treatment is not large enough, relative to the precision of the measurements, to determine whether she has responded to the treatment. Thus, it is often normal clinical practice to wait for 1 to 2 years before repeating the bone density measurement. The advantage of using markers of bone turnover to monitor response is that a significant change may be seen between 3 and 6 months after initiation of treatment. If markers are to be used in monitoring therapy, it is important to remember that the magnitude of the observed change per se may yield very little and possibly misleading information if it is not considered relative to the intraindividual variability of the marker concerned. For a woman who has two single measurements at baseline and after 6 months treatment, for example, the change must be greater than the least significant change (LSC) (described previously) for that marker if she is to be classified as a responder. An understanding of the time course of the changes in markers, particularly in the first 6 months, is also important in making decisions based on monitoring response with markers. In addition to being useful in assessing response to treatment, measuring markers of bone turnover during the first 6 months of treatment and reporting the results to the patient may encourage compliance (119).
VI. CONCLUSION Biochemical markers of bone turnover have proved to be useful, noninvasive, and relatively inexpensive tools for studying bone metabolism in population studies and are gradually becoming established in clinical practice. In the treatment of the individual postmenopausal woman, they
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may be useful as adjuncts to B M D and other diagnostic tests. Their main use, however, is in monitoring response to treatment. The continued development of new markers of bone turnover will increase our knowledge of the pathophysiology of osteoporosis and other metabolic bone diseases, and after further evaluation, these new markers may find a place in the clinical care of postmenopausal women.
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CHAPTER 27 Biochemical Markers of Bone Turnover 38. Halleen JM, Matalo SL, Suominen H, et al. Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J Bone Miner Res 20001;15:1337-1345. 39. Saftig P, Hunziker E, Everts V, et al. Functions of cathepsin K in bone resorption. Lessons from cathepsin K deficient mice. ddv Exp Med Bid 2000;477:293-303. 40. Holzer G, Noske H, Lang T, Holzer L, Willinger U. Soluble cathepsin K: a novel marker for the prediction of nontraumatic fractures? y Lab Clin Med 2005;146:13-17. 41. Panteghini M, Pagani F. Biological variation in urinary excretion of pyridinium crosslinks: recommendations for the optimum specimen. Ann Clin Biochem 1996;33:36-42. 42. Panteghini M, Pagani F. Biological variation in bone-derived biochemical markers in serum. &and y Clin Lab Invest 1995;55: 609-616. 43. Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. OsteoporosInt 2000;11:$30-$44. 44. Ju HS, Leung S, Brown B, et al. Comparison of analytical performance and biological variability of three bone resorption assays. Clin Cbem 1997;43:1570-1576. 45. Jensen JE, Sorensen HA, Kollerup G, Jensen LB, Sorensen OH. Biological variation of biochemical bone markers. ScandJ Clin Lab Invest Supp11994;219:36-39. 46. Blumsohn A, Herrington K, Hannon RA, et al. The effect of calcium supplementation on the circadian rhythm of bone resorption. J Clin Endocrino! Metab 1994;79:730-735. 47. Qyist P, Christgau P, Pedersen BJ, Schlemmer A, Christiansen C. Circadian variation in the serum concentration of C-terminal telopeptides of type I collagen (serum CTX): effects of gender, age, menopausal status, posture, daylight, serum cortisol and fasting. Bone 2002;31:57-61. 48. Nielsen HK, Brixen K, Mosekilde L. Diurnal rhythm in serum activity of wheat-germ lectin-precipitable alkaline phosphatase: temporal relationships with the diurnal rhythm of serum osteocalcin. Scand J Clin Lab Invest 1990;50:851-856. 49. Pedersen BJ, Schlemmer A, Rosenquist C, Hassager C, Christiansen C. Circadian rhythm in type I collagen formation in postmenopausal women with and without osteopenia. Osteoporos Int 1995;5: 472-477. 50. Eastell R, Simmons PS, Colwell A, et al. Nyctohemeral changes in bone turnover assessed by serum bone Gla-protein concentration and urinary deoxypyridinoline excretion: effects of growth and ageing. Clin Sci (Lond) 1992;83:375-382. 51. Schlemmer A, Hassager C, Pedersen BJ, Christiansen C. Posture, age, menopause, and osteopenia do not influence the circadian variation in the urinary excretion of pyridinium crosslinks. J Bone Miner Res 1994;9:1883-1888. 52. Hassager C, Risteli J, Risteli L, Jensen SB, Christiansen C. Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy premenopausal women. J Bone Miner Res 1992;7: 1307-1311. 53. Eastell R, Calvo MS, Burritt MF, et al. Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. J Clin Endocrinol Metab 1992;74:487-494. 54. Greenspan SL, Dresner-Pollak R, Parker RA, London D, Ferguson L. Diurnal variation of bone mineral turnover in elderly men and women. Calcif Tissue Int 1997;60:419-423. 55. Clowes JA, Allen HC, Prentis DM, Eastell R, Blumsohn A. Octreotide abolishes the acute decrease in bone turnover in response to oral glucose. J Clin Endocrinol Metab 2003;88:4867-4873. 56. Bjarnason NH, Henriksen EE, Alexandersen P, et al. Mechanism of circadian variation in bone resorption. Bone 2002;30:307-313. 57. Nielsen HK, Brixen K, Bouillon R, Mosekilde L. Changes in biochemical markers of osteoblastic activity during the menstrual cycle. J C/in Endocrino! Metab 1990;70:1431-1437.
347 58. Gorai I, Chaki O, Nakayama M, Minaguchi H. Urinary biochemical markers for bone resorption during the menstrual cycle. Cak~Tissue Int 1995;57:100-104. 59. Schlemmer A, Hassager C, Risteli J, et al. Possible variation in bone resorption during the normal menstrual cycle. Acta Endocrinol (Copenh) 1993;129:388-392. 60. Vanderschueren D, Gevers G, Dequeker J, et al. Seasonal variation in bone metabolism in young healthy subjects. Caki~ Tissue Int 1991;49:84-89. 61. Thomsen K, Eriksen EF, Jorgensen JC, Charles P, Mosekilde L. Seasonal variation of serum bone GLA protein. ScandJ Clin Lab Invest 1989;49:605-611. 62. Woitge HW, Scheidt-Nave C, Kissling C, et al. Seasonal variation of biochemical indexes of bone turnover: results of a population-based study. J Clin Endocrinol Metab 1998;83:68-75. 63. Woitge HW, Knothe A, Witte K, et al. Circaannual rhythms and interactions of vitamin D metabolites, parathyroid hormone, and biochemical markers of skeletal homeostasis: a prospective study. J Bone Miner Res 2000;15:2443-2450. 64. Blumsohn A, Naylor KE, Timm W, et al. Absence of marked seasonal change in bone turnover: a longitudinal and multicenter crosssectional study. J Bone Miner Res 2003;18:1274-1281. 65. Carnevale V, Modoni S, Pileri M, et al. Longitudinal evaluation of vitamin D status in healthy subjects from southern Italy: seasonal and gender differences. OsteoporosInt 2001;12:1026-1030. 66. Mallmin H, Ljunghall S, Larsson K. Biochemical markers of bone metabolism in patients with fracture of the distal forearm. C/in Orthop Relat Res 1993;295:259-263. 67. Ingle BM, Hay SM, Bottjer HM, Eastell R. Changes in bone mass and bone turnover following distal forearm fracture. Osteoporos Int 1999; 10:399-407. 68. Perry HM III, Jensen J, Kaiser FE, et al. The effects of thiazide diuretics on calcium metabolism in the aged. J Am Geriatr Soc 1993;41:818-822. 69. Ohishi T, Kushida K, Takahashi M, et al. Urinary bone resorption markers in patients with metabolic bone disorders. Bone 1994;15: 15-20. 70. Valimaki MJ, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res 1994;9:631-637. 71. Marshall LA, Cain DF, Dmowski WP, Chesnut CHIII. Urinary Ntelopeptides to monitor bone resorption while on GnRtt agonist therapy. Obstet Gyneco11996;87:350-354. 72. Ravn P, Fledelius C, Rosenquist C, Overgaard K, Christiansen C. High bone turnover is associated with low bone mass in both pre- and postmenopausal women. Bone 1996;19:291-298. 73. Ebeling PR, Atley LM, Guthrie JR, et al. Bone turnover markers and bone density across the menopausal transition. J Clin Endocrinol Metab 1996;81:3366-3371. 74. Perrien DS, Achenbach SJ, Bledsoe SE, et al. Bone turnover across the menopause transition: correlations with inhibins and FSH. J Clin Endocrinol Metab 2006;91:1848-1854. 75. Griesmacher A, Peichl P, Pointinger P, et al. Biochemical markers in menopausal women. ScandJ Clin Lab Invest Supp11997;227:64-72. 76. Hassager C, Colwell A, Assiri AM, et al. Effect of menopause and hormone replacement therapy on urinary excretion of pyridinium cross-links: a longitudinal and cross-sectional study. Clin Endocrinol (Oxf) 1992;37:45-50. 77. Uebelhart D, Gineyts E, Chapuy MC, Delmas PD. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner 1990;8:87-96. 78. Gorai I, Taguchi Y, Chaki O, Nakayama M, Minaguchi H. Specific changes of urinary excretion of cross-linked N-telopeptides of type I collagen in pre- and postmenopausal women: correlation with other markers of bone turnover. CalcifTissue Int 1997;60:317-322.
348 79. Garnero P, Gineyts E, Arbault P, Christiansen C, Delmas PD. Different effects of bisphosphonate and estrogen therapy on free and peptide-bound bone cross-links excretion. J Bone Miner Res 1995; 10:641-649. 80. Hassager C, Risteli J, Risteli L, Christiansen C. Effect of the menopause and hormone replacement therapy on the carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen. OsteoporosInt 1994;4:349-352. 81. Kerschan-Schindl K, Hawa G, Kudlacek S, Woloszczuk W, Pietschmann P. Serum levels ofcathepsin K decrease with age in both women and men. Exp Geronto12005;40:532-535. 82. Melkko J, Kauppila S, Niemi S, et al. Immunoassay for intact aminoterminal propeptide of human type I procollagen. Clin Chem 1996; 42:947-954. 83. Kelly PJ, Pocock NA, Sambrook PN, Eisman JA. Age and menopause-related changes in indices of bone turnover. J Clin Endocrinol Metab 1989;69:1160-1165. 84. Eastell R, Delmas PD, Hodgson SF, et al. Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers. J Clin Endocrinol Metab 1988;67:741-748. 85. Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 1996;11:337-349. 86. Valimaki MJ, Tahtela R, Jones JD, Peterson JM, Riggs BL. Bone resorption in healthy and osteoporotic postmenopausal women: comparison markers for serum carboxy-terminal telopeptide of type I collagen and urinary pyridinium cross-finks. Eur J Endocrinol 1994;131:258-262. 87. Kushida K, Takahashi M, Kawana K, Inoue T. Comparison of markers for bone formation and resorption in premenopausal and postmenopausal subjects, and osteoporosis patients. J Clin Endocrinol Metab 1995;80:2447-2450. 88. Eastell R, Robins SP, Colwell T, et al. Evaluation of bone turnover in type I osteoporosis using biochemical markers specific for both bone formation and bone resorption. OsteoporosInt 1993;3:255-260. 89. Schneider DL, Barrett-Connor EL. Urinary N-telopeptide levels discriminate normal, osteopenic, and osteoporotic bone mineral density. Arch Intern Med 1997;157:1241-1245. 90. Meier C, Meinhardt U, Greenfield JR, et al. Serum cathepsin K concentrations reflect osteoclastic activity in women with postmenopausal osteoporosis and patients with Paget's disease. Clin Lab 2006;52:1-10. 91. Rosen CJ, Hochberg MC, Bonnick SL, et al. Treatment with onceweekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 2005;20:141-151. 92. Rizzoli R, Greenspan SL, Bone GIII, et al. Two-year results of onceweekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 2002;17:1988-1996. 93. Hannon RA, Clowes JA, Eagleton AC, et al. Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption. Bone 2004;34:187-194. 94. Hansdottir H, Franzson L, Prestwood K, Sigurdsson G. The effect of raloxifene on markers of bone turnover in older women living in longterm care facilities. J A m Geriatr Soc 2004;52:779-783. 95. Reginster JY, Sarkar S, Zegels B, et al. Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk. Bone 2004;34:344-351. 96. Riggs B L, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 2005;20:177-184.
EASTELL AND HANNON 97. Chen P, Satterwhite JH, Licata AA, et al. Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res 2005;20:962-970. 98. McClung MR, San MJ, Miller PD, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med 2005;165:1762-1768. 99. Dobnig H, Sipos A, Jiang Y, et al. Early changes in biochemical markers of bone formation correlate with improvements in bone structure during teriparatide therapy. J Clin Endocrinol Metab 2005;90:3970-3977. 100. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N E n g l J M e d 2004;350:459-468. 101. Hui SL, Slemenda CW, Johnston CC Jr. The contribution of bone loss to postmenopausal osteoporosis. OsteoporosInt 1990;1:30-34. 102. Rogers A, Hannon RA, Eastell R. Biochemical markers as predictors of rates of bone loss after menopause. J Bone Miner Res 2000;15: 1398-1404. 103. Uebelhart D, Schlemmer A, Johansen JS, et al. Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 1991;72:367-373. 104. Mole PA, Walkinshaw MH, Robins SP, Paterson CR. Can urinary pyridinium crosslinks and urinary oestrogens predict bone mass and rate of bone loss after the menopause? Eur J Clin Invest 1992;22: 767-771. 105. Cosman F, Nieves J, Wilkinson C, et al. Bone density change and biochemical indices of skeletal turnover. Calcif Tissue Int 1996;58: 236-243. 106. Dresner-Pollak R, Parker RA, Poku M, et al. Biochemical markers of bone turnover reflect femoral bone loss in elderly women. CalcifTissue Int 1996;59:328-333. 107. Bauer DC, Sklarin PM, Stone KL, et al. Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures. J Bone Miner Res 1999; 14:1404-1410. 108. Garnero P, Sornay-Rendu E, Duboeuf F, Delmas PD. Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: the OFELY study. J Bone Miner Res 1999;14:1614-1621. 109. Hannon RA, Eastell R. Biochemical markers of bone turnover and fracture prediction. J Br Menopause Soc 2003;9:10-15. 110. Garnero P, Hausherr E, Chapuy MC, et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. JBone Miner Res 1996;11:1531-1538. 111. Melton LJ III, Khosla S, Atkinson EJ, O'Fallon WM, Riggs B L. Relationship of bone turnover to bone density and fractures. J Bone Miner Res 1997;12:1083-1091. 112. Sarkar S, Reginster JY, Crans GG, et al. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 2004;19:394-401. 113. Greenspan SL, Rosen HN, Parker RA. Early changes in serum Ntelopeptide and C-telopeptide cross-linked collagen type 1 predict long-term response to alendronate therapy in elderly women. J Clin Endocrinol Metab 2000;85:3537-3540. 114. Greenspan SL, Resnick NM, Parker RA. Early changes in biochemical markers of bone turnover are associated with long-term changes in bone mineral density in elderly women on alendronate, hormone replacement therapy, or combination therapy: a three-year, doubleblind, placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2005;90:2762-2767. 115. Ravn P, Thompson DE, Ross PD, Christiansen C. Biochemical markers for prediction of 4-year response in bone mass during bisphosphonate treatment for prevention of postmenopausal osteoporosis. Bone 2003;33:150-158.
CHAPTER 27 Biochemical Markers of Bone Turnover 116. Bauer DC, Garnero P, Bilezikian JP, et al. Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2006;91:1370-1375. 117. Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. JBone Miner Res 2003;18:1051-1056.
349 118. Sarkar S, Reginster JY, Crans GG, et al. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 2004;19:394-401. 119. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab 2004;89:1117-1123.
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; H A P T E R 2{
Interventions for Osteoporosis FERGUS S J . KEATING
GiggsHill Surgery,Thames Ditton, Surrey,UK KT7 0EB
JOHN C . STEVENSON
NationalHeart & Lung Institute, Imperial College London, Royal Brompton Hospital, London, UK SW3 6NP
I. THE MAGNITUDE OF THE DISEASE
tripling of the incidence of hip fracture may occur by 2040. A similar aging of the population is predicted in underdeveloped countries as infant and child mortality rates improve, and the consequent rise in osteoporosis incidence that will eventually ensue may impose an overwhelming financial burden on the health care systems of these countries.
Although previously underestimated as a major public health concern, osteoporosis is now recognized as one of the most important diseases facing women and men (to some lesser extent) of advancing age. Some 50% of women in the United Kingdom over 50 years of age (and 20% of men) will sustain an osteoporotic fracture (1). Postmenopausal osteoporosis accounts for the majority of the disease; however, although it is beyond the scope of this chapter, it should be remembered that other secondary causes account for a significant number of new cases of fracture each year. The extent of osteoporosis is highlighted by European statistics showing a yearly incidence of 60,000 hip fractures, 50,000 wrist fractures, and 120,000 vertebral fractures (1-3). In England and Wales alone, more than 1.14 million women have been diagnosed with postmenopausal osteoporosis following dual-energy x-ray absorptiometry (DEXA) scanning of the hip (4). In the United Kingdom, a woman has an approximate 17% lifetime risk of hip fracture (5), and the mortality 3 months post hip fracture is as high as 18% (6). Approximately 14,000 people will die each year in the United Kingdom as a result of hip fracture (7). The cost of treating all osteoporotic postmenopausal fractures in the United Kingdom is predicted to rise to s billion by 2020 (8). Moreover, the situation is only likely to worsen as the population of the developed world continues to age. In the United States, attributable costs for osteoporosis may be as high as $10 billion. Indeed, the growth in the elderly population of the United States is already exceeding the figures predicted, and if this trend were to continue, a T R E A T M E N T OF T H E POSTMENOPAUSAL W O M A N
II. DEFINITION OF OSTEOPOROSIS Osteoporosis has been defined as "a disease characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk" (9). Osteoporosis (porous bone) implies a histologic diagnosis of reduced bone tissue and deranged architecture but normal mineralization; however, the clinical diagnosis of the disease has been made traditionally on the occurrence of fragility fractures, principally at the femoral neck, spine, and distal forearm. The main obstacle to such a fracture-based diagnosis was that a patient previously described as normal became immediately osteoporotic on the occurrence of a fragility fracture, and this was inconsistent with our knowledge of the natural history of the disease. Such an approach also led inevitably to a delay in diagnosis of disease until an "end stage" was reached, and the opportunity was wasted to prevent the occurrence of the fracture. To overcome this dilemma in diagnosis, attempts have been made to define osteoporosis as a disease diagnosed at a certain low level of bone density, in the same way that hypertension as a disease is defined beyond a set level of blood pressure. It follows that for such a diagnosis to be viable, 351
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TABLE 28.1 World Health Organization Classification of Osteoporosis Normal: Bone mineral density (BMD) not more than 1 standard deviation (SD) below the young adult mean Osteopenia: BMD between 1 and 2.5 SDs below the young adult mean Osteoporosis: BMD more than 2.5 SDs below the young adult mean Established (severe) osteoporosis: BMD more than 2.5 SDs below the young adult mean in the presence of one or more fragility fractures
accurate, noninvasive, and reproducible methods of measuring bone density must be available. The advent of DEXA fulfilled these criteria at minimal radiation exposure and is currently the most prevalent method of bone densitometry in the United Kingdom and United States. Although much debate continues as to the correct level of bone mineral density (BMD) below which to assign a diagnosis of osteoporosis, the World Health Organization (WHO) proposed a stratified classification of osteoporosis in 1994 to encompass both systems of diagnosis, and this is summarized in Table 28.1 (10). Thus an individual would be termed osteoporotic if his or her BMD were less than 2.5 standard deviations (SDs) below the young adult range, regardless of whether a fracture had occurred. A further classification including values of BMD between 1 and 2.5 SD below the young adult mean was also included, and such individuals were termed osteopenic (low bone mass) and said to be at higher risk of future osteoporosis than the normal population. The W H O is currently revising these definitions of osteopenia and osteoporosis to include factors other than only BMD, and these new recommendations are awaited.
A. L o w B o n e D e n s i t y a n d Fragility Fractures Prospective studies have shown that with declining BMD, the risk of fragility fractures increases progressively and continuously (11,12), and fracture risk increases by up to threefold for every SD decrease in BMD (13). At 2.5 SDs below the young adult mean, 30% ofpostmenopausal women will be identified as having osteoporosis using BMD measurements from the spine, hip, or forearm, and this is roughly the equivalent lifetime risk for fractures at these sites (13). Decreased bone mass is associated with increased fracture risk across all skeletal sites but is most significant in terms of mortality and morbidity at the hip. There is an almost exponential rise in hip fracture incidence after age 50 until at least the ninth decade, and incidence rates reach approximately 3% per year among Caucasian women over age 85 in northern Europe and the United States (14). The associated mortality with hip fracture is around 20% at 1 year post-
fracture, and this often follows an extended period of hospitalization. Morbidity is also high; 10% of women sustaining hip fracture become dependent in actMties of daily 1Mng, and almost 50% are rendered dependent upon long-term institutionalized nursing care (15). Although hip fracture is most common in the elderly, it is not an insignificant problem for younger postmenopausal women. In the age group 50 to 80 years, around 36% of classical osteoporotic fractures occur in those younger than age 65 (16,17). In the United Kingdom, this amounts to over 100,000 fractures per year in women aged 50 to 65 years, more than 9000 of which are hip fractures (16,17). Although mortality rates are lower for vertebral and wrist fractures, morbidity is significant. Even asymptomatic vertebral fractures may lead to a reduction in actMties of daily 1Mng through progressive skeletal deformities such as kyphoscoliosis, and persistent pain may impinge on the patient's life, both physically and psychologically. Painful, symptomatic vertebral fractures often necessitate periods of bed rest for as long as 6 months. Incidence rates for vertebral fractures are more difficult to report due to the large number of subclinical fractures and variation in the methodology employed to assess vertebral deformity, but the same pattern of age-related, exponentially increased incidence rate is also seen with vertebral fracture as with hip fracture. One study of a population in the United States showed an annual incidence of 0.5% at age 50, rising to 4% at age 85 (16). However, more data are available concerning the prevalence of vertebral fracture, and one study reported rising age-related prevalence rates reaching a maximum of 20% at age 70 in a population of 2063 women in Puerto Rico and Michigan (United States) (18). A prevalence of wedge fracture of around 60% in women older than 70 years and a prevalence of crush fracture of 10% has previously been shown (19). The mortality associated with vertebral fracture is often overlooked, but the 5-year mortality has been estimated at 20% to 30% (17). Distal forearm fractures also show a steep rise in incidence in women with increasing age, but the rise tends to occur at an earlier age, and by around 60 years of age, the incidence rate begins to level off to around 0.5% of women per year (20). It is thought that the classic fall onto the outstretched hand producing the distal radius fracture becomes less common with advancing age as decreased proprioceptive and reflex responses diminish the speed of this defensive mechanism. Consequently, more falls occur directly onto the lower limb, which may in part contribute to the increase in hip fracture observed with increasing age. Distal radius fracture accounts for 50,000 hospital admissions per year in the United States and more than 6 million restricted activity days in people over 45 years of age (21). Persistent morbidity is also frequent, with chronic pain, loss of function, neuropathies, and posttraumatic arthritis, and many patients report poor functional outcome at 6 months post-fracture.
CHAPTER 28 Interventions for Osteoporosis
III. GENETIC A N D ENVIRONMENTAL INFLUENCES ON BONE MASS Peak bone mass is reached soon after the end of linear growth and is largely genetically determined, although environmental factors can influence the eventual final peak bone mass achieved (Table 28.2). Twin studies and family studies of bone mineral density have shown that genetic factors are probably the single most important influence on bone mass and osteoporotic fracture risk. Studies have revealed that as much as 70% to 85% of the interindividual variation in bone mass is genetically determined (22). Several genes are thought to contribute to the determination of bone mass, rather than a single gene or pair of genes contributing major effects. However, at present the exact number and precise function of these genes remains unclear. Candidate gene studies have identified potential contributors to osteoporotic risk, and these are shown in Table 28.3. Much work is still outstanding as to the relative contributions, if at all, of these and other genes, and further elucidation of the human genome will inevitably produce further candidate genes that may be shown to contribute to bone density. Other evidence from identical twin studies has shown that variation in bone mass increases with age, suggesting that bone loss may be more independent of genetic factors (23)
TABLE 28.2
Factors Affecting Bone Mass
Genetic Racial Geographical Environmental 1. In attaining peak bone mass Hormonal Physical activity Diet 2. After peak mass achieved Smoking Alcohol Physical activity Hormonal Diet
TABLE 28.3 Gene studied
Vitamin D receptor Estrogen receptor Transforming growth f actor-~ Interleukin-6 Collagen type I genes Collagenase From ref. 23.
353 Studies of incidence rates of osteoporotic fractures show that racial and geographic factors are important determinants of fracture risk, with European and American women having generally higher fracture rates than women from developing nations (24). Within developed nations, racial variations in fracture rates are also observed; for example, African-American women in the United States display a hip fracture rate approximately one-third lower than that of American Caucasian women (25). Hip fracture rates among black African women are lower still than African-American women (24), despite the evidence from the limited number of studies available demonstrating that black African women have similar or slightly less bone density than American Caucasian women and considerably less bone mass than African-American women (26,27). This evidence would suggest that within populations, bone density variation is the most influential variable of fracture rates but that other variables play an important role in the observed differences of fracture rates among countries. Peak bone mass declines from around middle age, although earlier in the proximal femur (28), and both men and women lose about 0.3% to 0.5% of their bone mass every year. Again, adverse environmental factors can further decrease these losses. Women experience an additional accelerated period of bone loss following their menopause, which may be as much as tenfold higher than the premenopausal rate of bone loss, and for the first 5 to 10 years of postmenopausal life, this loss can be even higher still. Consequently, bone mass may fall to about half of its peak value by around 80 years of age. The accelerated rate of bone loss in postmenopausal women results from increased bone turnover due to the effect of estrogen deficiency on the bone remodeling process described in the next section.
IV. BONE REMODELING A N D OSTEOPOROSIS As with almost all adult bone diseases, osteoporosis develops from a disorder of the bone remodeling process. Adult skeletal bone consists of cortical (compact) and tra-
Some Candidate Genes for Studying the Genetic Contribution to Osteoporosis Rationale for study Vitamin D regulates bone cell differentiation, bone turnover, and calcium homeostasis by interaction with the vitamin D receptor Estrogen regulates bone turnover and skeletal growth by interaction with the estrogen receptor Present in bone matrix; is thought to couple bone resorption and bone formation Regulates osteoclast differentiation; may mediate some actions of sex hormones in bone Type I collagen is the most abundant protein in bone A degradative enzyme involved in resorption of bone matrix
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becular (cancellous) bone and is continuously repaired and reformed by a process known as remodeling. It appears that bone remodeling is an essential process in land-based vertebrates to maintain the integrity of the skeleton. Cortical bone is dense and forms some 85% of the total body bone, predominantly in the long shafts of the appendicular skeleton. It is laid down concentrically around central canals, termed Haversian systems, that contain blood, lymphatics, nerves, and connective tissue. Trabecular bone, although forming only 15% of the adult bone, is relatively prominent at the ends of long bones and in the inner parts of flat bones. It consists of interconnecting trabeculae interspersed by the bone marrow. In the lumbar spine, as much as 65% of the bone is of the trabecular type. Bone remodeling occurs at discrete sites, known as bone remodeling units, on the bone surface of both trabecular and cortical bone. The process basically involves the removal of mineralized bone and its replacement with newly formed and mineralized osteoid. Central to the process are the actions of osteoclasts and osteoblasts. Osteoclasts, derived from the hematopoietic precursors of the monocyte-macrophage lineage, perform the resorption of mineralized bone by acidification and proteolytic digestion, and osteoblasts, descended from bone marrow pluripotent stromal stem cells, are responsible for the formation and subsequent mineralization of bone matrix. Remodeling always follows in a sequential, closely coupled pattern of resorption followed by formation, and the process takes about 3 to 4 months to complete, with resorption occupying the first 10 days or so. Remodeling occurs in discrete packages on both cortical (in the Haversian systems) and trabecular bone (on the trabecular surfaces), and at any one time, multiple bone remodeling units are at different stages of the bone remodeling process. In the development of osteoporosis, an imbalance exists between resorption and formation, with net bone loss. The most important influences on this are the effects of aging and the loss of gonadal function (see later discussion).
A. Bone Resorption Bone resorption first involves activation of the quiescent bone surface, with retraction of the lining cells (specialized osteoblasts) and proteolytic digestion of the endosteal membrane, resulting in exposure of the mineralized bone ready for osteoclastic resorption. The underlying mechanisms governing activation are not well understood; however, it seems that matrix metalloproteinases (released from osteoblasts) are involved in the removal of the endosteal membrane. It is also possible that activation is prompted by mechanical stresses acting on specific sites, transmitted via the osteocytic-canalicular network of the bone (29). Activation is followed by recruitment of the osteoclast precursors to the exposed bone and differentiation of these precursors into the
mature osteoclast. A series of steps achieves this, commencing with fusion of the precursors into a multinucleated cell. It has been demonstrated that the higher the number of nuclei within the cell, the more effective the osteoclastic bone resorption (30). Recent work has shown that osteoclastic fusion may occur in a similar fashion to trophoblastic cell fusion in the placenta using (E)-cadherin, an hemophilic calcium-dependent cell attachment molecule (31,32). Following fusion of the precursors, attachment to the bone surfaces occurs via integrins on the osteoclast cell membrane that bind to bone matrix molecules through specific RGD (Arg-Gly-Asp) sequences (33). The osteoclast then undergoes polarization, with realignment of the intracellular organelles and the development of a ruffled border, a specialized area of the cell membrane in proximity to the bone surface that is associated with the expression of the vacuolar ATPase proton pump, src proto-oncogene, and proteolytic enzymes required in the resorptive process. After resorption, osteoclastic action is terminated by cell apoptosis, characterized by the morphologic changes of nuclear chromatin condensation and separation of the osteoclast from the bone surface. This apoptosis may be the common end pathway in the action of both estrogens and bisphosphonates on bone, and Parfitt has linked the excessive osteoclastic activity associated with estrogen deficiency to the absence of an apoptosis stimulus (34).
B. Bone Formation Bone formation commences with chemotaxis of osteoblasts and their precursors to the site of the resorptive defect, and it is thought that this occurs as a result of the action of local factors released by the resorbing bone. In vitro studies by Mundy and co-workers demonstrated that cells with osteoblastic properties were chemotactically attracted by local factors produced by the resorbing bone (35,36). Transforming growth factor [3 (TGF-[3) has been demonstrated to be chemotactic for bone cells (37) and is released from resorbing bone. Platelet derived growth factors (PDGFs) are also possible mediators in this process and have been demonstrated to be chemotactic for certain mesenchymal cells, monocytes, neutrophils, and smooth muscle cells (30). It is also possible that structural proteins such as collagen and bone GLA protein act as chemotactic stimulants to osteoblastic congregation at resorptive sites (35,36). Following chemotaxis, the osteoblasts undergo proliferation, and it is likely that growth factors such as the TGF-[3 superfamily, PDGF, insulin growth factors 1 and 2 (IGF-1 and -2), and human basic fibroblast growth factors (hbFGFs) are mediators in this process. The precursors then undergo differentiation into mature osteoblasts. Bonederived growth factors such as IGF-1 and bone morphogenetic protein (BMP)-2 have been suggested as mediators in
CHAPTER28 Interventions for Osteoporosis
this stage, and interestingly, TGF-[3 may actually inhibit osteoblast differentiation, which suggests that it acts as a trigger early in the process of osteoblast recruitment and proliferation but must be removed or inactivated prior to differentiation of the osteoblasts. Differentiated osteoblasts subsequently lay down the new osteoid in the resorption cavity, which is then mineralized. Cessation of osteoblast activity is the final stage of bone remodeling, and again local factors, possibly TGF-[3, are central to this process.
C. Control of Remodeling A complex interrelationship between systemic hormones, mechanical stresses, and locally derived cytokines, prostaglandins, and growth factors is responsible for the control of bone remodeling, and the major compounds involved in this control are shown in Table 28.4. Adults show resorption and re-formation of approximately 25% of their trabecular bone, but only around 3% of their cortical bone, each year. Trabecular bone has a higher surface-to-volume ratio, and as much as 85% of the surface of trabecular bone is in contact with the bone marrow. Thus, it follows that control of remodeling is primarily under local control (38). Local control of remodeling is primarily affected by a large number of cytokines and growth factors, some of which can exert influence on both osteoblasts and osteoclasts, and many of which act interdependently. For example, the precursor of mature osteoblasts, the stromal-osteoblastic precursor cell, is stimulated by both local factors, such as interleukin (IL)-I and tumor necrosis factor (TNF), and by systemic hormones, such as parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D3 to produce in turn cytokines and growth factors, in particular IL-6 and IL-11, and these cytokines regulate the differentiation pathway of preosteoclasts. Indeed, the list of cytokines and colony stimulating factors involved in the development of osteoclasts, and therefore stimulation of their action, is large and includes IL-1, -3, -6, and -11; TNF; granulocyte-macrophage colony stimulating factor (GM-CSF); macrophage colony stimulating factor (MCSF); leukemia inhibitory factor; and stem cell factor (38). It seems that IL-6 may have a pivotal role in the osteoclastogenic process, in that it has been implicated in the stimulation of differentiation of the granulocyte-macrophage colony forming units (GM-CFU) into osteoclast precursors (39), also stimulates osteoclast formation, and, in combination with IL-1, stimulates bone resorption (38). It is also possible that IL-6 can stimulate mature osteoclasts, as receptors for IL-6 have been demonstrated on human osteoclastoma cells and were found to increase the resorptive activity of these cells (40). As observed previously, it has been shown that normal remodeling involves close coupling of the resorptive and formative processes. Here again, it is thought that local fac-
355 TABLE 28.4 Systematic Hormones and Local Factors Involved in the Control of Bone Remodeling Systemic Hormones Parathyroid hormone (PTH) Tri-iodothyronine Growth hormone (GH) Glucocorticoids 1,25 Dihydroxy-vitamin D3 Sex steroids Cytokines and Growth Factors Stimulate bone formation: Transforming growth factor-J3 (TGF-~) Insulin-like growth factors (IGFs) Platelet-derived growth factors (PDGFs) Fibroblast growth factors (FGFs) Bone morphogenetic proteins (BMPs) Stimulates bone resorption: Interleukin (IL)-I,-6,-8,-11 PDGFs Macrophage colony stimulating factor (M-CSF) Granulocyte/macrophage colony stimulating factor (GM-CSF) Epidermal growth factors (EGFs) Tumor necrosis factors (TNF) FGFs Leukemia inhibitory factor Inhibit bone resorption: Interferon-7 (IFN-(7) IL-4
tors are primarily involved in the regulation of this coupling. In particular, the TGF-[3 superfamily may be especially important. Bone resorption leads to the release of TGF-[3, as previously discussed, and this stimulates osteoblast precursor proliferation. The exposure, however, is transient, and subsequently the proliferating cells undergo differentiation into mature osteoblasts and express BMPs, which are autostimulatory upon osteoblasts, propagating the formation of mineralized bone.
V. THE TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS A. Estrogens In his classic observations of the link between osteoporosis and estrogen deficiency, Albright noted that 40 of 42 women with osteoporotic fractures were postmenopausal (41). It was first proposed that estrogen deficiency led to a decrease in osteoblast activity and a subsequent decrease in bone mass (42), but this explanation proved to be inadequate when a consistent decline in osteoblast activity was not shown in postmenopausal women (43). Various studies have showed that the cessation of ovarian function is associated
356 with an increase in bone turnover and a consequent decline in bone mass (44). The most usual cause of estrogen decline is the onset of menopause, either natural or surgical, and studies across all cultures have demonstrated bone loss. In addition, estrogen decline can result from ovarian failure secondary to anorexia, hyperprolactinemia, pituitary failure, and excessive exercise. Declining estrogen levels lead to an increase in the frequency of activation of remodeling cycles, with a subsequent increased rate of resorption and formation, as shown by the increased levels of markers for bone turnover in the serum and urine (serum alkaline phosphatase and osteocalcin; excretory products of type I collagen, such as hydroxyproline or pyridinoline cross-links of collagen) (45). An increase in the number of osteoclasts in trabecular bone is observed following the loss of ovarian activity. It has also been suggested that osteoclast aggression is increased in the estrogen deficient state, possibly due to the previously mentioned delay in osteoclast apoptosis at the termination of resorption, resulting in larger resorption cavities that can only be partially filled by osteoblast activity. Furthermore, with increased frequency of remodeling, the likelihood of simultaneous remodeling on opposite sides of trabeculae is increased, with a greater chance of complete transection of trabeculae and a consequent loss of template upon which further bone formation can occur, leading to the observed loss of bone mass and architecture characteristic of the disease. Fundamental differences exist between the patterns of bone loss seen with aging and loss of ovarian function. Postmenopausal bone loss is characteristically associated with excessive osteoclastic activity, as discussed previously, whereas bone loss associated with aging has been seen to be more related to a progressive decline in the number of osteoblasts available compared with the demand (46). The type of this bone loss also differs, with trabecular bone more affected in postmenopausal bone loss and cortical bone primarily affected by age-associated bone loss. Although the effects of estrogen deficiency on bone are well established, it has been difficult to describe the exact role of estrogens in modulating bone remodeling. It is known that pharmacologic doses of estrogens suppress the increased remodeling rates of postmenopausal women (47-49), and estrogen loss at menopause is associated with an apparent partial release from inhibition of skeletal resorption (50). Estrogen seems to act both directly and indirectly on bone. Eriksen et al. demonstrated evidence of estrogen acting through the classical estrogen receptor-mediated mechanism on cultured human osteoblast-like cells (51). Komm et al. showed that estrogen could act, via a direct receptormediated action, on osteoblast-like cells to enhance levels of type I procollagen and TGF-[3 mRNA levels (52) and argued that estrogen thus governed the transcriptional activity of the TGF-[3 gene in osteoblasts, which in turn could positively control the transcriptional activity of the type I
KEATING AND STEVENSON
collagen gene, thus providing a possible explanation for the observed effects of estrogen on bone remodeling. The indirect actions of estrogen on bone are mediated via cytokines and local growth factors. It has been proposed that TNF-cx and IL-1 both affect the initial step in estrogendeficiency bone loss. Both are released from the peripheral blood monocytes in excessive amounts in ovariectomized women and act as stimulators of bone resorption. This effect is antagonized by estrogen replacement. Further work on the TNF-ci cytokine has shown that permanent suppression of its activity can lead to protection against the increased bone turnover and bone loss associated with oophorectomy in mice (53). Further work on cytokines has shown that IL-6 production from bone marrow stromal and osteoblastic cell lines is inhibited by estrogen (54) and that this is mediated by an estrogen receptor-mediated inhibitory effect on the transcription gene for IL-6. Studies on ovariectomized mice showed that administration of 17~3-estradiol prevented the IL-6-mediated increases in osteoclast populations in trabecular bone. It can therefore be proposed that estrogen deficiency leads to in increase in expression of IL-6 and a consequent increased rate of osteoclastogenesis and therefore bone resorption. Furthermore, IL-6-deficient ovariectomized mice do not seem to undergo this bone loss associated with increased osteoclast numbers (38).
B. Hormone Replacement Therapy Epidemiologic and clinical data have consistently shown that hormone replacement therapy (HRT) results in a cessation of bone loss and an improvement in bone density with a subsequent reduction in risk of osteoporotic fracture (55-68). Earlier studies tended to use bone density measurements from the distal radius and the metacarpals, and therefore potential difficulty existed in attempting to extrapolate the results of these studies to the hip and spine, areas where trabecular bone is more prevalent. However, cross-sectional follow-up data from these earlier studies did show that similar effects were noted in the spine and hip (69). Lower doses than previously thought necessary are now proving effective (70-72), and a very low-dose transdermal estradiol product has recently been licensed for osteoporosis prevention by the U.S. Food and Drug Administration (FDA). The Women's Health Initiative (WHI) trials have confirmed the fracture reduction efficacy of HRT, including hip and spine fractures (73,74). These studies were of women aged 50 to 80 years, who were not known to have increased fracture risk and were supposed to be in general good health. With regard to the treatment of established osteoporosis, although it is likely to be effective, no appropriately sized studies to evaluate hip fracture prevention have been conducted with HRT in women with established osteoporosis. Whether very low-dose unopposed estrogen, with its minimal endo-
CHAPTER28 Interventions for Osteoporosis TABLE 28.5
Route Oral Transdermal Vaginal Subcutaneous Intramuscular
Estrogen Replacement Preparation
Tablets Patches, gels Creams/gels, rings, pessaries Implants
metrial stimulation and relative freedom from other side effects (72), will prove an effective and cheaper alternative for fracture prevention in these women remains to be determined. There is no doubting the efficacy of HRT for fracture prevention in postmenopausal women at increased risk but without previous fracture, and it may be best suited to younger postmenopausal women at increased risk. In such a population, HRT use for osteoporosis prevention would be cost effective (75). Hormone replacement can now be administered via a number of routes, and these are summarized in Table 28.5. There are several types of estrogens in common use in HRT preparations, and the most commonly used are conjugated equine estrogens (CEE), estradiol valerate, 17~-estradiol, and estrone sulphate. Studies have elucidated the optimum dosages of these estrogens for bone conservation, and the results are summarized in Table 28.6 (76-82). A higher dosage may be required for women who have undergone a premature menopause either due to surgery or for medical reasons, and more elderly women embarking on HRT may conserve bone on lower doses than listed, with the added benefit of minimizing the estrogenic side effects common in this group of patients. Unopposed estrogen use is advocated for women having undergone total hysterectomy, but additional progestogens are usually prescribed for women with an intact uterus embarking on HRT, to avoid the potential for endometrial hyperplasia and carcinoma. The addition of progestogen, either sequentially for 12 days each month, or as "bleed-free" continuous combined preparations, has been shown to abolish any increased risk of endometrial carcinoma compared with non-users of HRT (83). Both methods of combined HRT have been shown to produce bone-conserving effects, and there is some evidence to suggest that continuous combined HRT has a greater effect than sequential HRT (84,85). Progestogens derived from 19-norethisterone have been shown to be effective in reducing bone loss (84,86), possibly through their androgenic properties. Less-androgenic progestogens, such as dydrogesterone, have no effect on bone density (70). Although there is near unanimity among researchers on the beneficial effects of estrogen on bone density, far more debate exists regarding the timing and duration of treatment. HRT is not well tolerated in a substantial number of women,
357 TABLE 28.6 Commonly Used Estrogens and Standard Dosages Required to Preserve Bone Density Estrogen
Bone-Conserving Dose
Conjugated oral estrogens (72) Oral: estradiol valerate (77), 17~estradiol (71) Transdermal: 17~-estradiol (80) Percutaneous: 17~-estradiol (79) Subcutaneous: 17f3-estradiol (81-83)
0.3-0.625 mg daily 1-2 mg daily 50 gg daily 1.5 mg daily 25-50 mg every 6 months
Reference numbers are listed in parentheses.
and much attention has been drawn to the potential adverse effects of therapy, as discussed in the following section. Hormone replacement is most often commenced in the perimenopausal period, when symptomatic relief is often the most pressing indication for treatment, at least in the perception of the women affected. The duration of therapy has often been short term following the natural cessation of ovarian function and longer in the case of a surgically induced menopause. However, new data from a long-term prospective study suggest that even limited HRT use in women in the early menopause may result in later fracture reduction (87). 1. SAFETY OF H R T
In recent years, concerns regarding the safety of HRT have been expressed, first from large randomized clinical trials showing only minor risks (74,88), and secondly from an observational study (89) that appears to have overestimated the risk of breast cancer (90). This has led to certain regulatory authorities recommending that clinicians should only prescribe HRT for the prevention of osteoporosis "in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis" (90). Thus, it was recommended that HRT should no longer be prescribed freely for the prevention of osteoporosis. The concerns of the regulatory authorities about the safety of HRT have been challenged (90), and it has been suggested that their interpretation of the large clinical trials and one observational study, which they have primarily used as "evidence" for their recommendations, has been misguided. When given for the correct reasons, namely relief of menopausal symptoms or prevention of osteoporosis, the benefits of HRT far outweigh any risks.
2. RECOMMENDATIONS FOR H R T
A main indication for HRT remains the relief of postmenopausal symptoms, which brings about a major improvement in quality of life. No other therapy has proved
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more effective than HRT in this respect. It is also quite clear that HRT is an effective treatment for prevention of osteoporotic fractures in women without established disease. These women tend to be younger, because older women have an increasing prevalence of osteoporosis as defined by bone density criteria (91). HRT is less expensive than any of the alternatives, and thus its use for primary prevention should be actively encouraged, targeting postmenopausal women at high risk for fracture, such as those with osteopenia, family history of hip fracture, low body mass index, or history of corticosteroid use.
C. Bisphosphonates 1. PHYSIOLOGY
Bisphosphonates are stable analogues of pyrophosphate and share the same properties. Like pyrophosphate, they inhibit the precipitation of calcium phosphate from solution and inhibit crystal aggregation and the dissolution of crystals of hydroxyapatite. Bisphosphonates display a high affinity for hydroxyapatite and bone mineral, and this essentially limits their effects on bone. In a study using autoradiography with tritium labeled bisphosphonate, the highest concentration of the drug was found on the surface of the bone (92). Bisphosphonates were first recognized as inhibitors of bone resorption about 30 years ago (93,94). Bisphosphonates are effective in Paget's disease, hypercalcemia of malignancy, osteolytic bone metastasis, and osteoporosis. Gastrointestinal absorption of bisphosphonates is very low and if they are taken with or soon after even light meals, none will be absorbed. Approximately 20% of the circulating drug is retained by the skeleton (95), the rest being rapidly excreted unmodified by the kidney. Bisphosphonates bind strongly with hydroxyapatite crystals in the bone. Their skeletal half-life is long, perhaps up to 10 years or longer with certain bisphosphonates. The duration of biologic activity is very long in Paget's disease (months to years) but is shorter in patients with hypercalcemia of malignancy and even shorter in healthy postmenopausal women or patients with other metabolic bone disease (96). Little information has been published on the toxicity of bisphosphonates. Older studies examining etidronate have revealed little toxicity and no carcinogenicity, mitogenicity, or teratogenicity (97,98). Reproductive and developmental toxicity studies with alendronic acid and pamidronic acid have been conducted with rats and rabbits (99,100). No selective developmental toxicity was observed. However, at very high daily doses of pamidronate (10 times higher than the recommended human doses), a low incidence of shortened fetal long bones was noticed, associated with markedly low body weight. These effects are related to the mechanism of action of bisphosphonates. The drug prevents bone resorption in the pregnant animal, thus denying a source of calcium for
the growing fetus. In addition, it crosses the placenta, preventing fetal bone modeling. These findings suggest that bisphosphonates should be avoided in pregnancy unless absolutely indicated. 2. MODE OVACTION The mode of action of bisphosphonates has been studied extensively and appears to involve several possible mechanisms. At lower doses, bisphosphonates bind preferentially in the resorption pits under the osteoclasts; at higher doses, they may affect the mineralization associated with osteoblasts (101). The formation (adsorption) of calcium-bisphosphonate phase on the surface of the bone or enamel changes the bone physiochemical characteristics and can significantly reduce the rate of dissolution of the organic and inorganic substance. This leads to a shallowing of the resorption pits and a reduced rate of osteoclast migration and formation of new pits. At the cellular level, it appears that bisphosphonates are toxic to osteoclasts, leading to cellular death (102,103). As osteoclasts digest the bone surface of a bisphosphonate-treated subject, bisphosphonate is released and internalized by the osteoclast (104). Once internalized, bisphosphonates may interfere with the cytoskeleton, lead to loss of the ruffled border, or be directly cytotoxic (105). The micro-injection of bisphosphonates into isolated osteoclasts disrupts the cytoskeletal ring of action in polarized, resorbing osteoclasts (106). Bisphosphonates may also affect enzymes and then signal transduction cascades known to be responsible for osteoclast formation and activity (107). It is also possible that bisphosphonates affect bone resorption via release of a resorption inhibition factor of low molecular weight (50 years) 2416 PMW
Outcome Minimal increase in the incidence of hip (4.1 versus 1.1%) and arm (15.8 versus 13.1%) OA 1.8-fold increase in risk
0-1 year use 1-4 year use 4-10 year use > 10 year use
1.3-fold increase in risk 1.3-fold increase in risk 1.96-fold increase in risk 2.0-fold increase in risk
4-year use of HRT (prospective study) Ever-use versus no
No apparent effects
Ever-use versus no use
No effects
Nevitt et al. (59)
Knee pain and WOMAC scores
Maheu et al. (60)
Various measures of disease activity
PMW with prevalent CVD followed for 4 years 711 PMW 50-75 years 238 "painful" OA 240 "quiescent " "" OA 233 controls
Physician diagnosed or requiring treatment with pills or surgery
42,464 PMW (mean age 53 years) 12,521 with OA
No apparent effects
use
Beneficial effects
Parazzini et al. (61)
27% decrease in risk
CVD, cardiovasculardisease; HRT, hormone replacement therapy; OA, osteoarthritis; PMW, postmenopausalwomen.
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TABLE 30.3
Impact of Hormone Therapy on Osteoarthritis as Assessed by Imaging Technique-Based Diagnostic Diagnosis of OA
Beneficial effects Dennison et al. (63)
Radiography (hip)
Erb et al. ( 6 4 )
Radiography (hip or knee)
Nevitt et al. ( 6 5 )
Radiography (hip)
Participants PMW >45 y e a r s old 413 cases listed for hip replacement 413 controls 475 PMW (mean age 66.1 years) who underwent hip or knee replacement 4366 PMW (>65 years old) 539 with mild to moderate OA 214 with moderate to severe OA
Spector et al. (66)
HRT
Outcome
Bilateral oophorectomy Long-term use (>5 years) Short-term use 11.6% used hormones for a median of 5.4 years
1.9-fold increase in risk 40% decreased risk (NS) 70% increase in risk No apparent effects
Cross-sectional study (Low number of hormone users)
Current users
38% decreased risk
Largest crosssectional study
Current users who used HRT for less than 10 years Current users who had used HRT for at least 10 years Current users
25% decreased risk
Radiography of hand and knee (K-L index 2 +) Individual features of osteophytes and joint space narrowing Radiography (knee)
606 women (45-63 years old)
831 women (63-93 years)
Hormone use for at least 4 years
Wluka et al. (69)
Radiography of knee MRI of the knee
551 women (63-93 years) 42 users and 39 controls
Hormone use for 8 years Hormone use for at least 5 y e a r s
Cicuttini et al. (70)
MRI of patella
42 users and 39 controls
Hormone use for at least 5 years
Hannan et al. (67) Zhang et al. ( 6 8 )
Note
Cross-sectional study
43% decreased risk
69% decreased risk
Cross-sectional study
+ less joint space narrowing in the DIP joints 29% decreased risk for all OA 34% decreased risk for knee OA 60% decreased risk for knee OA Hormone use was associated with more articular cartilage No differences in patella cartilage
Prospective study
Prospective study Cross-sectional study Cross-sectional study
DIP, distal interphalangeal; HRT, hormone replacement therapy; MRI, magnetic resonance imaging;NS, non-significant; OA, osteoarthritis; PMW: postmenopausal women.
tion seems to be supported by the findings of an Italia study reported by Parazzini et al. (61), who found apparent benefits of H R T in a large population of early postmenopausal women who were an average of 53 years old at the time of assessment. A prospective analysis from the Chingford study (62) provides important clues as to why estrogen deficiency is an important risk factor for progressive OA and why hormone therapy is likely to provide beneficial effects in the early menopausal years. From the original study population of 1003 women, those women who had not received any bonemodifying medication, those who had radiographic informa-
tion on the 4-year progression of knee OA, and those who had baseline information on bone mineral density (BMD) were identified and separated into four groups as follows: controls (n = 50), progressive OA (n = 71), nonprogressive OA (n = 36), and osteoporosis (n = 59). The results demonstrated that bone resorption was increased in patients with progressive knee OA and was essentially unaltered in those with nonprogressive knee OA. The increase in bone resorption seen in patients with progressive knee OA was similar to that observed in patients with osteoporosis. These observations thus suggest that (1) the well-established effects of estrogen deficiency on bone turnover and related bone loss may
CHAPTER 30 Potentials of Estrogens in the Prevention of Osteoarthritis: What Do We Know and What Q.uestions are Still Pending? 399 also have implications for cartilage homeostasis and (2) the beneficial effects of hormone therapy in terms of inhibiting osteoclastic bone resorption might also provide benefits in terms of maintaining cartilage integrity if initiated in the early years of the menopause, when the impact of estrogen deficiency on bone loss is most pronounced. Table 30.3 lists major studies using imaging techniques as a basis for the diagnosis of joint lesions and OA. Interestingly, in this case most studies suggest decreased risk of OA associated with the use of HRT. Of these studies, some particular comments should be made. The Study of Osteoporotic Fractures published by Nevitt et al. (65) is a large cross-sectional analysis with validated radiographic data on hip OA. In this study, 539 mild-tomoderate cases and 214 moderate-to-severe cases of OA could be identified. The number of hormone users was also sufficiently high for proper statistical evaluation. Current users who used HRT for less than 10 years had a 25% decreased risk, whereas current users who used this therapy for more than 10 years had a 43% decreased risk for hip OA. The Framingham investigators published two reports regarding the effects of 4 and 8 years of HRT on the risk of OA; the former including 831 subjects and the latter including 551 subjects (67,68). Both analyses indicated moderate statistically nonsignificant protective effect against worsening of radiographic knee OA among elderly women. These findings corroborate the cross-sectional observations and point further to a potential benefit of female hormones in OA. Recently, a more advanced imaging technique, magnetic resonance imaging (MRI), has been introduced for a more direct visualization and morphometric assessment of articular cartilage. Preliminary studies using this technique indicated more articular cartilage in long-term users of HRT (>5 years) compared with never-users (69). Interestingly, the apparent benefits of HRT were seen in weight-bearing cartilage only, but not at other sites such as the patella (70).
IV. CONCLUSIONS AND PERSPECTIVES Currently hormone therapy is not recommended for primary prevention. The decision is based on findings of the Women's Health Initiative (WHI) study, which found risks exceeding benefits when the therapy was given as an estrogen plus progestin combination, and a balanced risk-benefit profile when the therapy was given as estrogen only (71,72). However, it is important to point out that the potential benefits of estrogen replacement for the prevention of OA have not been considered in the equation of the global index of risk and benefits. Current research on estrogen and OA appears to be conflicting, yet there is enough experimental
and clinical evidence to support further investigation into the therapeutic effects. Moreover, it remains to be clarified whether the conclusions of the W H I study would have been different had the majority of women in the study been in their early menopausal years. Hormone users in observational studies are women who initiate hormone therapy due to a need to control symptoms of estrogen deficiency arising in the early phase of the menopause. This period might actually open a therapeutic window for maximizing the multiple benefits of the therapy for effective long-term prevention of menopause-related diseases. In support of this line of thinking, we have recently shown that when applied in this critical period, even 2 to 3 years of H R T can bring lasting benefits for postmenopausal women after treatment withdrawal, in terms of prevention of osteoporotic fractures and cognitive decline (73,74). Another unanswered question is whether the safety profile of CEE plus medroxyprogesterone (MPA) is equally applicable to other combinations. In light of the W H I findings, the progestin component may carry greater importance for the coronary events and incidence of breast cancer during long-term therapy. Thus, estradiol with more novel progestins might confer different effects. Evaluation of progestins for their effects on insulin sensitivity and breast density is a crucial element of establishing safer combinations. Parenteral combination therapies, in particular ultralow-dose transdermal estradiol delivery systems carry great potential in this regard because they do not require continuous progestin supplementation (75). Finally, there are some methodologic issues worth mentioning with regard to the clinical assessment of the chondroprotective potential. The review illustrated that diversity of methods and selected end points had a considerable impact on the overall impression as to whether HRT carries chondroprotective effects. Therefore, there is an unmet need for standardizing and enhancing the accuracy and precision of methodology and thereby the reliability of our methodologic approach to the quantification of changes in articular cartilage. MRI allows direct three-dimensional visualization and quantification of articular cartilage and will likely improve the assessment of true chondroprotective effects of candidate drugs (76). In addition, much expectation regards the upcoming biomarkers. Because of their ability to respond rapidly to interventions, biologic markers will likely come to play an important role in the clinical development of novel structure-modifying agents (77). Biomarkers might also provide useful assistance in facilitating Phase I and II trials, which are supposed to define the optimal dose range of candidate drugs for large-scale assessments in Phase III trials. Randomized, double-blind, placebo-controlled trials using a methodologic approach that combines biomarkers
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with MRI will likely bring us closer to providing definitive answers as to whether hormone therapy administered in the early postmenopausal years carries the potential for decreasing the epidemiologic burden of OA.
References 1. Altman R, Asch E, Bloch D, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the knee. Arthritis Rheum 1986;29:1039-1049. 2. van Saase JL, van Romunde LK, Cats A, Vandenbroucke JP, Valkenburg HA. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 1989;48:271-280. 3. Oliveria SA, Felson DT, Reed JI, Cirillo PA, Walker AM. Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis Rheum 1995;38:1134-1141. 4. Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann Intern Med 2000;133:635-646. 5. Weinstein JN, Barmier JD. The Dartmouth atlas of musculoskeletal health care. Chicago: American Hospital Association Press, 2000. 6. Nelson DT, Nevitt MC. The effects of estrogen on osteoarthritis. Curt Opin Rheumato11998;10:269-272. 7. Felson DT, Zhang Y, Hannan MT, et al. The incidence and natural history of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum 1995;38:1500-1505. 8. Meachim G, Pedley RB. Implications of a sex difference in osteoarthrosis. Ann Rheum Dis 1980;39:199. 9. Srikanth VK, Fryer JL, Zhai G, et al. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage 2005;13:769-781. 10. Sylvia VL, Walton J, Lopez D, et al. 17-beta-Estradiol-BSA conjugates and 17-beta-estradiol regulate growth plate chondrocytes by common membrane associated mechanisms involving PKC dependent and independent signal transduction. J Cell Biochem 2001;81:413-429. 11. Evinger AJ III, Levin ER. Requirements for estrogen receptor alpha membrane localization and function. Steroids 2005;70:361-363. 12. Pelletier G. Localization of androgen and estrogen receptors in rat and primate tissues. Histol Histopatho12000; 15:1261-1270. 13. Richmond RS, Carlson CS, Register TC, Shanker G, Loeser RF. Functional estrogen receptors in adult articular cartilage: estrogen replacement therapy increases chondrocyte synthesis of proteoglycans and insulin-like growth factor binding protein 2. Arthritis Rheum 2000; 43:2081-2090. 14. Dayani N, Corvol MT, Robel P, et al. Estrogen receptors in cultured rabbit articular chondrocytes: influence of age. J Steroid Biochem 1988;31:351-356. 15. Classen H, Hassenpflug J, Schunke M, et al. Immunohistochemical detection of estrogen receptor alpha in articular chondrocytes from cows, pigs and humans: in situ and in vitro results. Ann Anat 2001;183:223-227. 16. Ushiyama T, Ueyama H, Inoue K, Ohkubo I, Hukuda S. Expression of genes for estrogen receptors alpha and bets in human articular chondrocytes. Osteoarthrits Cartilage 1999;7:560-566. 17. Nasatzky E, Schwartz Z, Soskolne WA, et al. Evidence for receptors specific for 17 beta-estradiol and testosterone in chondrocyte cultures. Connect Tissue Res 1994;30:277-294. 18. Richmond RS, Carlson CS, Register TC, Shanker G, Loeser RF. Estrogen replacement therapy increases chondrocyte synthesis of proteoglycans and insulin-like growth factor binding protein 2. Arthritis Rheum 2000;43:2081-2090.
19. Cheng P, Ma X, Xue Y, Li S, and Zhang Z. Effects of estradiol on proliferation and metabolism of rabbit mandibular condylar cartilage cells in vitro. Chin MedJ (Engl) 2003;116:1413-1417. 20. _Arevalo-Silva CA, Cao Y, Weng Y, et al. The effect of fibroblast growth factor and transforming growth factor-beta on porcine chondrocytes and tissue-engineered autologous elastic cartilage. Tissue Eng 2001;7:81-88. 21. Yang X, Chen L, Xu X, Li C, Huang C, Deng CX. TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Bio12001;153:35-46. 22. Goldaale JA, Frenkel SR, Dicesare PE. Estrogen and osteoarthritis.Am J Orthof 2004;33:71-80. 23. Saggese G, Federico G, Cinquianta L. In vitro effects of growth hormone and other hormones on chondrocytes and osteoblast-like cells. Acta Paediatr Supp11993;82:54-60. 24. Yaeger PC, Masi TL, De Ortiz JL, et al. Synergistic action of transforming growth factor-beta and insulin-like growth factor-I induces expression of type II collagen and aggrecan genes in adult human articular chondrocytes. Exp Cell Res 1997;237:318-325. 25. Kondo S, Cha SH, Xie WF, Sandell LJ. Cytoldne regulation of cartilage-derived retinoic acid-sensitive protein (CD-RAP) in primary articular chondrocytes: suppression by IL-1, bFGF, TGF beta and stimulation by IGF-1.J Orthop Res 2001;19:712-719. 26. Fernihough JK, Richmond RS, Carlson CS, et al. Estrogen replacement therapy modulation of the insulin-like growth factor system in monkey knee joints. Arthritis Rheum 1999;42:2103-2111. 27. Chambers MG, Bayliss MT, Mason RM. Chondrocyte cytokine and growth factor expression in murine osteoarthritis. Osteoarthritis Cartilage 1997;5:301-308. 28. Guerne PA, Carson D, Lotz M. IL-6 production by human chondrocytes: modulation of its synthesis by cytokines, growth factors and hormones in vitro. J Immuno11990;144:494-505. 29. Badger AM, Blake SM, Dodds RA, et al. Idoxifene, a novel selective estrogen receptor modulator, is effective in a rat model of adjuvantinduced arthritis. J Pharmacol Exp Ther 1999;291:1380-1386. 30. Richette P, Dumontier MF, Francois M, et al. Dual effects of 17 betaoestradiol on interleukin 1beta-induced proteoglycan degradation in chondrocytes. Ann Rheum Dis 2004;63:191-199. 31. Lee YJ, Lee EB, Kwon YE, et al. Effect of estrogen on the expression of matrix metalloproteinase (MMP)-I, MMP-3, and MMP-13 and tissue inhibitor of metalloproternase-1 in osteoarthritis chondrocytes. Rheumatol Int 2003;23:282-288. 32. Hui W, Rowan AD, Richards CD, Cawston TE. Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. Arthritis Rheum 2003;48:3404-3418. 33. Song YJ, Wu ZH, Lin SQ~Weng XS, Qiu GX. [The effect of estrogen and progestin on the expression of matrix metalloproteinases, tissue inhibitor of metalloproteinase and interleukin-1 beta mRNA in synovia of OA rabbit model]. Zhonghua Yi Xue Za Zhi 2003;83:498-503. 34. Schwartz Z, Gates PA, Nasatzky E, et al. Effect of 17beta-estradiol on chondrocyte membrane fluidity and phospholipid metabolism is membrane specific, sex-specific, and cell maturation-dependent. Biochem Biophys Acta 1996;1282:1-10. 35. Liehr JG, Roy D. Pro-oxidant and antioxidant effects of estrogens. In: Armstrong D, ed. Free radical and antioxidant protocols, pp. 425-435, Totowa, NJ: Humana, 1998:425-435. 36. Ayres S, Tang M, Subbiah MT. Estradiol-17 beta as an antioxidant: some distinct features when compared with common fat-soluble antioxidants. J Lab Clin Med 1996;128:367-375. 37. Claassen H, Schtinke M, Kurz B. Estradiol protects cultured articular chondrocytes from oxygen-radical-induced damage. Cell Tissue Res 2005;319:439-445.
CHAPTER 30 Potentials of Estrogens in the Prevention of Osteoarthritis: W h a t Do We Know and W h a t Questions are Still Pending? 38. Josefsson E, Tarkowski A. Suppression of type II collagen-induced arthritis by the endogenous estrogen metabolite 2-methoxyestradiol. Arthritis Rheum 1997;40:154-163. 39. Palmer RM, Hickery MS, Charles IG, Moncada S, Bayliss MT. Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun 1993;193:398-405. 40. Hoegh-Andersen P, Tanko LB, Andersen TL, et al. Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application. Arthritis Res Ther 2004;6:R169-R180. 41. Ren YX, Deng YZ. [An experimental study on effect of estrogen on osteoarthritis in female rats]. Zhongguo Xiu Fu ChongJian Wai Ke Za Zhi 2003;17:212-214. 42. Christgau S, Tanko L.B, Cloos PA, et al. Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM). Menopause 2004;11:508-518. 43. Rosner IA, Goldberg VM, Getzy L, Moskowitz RW. Effects of estrogen on cartilage and experimentally induced osteoarthritis. Arthritis Rheum 1979;22:52-58. 44. Tsai CL, Liu TK. Estradiol-induced knee osteoarthrosis in ovariectomized rabbits. Clin Orthop Relat Res 1993;291:295-302. 45. Turner AS, Athanasiou KA, Zhu CF, Alvis MR, Bryant HU. Biochemical effects of estrogen on articular cartilage in ovariectomized sheep Osteoarthritis Cartilage 1997;5:63-69. 46. Carlson CS, Loeser RF, Jayo MJ, et al. Osteoarthritis in cynomolgus macaques: a primate model of naturally occurring disease. J Orthop Res 1994;12:331-339. 47. Ham KD, Loeser RF, Lindgren BR, Carlson CS. Effects of long-term estrogen replacement therapy on osteoarthritis severity in cynomolgus monkeys. Arthritis Rheum 2002;46:1956-1964. 48. Ham KD, Carlson CS. Effects of estrogen replacement therapy on bone turnover in subchondral bone and epiphyseal metaphyseal cancellous bone of ovariectomized cynomolgus monkeys. J Bone Miner Res 2004;19:823-829. 49. Spector TD. Bisphosphonates: potential therapeutic agents for disease modification in osteoarthritis. Aging Clin Exp Res 2003;15:413-418. 50. Samanta A, Jones A, Regan M, Wilson S, Doherty M. Is osteoarthritis in women affected by hormonal changes or smoking? Br J Rheumatol 1993;32:366-370. 51. Cauley JA, Kwoh CK, Egeland G, et al. Serum sex hormones and severity of osteoarthritis of the hand. J Rheumato11993;20:1170-1175. 52. Spector TD, Perry LA, Jubb RW. Endogenous sex steroid levels in women with generalised osteoarthritis. Clin Rheumatol 1991;10: 316-319. 53. Sowers MF, Hochberg M, Crabbe JP, et al. Association of bone mineral density and sex hormone levels with osteoarthritis of the hand and knee in premenopausal women. Am J Epidemio11996;143:38-47. 54. Tsai CL, Liu TK, Chen TJ. Estrogen and osteoarthritis: a study of synovial estradiol and estradiol receptor binding in human osteoarthritic knees. Biochem Biophys Res Commun 1992;183:1287-1291. 55. Tanko LB, Bruun JM, Alexandersen P, et al. Novel associations between bioavailable estradiol and adipokines in elderly women with different phenotypes of obesity: implications for atherogenesis. Circulation 2004;110:2246-2252. 56. Von Muhlen D, Morton D, Von Muhlen CA, Barrett-Connor E. Postmenopausal estrogen and increased risk of clinical osteoarthritis at the hip, hand, and knee in older women. J l/VomensHealth Gend Based Med 2002;11:511-518. 57. Sandmark H, Hogstedt C, Lewold S, Vingard E. Osteoarthrosis of the knee in men and women in association with overweight, smoking, and hormone therapy. Ann Rheum Dis 1999;58:151-155. 58. Sahyoun NR, Brett KM, Hochberg MC, Pamuk ER. Estrogen replacement therapy and incidence of self-reported physician-diagnosed arthritis. Prev Med 1999;28:458-464.
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59. Nevitt MC, Felson DT, Williams EN, Grady D. The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: The Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial Arthritis Rheum 2001;44:811-818. 60. Maheu E, Dreiser RL, Guillou GB, Dewailly J. Hand osteoarthritis patients characteristics according to the existence of a hormone replacement therapy. Osteoarthritis Cartilage 2000;8:S33-$37. 61. Parazzini F. Menopausal status, hormone replacement therapy use and risk of self-reported physician-diagnosed osteoarthritis in women attending menopause clinics in Italy. Maturitas 2003;46:207-212. 62. Bettica P, Cline G, Hart DJ, Meyer J, Spector TD. Evidence for increased bone resorption in patients with progressive knee osteoarthritis: longitudinal results from the Chingford study. Arthritis Rheum 2002;46:3178-3184. 63. Dennison EM, Arden NK, Kellingray S, et al. Hormone replacement therapy, other reproductive variables and symptomatic hip osteoarthritis in elderly white women: a case-control study. Br J Rheumatol 1998;37:1198-1202. 64. Erb A, Brenner H, Gunther KP, Sturmer T. Hormone replacement therapy and patterns of osteoarthritis: baseline data from the Ulm Osteoarthritis Study. Ann Rheum Dis 2000;59:105-109. 65. Nevitt MC, Cummings SR, Lane NE, et al. Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 1996;156:2073-2080. 66. Spector TD, Nandra D, Hart DJ, Doyle DV. Is hormone replacement therapy protective for hand and knee osteoarthritis in women? The Chingford Study. Ann Rheum Dis 1997;56:432-434. 67. Hannan MT, Felson DT, Anderson JJ, Naimark A, Kannel WB. Estrogen use and radiographic osteoarthritis of the knee in women. The Framingham Osteoarthritis Study. Arthritis Rheum 1990;33:525-532. 68. Zhang Y, McAlindon TE, Hannan MT, et al. Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study. Arthritis Rheum 1998;41:1867-1873. 69. Wluka AE, Davis SR, Bailey M, Stuckey SL, Cicuttini FM. Users of oestrogen replacement therapy have more knee cartilage than nonusers. Ann Rheum Dis 2001;60:332-336. 70. Cicuttini FM, Wluka AE, Wang Y, Stuckey SL, Davis SR. Effect of estrogen replacement therapy on patella cartilage in healthy women. Clin Exp Rheumato12003;21:79-82. 71. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333. 72. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004 ;291:1701-1712. 73. Bagger YZ, Tanko LB, Alexandersen P, Qin G, Christiansen C. Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause 2005;12:12-17. 74. Bagger YZ, Tanko LB, Alexandersen P, et al. Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 2004;34:728-735. 75. Ettinger B, Ensrud KE, Wallace R, et al. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gyneco12004;104:443-451. 76. Eckstein F, Reiser M, Englmeier KH, Putz R. In vivo morphometry and functional analysis of human articular cartilage with quantitative magnetic resonance imaging-from image to data, from data to theory. Anat Embryol (Berl) 2001;203:147-173. 77. Garnero R Delmas PD. Biomarkers in osteoarthritis. Curr Opin Rheumato12003;15:641-646.
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SECTION VII
Cardiovascular Perhaps no other area has changed or advanced as much since the previous edition of this book as the subject of cardiovascular disease, in particular the effects of hormones on the cardiovascular system. This section updates our current understanding and provides the most recent data and hypotheses regarding the effects of hormones on the cardiovascular system. Although an attempt has been made to be comprehensive in covering this topic, it is not possible to cover everything in depth. Some of these potential deficiencies will be addressed here. For a great number of years, we have been reassured by data showing consistently that there was a coronary protective effect of estrogen. This led to many studies attempting to elucidate the various mechanisms of cardio-protection. Many protective mechanisms were found that tended to validate the observational data pointing to the cardio-protective effects of estrogen. Thus it was a reaction of confusion and disbelief when the findings of various secondary prevention trials and the estrogen plus progesterone arm of the Women's Health Initiative (WHI) were released, which showed no protection and an effect of "early harm" (increased number of coronary events) in the first year in older women who were prescribed hormones. It is now quite clear that there is no beneficial effect of estrogen in women with established coronary disease, as shown in the various secondary prevention studies, as well as a real concern for the effect of early harm if standard dose therapy is used and the woman is not on a statin. As will be reviewed in this section, the mechanism of this early harm is likely to be due to plaque instability and rupture leading to coronary thrombosis. Nevertheless, there are compelling data to suggest that initiating hormones at the onset of menopause in young healthy women may be protective and does not lead to the early harm phenomenon witnessed in older women. These findings parallel the observational literature on which we based the belief of the cardio-protective effect of estrogen. Among the many publications on this particular point and the excellent reviews the reader will find in this section, the reader might focus on several recent publications showing the benefit of estrogen in younger women in both W H I and the Nurses' Health Study (1,2) and the lack of evidence for early harm in a young healthy population (3). This section begins with an in-depth epidemiologic review of cardiovascular disease after menopause by George I. Gorodeski. Next, Richard H. Karas briefly reviews the multiple mechanisms whereby estrogen may be cardio-protective. These mechanisms are all valid but may not be effective in older women with established disease and/or certain risk factors. Next, Ronald Krauss revisits the changes in lipids after menopause and the effects of hormones. Note again that in trials such as The Heart and Estrogen/ Progestin Replacement Study (HERS) and W H I , whereas beneficial lipid changes were observed with hormones, there was no reduction in coronary events in older women with atherosclerosis. The next three chapters deal with inflammatory markers and coagulation factors in postmenopausal women without and with hormonal therapy. In general, estrogen decreases most inflammation markers, with the marked exception of CRP, which may be due to first-passage hepatic effects of oral therapy. The other important difference is in the matrix mellanoproteinases (MMPs), which are all important in explaining plaque instability and rupture. MMPs may also be influenced, at least in part, by hepatic metabolism. Next,
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Morris Notelovitz reviews the coagulation cascade and the influence of hormones, and Carolyn Westhoff summarizes the data regarding the influence of hormones on thrombosis and pulmonary embolism. There is no question that oral estrogen and the selective estrogen receptor modulators (SERMs), at least in standard doses, increase thrombosis risk. Nevertheless, in young healthy women this risk is relatively rare, given the low prevalence of these disorders. The risk may be further reduced with using small doses and/ or non-oral therapy. The next chapter, by Sven O. Skouby, reviews the topic of carbohydrate metabolism and the influence of hormones. The importance of this topic is immense given the increasing prevalence of obesity, metabolic syndrome, and diabetes. The data on the effects of hormones are confusing indeed and need to be interpreted with the knowledge of the type of hormonal preparation, dose, route of administration, and the characteristics of the woman being treated. We have shown recently that there are major differences in the effects of estrogen on a "normal" postmenopausal woman compared with a woman who has metabolic syndrome (4). The final two chapters in this section summarize our current understanding of the effects of hormones on coronary disease. First, Thomas B. Clarkson reviews data from the monkey model and very convincingly points to the importance of the timing of initiation of hormonal therapy, as discussed previously. Finally, Howard N. Hodis reviews the clinical trial data and comes to similar conclusions as Tom Clarkson; in essence stressing that data as presented in the past (WHI, for example) may not be taken at face value but should be interpreted in the context of the population studied and the totality of the literature available to us. I would be remiss in not mentioning two other points. Although discussed in several areas in this section, there are not specific chapters on hypertension and stroke. In previous editions, there was a dedicated chapter on hypertension. While not wanting to ignore the enormous epidemiologic importance of hypertension in women as reviewed in this section, the effects of hormones is relatively minor. In general, apart from a known idiosyncratic hypertensive response with standard doses of oral estrogen in a small percent of the population, most women receiving hormones have no change or even a reduction in blood pressure. A recent editorial makes these and other points (5). In terms of the risk of stroke, it appears that there is likely to be a small increase (20% to 30%) in the risk ofischemic (not hemorrhagic) stroke in older women receiving standard oral hormones. This increase is of borderline significance and appears to be confined to the older population, not to young women. Also, observational data have shown that lower than standard-dose therapy does not increase the risk of stroke (6).
References 1. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch Intern Med 2006;166:357-365. 2. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health (Larchmt) 2006;15:35-44. 3. Lobo R. Evaluation of cardiovascular event rates with hormone therapy in healthy, early postmenopausal women: results from 2 large clinical trials. Arch Intern Med 2004;164:482-484. 4. Chu MC, Cosper P, Nakhuda G, Lobo R. A comparison of oral and transdermal short-term estrogen therapy in postmenopausal women with metabolic syndrome. Fertil Steri12006;86:1669-1675. 5. Lobo R. What is the effect of estrogen on blood pressure after menopause? Menopause 2006;13:331-333. 6. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease.Ann Intern Med 2000;133:933-941.
~ H A P T E R 31
Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women EIRAN Z E V GORODESKI
GEORGE I. GORODES KI
Departmentof Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195 Department of Reproductive Biology, CASE (Case Western Reserve) University, Cleveland, OH 44106
I. B A C K G R O U N D
women undergo cardiovascular diagnostic and surgical interventions. The situation is further complicated by the lack of clear understanding of the impact of menopause and hypoestrogenism on the cardiovascular system. The hypothesis that estrogens confer cardiovascular protection remains unchallenged, but its translation into clinical practice in postmenopausal women has not been successful. Recent randomized controlled studies researching the possible cardiovascular protective role of estrogen in postmenopausal women have concluded that estrogens should not be considered for that indication alone. However, these conclusions have been challenged, and many questions remain unanswered. The largest growing segment of the U.S. population is women over the age of 75, and more than one-fourth of the female population is in their postreproductive years. Although certain forms of CVD can be treated medically or surgically, the most effective means to decrease the impact of CVD on women's health is by modifying the contribution of specific factors that increase CVD risks. The major contribution to decreasing morbidity and mortality of CVD in men was achieved by relatively simple measures such as changing lifestyle habits, eliminating cigarette smoking, and
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in women, outweighing other causes such as cancer, cerebrovascular disease, lung disease, accidents, diabetes mellitus, and infectious diseases. Understanding the epidemiology, pathophysiology, and risk factors of the disease is important for developing an evidencebased program to improve clinical outcome of the disease in women. CVD in women remains a focus of multidisciplinary research interest. Recent studies have established genderrelated differences in the prevalence of cardiovascular risk factors and clinical management of CVD. The observations suggest that CVD differs among women and men, thereby confirming the paradigm that information obtained from studies involving men should not be directly applied to women. Only recently have large-scale studies begun to include women in equal numbers to men. However, many current clinical decisions continue to be made based on past studies that targeted primarily men. This can probably explain the fact that although more women than men ultimately die of heart disease, a greater proportion of men than TREATMENT OF THE POSTMENOPAUSAL W O M A N
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lowering plasma lipid levels. Similar effects were recently reported in women, suggesting that early detection of risk factors and an active approach to prevent or lower the impact of risk factors could positively affect the outcome of CVD in women. This chapter describes the epidemiology and pathogenesis of CVD in women and the risk factors involved, with special emphasis on gender-related differences and the relation between estrogen deficiency and heart disease.
II. EPIDEMIOLOGY OF CVD IN W O M E N In 2002, a total of 1,244,123 deaths were recorded among U.S. women, 40% of which were due to CVD, significantly outweighing other causes of death (Fig. 31.1). Accordingly, a woman in the United States has a 29% lifetime chance of dying of CVD compared with lung cancer, 5%; breast cancer, 3%, and colorectal cancers, 2% (1-5). Age-adjusted mortality rates show that CVD is the leading cause of death in women after the age of 60 (Fig. 31.2). However, about one-third of deaths from CVD in women were premature, in women younger than 65 years, accounting for more than 100,000 cases of death per year (1). More than 55% of CVD
All causes
deaths were due to ischemic heart disease, which is commonly referred to as coronary heart disease (CHD) (Fig. 31.3), and is the single leading cause of CVD deaths in women and in men (1). In 2002 the incidence of C H D began to increase after age 45 and continued to increase thereafter (Fig. 31.4). Heart disease is the third leading chronic morbid condition in women, following arthritis and back and neck conditions, affecting an estimated 2.2 million women (2). Heart disease is also the leading cause of physician office visits among women, about 5.6 million annual visits, and the leading cause for hospitalizations of women, about 1.1 million annual hospitalizations (3). Modeling the Framingham Heart Study cohort epidemiologic data into a life-expectancy analysis suggests that 50-year-old females live 1.2 years after myocardial infarction (MI), and having ever suffered acute MI reduces life expectancy by 13 years (6). Therefore, C H D morbidity and mortality in women carry a worse clinical prognosis than cancer. However, because women are relatively immune from C H D at an early age, and because cancers precede CVD and C H D by about 1 decade, the fact remains that neither women nor their physicians fully appreciate the magnitude of CVD and C H D in women. In women 25 years and older, only 8% cite CVD as their greatest health
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CHAPTER31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women
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Death Rates (per 100,000 Population)
FIGURE 31.3 Major cardiovascular deaths. HT, hypertensive; Isch, ischemic. Modified from ref. 1, with permission.
concern and less than 30% report that their physician has discussed cardiovascular risk with them (7). Even when women were identified as having risk factors for CVD, there was lower utilization of standard accepted therapy by physicians as compared with men (8-10).
III. PATHOGENESIS OF CARDIAC ISCHEMIA Proper function of the myocardium depends on supply of oxygen and nutrients. Decreased supply is usually caused by decreased arterial blood flow due to coronary artery occlusion. Understanding the processes of coronary artery occlusion is the key in identifying risk factors that cause, sustain, and augment cardiac ischemia.
A. Injury and Inflammation The coronary arterial tree is susceptible to flow injuries due to its special branching pattern. Disturbances in blood flow occur at bending points near branching sites of large and medium-sized arteries in areas with high hemodynamic shear stress, and they cause a perpetual process of intimal insult, attraction of inflammatory cells, inflammation, and endothelial damage (11). The earliest atherosclerotic lesions
can be observed in utero as deposits of cholesterol esters (fatty streaks) and typically consist of macrophages and T-cells embedded in a thin layer of lipids in the intima of large muscular arteries (12). Fatty streaks already can be found in the coronary arteries in infancy (13-15). Intimal accumulation of low-density lipoprotein cholesterol (LDL-C) and its oxidation augment expression of surface molecules, such as vascular-cell adhesion molecule-I, and stimulate adhesion and migration of monocytes and lymphocytes into the subendothelial space (16,17). Monocytes that enter the newly formed plaque differentiate into macrophages; they scavenge oxidized LDL-C and dead-cell remnants and trigger an inflammatory cascade. Activated macrophages release an array of cytokines and growth factors that further attract monocytes, lymphocytes, and platelets, thereby adding to the pool of effector molecules that expand and perpetuate the inflammatory response. As this cycle is repeated, the plaque develops a fatty core covered by fibrous matrix that stabilizes the structure (18). Inflammation characterizes all phases of atherothrombosis and provides a critical pathophysiologic link between early lesion formation and plaque rupture leading to occlusion and infarction. In early stages of atheromatous lesion development, proinflammatory cytokines potentiate the expression of adhesion molecules on vascular endothelial cells; they stimulate recruitment of leucocytes to the arterial wall and the migration of monocytes into the subendothelial space. Mononuclear ceils in concert with intrinsic vascular cells release growth factors and cytokines that stimulate the proliferation of smooth muscle cells. Cytokines produced by the macrophages are also released systemically and induce
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the release of interleukin (IL)-6, which stimulates the production of acute-phase reactants by the liver and adipose tissue, including C-reactive protein (CRP), serum amyloid A, and fibrinogen. The four key cells that interact to accentuate formation of the atheroma are the monocytes-macrophages, platelets, endothelial cells, and smooth muscle cells. The main perpetuating factor of atherosclerosis is LDL-C, which is modified by oxidation, glycation, and enhanced local inflammation. After becoming trapped in the arterial wall, LDL-C particles become progressively more oxidized, form lipid peroxides, and facilitate accumulation of cholesterol esters. Modified LDL-C is chemotactic for circulating monocytes and stimulates proliferation of macrophages already in the lesion, as well as formation of fibrointimal thickening and of a capsule over an existing lesion (18,19). This cycle of events stimulates growth and thickening of the plaque, whereby the arterial wall responds by gradually dilating to maintain the diameter of the vessel lumen ("remodeling").
B. The Coronary Syndromes One consequence of this process is formation of a lipidrich plaque, narrowing of the lumen of the coronary artery, and stiffness and dysfunction of the vessel, resulting in stenosis. Coronary artery stenosis is a chronic process associated with maladaptation to exercise, resulting in negative oxygen balance and the classic clinical presentation of stable angina pectoris. Another scenario is the release by macrophages of tissue metalloproteinases that act in concert with other extracellular proinflammatory factors to degrade the fibrous cap and render the plaque vulnerable to rupture (20). In contrast to chronic stenosis, rupture of the atherosclerotic plaque resulting in coronary thrombosis (21) produces acute myocardial ischemia, collectively referred to as acute coronary syndromes. Coronary thrombosis usually results from destabilization and rupture of previously silent atherosclerotic plaque. Vulnerable or unstable plaque is the product of local inflammatory processes within the artery. Activated macrophages,T-cells, and mast cells produce cytokines, proteases, coagulation factors, free radicals, and vasoactive molecules, which destabilize the fibrous cap of the atherosclerotic plaque. Activation of matrix metalloproteinases and cysteine proteases further promote plaque rupture (22). Upon rupture, the thrombogenic lipid core of the plaque becomes exposed to the blood, thereby stimulating adhesion and activation of platelets and release of adenosine diphosphate, thromboxane A2, and serotonin, and triggering the recruitment and activation of surrounding platelets. Platelets exteriorize the glycoprotein IIb/IIIa receptor that binds fibrinogen and leads to the linking of adjacent platelets, thereby leading to a formation of hemostatic platelet
plug (23). In some patients, thrombosis in coronary arteries can result from superficial erosion of the intima without frank plaque rupture. This occurs as a result of apoptosis of endothelial cells and proteinase production in response to inflammatory mediators. Vasospasm of coronary arterioles is an additional mechanism of acute ischemia. Atherosclerosis impairs endothelial integrity and function and can result in diminished production and release of vasodilators such as nitric oxide, thereby increasing the vascular resistance of the coronary tree. Changes in the rheologic properties of the blood, and in particular increased viscosity, can contribute to increased coronary resistance and diminished blood flow in the coronary vessels (24,25). The clinical presentation of patients with acute coronary syndromes varies and is categorized according to electrocardiographic (ECG) and biochemical criteria. The spectrum of disease ranges from partial to complete thrombotic occlusion of the coronary artery. Patients with partial occlusion may present with unstable angina (UA) or non-ST elevation MI (NSTEMI). Unstable angina is ischemia without myocardial necrosis. Patients present with ischemic symptoms but without ECG changes or positive myocardial markers on blood testing. Patients with partial coronary artery occlusion who progress to myocardial necrosis usually present with N STEMI, defined as lack of ST elevation but with elevated myocardial markers. Complete arterial occlusion usually results in ST elevation MI (STEMI), defined by ST-elevations and positive myocardial markers (26). A majority of patients with STEMI ultimately develop Qzwaves (i.e., Q_w-MI) on ECG, implying transmural infarction, whereas in some no Qzwaves are evident (i.e., non-Qw-MI), implying partial transmurality (Fig. 31.5). Although non-Qw-MI may have infarct that is smaller than Q w-MI, it is often associated with higher incidence of late cardiac events as compared with QMI, including recurrent ischemia angina or MI. Long-term survival is similar for both types of MI (27).
Acute Coronary Syndrome
No ST Elevation
UnstableAngina
ST Elevation
No-Qw-MI ...........................
Qw-MI T
FIGURE 31.5 Classificationof acute coronarysyndromes.MI, myocardial infarction.Modifiedfrom res 26.
CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women
C. Gender Differences Fatty streak lesions of the coronary arteries are found in about half of infants less than I year of age, and their incidence in males and females is the same (28). Most lesions of early infancy reverse, but those that persist into childhood do not reverse (15,29). A few reports described coronary artery intimal layers that are thicker in male infants than in females, suggesting an inborn sex difference in the structure of the coronary artery that renders males more susceptible to ischemic heart disease (30). Other reports, however, have found no such sex difference in fetuses and children up to age 19 (31,32). In certain ethnic groups with unusually high prevalence of CAD, coronary artery intimal layers are thicker in males than in females (30). At all ages after puberty the incidence of fibrointimal fatty streak lesions is lower in women than in men (33), and the clinicopathologic patterns of C H D also differ between genders. Women are more likely to have nonobstructive CHD and single-vessel disease, whereas men are more likely to have obstructive multivessel or left main C H D (34). These observations suggest that female-specific atherogenesis-protective processes operate from puberty onward. In contrast, women have higher incidence of acute coronary ischemia due to vasoconstriction of the coronary arterial tree than do men (35). Chronic coronary ischemia due to severely stenotic vessels is frequently associated with formation of collaterals, which is a compensatory mechanism of arterial blood supply to the affected cardiac muscle (36). Relatively little is known about gender differences in the formation of cardiac collaterals. More is known about gender differences related to cardiac protection from the ischemia-reperfusion syndrome. Reperfusion of previously anoxemic tissues can lead to irreversible cell damage and cardiac death (37). Cells become necrotic and attract and activate polymorphonuclears and platelets, which could lead to impaired blood flow in the microvasculature, recurrent thrombosis, increased vascular resistance, accelerated necrosis, and cell death (38,39). Studies in women (40,41) and in animal models (42-47) have shown that estrogens protect the myocardium from the detrimental consequences of reperfusion, regardless of the status of the coronary circulation. Thus, it is apparent that gender-related differences in the pathogenesis of coronary atherosclerosis could also lead to gender differences in the incidence, prevalence, and clinical manifestations of CHD.
IV. RISK FACTORS FOR CARDIAC ISCHEMIA IN W O M E N Cardiac ischemia is the end result of genetic, constitutive, behavioral, and environmental factors that act in concert throughout life and result in progressive cardiac damage. Known risk factors for C H D in women include obesity,
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abnormal plasma lipids, hypertension, diabetes mellitus, cigarettes smoking, sedentary lifestyle, adverse genetic background, increased blood viscosity, stress, and autonomic imbalance, and estrogen deficiency. Usually more than one risk factor can be identified, but some risk factors have a stronger impact on the prevalence of the disease and are therefore considered "independent" or even "causative." Better understanding of how risk factors cause or affect C H D may direct caregivers in formulating more effective intervention protocols.
A. Obesity Obesity is a worldwide epidemic (48,49). In the United States, more than 60% of adults are either overweight or obese (50). Current clinical definitions of obesity in women are body mass index (BMI, body weight [in kg] divided by height [in m] squared), whereby a BMI -> 25 kg/m 2 is defined as overweight, and >- 30 kg/m 2 as obese; fat mass >35% of total body weight; and waist circumference -> 88 cm (37 inches) (51-53). Obese premenopausal women tend to have gluteal (hip or thigh) type obesity, also termed gynecoid obesity. After menopause the fat distribution changes to centralized (waist, androgenic, or truncal) obesity (53,54). The waist-to-hip ratio (WHR) or waist-to-thigh ratio (WTR) correlates with CHD. Increased W H R remains positively correlated with C H D even after controlling for hypertension, glucose intolerance, blood lipids, smoking, and BMI (55). Moreover, the gender-associated risk disappears after controlling for
WHR (53). Abdominal fat is located in two major compartments, subcutaneous and intraperitoneal (visceral). The subcutaneous adipose tissue is a much larger compartment than the intraperitoneal fat, and it is composed of truncal and gluteofemoral adipose tissues. The intraperitoneal adipose tissue consists of omental and mesenteric fat. The subcutaneous truncal fat and the intraperitoneal omental and mesenteric fat are related to metabolic risk (56). The mechanism by which centralized obesity confers an increased C H D risk is not completely understood. It could be the result of differential response of upper body versus lower body adipocytes to free fatty acid mobilization (52,57). Obesity develops as a result of positive energy balance, intake being higher than expenditure. Females have a greater prevalence of obesity as compared with males. The differences could be accounted for by a higher 24-hour energy expenditure in men compared with women. Men have higher basal and sleeping metabolic rates, whereby the basal rate accounts for 60% to 70% of total energy expenditure (58). Obesity is both an independent and an intermediary risk factor for cardiovascular mortality. Mortality begins to increase with BMI levels greater than 25 kg/m 2, and it
410 increases most dramatically as BMI levels surpass 30 kg/m 2 (relative risk [RR] 1.5) (59). Obesity is also a modifier of other risk factors including hypercholesterolemia, hypertension, Type 2 diabetes, hypertension, obstructive lung disease, sleep apnea, stroke, asthma, back and lower extremity weight-bearing degenerative problems, osteoarthritis, several forms of cancer, and depression (60). The mechanisms include modulation of atherogenic dyslipidemia, insulin resistance, proinflammatory state, and prothrombotic state. The age and smoking-adjusted RR of CHD is 1.8 in mild to moderately obese women and 3.3 among severely obese women (55). Overall, 70% of CHD in obese women and 40% of CHD in all women could be attributed to being overweight (55). The majority of obese persons who develop CVD have a clustering of risk factors described as the metabolic syndrome (61). This syndrome consists of atherogenic dyslipidemia (elevated serum triglycerides, apolipoprotein B, and LDL-C, plus low high-density lipoprotein cholesterol ([HDL-C]); hypertension; hyperglycemia and insulin resistance; and prothrombotic and proinflammatory states. Metabolic syndrome is defined if a person has three of the following five features (62): 1. Increased waist circumference (abdominal obesity >-102 cm in men and >-88 cm in women) 2. Elevated triglycerides (>- 150 mg/dL) 3. Reduced HDL-C (-- 100 mg/dL) Patients with diabetes (fasting glucose >- 126 mg/dL) are said to have the metabolic syndrome if two other features are present. Diagnosis of the metabolic syndrome is a useful
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clinical tool in identifying patients at risk for development of diabetes, CVD, and CHD (Fig. 31.6). 1. PREVALENCE OF OBESITY AND THE METABOLIC SYNDROME
The prevalence of obesity in the United States is escalating (Fig. 31.7). Two-thirds of individuals living in the United States are overweight, and 5% are obese (63); about 57% of Caucasian females and 77% of African-American females are overweight (64). Obesity is identifiable already in childhood: between 1976-1980 and 1999-2002 the prevalence of obesity in U.S. children doubled (65). In 2002 the prevalence of overweight Caucasian females aged 6 to 19 was 13%; of African-American and American-Mexican females, 19%. These levels increased to 60% in adults (Fig. 31.8) (66), and the age-adjusted prevalence of overweight and obesity were 65% and 30%, respectively (67) (see Fig. 31.8). AfricanAmerican females tend to be more overweight and obese than Caucasian or Mexican-American females (see Fig. 31.8). Equally disturbing are the age-related trends of the metabolic syndrome. In the United States, about 2% of 12to 19-year-old adolescent women can be characterized as having the metabolic syndrome (68); the prevalence rises to
Prevalence of Obesity Percent of Population 35
30
25
20
_- / /J/
15
10
FIGURE 31.6 CHD, CVD, and total mortality stratified by history of CVD, diabetes, and the metabolic syndrome. Modified from ref. 5.
.........
1 ..............
1960-62
I
I
I
1971-74
1976-80 Years
t988-94
. . . . . . . . . . .
!
1999-02
FIGURE 31.7 Prevalence of obesity and the metabolic syndrome in the United States. Modified from ref. 5.
CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women
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TABLE 31.1 Interpretations of Plasma Levels of LDL Cholesterol, Total Cholesterol, and Triglycerides Relative to C H D Risk*
Percent of Women 60 Caucasians African-Americans Mexican-Americans
LDL cholesterol
Total cholesterol
Triglycerides
40
Desirable (optimal) Near optimal Borderline h i g h High Very high
3)
0 Age:
6-11
12-19
_> 20
Overweight
_> 20
190
240
500
*All values in mg/dL. CHD, coronary heart disease; LDL, low-density lipoprotein. Data from ref. 62.
Obese
FIGURE 31.8 Age and ethnicity/race-dependent prevalence of overweight and obesity in women. Modified from ref. 5.
7% among women ages 20 to 29, and it escalates to 42% for ages 60 and older (69,70).
B. Abnormal Plasma Lipids Unfavorable plasma lipids are an independent causative factor for the development of CAD (62). LDL-C comprises 70% of the total serum cholesterol. It contains a single apolipoprotein (apo B) and is the major atherogenic lipoprotein. LDL-C is the primary target of cholesterol-lowering therapy, and most clinical trials show the efficacy of LDLlowering therapy for reducing risk for CHD. Because LDLC levels < 100 mg/dL are associated with a very low risk for CHD, they are referred to as optimal. Near-optimal LDL-C levels of 100-129 mg/dL are associated with some degree of atherogenesis, whereas higher levels of 130-159 mg/dL are associated with significant atherogenesis and are referred to as borderline. At high (160-189 mg/dL) and very high levels (-> 190 mg/dL), atherogenesis is markedly accelerated. Similar definitions for total cholesterol and triglycerides are shown in Table 31.1. With regard to HDL-C, studies have shown a continuous increase in C H D risk as H D L - C levels decline, but without a deflection point in the C H D versus H D L - C curve. Therefore, suggested low (i.e., undesirable) H D L cholesterol levels are defined as 60 mg/dL (62). An increase of 1% in plasma total cholesterol or LDLC increases the risk of C H D by 2%, and a decrease of 1% in H D L - C increases the risk by 2% to 4.7% (62). Elevated plasma triglycerides are also associated with increased risk
of C H D but are not an independent risk factor. Plasma H D L - C is an important predictive C H D risk factor in women, and elevated H D L - C levels above 55 mg/dL can modify the adverse effects of high total cholesterol and LDL-C levels (62). Unfavorable profiles of plasma lipids are found in persons with congenital and acquired hyperlipidemias and dyslipidemias, and these individuals are at an increased risk to die of C H D at a young age. Unfavorable plasma lipids can be also found in otherwise healthy asymptomatic children, adolescents, and young adults. In the Pathobiological Determinants of Atherosclerosis in Youth study (PDAY), investigators looked at coronary lesions of persons aged 15 to 34 years who died of accidental injury, homicide, or suicide (71). The extent of both fatty streaks and raised lesions (advanced lesions and fibrous plaques) in the right coronary artery was associated positively with non-HDL-C lipids levels, hypertension, impaired glucose tolerance, and obesity and associated negatively with HDL-C. After adjusting for race, sex, and smoking, unfavorable lipid profile was positively associated with both fatty streaks and raised lesions in the right coronary artery at ages 15 through 34, and lesions more than tripled through these ages (Fig. 31.9). Unfavorable plasma lipids are common in the adult population and may worsen with age. In the Framingham Study, levels of LDL-C in women increased after the age of 50 to 55. In contrast, levels of H D L - C in women remained essentially unchanged after the fifth decade (72). Other studies have shown that postmenopausal women have greater increases in LDL-C and greater decreases in H D L - C than age-adjusted premenopausal controls (73). In addition, acute changes after the menopause (within 6 months after cessation of menstrual periods) were observed in total cholesterol levels (6% increase), triglycerides (11% increase), and LDLC (10% increase). H D L - C levels have decreased gradually by 6% 2 years after menopause (74). One-third of postmenopausal women in the United States are at moderate
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A: Fatty Streaks
B: Raised Lesions
!--7 favorablelipids
I---] favorable!ipids
unfavomblelipids
P e r c e n t of W o m e n 6O
Caucasians African-Americas Mexican-Americans
4O
91~ unfavorableIlpids
2O
0
o
o
o T-
15-19
2 0 - 2 4 25-29
Age
30-34
15-19
2 0 - 2 4 25-29
Age
O P-
30-34
FIGURE 31.9 The meanextent(+ SE) of fattystreaksand raisedlesionsin the right coronaryarteryby 5-yearage groups in personswith a favorablelipoprotein profile (non-HDL-C < 108 mg/dL; HDL-C > 60 mg/dL) comparedwith an unfavorablelipoprotein profile (non-HDL-C > 150 mg/ dL, HDL-C < 43 mg/dL).Valueswere adjustedfor race,sex,and smoking. Modified from res 71.
risk and one-fourth at high risk of C H D as indicated by H D L - C levels lower than 45 mg/dL (62). The mechanism by which aging adversely affects lipid profile is unclear. LDL-C levels are likely increased as a result of age-related reduced capacity for its removal, mediated via reduced hepatic LDL receptor (75). Menopause-related changes in lipids could be the result of estrogen deficiency (see later discussion). Women with chronic anovulation, including those with polycystic ovarian syndrome (PCOS), have increased levels of LDL-C and decreased levels of HDL-C. Some of these patients also have insulin resistance and hyperandrogenemia (76,77).
1. P R E V A L E N C E OF H Y P E R L I P I D E M I A
The prevalence of high total serum cholesterol (->240 mg/dL) in women in the United States has decreased over the last 4 decades, but more than 18% still present with markedly elevated levels (78). Unfavorable plasma lipids can be detected already among children and adolescents ages 4 to 19 years. Caucasian women, in particular, have significantly higher average total cholesterol and LDL-C than do men and African-American women (Fig. 31.10). In 2002, 53% of Caucasian women had plasma total cholesterol ->200 mg/dL and 20% ->240 mg/dL; 43% had LDL-C ---130 mg/dL, and 14% H D L - C -< 40 mg/dL (see Fig. 31.10). These levels expose women to moderate to high degree of C H D risk (62).
O I-
AI
0
,
rl --I
o vI
(.~ --I I::I :I:
FIGURE 31.10 Prevalenceofhyperlipidemia in women. Modified from
ref. 5.
C. Hypertension Hypertension is a risk factor for CHD, stroke, and congestive heart failure, with the strongest impact in women (5,62). Hypertension is defined as systolic blood pressure ->140 mm Hg or diastolic blood pressure ->90 mm Hg. Both elevated systolic and diastolic blood pressure levels are independent risk factors, directly and positively associated with acute coronary events as well as with mortality from all cardiovascular causes (5,62). In 2002, hypertension was the direct cause of death of 4.7% of Caucasian and 22.8% of African-American women (1). African Americans develop hypertension earlier in life, and their average blood pressures are much higher. As a result, compared with Caucasians, African Americans have a 1.5 times greater rate of heart disease death (1,5,62). Yet 30% of persons with hypertension are unaware of having the disease or of its consequences (5,62). Hypertension is commonly diagnosed in patients who have other C H D risk factors such as obesity, unfavorable plasma lipid profile, and diabetes mellitus. The combination of hypertension and diabetes mellitus is of particular importance in women because diabetic patients frequently (50%) have hypertension and the prevalence of diabetes mellitus in hypertensive patients is also high (15% to 18%) (79).These women have also higher incidence of other atherogenic risk factors including dyslipidemia, hyperuricemia, and elevated fibrinogen levels (5,62). The association between obesity and hypertension could be the result of sympathetic nervous and renin-angiotensinaldosterone system activation because sodium and water
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CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women retention and blood pressure elevations are observed in obese individuals. Visceral obesity and the ectopic deposition of adipose tissue may be important in the activation of these systems, and in the damage of target organs that ensues (80). Due to its high prevalence, the attributable risk of hypertension for C H D is the highest of the known risk factors, reaching 55% as compared with 5% of diabetes mellitus and 2.8% of cigarettes smoking (79,81). Controlling hypertension reduces significantly the risk of CVD, but the reductions in acute coronary risks are less than expected, indicating that hypertension has had a chronic interrelated effect with other factors (5,62). The degree of risk imposed by hypertension is now recognized as a continuum and is associated with age. Beginning at a blood pressure of 115/75 mm Hg, CVD risk doubles with each increment of 20/10 mm Hg. Individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension, and individuals with a systolic blood pressure of 120-139 mm Hg or a diastolic blood pressure of 80-89 mm Hg should be considered pre-hypertensive and require healthpromoting lifestyle modifications to prevent CVD (82).
1. PREVALENCE OF HYPERTENSION
Before the age of 55, the age-adjusted prevalence of prehypertension and hypertension is greater in men than in women, but after that age a much higher percentage of women have hypertension than men, and the prevalence of the disease increases further with age. Forty percent of persons in the United States are normotensive, 31% are prehypertensive, and 29% are hypertensive. Stated differently, two-thirds of persons are either pre-hypertensive or hypertensive (5). Hypertension is two to three times more common in women taking oral contraceptives, especially in obese and older women (5). In 1999 to 2000, the prevalence of hypertension in the United States at ages 20 to 74 was 42% in African-American women compared with 28% in Caucasian and Latino females (78).
mortality, and the effects were aggravated by cigarettes smoking, hypertension, and obesity (84). Diabetes increases the incidence of MI (85), 28-day and 1-year mortality after MI (86), and the 2-year mortality rate in patients admitted with unstable angina or non-Qcwave MI (87). Persons with diabetes often have other associated CVD risk factors, including hypertension, dyslipidemia and obesity (88). In women, diabetes mellitus accelerates atherosclerosis and increases the risk of acute coronary ischemia (79). Impaired glucose tolerance and insulin resistance often occur jointly with hypertension obesity and unfavorable plasma lipid profile (79). This association has suggested that there are pre-existing genetic traits or metabolic factors in the causal pathway common to these conditions (89). Impaired handling of blood glucose, either as pre-diabetes (fasting glucose 100-125 mg/dL) or overt diabetes (fasting glucose - 126 mg/dL) can be associated with coronary atherosclerosis already at a young age. In the PDAY study (90), investigators found that an elevated glycosylated hemoglobin concentration (corresponding to an average blood glucose concentration of-> 150 mg/dL in the previous 2 or 3 months) was associated with increased fatty streaks and raised lesions of the right coronary artery. Most of the increases in coronary atherosclerosis occurred after age 25 (Fig. 31.11). A number of mechanisms were proposed by which hyperglycemia induces atherosclerosis. Transient hyperglycemia is associated with overproduction of superoxide by the mitochondrial electron transport chain (91). It activates signaling cascades culminating with decreased bioavailabil-
A: Fatty Streaks
B: Raised Lesions
50r normal g-Hb
BB elevatedg-Hb
normal g-Hb
BB elevated g-Hb
D. D i a b e t e s Mellitus Impaired handling of glucose, including insulin resistance insulin, insulin deficiency, and overt diabetes mellitus, is both an independent risk factor for CVD and a causative factor of premature mortality from C H D (5,62). Blood glucose levels are a graded independent risk factor for CVD even within a relatively normal blood sugar range (79). Women with diabetes mellitus lose the female-related advantage of CVD over men (83). The age-adjusted RR for C H D in women with diabetes mellitus is 3-7 (62). In the observational Nurses Health Study, diabetes was associated with a markedly increased risk of fatal and nonfatal MI, stroke, and all-cause
15-19
20-24 25-29 30-34 Age
15-19
20-24 25-29 30-34
Age
FIGURE 31.11 The mean extent (+ SE) of fatty streaks and raisedlesions in the right coronaryartery by 5-year age groups and normal glycosylated hemoglobin concentration (normal g-Hb < 8%) comparedwith elevated glycosylatedhemoglobin concentration (elevatedg-Hb >- 8%).Valueswere adjusted for race and sex.Modified from res 90, with permission.
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ity of nitric oxide and prostacyclin, increased synthesis of vasoconstrictor prostanoids and endothelin, and increased vascular permeability that leads to endothelial damage and atherosclerotic plaque formation. Persistent hyperglycemia stimulates resident macrophage activation and upregulation of CD36 protein with increased uptake of oxidized lowdensity lipoprotein, increased macrophage-induced matrix metalloproteinase (MMP) expression, adventitial inflammation, and vasa vasorum neovascularization (92,93). The ensuing inflammatory microangiopathic process could lead to plaque rupture and coronary thrombosis. In this regard hyperglycemic endothelial damage mirrors the process of classical atherosclerosis (94,95). Hyperglycemia can also adversely affect platelet function, resulting in an added risk for thrombosis. In addition, hyperglycemia can affect directly cardiac myocytes and cause cardiac autonomic neuropathy and cardiomyopathy (5,62). 1. PREVALENCEOF DIABETES MELLITUS
The prevalence of diagnosed type 2 diabetes mellitus, which accounts for more than 90% of all cases of diabetes, has increased during the last 3 decades. By 2025 it is projected to involve more than 5% of the world population (96). The increase in prevalence of diabetes parallels those of obesity and the Metabolic Syndrome (97). In 2002, among Caucasian, African-American, and MexicanAmerican women, pre-diabetes was diagnosed in 4.6%, 5.9%, and 7.2%, respectively. In those groups, diabetes was diagnosed in 4.7%, 12.6%, and 11.3%, respectively (5). Currently it is estimated that 40% of U.S. females ages 40 to 74 have pre-diabetes (5).
E. Cigarette S m o k i n g Cigarette smoking is the single most important preventable risk factor of CVD (99,100). In women younger than 55, cigarette smoking is directly responsible for 21% of all CVD mortality and for 50% of all acute coronary events (62,101). Cigarette smoking is an independent predictor of sudden cardiac death in patients with CHD (102), leading to a twofold to threefold increased risk of dying from CHD (103). Cigarette smoking is also directly related to and can potentiate other CHD risk factors (5,62). In women younger than age 44, cigarette smoking is dose related to MI, with an RR of 2.5 for those smoking I to 5 cigarettes per day, compared with nonsmokers, and rising to 74.6 for those smoking more than 40 cigarettes per day (104). In women, smoking "low-yield nicotine" cigarettes (less than 0.4 mg nicotine per cigarette) did not affect significantly CHD risk compared with smoking the "regular" high-yield nicotine cigarettes (more than 1.3 mg nicotine
per cigarette) (RRs of 4.2 and 4.7, respectively) (101,105). Exposure to passive, environmental, cigarette smoke also predisposes to cardiovascular events (106-110). Observational studies in women estimated that exposure to passive smoking is associated with a 15% increase in the risk of dying from heart disease compared with nonsmokers not exposed to passive smoking (110). Even smokeless tobacco has been shown to increase CVD risk compared with nonsmokers (108). Cessation of smoking is associated with an estimated 50% to 70% reduction in CHD risk. One year after quitting, the risk of CHD decreases by 50%, and within 2 to 3 years it approaches that of a nonsmoker (5,62,111). Fifteen years after quitting, a woman's RR of dying from CHD equals that of a lifetime nonsmoker (111). The adverse coronary effects of cigarette smoking are exerted via several known mechanisms. Nicotinic alkaloids stimulate the sympathetic nervous system and increase plasma free fatty acids and LDL-C levels (113,114). Nicotine increases platelet aggregability (115) and fibrinogen plasma levels (116,117), thereby increasing the risk of coronary thrombosis. Cigarette smoking increases inflammation, thrombosis, and oxidation of LDL-C, thereby increasing tissue oxidative stress (118). Cigarette smokers have a higher incidence of insulin resistance compared with nonsmokers (119), and their plasma lipids demonstrate an unfavorable profile: increased levels of total cholesterol and triglycerides, increased LDL-C VLDL-C and VLDL-triglycerides, and decreased HDL-C (120,121). In women, cigarette smoking provokes a low-estrogenic, high-androgenic milieu. Premenopausal women who smoke cigarettes are usually deficient in estrogen, and cigarette smoking eliminates the estrogen-protective effect on the cardiovascular system (122,123). Constituents of cigarette smoke adversely modify production and metabolism of estrogens, and cigarette smoking attenuates estrogen effects on target tissues (124). Premenopausal cigarette smokers have a lower incidence of gluteal (gynecoid) adipose tissue distribution and a higher incidence of central (abdominal) adipose tissue distribution (122). Cigarette smoking positively correlates with a risk of early natural menopause, greater prevalence of hirsutism, oligomenorrhea, and infertility in premenopausal women (125). Premenopausal and postmenopausal smokers have a lower incidence of estrogendependent cancers such as endometrial cancer (126,127), and smoking eliminates the protective effect of oral estrogens on hip fracture in postmenopausal women (123). At the cellular level, nicotinic alkaloids directly inhibit human granulosa cell aromatase activity and the conversion of androgens to estrogens (128). Cigarette smoking induces hepatic microsomal mixed-function oxidase systems that metabolize sex hormones. This effect enhances 2-hydroxylation, resulting in synthesis of non-agonistic estrogen metabolites (123,129).
CHAPTER31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women
1. PREVALENCE OF CIGARETTE SMOKING
During the past 4 decades, the prevalence of smoking among women has declined. In the United States, the prevalence of smoking decreased by 0.3% per year in the past decade, but the rate of smoking initiation increased by 1% per year (5,62). In 2003, 24.6% of female students (grades 9 to 12) reported current tobacco use (130), and the most common age of initiation was 14 to 15 (131). This has resulted in a relatively stable prevalence of smoking among women of about 26% (5). About 60% of people in the United States have biologic evidence of exposure to passive cigarette smoke (132).
E Sedentary Lifestyle Data from studies in men and secondary analyses in women suggest that sedentary lifestyle increases CHD risk in women and that physical activity counteracts these effects. The RR of CHD associated with physical inactMty ranges from 1.5 to 2.4 and is comparable to that observed for high blood cholesterol, high blood pressure, or cigarette smoking (133). Sedentary people have about twice the risk of developing or dying from CHD compared with active people, and 37% of deaths from CHD can be attributed to physical inactivity, second only to raised blood cholesterol (134). Regular moderate intensity physical activity, which is attainable for the majority of men and women, gives considerable protection against CHD (135). Cross-sectional studies report that middle-aged women with higher levels of physical actMty had lower weight, lower systolic and diastolic blood pressure levels, favorable lipid profile, and lower fasting glucose (136). Physical activity can moderate risks of obesity in men (137) and women (138). In women, moderate actMty decreases total cholesterol, LDL-C, and triglycerides and increases HDL-C levels (139,140). In the Nurses Health Study, vigorous to moderate activity such as walking was associated with a 46% decrease in the risk of developing diabetes compared with least physically active women (141). Studies in men showed that physical actMty also improves the prevention and management of type 2 diabetes in obese people (142). Potential mechanisms by which physical exercise decreases the risk of CHD are direct cardiac effects such as development of collateral coronary circulation and improvement of the functional myocardial work capacity; systemic effects such as lowered heart rate and blood pressure; modulation of CHD risk factors such as weight reduction, improvement in lipid profile, decreased platelet adhesiveness and aggregability, enhanced fibrinolysis, and decreased adrenergic response to stress; and decreased incidence of depression, which may further contribute to a sedentary lifestyle (143,144).
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1. PREVALENCE OF SEDENTARY LIFESTYLE
In 1999 to 2001 in the United States, 38% of Caucasian females, 55% of African-American females, and 57% of Hispanic or Latino females reported no leisure time physical activity (5).
G. Adverse Genetic Background Similar to other multifactorial polygenic diseases, most cases of CVD, CHD, and stroke involve interplay of various molecular and biochemical pathways with environmental factors. Among known genetic risk factors for CHD, family history is the most significant independent risk factor (145-147). Epidemiologic studies identified the heritability potential for most CHD risk factors, including total cholesterol (40% to 60%), HDL-C (45% to 75%), total triglycerides (40% to 80%), BMI (25% to 60%), systolic blood pressure (50% to 70%), diastolic blood pressure (50% to 65%), Lp(a) levels (90%), homocysteine levels (45%), type 2 diabetes (40% to 80%), and fibrinogen (20% to 50%) (147-150). Mendelian disorders associated with atherosclerosis, such as familial hypercholesterolemia (FH), explain only a small percentage of disease susceptibility. However, genetic studies of FH have contributed to the understanding of pathways for cholesterol homeostasis and to the development of lipidlowering drugs (151). Whole-genome scans of families with high prevalence of CHD revealed several loci linked to CHD (2q21-22, xq23-26 [152], and 16p13-pter [152,153]) or MI (14qter [154] and lp34-36 [155]), but thus far none of the underlying genes have been identified. Large-scale genome scans for diabetes, obesity, and hypertension have also failed to reveal specific loci accounting for the population variations, which suggests that many genes in concert determine the susceptibility to CHD (156,157). Contributing to this complexity are the confounding roles of age, ethnicity, and the environment (158). Gene polymorphism studies focused on relatively rare diseases and have presented evidence about point mutations that could be associated with CHD risk. For instance, CYPllB2, C-344T, and AT1R Al166C polymorphisms affect the autonomic modulation of heart rate that depends on sodium excretion (159). Similarly, the lipid response to diet could be modified by polymorphisms within the genes for apoE, apoB, apoCIII, lipoprotein lipase, hepatic lipase, endothelial lipase, the liver fatty acid-binding protein, the [33adrenergic receptor, adipsin, and the peroxisome proliferatoractivated receptor y (160). A large number of protein enzymes and receptors are involved in HDL metabolism, which regulates transport of cholesterol from peripheral cells to the liver. Mutations in the genes encoding these factors have been found to associ-
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ate with marked alterations in plasma HDL-C levels (161). Apolipoprotein A-I (ApoA-I) is the major protein constituent of the HDL particle (162), and ApoA-I and HDL have been shown to protect against atherosclerosis and CHD. The gene of ApoA-I is expressed in the liver and small intestine, and upon secretion into the plasma apoA-I is lapidated through ATP-binding cassette A1 (ABCA1)mediated efflux of free cholesterol and phospholipids from peripheral cells. This results in the formation of nascent disc-shaped HDL particles. Through the esterification of free cholesterol into cholesteryl ester by lecithin/cholesterol acyltransferase (LCAT), the nascent HDL particle can mature into larger and spherical HDL. The HDL-cholesteryl ester is transferred in part to apoB-containing lipoproteins in exchange for triglycerides by the action of cholesteryl ester transfer protein (CETP). Through this activity, tissuederived cholesterol can find its way to the liver via receptormediated uptake of LDL particles for secretion into bile. Recently, it was shown that hypo-o>lipoproteinemia due to mutations in apoA-I, ABCA1, and LCAT is associated with increased progression of atherosclerosis. In contrast, hyper-(x-lipoproteinemia as a result of loss of CETP function is associated with unaltered atherosclerosis progression (163). Gene polymorphisms of thrombosis functions can explain some of the estrogen-associated increased risk of thrombotic events observed in the The Heart and Estrogen/ Progestin Replacement Study (HERS) and Women's Health Initiative (WHI) trials (164). Suggested candidate genes are Factor V (AS06~G, Leiden), prothrombin (G20210-*A), Factor VII (A353-+G), plasminogen activator inhibitor-1 (4G/SG), t3-fibrinogen (G/A-455), and glycoprotein IIb/IIIa (pIA1/A2). Polymorphism of estrogen receptor (ER)-ot and ER-f3 can also explain differing responses to estrogen therapy. Naturally occurring splice variants of ER-oL and ER-[3 have been described, but only few point mutations were identified, and their biologic role is unclear (165,166). From the above it is apparent that CVD-CHD genomics is at its infancy, and future studies could provide important information about the genetics of these diseases. Understanding the genetics of CHD could improve the development of genotype-based tests and pharmacologic interventions based on genetic susceptibility.
H. Increased Blood Viscosity Increases in blood viscosity are associated with increased CHD risk. Plasma viscosity is higher in patients undergoing acute cardiovascular events such as stroke, MI, or sudden cardiac death (17,25,167,168). Increased blood viscosity can be caused by an increase in red cell mass or increased red cell deformity, increased plasma levels of fibrinogen and coagulation factors, and dehydration. CHD risk correlates with
increases in the activity of thrombogenic factors such as fibrinogen, procoagulants, and coagulation factors VII and VIII; with decreased activity of thrombolytic and fibrinolytic factors such as antithrombin III and plasminogen activator (25); and with conditions that promote platelets aggregation and adherence (17).
I. Depression Epidemiologic and observational studies have demonstrated an association between depression and cardiovascular disease (169-172). In the W H I Observational Study, depression was an independent predictor of CVD death (RR 1.5) after adjustment for multiple risk factors (172). Depression is also associated with the development of atherosclerosis (173), CHD (174), and a 2.5-fold increased risk of impaired cardiovascular outcome after MI (175). The mechanisms linking depression to CVD and CHD are unknown. Proposed mechanisms include sympathetic hyperactivity, increased platelet aggregation, lowered threshold for ventricular arrhythmias, and increased inflammation (176). Only a few studies have examined whether treatment of depression lowers CV-D risk, but no definitive conclusions could be drawn. A case-control study including 30- to 65year-old smokers (mostly premenopausal women) found an odds ratio (OR) of 0.35 for development of first MI among users of selective serotonin reuptake inhibitors (SSRIs) (177). However, a follow-up study showed that this association held only for SSRIs but not for other antidepressant medications, raising the possibility that SSRIs decrease MI risk through alternative mechanisms unassociated with depression (such as depletion of serotonin stores in platelets) (178). The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHED) trial, a randomized controlled clinical trial of depression treatment through cognitive behavior therapy and SSRI use, showed no increase in post-Ml event-free survival despite improved depression outcomes (179). As this study included mostly men, it is uncertain whether the results could be extrapolated to women.
J. Stress and Autonomic Imbalance Persons under stress are at an increased risk for CVD. In men, the risk of CHD in type A personalities (competitive, achievement oriented, time urgent, and hostile) is twofold higher than in type B personalities (those who lack type A characteristics) (180). The onset of acute coronary syndromes is more prevalent in awakening hours, 6 AM to 9 AM, compared with 6 PM to 12 l'M. (181--183), and these effects correlate with peak diurnal sympathetic activity (183). Little is known about the effects of stress on CVD and CHD in women.
CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women
The mechanisms by which stress modulates the risk of C H D are unclear. Stress can modify sympathetic neuroendocrine activity and the responses of the coronary vasculature to stimuli (180). Sympathetic hormones and glucocorticoids can promote the development of arteriosclerosis (17). In female animals, stress is associated with hypoestrogenism (185). In women, psychosocial stress exacerbates decreases in estrogen during the menstrual cycle and may lead to menstrual problems and infertility. Stressful life events are predictors of the premenstrual syndrome (PMS), possibly as a result of defective folliculogenesis and relative hypoestrogenism (185-187). Cardiac responses to [3-adrenergic sympathetic stimulation decline with age, as does the heart rate response to parasympathetic withdrawal (188). In postmenopausal women, the mean atrial effective refractory period is longer than in premenopausal women and agematched men. Experimentally, the atrial effective refractory period can be shortened during atrial pacing and during simultaneous atrioventricular pacing, but premenopausal women are relatively resistant to these effects compared with postmenopausal women and age-matched men (189). Arrhythmias are not considered a direct risk factor for CHD, but they could worsen CVD risk by weakening a failing heart. Most common among arrhythmias is atrial fibrillation (5). The incidence of atrial fibrillation is lower in women than in men (5). The lifetime risk for development of atrial fibrillation is 23% for women 40 years of age and older, and the mean age of developing atrial fibrillation in women is about 74 (5). In contrast to atrial fibrillation, women are at a greater risk for developing symptomatic ventricular arrhythmias and sudden death than men (190). The female gender is considered an independent risk factor for syncope and sudden death in the congenital long Q_T syndrome. Prolongation of the Q T interval is associated with increased risk of arrhythmia C H D and mortality. The higher propensity toward ventricular arrhythmia in females is associated with differences in repolarization and longer rate-corrected Q T intervals (191,192).
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L. Gender-Related Differences in CHD Age-adjusted death rates increase exponentially after age 50, and significantly more so in men than in women (Fig. 31.12). In both sexes the leading causes of death are CVD (see Fig. 31.1), specifically C H D (Fig. 31.13), followed by cancer deaths (see Fig. 31.1). Prior to age 60, cancer deaths contribute relatively little to the gender-mortality gap (see Fig. 31.2), which suggests that the gender-related difference in mortality rates is mainly due to CHD. Although death rates from CVD and C H D are lower in women than in men (see Fig. 31.13), more women than men die of CVD because they have a longer life expectancy. In 2002, 488,946 women and 429,682 men died of major cardiovascular diseases in the United States (1). In childhood, CVD is rare and is mostly attributed to congenital heart disease (1). C H D mortality rates begin to increase by the second decade of life, at which age the maleto-female risk ratio increases and remains high throughout life (see Fig. 31.12). The gender gap narrows at more advanced ages, but even after age 85 the age-related gender mortality gap is substantial (see Fig. 31.12). These observations suggest that women are relatively protected from developing C H D at early adulthood and that the effect continues into advanced age.
Death Rates- All Causes per 100,000 Population 18000
15000 Men Women 12000
9000
K. Compounded Risk Factors 6000
In both women and men, risk factors for CVD and CHD are usually clustered: among persons with two risk factors, the most common combination is hypertension and hypercholesterolemia; among those with three risk factors, hypertension, hypercholesterolemia, and obesity; and among those with four risk factors, hypertension, hypercholesterolemia, obesity, and cigarette smoking or diabetes (5). However, risk profiles for acute ischemic syndromes differ among the genders: women tend to be older and less likely to have ever smoked; they have higher rates of associated diabetes, hypertension, and hypercholesterolemia; and they have lower incidence of prior MI, angioplasty, and coronary artery bypass surgery (193).
3000
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Age FIGURE 31.12 Age- and sex-adjusted mortality rates in the United States. Modified from ref. 1, with permission.
GORODESKI AND GORODESKI
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toms, illness, short and long-term disability, and poorer health than men (194). Women use preventive and curative medical services more frequently, including visits to caregivers, over-the-counter and prescription medications, hospitalizations (other than childbirth), psychiatric treatment, diagnostic tests, and surgical procedures (5,195). Recent reports indicate that although the age-related prevalence of CVD morbidity appears similar in women and men (Fig. 31.14, A), the age-related prevalence of hypertension (Fig. 31.14, B) and angina pectoris (Fig. 31.14, C) are higher in women than in men. In contrast, the prevalence of diagnosed cardiac conditions such as C H D (Fig. 31.15, A), acute MI (Fig. 31.15, B), and heart failure (Fig. 31.15, C) are lower in women than in men. The reason for these trends appears to be reporting bias, namely over-reporting by women and under-reporting by men, indicating greater health awareness by women. In addition to differences in CVD morbidity, genderrelated differences were also described relative to the clinical presentation of patients with ischemic heart disease, use of coronary diagnostic invasive studies, coronary findings in women, clinical and surgical management, outcome, and prognosis. These differences are discussed in greater detail in the following sections.
causes
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Women Men
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Death Rates (per 100,000 Population)
1. CLINICAL PRESENTATION
FIGURE. 31.13 Gender-dependent total cause and CVD-related mortality rates in the United States. Modified from res 1, with permission.
In the United States, the incidence of CHD in women lags behind men by 10 years; for MI and sudden death, by 20 years (196-197). More women than men have their initial manifestation of C H D as angina pectoris (65% versus 35%, respectively) (198), while fewer women than men suffer an acute MI as their first manifestation (29% versus 43%, respectively) (5). Among hospitalized patients with acute coronary syndromes, MI develops in a smaller percentage of
Gender-related differences are also observed relative to CVD morbidity. These phenomena are usually described in terms of disease prevalence based on self-reporting, visits to physicians, and hospital discharge coding. Past reports suggested that from early childhood women report more symp-
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CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women
/
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. 6
8
FIGURE 31.15
Gender-related prevalence o f C H D (A), acute MI (B), and congestive heart failure (C). Modified from ref. 5.
women than men (198-200). However, 36% of all women with C H D present with sudden cardiac death or fatal MI (201). Approximately 64% of women and 50% of men who died suddenly of C H D had no previous symptoms of the disease (5). In the United States, the average age of first heart attack is 65.8 for men and 70.4 for women (5), and the lifetime risk of developing C H D after age 40 is 49% for men and 32% for women. Analysis of annual rates of new MI or C H D death during 1989-2000 show similar racial trends but different gender trends (Fig. 31.16). At presentation, women usually have milder symptomatology than men, despite usually more severe disease (202). Chest pain is the most common symptom of MI in both men and women (203,204), but it is less predictive in women than in men and tends to subside more quickly (205). Women tend to complain of more back and jaw pain and are more likely to experience atypical symptoms such as shortness of breath, loss of appetite, indigestion, nausea and/or vomiting, palpitations, dizziness, fatigue, and syncope (205-208). Among MI patients younger than 65 years of age, fewer women than men present with ST elevation and fewer develop Qzwave MI, whereas in patients ---65 years old, there is no significant sex difference (209). In contrast to women, men are more likely to have a Qzwave infarction (210). Women younger than 65 years of age are more likely than men of the same age to be discharged with a diagnosis of unstable angina (211). These gender-related differences could be attributed to the greater lack of recognition of acute MI in women than in men (5,62,202).
2. USE OF DIAGNOSTIC INVASIVE STUDIES
Women are referred less often than men for coronary artery evaluation (Fig. 31.17), even when they have a positive exercise test (5,8). They are referred at a more advanced
Annual Rate (per 1000 persons) 60 -
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stage of disease, are less likely to be diagnosed initially of having an acute ischemic heart condition, and take longer to be admitted for observation and treatment (5). The reasons for the decreased rate of referral for coronary testing are numerous and include the following: 9 Women more often present with an atypical pattern of chest pain. ~ Historically, women have been known to have nonobstructive C H D and single-vessel disease (34). ~ Women have less common causes of ischemia such as vasospastic and microvascular angina, as well as syndromes of nonischemic chest pain, such as mitral valve prolapse (212). ~ Women are more risk averse in their medical decisionmaking (213).
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TABLE 31.2 Gender Differences in the Prevalence of Nonobstructive ("Normal") Coronary Angiogram Diagnostic Cardiac Cath eterizations
Acute coronary syndrome Unstable angina No ST-elevation MI ST-elevation MI
Angioplasty
Women
Men
18% 28% 9% 10%
9% 11% 4% 7%
MI, myocardial infarction. Modified from ref. 214, with permission.
Open Heart Surgery
Cardiac Bypass Revascularization
Pacemakers and Implantable Defibrillators
Men Women 0
200
400
600
800
I000
Estimated No of Procedures, 2002
FIGURE 31.17 Gender differences in invasive diagnostic coronary procedures and cardiac surgical interventions. Modified from res 5.
9 Many physicians believe that angina pectoris in women is a benign disease and know that stress testing is less accurate for the diagnosis of C H D (5). 9 The fact that women with acute MI are on average 7 to 8 years older than men seems to contribute to the reluctance to perform invasive procedures (5).
3. CORONARY FINDINGS IN WOMEN
Three-vessel and left main C H D are more common in men than in women (211), and women are less likely than age-matched men to have obstructive C H D (5). Normal coronary angiograms ("nonobstructive atherosclerotic coronary disease") are present in 9% to 28% of women presenting with acute coronary syndromes compared with 4% to 11% in men (Table 31.2) (214). In some women with evidence of myocardial ischemia or infarction and normal coronary arteries, symptoms may be indistinguishable from those with obstructive coronary artery disease. In these women, pathologically important atherosclerotic coronary disease may be present even in the absence of angiographically observed stenosis (214). Advanced coronary perfusion imaging techniques will usually demonstrate vascular dysfunction in 50% to 60%, and 20% of those will have athero-
sclerosis-related endothelial dysfunction, as is evident by abnormal acetylcholine perfusion test (214). Most women with acute coronary syndromes and nonobstructive coronary angiograms will have positive exerciserelated ECG changes suggestive of ischemia. Although most have a good prognosis with regard to MI and cardiovascular mortality (215), some will have limitations in daily activities because of pain (216) and will be erroneously diagnosed as having other vascular disorders such as hot flushes, Raynaud's phenomena, and migraine (217,218). Of equal concern is the fact that unstable angina with "normal" coronary angiogram carries a 2% risk of death or MI at 30 days of follow-up (219,220).
4. CLINICAL AND SURGICAL MANAGEMENT Following the demonstration of normal or near-normal coronary arteries, women with angina are often told that they have no significant heart disease and are offered no specific treatment beyond reassurance. Even when women are identified as having risk factors for CVD, physicians less often use standard accepted therapy in women than in men. Compared with men with similar cardiovascular risk profiles, women are less likely to undergo additional coronary evaluation (38% versus 62%) or coronary revascularization (2% versus 5%). Less aggressive lipid-modifying strategies are used when treating women compared with men with similar risk profiles (8-10). The complacency and misunderstanding of the gravity of C H D outcome in women is best evident from a report that women took longer to arrive at the hospital after infarction than did men (median time 2.6 hr for women versus 2.0 hr for men) (221). Studies from a decade ago (late 1990s) reported gender differences in procedural outcomes after elective percutaneous transluminal coronary angioplasty. These differences could have been the result of the presence of more comorbidities and worse clinical characteristics in women such as older age, unstable angina, congestive heart failure, diabetes mellitus, and hypertension than in men. Women have a smaller vessel diameter, more coronary tortuosity, and different plaque composition compared with men, which could
CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women lead to a higher dissection rate and a greater number of procedural complications. Increased awareness to these conditions has resulted in inclusion of more women in surgical coronary procedures. With the introduction of more refined surgical techniques and the more aggressive use of antithrombotic drugs, current procedures are almost equally safe and provide similar outcomes in women and men, despite worse baseline characteristics in women (222). Nevertheless, recent reports still describe underutilization of some procedures and facilities for women. In 2002 an estimated 6.8 million inpatient cardiovascular operations and procedures were performed in the United States; 4.0 million were performed on men but only 2.8 million on women. Studies also reported underutilization of reperfusion therapy (men 68.8%; women 49.7%), administration of beta blockers (men 76.0%; women 66.0%) (221), and cardiac rehabilitation after acute M1 (see Fig. 31.17)(5).
5. OUTCOME AND PROGNOSIS
Data about the immediate and long-term outcome of acute coronary syndromes show that women fare less well than men and that, once C H D is diagnosed, the case fatality rate for women exceeds that for men (5). Although these data should be interpreted with caution because of the more advanced age with which women present with new cardiac event, some studies reported that the age-adjusted hospital mortality in cases of acute MI in women equals that in men. Those studies also reported that women have greater risk for congestive heart failure, stroke, and reinfarction than men, even after age adjustment (200,223,224). During hospitalization for the acute MI, the mortality rate in women is more than doubled compared with men (18.6% versus 8.4%, respectively) (221). The prognosis of women with unstable angina and nonobstructive atherosclerotic coronary artery disease includes a 2% risk of death or MI at 30 days of follow-up (214). Approximately 38% to 39% of women who have an acute MI die within 1 year, compared with 25% to 31% of men. Twenty percent of women versus 15% of men will have repeat acute M1 during the first 4 to 6 years after the first episode. Six percent of women and 7% of men will experience sudden death; about 11% of women and 8% of men will have a stroke, and 46% of women and 22% of men will be disabled with heart failure (5). Women are less likely than men to return to work during the first 2 years after the acute MI. Attributed reasons to this phenomenon are a more advanced age of women at their index event and gender differences in behavioral response to illness (225). Women use cardiac rehabilitation services less frequently than men and when they enroll, women present differently, being older and having greater medical comorbidities (226). Women under age 55 have worse prognosis than men, with greater recurrence of MI and higher mortality. Women under age 55 have less favorable near-term
421
outcomes after myocardial revascularization procedures than men and are twice as likely to die after an acute MI than age-matched men (5). One of the consequences of ischemic heart disease is congestive heart failure. The incidence of congestive heart failure is 10 per 1000 population after age 65. The overall prevalence rates of congestive heart failure are similar in men and women, but the incidence is higher for men in age groups 54 to 74 (see Fig. 31.15, C). The etiology and risk factors for congestive heart failure also differ between men and women. Ischemic heart disease is the most common cause of heart failure in men of all ages. Heart failure in younger women is more often due to nonischemic heart disease, but older women are more likely than men to develop heart failure after MI and interventional procedures. Hypertension, diastolic dysfunction, diabetes, obesity, and inactivity are risk factors for congestive heart failure in women, whereas alcohol abuse, cigarette smoking, cardiomyopathy, ischemic heart disease, and systolic dysfunction are more important risk factors in men (227). Women tend to be older when diagnosed with heart failure and have better ventricular function, less ischemic heart disease, atrial fibrillation, and ventricular arrhythmias. Compared with men, women benefit less from established treatments and experience a lower overall quality of life (228). However, women have better long-term survival (229).
6. GENDER DIFFERENCES: BY WHAT MECHANISMS?
Studies by the PDAY group showed that coronary artery fatty streaks and raised atherotic lesions can be found as early as childhood and progress in extent through ages 15 to 34 in both men and women. However, women have about one-half the extent of raised lesions at all ages thereafter (Fig. 31.18) (230). These results are consistent with other studies (231,232), which indicate that the coronary arteries of women and men have an equal extent of fatty streaks but that women have less extensive raised lesions. A possible explanation for the delayed progression of raised coronary lesions in women is the H D L mechanism because, regardless of race and ethnicity, the single major C H D risk factor with a significantly higher prevalence in men versus women is low H D L - C (20 years, 1.71. This trend is statistically significant (p = 0.036) (256). Similar trends were reported in the estrogen-only W H I trial (257,279a). Interestingly, in the W H I observational arm (288), estrogen-progestin treatment was associated with reduced C H D risks (RR 0.71), despite increased risks of vascular thromboembolic events (RR 1.06-1.17) and similar to the results obtained in the observational Nurses Health Study (289,289a). The most likely explanation is the younger age of participants and earlier start of hormone treatment in the women enrolled in the W H I observational arm compared with the W H I randomized trial.
429
This conclusion is supported by a number of previous studies. For instance, in rabbits, estrogens had either a beneficial or adverse effect depending on the state of the arteries. Animals with healthy arteries showed a protective effect of estrogen, but in those with damaged arteries the effect was adverse (290). Monkeys randomized to postmenopausal hormones at the time of oophorectomy had substantially reduced coronary atherosclerosis compared with those given placebo. In contrast, when hormones were begun 2 years after surgical menopause (equivalent to about 6 human years), no such protection was observed (291-295). In women, the effect of estrogen on acetylcholine-induced vasodilatation differs markedly according to the presence or absence of coronary atherosclerosis (296). Randomized trials of women with C H D in the HERS and ERA trials did not show beneficial effects of estrogen, but in younger postmenopausal women there was a reduction in progression of atherosclerosis in the treated group compared with those given placebo (296). 9 The decision to terminate the estrogen-progestin W H I study was based on the nominal, unadjusted RRs of breast cancer and cardiovascular events. When the number of statistical tests is taken into account (i.e., adjusted for multiple testing), all the "significant" test results other than those for deep vascular thromboembolic events were no longer significant, indicating that the minor, non-significant increase in RRs in many conditions could have been explained by chance alone (287).
E. Differences among the Conclusions of the Observational and Randomized Trials The disparity among findings from the observational studies and the randomized trials on the effects of hormone replacement on CVD and C H D have created considerable debate among caregivers, researchers, and patients. Pooled estimates from observational studies inferred a relative CVD reduction of about 50% with ever-use of hormone replacement, supporting a cardioprotective role for estrogens that is unlikely to be explained by confounding factors (289). Similar results were recorded in the W H I observational arm, as described previously (288). By contrast, the randomized W H I studies in supposedly healthy women found hormone replacement to either have null effect (257) or slightly increased risk of C H D (256). One possible explanation for this apparent disparity is the potential for confounding in the observational studies. For instance, in the Nurses Health Study, estrogen users tended to be healthier than those not on hormone treatment. The difficulty with this explanation is that no disparity was found between the Nurses Health Study and the
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W H I trials with regard to risk estimates for breast cancer, stroke, and others (297). Another possible explanation is that observational studies are limited in capturing acute effects. The increase in C H D events in W H I was concentrated in the initial year after starting hormones. This short-term effect would tend to be missed in observational studies, even with fairly frequent updating of exposure. However, re-analyses of observational data should be able to test this speculation. Indeed, reanalysis of the Nurses Health Study showed that there was a higher rate of recurrent coronary events in women with a prior history of cardiovascular disease, fitting with the W H I data (298). Moreover, it was shown that the risk of C H D depended on start of hormone replacement from the time of menopause: the RR of C H D was 0.72 if treatment with estrogen plus progestin started 1 to 4 years after menopause versus 0.9 if started more than 10 years after menopause. For estrogen-only treatment the RRs were 0.66 and 0.67, respectively (299). In addition, a meta-analysis of observational studies focusing on older postmenopausal women was consistent with recent randomized trials, and it demonstrated an almost identical increase in CVD RR, being 1.28 in the secondary prevention of CVD events (300). The likely explanation for the disparity between the observational studies and the randomized trials is therefore that women who participated in the trials were different from those who participated in the observational studies. Past observational studies reflected common clinical practice whereby women were typically initiated on postmenopausal hormones at a relatively young age and earlier after the beginning of menopause. In contrast, two-thirds of the participants in the W H I began the trial at an age older than 60, and about 10 years after the start of menopause. These women most likely had already an established atherosclerosis upon entry into the trial and were more prone to the prothrombotic effects of the hormone treatment (301). In the case of the W H I trials, a large number of the participants were not healthy postmenopausal women, and the W H I trials cannot answer the question of the primary C H D preventive role of estrogen in postmenopausal women (301).
F. Current Stand on Hormone Treatment for Postmenopausal Women Based on the previous discussion, the following conclusions are advanced: 9 Estrogen is a vasculo- and cardio-protective hormone in females, and the menopause transition renders a woman at an added increased risk for CHD. 9 Estrogen should not be used as first-choice treatment in women with established C H D or at increased C H D risk.
9 Oral, but not transdermal, estrogen replacement therapy is associated with risk of venous thromboembolism in postmenopausal women (302). 9 The W H I trials did not effectively address the issue of primary prevention of C H D with estrogen, and the current understanding in this matter still depends on the results of the observational studies such as the Nurses Health Study. One of the conclusions from these studies is that estrogen replacement therapy beginning early after menopause reduces overall risks of CHD. 9 When taking into consideration how early after menopause to start hormone replacement therapy in otherwise healthy woman without clinically apparent CHD, it is important to understand that coronary disease begins premenopausally and that menopause may be preceded by years of gradual declining estrogen activity. Studies in monkeys revealed the importance of premenopausal estrogen treatment in reducing the risk of atherosclerosis (303). 9 Current experimental, clinical, and observational data do not provide evidence that progestins attenuate estrogen's cardiovascular benefits (304). 9 Considerations whether and when to start hormone replacement therapy should be individualized to the patient's needs, emphasizing her global versus cardiovascular risk profile.
VI. CHD RISK ASSESSMENT Understanding the epidemiologic profile of patients at risk can predict development of C H D and its long-term outcome in 50% to 75% of cases (305-308). However, most models, including the Framingham Risk Score, fall short of predicting near-furore events in individual patients, and these models do not effectively predict occurrence of acute coronary syndromes and sudden death. Acute coronary events are the culmination of processes aggravated by thrombogenic background that promotes thrombus formation at the site of the coronary plaque and by myocardial electrical instability and susceptible autonomic tone that could lead to fatal arrhythmia. Accordingly, the modern approach to C H D risk assessment advocates early identification of the Vulnerable Patient along with the Vulnerable Blood and the Vulnerable Myocardium (309,310). Risk assessment of the Vulnerable Woman is based on the 10-year Framingham Risk Score Calculator (311). It classifies the risk of heart disease as high, intermediate, or low. Tabulation is based on scoring points for the parameters of age, smoking, plasma total- and HDL-cholesterol, and systolic blood pressure (Tables 31.3 to 31.7). The added points are transformed to a 10-year risk as a percentage, so that a risk ->20% in 10 years is considered high risk, intermediate
431
CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women TABLE 31.6 The Framingham C H D Risk Score Calculator: H D L Cholesterol as a Risk Factor
TABLE 31.3 The Framingham C H D Risk Score Calculator: Age as a Risk Factor Age
Points
HDL (mg/dL)
Points
20-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
-7 -3 0 3 6 8 10 12 14 16
>-60 50-59 40-49 40 kg/m 2, or BMI _> 35 kg/m 2 with obesity-related disease when less invasive measures have failed. Bariatric surgical procedures usually fall into two categories: gastric bypass and gastroplasty. Mean weight loss is 60 to 100 lbs, but the procedures carry significant postoperative morbidity and mortality risks (320,321). Review of 136 bariatric surgery studies revealed that more than 72% of patients undergoing the procedure were women, with a mean age of 39 years and baseline mean BMI of 46.9 kg/m 2 (322). The surgery resolved or improved diabetes, hypertension, hyperlipidemia, and obstructive sleep apnea in more than 70% of the patients (322). The concept of dietary modifications, in contrast to the more drastic measures of dietary restrictions and active interventions for weight loss, was tested in the W H I Dietary Modification Trial, which was a randomized intervention trial of more than 48,000 postmenopausal women. About 40% were randomized to an intervention arm that included group and individual sessions to promote a decrease in fat intake and increases in vegetable, fruit, and grain consumption but did not include weight loss or caloric restriction goals. About 60% of the women comprised the control group and received diet-related education materials. Compared with the control group, women in the intervention group lost 1.9 kg at 1 year and 0.4 kg at 7.5 years (p < 0.01-0.1). No tendency toward weight gain was observed in intervention group women overall or when stratified by age, ethnicity, or BMI. Weight loss was greatest among women in either group who decreased their percentage of energy from fat. A similar but lesser trend was observed with increases in vegetable and fruit servings, and a non-significant trend toward weight loss occurred with increasing intake of fiber (322a).
433
Over a mean of 8.1 years, the dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women. However, it achieved mild effects on CVD risk factors: LDL-C levels, diastolic blood pressure, and factor VlIc levels were significantly reduced by 3.55 mg/dL, 0.31 mm Hg, and 4.29%, respectively. In contrast, levels of H D L - C triglycerides, glucose, and insulin did not significantly differ in the intervention versus comparison groups (322b). At present it is difficult to draw definitive conclusions from those studies and their overall negative results. Despite their size and careful execution, criticisms presented above relative to the W H I Hormone Trials about participants' age and health condition apply to the W H I Dietary Modification Trial as well. Exercise, defined as formal training-type activity that can also include recreational sport, should not be confused with physical activity, which is activity at work and leisure, including sport. Moderate-intensity physical activity is defined as expending 5 to 7.5 kcal/min or exercising at 60% to 70% of maximum heart rate or at 60% of VO2max (e.g., brisk walking, swimming, or cycling). Regular exercise increases myocardial contractility and improves electrical stability; decreases heart rate at rest and at submaximal cardiac output; improves endothelial function and flow-mediated dilatation; and stimulates formation of collaterals. At the cellular level, platelet aggregation is reduced and fibrinolytic activity is increased. Inflammatory factors such as CRP are reduced; and lipid oxidation during activity and in postexercise recovery is increased, as are lipoprotein lipase activity, tissue sensitivity to insulin, and disposal of glucose (323,324). Studies conducted mostly in men showed the benefits of moderate exercise for cardiovascular health (325-327). The health risks of obesity in men could be controlled if a person is physically active and fit (137). Moderate exercise decreases total cholesterol LDL-C and triglycerides and increases H D L - C (139,140). Moderate exercise also improves hypertension (80,328) and type 2 diabetes (142). Physical activity halves the risk of type 2 diabetes, CHD, and stroke (134,135) and reduces the risks of hip and vertebral fractures, colon cancer, anxiety, depression, and cognitive decline with age (134). Two observational studies analyzed effects of exercise on C H D and overall mortality in women. In the Nurses Health Study, there was a graded inverse association between physical activity and C H D risk. Walking and vigorous exercise were associated with substantial reductions in C H D risk: women who walked 3 hours per week or exercised vigorously for 1.5 hour per week had 30% to 40% reduced RR of C H D compared with sedentary women, and women who became active in middle or late adulthood had decreased risk of C H D when compared with long-term sedentary counterparts (329). In the Nurses Health Study, vigorous to
434
GORODESKI AND GORODESKI
Diet Only . . . . .
~................
~ ~
..........
Diet + Walking ~
~ ~ 1 ...........- -
Diet + Aerobic Dance ~ / A .........- -
~ ~ ..........
g FmtJRE 31.21 Exercise effects, alone or in combination with diet on body weight parameters. BMI, body mass index; IFA, intraabdominal fat area; SFA, subcutaneous fat area. Modified from ref. 138, with permission.
'2 L
0.80 i~ 0.60 ~. 0.40 0.20 0.00
~,
6
9 eo :~
la e. o z
Time Spent Walking per wk
, .......................
The popular fear that vigorous exercise can trigger cardiac arrest or sudden death has been disproportionally exaggerated. Data obtained predominantly in men reported an absolute risk of sudden death during, and up to 30 minutes after, vigorous exercise of I case per 1.51 million episodes of exertion (332). The increased risk was only seen in men with hypertension (treated or untreated) (333), and it could be significantly reduced by a habitual exercise program. Contraindications to exercise include unstable angina, uncontrolled diabetes, uncontrolled hypertension, exercise-induced arrhythmias, severe stenotic or regurgitant valvular disease, and hypertrophic cardiomyopathy (134).
1.00
|
~
Usual Walking Pace (km/h)
FIGURE 31.22 Exercise effects on C H D risk. Modified from ref. 331, with permission.
moderate exercise was associated with 46% decreased RR of developing diabetes (141). In the Iowa Women's Health Study, which focused on postmenopausal women ages 55 to 69, women who engaged in moderate activities ->4 times a week had 47% reduced RR of cardiovascular mortality than those who did so rarely or not at all. Participants in vigorous activities ->4 times a week had 80% lower RR (330). A study of Japanese women showed that exercise augments diet effects on weight reduction and loss of intra-abdominal and subcutaneous fat (Fig. 31.21) (138). Vigorous intensity activity confers maximal cardiovascular benefit (Fig. 31.22) (331). However, regular moderate intensity physical activity, which is attainable for the majority of women and men, gives considerable protection against C H D (135). Therefore, walking is suggested as the most practical exercise from which the population can achieve such improvements in health (134).
B. Early Diagnosis and Treatment of Associated Medical Conditions A number of known medical conditions can increase the risk of C H D if not treated. Women with type 2 diabetes mellitus should be monitored for HbA1c goal 130/80 mm Hg if the patient has diabetes), drugs should be used to control the hypertension. Current recommendations (82) do not clearly address gender-related issues other than pregnancy and birth control pills. However, as widely adopted also for women (5,62), they are as follows: 1. Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensinreceptor blockers, [3-blockers, calcium channel blockers). 2. Most patients with hypertension will require two or more antihypertensive medications to achieve goal blood pressure. 3. If blood pressure is more than 20/10 mm Hg above goal blood pressure, consideration should be given to initiating therapy with two agents, one of which should be a thiazide-type diuretic. Women post-MI or those with chronic angina or chest pain should be treated with ~3-blockers. Women with a history of heart failure should be treated with angiotensin converting enzyme (ACE) inhibitor therapy or angiotensin receptor blocker (ARB); atrial fibrillation should be controlled and warfarin therapy (or 325 mg of aspirin daily) is indicated; and high-risk women with depression should be aggressively treated (7,311). Antioxidant supplements, such as vitamin E and beta carotene, should not be used to prevent heart disease. Severn clinical trials have shown no benefit, and some have shown an unexpected increase in hemorrhagic strokes (7,311). The use of low-dose aspirin is recommended for secondary prevention in women with pre-existing CHD. However, the use of aspirin for primary prevention of C H D in healthy women remains a controversial topic. The Women's Health Study, a randomized placebo controlled trial of low-dose aspirin (100 mg every other day) in 39,876 perimenopausal, healthy health professionals at an average age of 54 showed no statistically significant benefit relative to the combined end point of MI, stroke, and mortality (336). The only derived benefit was a 34% reduction in RR of the secondary end point of ischemic stroke. These results contradict prior findings in men in whom daily use of aspirin reduced the risk of MI but not of stroke (337). However, questions have been raised about whether the dose of aspirin used in the Women's Health Study was too low and whether the results could be generalized to healthy women with greater C H D risk factors. Aspirin for low-risk patients is not recommended because the risks of gastrointestinal bleeding outweigh the potential benefits.
435
C. L i p i d L o w e r i n g T r e a t m e n t The association between cardiovascular events and LDLC is well established, and LDL-C is the primary target of therapy both in men and women (338). LDL-C comprises 60% to 70% of the total serum cholesterol and is the major atherogenic lipoprotein (62). Because LDL-C levels 190 mg/dL) atherogenesis is markedly accelerated (62). Similar definitions for total cholesterol and triglycerides are shown in Table 31.9. HDL-C is also an important predictor for coronary events (339), and it has a greater predictive potential in women than in men (340-342). Because there is a continuous rise in risk for C H D as H D L - C levels decline and no inflection point in the C H D versus H D L - C curve (62), low H D L - C levels are defined as 60 mg/dL (62,311). Lipoprotein(a), which is unaffected by diet, exercise, and most lipid-modifying medications, is an independent predictor of the risk of recurrent C H D in postmenopausal women (343), but it is not used routinely for treatment evaluation. The intensity of LDL lowering therapy should be adjusted to the individual's absolute risk for CHD. For that purpose, risk assessment of major independent risk factors is based on the 10-year risk assessment Framingham scoring shown in Table 31.8, with some differences. Three categories of C H D risk are identified (62) as established CHD and CHD risk equivalents, multiple (2+) risk factors, and 0-1 risk factor. The major risk factors include age (->55 years in women), cigarette smoking, low H D L - C ( 140/90 mm Hg or on anti-
TABLE 31.9 Interpretations of Plasma Levels of LDL Cholesterol, Total Cholesterol, and Triglycerides in Terms of C H D Risk* LDL cholesterol Desirable (optimal) Near optimal Borderline h i g h High Very high
Total cholesterol
Triglycerides
190
240
500
*Allvalues in mg/dL. CHD, coronaryheart disease; LDL, low-densitylipoprotein. Modified from ref. 62.
436
GORODESKIAND GORODV.SKI
TABLE 31.10 Goals of Lipid-Lowering Therapy for Primary Prevention of CHD Based on LDL Cholesterol Levels LDL Cholesterol Risk category Multiple (2 +) risk factors 0-1 risk factor
10-year risk for CHD
Level at which to consider drug therapy
Primary goal of therapy
>20% (includes CHD risk equivalents) 10-20% 100 mg/dL ->130 mg/dL >-160 mg/dL >-190 mg/dL
0.97, p < 0.01-0.04). By extrapolation, the following parameters were calculated: (1) points of intersection between the early and late increases of life expectancy in Caucasians (designated as "turning points") (see Figs. 31.25 and 31.26); (2) "maximal" life expectancies; and (3) years to reach the "maximal" life expectancy. These parameters are shown in Table 31.12, suggesting significant differences in these parameters between women and men, Caucasians and African Americans. To better understand those trends, rates of the 10 leading causes of deaths were compared among Caucasian women
CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal Women
441
TABLE 31.12 Life Expectancy Parameters* "Turningpoint" in life expectancy Caucasian women Caucasian men African-American women African-American men
Maximal life expectancy
kkkkkkkkkklkkiP ~ a '
Year to reach maximal life expectancy
1970 1970
82.5 83.0 77.0
2010 2065 2030
N/A
78.0
2100
I
!
Caucasian Wmnm
i
Caucasian
L
Men
0 ~'~
1975
*Calculated from Figs. 31.25 and 31.26.
~:.oa2
~
and men for the years 1960 (the pre-plateau of the early increase in life expectancy) and 2002 (latest available data) (Fig. 31.27). The greater life expectancy in Caucasian women compared with Caucasian men could be explained by the lower death rates from heart disease in women. In both groups, death rates from heart disease decreased significantly from 1960 to 2002. During that period, cancer mortality rates increased in both groups, but the increases were smaller in women than in men (see Fig. 31.27). Therefore, it is possible that (1) the steep increases in life expectancy after 1970 in Caucasians were due to decreases in deaths from heart disease and (2) decreases in heart disease mortality in Caucasian men were offset by increases in cancer mortality, thereby tempering the increase in life expectancy compared with Caucasian women. The predictions presented in Figs. 31.25 and 31.26 and in Table 31.12 are similar to those recently published by the Social Security Administration (382), which predicted that life expectancy in the United States will continue its steady increases, reaching the mid-80s later in the 21st century. The predicted linear increases in life expectancy of Caucasians suggest that if present health and mortality trends continue at their current pace, Caucasian women will reach the maximal predicted life expectancy sooner than Caucasian men (about 83 years of age for both sexes). Caucasian women will reach this target around the year 2010 and Caucasian men around the year 2065 (see Table 31.12).
B. An Alternative Hypothesis of Life Expectancy in Women in the United States The alternative and more ominous hypothesis is that both women and men have already reached their peak life expectancy and that in the future, life expectancy will either remain at its current level or will decrease if current trends of morbidity continue. Furthermore, decreases in life expectancy will be greater in women than in men (381). This hypothesis is supported by two groups of data. First, mortal-
19rio 1975
J
kip
i
!
i
s F
Af[ic~-American Women
L.,
African. Amer ica. Men
F 1975 2002 9
2002
|
10o 200 300 tOO Death Ra~e~fperlO0.Dl~ P~pul~on)
5o0 0
100 Death ~
~
300 800 ~er tOO,0~ Pepulation)
~1o
FIGURE 31.27 Major causes of death in the United States in years 1960, 1975, and 2002. Modified from ref. 1, with permission.
ity rates of colon/rectum cancers in women decreased through the 1950s and breast cancer mortality decreased in the past decade. However, mortality rates of lung/bronchus cancers, which are the leading cancers in women, have increased since the 1960s (Fig. 31.28). In men, mortality rates of all three leading cancers (lung/bronchus, prostate, and colon/rectum) have been declining since the past decade (see Fig. 31.28). If these trends continue into the next decade, rates of cancer mortality will increase more in women than men. The second argument is that rates of C H D risk factors (including obesity, hypercholesterolemia, hypertension, and physical inactivity) are escalating at a greater pace in women than in men (5). The prevalence of these risk factors already has increased in teenager females as compared with males and remains higher in women than in agematched men (5,381). Therefore, if increases in C H D risk factors such as obesity remain constant, the overall negative effect on life expectancy in the United States will be a reduction in life expectancy of one-third to three-fourths
442
GORODESKI AND GORODESKI
FIGURE 31.28 Cancer causes of deaths in the United States. Modified from res 1, with permission.
FIGURE 31.29 Age-related deaths in the United States in years 1968, 1978, and 2002. Modified from ref. 1, with permission.
of a year (381). This prediction applies to both women and men, and in particular to African Americans in whom escalating rates of C H D risk factors and cancer mortality determine the lower predicted life expectancy (ages 77 and 78 in African-American women and men, respectively; see Figs. 31.24 to 31.26, Table 31.12, and [1]).
9 The clinical management of women should be directed to maintain the achievements in health care that were gained in the past 4 decades in order to avoid reversal of the life expectancy trends. Women, more so than men, are at a greater perceived risk of developing heart disease and therefore for dying at an earlier age than in previous years. 9 Physicians will be faced with an increasing dilemma of having to screen for and diagnose heart disease in women at earlier phases of life, despite the low accuracy of current cardiovascular screening/diagnostic methods in women. 9 Statins are considered a breakthrough in the management of lipidemia, and their use since the mid-1980s has been associated with decreases in C H D risks and mortality (385). The accelerated increase in life expectancy in women around the 1970s occurred before statins were used, and their effect on life expectancy in women is unclear. It can be argued that the use of statins in women has not been popularized as in men. On the other hand, a period of 10-15 years should have produced an impact on cardiovascular mortality and on the estimates of life expectancy. Therefore, whether statins will increase life expectancy in women or will only maintain the current level of longevity remains to be seen.
C. Conclusions One of the questions raised in life expectancy analyses is their relevance to life span and longevity. Life span is defined as the recordable longest observed age at death of a human individual (383), which at present is 122 years (384). Usually, records of life span have little relevance because genetic, environmental, and lifestyle diversity guarantees that an overwhelming majority of the population will die long before attaining the age of the longest-lived individual. More pertinent to life expectancy analyses is the parameter of the amount of life gained (i.e., longevity). As shown in Fig. 31.29, in the United States between the years 1978 and 2002, there was an average gain of about 5 years of life, thereby approaching the projected life expectancy of about 83 years. In summary, even if current trends of morbidity continue, there will be only small additional net gain in longevity. From the above discussion, the following conclusions can be drawn: 9 Current mortality data support the hypothesis that in the 21st-century Caucasian women and men will reach life expectancy of about 83 years of age, which appears to be the maximal life expectancy. An alternative hypothesis is that if current trends of morbidity continue, life expectancy will decline in future years.
In summary, C H D in women is predicted to become the pandemic of the 21st century due to escalating increases in C H D risk factors from childhood. The consequences to women could be an earlier onset of CHD, increased prevalence of cardiovascular morbidity and diminished quality of life, decreased life expectancy, and premature death. Active prevention of C H D in women should aim at attenuating the
CHAPTER 31 Epidemiology and Risk Factors of Cardiovascular Disease in Postmenopausal W o m e n
impact of cardiovascular risk factors, beginning as early as childhood. Efforts should include control of eating habits and diet; early detection of plasma lipidemia, diabetes, and hypertension; avoidance of primary and secondary cigarette smoking; and providing education and support for the proper active lifestyle. The role of estrogen replacement in perimenopausal and postmenopausal women for the primary prevention of CVD remains to be determined.
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319. Skender ML, Goodrick GK, Del Junco DJ, et al. Comparison of 2-year weight loss trends in behavioral treatments of obesity: diet, exercise, and combination interventions. J Am Diet Assoc 1996;96: 342-346. 320. Hall JC, Watts JM, O'Brien PE, et al. Gastric surgery for morbid obesity. The Adelaide Study. Ann Surg 1990;211:419-427. 321. Ashley S, Bird DL, Sugden G, Royston CM. Vertical banded gastroplasty for the treatment of morbid obesity. BrJ Surg 1993;80:14211423. 322. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. J A m Med Assoc 2004;292:17241737. 322a. Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: the Women's Health Initiative Dietary Modification Trial.JAm MedAssoc 2006;295:39-49. 322b. Howard BV, Van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: The Women's Health Initiative Randomized Controlled Dietary Modification Trial. J Am Med Assoc 2006;295:655-666. 323. Bouchard C. Physical activity and prevention of cardiovascular diseases: potential mechanisms. In: Leon AS, ed. Physical activity and cardiovascular health. Champaign, IL: Human Kinetics, 1997:48-56. 324. Press V, Freestone 1, George CE Physical activity: the evidence of benefit in the prevention of coronary heart disease. Q J Med 2003;96:245-251. 325. Morris JN, Everitt MG, Pollard R, Chave SPW, Semmence AM. Vigorous exercise in leisure-time: protection against coronary heart disease. Lancet 1980;2:1207-1210. 326. Lee IM, Hsieh CC, Paffenbarger RS. Exercise intensity and longevity in men: Harvard Alumni Health Study. J A m Med Assoc 1995;273: 1179-1184. 327. American College of Sports Medicine. Guidelinesfor exercise testing and prescription. Philadelphia, Lippincott, Williams & Wilkins, 2000. 328. Hagberg JM, Park JJ, Brown MD. The role of exercise training in the treatment of hypertension. Sports Med 2000;30:193-206. 329. Manson JE, Hu FB, Rich-Edwards JW, et al. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. N EnglJMed 1999;341:650-658. 330. Kushi LH, Fee RM, Folsom AR, et al. Physical activity and mortality in postmenopausal women. JAm MedAssoc 1997;277:1287-1292. 331. Lee IM, Rexrode KM, Cook NR, Manson JE, Buring JE. Physical activity and coronary heart disease in women: is "no pain, no gain" passfi?JAm MedAssoc 2001;285:1447-1454. 332. Albert CM, Mittleman MA, Chae CU, et al. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med 2000;343:1355-1361. 333. Shaper AG, Wannamethee G, Walker M. Physical activity, hypertension and risk of heart attack in men without incidence of ischaemic heart disease. J Hum Hypertens 1994;8:3-10. 334. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N EnglJ Med 2002;346:393-403. 335. Lindstrom J, Louheranta A, Mannelin M, et al. Lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003;26:3230-3236. 336. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N EnglJ Med 2005;352:1293-1304. 337. Eidelman RS, Hebert PR, Weisman SM, Hennekens CH. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern IVied2003;163:2006-2010. 338. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation2004;109:672693.
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2 H A P T E R 3~
Mechanisms of Action of Estrogen on the Cardiovascular System RICHARD H.
KARAS
Molecular Cardiology Research Center, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA 02111
I. I N T R O D U C T I O N There is abundant evidence that estrogen regulates important aspects of cardiovascular function and affects the risk of developing cardiovascular disease (CVD). Populationbased studies have demonstrated differences between women and men in the pattern of onset of CVD, particularly as it relates to hormonal status and age-specific rates of disease, strongly supporting that endogenously produced estrogens reduce the risk of CVD (1,2). Based on such observations, a hypothesis emerged that postmenopausal treatment with exogenous estrogen will also reduce CVD risk. This hypothesis was first tested in observational and epidemiologic studies that in aggregate supported the idea that postmenopausal estrogen treatment did indeed protect against CVD (3). This then led to a number of randomized controlled trials of postmenopausal hormone therapies, largely with estrogen and a progestin combined, that did not demonstrate the expected benefits (4,5), as is discussed in more detail in Chapter 39. Although the discordant results between the observational studies and randomized controlled trials have led to considerable controversy in this field (6-9), several points are clear. First, it is quite clear that the original hypothesis, that postmenopausal hormone therapy will exert broad and extensive cardioprotective effects, in a manner analogous to the cholesterol-lowering statins, is not true. A second aspect supported by these studies is that a variety of factors, including patient-specific factors such as age and the underlying status of the cardiovascular system, TREATMENT OF THE POSTMENOPAUSAL WOMAN
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as well as agent-specific factors such as what actual compound, alone or in combination, is being given and at what dose and by what mode of administration, all have an important impact on the cardiovascular effects of hormone therapy. Finally, a third point that is clear is that the cardiovascular effects of estrogen are complex and include a mixture of both potentially beneficial and potentially harmful effects. Thus, it is imperative that we learn more about the mechanisms of action of estrogen on the cardiovascular system so that we can learn to better use postmenopausal hormone therapy in an appropriate manner to reduce CVD risk when possible. CVD remains the leading cause of death for both women and men in the United States. The majority of the morbidity and mortality associated with CVD results from either diseases of the heart itself, including arrhythmias, cardiomyopathic disorders, and valvular diseases, or from diseases of the vasculature, of which atherosclerosis and the myocardial infarctions and strokes that it causes are the most prominent and prevalent. Venous diseases, particularly venous thrombosis and thromboembolism, are less prevalent than atherosclerosis, but their consideration is also relevant to hormone therapy. Currently, we have considerably more information regarding the effects of estrogens on vascular diseases and atherosclerosis than we do regarding the effects of estrogen on the heart itself. Atherosclerosis is a complicated disease, in part because it results from an interplay of many factors, including inflammation, thrombosis, hemodynamics, and oxidative state, all unfolding on a background of underlying Copyright 9 2007 by Elsevier,Inc. All rights of reproduction in any form reserved.
454 variability in genetic susceptibility to this disease. As a result, in the sections that follow, I will review the effects of estrogen on each of these etiologic aspects of the atherosclerotic process.
II. SYSTEMIC AND DIRECT EFFECTS OF ESTROGEN ON THE CARD I OVAS CULAR SYSTEM The mechanisms of action of estrogen on the cardiovascular system can be categorized in a variety of ways, but one useful method is to consider effects on systemic or circulating factors separately from direct effects on the heart and vascular beds (reviewed in [10]). The fact that estrogen regulates a variety of systemic factors relevant to CVD has been known for many years. The ability of estrogen to directly regulate the structure and function of cardiovascular cells and tissues has been appreciated only for about the past 10 to 15 years. Each of these aspects will now be discussed in turn, beginning with the direct effects of estrogen on the cardiovascular system.
A. Direct Cardiovascular Effects of Estrogen The predominant cells in the cardiovascular system are cardiomyocytes, vascular smooth muscle cells (VSMCs), and vascular endothelial cells (ECs), and all have been shown to express estrogen receptors (reviewed in [11]). There are extensive data from cell culture models that estrogen regulates critically important processes in each of these cell types. For example, estrogen inhibits VSMC proliferation and migration. Interestingly, estrogen has the opposite effect on ECs in that it promotes proliferation and migration in these cells. This is yet another important example of the ability of estrogen to exert opposite effects depending on the specific cell type examined. Estrogen has also been shown to regulate apoptosis in vascular (12) and cardiac cells (13). Animal models have also contributed extensively to our understanding of the direct cardiovascular effects of estrogen. Indeed, animal models ranging from mice to monkeys, including hyperlipidemic models, vascular injury models, and genetically altered animals, have been used to demonstrate the potential for atheroprotective effects of estrogen (see Chapter 38 or [14]). Animal models have also contributed importantly to the hypothesis that the timing of initiation of hormone therapy may have a significant impact on its potential for cardiovascular benefit, or lack thereof, and this is discussed in detail in Chapter 38. These studies have also contributed to our understanding of the multiple mechanisms by which estrogen regulates the cardiovascular system. For example, as discussed in more detail later, estrogen
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has been shown to accelerate re-endothelialization following direct vascular injury in the mouse (15), in part by increasing the contribution of circulating progenitor cells (16), and this process limits the response to injury and subsequent VSMC hyperproliferation. Interestingly, atheroprotective effects of estrogen are no longer evident in mice devoid of monocyte chemoattractant protein-1 (MCP-1), suggesting an important link to the inflammatory system. The importance of estrogen-mediated effects on the inflammatory status of the vessel itself is also supported by studies demonstrating that in women, estrogen reduces levels of both vascular cell adhesion molecule (VCAM) and inflammatory cell adhesion molecule (ICAM) (16). These proteins are expressed on the surface of ECs and play an important role in allowing circulating inflammatory cells to adhere to the luminal surface of the artery, a prerequisite for their subsequent vessel wall invasion. Estrogen also upregulares the expression of matrix metalloproteinases (MMPs), including specifically MMP9 (17). MMPs are proteins that degrade extracellular matrix and thus have an important role in vessel wall remodeling. Estrogen's effects on MMP9 are also interesting because of their potential importance for the differential effects of early versus late administration of hormone therapy to postmenopausal women, discussed in Chapter 38. In women with relatively normal arteries, estrogeninduced increases in MMP9 expression could be beneficial in that this may enhance "positive remodeling" of the artery, a process by which the vessel expands in diameter and preserves lumen size. In contrast, in women with more advanced atherosclerotic plaques, estrogen-induced increases in MMP9 expression might contribute to plaque erosion and thus subsequent acute coronary syndromes. In addition to these effects on vascular structure, estrogen also alters vascular function in important ways. The beststudied example of this is the acute vasodilatory response to estrogen administration. In both monkeys and humans, a single dose of estrogen induces relaxation of the coronary arteries within a few minutes of exposure (18,19). This effect has been studied in detail because it is interesting for many reasons. First, the acute vasodilatory effects of estrogen result from estrogen-induced increases in nitric oxide bioavailability in the artery, and nitric oxide is one of the most potent anti-atherogenic, endogenously produced compounds known. In addition, other interventions such as statins, that also increase arterial vasodilation via this pathway, have been shown to decrease CV-D risk. Interestingly, the ability of estrogen to induce vasodilation is impaired in individuals with diabetes mellitus or with other risk factors for coronary disease or established atherosclerosis (20), lending further support to the hypothesis that the vascular effects of estrogen depend in part on the state of health of the vasculature at the time it is being administered. The signaling mechanisms that mediate the acute vasodilatory effects of estrogen are discussed in the following section.
CHAPTER 32 Mechanisms of Action of Estrogen on the Cardiovascular System 1. ESTROGEN-MEDIATED SIGNALING IN THE CARDIOVASCULAR SYSTEM
In general, estrogen regulates cell function by activating estrogen receptors (ERs), of which two are known, ER-oL and ER-[3. Estrogen receptors are expressed in the heart and the vasculature in cardiomyocytes, ECs, and VSMCs, strongly supporting the idea that the cardiovascular system is an end organ target for estrogen action (reviewed in [10]). Both ER-e~ and ER-[~ have been implicated in mediating processes important for cardiovascular function. For example, estrogen-mediated reductions in the response to vascular injury are not observed in mice devoid of ER-ot (21), but they are in wild-type mice. A role for ER-[~ in vascular function is supported by the observation that mice devoid of ER-[3 have abnormal regulation of vasomotor tone and are hypertensive (22). Classically, ERs are thought to transduce estrogen's effects by acting as ligand-activated transcription factors that regulate gene expression in response to hormone binding. These effects are often referred to as "genomic" effects of estrogen as they require alterations in gene expression. It is now clear, however, that estrogen-dependent signaling and ER function are much more complex than this (Fig. 32.1) (see color insert). For example, as shown in Fig. 32.1, point 1 (see color insert), ERs interact with a variety of other proteins that exert important effects on the manner in which the ligand-bound receptor alters gene expression (23). In addition, it has also been shown that vascular ERs can be transcriptionally activated in the absence of hormone binding by direct phosphorylation of the receptor by a variety of kinases (see Fig. 32.1, point 3) (see color insert), a process referred to as ligandindependent activation of the receptor (24). This adds another
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layer of complexity to the genomic effects of these receptors as there can be cross-talk between the ligand-dependent and ligand-independent activation pathways. Further complexity in ER-dependent signaling results from the fact that ERs also regulate their own transcription, as well as that of other steroid hormone receptors and other nonsteroid hormone receptor transcription factors (see Fig. 32.1, points 4 and 6) (see color insert). Finally, there are genetic polymorphisms in the ER genes that may also alter receptor-mediated downstream responses (see Fig. 32.1, point 5) (see color insert). As noted earlier, estrogen can also exert vasodilatory and other vascular cell effects within a matter of minutes after exposure. These effects occur too rapidly to be mediated by changes in gene expression, and they continue to occur in cells treated with inhibitors of gene transcription. Thus, these rapid effects are often referred to as "nongenomic" signaling pathways (reviewed in [25]). More recently discovered than the genomic pathways, the best-studied nongenomic pathway in the vasculature involves the rapid activation of the enzyme that produces nitric oxide in endothelial cells, eNOS (reviewed in [25]). Interestingly, these nongenomic effects of estrogen are also mediated by the same receptors, ER-ot and ER-[3, as are the genomic effects. However, the receptors that mediate nongenomic eNOS activation are localized to the cell membrane in specialized signaling modules called caveolae, rather than in the nucleus, and it is in the caveolae that the receptors initiate these signaling cascades by activating a variety of specific kinases (see Fig. 32.1, point 2) (see color insert). The cell membrane-associated ERs form signaling complexes with other proteins by binding to a scaffold protein called striatin, which allows the receptor, by still currently unknown mechanisms, to activate specific kinases that FIOURE 32.1 Molecularmechanisms that mediate cardiovasculareffects of estrogen and estrogen receptors (ERs). ERs regulate cardiovascularcell function by regulatinggene expression.They do so by interacting with a variety of proteins important for these transcriptional regulatorypathways (point 1). The transcriptional activityof the receptor is also regulated by direct phosphorylation(point 3). ERs also regulate the expression of other transcription factors, including other sex steroid hormone receptors and non-sex hormone receptor transcription factors (points 4 and 6). Genetic polymorphismsin the receptors also contribute to interindividual responses to hormone treatment (point 5). Finally,in addition to these regulatorypathways that are all related to genomic effects, cell membrane-associated ERs can also regulate cellular functions by nongenomic pathways that involve the rapid activation of various kinase cascades (point 2). CoA, coactivator; CoR, corepressor; GFR, growth factor receptor; NHR, non-SSHR nuclear receptors; SSHR, sex steroid hormone receptor; SSHRE, SSH response element; TFs, transcription factors. From ref. 11, with permission.
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in turn phosphorylate eNOS and activate its enzymatic activity (26). The potential to ultimately identify novel pharmacologic compounds that can selectively activate these nongenomic vasodilatory pathways, without activating the classical genomic signaling pathways, holds great promise as novel therapeutic strategies for diseases such as atherosclerosis, hypertension, and heart failure.
B. Systemic Effects of Estrogen on the Cardiovascular System As noted earlier, in addition to the direct effects of estrogen on the cardiovascular system, estrogen regulates a variety of systemic or circulating factors that can also affect the cardiovascular system. These systemic effects include those on circulating factors including lipids, coagulation and fibrinolytic factors, inflammatory factors, vasoactive hormones, oxidative state, and metabolic state. These will now be reviewed.
1. EFFECTS OF ESTROGEN ON CIRCULATING LIPIDS
The lipid effects of estrogen are a good example of the complex mixture of both potentially beneficial and potentially harmful effects that estrogen can exert. Oral estrogen has long been known to lower circulating levels of lowdensity lipoprotein (LDL) cholesterol and to increase levels of high-density lipoprotein (HDL) cholesterol (27). Both effects of course would be expected to reduce CVD risk. Similarly, oral estrogen also lowers the atherogenic Lp(a) particle (28). In contrast, however, oral estrogen can raise triglycerides, a potentially harmful effect. It is important to note that these effects on circulating lipids result primarily from changes in hepatic production of lipid particles, and thus they occur with oral estrogen due to a first-pass hepatic effect, but not with other forms of administration such as transdermal patches. In the randomized, controlled clinical trials mentioned previously, the expected changes in lipid profiles were indeed observed, but in the populations studied, these lipid changes were not accompanied by the anticipated decrease in CVD risk (4,5,29). The reasons for this discordance are unclear. One suggestion is that the changes in LDL and H D L cholesterol, for example, do not occur in the specific subgroups of cholesterol particles that would be associated with reductions in CVD risk (30), but this hypothesis requires further testing.
2. EFFECTS OF ESTROGEN ON CIRCULATING COAGULATION AND FIBRINOLYTIC FACTORS
The effects of estrogen on coagulation and fibrinolytic factors are also largely the result of first-pass hepatic effects, and thus they occur primarily with oral administration of hormone (reviewed in [10]). Overall, hormone therapy is
generally considered to create a mildly hypercoagulable state. However, as one might expect, it also presents complexities that result from a mixture of opposing effects. First, although some procoagulant and antifibrinolytic factors do increase in abundance with estrogen therapy, in some cases these effects are offset by opposing effects on anticoagulant or profibrinolytic proteins. For example, while plasminogen activator inhibitor I (PAI-I) levels are decreased by estrogen, so are levels of the opposing tissue plasminogen activator (tPA) (31,32). Recent clinical trial data have supported the idea that the overall effect of hormone therapy is to produce a tendency toward coagulation as the risks of venous thrombosis and venous thromboembolism are increased (4,33). However, these studies used combination therapy including both estrogen and a progestin. Interestingly, the very recently reported results from the estrogen-alone arm of the Women's Health Initiative (WHI) demonstrated considerably and significantly smaller increases in risk for venous thrombosis and thromboembolism than that observed in the combined hormone therapy arm of the W H I (34), suggesting that part of the increased risk attributed to hormone therapy may be due to the progestin component. It is also important to differentiate effects of estrogen on coagulation in the venous circulation versus those in the arterial circulation. The thrombotic events of clinical relevance on the venous side are primarily due to activation of the coagulation cascade, and they are treated with anticoagulants such as coumadin. In contrast, however, the clinically relevant thrombotic events in the arterial vasculature are primarily driven by platelet activation, and thus they are primarily treated with antiplatelet agents such as aspirin. Little is known regarding the effects of estrogen on platelet function, but the existing data suggest that estrogen may inhibit platelet activation (35). Thus, care must be used when interpreting the effects of estrogen on the coagulation and fibrinolytic systems in terms of the impact this has on arterial atherothrombotic events. 3. EFFECTS OF ESTROGEN ON CIRCULATING INFLAMMATORY MARKERS Over the past several years, our understanding of the importance of inflammation in the pathophysiology of CVD has increased tremendously. Thus, there is interest in the effects of estrogen on the relevant aspects of inflammation as well. Much of the attention in this field has focused on the potential role of increases in circulating levels of C-reactive protein (CRP). This results in part because CRP is the inflammatory marker that has the most demonstrated relevance to clinical medicine (36). Although there is considerable evidence that CRP levels are predictive, and independently so, of CVD risk (37), it remains debated whether this is because CRP is a marker for other etiologic factors or because it directly contributes to the atherosclerotic process. In either
CHAPTER 32 Mechanisms of Action of Estrogen on the Cardiovascular System case, evidence suggests that oral estrogen increases circulating levels of CRP, whereas transdermal estrogen does not (38), again highlighting the potential importance of route of administration on the effects of estrogen. It is interesting to note, however, that an analysis of the observational Cardiovascular Health Study showed that regardless of levels of CRP, women who were taking hormone therapy had a lower risk of CVD than those who were not taking it (39). Because of the focus on CRP, many people refer to estrogen as "pro-inflammatory." However, the situation is not quite that clear, and this term is likely not very useful. For example, many other circulating levels of inflammatory markers are reduced by estrogen. This includes interleukin (IL)-6, an important regulator of hepatic CRP production (16). In addition, IL-1 and MCP-1 levels also are reduced by estrogen (16). An additional example of the difficulty of labels such as "pro-inflammatory" can be found by looking at the effects of estrogen on cyclooxygenase 2 (Cox2), an enzyme important for production of specific prostaglandins. In animal models, estrogen increases Cox2 levels, and the atheroprotective effects of estrogen in a hyperlipidemic mouse model are lost in mice devoid of Cox2, supporting the idea that activation of Cox2 plays an important role in the atheroprotective effects of estrogen (40). Thus, it is important to consider the complexity of effects of estrogen on the inflammatory system and to integrate the effects of estrogen on specific components of this system when assessing the contribution of inflammatory system changes to the effects of estrogen on the cardiovascular system.
4. EFFECTS OF ESTROGEN ON CIRCULATING VASOACTIVE HORMONES
As discussed further in a later section, the state of contraction or relaxation of the arterial system has important consequences for CVD risk. Although it is an admitted oversimplification, it is useful to realize that, in a broad sense, factors that promote vasoconstriction are in general associated with increased CVD risk, whereas factors that promote vasorelaxation are associate with reduced CVD risk. Overall, estrogen appears to reduce levels of vasoconstrictors and increase circulating levels ofvasodilators (reviewed in [10]). For example, estrogen has been shown to decrease circulating levels of the vasoconstrictors angiotensin II, renin, and endothelin; on the other hand, estrogen has been shown to increase levels of the vasodilator prostacyclin (produced by Cox2) and to increase the bioavailability of nitric oxide, a centrally important vasodilator discussed later.
5. EFFECTS OF ESTROGEN ON OXIDATIVE STATE
Increased levels of oxidation have been associated with a pro-atherosclerotic effect and an increase in CVD risk. Increased levels of oxidized LDL cholesterol, a particularly
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atherogenic form of LDL, likely contributes to this. In addition, a large body of data demonstrates that alterations in the overall oxidation/reduction state of ceils have very important influences on cell signaling and cell function. Certain forms of estrogen have been shown to exert antioxidant effects using in vitro assays (41). The extent to which antioxidant effects of estrogen contribute to effects on the cardiovascular system are currently unclear.
6. EFFECTS OF ESTROGEN ON METABOLIC STATE
The importance of a constellation of metabolic changes in contributing to CVD risk is increasingly being appreciated and is currently an area of intensive research. The "metabolic syndrome," consisting of central adiposity, hypertension, a procoagulant state, and glucose intolerance, is emerging as a major contributor to CVD risk, as, of course, is diabetes mellitus. Previous studies have suggested that estrogen can favorably affect glucose metabolism by enhancing insulin sensitivity (42), and these findings have been confirmed and extended by recent analyses reporting a reduction in self-reported incidence of diabetes mellitus in recent combined hormone therapy trials (43,44). This is an intriguing finding, but, as is the case for lipids, it remains unclear why a reduction in the risk of diabetes observed in this study was not accompanied by the expected reduction in cardiovascular events. Recent data from both human and animal studies also suggest that estrogen has favorable effects on body weight (45,46). 7. EFFECTS OF ESTROGEN ON PROGENITOR CELLS
Another rapidly emerging and evolving area of research in CVD has identified circulating progenitor cells, particularly EC progenitor cells, as playing a potentially important role in protecting against atherosclerosis and in recovery from cardiovascular insults or injury after they have occurred. There is increasing evidence, primarily from animal studies, that estrogen increases the quantity of circulating progenitor cells by increasing their mobilization from the bone marrow and that estrogen also enhances the ability of these cells to repair vascular injury (47). This is a very new area of inquiry that will bear close follow-up as the field moves forward.
III. SUMMARY There is abundant evidence that estrogen regulates many processes central to the physiology and pathophysiology of the cardiovascular system. To date, clinical trials have provided confusing and conflicting data as to how postmenopausal hormone therapy alters cardiovascular disease risk. It is clear from these studies and others that the cardiovascular
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FIGURE 32.2 The importance of timing of initiation of hormone therapy on its cardiovascular effects. The "timing hypothesis" states that the effects of hormone therapy on cardiovascular disease differs between early and later stages of atherosclerosis. Atherosclerosis is characterized by the gradual loss of vascular protective mechanisms and the emergence of advanced, unstable lesions. Estrogen's effects on vascular cells differ depending on the state or progression of atherosclerosis in the exposed vessels. CAMs, cell adhesion molecules; Cox2, cyclooxygenase 2; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein 1; MMR matrix metalloproteinase; TNF-ot, tumor necrosis factor-el; VSMC, vascular smooth muscle cell. From ref. 11, with permission.
effects of estrogen are complex and include both potentially beneficial and potentially harmful effects (Fig. 32.2) (see color insert). Furthermore, increasing evidence supports the idea that one of the factors having an important impact on the relative balance of beneficial versus harmful cardiovascular effects of estrogen is the timing of initiation of treatment as it relates to the extent of underlying atherosclerosis, as depicted in Fig. 32.2 (see color insert). Estrogen regulates both systemic (or circulating) factors relevant to cardiovascular function, but it also has direct effects on the heart and vasculature. The systemic effects include effects on circulating lipids, inflammatory markers, coagulation/fibrinolysis, oxidative state, vasoactive hormones, metabolic state, and progenitor cells. The direct effects of estrogen on cardiovascular cells include effects on cell growth, migration, and survival. The molecular mechanisms that mediate the cardiovascular effects of estrogen include genomic effects resulting from changes in gene expression, as well as nongenomic effects activating specific signaling pathways within cells. It is hoped that through a better understanding of the mechanisms that mediate estrogen's actions on the cardiovascular system, we can develop novel therapeutic strategies that manipulate this pathways in such a way as to allow us to reduce the risk of this leading cause of death in women.
References 1. Barrett-Connor E. Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation 1997;95:252-264. 2. Barrett-Conor E, Bush TL. Estrogen and coronary heart disease in women.JAm Meddssoc 1991; 265:1861-1867. 3. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Meat 1992;117:1016-1037. 4. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAm MedAssoc 1998;280:605-613. 5. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N EnglJ Med 2003;349:523-534. 6. Clarkson TB. The new conundrum: do estrogens have any cardiovascular benefits? IntJ Fertil WomensMed 2002;47:61-68. 7. Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N EnglJ Med 2003;348: 645-650. 8. Karas RH, Clarkson TB. Considerations in interpreting the cardiovascular effects of hormone replacement therapy observed in the WHI: timing is everything. MenopausalMed 2003;10:8-12. 9. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991;325: 756-762. 10. Mendelsohn ME, Karas RH. Mechanisms of disease: the protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801-1811. 11. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science2005;308:1.
CHAPTER 32 Mechanisms of Action of Estrogen on the Cardiovascular System 12. Spyridopoulos I, Sullivan AB, Kearney M, Isner JM, Losordo DW. Estrogen-receptor-mediated inhibition of human endothelial cell apoptosis-estradiol as a survival factor. Circulation 1997;95:1505-1514. 13. Van Eickels M, Patten RD, Aronovitz M, et al. 17 Beta-estradiol decreases infarct size but increases cardiac remodeling and mortality in mice with myocardial infarction. JAm Coll Cardio12003;41:2084-2094. 14. Karas RH. Animal models of the cardiovascular effects of exogenous hormones. Am J Cardio12002;90:22F-25F. 15. Krasinski K, Spyridopoulos I, Asahara T, et al. Estradiol accelerates functional endothelial recovery after arterial injury. Circulation 1997; 95:1768-1772. 16. Koh KK, Shin M-S, Sakuma I, et al. Effects of conventional or lower doses of hormone replacement therapy in postmenopausal women. Artheroscler Thromb VascBio12004;24:1516-1521. 17. Zanger D, Yang B K, Ardans J, et al. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management.JAm Coll Cardio12000;36:1797-1802. 18. Reis SE, Gloth ST, Blumenthal RS, et al. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation 1994;89:52-60. 19. Williams JK, Adams MR, Herrington DM, Clarkson TB. Short-term administration of estrogen and vascular responses of atherosclerotic coronary arteries.JAm Coll Cardio11992;20:452-457. 20. Herrington DM, Espleland MA, Crouse JR III, et al. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb VascBid 2001;21:1955-1961. 21. Pare G, Krust A, Karas RH, et al. Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res 2002;90:1087-1092. 22. Zhu Y, Bian Z, Lu P, et al. Abnormal vascular function and hypertension in mice deficient in estrogen receptor-b. Science 2002;295: 505-508. 23. Tsai MJ, O'Malley BW. Molecular mechanisms of action of steroid/ thyroid receptor superfamily members. Annu Rev Biochem 1994: 451-486. 24. Karas RH, Gauer EA, Bieber HE, Baur WE, Mendelsohn ME. Growth factor activation of the estrogen receptor in vascular cells occurs via a MAP kinase-independent pathway. J Clin Invest 1998;101: 2851-2861. 25. Mendelsohn ME. Genomic and nongenomic effects of estrogen in the vasculture. Am J Cardio12002;90:3 F-6 E 26. Lu Q~ Pallas DC, Surks HK, et al. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial N O synthase by estrogen receptor-alpha. PNAS 2004; 101:1712617131. 27. Writing Group for the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.JAm MedAssoc 1995;273:199-208. 28. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.JAm MedAssoc 2000;283:1845-1852. 29. Shlipak MG, Chaput LA, Vittinghoff E, et al. Lipid changes on hormone therapy and coronary heart disease events in the Heart and Estrogen/Progestin Replacement Study (HERS). Am Heart J 2003; 146:870-875.
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30. Wakatsuki A, Ikenoue N, Izumiya C, Okatani Y, Sagara Y. Effect of estrogen and simvastatin on low-density lipoprotein subclasses in hypercholesterolemic postmenopausal women. Obstet Gynecol 1998; 92:367-372. 31. Koh KK, Mincemoyer R, Bui MN, et al. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N EnglJ Med 1997;336:683-690. 32. Gebara OC, Mittleman MA, Sutherland P, et al. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995;91:1952-1958. 33. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women.JAm MedAssoc 2002;288:321-333. 34. Curb JD, Prentiss RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006;166:772-780. 35. Bar J, Tepper R, Fuchs J, et al. The effect of estrogen replacement therapy on platelet aggregation and adenosine triphosphate release in postmenopausal women. Obstet Gyneco11993;81:261-264. 36. Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat C/in Pract Cardiovasc Med 2005;2:29-36. 37. Ridker PM, Hennekens C, Buring J, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N EnglJ Med 2000;342:836-843. 38. Decensi A, Omodei U, Robertson C, et al. Effect of transdermal estradiol and oral conjugated estrogen of C-reactive protein in retinoidplacebo trial in healthy women. Circulation 2003;106:1224-1228. 39. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N E n g l J M e d 2002;347:15571565. 40. Egan KM, Lawson JA, Fries S, et al. COX-2-derived prostacyclin confers atheroprotection on female mice. Science 2004;306:1954-1957. 41. Shwaery GT, Vita JA, Keaney JF Jr. Antioxidant protection of LDL by physiological concentrations of 1713-estradiol-requirement for estradiol modification. Circulation 1997;95:1378-1385. 42. Nabulsi AA, Folsom AR, White A, et al. Association of hormonereplacement therapy with various cardiovascular risk factors in postmenopausal women. N EnglJ Med 1993;328:1069-1075. 43. Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/Progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:1-9. 44. Margolis KL, Bonds DE, Rodabough RJ, et al. Effect ofoestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia 2004;47:1175-1187. 45. Simpson ER, McInnes KJ. Sex and fat--can one factor handle both? Cell Metab 2005;2:346-347. 46. D'Eon TM, Souza SC, Aronovitz M, et al. Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative. J Biol Chem 2005;280:3598335991. 47. Strehlow K, Werner N, Bohm M, et al. Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Circulation 2003;107:3059-3065.
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Llplds and Llpoprotelns and Effects of Hormone Therapy RONALD M. KRAUSS Children'sHospital & Research Center Oakland, Oakland, CA 94609
I. MAJOR LIPOPROTEINS AND METABOLIC PATHWAYS
Levels of plasma lipids and lipoproteins are strong predictors for the development of atherosclerotic cardiovascular disease in postmenopausal women (1). In women, as in men, numerous factors contribute to variations in plasma lipoproteins that may affect cardiovascular disease risk. These include age, dietary components, adiposity, genetic traits, and hormonal changes. Each of these factors may operate to varying degrees in determining changes in plasma lipoprotein profiles accompanying menopause. Cross-sectional (2,3) and longitudinal studies (3-5) have suggested increases in levels of cholesterol, low-density lipoproteins (LDLs), and triglyceride-rich lipoproteins associated with menopause. Levels of high-density lipoproteins (HDLs), which are higher in women than men and are thought to contribute to relative protection of premenopausal women from cardiovascular disease, remain relatively constant in the years following menopause (6), although small and perhaps transient reductions in the HDL-2 subfraction have been reported in relation to reduced estradiol level following menopause (4,5). Despite these associations, it has been difficult to determine the role of endogenous hormones in influencing the plasma lipoproteins of postmenopausal women. In principle, the effects of hormone replacement should act to reverse any alterations in lipoprotein metabolism that are due to postmenopausal hormone changes. However, although there may be beneficial effects on lipoproteins, hormone treatment does not restore a premenopausal lipoprotein profile. Furthermore, there is now compelling evidence that although premenopausal hormonal status contributes to protection from cardiovascular disease, exogenous hormoneinduced lipoprotein changes do not result in reduced incidence of cardiovascular disease, and can in fact increase disease risk. T R E A T M E N T OF T H E POSTMENOPAUSAL W O M A N
A. A t h e r o g e n i c Lipoproteins Endogenously synthesized triglycerides are secreted, along with cholesterol and phospholipids, in the form of very-lowdensity lipoproteins (VLDLs, density < 1.006 g/ml). VLDLs comprise an array of particles, each of which contains one molecule of a high-molecular-weight structural protein, apoB100, and varying amounts of lipids and smaller proteins, apoEs and apoCs. The triglycerides in VLDLs are hydrolyzed in peripheral tissues by the action of lipoprotein lipase, releasing VLDL surface lipids, apoEs and apoCs, which may be transferred to HDLs. Triglyceride-depleted VLDL remnants are returned to the liver and taken up by receptor-mediated processes, which are incompletely understood. There is evidence that LDL receptors, LDL receptorlike proteins, and perhaps other uptake mechanisms are involved (Fig. 33.1). Similar pathways operate in the metabolism of exogenously derived fat, which is transported in plasma in intestinally derived chylomicron particles (not shown in Fig. 33.1). Chylomicrons have a structure similar to that of VLDLs but are generally much larger and contain a smaller molecular weight form of apoB, designated apoB48. Larger VLDL and chylomicron remnants are generally cleared from plasma over the course of several hours. However, smaller VLDL particles may be metabolized more slowly and accumulate in plasma as cholesteryl ester-rich remnants. Prolonged residence of these particles in plasma may result in further cholesterol enrichment by transfer of cholesteryl ester from HDLs through the action of cholesteryl ester transfer 461
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FIGURE 33.1 pathways.
RONALDM. KRAUSS
Major lipoproteins and metabolic
protein. This process, in conjunction with progressive loss of triglyceride and smaller protein constituents from VLDL remnants, results in the formation of intermediate-density lipoproteins (IDLs, density 1.006-1.019 g/mL) and ultimately in the production of LDLs (density 1.019-1.063 g/mL). LDL particles retain apoB-100 and cholesteryl esters as the principal protein and lipid components, respectively, and are responsible for the bulk of cholesterol transport in plasma. As is the case for VLDLs, both IDLs and LDLs are heterogeneous, comprising multiple subpopulations differing in size, density, and composition. The metabolic and possible pathologic features of certain subclasses, particularly small, dense LDLs, have been reviewed elsewhere (7,8). The major fraction of both IDLs and LDLs are cleared from plasma by hepatic LDL receptors, which recognize both apoE and apoB-100 as ligands. This process is much slower than that for remnant clearance, resulting in LDL plasma residence times of several days. Alterations in composition of LDLs (and perhaps that oflDLs and remnants) may occur, likely related in part to prolongation of their circulation in plasma and to interaction with tissues. Transport of these lipoproteins into the subendothelial space of arteries, and their retention by arterial proteoglycans, can lead to oxidative changes and other modifications (9). Oxidized lipoprotein lipids can trigger release of cytokines from arterial macrophages. These inflammatory agents have a wide range of effects including cellular proliferation and recruitment of more macrophages. Unregulated uptake of modified lipoproteins by macrophages can in turn lead to cholesterol engorgement of these cells and the development of an early atherosclerotic plaque, designated a fatty streak. Excess arterial lipoprotein influx and the disruption of
cholesterol-enriched cells produces extracellular cholesterol deposition in the form of a lipid "core" that is covered by a raised fibrous cap. An increase in size of the lipid core, together with a weakening of the fibrous cap and perhaps vasoconstriction due to altered endothelial function, can lead to rupture of the atherosclerotic lesion and further inflammatory and procoagulant changes with resultant thrombus formation and vessel occlusion (10). Recently another type of lipoprotein particle, Lp(a), has been recognized as a factor of potential importance in the development of atherosclerosis (11). Lp(a) contains apoB100 complexed with another large protein, apo(a), which is highly homologous to plasminogen. Plasma concentrations of Lp(a) vary over a wide range in the general population and appear to be under strong genetic influence. Lp(a) levels have been highly correlated with coronary disease risk in epidemiologic studies, and apo(a) has been demonstrated in arterial lesions by immunochemical techniques. Although the mechanisms for the involvement of Lp(a) in atherosclerosis are not known, the interactions of apo(a) with the arterial endothelium, and perhaps also with the fibrinolytic system, may be of importance.
B. High-Density Lipoproteins HDLs comprise a complex array of particles with differing lipid and protein composition and metabolic behavior (12). Most HDL particles contain the protein apoAI, derived from both liver and intestine, and certain subpopulations also contain varying amounts of apoAII as well as apoCs and apoEs. The bulk of HDLs are thought to arise
CHAVTE~33 Lipids and Lipoproteins and Effects of Hormone Therapy from lipid-poor precursor particles secreted by both the liver and intestine, which acquire additional lipids and undergo a variety of transformations during their circulation in the blood. HDL lipids are derived both from the metabolism of apoB-containing lipoproteins, as described earlier, and from the direct uptake of cellular lipids, in particular, unesterified cholesterol. The enzyme lecithin:cholesterol acyltransferase (LCAT), activated by apoAI, converts unesterified to esterifled cholesterol and participates in the transformation of nascent HDLs in a stepwise manner to a series of progressively larger particles with increasing cholesterol and apoprotein content. The smaller and denser HDL subclasses are designated as HDL-3, while the larger and more buoyant are designated as HDL-2. Within both HDL-3 and HDL2, there are multiple discrete subspecies with differing content of apoAI and apoAII as well as other constituents. Of particular note is the largest major HDL subspecies, HDL2b, which contains four molecules of apoAI without apoAII. Levels of HDL-2b are higher in women than in men and in both sexes correlate with plasma concentrations of HDL cholesterol. HDL components leave the plasma by a variety of pathways. As described earlier, cholesteryl ester transfer protein may mediate cholesterol movement from HDLs to apoBcontaining lipoproteins, particularly lipolytic remnants, in exchange for triglycerides. The acceptor particles may then be taken up by LDL or remnant receptors. Subpopulations of HDLs containing apoE also may be cleared directly by such receptors. Alternately, HDLs may deliver cholesterol directly to tissues, either by selective uptake of HDL lipids or removal of intact HDL particles. A receptor, SR-B1, which is highly expressed in the liver as well as in adrenal and gonadal tissue, has been found to mediate tissue uptake of HDL cholesterol (13). Another key protein involved in HDL metabolism is ABCA1 (14). ABCA1 is a membrane transporter that facilitates the uptake of cholesterol and phospholipids from tissues by ApoA1. It plays a critical role in the hepatic biogenesis of HDL particles and is also a mediator of cholesterol efflux from tissues, including arterial macrophages. Recently a related transporter, ABCG1, has been found to have even greater capacity for promoting cholesterol uptake from tissues to large HDL-2 particles (15). Another mechanism implicated in regulating plasma HDL levels is the activity of hepatic lipase, an enzyme that catalyzes the hydrolysis of HDL phospholipids and triglycerides and potentiates hepatic HDL lipid uptake. Variations of hepatic lipase activity measured in postheparin plasma have been strongly inversely correlated with levels of HDL cholesterol. It has also been proposed that triglycerideenriched HDLs resulting from accelerated cholesterol/ triglyceride exchange are catabolized and perhaps more rapidly cleared as a result of hepatic lipase activity. The potential ability of HDLs to mediate delivery of cholesterol from peripheral tissues to the liver has led to
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the hypothesis that HDLs have an anti-atherogenic effect by promoting "reverse cholesterol transport." However, a number of other factors may underlie the inverse relationship of HDL cholesterol to risk of atherosclerotic cardiovascular disease (16). For example, levels of HDL cholesterol are determined in part by the efficacy of clearance of triglyceride-rich lipoproteins and their remnants. Thus, high HDL levels may reflect lower levels or shorter plasma residence time of potentially atherogenic remnant particles. In addition, recent evidence suggests that HDLs may reduce the accumulation of lipid peroxides in LDLs. A direct effect of increased apoAI production in atherosclerosis prevention has been demonstrated in transgenic mice overexpressing the human apoAI gene (17). This suggests that, whatever the mechanism, genetic and other factors regulating apoAI synthesis may have important antiatherogenic effects.
II. EFFECTS OF ESTROGENS ON PLASMA LIPOPROTEIN METABOLISM Estrogen treatment has been shown to increase both the rate of hepatic triglyceride production and of VLDL apoB100 secretion (Fig. 33.2). Walsh et al. (18) have reported that oral micronized estradiol at a dose of 2 mg/day increased the production of apoB in large VLDL particles (of Svedberg flotation rate or Sf 60 to 400) to a much greater extent than smaller VLDL particles (Sf 20 to 60). Most of the additional large VLDLs were cleared directly from plasma, with a smaller portion converted to smaller VLDLs and LDLs. In addition, there was an increased fractional catabolic rate of LDLs. The latter finding is consistent with evidence from animal studies that estrogens increase the number of hepatic LDL receptors. The net influence of estrogens on apoB-containing lipoproteins thus depends on the balance between increased production of large, triglyceride-rich VLDLs and increased clearance of these particles as well as cholesterolrich remnants and LDLs. There is little information as to the metabolic mechanisms by which estrogens influence HDL levels. In nonhuman primates, estrogen treatment has been found to increase both apoA-1 and apoA-2 production rates (19). High-dose ethinyl estradiol treatment of premenopausal women was shown to increase production rates of HDL apoAI in particular (20). On the other hand, estrogen treatment results in significant suppression of hepatic lipase activity (21,22), and reduced HDL fractional clearance was reported in a study in postmenopausal women. Either increased apoAI production or reduced hepatic lipase activity might be expected to induce a preferential increase in HDL-2 subclasses. Estrogen has been shown to induce dramatic suppression of the SR-B1 (HDL) receptor in the liver, an effect that may also contribute to accumulation of cholesterol-rich HDL particles in plasma (23).
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FIC;URE 33.2 Effects of estrogens on plasma lipoprotein metabolism.
III. PROGESTIN EFFECTS ON LIPOPROTEIN METABOLISM The practice of using progestins to counteract estrogeninduced endometrial hyperplasia raises the question of what effects this may have on lipoprotein metabolism. Natural progesterone, although not extensively studied, has not been found to cause significant changes in levels of plasma lipoproreins (24-27). On the other hand, synthetic progestins, particularly those with evidence of androgenic activity (e.g., norethindrone, levonorgestrel), may have significant metabolic effects. The best documented effect of androgenic progestins on lipoprotein metabolism is increased hepatic lipase activity, which in turn has been strongly correlated with reduced levels of HDL cholesterol, particularly in the HDL-2 subclasses (21). Androgenic progestins are also known to reduce triglyceride levels (22), although the mechanism of this effect is not understood. Some effects of these agents may also be mediated by insulin resistance, which has been associated with a dyslipidemia characterized by increased levels of VLDLs and reduced levels of HDL cholesterol (27).
sources of variation, including study designs, size and characteristics of study populations, hormone formulations, treatment regimens, duration of use, and laboratory methodology. The Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial has provided the most definitive information to date as to the effects of unopposed estrogen and various combination hormone treatment regimens on plasma lipoproteins and other risk factors for coronary heart disease (30). In this 3-year, double-blind study, 875 healthy postmenopausal women aged 45 to 64 were randomly assigned to placebo or treatment with conjugated equine estrogens (CEEs) 0.625 mg/day, alone or in combination with cyclic medroxyprogesterone acetate (MPA) 10 mg/day for 12 days/month, continuous MPA 2.5 mg/day, or cyclic micronized progesterone 200 mg/day for 12 days/month. The major findings from this and earlier studies may be summarized as follows.
A. Estrogen Therapy 1. Plasma triglyceride and VLDL levels increase in a dosedependent manner. In the Lipid Research Clinics of North
IV. EFFECTS OF POSTMENOPAUSAL HORMONE TREATMENT ON PLASMA LIPID AND LIPOPROTEIN CHOLESTEROL LEVELS A large number of cross-sectional and longitudinal studies have assessed the influence of postmenopausal hormone treatment on plasma lipoprotein concentrations (reviewed in [28,29]). The findings of these studies reflect a number of
America Study (LRC), a comparison of 370 nonmenstruating, 45- to 64-year-old women not using estrogens versus 239 women using equine estrogens at varying doses demonstrated a 26% higher median triglyceride level in the estrogen users (31). A summary analysis of 10 randomized and crossover studies employing conjugated estrogens, adjusted for variables including sample size (ranging from 6 to 265 women) and duration of treatment (ranging from 1 to 12 months), revealed an overall increase in triglycerides of 20%, with levels increasing as a function of estrogen dose (32). A similar mean increase
CHAPTER 33 Lipids and Lipoproteins and Effects of Hormone Therapy (24%) was observed by Walsh et al. (18) in a doubleblind, placebo-controlled crossover study of 31 postmenopausal women treated with CEE for 3 months at a dose of 0.625 mg/day, while the mean increase at 1.25 mg/day was substantially greater (38%). These findings are consistent with those of the PEPI trial, in which CEE 0.625 mg/day resulted in a 25% increase in plasma triglyceride among adherent subjects (33). It should be noted that these studies were carried out in normolipidemic women. Women with primary hypertriglyceridemia may develop severe hyperlipemia on estrogen replacement therapy (34), and in such patients, estrogens should be used with caution and only after therapeutic reduction of triglyceride levels to less than 500 mg/dL. 2. Plasma total and LDL cholesterol levels decrease. In the LRC study, median LDL cholesterol was 11% lower in CEE users versus nonusers (31). Three other large crosssectional studies revealed similar reductions in LDL cholesterol (35-37), with dose-response effects between -0.9 to 1.25 rag/day reported in two of the studies (35,37). In the study by Walsh et al. (18), the reductions were somewhat greater: 15% at the lower dose and 19% at the higher dose, with a nonsignificant dosage effect. LDL cholesterol reduction with CEE 0.625 rag/day in the PEPI trial was 10% (31), with a somewhat greater effect when the analyses were restricted to adherent subjects (33).
3. Plasma HDL cholesterol levels increase, principally HDL-2. Median H D L cholesterol was found to be 10% higher in users of conjugated estrogens in the LRC study (31), with similar increases observed in three other crosssectional studies (35-37), two of which detected an apparent effect of dose (35,37). In the 10 prospective trials summarized by Bush and Miller (32), the average adjusted increase was also 10%, without an apparent dose effect. The PEPI trial observed an H D L cholesterol increase of 9% with CEE 0.625 mg/dL (30) and a 13% increase among adherent subjects (32). In the studies of Sherwin and Gelfand (38) and Walsh et al. (18), increases in H D L cholesterol were 14% and 16% at CEE 0.625 rag/day and 19% and 18% at 1.25 rag/day, suggestive of a small but not significant dose dependence. As in a number of other studies (39,40), the increase was restricted to the HDL-2 subclasses. Thus, as is the case with LDL cholesterol, there may be saturation of the effects of CEE at 0.625 rag/day, although there is clearly much interindividual variation in response. 4. The lipid and lipoprotein effects of estrogens are greater with oral than with systemic administration. A number of studies have indicated that systemic estrogen therapy, administered as percutaneous estradiol patches or creams, have little or no impact on plasma lipid and lipoprotein cholesterol levels (41-47). Other studies, however, have detected moderate increases in levels of HDLs (40,48-50)
465 and reductions in LDLs (26,50,51). Although there are a number of differences in experimental methodology among these studies, it has been pointed out that some differences in the findings may be related to the relatively greater plasma levels of systematically administered estrogens required to achieve intrahepatic hormone levels comparable with those achieved via the portal circulation after oral administration (18).
B. Combination Hormone Therapy The effects ofestrogen/progestin combinations on plasma lipid and lipoprotein cholesterol levels in postmenopausal women have been examined in a large number of studies employing various hormonal replacement regimens, as reviewed elsewhere (28,29). The following represents general observations that may be drawn from an overview of these and other studies, including the PEPI trial (30,31):
1. The metabolic effects of addedprogestin are related to the dose and relative androgenic potency of the hormone preparation and the concomitant dose of estrogen. On a weight basis, the C21-hydroxyprogesterone derivatives (e.g., medroxyprogesterone and medrogestone) are less metabolically active than the 19-nortestosterone derivatives (e.g., norethindrone) and levonorgestrel (23,52,53). Progesterone appears to be relatively inert in its effects on lipoprotein metabolism (23). 2. Addition of progestin has small and variable effects on levels ofplasma triglyceride and VLDL levels compared with those produced by estrogen alone. In the PEPI trial, among adherent subjects, triglycerides increased 15% to 20% in each opposed CEE arm versus 25% with CEE alone, although this difference was not statistically significant (33). Estrogen-induced increases in triglyceride level tend to be blunted to a greater extent by the more androgenic progestins (54). This may be related to the finding that a combination of estradiol and (d,1)-norgestrel results in increased fractional VLDL apoB clearance without an increase in VLDL apoB production rate (54). Recently it has been reported that levels of remnant-like lipoproteins, a subgroup of triglyceride-rich lipoprotein particles with potentially atherogenic properties, are reduced by conjugated estrogens with or without the addition of MPA, but the clinical significance of this observation is not known (55). 3. Estrogen-induced reductions in LDL cholesterol are affected minimally, if at all, by addition of conventional doses ofprogestins. A number of studies have shown similar reductions of LDL cholesterol with or without the concomitant administration ofprogestins (28,30,51,54). Although this would appear to suggest minimal interference of progestogens with the beneficial effects of estrogen on LDL metabolism, it has been reported that an oral
466 estradiol-norgestrel combination decreased LDL apoB production rate without affecting fractional LDL apoB clearance (56). This finding stands in contrast to the report that estrogen therapy alone reduces LDL levels primarily by increasing fractional LDL apoB catabolic rate (18). Thus, estrogens and estrogen/progestin combinations might alter LDL levels by different mechanisms, and this could conceivably have consequences for the prediction of effects on coronary disease risk. 4. Mos@rogestins attenuate estrogen-induced increases in H D L cholesterol (principally HDL-2). Although this effect has been reported to be more pronounced with high doses of 19-nortestosterone derivatives or levonorgestrel than with 21-hydroxyprogesterone derivatives, substantial reversal of estrogen-induced increases in HDL and HDL2 cholesterol have been observed with endometrialsuppressive doses of cyclic medroxyprogesterone (10 rag), norethindrone (1 mg), and (d,1)-norgestrel (0.15 mg) (25,50). In PEPI, HDL cholesterol increased by only 2% with either the cyclic or continuous CEE/MPA regimen (30) and by 7% with the CEE/micronized progesterone combination. Among adherent subjects, these increases were significantly less than with unopposed CEE (33). 5. Observational studies of lipid and lipoprotein levels in older users of combination hormone replacement therapy have not demonstrated the effects on H D L levels observed in shortterm clinical trials. A cross-sectional study in a retirement community in California showed no differences in plasma triglyceride, L D L cholesterol, or HDL cholesterol levels in users of estrogen-only versus combination hormone replacement therapy (36). Similar results have been observed recently in studies carried out in a second California retirement community (37). In the latter study, there were also no detectable differences in lipids and lipoproteins with doses of medroxyprogesterone ranging from 2.5 to 10 mg/day, administered from 5 to 25 days/month in combination with estrogen. In both studies, differences in lipid and lipoprotein levels between nonusers of hormones and estrogen-only users were comparable to those reviewed earlier. Although multiple explanations might be offered for these results, ranging from subject selection to poor progestin compliance, it should also be noted that longer-term prospective treatment trials (e.g., >3 years) have not been performed in older women, and it is possible that progestin-induced alterations of lipoproteins (notably HDLs) become attenuated over time.
C. Selective Estrogen Receptor Modulators Effects on lipoproteins and other cardiovascular risk markers have been described for selective estrogen receptor modulators (SERMs) that have estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and
RONALD M. KRAUSS
uterus (57). At two doses of raloxifene, LDL cholesterol was reduced by 12%, similar to the effects of estrogen and hormone treatment. In contrast to hormone treatment, however, there were no significant increases in triglyceride or HDL cholesterol, although HDL-2 was increased by 11%. Similar lipoprotein effects have been observed in cholesterol-fed nonhuman primates, in which raloxifene, unlike CEE, had no benefit on atherosclerosis severity (58).
V. EFFECTS OF HORMONE REPLACEMENT THERAPY ON OTHER LIPOPROTEIN PARAMETERS THAT MAY AFFE CT CARD I OVAS CULAR DISEASE RISK Several recent studies have found reductions in levels of Lp(a) with hormone replacement therapy (59,60). In PEPI, these ranged from 17% to 23% in comparison with placebo and did not differ significantly among treatment arms (59). A post hoc analysis of the Heart and Estrogen/progestin Replacement Study also showed that combination hormone treatment lowered Lp(a) levels and, moreover, that coronary heart disease events were more favorably affected in women with higher versus lower Lp(a) levels (61). Raloxifene has also been reported to lower Lp(a), but to a significantly lesser extent (57). Thus, although there is no definitive evidence as to the benefits of Lp(a) reduction on cardiovascular disease risk, hormone treatment is one of the few therapies capable of lowering elevated Lp(a) levels. Changes in composition and metabolism of atherogenic lipoproteins may have an impact on cardiovascular risk that is not reflected in standard measurements of their plasma levels. Estrogens have been shown to increase triglyceride content of LDLs as well as other lipoprotein classes (31,40), but these changes have not been directly related to altered cardiovascular disease risk. Reductions in levels of plasma apoB-100 have been reported with estrogen replacement (62) and with combined estrogen/progestin therapy (63), but these reductions are not as great as for LDL cholesterol (40,63). This is due to preferential reduction in levels of large, buoyant LDL subspecies with a higher ratio of cholesterol to apoB LDL than is found in smaller denser LDL (64,65). Metabolic studies have indicated that estrogen induces increased turnover of both large and small LDL and that the preferential reduction in plasma levels of large LDL is due to a reduced rate of production of these particles (65). Although smaller LDL particles signify increased risk for coronary heart disease (8,66,67), the clinical implications of the differing effects of estrogen on metabolism of larger and smaller LDL particles are not known. Estrogens have also been found to increase plasma clearance of potentially ath-
CHAPTER 33 Lipids and Lipoproteins and Effects of Hormone Therapy erogenic remnants formed during the course of postprandial triglyceride-rich lipoprotein metabolism (68), an effect consistent with the earlier demonstration of an increase in fractional catabolic rate of smaller V L D L particles (18). Finally, although estrogens have been found to reduce susceptibility of L D L s (69-71) and H D L (71) to oxidative modification, it has not been established to what extent this may contribute to protection from L D L oxidation and atherosclerosis in vivo.
VI. RELATION OF H O R M O N E TREATMENT EFFECTS ON PLASMA LIPOPROTEINS TO CARDIOVASCULAR DISEASE RISK Despite observational data suggesting that higher H D L cholesterol could contribute to reduced cardiovascular disease risk in hormone users (71) and the potential further reduction that could be expected from L D L lowering, such benefits have not been demonstrated in clinical trials of estrogen treatment, either alone or in combination with progestin (72-74). Moreover, in the Women's Health Initiative ( W H I ) , a small but significant increase in risk of myocardial infarction and stroke was observed with combination hormone treatment (74). A number of possible explanations have been suggested for these results. As noted previously, estrogen-induced reductions in L D L cholesterol are due primarily to lower levels of larger L D L particles, which are less strongly related to C V D risk than smaller L D L (8,66). It has been shown recently that postmenopausal women with coronary atherosclerosis manifested by coronary artery calcification had higher levels of large V L D L and small L D L particles, higher L D L particle concentration, and smaller mean L D L size compared with women with no detectable coronary artery calcification. It was suggested that the finding of a lack of benefit of hormonal therapy on coronary artery calcium in this cohort could be attributed in part to the finding that despite having lower levels of L D L cholesterol, hormone users had no reduction in concentrations of total L D L particles or small L D L and also had higher levels of V L D L particles (75). It is also conceivable that the nature of the estrogeninduced changes in H D L metabolism do not confer the same anti-atherogenic benefit as that associated with other causes of higher H D L . Another possibility, discussed in Chapter 34, is that pro-inflammatory and/or prothrombotic effects of hormonal treatment counteract anti-atherogenic lipoprotein changes, although there is as yet no direct evidence to support this explanation. In addition, as suggested recently (76), any potential cardioprotection afforded by estrogen in the postmenopause may require earlier hormone
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exposure than was the case in the trials conducted to date. Finally, there may be subsets of women who are predisposed to either protective or adverse metabolic effects of hormonal treatment, possibly on a genetic basis, and the impact of hormones on C V D risk in these groups are not discriminated in the data from the overall population.
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468 21. Tikkanen MJ, Nikkila EA, Kuusi T, et al. High density lipoprotein-2 and hepatic lipase: reciprocal changes produced by estrogen and Norgestrel. J Clin EndocrinolMetab 1982;54:1113-1117. 22. Landschulz KT, Pathak RK, Rigotti A, et al. Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat.J Clin Invest 1996;98:984-995. 23. Krauss RM. Effects of progestational agents on serum lipids and lipoproteins. J Reprod Med 1982;27:503-510. 24. Fahraeus L, Larsson CU, Wallentin L. L-norgestrel and progesterone have different influences on plasma lipoproteins. Eur J Clin Invest 1983;13:447-453. 25. Ottosson UB, Johansson BG, Von Schoultz B. Subfractions of highdensity lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gyneco11985;151:746-750. 26. Jensen J, Riis BJ, Strom V, et al. Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gyneco11987;156:66-71. 27. Laws A, Reaven GM. Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations. J Intern Med 1992;231:25-30. 28. Rijpkema AHM, Van der Sanden AA, Ruijs AHC. Effects of postmenopausal oestrogen-progestogen replacement therapy on serum lipids and lipoproteins: a review. Maturitas 1990;12:259-285. 29. Sacks FM, Walsh BW. The effects of reproductive hormones on serum lipoproteins: unresolved issues in biology and clinical practice. Ann N YAcad Sci 1990;592:272-285. 30. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAm MedAssoc 1995;273:199-208. 31. Wahl P, Walden C, Knopp R, et al. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983;308: 862-867. 32. Bush TL, Miller VT. Effects of pharmacologic agents used during menopause: impact on lipids and lipoproteins. In: Mishell DR, ed. Menopause: physiology and pharmacology. Chicago: Year Book Medical Publishers, 1987:187-208. 33. Barrett-Connor E, Slone S, Greendale G, et al. The Postmenopausal Estrogen/Progestin Interventions Study: primary outcomes in adherent women. Maturitas 1997;27:261-274. 34. Glueck CJ, Scheel D, Fishback J, et al. Estrogen-induced pancreatitis in patients with previously covert familial type V hyperlipoproteinemia. Metabolism 1972;21:657-666. 35. Krauss RM, Perlman JA, Ray R, et al. Effects of estrogen dose and smoking on lipid and lipoprotein levels in postmenopausal women.Am J Obstet Gyneco11988;158:1606-1611. 36. Barrett-Connor CE, Wingard DL, Criqui MH. Postmenopausal estrogen use and heart disease risk factors in the 1980s. Rancho Bernardo, Calif, revisited.JAm MedAssoc 1989;261:2095-2100. 37. Paganini-Hill A, Dworsky R, Krauss RM. Hormone replacement therapy, hormone levels, and lipoprotein cholesterol concentrations in elderly women. Am J Obstet Gyneco11996;174:897-902. 38. Sherwin BB, Gelfand MM. A prospective one-year study of estrogen and progestin in postmenopausal women: effects on clinical symptoms and lipoprotein lipids. Obstet Gyneco11989;73:759-766. 39. Krauss RM, Lindgren FT, Wingerd J, et al. Effects of estrogens and progestins on high density lipoproteins. Lipids 1979;14:113-118. 40. Moorjani S, Dupont A, Labrie F, et al. Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with utrogestan in menopausal women.J Clin EndocrinolMetab 1991;73:373-379. 41. Fahraeus L, Larsson-Cohn U, Wallentin L. Lipoprotein during oral and cutaneous administration of estradiol-17b to menopausal women. Acta Endocrinol Copenh 1982;101:597-602.
RONALD M. KRAUSS 42. Elkik F, Gompel A, Mercier-Bodard C. Effects of percutaneous estradiol and conjugated estrogens on the level of plasma proteins and triglycerides in postmenopausal women. Am J Obstet Gynecol1982;143: 888-892. 43. Basdevant A, De Lignieres B, Guy-Grand B. Differential lipemic and hormonal responses to oral and parenteral 17 beta-estradiol in postmenopausal women. Am J Obstet Gyneco11983;147:77-81. 44. Mandel FP, Geola FL, Meldrum DR. Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women. J Clin EndocrinolMetab 1983;57:133-139. 45. Farish ECD, Fletcher DM, Hart F, et al. The effects of hormone implants on serum lipoproteins and steroid hormones in bilaterally oophorectomised women. Acta Endocrinol (Copenh) 1984;106:116-120. 46. Chetkowski RJ, Meldrum DR, Steingold KA, et al. Biologic effects of transdermal estradiol. N EnglJ Med 1986;314:1615-1620. 47. De Lignieres B, Basdevant A, Thomas G, et al. Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration. J Clin EndocrinolMetab 1986;62:536-541. 48. Lobo RA, March CM, Goebelsmann U, et al. Subdermal estradiol pellets following hysterectomy and oophorectomy. Effect upon serum estrone, estradiol, luteinizing hormone, follicle-stimulating hormone, corticosteroid binding globulin-binding capacity, testosterone-estradiol binding globulin-binding capacity, lipids, and hot flushes. Am J Obstet Gyneco11980;138:714-719. 49. Stanczyk FZ, Shoupe D, Nunez V, et al. A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Obstet Gyneco11988;159:1540-1546. 50. Sharf M, Oettinger M, Lanir A, et al. Lipid and lipoprotein levels following pure estradiol implantation in postmenopausal women. Gynecol Obstet Invest 1985;19:207-212. 51. Crook D, Cust MP, Gangar KF, et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on serum lipids and lipoproteins. Am J Obstet Gyneco11992;166:950-955. 52. Dorflinger LJ. Relative potency of progestins used in oral contraceptives. Contraception 1985;31:557-570. 53. Sonnendecker EW, Polakow ES, Benade AJ, Simchowitz E. Serum lipoprotein effects of conjugated estrogen and a sequential conjugated estrogen-medrogestone regimen in hysterectomized postmenopausal women. A m J Obstet Gyneco11989;1:1128-1134. 54. Miller VT, Muesing RA, LaRosa JC, et al. Effects of conjugated equine estrogen with and without three different progestogens on lipoproteins, high-density lipoprotein sub-fractions, and apolipoprotein A-I. Obstet Gyneco11991;77:235-240. 55. Lamon-Fava S, Posfai B, Asztalos BF, et al. Effects of estrogen and medroxyprogesterone acetate on subpopulations of triglyceride-rich lipoproteins and high-density lipoproteins. Metabolism 2003;52:13301336. 56. Wolfe BM, Huff MW. Effects of combined estrogen and progestin administration on plasma lipoprotein metabolism in postmenopausal women.J Clin Invest 1989;83:40-45. 57. Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAm MedAssoc 1998;279:1445-1451. 58. Clarkson TB, Anthony MS, Jerome CP. Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab 1998;83:721-726. 59. Soma M, Fumagalli R, Paoletti R, et al. Plasma Lp(a) concentration after oestrogen and progestogen in postmenopausal women. Lancet 1991;337:612. 60. Espeland MA, Marcovina SM, Miller V, et al. Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. Circulation 1998;97:979-986. 61. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.JAm MedAssoc 2000;283:1845-1852.
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The Effects of Hormone Therapy on Inflammatory, 9 ly"tic Hemostatlc,9 and Fibrlno Markers in Postmenopausal
Women KWANG K O N K O H
BYUNG-Koo Y O O N C. NOEL BAIREY M E R Z
ICHIRO SAKUMA
VascularMedicine and Atherosclerosis Unit, Division of Cardiology, Gil Medical Center, Gachon Medical School, Namdong-Gu, Incheon, Korea 405-760 Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea Division of Cardiology, Department of Medicine, Cedars-Sinai Research Institute, CedarsSinai Medical Center; Department of Medicine, University of California School of Medicine, Los Angeles, CA 90048 CardiovascularMedicine, Hokko Memorial Hospital, Sapporo, Japan
ROBERT W . REBAR American Society for Reproductive Medicine, Birmingham, AL 35216
I. I N T R O D U C T I O N
hinges on thrombogenic as well as inflammatory cellular and molecular pathways. Hormone therapy (HT) has both anti-inflammatory and pro-inflammatory effects and HT activates coagulation and improves fibrinolysis (1,4). These effects depend on the route of administration, doses of estrogen, the age of the woman, and presence of coronary artery disease or the coexistence of other risk factors for hypercoagulability. In this review, we discuss the effects of HT on inflammation, hemostasis, and fibrinolysis markers and briefly discuss the
Estrogen deficiency is associated with endothelial dysfunction accompanied by inflammation in the vessel wall, increased lipoprotein oxidation, smooth muscle cell proliferation, extracellular matrix deposition, accumulation of lipid-rich material, activation of platelets, and thrombus formation (1). These pathogenic features contribute to the development of atherosclerosis and coronary heart disease (1-3). The clinical manifestation of atherosclerotic disease TREATMENT OF THE POSTMENOPAUSAL WOMAN
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KOH E T
effects of lower doses of H T and tibolone in postmenopausal women.
II. EFFECTS OF HORMONE THERAPY ON INFLAMMATION MARKERS The acute and chronic manifestations of atherosclerosis are increasingly being considered as a consequence of a chronic inflammatory process (2). Once activated by injury, endothelial and smooth muscle cells of large arteries become transcriptionally active and synthesize proinflammatory proteins. The gene transcription of many adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular CAM-1 (ICAM-1), is regulated by a nuclear transcription factor, NF-KB, normally maintained in an inactive state. In addition to VCAM-1, ICAM-1, and E-selectin, NF-KB also activates transcription of genes encoding chemoattractant factors, such as monocyte chemotactic peptide and macrophage stimulatory factor, which attract monocytes into the vessel wall (Fig. 34.1) (1). NF-KB additionally increases the synthesis and release of cytokines such as interleukin (IL)-I, IL-2, and IL-6, which activate inflammatory cells, enhancing their attachment to the vessel wall (1). 17]3-estradiol (E2) bound to the estrogen receptor (ER)-cx has shown to antagonize NF-KB activity in human hepatoma HepG2 cells (5).
A. C-Reactive Protein Obesity as well as age are positively correlated with C-reactive protein (CRP) concentrations (6,7). Messenger cytokines including IL-1 and TNF-ci, released by adipose tissue, contribute to the increase in levels of CRP. This
FIGURE34.1 Manystimuli initiate transcription of genes in endothelium that encode protein mediators of inflammation and hemostasis.Estrogens may modulate this processby inhibiting activationof nuclear transcription factor,NF-KB. (Modifiedfrom ref. 1, with permission.)
AL.
cross-talk between inflammation and metabolism might have a greater impact on coronary heart disease risk in women than in men (8). Mthough IL-6 levels increase following natural or surgical menopause (9,10), CRP concentrations are not influenced by menopause per se (11). Nested case-control analyses of the Women's Health Study (12) and the Nurses' Health Study (13) reported the predictive value of CRP in determining the risk of future cardiovascular events in women as well as men. Orally administered estrogens increase blood CRP levels (14-20) and maintain this sustained increase up to 3 years (15). The CRP increase by oral estrogen might be higher in heavier women (21). In contrast, transdermal estradiol significantly lowers CRP levels (22,23) or does not change levels in healthy postmenopausal women (16,21). In premenopausal women, CRP correlates inversely with blood estradiol concentrations during the menstrual cycle (24). In 389 postmenopausal women with increased cardiovascular risk, CRP levels significantly increased after 6 months of H T when compared with baseline. On the contrary, other inflammatory markers such as plasma levels of E-selectin, ICAM-1, VCAM-1, IL-6, and s-thrombomodulin are significantly decreased after H T (20). These observations strongly suggest that the CRP increase after oral H T might be related to metabolic hepatic activation rather than a systemic proinflammatory response. Co-administered medroxyprogesterone acetate (MPA) for 3 months may attenuate the action of conjugated equine estrogen (CEE) in a dose-dependent manner in healthy postmenopausal women (mean age 52 years, mean body mass index [BMI] 21.8 kg/m 2) (25). Compared with CEE alone, the addition of MPA at 2.5 mg increased CRP significantly, but to a less degree, and 5 mg of MPA was found to abolish the C RP increase. Other studies have confirmed the impact of MPA at 2.5 mg (15,26). The
CHAPTER34 The Effects of Hormone Therapy on Inflammatory, Hemostatic, and Fibrinolytic Markers in Postmenopausal Women 473 in humans has been suggested by its localization in atherosclerotic plaques. Transendothelial migration and differentiation of monocytes into macrophages in the subendothelial space is also controlled by monocyte chemoattractant protein-1 (MCP-1). In vitro and animal studies have demonstrated that estrogens suppress gene expressions of CAMs (33,34), MCP-1 (34-36), T N F - a (37), and IL-6 (34,38). Blood levels of the soluble CAMs, chemokines, and cytokines are potential candidates as markers of inflammation. At present, however, these assays remain research tools and are not appropriate for routine use in the clinical laboratory (39). Soluble CAMs (40-42) and MCP-1 (43,44) might reflect a local arterial inflammatory reaction. Koh et al. (45) first showed that transdermal estradiol alone or combined with MPA decreases ICAM-1 levels. CEE 0.625 mg also decreases E-selectin (15,25,45-47), and both ICAM-1 and VCAM-1 levels are reduced (26,46). C E E + M P A also consistently resulted in a decrease of soluble CAMS as well as E-selectin (Fig. 34.2) (15,25,26,47). C E E + M P showed a reduction comparable to that of C E E + M P A (15,47). A significant correlation has been found between the mean maximum carotid intimal medial thickness and MCP-1 levels at baseline in postmenopausal women. In this study, E2 significantly reduced MCP-1 levels (48). MCP-1 concentrations were also lowered by both progestogens in combination with CEE by a similar degree (see Fig. 34.2) (47,49). TNF-c~ is a multifunctional circulating cytokine derived from endothelial and smooth muscle cells as well as macrophages associated with coronary atheroma. Furthermore, TNF-e~ enhances the rate of monocyte recruitment into developing atherosclerotic lesions. CEE with MP or MPA significantly reduced TNF-R levels from baseline in hypertensive or overweight postmenopausal women (50). This observation appears to be consistent with the findings of
effects of micronized progesterone (MP) also have been studied. Koh et al. (27) demonstrated that MP 100 mg with CEE 0.625 mg daily for 2 months led to significant CRP increases in healthy postmenopausal women (mean age 57 years, mean BMI 24.8 kg/m2). Of note, MP 100 mg with CEE 0.3 mg daily did not increase CRP, which suggests a dose-dependency of oral estrogen similar to that of MPA. According to the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, there are no long-term differences in CRP levels between C E E + M P A and C E E + M P (15). However, the controversy regarding the significance of the pro-inflammatory effects of estrogen persists (28-30). The Women's Health Initiative (WHI) observational study confirmed that the increase in CRP levels with oral HT is not linked to the increase in the risk of coronary heart disease (31). This result is consistent with the report that there is no relationship between CRP and the Framingham Coronary Heart Disease Risk Score among women taking HT (32). Nonetheless, because CRP has several important atherogenic properties in addition to being an inflammation biomarker (28), the oral estrogen-induced CRP increase over several years may have the potential to contribute to atherosclerosis progression. B. Cell A d h e s i o n M o l e c u l e s , C h e m o k i n e s , and C y t o k i n e s The initial step of recruitment of circulating leukocytes to a specific locus of inflammation is the contact of leukocytes with activated endothelium, which is mediated by the selectin family, including E-selectin and P-selectin. Thereafter, ICAM-1 and VCAM-1 facilitate firm attachment (1,8). The pathophysiologic relevance of cell adhesion molecule (CAM)
6O 50oo > o3 u
1000
PGln mutation in the gene for factor V (factor V Leiden). N EnglJ Med 1997;336: 399-403. 28. Rosenberg RD. Actions and interactions of antithrombin and hepatin. N EnglJ Med 1975;292:146-151. 29. Jordan RE, Fayreau LV, Braswell EH, Rosenberg RE). Heparin with two binding sites for anti-thrombin or platelet factor 4. J Biol Chem 1982;257:400-406. 30. Egeberg O. Inherited anti-thrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965;13:516-530. 31. Jesperson J, Peterson KR, Skouby SO. Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid. A m J Obstet Gyneco11990;163:396-403. 32. Sprengers ED, Kluft C. Plasminogen-activated inhibitors. Blood 1987;69:381-387. 33. Lindoff C, Peterson F, Lecander I, Martinsson G, Astedt B. Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease. Maturitas 1996;24:43-50. 34. Koh K, Mincemoyer R, Bui M, et al. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997;336:683-690. 35. Lijnen HB, Hoylaerts M, CoHen D. Isolation and characterization of a human plasma protein with affinity for the lysine binding sites in plasminogen. Role of the regulation of fibrinolysis and identification of histidine-rich glucoprotein. J Biol Chem 1980; 255:10214-10222. 36. Haukkamaa M, Morgan WT, Koskelo E Serum histamine-rich glycoprotein during pregnancy and hormone treatment. ScandJ Clin Lab Invest 1983;43:591-595. 37. Conard J, Gompel A, Pelissier C, Mirabel C, Basdevant A. Fibrinogen and plasminogen modifications during oral estradiol replacement therapy. Fertil Steri11997;68:449-453. 38. Aoki N, Saito H, Kamiya T, et al. Congenital deficiency of alpha 2-plasmin inhibitor associated with severe hemorrhagic tendency. J Clin Invest 1979;63:877-884. 39. Kluft C. Disorders of the hemostatic system and the risk of the development of thrombotic and cardiovascular disease: limitation of laboratory diagnosis. Am J Obstet Gyneco11990;163:305-312. 40. Kelleher CE. Clinical aspects of the relationship between oral contraceptives and abnormalities of the hemostatic system: relation to the development of cardiovascular disease. Am J Obstet Gynecol 1990; 163:392-395. 41. Conway EM, Bauer KA, Barzegar J, Rosenberg RD. Suppression of hemostatic system activation by oral anti-coagulants in the blood of patients with thrombotic diathesis. J Clin Invest 1987;80:1533-1544. 42. Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991;324:18651875. 43. Bounameaux H, Cirafici P, de Moerloose P, et al. Measurement of d-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet 1990;1:96-200. 43a. Ray P, Bellick B, BiroUeau S, et al. Referent d-dimer enzyme-linked immunosorbent assay testing is of limited value in the exclusion of thromboembolic disease: result of a practical study in an ED. Am J E merg Med 2006;24:313-318. 44. Altes A, Souto J, Mateo J, Borrell M, Fontcuberta J. Activated protein C resistance assay when applied in the general population.AmJ Obstet Gyneco11997;176:358-359. 45. Stary HE. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 1989; 99:119-132. 46. Davies MJ, Woolf N, Rowles PM, Pepper J. Morphology of the endometrium over atherosclerotic plaques in human coronary arteries. Br HeartJ 1988;60:459-464.
489 47. Smith EB, Kean A, Grant A, Stirk C. Fate of fibrinogen in human arterial intima. Arteriosclerosis 1990;10:263-275. 48. Little WC. Angiographic assessment of the culprit coronary artery lesion before acute myocardial infarction. Am J Cardiol 1990;66: 44G-47G. 49. Falk E. Unstable angina with fatal outcome: dynamic coronary artery thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985;71:699-708. 50. Foster V, Griggs TR. Porcine yon WiUebrand disease: implications for the pathophysiology of atherosclerosis and thrombosis. Prog Hemost Thromb 1968;8:159-183. 51. Manson JE, Stampfer MJ, Colditz GA, et al. A prospective study of aspirin use and primary prevention of cardiovascular disease in women. JAm MedAssoc 1991;266:521-527. 52. Loscalzo J. A unique risk factor for athero-thrombotic disease. Arteriosclerosis 1990;10:672-679. 53. Hajjar KA, Gavish O, Breslow JL, Nachman RL. Lipoprotein (a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989;339:303-305. 54. Smith EB, Cochran S. Factors influencing the accumulation in fibrous plaques of lipid derived from low-density lipoprotein. II: Preferential immobilization of lipoprotein (a): LP (a). Arteriosclerosis 1990;84:173-181. 55. Lobo RA, Notelovitz M, Bernstein L, et al. Lipoprotein(a) relationship to cardiovascular disease risk factors, exercise and estrogen. Am J Obstet Gyneco11992;166:1182-1190. 56. Henricksen P, Angelin B, Berglund L. Hormonal effects of serum Lp(a) levels: marked reduction during estrogen treatment in males with prostatic cancer [Abstract]. Arterioscler Thromb VaseBiol 1991; 11:1423a. 57. Gilabert J, Estelles A, Cano A, et al. The effect of estrogen replacement therapy with or without progestogen on the fibrinolytic system and coagulation inhibitors in postmenopausal status. Am J Obstet Gyneco11995;173:1849-1854. 58. Bush TL, Barrett-Connor E. Noncontraceptive estrogen use and cardiovascular disease. Epidemiol Rev 1985;7:89-104. 59. Notelovitz M, Ware M. Coagulation risks with postmenopausal oestrogen therapy [Review Article]. In: Studd J, ed. Progress in obstetricsand gynecology, vol 2. Edinburgh: Churchill-Livingstone, 1983:228-240. 60. Young RL, Goepfert AR, Goldzieher HW. Estrogen replacement therapy is not conducive of venous thromboembolism. Maturitas 1991;13:189-192. 61. Kessler CM, Szymanski LM, Shamsipour Z, et al. Estrogen replacement therapy and coagulation: relationship to lipid and lipoprotein changes. Obstet Gyneco11997;89:326-331. 62. Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonen E. Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. The Menopause Study Group. Obstet Gyneco11994;84:987-995. 63. Chetkowski RJ, Meldrum DR, Steingold KA, et al. Biologic effects of transdermal estradiol. N EnglJ Med 1986;314:1615-1620. 64. Scarabin PY, Oger E, Bureau GP, ESTHER Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428-432. 65. Lobo RA. The rationale for low-dose hormonal therapy. Endocrine 2004;24:217-221. [Review.] 66. Notelovitz M, Kitchens CS, Rappaport Y, et al. Menopausal status associated with increased inhibition of blood coagulation. Am J Obstet Gyneco11981;141:149-152. 67. Meade TW, Dyer S, Howarth OJ, et al. Anti-thrombin III and procoagulant activity: sex differences and effects of the menopause. Br J Haemato11990;74;77-81.
490 68. Bourne T, Hillard TC, Whitehead MI, et al. Oestrogens, arterial status, and postmenopausal women. Lancet 1990;325:1470-1471. 69. Daly E, Vessey M, Hawkins M, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348: 977-980. 70. Jick H, Derby L, Myers M, Vasilakis C, Newton K. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981-983. 71. Grodstein F, Stampfer M, Goldhaber S, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983-987. 72. Aylward M. Coagulation factors in opposed and unopposed oestrogen treatment at the climacteric. PostgradMedJ 1978;54:31-37. 73. Notelovitz M, Kitchens C, Coone R, et al. Low-dose oral contraceptive usage and coagulation. Am J Obstet Gyneco11981;141:71-76. 74. Belier FK, Ebelt E Effects of oral contraceptives on blood coagulation: a review. Obstet GynecolSurv 1985;44:425-436. 75. Notelovitz M, Kitchens C, Ware M, et al. Combination estrogen and progestogen replacement therapy does not adversely affect coagulation. Obstet Gyneco11983;62:596-600. 76. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multi centre case-control study. Lancet 1995;346:1575-1582. 77. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestogens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995;346:1582-1588. 78. Jick H, Jick S, Gurewich V, Myers M, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptive with differing progestogen components. Lancet 1995;346:1589-1593. 79. Bloemenkamp K, Rosendaal F, Helmerhorst F, Buller H, Vandenbroucke J. Enhancement by factor V Leiden mutation of risk of deepvein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995;346;1593-1596. 80. Spitzer W, Lewis M, Heinemann L, Thorogood M, MacRae K. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996;312: 83-88. 81. Lewis M, Spitzer W, Heinemann L, et al. Third generation oral contractive and risk of myocardial infarction: an international casecontrol study. BMJ 1996;312:88-90. 82. Notelovitz M, Ware M. Coagulation risks with postmenopausal oestrogen therapy [Review article]. In: Studd J, ed. Progress in obstetricsand gynecology, vol 2. Edinburgh: Churchill-Livingstone, 1983:228-240. 83. Young RL, Goepfert AR, Goldzieher HW: Estrogen replacement therapy is not conducive of venous thromboembolism. Maturitas 1991;13:189-192. 84. Kessler C, Szymanski L, Shamsipour Z, et al. Estrogen replacement therapy and coagulation: relationship to lipid and lipoprotein changes. Obstet Gyneco11997;89:326-331.
MORRIS NOTELOVITZ 85. Lobo R, Pickar J, Wild R, Walsh B, Hirvonen E. Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gyneco11994;84:987-995. 86. Chetkowski RJ, Meldrum DR, Steingold KA, et al. Biologic effects of transdermal estradiol. N EnglJ Med 1986;314:1615-1620. 87. Steingold KA, Matt DW, de Ziegler D, et al. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab 1991;73:275-280. 88. Boschetti C, Cortellaro M, Nencione T, et al. Short- and long-term effects of hormone replacement therapy (transdermal estradiol vs. oral conjugated equine estrogens, combined with medroxyprogesterone acetate) on blood coagulation factors in post-menopausal women. Thromb Res 1991;62:1-8. 89. Notelovitz M, Greig HBW. Natural estrogen and anti-thrombin III activity in postmenopausal women. J Reprod Med 1976;16:87-90. 90. Notelovitz M, Kitchens CS, Ware MD. Coagulation and fibrinolysis in estrogen treated surgically menopausal women. Obstet Gynecol 1984;63:621-625. 91. Lindberg UB, Crona N, Stigendal L, et al. A comparison between effects of estradiol valerate and low dose ethinyl estradiol on hemostasis parameters. Thromb Haemos 1989;61:65-69. 92. WinNer U. Effects of androgens on haemostasis. Maturitas 1996; 24:147-155. 93. Notelovitz M, Johnston M, Smith S, Kitchen C. Metabolic and hormonal effects of 25 mg and 50 mg 17~-estradiol implants in surgically menopausal women. Obstet Gyneco11987;70:749-754. 94. Clarke RJ, Mayo G, Price I, Fitzgerald GA. Suppression of thromboxane A, but not of systemic prostacyclin by controlled-release aspirin. NEnglJMed 1991;325:1137-1141. 95. Osterud B, Olsen JO, Wilsgard L. Effect of strenuous exercise on blood monocytes and their relation to coagulation. Med Sci Sports Exercise 1989;21:374-378. 96. Bartsch P, Haeberli A, Straub PW. Blood coagulation after longdistance running: anti-thrombin III prevents fibrin formation. Thromb Haemost 1990;6:430-434. 97. Notelovitz M, Zauner C, McKenzie L, et al. The effect of low-dose oral contraceptives on cardiorespiratory function, coagulation, and lipids in exercising young women: a preliminary report. Am J Obstet Gyneco11987;156:591-598. 98. Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? Lancet 1990;336:129-133. 99. Kane JT, Malloy IM, Ports TA, et al. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.JAm MedAssoc 1990;264:3007-3012. 100. Sullivan IM, Vanderzwaag R, Lemp G, et al. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Ann Intern Med 1988;108:358-363.
Risk of Pulmonary Embolism/Venous Thrombosis CAROLYN WESTHOFF
Columbia University Medical Center, New York, NY 10032
I. CLINICAL ENTITIES
Clots in the leg may be silent, recognized only after a pulmonary embolism has occurred, if then, or they may come to clinical attention due to swelling and pain in the extremity. In clinically recognized cases of deep vein thrombosis of the leg, the main symptoms are swelling (88%), pain (56%), and tenderness (55%). Symptoms such as redness, palpable venous cord, or a positive Homans' sign are present in only a minority of confirmed cases (2). Pulmonary emboli present with dyspnea (80%), pleuritic chest pain (60%), and cough (41%) (3). On ausculation, 60% of angiogramconfirmed cases have audible crackles. There is no important difference between men and women in the frequency of these presenting complaints. Because of difficulties in diagnosing these conditions, it is likely that many milder cases may be unrecognized. The sequelae of venous thrombosis are immediate death due to pulmonary embolism, recurrent symptomatic or asymptomatic thrombosis with repeated risk of embolism, and the development of postphlebitic syndrome. The postphlebitic syndrome encompasses chronic swelling, skin changes including ulceration, and chronic pain interfering with ambulation (4). These chronic symptoms can also be associated with superficial phlebitis. The main goal of treatment of deep vein thrombophlebitis (DVT) is to prevent
Venous thrombosis mainly presents in the deep veins of the leg or in the lung but can also occur elsewhere, including the brain, retina, liver, mesentery, and upper extremities. Clots originating in the upper extremity are relatively rare and are usually sequelae of medical procedures such as catheter placement (1). Thrombophlebitis is a clinical syndrome of pain and swelling in the leg that originates as a valve pocket thrombus, most often in the soleal vein or posterior tibial or popliteal veins, during some period of stasis. Such a thrombus may propagate upward to the femoral and iliac veins, where pieces then break off into the venous circulation to become trapped in the lung as a pulmonary embolus. It is thought that distal leg clots do not embolize until after upward propagation to the thigh; however, clots may originate in the thigh or pelvis rather than in the leg. Further propagation in the lung or showers of emboli can be fatal. In most cases of pulmonary embolism it is possible to identify an apparent source clot in the lower extremity. About two-thirds of clinically recognized cases of venous thromboembolism (VTE) present with a venous thrombosis in the lower extremity only, and the remaining one-third presents as a pulmonary embolus with or without a symptomatic clot in the leg. TREATMENT OF THE POSTMENOPAUSAL WOMAN
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492 pulmonary embolism (PE), prevent recurrence of thrombosis, and prevent the postphlebitic syndrome.
II. DIAGNOSIS A N D TREATMENT The method of diagnosis of clots depends primarily on the location of the suspected clot. Proximal thrombi (that is, above the knee) are diagnosed by real-time B-mode compression ultrasound with high sensitivity and high positive predictive value. This test is safe, noninvasive, and widely available. If the patient has had clots previously, compressability may be abnormal, and thus sonography will be less helpful for diagnosis of recurrent clots; it is also less usefid for distal clots. Contrast venography is still the standard for diagnosis of thrombi and is more accurate than sonogram when distal thrombi are suspected. Because venography is invasive and more difficult to perform, its use is limited to cases in which sonography is not helpful. Magnetic resonance imaging is proving to be useful for diagnosis but has not replaced other modalities, except perhaps in pregnant women (5). A suspected pulmonary embolus is first evaluated by a chest radiograph plus perfusion scan or by a ventilation-perfusion (WQ.) scan in which anatomic mismatches between air flow and blood flow in the lung may indicate the location of an embolus. The advantage of doing the perfusion scan as the first diagnostic test is that it is noninvasive and does not require highly specialized skills to carry out. A multicenter study, Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), was carried out to assess the performance characteristics of WQ.scans used to assess 931 adults suspected of PE (3). A high-probability perfusion scan in women has a sensitivity of 41% and a positive predictive value for a PE of 86%. An intermediate- or high-probability WQ scan has a sensitivity of 84% and a positive predictive value of 44%. Thus, scans that are intermediate probability or nondiagnostic usually require proceeding to a pulmonary angiogram for a definitive diagnosis in order to avoid unnecessary treatment for those patients who will prove, by angiogram, to be negative for PE. Several useful diagnostic algorithms are available to guide patient assessment (6). Conventional treatment of DVT and PE has been intravenous unfractionated heparin during hospitalization followed by 3 to 6 months of oral anticoagulant therapy (OAT). Despite the ongoing risk of DVT recurrence, OAT is typically not continued past 6 months due to the risk of hemorrhage. Initial thrombolytic therapy in the acute phase is not widely used due to the risks of hemorrhage. Use ofthrombectomy or inferior vena cava filters is considered in selected patients with large thrombi or when adequate anticoagulation has not prevented recurrences. Also, treatment has been initiated with subcutaneous low-molecular-weight heparin (LMWH) used at home without laboratory dose adjustment. This appears to be at least similiar to unfractionated heparin in the prevention
CAROLYNWESTHOFF
of thrombus extension, death, hemorrhage, and recurrence of VTE events (7). An advantage of L M W H is that it can be used at home without laboratory monitoring; a disadvantage is its greater expense. The duration of subsequent therapy with OAT is extended, possibly for fife, in patients who have a continuing risk for VTE, such as those with cancer and those with an inherited predisposition.
III. PATHOPHYSIOLOGY The underlying causes of venous thrombosis have not been better described than by Virchow, who proposed in the nineteenth century that hypercoagulability, injury to the vessel wall, and circulatory stasis cause intravascular thrombosis. The disease was not described in antiquity, and Dexter proposes that the emergence of venous thrombosis as a major medical problem is due to the modern increase in chair sitting (8). Multiple factors are required for a venous clot to occur because each factor alone m t h a t is, stasis or injury or hypercoagulability--is only rarely associated with a clinically evident thrombus. Most of the recognized risk factors for VTE have an obvious connection to stasis, injury, or hypercoagulability. The coagulation system is a dynamic balance between procoagulant and anticoagulant factors. The coagulation system factors related to arterial thrombosis appear to be distinct from those related to venous thrombosis. The risk of venous clots has been linked to deficiencies of several anticoagulant factors. In particular, inherited deficiencies of protein C, protein S, and antithrombin III confer an increased risk of clinically apparent venous clots. Acquired or inherited resistance to activated protein C (APC resistance) also leads to increased risk of thromboses. APC resistance can be measured genotypically or phenotypicaUy. Genetic assays aim to identify in factor V an autosomal recessive point mutation called the Leiden mutation (9), which causes APC resistance. Phenotypic assays measure the resistance to cleavage of the factor V complex in the presence of activated protein C; this phenotype favors coagulation. The APCresistent phenotype is present in individuals with the Leiden factor V mutation (10), and also, in a brief report from the World Health Organization Monitored Investigation of Cardiac Disease (MONICA) survey, the APC-resistant phenotype has been associated with oral contraceptive (OC) users, hormone replacement therapy (HRT) users, and those with a body mass index (BMI) greater than 30 kg/m 2 (11). Screening of asymptomatic individuals for these inherited predispositions or for acquired APC resistance is not indicated on any routine basis. A genetically determined abnormality in prothrombin (a procoagulant) has been identified in thrombophilic families (12). This and other specific inherited or acquired abnormalities of the coagulation system are suspected to increase the risk of venous thrombosis. Additional genetic
CHAPTER 36 Risk of Pulmonary Embolism/Venous Thrombosis
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studies will continue to pinpoint specific mutations in clotting factors that increase susceptibility to venous thrombosis, but these are likely to be rare and are currently not well established.
Age-specific incidence rates in women are generally similar to those obtained in the Worcester study; the higher rates observed for PE among the older women may reflect the inclusion of cases diagnosed post-mortem, a category that was missing in the other studies. A similar study evaluated DVT in Malmo, Sweden, a city of 230,000. Subjects included all patients referred for phlebography (venogram) for suspected DVT in 1987 (15). There was only one source of diagnostic testing for this population, and phlebography was the test of choice at the time of the study. There were 366 tests positive for DVT of 1009 referrals, including 189 women aged 40 years or older. Some of these cases may have been diagnosed and treated solely as outpatients, in contrast to most other studies that have considered only inpatient cases. Patients presenting with a primary pulmonary embolus were not included in this study, but PE was clinically suspected in 5% of the cases with DVT. As in the previous cohorts, the incidence rates increased with age and were similar in men and women. The incidence rates in Malmo may appear higher than those in Worcester because of the possible inclusion of outpatients and the inclusion of a few patients with PE in the DVT group and because new (76%) and recurrent (24%) cases were not separated. Fatality rates were not presented. Participants in the Nurses' Health Study ( N H S ) w e r e evaluated for the occurrence of PE between 1976 and 1992 (16). Medical records were examined for all of the 280 PEs that were reported by questionnaire or by death certificate. All but 36 of these cases occurred in women 40 years or older. Age-specific incidence rates are shown in Table 36.1; a rate for women older than 70 years is not calculated because very few members of the cohort had yet reached that age. Mortality rates were not presented. Based on the Tecumseh, Worcester, Malmo, and N H S cohorts, about one-quarter to one-third of all cases of PE and V T E among women over 40 years old are recurrences. The risk of a recurrence, even after 6 months of anticoagulant treatment, is much greater than the risk of a first event. In an 8-year study of 355 consecutive, new V T E cases in Padua, Italy, where the cases were diagnosed from 1986 to 1987, 78 patients experienced a recurrent venous thrombotic event during follow-up, including 9 fatal pulmonary emboli (4). The recurrences accrued gradually with a cumulative recurrence rate of 30% at 8 years. Those cases whose primary V T E was secondary to surgery or trauma had a decreased risk of recurrence. Whether sex or age influenced recurrence risk was not presented. Mortality at 8 years was 30% and was mainly related to cancer. After 8 years of follow-up, 29% of subjects developed post-thrombotic syndrome. In a similar study from Cleveland (17), 124 cases with venogramconfirmed V T E diagnosed in 1984 and 1985 were followed until recurrence or death; follow-up ended in 1992. During follow-up, 42% of the cases died; the main predictors of
IV. I N C I D E N C E A N D PROGNOSIS Several cohort studies have quantified the incidence of venous thrombosis and pulmonary embolism by identification of all new cases arising in a defined population. The first of these was the Tecumseh Community Health Study, whereby 9000 individuals of all ages in a city in Michigan were questioned and examined repeatedly in several cycles from 1957 to 1969 (13). Most of the 169 first thrombotic events and the 63 recurrent events were identified by report of the participants without further validation. The incidence of these events increased with age, and men and women over age 40 experienced similar rates of DVT and PE. Because there were only 45 cases reported by women over age 40, the incidence rates are imprecise, but nonetheless they are similar to those obtained subsequently in larger studies with more uniform and complete surveillance of the population. These investigators estimated there would be about 250,000 clinically recognized cases annually in the United States, of which nearly half would occur in women over age 40 years. The Worcester DVT study calculated incidence rates for V T E based on discharge diagnoses from all 16 hospitals covering the Worcester Standard Metropolitan Statistical Area (1985 population, 379,953) from July 1985 through December 1986. All medical records with an eligible discharge diagnosis were reviewed to identify cases living in the catchment area and to confirm the diagnoses (2). In total there were 615 cases included in the analysis--405 initial episodes and 210 recurrent episodes. W h e n extrapolated to the U.S. population, this study predicts about 170,000 initial and 99,000 recurrent cases annually, with nearly half of these in women over 40 years old. This study also identified an increase in risk with age and similar incidence rates for men and women. Age-specific incidence rates for first events in women over 40 are given in Table 36.1; the number of subjects used to calculate these rates was estimated from information in the paper. Overall, 12% of patients with a first episode died in the hospital, 5% after DVT, and 23% after PE. Case fatality was similar for men and women and increased with age. Immediate case fatality was only 2% below age 40 years but was 10% from ages 40 to 59 years and 11% from ages 60 to 79 years. All patients in the Worcester cohort who were discharged alive were followed for 2 to 3.5 years, and 30% of the patients died during the follow-up interval. Long-term survival depended on age but not on sex or whether the initial event was a PE or a DVT. Mayo Clinic investigators assessed the incidence of DVT from 1966 through 1990 in Olmsted County, M N (14).
494
CAROLYN WESTHOFF
TABLE 36.1 Age (Years) 40-49 50-59 60-69 70-79 Cases (N)
Incidence of Venous Thrombosis and Pulmonary Embolism in Women >40 Years Old a Worcester 1.0 4.2 9.9 21.1 129b
Venous thrombosis Mayo 4.9 5.6 9.8 16.2 282
Malmo
Worcester
9.7 10.3 21.7 42.9 189
0 1.1 6.2 6.9 54 b
Pulmonary embolism Mayo 4.1 6.6 13.7 26.9 365
NHS 1.3 1.8 3.2 m 344
aCases per 10,000 women per year. Rates from Worcester include only first events; rates from Malmo and the Nurses' Health Study (NHS) may include patients with recurrent thromboses or emboli. bThe numbers of cases from Worchester were calculated from data in the paper.
death were cancer, stroke, or age greater than 75 years at the initial diagnosis. Chronic symptoms of pain, swelling, or discoloration in the affected leg were reported by 42%, and a recurrence was diagnosed in 15% of patients. These follow-up studies indicate that chronic symptoms and recurrence are common after a first VTE even in patients who receive a full 6-month course of anticoagulation. Little else is known about the distribution of VTE in the general population. A study of all 23,000 VTE hospital discharges in California from 1991 through 1994 found that about 75% of cases are idiopathic and 25% are secondary to cancer, surgery, trauma, or another medical event (18). This study also revealed that the risk among African Americans was higher than among Caucasians for idiopathic events (relative risk [RR], 1.3; 95% confidence interval [CT], 1.1-1.5). The risk for Hispanics for idiopathic events was lower (RR, 0.6; 95% CI, 0.5-0.7) as was the risk for Asians (RR, 0.26; 95% CI, 0.2-0.3). The risk for secondary VTE was similar for Caucasians, African Americans, and Hispanics but was lower for Asians.
A. Risks o f V T E w i t h C o n g e n i t a l or A c q u i r e d Causes o f H y p e r c o a g u l a b i l i t y Familial clustering of VTE has allowed the investigation and recognition of several inherited disorders of coagulation that are associated with a dramatically increased risk of VTE. In population-based studies, however, the risk of thrombosis in the presence of specific genetically determined abnormalities is sometimes lower than the risk as estimated in studies of affected families; this suggests that for certain abnormalities, members of strongly affected families may have additional, unrecognized abnormalities that generate higher risks than seen in otherwise unselected individuals with the same defect (19). Bearing in mind these discrepancies, the frequency of each of the major genetic predispositions and estimates of the associated risk will be presented.
The prevalence of protein C deficiency has been estimated in large studies of blood donors to be about 0.2% to 0.4% (20). Among patients experiencing a first VTE episode, the prevalence is about 3% and is even higher among patients with recurrent VTE. The relative risk of VTE from family studies is about 8 and from a populationbased study is 6.5, which shows good agreement (21-23). DVT of the leg is the most common manifestation, and one-half of predisposed individuals will not experience a first clinical event until after age 40 years. The prevalence of protein S deficiency in a study of Scottish blood donors was 0.2% (24). Among patients with a first VTE episode, the prevalence of protein S deficiency is about 1% to 2% and seems to be higher among patients with recurrent thrombosis (23). There may be phenotypic variations in protein S deficiency, and the relative risks for VTE for individuals with this class of clotting abnormality have not been precisely quantified. Antithrombin III deficiencies are rare, occurring in only 0.02% of unselected blood donors (20), in whom the relative risk for VTE may be as high as 50 (23,25), and the first VTE event will often occur before age 25 years, which makes this the most serious of the inherited predispositions. The most common of the inherited predispositions may be APC resistance due to a point mutation in factor V (26). The population prevalence is between 3% and 6% and is greater among Caucasians than in other racial groups (27). The RR of VTE in individuals with this mutation is about 8 compared with the unaffected population, and the risk may be substantially higher for homozygotes (28). A first event in an affected individual may occur at any age. Altogether, about 30% of individuals with a first VTE event occurring in the absence of a predisposing clinical situation will have one of these underlying genetically determined abnormalities of the coagulation system. Another recently described mutation is a prothrombin variant from G to A at position 20210, which is present in 1% to 4% of European populations and leads to an increase in prothrombin levels (29). This variation may be associated with a threefold increase in VTE (12). The APC
CHaeTER 36 Risk of Pulmonary Embolism/Venous Thrombosis
495 TABLE 36.2 Risk Factors for V T E in Hospitalized Women Aged >40 Years Old
resistance due to the Leiden mutation is the most common of these genetic abnormalities identified thus far (9).
B. Risks of VTE with Clinically Identified Risk Factors The strongest risk factors for V T E have been readily identified clinically without the use of laboratory or epidemiologic studies to establish risk. Immobilization with or without injury is the hallmark of these risk factors. V T E associated with any of these antecedent factors is generally referred to as secondary VTE because the clot is presumed to have arisen as a result of a specific precipitating event. In most series of consecutive cases, from 40% to 80% of all subjects are considered to have a V T E that is secondary to a clinically recognized precipitating event. In studies to assess more subtle causes of VTE, those V T E patients with any of these major risk factors are excluded. Due to this approach, it is essentially unknown how cofactors might increase risk in the large proportion of V T E patients who have a precipitating factor. Studies of clinical risk factors have not presented separate analyses regarding menopausal women, but there is no a priori reason to suspect important differences in risk factors by age or sex. Overall, there is an increase in V T E risk after age 40 years, but much of this increase is probably due to the increased prevalence of the underlying medical risk factors with increasing age. Many V T E events occur after hospitalization for another problem and are not themselves the primary reason for the hospitalization. Risk of V T E occurring in patients who are already hospitalized has been well characterized. A risk classification for women over age 40 modified from the Thromboembolic Risk Factors ( T H R I F T ) Consensus Group (30) is presented in Table 36.2. Women who fall into the low-risk group do not warrant prophylactic anticoagulation, but for those in the moderate- or high-risk groups routine prophylaxis is advisable. A meta-analysis of the incidence of D V T following general surgery indicates that effective prophylactic measures include low-dose heparin, graduated elastic compression stockings, and intermittent pneumatic compression (31). In the P I O P E D study several risk factors were present among women who were referred for evaluation for possible PE (3), these included surgery within 3 months before the onset of symptoms (38%), immobilization (35%), malignancy (28%), a history of previous phlebitis (18%), stroke (7%), and trauma (7%). After evaluation, these factors were associated with a 50% or greater increased risk of a positive angiogram among the women in the study population. An increased risk of either deep vein thrombosis or pulmonary embolus has been identified in such patients in numerous studies (32).
Risk
Reason for hospitalization
40%
Adapted from THRIFT Consensus Group (30).
C. Other Risk Factors for Primary or Idiopathic VTE Few studies have evaluated causes of V T E after excluding cases with strong precipitating factors. The main exposures of interest have been weight, smoking, chronic medical conditions, and use of exogenous hormones. Use of hormones will be discussed separately later. Some studies have identified modestly increased risks for V T E in women with chronic medical conditions such as hypertension, diabetes mellitus, and gallbladder disease (33,34). Because evaluation of hormone use has often been a primary goal of the analyses, women with these conditions have often been excluded in order to control for confounding. Overall, evaluation of risk associated with the common chronic medical conditions has not been illuminating. Obesity, when defined as a BMI, has generally been found to be a risk factor for VTE. Obesity had no effect on V T E risk only in the Walnut Creek Contraceptive Drug Study, in which obesity was defined as weight 15% above the cohort mean (35), this study included 38 cases, of which 23 were 40 years or older. In the Nurses' Health Study there were 125 women who reported an idiopathic pulmonary embolism. Among these women, obesity (defined as a BMI > 29 kg/m 2) was associated with a relative risk of 2.9 (95% CI, 1.5-5.4). Most of these cases were older than 40 years, and the increased risk associated with obesity held for all ages (16). In a U.K. cohort that included 292 female V T E cases aged 50 to 79 years, a BMI of 26 kg/m 2 or greater had an RR for V T E of 2.0 (95% CI, 1.4-2.9) compared with
496
CAROLYN WESTHOFF
women with a BMI of 25 kg/m 2 or less (34). Large studies of OCs and thrombosis included younger study populations, but all have identified obesity as a risk factor for VTE (36-38). The evidence supports an increased risk of VTE in obese women in the menopausal age group as well as in younger women. There are no data concerning VTE and obesity in men. The data for smoking are less consistent. Studies in younger women find little or no increased risk of VTE in current smokers (36-38). The large U.K. cohort of women aged 50 to 79 years identified an RR of 1.2 (95% CI, 0.9-1.7) for V T E among current smokers compared with never smokers (34). Among the 125 idiopathic PE cases from the NHS, there was an RR of 1.9 (95% CI, 0.9-3.7) for women who smoked 25 to 34 cigarettes daily and an RR of 3.3 (95% CI, 1.7-6.5) for women who smoked 35 or more cigarettes daily compared with nonsmokers (16). In sum, cigarette smoking is not an important explanatory variable for V T E in women, regardless of age.
D. Hormonal Risk Factors for Venous Thromboembolism Case reports followed very soon by epidemiologic studies showed that use of the old, high-dose OCs were associated with an increased risk of venous thrombosis, including pulmonary embolus (39). As the dose of estrogen in the OC decreased, there was a concomitant decrease in VTE risk (40). This led to the conclusion that the risk of VTE in OC users was linked to the estrogen dose, a concept that was little challenged over the past 2 decades (41). Because the dose of estrogen in H R T is so much lower than the dose in even the lowest-dose OCs, it seemed unlikely that H R T would be likely to cause any problem with venous clots (42). The original studies (Table 36.3) that attempted to assess risk of V T E in H R T users supported this line of thought. The first report came from the Boston Collaborative Drug Surveillance Program (43) and reported on 18 cases of VTE. O f the cases, 14% were H R T users, and of the controls, 8% were users; if the study were larger these percentages would have indicated an increased risk. The authors correctly concluded "significant associations were not present"; however, the small number of cases and rare use of H R T meant that the study did not have statistical power to detect an association. The next report came from the Walnut Creek Contraceptive Drug Study (33,35) and included 17 cases, of whom 12% used HRT; 15% of the controls used HRT. This does not indicate any hint of increased risk, but again, due to the small number of cases and limited use of H R T the study lacked statistical power to detect an association. Both of these studies excluded the majority of cases to focus on idiopathic V T E only. In con-
TABLE 36.3 Current H R T Use and VTE Risk: The Early Negative Studies
Years
Number of cases
BCDSP (42) Nachtigall (44)
1972 1969-1978
18 30
Petitti ( 3 3 ) Devor ( 4 5 )
1969-1976 1980-1987
17 121
Study
Adjusted relativerisk (95% CI) 2.3 (0.6-8.0) ~ 0.85 (NS; CI not provided) 0.7 (0.2-2.5)* 0.6 (0.2-1.8)
*Relative risk and confidence interval (CI) not provided in original publication but subsequently estimated by Douketis (64). N S, not significant.
trast, NachtigaU (44) excluded none of the cases; in this randomized controlled trial of chronically ill, permanently hospitalized women, 84 women were randomized to an oral H R T regimen for 10 years, and 84 controls received placebo. These 168 women experienced 30 V T E events--a number that is at least 10 times greater than the largest expected number calculated from incidence rates in Table 36.1. The high rate of V T E in this population may have been due to limited mobility of the subjects during their chronic hospitalization. There are also cases of superficial thrombophlebitis included, and no requirement for confirmatory diagnostic tests. There was no indication of increased V T E risk among the women randomized to HRT; however, it is difficult to interpret this finding in this unusual population. Devor (45) also included all cases of V T E in a hospital-based case-control analysis. Based on 121 cases, there was no evidence of excess risk in the H R T users. The overall analysis showed no increase in risk associated with HRT, but when subsets of cases were excluded (such as women with a previous thrombosis) the RR increased. As is true for other consecutive, unselected series of V T E cases, most of the cases in this study were secondary to a known predisposing factor. These four early evaluations of the H R T - V T E association did not indicate an increased risk, but the first two studies were too small for a precise or sophisticated analysis, and the randomized trial included an unusual population. Finally, the larger case-control study included so many women with secondary V T E and other serious diseases that it is difficult to assess whether H R T would have been given to these women by the physicians who were caring for their medical illnesses. With the clarity of hindsight, it appears that none of these early studies had a design or number of cases appropriate to address the question.
CHAPTER 36 Risk of Pulmonary Embolism/Venous Thrombosis
E. Studies of the H R T - V T E Association Starting in 1996, a series of new large studies began to be published (Table 36.4), suggesting an increased risk of both deep vein thrombosis and pulmonary embolus among current users of HRT. These new studies include data from two large prospective cohort studies, the Nurses' Health Study (46) and the Oxford-Family Planning Association cohort (47), from an historical cohort study of the Group Health Incorporated (GHI) medical plan database (48), from an historical cohort study using record linkage with the U.K. General Practice Research Database (34), from a record linkage study using medical databases in Italy (49), from hospital-based case-control studies in the United Kingdom (50), in France (51), and a multicenter hospital-based casecontrol study (52), from a population-based case-control study in Washington State (53), and, finally, from two randomized controlled trials, the Heart and Estrogen/progestin Replacement Study (HERS) trial (54,55) and the Women's Health Initiative (56), both from the United States (54). All of these studies summarized in Table 36.4 consider just those cases with a first episode of VTE. All of the studies excluded cases and controls with risk factors for V T E (e.g., cancer, fracture, and stroke), as well as excluding cases with superficial phlebitis. All of the studies described specific diagnostic criteria that were required for inclusion as a case. TABLE 36.4
Risk of Primary V T E among Current H R T Users m Subsequent Studies Adjusted relative risk (95% CI)
Study Grodstein (58) Daly (letter)(47) Daly (47) Jick (48) Spitzer (38) Varas-Lorenzo (49) Hulley (54) Douketis (52) Cushman (56)
Number of cases 123 18 103 42
Current use
First-year use
2.1 (1.2-3.8)
Not calculated Not calculated 6.7 (2.1-21.3) 6.7 (1.5-30.8) 4.6 (2.5- 8.4) 2.9 (1.2-6.9)
2.2 (0.6-7.9)
171
3.5 3.6 2.1 2.3
46 95 147
2.9 (1.5-5.6) 1.9 (1.2-3.2) 2.1 (1.6-2.7)
Smith (53)
586
Scarabin (51)
155
1.7 (1.2-2.2) a 0.9 (0.7-1.2) b 3.5 (1.8-6.8) c 0.9 (0.5-1.6) d
292
aConjugated equine estrogen. bEsterified estrogen. COral estrogen. dTransdermal estrogen.
(1.8-7.0) (1.6- 7.8) (1.4-3.2) (1.0-5.3)
3.3 (1.1-10.1) Not calculated 4.0 (Not calculated) Not calculated 8.1 (0.9-7.4) 1.5 (0.3-6.9)
497 Mthough the methodology differed and the stringency of the diagnostic criteria varied somewhat between studies, the RRs shown in Table 36.4 are nonetheless extremely similar, and indicate a risk among current H R T users that is two to three times the risk among nonusers. Unlike previous smaller studies, these studies were able to assess risks in some subgroups of H R T users. The most consistent finding was that the increased risk of V T E was greatest in or limited to the first year of H R T use. Until recently, the usual approach to analysis was to look for increased risk as the time of exposure increased (e.g., the risk of lung cancer increases with increasing years of cigarette smoking). The notion of looking for an early, transient risk is more recent and an understanding of these consistent results is not yet established. Other studies indicate that the increased risk of V T E in OC users may also be early and transient (38,57). Other subgroup analyses have attempted to assess conventional markers of risk such as dose. In these analyses, there was an indication of an increased risk of V T E with higher estrogen doses in two studies (36,53), but no dose-response effect in the others that were able to assess dose (46,50,58). The studies did generally agree on little or no excess risk in past users (46,49,50,58). The populations that were studied often included only a few H R T users or a limited range of H R T regimens; therefore, the investigators had a limited ability to compare risks among regimens. In addition to the studies listed above, the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial also evaluated phlebitis in women randomly assigned to five different H R T regimens; although there was a suggestion of an increased risk of V T E among the subjects receiving active treatment, this outcome was too rare to allow comparisons among the groups (59). The most recent studies have provided some evidence to distinguish the risks of opposed versus unopposed estrogen, of oral versus other mutes of administration, or between different formulations. Scarabin (51) found increased risk in users of oral estrogen but not in users of a transdermal formulation. In the Douketis study (52), few women used a transdermal hormone; among users of the oral preparations the excess risk was seen in users of estrogen plus progestin (RR 2.7, 95% CI 1.4-5.1) and not in users of estrogen alone (RR 1.2, 95% CI 0.6-2.6). Smith (53) also found an excess risk in combined rather than estrogen-only users (RR 1.6, 95% CI 1.1-2.6). In addition, Smith reported an excess risk limited to users of oral conjugated equine estrogen users (RR 1.65) and not in users of esterified estrogen (RR 0.92). The vast majority of V T E cases in women in the menopausal age group are secondary to other identifiable risk factors. The incidence of cases that might be attributed to H R T use can be calculated from the cohort studies. In the G H I cohort there were about two extra V T E cases per 10,000 H R T users per year (48). An estimate based on U.K. incidence data similarly suggested about two additional cases per
498 10,000 H R T users per year (50). In the HERS study the excess risk was about 7 cases per 1000 in year 1 and about 2 cases per 1000 in years 4 and 5 (54); however, women were selected for that randomized trial based on diagnosed cardiovascular disease, and they appear to have a much higher baseline risk for V T E than do women in the general population. The HERS results do suggest that women with an increased baseline risk of V T E may experience many more cases of V T E if using H R T than is seen among low-risk women. Moreover, Hoibraaten (60) carried out a randomized trial of H R T use in women with a history of VTE; the trial was stopped because of an excess risk of recurrent V T E among the women randomized to H R T (10.7% versus 2.3% among placebo users). This further substantiates the notion that women at high risk of V T E should avoid HRT. Data from the Women's Health Initiative ( W H I ) are comparable to the findings above, showing approximately a twofold increase in risk (see Chapters 45 and 46). O f interest, in W H I there appeared to be a greater risk among women treated with estrogen plus progestogen compared with hysterectomized women on estrogen alone, despite a higher risk status in the latter group. These data suggest but do not prove a greater risk with added progestogens. Some data are accumulating about the risk of V T E in women using the other, newer selective estrogen receptor modulators. Tamoxifen has the longest and widest use of these and has been associated with increased risk of V T E at a magnitude similar to the studies of estrogen (61). Tibolone, a nonestrogen treatment for hot flushes, was evaluated in some of the European studies with RRs for V T E slightly lower than those seen for estrogen; however, the number of users of tibolone in these studies was small and therefore the RR estimate thus far must be considered imprecise (46). Raloxifene use in placebo-controlled clinical trials has been associated with an RR of V T E of about 3.0 (62), and this excess is noted in the product labeling (63).
V. CLINICAL RECOMMENDATIONS Venous thromboembolism is a common problem among women in the menopausal age group and is most likely to occur among women with predisposing medical problems. In large part, V T E increases with age because the predisposing problems become more common with advancing age. Among healthy, low-risk women, even after age 40, the risk of V T E is probably about 1 to 2 new cases per 10,000 women per year. In this population, the risk of V T E for women using H R T may increase two- to threefold from this low level, yielding somewhere between 1 and 6 additional cases per 10,000 H R T users. This is comparable both in relative and absolute terms to the increased risk seen among younger women who use OCs. As with younger women and OCs, this risk of V T E in H R T users needs to be communicated to potential H R T
CAROLYNWESTHOFF users so that they can weigh this along with all other risks and benefits in making a decision to use HRT. The V T E risks may be smaller with the use of estrogen alone, with the use of esterified rather than conjugated estrogens, and with the use of transdermal rather than oral preparations; however, each of these associations needs further substantiation. Among menopausal women with chronic medical problems, with a previous DVT, with an inherited predisposition, or among women who will be having surgery or hospitalization for some other reasons, the baseline risk of a V T E is substantially higher. The results from the HERS trial (47) indicate that the women in that trial with known heart disease had a baseline risk of V T E of at least 20/10,000 women per year and that H R T use in these women increased that risk threefold. The proportional increase was the same as that seen in low-risk women, but because their baseline risk of V T E was higher, this increase in risk may translate into 20 to 40 additional cases per 10,000 users per year. Because most of the studies agree that the excess risk is concentrated in the first 1 to 2 years of H R T use, this information is most important for women who are considering whether to initiate HRT. Although there are no specific relevant data regarding the risk of V T E among hospitalized H R T users, it appears prudent to consider discontinuing oral H R T in women who are going to undergo major surgery or who develop a medical problem that is associated with immobilization or an other disease associated with a high risk of VTE. Among women who are currently being treated with anticoagulants, there are no data to indicate whether H R T use would modify their risk of a recurrent event. References 1. Ault M, Artal R. Upper extremityDVT: What is the risk?Arch Intern Med 1998;158:1950-1951. 2. AndersonFA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospitalincidence and case-fatalityrates of deep vein thrombosis and pulmonaryembolism.The Worcester DT Study.Arch Intern Med 1991;151:933-938. 3. Q.uinnD, Thompson B, Terrin M, et al. A prospectiveinvestigation of pulmonary embolism in women and men.J A m MedAssoc 1992;268: 1689-1696. 4. PrandoniP, LensingAW, Cogo AJ, et al. The long-term clinicalcourse of acute deep venous thrombosis.Ann Intern Med 1996;125:1-7. 5. Baker W. Diagnosis of deep vein thrombosis and pulmonary embolism. Curr Concepts Thromb 1998;82:475-495. 6. Merli G. Diagnostic assessment of deep venous thrombosis and pulmonary embolism.Am J Med 2005;118:3S- 12S. 7. Haas S.Treatment of deep venousthrombosisand pulmonaryembolism. Current recommendations.Curr Concepts Thromb 1998;82:495-510. 8. DexterL. President'sAddress:The chair and venous thrombosis. Tram Am Clin ClimatolAssoc 1973;84:1-15. 9. Dahlback B, HiUarp A, Rosen S, Zoller B. Resistance to activated protein C, the FV.'Qs~ allele, and venous thrombosis. Ann Hematol 1996;72:166-176. 10. Bertina R, KoelemanB, KosterT, et al. Mutation in blood coagulation factorV associatedwith resistanceto activatedprotein C. Nature (London) 1994;369:64-67.
CrtheVE~ 36 Risk of Pulmonary Embolism/Venous Thrombosis 11. Lowe GDO, Rumley A, Woodward M, Reid E. End of the line for "third-generation" pill controversy? Lancet 1996;349:1113-1114. 12. Poort S, Rosendaal F, Reitsma P, Bertina R. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-3703. 13. Coon W, Willis P, Keller J. Venous thromboembolism and other venous disease in the Tecumseh community health study. Circulation 1973;47:839-846. 14. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism. Arch Intern IVied 1998;158:585-593. 15. Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992;232:155-160. 16. Goldhaber S, Grodstein F, Stampfer M, et al. A prospective study of risk factors for pulmonary embolism in women. J Am Med Assoc 1997;277:642-645. 17. Beyth R, Cohen A, Landefield C. Long-term outcomes of deep-vein thrombosis. Arch Intern Med 1995;155:1031-1037. 18. White R, Zhou H, Romano P. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998;128:737-740. 19. Rosendaal E Risk factors for venous thrombosis: prevalence, risk, and interaction. Semin Hemato11997;34:171 - 187. 20. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemostasis 1995;73:87-93. 21. Allaart C, Briet E. Familial venous thrombophilia. In: Bloom A, Forbes C, Thomas D, et al, eds. Hemostasis and thrombosis. New York: Churchill-Livingstone, 1994:1349-1360. 22. Bovill EG, Bauer KA, Dickermann JD, Callas P, West B. The clinical spectrum ofheterozygous protein C deficiency in a large New England kindred. Blood 1989;73:712-717. 23. Koster T, Rosendaal FR, Briet E, et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden thrombophilia study). Blood 1995;85:2756- 2761. 24. Beauchamp NJ, Dykes AC, Parikh N, Tait RC, Daly ME. The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population. BrJ Haemotology 2004;125:647-654. 25. Hiejboer H, Brandjes DP, Buller HR, Sturk A, Ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N EnglJ Med 1990;323:1512-1516. 26. Dahlback B, Carlsson M, Svensson R Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc NatlAcad Sci U S i11993;90:1004-1008. 27. Ridker PM, Hennekens CH, Lindpainter K, et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. NEngl JMed 1995;332:912-917. 28. Vandenbroucke J, Helmerhorst E Risk of venous thrombosis with hormone-replacement therapy. Lancet 1996;348:972. 29. Rosendaal FR, Doggen CJM, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998;79: 706- 708. 30. THRIFT Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. Br MedJ 1992;305:567-574. 31. Clagett G, Reisch J. Prevention of venous thromboembolism in general surgical patients. Results of recta-analysis. Ann Surg 1988;208: 227-240. 32. Salzman E, Hirsch J. The epidemiology, pathogenesis, and natural history of venous thrombosis. In: Coleman R, Hirsch J, Marder V, Salzman E, eds. Hemostasis and thrombosis: bas# principles and clinicalpractice. Philadelphia: Lippincott, 1994:1275-1296.
499 33. Petitti D, Wingerd J, Pellegrin F, Ramcharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. J Am Med Assoc 1979;242:1150-1154. 34. Gutthann SP, Garcia Rodriguez LA, Castellsague J, Oliart AD. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. Br MedJ 1997;314:796-800. 35. Petitti D, Wingerd J, Pellegrin F, Ramcharan S. Oral contraceptives, smoking, and other factors in relation to risk of venous thromboembolic disease. Am J Efidemio11978;108:480-485. 36. Jick H, Jick S, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestogen components. Lancet 1995;346:1589-1592. 37. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995;346:1582-1588. 38. Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Br MedJ 1996; 312:83-88. 39. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolism disease and the steroidal content of oral contraceptives: a report to the Committee on Safety of Drugs. Br MedJ 1970;2:203-209. 40. Gerstman BB, Piper JM, Tomita DK, et al. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am JEfidemio11991;133:32-37. 41. Realini J, Goldzieher J. Oral contraceptives and cardiovascular disease: a critique of the epidemiological studies. _//mJ Obstet Gyneco11985;152: 729-798. 42. Lobo R. Estrogen and the risk of coagulopathy. Am J Med 1992; 92:283-285. 43. Boston Collaborative Drug Surveillance Program. Surgically confirmed gallbladder disease, venous thromboembolism, and breast tumors in relation to postmenopausal estrogen therapy. N EnglJ Med 1974;290:15-19. 44. Nachtigall L, Nachtigall R, Nachtigall R, Beckman E. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gyneco11979;54:74-79. 45. Devor M, Barred-Connor E, Renvall M, Feigal D Jr, Ramsdell J. Estrogen replacement therapy and the risk of venous thrombosis. Am J Med 1992;92:275-282. 46. Grodstein F, Stampfer M, Manson I, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N EnglJ Med 1996;335:453-461. 47. Daly E, Vessey MP, Painter R, Hawkins M. Case-control study of venous thromboembolism risk in users of hormone replacement therapy. Lancet 1996;348:1027. 48. Jick H, Derby L, Myers M, Vasilakis C, Newton K. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981-983. 49. Varas-Lorenzo C, Garcia-Rodriguez L, Cattaruzzi C, et al. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in Southern Europe. Am J E f i demio11998;147:387-390. 50. Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348: 977-980. 51. Scarabin P, Oger E, Plu-Bureau G, on behalf of the EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428-432. 52. Douketis JD, Julian JA, Kearon C, et al. Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study. J Thromb Haemostasis 2005;3:943-948.
500 53. Smith NL, Heckbert SR, Lemaitre RN, et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. J A m MedAssoc 2004;292:1581-1587. 54. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J A m MedAssoc 1998;280:605-613. 55. Grady D, Wenger NK, Herrington D, et al., for the Heart and Estrogen/ Progestin Replacement Study Research Group. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/Progestin Replacement Study. Ann Intern Med 2000;vl 32:689 - 696. 56. Cushman M, Kuller LH, Prentice R, et al., for the Women's Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. J A m MedAssoc 2004;292:1573-1580. 57. Lidegaard O. Thrombotic diseases in young women and the influence of oral contraceptives. Am J Obset Gyneco11998;179:$62- $67. 58. Grodstein F, Stampfer M, Goldhaber S, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983-987.
CAROLYNWESTHOFF 59. Writing Group for the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women.JAm MedAssoc 1995;273:199-208. 60. Hoibraaten E, Qyigstad E, Arnesen H, et al. Increased risk of recurrent venous thromboembolism during hormone replacement therapy. Thromb Haemostasis 2000;84:961 - 967. 61. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989;320:479-484. 62. Delmas P, Mitlak B, Christiaansen C. Effects of raloxifene in post menopausal women (letter). N EnglJ Med 1998;338:1313 - 1314. 63. Eli Lilly and Company. Evista product information. Indianapolis, IN: Eli Lilly and Company, 1998. 64. Douketis JD, GinsbergJS, Holbrook A, et al. A reevaluation of the risk for venous thromboembolism with the use of oral contraceptives and hormone replacement therapy. Arch Intern Med 1997;157:1522-1530.
;HAPTER 3,
Glucose Metabolism After Menopause SVEN O . S KOUBY Department of Obstetrics and Gynecology, Frederiksberg Hospital, University of Copenhagen, Denmark STEN MADSBAD
Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
I. I N T R O D U C T I O N
This chapter discusses the impact of endogenous and exogenous sex steroids on the age-dependent decrease in glucose tolerance in normal women and the glycemic and metabolic control of women with type 2 diabetes.
Changes in the environment and in human behavior and lifestyle, in conjunction with genetic susceptibility, have resulted in a dramatic increase in the incidence and prevalence of diabetes worldwide. It has been estimated that there will be a 42% increase in cases of diabetes in developed countries, from 51 million to 72 million; and a 170% increase in developing countries, from 84 million to 228 million (1). The prevalence of the metabolic syndrome in nondiabetic adults in Europe has been reported to be as high as 15%. The rapid escalation of the number of people with type 2 diabetes and diabetes-related cardiovascular disease demands urgent action, focused on prevention. An important rule of any prevention strategy is the identification of individuals who are at high risk. In women, increased body weight and central body fat distribution are often observed throughout the climacteric period, and the prevalence of metabolic syndrome increases dramatically after the age of 40 (2). It has been reported that the decline in insulin sensitivity following the menopause relates largely to age rather to menopause itself (3). A large communitybased population survey indicated that in postmenopausal women, the years since menopause confers a negative influence on glucose tolerance, and the risk of impaired glucose tolerance increases by 6% for each year after menopause (4). TREATMENT OF THE POSTMENOPAUSAL WOMAN
II. T H E METABOLIC SYNDROME The metabolic syndrome is also known as the insulin resistance syndrome (5) and as syndrome X (6). The cluster of metabolic abnormalities includes glucose intolerance, insulin resistance, central obesity, dyslipidemia, and hypertension, all well-documented risk factors for cardiovascular disease (7). There is wide variation in the prevalence in men and women. In global studies, the prevalence varies in urban populations from 8% to 24% in men and from 7% to 43% in women. A very consistent finding is that the prevalence of the metabolic syndrome is highly age dependent. The prevalence of the metabolic syndrome in the United States (National Health and Nutrition Examination Survey [NHANES III]) increased from 7% in participants aged 20-29 years to 44% and 42% for those aged 60-69 years and those at least 70 years old, respectively (8). The metabolic syndrome is associated with an increased risk of both diabetes (9) and cardiovascular disease (10) (Fig. 37.1). The most accepted and unifying hypothesis to describe the pathophysiology of the 501
Copyright 9 2007by Elsevier,Inc. All rightsof reproductionin anyformreserved.
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FICURE 37.1 permission.)
The metabolic syndrome increases cardiovascular risk. (From ref. 10, with
metabolic syndrome is the existence of insulin resistance. A major contributor to the development of insulin resistance is an overabundance of circulating fatty acids. The association of the metabolic syndrome with inflammation also is well documented (11). The increases in pro-inflammatory cytokines including interleukin (IL)-6, resistin, tumour necrosis factor-el (TNF-ci) and C-reactive protein reflect overproduction by the expanded adipose tissue mass, particularly the increase in visceral fat. Adiponectin is an anti-inflammatory cytoldne that is produced exclusively by adipocytes. Adiponectin both enhances insulin sensitivity and inhibits many steps in the inflammatory process (12). An alternative concept to explain the metabolic syndrome is leptin resistance (13). Abnormalities of both low adiponectin and high leptin have been documented in obesity and diabetes as well as in postmenopausal women with metabolic syndrome (13a). Several investigative techniques have been devised for the in vivo assessment of resistance to insulin-stimulated glucose uptake. All have limitations, and none are suitable for routine clinical use. The euglycemic clamp technique, which involves simultaneous infusions of insulin and glucose, has been used extensively and is considered an important standard. However, the method is complex, somewhat invasive, and resource demanding. A computer (minimal model) modeling of an intravenous glucose tolerance test (IVGTT) is easier to carry out, although the differential equations necessary to assess simultaneous changes in glucose and insulin concentrations are complex. Many consider this to be the gold standard technique. Alternative methods involve comparison of glucose and insulin changes after a standard oral glucose tolerance test (13b), the intravenous insulin tolerance test (13c), and the use of fasting blood alone to assess the glucose/insulin ratio or calculations of Homeostatic Model Assessment (HOMA) (13d) and The Q.uantative Insulin Check Index (QUICKI) (13e). All these techniques have been found to correlate well with each other in the absence of overt diabetes (14).
A. Sex Steroids and Carbohydrate Metabolism Several conditions suggest important relationships between insulin sensitivity and sex steroids. Examples include the increased insulin resistance during the high estrogen and progesterone state of pregnancy, during the luteal phase of the menstrual cycle, and in women with high androgen production (e.g., polycystic ovarian syndrome [PCOS], stromal hyperthecosis). In the context of sex steroids, it is also of interest that during the reproductive years, insulin sensitivity to glucose is greater in women than in men. Levels of Sex Hormone Binding Globulin (SHBG) reflect in part endogenous estrogen status, with higher levels of SHBG correlating with higher estrogen status. The San Antonio Heart Study demonstrated that SHBG is negatively correlated with fasting insulin and insulin and glucose responses to oral glucose (15). Thus, the metabolic effects of endogenous estrogen suggest that estrogen replacement therapy may have the potential to reverse the cluster of metabolic changes included in the metabolic syndrome. Some discrepancies, however, exist because of the difference between the physiologic and pharmacologic actions of endogenous and exogenously administered sex steroids. Exogenous sex steroids with estrogen and progestogen represent a wide spectrum of hormones with different molecular structures and also differences in their pharmacokinetic properties and pharmacodynamic effects. Estrogens may be natural or equine from genuine sources or artificial with or without a steroid structure. The progestogens represent an even wider array of hormonal compounds with progesterone-like activity and some having partial androgen, antiandrogen, mineralocorticoid, or antimineralocorticoid activities (16). Moreover, the sex steroids are available in various formulations such as patches, implants, and various vaginal preparations, which have no first-pass hepatic effect. Such differences in pharmacokinetic properties will also influence the metabolic impact of hormonal treatment. In animal studies it has been shown that 17[3-estradiol (E2)
CHAPTER 37 Glucose Metabolism After Menopause treatment enhances insulin secretion in islet cells and thereby augments the insulin response to glucose and reduces insulin resistance (17). Also, natural progesterone may result in an increased insulin response to glucose, probably due to decreased insulin sensitivity in target tissues resulting in increased beta cell responsiveness. Much of our knowledge about the effect of the exogenous sex steroids on glucose metabolism in women is derived from studies using oral contraceptives (OCs). When administering OCs, often there is a decrease in glucose tolerance, concomitant with a hyperinsulinemic response to the glucose load. The impact on glucose metabolism has been shown to be clearly dose dependent, and the low-dose types of combined OCs have far less of an impact on glucose tolerance; most often there is no deterioration in the glucose curve whereas hyperinsulinemia and decreased insulin sensitivity can still be observed (18). Several investigations on hormonal administration and insulin sensitivity and glucose tolerance have been reported, but the conclusions are not uniform. Some of these discrepancies may be due to differences in the routes of administration. Following oral administration, hormones pass directly from the gut to the liver via the portal vein, giving a high local concentration that markedly affects hepatic metabolism. In contrast, transdermal administration avoids first-pass metabolism, and it is therefore not surprising to find different effects with oral compared with parenteral administration. Barret-Connor and Laakso have published results from a comparative study on post-challenge glucose and insulin levels in women using no hormonal therapy (HT), unopposed conjugated estrogen (CEE), and CEE plus medroxyprogesterone acetate (MPA) (19). The glucose and insulin values were adjusted for age and body mass index (BMI) before comparisons were made. Fasting glucose levels were significantly lower in the estrogen-treated group compared with the untreated group. No difference was seen between the CEE + MPA group compared with the group with unopposed CEE treatment, but fasting insulin values were lower in the estrogen-treated group compared with the group with no treatment. In contrast, Cagnacci et al. (20) found no significant effect on fasting insulin levels or beta cell sensitivity to oral glucose with CEE. This group compared the oral intake of CEE with transdermal administration of E2. Following the transdermal administration, fasting insulin levels decreased and the beta cell responses to glucose increased, indicating an increase in insulin sensitivity. The study is interesting because it evaluated the significance of the estrogen effect on the liver for glucose homeostasis, and in contrast to oral CEE, transdermal estrogen increased hepatic insulin clearance. Godsland et al. (21) have compared insulin sensitivity using the IVGTT, "minimal model" technique during the sequential intake of oral CEE plus levonorgestrel (LNG) and transdermal administration of E2 plus oral norethisterone (NET). Oral intake of
503 C E E + L N G caused a decrease in glucose tolerance and an overall increased plasma insulin response. Insulin resistance was greater during the combined phase compared with the estrogen-only phase. The transdermal regimen had relatively few effects on insulin metabolism, although the first-phase beta cell insulin secretion was enhanced. Both regimens increased hepatic insulin uptake. This study therefore suggests that the addition of a progestogen to estrogen therapy may markedly influence the effect on glucose metabolism in parallel to the observations made during administration of OCs. Lindheim et al. demonstrated the impact of dose, showing a bimodal effect of oral CEE estrogens on insulin sensitivity with an improvement occurring with the lower dose of 0.625 mg but with deterioration with the dose of 1.25 mg (22). The authors suggested that this effect may be related to the first-pass hepatic-portal effect in that transdermal E2 (0.1 mg), which may be equated more closely with the larger dose of oral estrogen (1.25 mg), improved insulin sensitivity. In the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), in which oral micronized E2 (1 mg) was used alone for 2 years, there was statistical improvement in glucose, insulin, and hemoglobin (Hgb) Alc (22a). Progestogens, however, appeared to attenuate the beneficial effects of transdermal estrogen and may alter the clearance of insulin (23). This observation may be related to the dose and type of progestogen. Duncan et al. (24) found no beneficial effect of unopposed oral and transdermal E2 on insulin sensitivity and suggested that the addition of an oral progesterone (NET) confers no clinically important risk or benefit. Gaspard et al. (25) found that after 2 years of treatment with oral E2 combined sequentially with dydrogesterone (DG), presumably a metabolically more neutral progesterone deriviate, the oral glucose tolerance test (OGTT) was unaffected, but there was a decreased area under the insulin curve as well as fasting insulin values indicating an improvement in insulin sensitivity. Using transdermal E2 and the same progestogen, Cucinelli et al. (26) demonstrated with the euglycemic clamp technique an amelioration of insulin resistance after 12 weeks of treatment. Using both a high-dose (2 mg) and low-dose (1 mg) oral regimen of E2 combined with DG for 24 months, Godsland et al. (27), applying the minimal model, found favorable effects on insulin secretion and elimination in menopausal women. When comparing oral E2 (2 mg) plus DG with tibolone in obese women (BMI -> 27), Morin-Papunen et al. (28) found that following 12 months of tibolone, whole-body glucose uptake decreased, contrasted with the effect of oral E2 + DG using the euglycemic technique. Comparing also oral tibolone with oral CEE (0.625 mg) plus MPA (5 mg) Wiegratz et al. (29) found no significant changes with either treatment in the results obtained from OGTTs performed at baseline and after 6 months in nonobese women. We have examined the impact on glucose metabolism and insulin sensitivity from oral administration of 2 mg E2 in combination with the intrauterine delivery
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system o f L N G (Mirena) and compared the results with data obtained with a continuous combined treatment with 2 mg E2 plus 1 mg Norethindrone Acetate (NETA). After 6 months, no changes were observed in the OGTTs and insulin sensitivity using the minimal model technique. One of the largest randomized comparative studies on H T and risk markers for a deterioration of glucose metabolism was the Postmenopausal Estrogen/Progestin Intervention Study (PEPI), a 3-year trial to assess effects of four hormone regimens on cardiovascular risk factors (30). In 788 women, the impact of the hormone regimens was determined on insulin and glucose concentrations measured during a standard OGTT. When compared with women taking placebo, those taking CEE at 0.625 mg/day with or without a progestational agent had lower mean fasting insulin levels, lower mean fasting glucose levels, and higher mean 2-hour glucose levels. No significant differences were apparent between women taking CEE plus progestin regimens: MPA (2.5 mg daily), continuous CEE plus MPA, CEE and MPA at 10 mg on days 1-12, and micronized progesterone (MP) cyclically at 200 mg on days 1-12. The impact of H T on insulin and glucose depended on baseline levels of fasting insulin and 1-hour glucose. However, the treatment effects on carbohydrate metabolism appeared to be consistent across participant subgroups. The interpretation was that oral H T involving 0.625 mg/day of CEE may modestly decrease fasting levels of insulin and glucose. Post-challenge glucose concentrations are increased, which may indicate delayed glucose clearance. In WHI, there was a reduction in glucose and insulin in women receiving CEE 0.625 mg with MPA 2.5 mg (30a). H O M A was significantly decreased at 1 year (p < 0.05) but returned to baseline thereafter (Fig. 37.2). On the contrary, with this same regimen, sites showed no improvement and
a 17% reduction in insulin sensitivity at 6 months, which persisted for 2 years using the englycemic hyperinsulinemic clamp technique. In summary, oral estrogen (at low to moderate doses) seems to result in a mild improvement in insulin sensitivity in most but not all studies. Transdermal estrogen may be more favorable in this regard, particularly in some women. The addition of progestogens may or may not attenuate these responses based on the dose and type of progestogens. Finally, the age and metabolic status of the women studied may influence the findings.
III. HORMONAL THERAPY AND DIABETES Only a few studies have evaluated the effect of H T on diabetes incidence. In the Heart and Estrogen/Progestin Replacement Study (HERS), 2763 postmenopausal women with documented coronary heart disease (CHD)were randomly assigned to daily estrogen plus progestogen therapy or to placebo (31). The effect of H T on fasting glucose levels and incident diabetes over 4 years of follow-up was evaluated. A total of 2029 women without diabetes were included. Incident diabetes was defined by self-report of diabetes or disease complication, fasting glucose level of 6.9 mmol/L or greater (-> 126 mg/dL), or initiation of therapy with diabetes medication. Fasting glucose levels increased significantly among women assigned to placebo but did not change among women receiving HT. The incidence of diabetes was 6.2% in the H T group and 9.5% in the placebo group (hazard ratio [HR] 0.65; 95% confidence interval [CI], 0.48-0.89), corresponding to a 35% lower incidence among H T users. The number needed to treat for benefit to prevent
FIGURE 37.2 Women's Health Initiative CEE+MPA study: change in insulin resistance, calculated from fasting glucose and insulin according to the homeostasis model assessment of insulin resistance (HOMA-IR): insulin x (glucose/22.5); values are mean _+ SE; ap < 0.05 versus placebo. (From ref. 33, with permission.)
CHAPTER 37 Glucose Metabolism After Menopause one case of diabetes was 30. Changes in weight and waist circumference did not mediate this effect. Obviously, evaluation of the preventive effect of H T on the occurrence of type 2 diabetes was not the primary objective of HERS, and only one combination (0.625 mg of CEE plus 2.5 mg of MPA) was considered. Previous research examining the effect of H T on the development of diabetes has been inconclusive, and no long-term randomized clinical trial data have been available. The findings, however, are in accordance with the observational findings of the Nurses' Health Study, in which the influence of H T on the subsequent development of diabetes was examined in a prospective cohort of 21,028 postmenopausal U.S. women aged 30 to 55 years and free of diagnosed diabetes in 1976 (32). During 12 years of followup, it was confirmed that current H T users had a relative risk of diabetes of 0.80 (95% CI, 0.67-0.96) as compared with never users, after adjustment for age and BMI. In addition, the W H I also offers new insights into how diabetes may be prevented in women during H T (33). The study was designed to examine the effect of postmenopausal hormone replacement on a number of health outcomes, with a primary end point of coronary heart disease death or nonfatal myocardial infarction. In the estrogen/progestin arm, more than 15,000 women were randomized to receive either 0.625 mg of CEE plus 2.5 mg of MPA or placebo each day during 5.6 years of follow-up. The participants were women aged 50 to 79, and all had an intact uterus. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycemic medications. Fasting glucose, insulin, and lipoproteins were measured in a random sample at baseline and at 1 and 3 years. The cumulative incidence of treated diabetes was 3.5% in the H T group and 4.2% in the placebo group (HR 0.79; 95% CI, 0.67-0.93) (see Fig. 37.2). There was little change in the hazard ratio after adjustment for changes in BMI and waist circumference. During the first year of follow-up, changes in fasting glucose and insulin indicated a significant fall in insulin resistance in actively treated women compared with the control subjects (Fig. 37.3). The interpretation of the data suggests that combined therapy with estrogen and progestin reduces the incidence of type 2 diabetes.
FIGURE 37.3 Women's Health Initiative CEE+MPA study: incidence of diabetes. (From ref. 33, with permission.)
505 Thus, the study confirms the observations made in the HERS and Nurses' Health Study trials. Although the results of these studies are consistent in showing that women on H T are less likely to progress to type 2 diabetes, it is unclear if these results should favor the prescription of H T to diabetic women. In a number of smaller studies, women with diabetes benefited from HT, either in terms of glucose excursions over time (33a), improved levels of Hgb AIC (33b), or an overall marginal improvement in the metabolic profile (33c,34). The search for the "optimal" and "low-dose" H T is still needed but not easy to define due to varying effects of the same compound in different target organs. The reported increased risk of stroke and "early harm" coronary risk in older women is of concern and points to the importance of adjusting underlying risk factors such as hypertension, hyperlipidemia, and elevated plasma glucose. These high-risk factors that accelerate atherosclerosis potentially place diabetic women at greater risk for early harm when using standard-dose oral therapy.
IV. CONCLUSION The association between deterioration of glucose metabolism and C H D has been observed in numerous studies. In the past few decades, research has demonstrated that the commonly used term insulin resistance syndrome promotes atherothrombosis and includes several components: insulin resistance with or without glucose intolerance, abdominal obesity, atherogenic dyslipidemia, raised blood pressure, a proinflammatory state, and a prothrombotic state. In the vessel wall, insulin stimulates proliferation and migration of smooth muscle cells as well as binding of low-density lipoproteins to receptors in monocytes, and it also influences the activity of major enzymes involved in lipogenesis. In any given woman, insulin resistance is largely genetically determined, with its clinical expression is linked to age, and is more frequently encountered in middle-aged women compared with men. Endogenous and exogenous sex steroids appear to have a modulating effect. In postmenopausal women, exogenous estrogens may decrease insulin resistance, although the effect may be blunted by the increased synthesis of growth factors and decreased hepatic insulin clearance following the first-pass effect of orally administered hormones. Moreover, administration of progestogens together with estrogens may counteract the estrogenic effects on insulin resistance. Although the data are inconclusive, low-dose oral estrogen as well as transdermal therapy may be preferable from a metabolic point of view. Presently the results from the HERS and W H I are encouraging in terms of prevention of type 2 diabetes with the postmenopausal use of HT, although more information is needed before clinical recommendations or guidelines can
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SKOUBYAND MADSBAD
be rendered. In diabetic women, HT may have a bimodal effect, preventing the development of CHD in women without pre-existing coronary heart disease but accelerating the risk in those with established disease.
References 1. King H, Aubert RE, Herman WH. Global burden of diabetes, 19952025: prevalence, numerical estimates, and projections. Diabetes Care 1998:21;1414-1431. 2. King H, Rewers M. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. W H O Ad Hoc Diabetes Reporting Group. Diabetes Care 1993;16:157-177. 3. Walton C, Godsland I, Proudler A, Wynn W, Stevenson JC. The effects of the menopause on insulin sensitivity, secretion and elimination in nonobsese, healthy women. EurJ Clin Invest 1993;23:466-473. 4. Wu SI, Chou P, Tsai ST. The impact of years since menopause on the development of impaired glucose tolerance. Clin Epidemiol 2001;54: 117-120. 5. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173 - 194. 6. Reaven M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-1607. 7. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24:683 -689. 8. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.JAm MedAssoc 2002;287:356- 359. 9. Grundy SM, Hansen B, Smith SC Jr, Cleeman JI, Kahn RA. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 2004;109:551-556. 10. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;21:2709-2716. 11. Sutherland J, McKinnley B, Eckel RH. The metabolic syndrome and inflammation. Metabolic 8yndr Rel Disord 2004;2:82-104. 12. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. BrJNutr 2004;92:347- 355. 13. Nawrocki AR, Scherer PE. The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation. Curr Opin Pharmaco12004;4:281-289. 13a. Chu MC, Cosper P, Orio F, Carmina E, Lobo RA. Insulin resistance in postmenopausal women with metabolic syndrome and the measurements of adiponectin, leptin, resistin, and ghrelin. Am J Obstet Gynecol 2006;194:100-104. 13b. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999;22:1462-1470. 13c. Lindheim SR, Buchanan TA, Duffy DM, et al. Comparison of estimates of insulin sensitivity in pre- and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test. J Soc GynecolInvestig 1994;1:150-154. 13d. Stumvoll M, Mitrakou A, Pimenta W, et al. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 2000;23:295-301. 13e. Katz A, Nambi SS, Mather K, et al. Q.uantitative insulin sensitMty check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402-2410.
14. Matthews DR, HoskerJP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-ceU function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-419. 15. Goodman-Gruen D, Barrett-Connor E. Sex hormone-binding globulin and glucose tolerance in postmenopausal women. The Rancho Bernardo Study. Diabetes Care 1997;20:645-649. 16. Sitruk-Ware R. Pharmacological profile of progestins. Maturitas 2004;47:277-283. 17. Kurmagai S, Hokmang A, Bjorntorp P. The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol &and 1993;49:91-97. 18. Skouby SO. Oral contraceptives: effect on glucose and lipid metabolism in previous gestational diabetic women and in insulin dependent diabetic women--a clinical and biochemical assessment. Dan Med Bull 1988;35:157-167. 19. Barret-Connor E, Laakso M. Ischemic heart disease risk in postmenopausal women. Effects of estrogen use on glucose and insulin levels. Arteriosclerosis 1990; 10:531 - 534. 20. Cagnacci A, Soldani R, Carriero PL, et al. Effects of low doses of transdermal 17-beta estradiol on carbohydrate metabolism in postmenopausal women. J Clin Endocrinol Metab 1992:74:1396-1400. 21. Godsland IF, Gangar K, Walton C, et al. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism 1993;42:846-853. 22. Lindheim SR, Buchanan TA, Dully DM, et al. Comparison of estimates of insulin sensitivity in pre- and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test.J Soc GynecolInvestig 1994;1:150-154. 22a. Hodis HN, Mack WJ, Lobo RA; Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial.Ann Intern Med 2001;135:939-953. 23. Lindheim SR, Duffy DM, Kojima T, et al. The route of administration influences the effect of estrogen on insulin sensitivity in postmenopausal women. Fertil Steri11994;62:1176-1180. 24. Duncan AC, Lyall H, Roberts RN, et al. The effect of estradiol and a combined estradiol/progestagen preparation on insulin sensitivity in healthy postmenopausal women. J Clin Endocrinol Metab 1999;84: 2402-2407. 25. Gaspard UJ, Wery OJ, Scheen AJ, Jaminet C, Lefebvre PJ. Long-term effects of oral estradiol and dydrogesterone on carbohydrate metabolism in postmenopausal women. Climacteric 1999;2:93-100. 26. CucineUi F, Paparella P, Soranna L, et al. Differential effect of transdermal estrogen plus progestagen replacement therapy on insulin metabolism in postmenopausal women: relation to their insulinemic secretion. EurJ Endocrino11999;140:215-223. 27. Godsland IF, Manassiev NA, Felton CV, et al. Effects of low and high dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women. Clin Endocrino12004; 60:541-549. 28. Morin-Papunen LC, Vauhkonen I, Ruokonen A, Tapanainen JS, Raudaskoski T. Effects of tibolone and cyclic hormone replacement therapy on glucose metabolism in non-diabetic obese postmenopausal women: a randomized study. EurJ Endocrino12004;150:705-714. 29. Wiegratz I, Starflinger F, TetzloffW, et al. Effect of tibolone compared with sequential hormone replacement therapy on carbohydrate metabolism in postmenopausal women. Maturitas 2002;41:133-141. 30. Espeland MA, Hogan PE, Fineberg SE, et al. Effect ofpostmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators (Postmenopausal EstrogerdProgestin Interventions). Diabetes Care 1998;21:1589-1595. 30a. Margolis KL, Bonds DE, Rodabough RJ. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologica 2004; 47:1175-1187.
CHAPTER 37 Glucose Metabolism After Menopause 31. Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/Progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:1-9. 32. Manson JE, Rimm EB, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and subsequent incidence of noninsulin-dependent diabetes mellitus. Ann Epidemio11992;2:665-673. 33. Margolis KL, Bonds DE, Rodabough RJ, Women's Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia 2004;47:1175-1187. 33a. Friday KE, Dong C, Fontenot RU. Conjugated equine estrogen improves glycemic control and blood lipoproteins in postmenopausal women with type 2 diabetes.J Clin End Metab 2001;86:48-52.
507 33b. Ferrara A, Karter AJ, Ackerson LM, et al. Hormone replacement therapy is associated with better glycemic control in women with type 2 diabetes: The Northern California Kaiser Permanente Diabetes Registry. Diabetes Care 2001;24:1144-1150. 33c. Manning PJ, Allum A, Jones S, Sutherland WH, Williams SM. The effect of hormone replacement therapy on cardiovascular risk factors in type 2 diabetes: a randomized controlled trial. Arch Intern Med 2001; 161:1772-1776. 34. Anderson B, Mattsson L-A, Hahn L, et al. Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997;82:638-643.
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2 H A P T E R 3t
Stage of Reproductive Life, Atherosclerosis Progression and Estrogen Effects on Coronary Artery
Atherosclerosis THOMAS
B.
CLARKSON
Wake Forest University School of Medicine, Comparative Medicine Clinical Research Center, Winston-Salem, NC 27157
JAY R. N A P L A N
Wake Forest University School of Medicine, Comparative Medicine Clinical Research Center, Winston-Salem, NC 27157
I. I N T R O D U C T I O N
following the perimenopause accounts for the large increase in CHD observed among women over 55 years of age. Not surprisingly, many investigators also concluded that postmenopausal estrogen therapy would be cardioprotective. Today, that belief has come to be questioned by some, perhaps most, health care professionals. Much of the doubt about the potential cardioprotective benefits of estrogen therapy (ET) comes from those who would extend to perimenopausal/early postmenopausal women the results of two randomized trials conducted with women 14 to 18 years postmenopausal (the Heart and Estrogen/Progestin Replacement Study [HERS] and the Women's Health Initiative [WHI]) (1,2). In both HERS and WHI, the initiation of hormone therapy (HT) was associated with increased CHD
Coronary heart disease (CHD) (and underlying coronary artery atherosclerosis) remains the largest cause of death among women over 55 years of age, with CHD mortality exceeding by several-fold the combined deaths due to cancers of the lung, breast, colon, and endometrium. A large body of experimental and epidemiologic evidence suggests that although normal levels of premenopausal estrogen inhibit the development of coronary artery atherosclerosis, estrogen deficiency (as occurs with premenopausal ovarian dysfunction or following surgical or natural menopause) is a major contributor to atherosclerosis progression. In this view, the relative decline in estrogen production during and TREATMENT OF THE POSTMENOPAUSAL WOMAN
509
Copyright 9 2007by Elsevier,Inc. All rights of reproductionin any formreserved.
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CLARKSON AND KAPLAN
events during the first year of treatment. These findings appeared to contrast with experimental and observational data published in the 1990s. Numerous studies of monkeys provide evidence that ET begun immediately following surgical menopause inhibits the progression of coronary artery atherosclerosis by about 70% (3-5). Moreover, the results of large observational studies, such as that of 121,700 female nurses 30 to 55 years of age, suggest that H T initiated around the time of menopause reduces the risk for a major coronary event by about 50% (6,7). The foregoing contrast between the experimental/ observational studies and the clinical trials resulted in confusion about whether and to what extent estrogens had cardiovascular benefits at any life stage and, equally important, challenged the medical research community to reconcile the various studies into one consistent concept. Following considerable debate and reexamination of the relevant data, there is an emerging consensus that the disparate results of the clinical trials and observational studies reflect the fact that the effects of estrogen on arteries are contingent on the stage of reproductive life and the extent of underlying atherosclerosis. Specifically, estrogen appears to exert beneficial effects in premenopausal and perimenopausal women and women in whom atherosclerosis is minimal. Effects are diminished in postmenopausal women and women in whom atherosclerosis is extensive. The two-part conceptual framework for current thinking about cardiovascular effects of estrogens is illustrated in Fig. 38.1. Fig. 38-1, A, depicts the premenopausal period as important in determining the extensiveness of atherosclerosis at the beginning of the perimenopausal transition, which in turn determines the trajectory for plaque progression during the postmenopausal period. This figure implies that investigators should focus attention on the determinates of "high" and "low" risk during the premenopausal years. Fig. 38.1, B, illustrates the idea that estrogen's arterial benefits vary with menopausal status, which we have come to A
understand is largely inseparable from the degree of progression of subclinical atherosclerosis. Hence, benefits are considerable during premenopausal years and the perimenopausal transition when estrogen receptors (ERs) are intact and there is minimal atherosclerosis. However, there is little or no beneficial effect following 6 or more postmenopausal years, when receptor function is impaired and atherosclerosis is present. In this chapter, we summarize the evidence that the W H I was a seconaary intervention trial and elaborate the data supporting the conceptual framework described previously. After considering the results of the major observational studies, clinical trials, and experimental investigations, we conclude that primary cardiovascular benefits of estrogens are both rational and likely.
II. PROGRESSION OF CORONARY ARTERYATHEROSCLEROSIS A M O N G NORTH AMERICAN WOMEN Recognition that coronary artery atherosclerosis has its origin in childhood and progresses with each reproductive state is important in understanding the conceptual framework about estrogen's arterial effects (Fig. 38.2). Three sources of data provide information about the progression of subclinical coronary artery atherosclerosis of the average American woman. The muhicenter Pathologic Determinants of Atherosclerosis in Youth (PDAY) study provides information on the premenopausal precursors (fatty streaks) of postmenopausal coronary artery plaques (raised lesions) (8). The numbers shown in the lumen of the premenopausal women refer to the surface of coronary arteries with fatty streaks. Among both white and black women up to 35 years of age, the majority (about 70%) have fatty streaks. Only about onethird of these premenopausal women have the early stages of B §
Clinical Events Plaque ~ H i gRishk /
/
7 v
/
Fatty Streaks Normal ~ Artery
+
Hypothetical+ Arterial Benefits of + Estrogens +
Low Risk Pre Peri Post Menopausal Status
0
Pro
Peri Post Menopausal Status
FIGURE 38.1 Progressionof premenopausal atherosclerosis determines the coronary artery plaques extent at the time of perimenopausal transition and sets the trajectoryfor extent of postmenopausal atherosclerosis extent (A). Estrogen's arterial benefits varywith reproductive stage, being of key importance premenopausallyand perimenopausallybut losing benefits after the first 6 postmenopausalyears (B).
CHAPTER 38 Stage of Reproductive Life, Atherosclerosis Progression
FIGURE 38.2 The natural history of atherosclerosis among women in the United States is depicted schematically. ET, estrogen therapy; HT, hormone therapy.
atherosclerotic plaques, and the extent is small, covering only about 15% of the surface of the coronary artery. Data on adult and postmenopausal women have come largely from autopsies of women dying of accidental deaths. During the perimenopausal transition and the early years of the menopause (35-45 years), plaques become larger and fibrous caps begin to develop. By age 55, plaques are larger still, fibrous caps are more distinct, and atheronecrosis and calcification are often present (9). In vivo arterial imaging (via ultrasound) also reveals the presence of focal lesions late in the premenopausal phase and during the perimenopausal transition (10,11). Among women older than 65 years the amount of atheronecrosis increases, and inflammatory processes are often apparent within the lesion, particularly within the shoulders of the fibrous caps (12,13). Electron beam tomography (EBT) data support the pathologic studies. Coronary artery calcification, which is always associated with necrosis, begins at about age 55 and becomes distinct in most women by age 60 to 64. Specifically, it has been reported that about 60% of women reach the 90th percentile of coronary calcification by age 60 to 64 years (13). Generally, plaque instability, associated with the inflammatory process (primarily increases in metalloproteinase activities), coincides with increasing calcification.
III. PRIMARY VERSUS S E C O N D A R Y P R E V E N T I O N ~ C H D VERSUS CO RONARY ARTERY ATHEROSCLEROSIS There is much confusion concerning use of the terms
primary and secondary prevention in relation to estrogen's cardiovascular effects. Primary prevention of atherosclerosis at the vascular level refers to inhibiting the progression of coronary artery fatty streaks and small plaques (common in women at the time of perimenopausal transition) to advanced atherosclerotic plaques (common in women 5 to 15 years postmenopause). In contrast, primaryprevention of CHD generally refers to inhibiting the progression of complicated
511 atherosclerotic plaques to clinical C H D events. The results of the W H I suggest that H T is not associated with primary prevention of CHD. However, this trial did not test whether there was primary prevention of atherosclerosis progression because the participants were at an age that would already have had advanced (although subclinical) plaques when treatment was initiated. As mentioned previously, data from studies of monkeys as well as women indicate that the effect of ET and H T are robust when treatment is initiated at the life stage in which fatty streaks are progressing to plaques (primary prevention of atherosclerosis). However, the recent clinical trials (WHI and HERS) tell us that E T / H T initiated at the complicated plaque stage (beyond about 60 years of age) does not result in C H D benefit.
IV. P R E M E N O P A U S A L D E T E R M I N A N T S OF C O R O N A R Y ARTERY A T H E R O S C L E R O S I S PROGRESSION Conceptually, whether indMduals are at high or low risk for progression of coronary artery atherosclerosis during their premenopausal years determines the extent of intimal lesion present at the time of the perimenopausal transition, which in turn likely establishes the trajectory for plaque progression postmenopausally (see Fig. 38.1, A). Consequently, identifying the risk factors for atherosclerosis progression during the premenopausal period comprises a potentially fruitful focus for research. A close examination of the multicenter PDAY study provides quantitative data about the progression of coronary artery lesions during the important premenopausal years (age 15 to 34 years) (14). Fig. 38.3, A and B, depict the changes with increasing age. During the years from age 15 to 34, the surface area of women's coronary arteries having fatty streaks (the likely precursor of atherosclerotic plaques or raised lesions) increases from about 2% to about 8% with a rather large variation as indicated by the standard error bars (see Fig. 38.3, A). The most rapid increase in fatty streak extent is from ages 25-29 to 30-34, and the variation seen suggests that the population contained both high- and lowrisk individuals. By ages 30 to 34 years, a portion of the fatty streaks have presumably progressed to raised lesions that now occupy about 1% of the surface area of coronary arteries (see Fig. 38.3, B). The two risk factors that appear to be of the most importance in determining a high versus a low trajectory for premenopausal atherosclerosis progression are plasma lipid profiles and ovarian dysfunction (estradiol deficiency), which are not necessarily independent. The evidence supporting the role of these two risk factors is reviewed in the following paragraphs.
512
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CLARKSON AND KAPLAN
lo I
B 4
g
10
8
O > r
6
>
Fatty Streaks
Raised Lesions
~s
7
O ;> c
5 4
102
ESPRIT (19)
62.6
16
WHI-EP (20,21)
63.3
13.4
WHI-E (22,23)
63.6
Oral CEE 0.625 mg + MPA 2.5 mg Transdermal 1713-E2 alone or sequential NE Oral E2-V 2 mg alone
4.1 2.6 2.0
0.79 (95% CI, 0.50-1.27)
Primary Prevention
>102
Oral CEE 0.625 mg + MPA 2.5 mg
5.2
Oral CEE 0.625 mg alone
6.8
1At randomization. 2Exact information has not been published. HERS, Heart and Estrogen/progestin Replacement Study; PHASE, Papworth HRT Atherosclerosis Study; ESPRIT, Estrogen in the Prevention of Reinfarction Trial; WHI-EP, Women's Health Initiative Estrogen+ Progestin Trial; WHI-E, Women's Health Initiative Estrogen Trial; CEE, conjugated equine estrogen; MPA, medroxyprogesteroneacetate; 17~-E2, 1713-estradiol;NE, norethisterone; E2-V, estradiol valerate; uCI, unadjusted confidence interval, describes the variabilityof the point estimate that would arise from a simple trial for a single outcome; aCI, adjusted confidence interval, describes the variabilityof the point estimate corrected for multiple outcome analyses.
artery revascularization, or angiographic evidence of coronary artery disease. After an average 4.1 years of randomized treatment, there was no significant difference between the C E E + M P A - t r e a t e d (172 women with events) and placebotreated (176 women with events) groups in the incidence of the primary trial end point (hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.80-1.22). Although the overall treatment effect was null, there was a statistically significant time trend in coronary heart disease events. In the first year of randomized treatment, the incidence of coronary heart disease events was significantly greater in the C E E + M P A treated group relative to the placebo treated group (57 events versus 38 events). After the first year of randomized treatment, there was a statistically significant trend toward a reduction in the primary trial end point in years 4 and 5 in the C E E + M P A treated group compared with the placebo group (p -- 0.009 for trend) (Fig. 39.3). The greater incidence of coronary heart disease events in the first year of randomized treatment in the C E E + M P A - t r e a t e d versus placebo-treated group was only significant among the women not using statins at baseline (HR, 1.75; 95% CI, 1.02-3.03,p = 0.04) (Fig. 39.4). Among the women using statins at baseline, the H R was not
FIGURE 39.3 Percent(incidence), absolute number, relative risk, and 95% confidence intervalfor coronaryheart disease events by year in the Heart and Estrogen/Progestin Replacement Study (HERS). CEE+MPA = conjugated equine estrogen 0.625 mg plus medroxyprogesteroneacetate 2.5 mg daily. P = trend in relative risk over time.
532
HoDis AND MACK
B. Papworth Hormone Replacement Therapy Atherosclerosis Study
FIGURE 39.4
Effectof statin use on coronaryheart disease events in the Heart and Estrogen/Progestin Replacement Study (HERS). Among the women who did not use statins, the incidence of coronary heart disease in the first year of randomization was greaterin the conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily (CEE+MPA) group relative to placebo,whereas in women who used statins there was no difference between treatment groups.
significantly different between the C E E + M P A - t r e a t e d and placebo-treated groups (HR, 1.34; 95% CI, 0.63-2.86, p = 0.45) (16). Statins most likely prevent atherosclerotic plaque rupture that may be induced under certain circumstances by CEE + MPA (see VIII. Evidence for a Duality of CEE + MPA Therapy on Coronary Heart Disease). Overall mortality did not differ between the C E E + M P A - t r e a t e d group (131 deaths) and the placebo-treated group (123 deaths) in HERS (HR, 1.08; CI, 0.84-1.38). There was no significant difference between hormone therapy and placebo in breast cancer incidence. In an unblinded, open-label, mean follow-up of 2.7 years of the HERS subjects in which all event data were selfreported, there was no difference in coronary heart disease events between women originally assigned to the C E E + MPA-treated group and the placebo-treated group (17). As an unblinded, open-label follow-up, the data require careful interpretation. For example, during the follow-up period, less than half of the women originally assigned to the C E E + MPA-treated group were actually using C E E + M P A , with only 45% of the cohort adherent to the hormone regimen, and 8% of the original placebo-treated group were taking hormone therapy. In addition, 36% of the C E E + M P A - t r e a t e d group and 39% of the placebo-treated group were using statins while 80% of all subjects were using aspirin during the follow-up period. Although the authors interpreted these data as indicating that CEE + M P A therapy had no long-term effect on coronary heart disease, an equally likely interpretation is that continued hormone therapy is required to maintain the beneficial effects of hormone therapy on the reduction of coronary heart disease events as seen in the latter years of the HERS randomized trial (15).
A total of 255 postmenopausal women older than 55 years with at least one coronary artery lesion of 50% diameter stenosis or greater who were admitted for coronary angiography were randomized to the Papworth Hormone Replacement Therapy Atherosclerosis Study (PHASE) (18). P H A S E was a prospective, open-label, blind end point study of transdermal hormone therapy versus placebo. Allocation was to transdermal estrogen (n = 58), sequential estrogen/progestogen therapy (n - 76), or placebo (n = 121). Women randomized to active treatment received transdermal 1713-estradiol 320 gg/day; those with a prior hysterectomy received 1713estradiol alone and those women with an intact uterus additionally received transdermal norethisterone 480 gg/day sequentially for 14 days of each 28-day cycle. Women were postmenopausal for at least 5 years; the average age of the women who received active treatment was 66.3 ___ 11.2 years, and for those in the placebo group, the average age was 67.0 ___ 11.8 years. A total of 53 subjects (40%) dropped out of the active treatment group, and 8 subjects (7%) dropped out of the placebo group. After an average 2.5 years of randomized treatment, there were 53 primary trial end point events (nonfatal myocardial infarction, coronary heart disease death, or hospitalization with unstable angina) in the active treatment group and 37 primary trial end point events in the placebo group. In the intention-to-treat analysis, there was no significant difference in the primary trial end point event rate (Event Rate Ratio, 1.29; 95% CI, 0.84-1.95; p = 0.24) between the active treatment group (15.4%) and the placebo group (11.9%). However, this study was limited by very low power to test event rate differences.
C. Estrogen in the Prevention of Reinfarction Trial The Estrogen in the Prevention of Reinfarction Trial (ESPRIT) was designed to test whether estrogen alone would reduce the primary trial end points of nonfatal myocardial infarction or cardiac death and all-cause mortality relative to women who received placebo treatment (19). Postmenopausal women ages 50 to 69 years who survived a first myocardial infarction were randomized to estradiol valerate 2 mg daily (n = 513) or placebo (n = 504). The ESPRIT cohort consisted of 1017 postmenopausal women who were on average 62.6 years old, were approximately 16 years since menopause at baseline, and had pre-existing cardiovascular disease defined as a prior history of myocardial infarction. After 2 years of randomized treatment, there were 62 nonfatal myocardial infarctions or cardiac deaths in the estradiol group and 61 such events in the placebo group,
CHAPTER 39 Randomized Controlled Trials and the Effects of Postmenopausal Hormone Therapy TABLE 39.2
533
Cumulative Number and Relative Risk of Overall Mortality and Cardiac Death in the Estrogen in the Prevention of Reinfarction Trial (ESPRIT) Any death 1
Time to events (months)
Estradiol valerate (n = 513)
Placebo (n = 504)
Relative risk (95% confidence interval)
3 6 12 18 24
8 14 20 27 32
14 20 30 39 39
0.56 (0.23-1.33) 0.68 (0.34-1.35) 0.65 (0.37-1.14) 0.67 (0.41-1.10) 0.79 (0.50-1.27)
Cardiac death2
P-value
Estradiol valerate (n = 513)
Placebo (n = 504)
Relative risk (95% confidence interval)
P-value
0.19 0.27 0.13 0.11 0.34
4 9 14 19 21
12 18 25 30 30
0.33 (0.11-1.01) 0.49 (0.22-1.09) 0.54 (0.28-1.05) 0.61 (0.35-1.09) 0.68 (0.39-1.19)
0.052 0.079 0.059 0.096 0.170
171 total deaths. 251 cardiac deaths.
with 32 deaths from any cause in the estradiol group and 39 such events in the placebo group. There was no significant difference between the estradiol-treated and placebo-treated groups in any of the primary trial end points of nonfatal myocardial infarction or cardiac death (rate ratio [RR], 0.99; 95% CI, 0.70-1.41; p = 0.97) and all-cause mortality (RR, 0.79; 95% CI, 0.50-1.27; p - 0.34). Although not significantly different, the relative risks of any death and cardiac death were lower in the estradiol-treated group than the placebo-treated group by 21% to 44% and 32% to 67%, respectively, throughout the 2-year trial, with both end points being lowest after 3 months of randomization (Table 39.2).
D. W o m e n ' s H e a l t h I n i t i a t i v e The Women's Health Initiative (WHI) was a parallel, placebo-controlled trial classified as primary prevention (although 10.2% of the women had known cardiovascular disease at baseline) of 27,347 postmenopausal women ages 50 to 79 years who were randomized according to hysterectomy status. Women with an intact uterus were randomized to oral daily continuous combined CEE 0.625 mg plus MPA 2.5 mg (Prempro | Wyeth-Ayerst) (n = 8506) or placebo ( n - 8102) (20,21), and women who had a prior hysterectomy were randomized to oral daily CEE 0.625 mg (Premarin | Wyeth-Ayerst) (n = 5310) or placebo (n - 5429) (22,23). The primary trial end point was the combined incidence of nonfatal myocardial infarction and coronary heart disease death. The initially planned duration of the W H I trials was 8.5 years. On May 31, 2002, after an average follow-up of 5.2 years, the Data and Safety Monitoring Board stopped the C E E + M P A trial (WHI-EP), and on February 2, 2004 the National Institutes of Health (the funding source of the trial) unilaterally stopped the CEE trial (WHI-E) after an average follow-up of 6.8 years. The W H I - E P cohort consisted of 16,608 postmenopausal women (Fig. 39.5) who were on average 63.3 + 7.1 years old
I
wo~176
.... [
! 18,845 Reported No Hysterectomy
1
3,444 9 Unblinded
[-~
42% 9 Discontinued CEE+MPA
I "38% Discontinued Placebo
6% 9 Started HT on Own
[ 11% 9 Started HT on Own
Unblind~
FIGURE39.5 Studyflowchart of the conjugatedequineestrogen0.625 mg plus medroxyprogesteroneacetate 2.5 mg daily (CEE+MPA) arm of the Women's Health Initiative (WHI) trial. HT - hormonetherapy.
(two-thirds were 60 years and older) with an average body mass index (BMI) of 28.5 kg/m 2 (34.1% of the subjects had a BMI of 30 kg/m 2 or greater); 7.6% of the women had known cardiovascular disease at baseline (20). Women with menopausal symptoms such as hot flushes that would have precluded randomization to placebo were excluded. After an average 5.2 years of randomized treatment, there was no significant difference between the C E E + M P A - t r e a t e d (annualized percentage of events 0.39) and placebo-treated (annualized percentage of events 0.33) groups in the incidence of the primary trial end point of nonfatal myocardial infarction and coronary heart disease death (HR, 1.24; 95% unadjusted CI, 1.00-1.54; 95% adjusted CI, 0.97-1.60)(21). Although the overall treatment effect was null, there was a statistically significant time trend toward the reduction of coronary heart disease events (Fig. 39.6). In the first year of randomized treatment, the incidence of coronary heart disease events was significantly greater in the C E E + MPA-treated group relative to the placebo-treated group (42 events versus 23 events) as analyzed with the unadjusted
534
HODIS AND MACK
FIGURE 39.6 Percent (incidence), absolute number, relative risk, and 95% confidence interval for coronary heart disease events by year in the Women's Health Initiative (WHI) estrogen plus progestin (E+P) trial. C E E + M P A = conjugated equine estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg daily. P is for the trend in relative risk over time.
statistic (HR, 1.81; 95% unadjusted CI, 1.09-3.01). These data have not been reported using the adjusted analysis for multiple comparisons. After the first year of randomized treatment, there was a statistic@ significant trend toward a reduction in the primary trial end point in year 6 and beyond in the C E E + M P A - t r e a t e d group compared with the placebo-treated group (p = 0.02 for trend). Overall mortality did not differ between treatment groups in W H I - E R Further analysis of the W H I - E P results indicated a statistically significant trend in the treatment effect of C E E + M P A on coronary heart disease according to time since menopause (Fig. 39.7) (24). Women in the C E E + M P A - t r e a t e d group who were less than 10 years postmenopausal had an 11%
Years
Since
reduced risk for coronary heart disease compared with placebo, those who were 10 to 19 years postmenopausal had a 22% increased risk for coronary heart disease, and those who were 20 years or more postmenopausal had a 71% increased risk for coronary heart disease. As two-thirds of the W H I - E P cohort was 60 years old or older, the majority of women randomized to this trial were 10 years or more (average of 13.4 years) postmenopausal at baseline (25). In WHI-EP, 87% of the coronary heart disease events occurred among the women randomized to C E E + M P A 10 years or more after menopause (24). Data regarding the event rates of C E E + M P A versus placebo treatment by time since menopause are not available. Because the majority of coronary heart disease events occurred among women randomized to CEE + M P A 10 years or more after menopause, these data are important in understanding whether the early increase in coronary heart disease events in the CEE + M P A group relative to placebo group was dependent upon when a woman initiated C E E + M P A therapy relative to her time since menopause. Importantly, analysis of both W H I - E P and HERS indicates that CEE + MPA significantly reduces the incidence of diabetes mellims. In WHI-EP, C E E + M P A reduced new onset diabetes meUitus by 21% (HR, 0.79; 95% CI, 0.67-0.93) relative to placebo (Fig. 39.8) (26). In HERS, C E E + M P A reduced new-onset diabetes mellitus by 35% (HR, 0.65; 95% CI, 0.48-0.89) relative to placebo (27). These findings have profound importance as more than 75% of diabetics die from cardiovascular disease and cardiovascular morbidity in women is greater than that in men (28). Additionally, the lifetime residual risk of new-onset diabetes in women 50 years old is (30%) 3000 cases per 10,000 women; for Hispanic and African-American women, it is (40%) 4000 cases per 10,000 women (29). As such, W H I EP and HERS predict a lifetime residual risk reduction of 0.06 -
Menopause 1.5 mg
Estrogen Dosage and Stroke in the Nurses' Health Study
Person-years of s
No. of cases
313,661 19,964 116,150 39,026
290 9 124 46
Age-adjusted relative risk (95% confidence interval) 1.0 (reference) 0.43 (0.22-0.83) 1.11 (0.90-1.37) 1.58 (1.16-2.15)
Multivariate-adjusted relative risk (95% confidence interval) 1 0.54 (0.28-1.06) 1.35 (1.08-1.68) 1.63 (1.18-2.26)
1Adjusted for age, body mass index, history of diabetes, hypertension, hypercholesterolemia,age at menopause, cigarette smoking, and parental history of coronary heart disease.
analyses. Combined stroke followed the same pattern as nonfatal stroke in both W H I - E P (20,93) and W H I - E (22, 94). The fully adjudicated W H I data showed a lower C E E and C E E + M P A risk of combined stroke than that originally reported from W H I - E and W H I - E P (93,94). Although the cumulated data do not conclusively indicate that hormone therapy significantly increases stroke relative to placebo, the randomized controlled trials do indicate a consistent increase in the point estimate of risk. However, the time- and age-related stroke data from the W H I indicate that the risk of stroke from hormone therapy when initiated in close proximity to menopause or in young postmenopausal women is rare. In W H I - E P , the risk of stroke was 3 additional cases per 10,000 women per year of C E E + M P A therapy for women within 5 years of menopause and 6 additional cases per 10,000 women per year of C E E § therapy for women 5 years to less than 10 years since menopause (93). In W H I - E , the risk of stroke in women less than 60 years old was 1 additional case per 10,000 women per year of C E E therapy (94). In addition, the W H I - E P randomized
controlled trial data indicate that increasing duration of C E E + M P A therapy reduces the risk of stroke (12). The risk from stroke was reduced 26% in the women who used C E E + M P A for more than 5 years (see Table 39.7) (12). The reduction in stroke risk associated with hormone therapy was consistent between the W H I - E P trial and the W H I observational study of E + P (see Table 39.7) (12). Data from the Nurses' Health Study indicate that stroke risk associated with hormone therapy may be a function of estrogen dosage (Table 39.10) (47).
XI. VENOUS THROMBOEMBOLIC EVENTS AND POSTMENOPAUSAL HORMONE THERAPY Venous thromboembolism (VTE) is a disease process comprised of two different outcomes, deep vein thrombosis (DVT) and pulmonary embolism (PE). For DVT, there are
CHAPTER 39 Randomized Controlled Trials and the Effects of Postmenopausal Hormone Therapy two distinct clinical entities classified according to location: calf and other. Calf DVTs are considered clinically benign and typically not treated because pathophysiologically they are rarely associated with PE. To date, the distinction between calf and other DVT locations associated with randomization in hormone therapy trials of cardiovascular disease have not been published. Although there was a twofold greater risk of VTE in the CEE + M P A group relative to the placebo group in WHI-EP, the increase in the absolute risk was small (Table 39.11) (95). The increased relative risk for VTE was greatest in the first year and significantly decreased but remained elevated over time: H R for VTE was 4.01 (CIs not reported) in year I of treatment, 1.97 in year 2, 1.74 in year 3, 1.70 in year 4, 2.90 in year 5, and 1.04 in year 6 and beyond (p for trend = 0.01) (95). The elevated absolute risk of VTE was lowest for women who were younger than 60 years old when randomized. In women younger than 60 years old, there were 11 additional cases of VTE per 10,000 women per year of CEE + M P A therapy versus 51 additional cases of VTE per 10,000 women per year of C E E + M P A therapy in women older than 60 years old (95). In HERS, C E E + M P A was associated with a 2.7-fold increased risk for VTE relative to placebo (96). Although DVT and PE were similarly increased in the C E E + M P A group, PE was not statistically different than placebo (see Table 39.11). The increase in the absolute risk of VTE from CEE + M P A was small. Similar to WHI-EP, over 6.8 years of follow-up, the H R for VTE declined from 2.66 during HERS (15,96) to 1.40 during the open label follow-up of 2.7 years (17) (test for time trend, p = 0.08). The results from W H I - E showed a nonsignificant RR of 1.32 with respect to the risk of VTE with CEE alone relative to placebo (97). The absolute risk for VTE was lowest for women who were less than 60 years old when randomized to W H I - E . For women younger than 60 years old, there were 4 additional cases of VTE per 10,000 women per year of CEE therapy versus 18 additional cases of VTE per 10,000 women per year of CEE therapy in women older than 60 years old (97). Analyzed separately, DVT with CEE alone was significantly increased relative to placebo, whereas the risk of PE was not (see Table 39.11). Comparison of the results from W H I - E P (HR, 2.1) and W H I - E (HR, 1.3) suggest that the VTE risk associated with CEE alone is less than the risk associated with C E E + M P A (62% increased risk associated with MPA relative to CEE alone). The results with estradiol alone from W E S T (84) are consistent with the W H I - E results with respect to the risk of VTE with CEE alone (97). In WEST, VTE and DVT were nonsignificantly lower in the estradiol group relative to placebo, whereas there was no effect on PE (see Table 39.11). The cumulated data suggest that the increased risk of VTE associated with C E E + M P A is not generalizable to CEE alone or to other forms of estrogen. In a case-control
553
TABLE 39.11 Relative and Absolute Risks ofVTE, DVT, and PE in Randomized Controlled Trials of Postmenopausal Hormone Therapy Absolute risk events per 10,000 women per year Trial and outcome WHI-EP (95) VTE DVT PE WHI-E (97) VTE DVT PE HERS (96) VTE DVT PE WEST (84)
Relative risk (95% CI)
Placebo
2.06 (1.57-2.70) 1.95 (1.43-2.67) 2.13 (1.45-3.11)
17 13 8
1.32 (0.99-1.75) 1.47 (1.06-2.06) 1.37 (0.90-2.07)
22 15 10
2.7 (1.4-5.0) 2.8 (1.3-6.0) 2.8 (0.9-8.7)
23 16 7
0.8 (0.2-3.4) 0.5 (0.0- 5.8) 1.0 (0.1-7.1)
44 22 22
Hormone therapy CEE + MPA 35 26 18 CEE alone 30 23 14 CEE +MPA 62 44 19 17[3-Estradiol alone
VTE DVT PE
32 11 21
VTE, venousthromboembolism;DVT,deep vein thrombosis;PE, pulmonaryembolus;WHI-EP, Women'sHealth Initiative Estrogen+ ProgestinTrial;WHI-E, Women'sHealth Initiative EstrogenTrial; HERS, Heart and Estrogen/progestinReplacement Study;WEST, Women's Estrogenfor StrokeTrial; CEE, conjugatedequine estrogen; MPA, medroxyprogesteroneacetate. study of 586 incident VTE cases and 2268 controls, compared with women not currently using hormone therapy, current users of esterified estrogen alone, esterified estrogen plus MPA, and CEE alone did not have an increased risk for VTE, whereas current users of CEE + MPA had a twofold statistically significant increased risk for VTE compared with nonusers of hormone therapy (Table 39.12) (98). In combination with MPA, esterified estrogen (OR, 1.08) and CEE (OR, 2.17) had increased relative risks for VTE; C E E + M P A was statistically significant (see Table 39.12). The increased risk for VTE associated with C E E + M P A (OR, 2.17) in this case-control study was similar to the relative risk reported from HERS (HR, 2.7) and W H I - E P (HR, 2.06). The relative risk for VTE associated with CEE alone (OR, 1.31) in this case-control study was similar to W H I - E (HR, 1.33). Esterified estrogen alone (OR, 0.78) was also similar to estradiol alone in W E S T (RR, 0.8). Most studies of VTE risk in hormone users have been conducted in women using orally administered exogenous hormones. Theoretically, non-oral routes of administration of hormone therapy should be associated with lower risk of VTE than
554 TABLE 39.12
HODIS AND MACK Risk of Venous Thrombembolism with Current Use of Different Hormone Therapies: Puget Sound Group Health Cooperative Case-Control Study
Participants, No. 1 Cases Controls Odds Ratio (95% CI)
None
EE alone
EE +MPA
CEE alone
372 1439
39 278
47 237
57 167
Reference
0.78 (0.53-1.15)
1.08 (0.75-1.56)
1.31 (0.91-1.88)
CEE +MPA 64 122 2.17 (1.49-3.14)
1Excludes 7 case and 25 control subjectswho were current users of estrogens other than EE and CEE. EE, esterified estrogens;CEE, conjugatedequine estrogen;MPA, medroxyprogesteroneacetate.
Overall mortality in HERS (HR, 1.08; 95% CI, 0.84-1.38), W H I - E P (HR, 0.98; 95% unadjusted CI, 0.82-1.18; 95% adjusted CI, 0.70-1.37) and W H I - E (HR, 1.04; 95% unadjusted CI, 0.88-1.22; 95% adjusted CI, 0.81 - 1.32) was unaffected by CEE + M P A and CEE therapies (Figures 39.21 to 39.23) (see Table 39.1). However, there was crossover in mortality risk between placebo and the C E E + M P A (see Fig. 39.22) and CEE (see Fig. 39.23) therapies after 5 to 6 years in W H I , suggesting a trend to decreasing mortality in the hormone group relative to placebo with longer duration of hormone therapy, as seen in previous observational studies (52). ESPRIT also showed a
nonsignificant reduction in cardiac and overall mortalities with estradiol alone (see Table 39.2) (19). To examine the effect of hormone therapy on overall mortality according to age, a meta-analysis of randomized controlled trials reporting at least 1 death in postmenopausal women comparing hormone therapy with placebo of at least 6 months duration was conducted (Table 39.13) (99). In this study, the effect of hormone therapy on overall mortality was null (OR, 0.98; 95% CI, 0.87-1.12). However, when the data were examined by the age of subjects, a statistically significant reduction in overall mortality was found for subjects less than 60 years old (mean age 54 years). The magnitude of the reduction in overall mortality of 39% (OR, 0.61; 95% CI, 0.39-0.95) for the women younger than 60 years old was similar to that of observational studies (3-12). The point estimate as well as the confidence interval for the reduction in overall mortality in the women less than 60 years old from this large meta-analysis are quite comparable to those of the largest observational study, the Nurses' Health Study (HR, 0.63; 95% CI, 0.56-0.70) (47). The age of initiation
FIGURE 39.21 All-causemortality (cumulative incidence) with conjugated equine estrogen0.625 mg plus medroxyprogesteroneacetate 2.5 mg daily (CEE+MPA) in the Heart and Estrogen/Progestin Replacement Study (HERS).
FIGURE 39.22 All-causemortality (cumulative incidence) with conjugated equine estrogen 0.625 mg plus medroxyprogesteroneacetate 2.5 mg daily (CEE+MPA) in the Women'sHealth Initiative (WHI) trial of estrogen plus progestin.
oral hormone therapy because of avoidance of the first-pass liver effects on procoagulation.
XII. MORTALITY AND POSTMENOPAUSAL H O R M O N E THERAPY
CHAPTER 39 Randomized Controlled Trials and the Effects of Postmenopausal Hormone Therapy 0.05-
- -
....
,~
XIII. CLINICAL PERSPECTIVE OF POSTMENOPAUSAL H O R M O N E THERAPY
Placebo CEE
t
J
0.03-
-~'~'E . ~,. ~ , 0
=
0.02-
= 0
0.01-
0.0C,
0
,
1
,
2
i
3
--
~
4
,
5
,
6
~
7
,
8
Years
FIGURE 39.23 All-cause mortality (cumulative incidence) with conjugated equine estrogen 0.625 mg daily (CEE) in the Women's Health Initiative ( W H I ) trial of estrogen alone.
of hormone therapy of the women in the observational studies and the age of the younger women randomized to the clinical trials examined in the meta-analysis is similar. On the other hand, in this study, the effect of hormone therapy on overall mortality in women greater than 60 years old (OR, 1.03; 95% CI, 0.90-1.18) was similar to that reported by HERS (HR, 1.08; 95% CI, 0.84-1.38), W H I - E P (HR, 0.98; 95% unadjusted CI, 0.82-1.18; 95% adjusted CI, 0.70-1.37) and W H I - E (HR, 1.04; 95% unadjusted CI, 0.88-1.22; 95% adjusted CI, 0.81-1.32). Similar to the effect of hormone therapy on coronary heart disease events, both duration and time of initiation of hormone therapy appear to be important in reducing overall mortality. These results parallel observational studies (3-12,52). 39.13 Cohort Characteristics of Meta-Analysis of Randomized Controlled Trials of Hormone Therapy and Mortality in Younger and Older Women
TABLE
Number of trials Number of participants Patient-years Mean duration of follow-up (years) Range of follow-up (years) Mean study size (number of participants) Range of study size (number of participants) Mean age at baseline (hormone therapy), years _+ SD Mean age at baseline (placebo), years _+ SD Age range (years) Mean dropout rate (hormone therapy) Mean dropout rate (placebo) SD, standard deviation.
555
30 26,708 119,118 4.46 0.7-10 890 52-16,608 62.2 _+ 8.9 63.4 _+ 9.1 36-87 11.5% 10.6%
Because hormones exert systemic effects, weighing the benefits and side effects of hormone therapy is important. Although formal analyses to compare the benefits and side effects of hormone therapy have not been conducted, W H I - E P is interpreted by some as indicating that the benefits are outweighed by the side effects. This oversimplification of data from a single clinical trial that used one hormone therapy regimen and dosage when placed into perspective to the totality of data has been interpreted with an opposite conclusion~ that the benefits outweigh the side effects (14). Furthermore, conclusions comparing benefits and side effects have been based on the initial W H I - E P report that stated a significantly increased risk (in the unadjusted analysis) for coronary heart disease with CEE + MPA therapy (20) but later was shown not to be statistically significant when the fully adjudicated data were analyzed (12,21). Additionally, these conclusions have not considered the trends in reduction in coronary heart disease risk with longer duration of therapy or time of initiation of hormone therapy in relation to menopause (21,24), the age dependency of benefit of hormone therapy on cardiovascular disease (22,23), reduction in new-onset diabetes mellitus (26), or reduction in absolute risk of breast cancer, as shown in W H I - E (22,100). Any single randomized controlled trial does not provide complete information for determination of benefits and side effects for all specific hormones, dosages, or regimens. Based on the W H I - E P and W H I - E data as well as the cumulated studies, side effects of hormone therapy are clearly not a class effect. In addition, current randomized controlled trial data do not provide adequate information for the determination of the long-term benefits or side effects of hormone therapy. No randomized controlled trial has been conducted with sufficient follow-up to do so. Randomized controlled trials provide information for up to 6.8 years, the approximate point at which the beneficial effects of hormone therapy on coronary heart disease begin to manifest. Consequently, short-term use of hormone therapy may not provide for the full expression of the benefits of estrogen and may paradoxically give the appearance of greater side effects than benefits. The cumulated data indicate that continued exposure to exogenous estrogen is required for continued beneficial expression of estrogen on its target organs such as the cardiovascular and skeletal systems. Once hormone therapy is stopped, the beneficial effects on coronary heart disease and osteoporosis rapidly disappear (17,57,101,102). Exposure to hormone therapy reduces coronary heart disease, osteoporosis, new-onset diabetes mellitus, and overall mortality. Unfortunately, as only observational studies have
556
HODIS AND MACK
provided long-term information about hormone therapy, the long-term side effects essentially remain unknown and determination of long-term risk-benefits cannot be determined with currently available data. Considering the relatively short-term benefits and side effects from randomized controlled trials, the cumulated data indicate a balance between benefit and side effects (14). Table 39.14 provides the most recent information published from W H I - E P . Overall, the effect of oral daily continuous combined C E E + M P A on coronary heart disease risk was elevated but null (with a significant time trend to benefit) (21), increased the relative risk of breast cancer with borderline significance in one statistic (unadjusted) and nonsignificance in another (adjusted) (103), increased the relative risk of stroke with significance in one statistic (unadjusted) and nonsignificance in another (adjusted) (93), and increased the risk for V T E (95). Although of small magnitude, W H I EP is the only randomized controlled trial that has shown an increased relative risk of breast cancer with any hormone therapy. On the other hand, C E E + M P A resulted in significant reductions in colorectal cancer (104), osteoporotic bone fractures (105), and new-onset diabetes mellitus (26). Only reductions in colorectal cancer and bone fracture and increased V T E were statistically significant with both the unadjusted and adjusted analyses. In W H I - E , the overall effect of oral C E E alone on coronary heart disease was null
TABLE 39.14
(with a significant reduction in several composite coronary heart disease outcomes in women less than 60 years old) (22,23), as was the effect on breast cancer (100), colorectal cancer (22), and VTE (97) (Table 39.15). The relative risk of stroke was significantly increased in one statistic (unadjusted) and nonsignificant in another (adjusted) (22,94). On the other hand, C E E alone significantly reduced osteoporotic bone fractures (22). Only the reduction in bone fractures was statistically significant in both the unadjusted and adjusted analyses. Other randomized controlled trials add further to the mixed picture of benefits and side effects, with HERS showing no effect on stroke and breast cancer but increased VTE; W E S T showing no effect on stroke, breast cancer, or VTE; and E S P R I T showing nonsignificant risk reduction for overall and cardiac mortality. The mixed picture of benefits and side effects of hormone therapy may be driven by variation in the populations studied, sample size variation, varying follow-up, and differences in hormone therapies. In the final analysis, however, side effects with the hormone therapy regimens studied thus far are consistent with observational studies and gravitate toward the null. The one exception is VTE, where the risk with oral daily continuous combined C E E 0.625 mg plus MPA 2.5 mg appears to be elevated. It is important to understand absolute risks in relation to the acceptable standard for the practice of medicine and use
Women's Health Initiative Estrogen + Progestin Trial Outcomes ,
No. of subjects (annualized %)1 Outcome Coronary heart disease (21) Stroke (93) Venous thromboembolism (95) Breast cancer (invasive) (103) Colorectal cancer (104) Total fractures (105) New-onset diabetes (26)6
CEE + MPA 2 (N = 8506)
Placebo (N = 8102)
188 (0.39) 151 (0.31)
147 (0.33) 107 (0.24)
167 (0.35)
Adjusted
Increased absolute benefit per 10,000 women/year
95% CI 3
Unadjusted 95% CI 4
1.24 1.31
0.97-1.60 0.93-1.84
1.00-1.54 1.02-1.68
76 (0.17)
2.06
NR s
1.57-2.70
199 (0.42)
150 (0.33)
1.24
0.97-1.59
1.01-1.54
43 (0.09)
72 (0.16)
0.56
0.33-0.94
0.38-0.81
733 (1.52)
896 (1.99)
0.76
NR 5
0.69-0.83
47
277 (0.61)
324 (0.76)
0.79
NR
0.67-0.93
15
Hazard ratio
Increased absolute risk per 10,000 women/year
18
1Mean follow-up time = 5.6 years. 2Conjugated equine estrogen 0.625 mg + medroxyprogesteroneacetate 2.5 mg daily. 3Adjusted 95% CI, confidence interval describes the variabilityof the point estimate corrected for multiple outcome analyses. 4Unadjusted 95% CI, confidence interval describes the variabilityof the point estimate that would arise from a simple trial for a single outcome. SNot reported in updated report. Reported as significant in original manuscript from Women's Health Initiative Estrogen+ Progestin Trial (20). 6CEE+MPA = 8014 subjects; Placebo = 7627 subjects.
CHAPTER 39 Randomized Controlled Trials and the Effects of Postmenopausal Hormone Therapy
TABLE 39.15
557
Women's Health Initiative Estrogen Trial Outcomes
No. of subjects (annualized %)1
Increased absolute benefit per 10,000 women/year
Increased absolute risk per 10,000 women/year
CEE 2 (N = 5310)
Placebo (N = 5429)
Hazard ratio
Adjusted 95% CI 3
Unadjusted 95% CI 4
Coronary heart disease (23)
201 (0.53)
217 (0.56)
0.95
0.76-1.19
0.79-1.16
Stroke (94)
168 (0.45)
127 (0.33)
1.37
NR 5
1.09-1.73
12
Venous thromboembolism (97)
111 (0.30)
86 (0.22)
1.32
NR 5
0.99-1.75
8
Breast cancer (invasive) (100)
104 (0.28)
133 (0.34)
0.806
NR s
0.62-1.04
61 (0.17)
58 (0.16)
1.08
0.63-1.86
0.75-1.55
503 (1.39)
724 (1.95)
0.70
0.59-0.83
0.63-0.79
Outcome
Colorectal cancer (22) Total fractures (22)
3
6 1 56
1Mean follow-up time = 6.8 years for colorectal cancer and total fractures; 7.1 years of follow-up time for other end points. 2Conjugated equine estrogen, 0.625 mg daily. 3Adjusted 95% CI, confidence interval describes the variabilityof the point estimate corrected for multiple outcome analyses. 4Unadjusted 95% CI, confidence interval describes the variabilityof the point estimate that would arise from a simple trial for a single outcome. 5Not reported in updated report. Reported as nonsignificant in original manuscipt from Women's Health Initiative Estrogen Trial (22). 6Total breast cancer incidence statisticallysignificantlyreduced in CEE versus placebo in adherent subjects (hazard ratio -- 0.67, 95% CI, 0.47-0.97). Statistically significant reduction of ductal (most common) breast cancer in subjects randomized to CEE versus placebo (hazard ratio = 0.71, 95% CI, 0.52-0.99) (100). of medications. As demonstrated by W H I , the side effects of C E E + M P A and C E E alone are of small magnitude (less than 1 additional case per 1,000 women) and, according to the World Health Organization Council for International Organization of Medical Sciences (CIOMS), are considered rare (Table 39.16) (106). The side effects are even rarer in women who are within 5 years of menopause or younger than 60 years old when initiating hormone therapy. The development of side effects with any long-term therapy should be kept in perspective, especially those used for the primary prevention of cardiovascular disease. As such, it is highly instructive to view the benefits and side
TABLE 39.16 World Health Organization Council for International Organizations of Medical Sciences frequency of Adverse Drug Reactions Category Very common Common (frequent) Uncommon (infrequent) Rare Very rare
Absolute frequency
Percentage frequency
-> 1/10 -> 1/100- 10% -> 1%-- 1/1000- 1/10,000- 2 cm and/or positive retroperitoneal or inguinal nodes. Growth involving one or both ovaries with distant metastasis. Pleural effusion containing malignant cells. Parenchymal
I
IA IB
IC II IIA IIB IIC
positive retroperitoneal or inguinal nodes
liver metastasis
after any duration of use of estrogen and progestin combination H R T (17). Similar results were reported by Rodriguez et al. (18), who additionally showed an increased risk in former users of ERT for more than 10 years (RR 1.55). Benign gynecologic diseases such as endometriosis (19,20), with an RR of 1.32, have also been linked to a higher risk of developing ovarian cancer, most commonly clear cell and endometrioid types (21). At present, a family history of ovarian cancer is the strongest risk factor for the development of EOC. The RR of E O C for a woman with one first-degree relative with ovarian cancer is 3.1; with two or more affected relatives, it is 12 (22).
B. H e r i t a b l e F a c t o r s About 10% of EOCs are hereditary, with the presently recognized BRCA1 or BRCA2 mutations accounting for 90% of cases and hereditary nonpolyposis colorectal syndrome, or Lynch II syndrome (HNPCC), accounting for the remaining 10% (2,23). The frequency of the BRCA mutation significantly varies among various ethnic groups, with approximately 2% of Ashkenazi Jewish women having one of three founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) (24), as compared with 0.2% of the North American population (23). Of women who develop EOC, 30% to 40% of Ashkenazi Jewish women and 10% to 13% of the North American population will carry the BRCA mutation. BRCA1 and BRCA2 are located on chromosomes 17q21 and 13q12-13 respectively and code large tumor suppressor genes involved in repair of D N A damage, transcriptional regulation of gene expression,
and inhibition of cell proliferation (2). The risk of developing breast cancer with either BRCA1 or BRCA2 mutations ranges from 50% to 85%. The majority of these breast cancers have been shown to be E R / P R and Her 2 neu negative (24a,24b). Women with a BRCA1 mutation have a 30% to 40% lifetime risk of developing E O C and with BRCA2 a 15% to 25% lifetime risk. Mutations within the ovarian cancer cluster region of BRCA2 increase the risk of E O C to 20% and mutations outside this region to 11% (25). Hereditary EOCs are predominantly serous carcinomas, high grade, late stage, nonmucinous or borderline, but have longer overall survival and recurrence-free intervals after chemotherapy (26). The improved response to chemotherapy may be due to the increased sensitivity of BRCAdeficient cells to DNA-damaging agents such as platinum (26). In addition to the increased risk in breast cancer and EOC, BRCA1 mutation carriers have an increased risk of prostate and colon cancer and in those BRCA2 carriers an increased risk of prostate, pancreatic, gallbladder, and
TABLE 43.2. Lifetime Risk of Breast and Ovarian Cancer in BRC/I1 and BRCA2 Mutation Carriers
BRCA1 BRCA2
Breast cancer
Ovarian cancer
50- 85% 50- 85%
30-40% 15-25%
Other malignancies Prostate, colon Pancreatic, gallbladder, melanoma, gastric, male breast cancer
595
CHAPTER 43 Ovarian Cancer and Its Detection gastric cancer, malignant melanoma, and male breast cancer (2). EOC associated with a BRCA1 mutation generally presents at an average age of 51 years compared with BRCA2 mutations and sporadic EOC, which presents later at 57.5 years. With these findings, in 1995 a consensus panel of the National Institutes of Health stated, "The risk of ovarian cancer in women from families with hereditary ovarian cancer syndromes is sufficiently high to recommend prophylactic oophorectomy in these women at 35 years of age or after childbearing is completed" (27). In addition to an increased risk of breast and ovarian cancer, BRCA1 and BRCA2 carriers at time of bilateral salpingo-oophorectomy (BSO) were found to have a higher incidence of fallopian tube cancer (27a,27b). Thus, it is suggested that the entire ovary and fallopian tube be removed, serially sectioned, and pathologically examined (28). Additionally a thorough inspection of the abdomen and pelvis and peritoneal washings are advocated, and directed peritoneal and omental biopsies are our practice whenever any suspicious anomalies are visualized (29). BRCA1 and BRCA2 carriers undergoing a riskreducing BSO decrease their risk of subsequent ovarian and fallopian tube cancer by 99% and breast cancer by 50% to 68%. The incidence of primary peritoneal cancer may be unaffected and has been reported in up to 3% of women after BSO (30-32). Three hereditary syndromes have also been identified as having an increased risk of EOC. They are the Lynch syndrome II associated with HNPCC, hereditary site-specific ovarian cancer, and hereditary breast and ovarian cancer (33).
1. WHO SHOULD BE TESTED?
Individuals with a family history suggestive of an inherited malignancy syndrome or those with a living affected relative should be considered for testing. These include the following individuals: those with a diagnosis of breast or EOC before age 30, those with a significant family history of breast or EOC (one or more affected first-degree relatives), those with a blood relative with a known mutation in BRCA1 or BRCA2, and Ashkenazi women who have breast cancer or EOC or a family history of either. Because approximately 40% of Jewish women with EOC treated at our institutions had a BRCA1 or BRCA2 mutation, we now offer all affected Jewish women formal genetic counseling by board-certified genetic counselors and geneticists and testing when indicated by pedigree analysis. The benefits of genetic testing for the BRC,4 genes include the identification of those individuals at increased risk for the development of breast cancer or EOC, individualizing surveillance measures to enhance early detection of cancer, offering prophylactic surgery such as mastectomy or bilateral salpingooophorectomy (BSO), offering chemopreventatives (such as oral contraceptives or Tamoxifen), enrolling in clinical trials for those at increased risk, and knowledge of the potential
for passing the mutation to future generations (2,34). Genetic testing for BRCA1 and BRCA2 mutations may involve sequencing of the entire coding region of the two genes in families who have not had previous genetic testing or "multisite analysis" with sequencing of specific regions known to have mutated in an affected family member or the sequencing of three known founder mutations in the Ashkenazi Jewish population. Genetic testing for mutations in these genes also has potential risks: adverse psychologic effects, disruption of family dynamics, insurance or employer discrimination, and potential for revealing nonpaternity. Prior to genetic testing it is imperative to assess for whom such testing is appropriate, provide expert genetic counseling on the implications of genetic testing, and obtain individual consent.
2. WHAT TO DO WITH THE GENETIC TEST RESULTS?
The ethical, legal, and psychologic considerations of genetic testing for inherited cancer syndromes are substantial and thus justify the need for expert counseling prior to and appropriate care after the results are available. The American Society of Clinical Oncology (ASCO) and the Ethical, Legal, and Social Issues branch of the Human Genome Project emphasize the importance of expert counseling for genetic testing.
II. S C R E E N I N G FOR EOC To better understand the role of a screening test, a few basic concepts will be reviewed. Sensitivity is defined as the percentage of patients with the disease who are correctly identified by a positive test result. Specificity is the percentage of patients without the disease who are correctly identified by a negative test result. Thus, a test with 98% specificity would result in 50 procedures for every case of EOC detected on screening in postmenopausal women. Positive predictive value (PPV) is the percentage of patients with a positive test result who also have the disease. Negative predictive value is the percentage of patients with a negative test result who do not have the disease. An effective screening test for a relatively rare disease such as ovarian cancer requires a sensitivity greater than 75%, specificity greater than 99.6%, and positive predictive value of more than 10%, although lower specificity may be acceptable in those women appropriately identified to be within the high-risk population. Unfortunately there are no effective screening strategies for the detection of early-stage ovarian cancer. Commonly used modalities include the pelvic exam, transvaginal ultrasound (TVUS), serum marker CA-125, or a combination thereof. Although a pelvic exam has an important role in the gynecologic care of women, Grover et al. (35) found that the bimanual exam has little value as a screening tool for EOC.
596 The TVUS remains the best diagnostic imaging modality to evaluate the adnexa. Ultrasound characteristics associated with an increased risk of ovarian malignancy include the presence of solid components, papillary excrescences, increased ovarian volume incorporated as part of the morphology index (MI) (36), and vascular analysis using tools such as Doppler velocimetry. Although these characteristics may be helpful in determining risk of malignancy, numerous studies have found that TVUS is not effective as a sole screening tool for EOC in asymptomatic women. Van Nagell et al. (37) performed ultrasound on 14,469 asymptomatic women, of which 180 underwent surgery for a persistent ultrasound abnormalities. Seventeen patients were found to have EOC. Four patients developed cancer within 12 months of normal results on screening, and four patients developed cancer more than 12 months after a normal screening. As a screening tool, the positive predictive value of TVUS was 9.4%, with 11 benign tumors removed for every one malignancy detected. Excluding granulosa and borderline ovarian tumors, the PPV of TVUS as a routine screening tool falls below the cutoff of 10%. Fishman et al. (38) recently reported the results of TVUS screening in a cohort of 4526 high-risk women referred to the national ovarian cancer early detection program. High risk was defined by (1) one or more affected first-degree relatives with ovarian cancer; (2) a personal history of breast or ovarian cancer; (3) multiple first- and second-degree relatives with breast or ovarian cancer; (4) BRCA mutation carrier; or (5) membership in a recognized familial cancer syndrome. A total of 12,709 TVUS were performed, with 98 persistent adnexal masses identified. Forty-nine surgeries were performed, resulting in findings of 12 malignancies and 37 benign ovarian masses. The malignancies were classified as four primary peritoneal, four fallopian tube, two EOC, and two endometrial carcinomas. All EOC and fallopian tube malignancies were found at advanced stages (IIIA-IIIC), limiting the use of TVUS as a screening tool for the early detection of EOC. These studies confirm the results of multiple studies suggesting the limited utility of TVUS as a sole screening tool in asymptomatic high-risk women for the accurate detection of early-stage disease. Recent sonographic developments involving improved scanning with harmonics and pulse inversion and the use of contrast agents justify the hope that the sonographic depiction of tumor microvascularity will provide visualization of vascular changes associated with early-stage rather than advanced disease. A variety of tumors markers have been studied for EOC, the most common of which is the CA125. CA125 is a tumor antigen encoding MUC16 first found to be elevated in patients with advanced nonmucinous ovarian cancer (39). A serum level of less than 35 U/mL is often accepted as normal; however, values after hysterectomy and in postmenopausal women may be lower (2). Eighty-five percent of patients with nonmucinous EOC will have elevated levels of CA125. However, approximately 47% of women with stage
GOGOI ET AL.
1 EOC have elevated CA125 levels, compared with greater than 90% with advanced EOC. Complicating the picture is the fact that CA125 can be elevated in many nongynecologic conditions, including pancreatic, breast, colon, and lung cancers; pregnancy; and benign gynecologic conditions, including endometriosis, menstrual cycle, fibroids, salpingitis, and benign ovarian neoplasms. CA125 as a sole screening test in a low-risk population has a sensitivity of 100% and a specificity of 97%, but a positive predictive value of only 2.8%, thus limiting its utility as a single screening tool for EOC (2). However, a CA125 in combination with TVUS increased the PPV of detecting EOC to 26.8% (40). Jacobs et al. (41) further analyzed the value of serial CA125 screening and TVUS. Postmenopausal women were randomized to either three annual screens with CA125 and ultrasound or a control group. Women were followed for 7 years for development of EOC or fallopian tube cancers. The study identified 468 women with an elevated CA125, with 29 undergoing surgery. Six cancers were identified, with a positive predictive value of 20.7%. Thus, although CA125 alone seems to have little efficacy as a screening tool, the combination of CA125 and TVUS is being further investigated in larger randomized clinical trials. Currently the use of CA125 should be limited to surveillance of known EOC, fallopian tube or primary peritoneal malignancies, or as preoperative evaluation of a known pelvic mass. In addition, numerous other tumor markers, including CA19-9, CEA, M-CSF, and LPA, are being evaluated for their role along with CA125 as part of a panel of screening markers for EOC. Ongoing studies evaluating the role of combined screening approaches for EOC include the Prostate, Lung, Colorectal, and Ovarian cancer screening trial (PLCO) enrolling 74,000 women into a control or an intervention arm receiving baseline CA125 and TVUS followed by annual CA125 and every-3-year TVUS screening (41a). Preliminary findings report a PPV of 3.7% for an abnormal CA125, 1% for an abnormal TVUS, and 23.5% if both tests are abnormal. Another ongoing trial is the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which is a randomized trial enrolling women in one of three arms: no screening, annual screen with CA125 followed by ultrasound, or annual ultrasound screening alone. The trial is due to close in 2010 with an estimated 200,000 women enrolling (2).
III. N E W SCREENING MODALITIES Better insights into the biologic basis of cancer and the tumor-host microenvironment have facilitated development of novel screening modalities for EOC. It has been shown that changes in the host proteome may be one of the earliest signs of tumor progression. Tumor cells interacting with the surrounding stroma, extracellular matrix, organ
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CHAPTER 43 Ovarian Cancer and Its Detection
parenchyma, and vascular and immune cells create protein modifications that influence both protein function and response to treatment and may represent a biomarker record of the tumor-host interaction. Using the technique of surface-enhanced laser desorption ionization time of flight (SELDI-TOF), Petricoin et al. (42) analyzed the serum protein profiles of 50 healthy women and 50 women with ovarian cancer. A computer-generated algorithm was derived and subsequently tested on an independent group of 116 samples (50 ovarian cancer cases and 66 control subjects). The algorithm successfully identified all 50 cases of ovarian cancer and 63 of 66 control cases with a PPV of 94% compared with 35% for a CA125. Using similar proteomic technology, Zhang et al. (42a) identified three biomarkers (apolipoprotein A, transthyretin, and a cleavage fragment of inter-el-trypsin inhibitor) that as a panel had a higher sensitivity (74% versus 65%) and equal specificity to that of CA125 alone. Improvements in proteomic technology include the use of serum albumin as a "protein sink" to amplify low abundance and low-molecular-weight proteins, improving mass spectroscopy analysis of the serum proteome. Using sera from 110 patients (40 high-risk patients without cancer, 30 with stage 1, and 40 with stage III), more than 700 peptides were identified from proteins not previously reported to circulate in blood from patients with ovarian cancer (42b). It is hoped that these types of approaches will increase our knowledge of circulating proteins in ovarian cancer patients, allowing further validation of their use as potential biomarkers for EOC. Advances in EOC biology have redefined critical components of the metastatic process~specifically, how cellular adhesion, migration, extraceUular matrix degradation, invasion, proliferation, apoptosis, and neovascularization are all significantly influenced by biologically active lipids such as lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), and lysophosphatidylcholine (LPC). To study the role of LPA as a screening marker for EOC, Xu et al. (43) evaluated LPA levels in patients with ovarian cancer, other gynecologic cancers, benign gynecologic diseases, breast cancers, and leukemias and healthy control subjects. Using a cutoff of 1.31aM, Xu reported elevated plasma LPA levels in 9 of 10 patients with stage I; 24 of 24 patients with stage II, III, and IV ovarian cancer; and 14 of 14 patients with recurrent ovarian cancer. The majority of patients with other gynecologic cancers (33 of 36) also showed elevated LPA levels compared with control subjects. In particular, LPA levels were elevated in 6 of 6 patients with cervical cancer. In contrast, elevated plasma LPA levels were detected in only a minority of healthy control subjects (5 of 48) and patients with benign gynecologic diseases (4 of 18) and in none of the patients with breast cancer (0 of 11) or leukemia (0 of 5). CA125 data from the same group of ovarian cancer patients revealed a substantially lower rate of detection, compared with LPA, especially in stage I. These results suggested that LPA represents a promising marker for the early detection of
ovarian cancer. Other factors showing promise as biomarkers for EOC detection include human kallikrein 6 (hK6) (44,45) and epidermal growth factor receptor (EGFR) (46). Although the incidence of EOC continues to rise in the United States, considerable progress has been made in understanding both the biology and heredity of the disease, advancing screening tools and new methods of treatment. We believe that future progress in early EOC detection lies in understanding the impact of the tumor-host microenvironment and the role of the host in allowing tumor progression. The use and refinement of serum proteomic technology allows new insights into the subtle changes in the proteome that may occur at the onset of tumor progression. We hope that the new knowledge gained through these technologies has continued use for the accurate detection of early stage EOC, targeted therapies, and an overall improvement in women's health care.
References 1. American Cancer Society Facts and Figures 2005. 2. Hoskins WJ. Principlesandpractice ofgynecologic oncology, 4th ed. 2005, Philadelphia: Lippincott Williams & Wilkins, 2005:xix. 3. Gwinn ML, Lee NC, Rhodes PH, Layde PM, Rubin GL. Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemio11990;43:559-568. 4. Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol 1994;140: 585-597. 5. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemio11992;136:1184-1203. 6. The reduction in risk of ovarian cancer associated with oral-contraceptive use. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N EnglJ Med 1987;316:650-655. 7. Epithelial ovarian cancer and combined oral contraceptives. The W H O Collaborative Study of Neoplasia and Steroid Contraceptives.
IntJ Epidemio11989;18:538-545. 7a. Whittemore AS, Balise RR, Pharoah PD, Dicioccio RA, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. BrJ Cancer2004;91:1911-1915. 8. Ness RB, Grisso JA, Klapper J, et al. Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. SHARE Study Group. Steroid Hormones and Reproductions. Am J Epidemio12000;152:233 - 241. 9. Rosenblatt KA, Thomas DB, Noonan EA. High-dose and low-dose combined oral contraceptives: protection against epithelial ovarian cancer and the length of the protective effect. The W H O Collaborative Study of Neoplasia and Steroid Contraceptives. EurJ Cancer1992;28A: 1872-1876. 10. Royar J, Becher H, Chang-Claude J. Low-dose oral contraceptives: protective effect on ovarian cancer risk. IntJ Cancer2001;95:370-374. 11. Depot-medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. The W H O Collaborative Study of Neoplasia and Steroid Contraceptives. IntJ Cancer 1991;49:191-195. 12. Whittemore AS, Wu ML, Paffenbarger RS, et al. Epithelial ovarian cancer and the ability to conceive. CancerRes 1989;49:4047-4052.
598 13. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331: 771-776. 14. Kreiger N, Sloan M, Cotterchio M, Parsons P. Surgical procedures associated with risk of ovarian cancer. IntJEpidemio11997;26:710- 715. 15. Hankinson SE, Hunter DJ, Colditz GA, et al., Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 1993;270:2813-2818. 16. Green A, Purdie D, Bain C, et al. Tubal sterilisation, hysterectomy and decreased risk of ovarian cancer. Survey of Women's Health Study Group. IntJ Cancer 1997;71:948-951. 17. Lacey JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-341. 18. Rodriguez C, Patel AV, Calle EE. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001;285:1460-1465. 19. Ness RB. Endometriosis and ovarian cancer: thoughts on shared pathophysiology. Am J Obstet Gyneco12003;189:280-294. 20. Modugno F, Ness RB, Allen GO, et al. Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis. Am J Obstet Gyneco12004;191:733-740. 21. Van Gorp T, Amant F, Neven P, Vergote I, Moerman P. Endometriosis and the development of malignant tumours of the pelvis. A review of literature. Best Pract Res Clin Obstet Gynaeco12004;18:349-371. 22. Stratton JF, Pharoah P, Smith SK, Easton D, Ponder BA. A systematic review and meta-analysis of family history and risk of ovarian cancer. BrJ Obstet Gynaeco11998;105:493-499. 23. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline B RCA1 and B RCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 2001;68:700- 710. 24. Moslehi R, Chu W, Karlan B, et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer.//m J Hum Genet 2000;66:1259-1272. 24a. Grushko TA, Blackwood MA, Schumm PL, et al. Molecularcytogenetic analysis ofHER-2/neu gene in BRCAl-associated breast cancers. CancerRes 2002;62:1481-1488 24b. Musolino A, Naldi N, Michiara M, Bella MA, et al. A breast cancer patient from Italy with germline mutations in both the BRCA1 and BRCA2 genes. Breast CancerRes Treat 2005;91:203-205. 25. Thompson D, Easton D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet2001 ;68:410- 419. 26. Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.JAM//2000;283:2260-2265. 27. NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. J./IM_/11995;273:491-497. 27a. Carcangiu ML, Peissel B, Pasini B, et al. Incidental carcinomas in prophylactic specimens in B RCA1 and B RCA2 germ-line mutation carriers, with emphasis on fallopian tube lesions: report of 6 cases and review of the literature. Am J Surg Patho12006;30:1222-1230. 27b. Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation.JAMd 2006;296:185-192. 28. Paley PJ, Swisher EM, Garcia RL, et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Onco12001;80:176 -180. 29. Powell CB, Kenley E, Chen LM, et al. Risk-reducing salpingooophorectomy in B RCA mutation carriers: role of serial sectioning in the detection of occult malignancy. J Clin Oncol 2005;23: 127-132.
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30. Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingooophorectomy in women with a BRCA1 or BRCA2 mutation. NEngl JMed 2002;346:1609-1615. 31. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of B RCA1 or B RCA2 mutations. N Engl J Med 2002;346:1616-1622. 32. Rutter JL, Wacholder S, Chetrit A, et al. Gynecologic surgeries and risk of ovarian cancer in women with B RCA1 and B RCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl CancerInst 2003;95:1072-1078. 33. Pharoah PD, Ponder BA. The genetics of ovarian cancer. Best PractRes Clin Obstet Gynaeco12002;16:449-468. 34. Fishman DA, Bozorgi K. The scientific basis of early detection of epithelial ovarian cancer: the National Ovarian Cancer Early Detection Program (NOCEDP). CancerTreat Res 2002;107:3-28. 35. Grover SR, Q.uinn MA. Is there any value in bimanual pelvic examination as a screening test. MedJAust 1995;162:408-410. 36. DePriest PD, Shenson D, Fried A, et al. A morphology index based on sonographic findings in ovarian cancer. GynecolOnco11993;51:7-11. 37. Van Nagell JR Jr, DePriest PD, Reedy MB, et al. The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. GynecolOnco12000;77:350-356. 38. Fishman DA, Cohen L, Blank SV, et al. The role of ultrasound evaluation in the detection of early-stage epithelial ovarian cancer. Am J Obstet Gyneco12005;192:1214-1221; discussion 1221-1222. 39. Bast RC Jr, Klug TL, St John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N EnglJ Med 1983;309:883- 887. 40. Jacobs I, Davies AP, Bridges J, et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. Br MedJ 1993;306:1030-1034. 41. Jacobs IJ, Skates SJ, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999;353:1207-1210. 41a. Buys SS, Partridge E, Greene MH, et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial. Am J Obstet Gyneco12005;193:1630-1639. 42. Petricoin EF, Ardekani AM, Hitt BA, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002;359:572-577. 42a. Zhang Z, Bast RC, Yu Y, Li J, et al. Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 2004;64:5882- 5890. 42b. Lowenthal MS, Mehta AI, Frogale K, et al. Analysis of albuminassociated peptides and proteins from ovarian cancer patients. Clin Chem 2005;51:1933-1945. 43. Xu Y, Shen Z, Wiper DW, et al. Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA 1998;280: 719-723. 44. Ghosh MC, Grass L, Soosaipillai A, Sotiropoulou G, Diamandis EP. Human kallikrein 6 degrades extracellular matrix proteins and may enhance the metastatic potential of tumour cells. TumourBid 2004;25: 193-199. 45. Rosen DG, Wang L, Atkinson JN, et al. Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol Onco12005;99:267- 277. 46. Baron AT, Cora EM, Lafliy JM, et al. Soluble epidermal growth factor receptor (sEGFR/sErbB1) as a potential risk, screening, and diagnostic serum biomarker of epithelial ovarian cancer. CancerEpidemiolBiomarkers Prey 2003;12:103-113.
~HAPTER 4 z
Hormone Replacement Therapy in Menopause and Breast, Colorectal, and Lung Cancer: An Update CARLO LA V E C C H I A
Istituto di Ricerche Farmacologiche "Mario Negri," 20157 Milano, Italy; Istituto di Statistica Medica e Biometria, Universit/l degli Studi di Milano, 20133 Milano, Italy
that reanalysis, menopause HRT increased (discussed earlier) breast cancer risk by about 2.3% per year of use. The effect of steroid hormones is, however, thought to act on the later stages of the process of carcinogenesis (i.e., they are promoters). Consequently, the increased breast cancer risk associated with HRT declines within a few years after stopping use (2-5). An additional question left open by the collaborative reanalysis was the impact on breast cancer risk of the combination of estrogens and progestogens, a therapy effective in reducing the excess endometrial cancer risk associated with estrogen use alone (2). In the American Nurses' Health Study cohort (6) the relative risks (RRs) were 1.3 for estrogens alone, and 1.4 (95% confidence interval [CI] 1.2-1.7) for estrogens plus progestins. Recent studies are reviewed here, including observational (cohort and case-control studies) and randomized controlled trials. A case-control study in Sweden, involving 3345 women with breast cancer, found a trend of increasing risk with duration of different types of combined estrogen-progestin
Hormone replacement therapy (HRT) in menopause has been related to the risk of cancers of the breast, the female genital tract, the large bowel, and the lung. Breast, colorectal, and lung cancers, however, are the key issues on an individual risk and public health level, because no material endometrial cancer risk is related to combined estrogen-progestin treatment, and the possible association between HRT, cervical, and ovarian cancer remains undefined (1,2). This chapter, therefore, will review available knowledge on HRT and breast, colorectal, and lung cancers. Another analysis of the risk of breast cancer can be found in Chapter 40.
I. BREAST CANCER Most data on menopause, HRT, and breast cancer risk available until the mid-1990s were included in a collaborative reanalysis of individual data from 51 epidemiologic studies, based on more than 52,000 women with breast cancer and 108,000 without breast cancer (3,4). According to TREATMENT o r THE POSTMENOPAUSAL W O M A N
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600 use (RR = 2.4 for women treated for at least 10 years) (7). A report on 46,355 participants followed for a mean of 10.2 years in the Breast Cancer Detection and Demonstration Project (8) showed that women who had used combined estrogens and progestins had an RR of 1.4 (95% CI 1.1-1.8) of developing breast cancer compared with neverusers. The risk from combined therapy was greater than that observed with unopposed estrogens (RR = 1.2; 95% CI 1.0-1.4). In that study, too, women who had used H R T in the past but had stopped did not have an increased risk. Likewise, a population-based case-control study of 1897 postmenopausal cases and 1637 postmenopausal population controls from Los Angeles County (9) found an RR of 1.06 (95% CI 0.97-1.15) for each 5 years of estrogen therapy, but of 1.24 (95% CI 1.07-1.45) for combined estrogenprogestin treatment. The excess risk for combined therapy was around 5% per year. In a cohort study of 29,508 women for Sweden, followed up between 1990 and 2001, and including 556 breast cancer cases, the RR was significantly elevated in women who had used continuous combined HRT, and nonsignificant excess risks were also observed among longterm users of combined sequential H R T (RR = 2.2), progestogen only (RR = 3.7), and estriol only (RR = 1.9). No excess risk was observed after 5 years or longer since stopping use (10). Likewise, another cohort study for southern Sweden, including 6586 women and 101 breast cancer cases, found an excess risk (RR = 3.3) for users of combined continuos H R T (11). In a multicentric case-control study of 1870 cases and 1953 controls from the United States, continuous combined H R T was associated with increasing breast cancer risk among users for 3 years or more (RR = 1.5) (12). Mammographic density was also related to combined HRT, more than to estrogens alone, in the Postmenopausal Estrogen/ Progestin Interventions (PEPI) trial (13). Likewise, in the Women's Health Study (14), a prospective investigation of 17,835 women randomized to aspirin and vitamin E (but not to HRT), the RR was 1.0 for ever use of estrogens only but 1.4 for estrogen/progestogen HRT. The RR was 1.8 for continuous progestogen administration. In a case-control study of 975 cases at 1007 controls from Washington State (15), women who had used estrogen replacement therapy (ERT) had no appreciable excess risk of breast cancer, even for 25 years of use or longer. Users of combined HRT, however, had an overall 1.7-fold (95% CI 1.3-2.2) increased risk of breast cancer, including a 2.7-fold increased risk of invasive lobular carcinoma, a 1.5-fold increased risk of ductal carcinoma, and a 2.0-fold increased risk of E R + / P R + breast cancers. The risk increases with increasing duration of use (15). This reflects the observation of a substantial rise in the incidence of lobular cancers in population-based series (16,17).
CARLO LA VECCHIA
In the prospective observational Million Women Study (18), including 9364 incidents of invasive breast cancer, current but not past H R T users were at increased risk (RR = 1.66). The association was stronger for users of estrogen-progestogen preparations (RR = 2.0) but was observed also for estrogens only (RR = 1.3) and tibolone (RR = 1.45). The RRs were increased for oral, transdermal, and implanted formulations. Likewise, in the Danish Nurses cohort study (19), based on 244 breast cancer cases, the RR was 2.0 for estrogens only, 2.7 for estrogen-progestogen, 4.3 for tibolone, and 4.2 for H R T with androgen-like progestins. The RR estimates were not heterogeneous across types of preparations. With reference to intervention studies, relevant information on cancer risk in users of combined H R T derives from the Women's Health Initiative ( W H I ) (20), a randomized controlled primary prevention trial including 8506 women aged 50 to 70 treated with combined H R T and 8102 untreated women. The combined treatment was discontinued in July 2002 when the U.S. National Institutes of Health issued a press release stating that the combination hormone medication used in the trial posed more risks than benefits. This was based on increased risks of invasive breast cancer, cardiovascular disease, stroke, and blood clots. An additional estrogen-only compared with placebo treatment group of the same trial was stopped on March 2, 2004, on the basis of an increased risk of stroke in treated women (21). For the combined H R T treatment, no difference in risk was observed during the first 4 years after starting treatment, but an excess risk of breast cancer was evident thereafter. At a 7-year follow-up, 166 breast cancer cases were registered in the H R T group versus 124 in the placebo group, corresponding to an RR of 1.24 (95% CI 1.03-1.66). In the estrogen-only section of the W H I , based on 10,739 postmenopausal women ages 50 to 79 with prior hysterectomy, at 8-year follow-up, 94 invasive breast cancers were observed in the treated group versus 124 in the placebo group. The corresponding RR was 0.77 (95% CI 0.59-1.01) (22). Data from two other smaller randomized studies are available, one (Heart and Estrogen-Progestin Replacement Study [HERS]) with combined estrogen-progestogen therapy (23), and one (Women's Estrogen for Stroke Trial [WEST]) with estrogen only (24). In a combined analysis of the three randomized trials (25), 205 cases of breast cancer were observed in the treated groups, versus 154 in the placebo one, corresponding to a pooled RR of 1.27 (95% CI 1.03-1.56). Thus, the apparent excess breast cancer risk in H R T users in all four available randomized clinical trials (RCT) (RR = 1.12) is attributable to combined estrogen-progestogen therapy only. Likewise, with relevance to the global index score in the W H I , including vascular disease, breast and colon
CHAPTER 44 Hormone Replacement Therapy in Menopause and Breast, Colorectal, and Lung Cancer: An Update cancer, hip fractures, and death, the estrogen-alone component (RR = 1.01; 95% CI 0.91-1.12) was more favorable than estrogen-progestogen (RR = 1.15; 95% CI 1.03-1.26) (20,22,26). Although H R T has been associated with an increased incidence of breast cancer, its use appeared to lead to improved prognosis in some observational studies. Thus, in the American Cancer Society Cancer Prevention Study II (27), breast cancer mortality did not increase with estrogen use overall, and no excess risk was observed for thin or heavy women. This effect may be due to increased breast cancer surveillance among H R T users. However, in the W H I , invasive breast cancers diagnosed in the estrogen plus progestogen group were similar in histology and grade but were larger and at a more advanced stage. Thus, the results from the W H I did not confirm the suggestion that breast cancers in women using H R T have a more favorable prognosis. Further, after 1 year, the percentage of women with abnormal mammograms was greater in the H R T group (28). Likewise, in the Million Women study, there was no consistent suggestion that prognostic indicators were more favorable among women who had ever used H R T (18). In conclusion, the evidence from observational epidemiologic studies (cohort and case-control), as well as from randomized clinical trials, indicates that the risk of breast cancer (mainly lobular cancer) is elevated among women using (combined) HRT, increases with longer duration of use, is reduced after cessation of use, and levels off after stopping use. Prognosis does not appear to be more favorable in women who had used HRT.
II. COLORECTAL CANCER Colorectal cancer is the most common cancer in nonsmokers of both sexes combined and the second leading cause of cancer death for both sexes combined in western countries (29,30). A male predominance in colorectal cancer mortality was found in most countries of the world, except a few Latin American ones, such as Cuba or Colombia (31). During the 1980s and early 1990s, mortality trends from colorectal cancer have been more favorable in women than in men in Europe (32). This may be due to healthier dietary and lifestyle patterns in women, but also to a potential protective effect of exposure to exogenous female hormones (i.e., H R T and perhaps oral contraceptives) (33-35). However, data on reproductive and menstrual correlates of colorectal cancer risk are inconclusive. Moderate inverse associations with parity and oral contraceptive use have been reported, but a possible favorable role of later age at menopause is unclear (36-42). In the Framingham study (43), higher bone mass, which is likely related to greater
601
cumulative estrogen exposure, was associated to a reduced risk of colorectal cancer. Some reviews and meta-analyses, including data from several observational studies until 1998 (1,33,44-47), estimated an approximately 20% reduced risk of colorectal cancer among H R T users. Several biologic hypotheses supporting such an inverse association were postulated. Female hormones may confer a protection against colorectal cancer as a result of changes in bile synthesis, which may lead to reduced concentration of bile acids in the colon (48,49). Estrogens inhibit the growth of colon cancer cells in vitro, and estrogen receptors have been identified in normal and neoplastic colon epithelial cells. The estrogen receptor (ER) gene may play a tumor suppressor role, because the hypermethylation of the promotor region of the ER gene results in a reduced expression and deregulated growth in colonic mucosa, and has been associated with apoptosis (50). Estrogens have been associated with reduced risk of microsatellite instability positive colon cancer (51). Estrogens may also reduce serum levels of insulin-like growth factor-1 (IGF-1), a mitogen that may play an important role in the pathophysiology of colorectal and other cancers (46,52). Between 1980 and 2000, use of combined H R T had increased among postmenopausal women in western countries: An estimated 20 million women worldwide were using H R T in the early 2000s (4,25). With the publication of several trials of H R T (particularly the Women's Health Initiative) showing excess vascular mortality among users, the prevalence of H R T use has substantially declined over the last few years in the United States (53,54) and probably in Europe as well. It is therefore useful to update the results of observational studies and randomized clinical studies on H R T and colorectal cancer published over the last few years. At least nine cohort studies (Table 44.1) reported information on H R T use and colorectal cancer risk, including a total of more than 2500 cases (2). Most studies showed relative risks around or below unity. A significant inverse association was found in two cohort investigations, including the largest one, focusing on fatal colon cancers. Two studies also suggested that H R T use may improve shortterm survival after a diagnosis of colon cancer (55,56). Table 44.2 considers case-control investigations. O f 14 case-control studies for a total of more than 6000 cases, 5 reported 20% to 40% risk reductions among ever-users of HRT. Two additional investigations showed moderate, nonsignificant inverse associations. Studies showing an inverse association between H R T and colorectal cancer were among the largest ones. Differences in RRs by duration of H R T use and anatomic subsite were not consistent, but the apparent protection tended to be stronger among recent users. Therefore, available observational
USA, Nurses' Health Study
Iowa, USA
USA, Cancer Prevention Study II
Chute et al., 1991 (84) and Grodstein et al., 1998 (62)
Bostick et al., 1994 (85) and Folsom et al., 1995 (86) Calle et al., 1995 (63)
Finland
Pukkala et al., 2001 (90)
7,701 (14.5 years) 249 66
59,002 (14 years) 47O
Long cycle HRT Monthly cycle HRT
Unopp. HRT Opposed HRT Any HRT
Former users Current users
Current users Past users
Opposed HRT Any type
Estriol
HRT
0.81 (0.63-1.04)
0.99 (0.79-1.2)
1.0 (0.7-1.5)
0.8 (0.7-1.1)
(0.5 -0.8)
0.7
1.00 (ns)
Colon-rectum
0.85 (0.63-1.1) 0.67 (0.34-1.2)
1.1 (0.7-1.5) 1.4 (0.7-2.5) 1.1 (0.81-1.6) 0.70 + (0.45-1.09)
1.3 (0.9-1.9)
0.8 (0.6-1.1) 0.7 (0.5-1.1) 0.7 (0.6-0.8)
0.9 (0.7-1.1) 1.0 (0.8-1.3) 0.6 (0.4-1.0) 0.9 (0.7-1.2) 0.6 (0.5-0.9) 0.9 (0.7-1.1)
Colon
1.1 (0.59-1.9) 0.52 + (0.21-1.31)
1.2 (0.7-2.3)
0.6 (0.3-1.2)
0.9 (0.7-1.2) 0.8 (0.5-1.2) 0.8 (0.4-1.3) 0.9 (0.7-1.1) 0.7 (0.4-1.1) 0.8 (0.5-1.2)
Rectum
Relative risk, RR (95% confidence interval) (ever- vs. never-users)
RR = 0.75 for -> 5-year use
Significant trend (RR for > 11 year use = 0.5; 95% CI 0.4-0.8) RR = 0.7 (0.2-2.6) for -> 5-year use No effect
Inverse trend (RR = 0.31 for -5-year use 0.7; 95% CI 0.5-1.0)
No effect (RR -> 8 year use = 1.02; 95% CI 0.6-1.8) No effect
Duration of use
RR for recent use = 0.66 (0.44-0.98)
RR for recent use = 0.78 (0.55,1.1)
Stronger effect among current users (RR = 0.5, 0.4-0.8) Not shown
No effect
0.8-~.2)
No risk reduction after 5 years of discontinuation (RR = 0.9;
Not shown
Not shown
Recency of use
Cohort Studies of H o r m o n e Replacement Therapy and Colorectal Cancer
BCDDP, Breast Cancer Detection Demonstration Project; BMI, body mass index; ns, not significant; W/H, waist/hip ratio; OC, oral contraceptives; +, recent users (- 6-year use: 1.0 (0.6-1.6)
Current users: Former users:
0.5 (0.3-0.9) 0.6 (0.4-0.8)
15 years North America
206:618 (neighbors)
China
Gerhardsson de Verdier and London, 1992 (98)
Sweden
299:276 (population)
Jacobs et al., 1994 (38)
Seattle, USA
148:138 (population)
Newcomb and Storer, 1995 (57)
Wisconsin, USA
694:1622 (population)
1.5 (0.8-2.7) 1.1 (0.7-1.9)
1.3 (0.9-2.0) 1.1 (0.6-1.8) 1.1 (0.6-1.9)
Unopposed HRT Opposed HRT Any HRT (recent use)
Kampman et al., 1997 (99)
USA, KPMC
815:1019 (KPMC members)
Yood et al., 1998 (100)
Detroit, USA
60:143 (HMO members)
Jacobs et al., 1999 (101)
Seattle, USA
341:1679 HMO
Prihartono et al., 2000 (102)
Massachusetts, USA
404:404 population
Csizmadi et al., 2004 (59)
Saskatchewan, Canada
1197:4669 population
Current use Past use
0.3 (0.1-1.0) 0.4 (0.1-1.4) -1.0
Oral Transdermal
0.82 (0.70-0.97) 0.40 (0.39-0.9)
BMI, body mass index; HMO, health maintenance organization; KPMC, Kaiser Permanente Medical Care; OC, oral contraceptives.
confidence interval) (ever- vs. never-users) Colon
Rectum
0.8 (0.4-1.5)
--
0.6 (o.5-o.9)
Duration of use
Recency of use
Adjustment and comments
No trend
Not shown
Age
1.5 (0.8- 3.0)
0.2 (o.o-o.8)
0.5 (0.3-0.7)
Not shown
Not shown
No trend Significant (RR for -> 2-year use = 0.5; 0.3-0.8)
Not shown RR -> 10 years since last use: 0.5; 0.3-1.0
No effect
Not shown
Cancer family history, parity, menopause, exercise, fat, alcohol, and calcium intake
Unadjusted (but unaltered by exercise, saturated fat intake, and years in the U.S.) Artificial menopause was a risk factor in China Age Hormone use included both HRT and OC, but mostly HRT Age, vitamin intake and hysterectomy. Greater protection in multiparous women Age, alcohol, BMI, cancer family history, and sigmoidoscopy
2.1 p = 0.14 2.9 p = 0.01
0.5 p = 0.23 p = 0.56
Not shown Mostly shortduration use
Not shown
0.6 (0.4-1.0)
0.7 (0.4-1.3)
No trend
Not shown
Significant trend (RR -> 5-year use = 0.5; 0.2-0.9) Significant trend (p = 0.002)
RR in current users = 0.5; 0.3-1.0
0.6 (0.4-1.0)
0.5 (0.3-0.9) 0.5 (0.3-1.1) o.7 (0.6-0.9) (recent use)
0.90 (0.46-1.76) 1.1 (0.5-2.5) 1.2 (0.8-1.6) (recent use)
0.8 (0.7-1.0)
0.8 (0.5-1.2)
1.7 (0.8-3.6)
Reproductive variables (diet was uninfluent Age and parity. No distinction was possible between HRT and OC use Age, parity, hysterectomy Age, education, cancer family history, BMI, parity, menopause, OC, and energy intake
Lower RR for < 10 years since last use = 0.5; 0.4-0.8, for colon
No trend (RR -> 10 yr use = 0.86) Not shown
RR for recent use = 0.71, (0.56-0.89) Not shown
No trend in risk
No association with recent use RR = 0.6 of colon cancer among recent users For >- 3 years use RR 0.75 for oral, 0.33 for transdermal
Age, cancer family history, aspirin and energy intake, OC, and exercise Age, race, reproductive variables, dietary habits, and colonoscopy Age Fat, fruit, vegetable intake; physical exercise; colorectal cancer screening Age
606 In conclusion, available data from randomized clinical trials do not support the use of combined H R T nor of estrogen alone to reduce colorectal cancer mortality.
III. LUNG CANCER Lung cancer is the leading cause of cancer mortality among women in the United States (31), and mortality from lung cancer in women has been substantially increasing across Europe over the last few decades (73). Thus, any influence of H R T on lung cancer risk would be of major public health importance. Epidemiologic data on H R T and lung cancer risk have therefore been updated here (1,2). A cohort study in Sweden of 23,244 women followed for 6.7 years suggested a moderate excess risk of lung cancer associated with use of estrogens (RR = 1.3; 95% CI 0.9-1.7) (74). No information was available on duration of use or any other risk factors. Two case-control studies from the United States have examined the relation of H R T use to risk of adenocarcinoma of the lung. A hospital-based casecontrol study of 181 cases found a 70% excess risk associated with estrogen replacement therapy, with the RR increasing twofold for smokers of 25 or more years (75). However, residual confounding by smoking remains possible, and in another population-based case-control study from Los Angeles County, California, including 336 cases, no significant relation was found between H R T use and lung cancer risk (RR 1.3; 95% CI 0.7-2.2) (76). Likewise, in a multicentric U.S. case-control study including 662 women with lung cancer and 4621 control subjects, the RR was 1.0 (95% CI 0.7-1.4) for E R T use, and also 1.0 for users of conjugated estrogens only, in the absence of any consistent trend with duration or any other time factors (77). In a population-based case-control study of 811 lung cancer cases 912 and controls from Germany, the RR for ever H R T use was 0.69 (95% CI 0.57-0.92), but again no relation was evident with duration, age at first use, and calendar year of use (78). In a cohort study of 28,508 women ages 25 to 65 from Sweden followed-up between 1990 and 1999, a nonsignificant decreased risk of lung cancer (RR = 0.73) was observed, although the risk of all tobacco-related neoplasms was significantly reduced (RR = 0.24) (79). In a case-control study of 499 lung cancer cases and 519 population controls from Texas, the multivariate RR was 0.66 (95% CI 0.51-0.89) for ever H R T use. The risk was significantly reduced in current, moderate smokers only and in a subgroup of genetically susceptible women (80), although the definition of susceptibility remains open to discussion. In the W H I randomized clinical trial (20), combined estrogen H R T was unrelated to lung cancer risk (RR = 1.04; 95% CI 0.71-1.53).
CARLO LA VECCHIA
Thus, taken together, observational studies and the limited available evidence from randomized clinical trials do not show any consistent association between H R T and lung cancer risk, because there are a similar number of studies showing RRs about unity, no association, or RRs below unity. The absence of material association between H R T and lung cancer risk is plausible, because it is now clear that women are not more susceptible to lung cancer than men for similar level of smoking (81,82), thus indicating that female hormones do not have a relevant role in lung carcinogens. Indeed, given the prominent role of tobacco smoking in lung cancer, minor differences in quantity or duration of smoking may have caused differences in risk as those observed in several studies between H R T users and nonusers.
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CHAPTER 44 H o r m o n e Replacement Therapy in Menopause and Breast, Colorectal, and Lung Cancer: An Update 15. Li C, Malone ICE, Porter PL, et al. Relationship between long durations and different regiments of hormone therapy and risk of breast cancer. JAMA 2003;289:3254- 3263. 16. Verkooijen HM, Fioretta G, Vlastos G, et al. Important increase of invasive lobular breast cancer incidence in Geneva, Switzerland. Int J Cancer 2003;104:778- 781. 17. Levi F, Te V-C, Randimbison L, La Vecchia C. Increase in lobular breast cancer incidence in Switzerland. Int J Cancer 2003;107: 164-165. 18. Million Women Study Collaborators. Breast cancer and hormonereplacement therapy in the Million Women Study. Lancet 2003;362: 419-427. 19. Stahlberg C, Pedersen AT, Lynge E, et al. Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe. IntJ Cancer 2004;109:721-727. 20. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321 - 333. 21. Powledge TM. NIH terminates W H I oestrogen-only study. Lancet 2004;363:870. 22. Women's Health Initiative Steering Committee. Effect of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701 - 1712. 23. Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66. 24. Viscoli CM, Brass LM, Kernan WN, et al. A clinical trial of estrogenreplacement therapy after ischemic stroke. N Engl J Med 2001;345: 1243 - 1249. 25. Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 2002;360: 942-944. 26. Hulley SB, Grady D. The W H I estrogen-alone trial. Do things look any better? JAMA 2004;291:1769-1771. 27. Rodriguez C, Calle EE, Patel AV, et al. Effect of body mass on the association between estrogen replacement therapy and mortality among elderly US women. Am J EDidemio12001;153:145-152. 28. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAAdA 2003;289:3243-3253. 29. Parkin DM, Bray F, Ferlay J, Pisani R Estimating the world cancer burden: Globocan 2000. IntJ Cancer 2001;94:153-156. 30. Levi F, Lucchini F, Negri E, Boyle P, La Vecchia C. Cancer mortality in Europe, 1995-1999, and an overview of trends since 1960. Int J Cancer 2004;110:155-169. 31. Bosetti C, Malvezzi M, Chatenoud L, et al. Trends in cancer mortality in the Americas, 1970-2000. Ann Onco12005;16:489-511. 32. Fernandez E, Bosetti C, La Vecchia C, et al. Sex differences in colorectal cancer mortality in Europe, 1955-1996. EurJ Cancer Prev 2000a; 9:99 - 104. 33. Fernandez E, Franceschi S, La Vecchia C. Colorectal cancer and hormone replacement therapy: a review of epidemiological studies. J Br Menop Soc 2000;6:8-14. 34. Fernandez E, La Vecchia C, Balducci A, et al. Oral contraceptives and colorectal cancer risk: A meta-analysis. BrJ Cancer 2001;84:722-727. 35. Fernandez E, Gallus S, Bosetti C, et al. Hormone replacement therapy and cancer risk: a systematic analysis from a network of case-control studies. IntJ Cancer 2003;105:408-412. 36. Negri E, La Vecchia C, Parazzini F, et al. Reproductive and menstrual factors and risk of colorectal cancer. CancerRes 1989;49:7158-7161. 37. La Vecchia C, Franceschi S. Reproductive factors and colorectal cancer. Cancer Causes Control 1991;2:193-200.
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38. Jacobs EJ, White E, Weiss NS. Exogenous hormones, reproductive history, and colon cancer (Seattle, Washington, USA). Cancer Causes Control 1994;5:359-366. 39. Martinez ME, Grodstein F, Giovannucci E, et al. A prospective study of reproductive factors, oral contraceptive use, and risk of colorectal cancer. CancerEDidemiol Biomarkers Prev 1997;6:1-5. 40. Talamini R, Franceschi S, Dal Maso L, et al. The influence of reproductive and hormonal factors on the risk of colon and rectal cancer in women. EurJ Cancer 1998;34:1070-1076. 41. Franceschi S, Gallus S, Talamini R, et al. Menopause and colorectal cancer. BrJ Cancer 2000;82:1860-1862. 42. Van Wayenburg C, van der Schouw YT, van Noord PA, Peetersw PHM. Age at menopause, body mass index, and the risk of colorectal cancer mortality in the Dutch Diagnostich Onderzoek Mammacarcinoom (DOM) cohort. Epidemiology 2000;11:304- 308. 43. Zhang Y, Felson DT, Ellison RC, et al. Bone mass and the risk of colon cancer among postmenopausal women. Am J Epidemiol 2001;153: 31-37. 44. Franceschi S, La Vecchia C. Colorectal cancer and hormone replacement therapy: an unexpected finding. EurJ Cancer 1998;7:427-438. 45. H6bert-Croteau N. A meta-analysis of hormone replacement therapy and colon cancer among women. Am J Epidemiol 1998;147(suppl): $87 (Abs 345). 46. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. AmJMed 1999;106:574-582. 47. Nanda K, Bastian LA, Haselblad V, Simel SL. Hormone replacement therapy and the risk of colorectal cancer: a meta-analysis. Obstet Gynecol 1999;93:880-888. 48. McMichael AJ, Potter JD. Host factors in carcinogenesis: certain bileacid metabolic profiles that selectively increase the risk of proximal colon cancer. J Natl CancerInst 1985;75:185-191. 49. Costarelli V, Key TJ, Appleby PN, et al. A prospective study of serum bile acid concentrations and colorectal cancer risk in post-menopausal women on the Island of Guernsey. BrJ Cancer 2002;86:1741-1744. 50. Carothers AM, Hughes SA, Ortega D, Bertagnolli MM. 2Methoxyestradiol induces p53-associated apoptosis of colorectal cancer cells. CancerLett 2002;187:77-86. 51. Slattery ML, Potter JD, Curtin K, et al. Estrogen reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. CancerRes 2001;61:126-130. 52. Manousos O, Souglakos J, Bosetti C, et al. IGF-I and IGF-II in relation to colorectal cancer. IntJ Cancer 1999;83:15-17. 53. Buist DS, Newton KM, Miglioretti DL, et al. Hormone therapy prescribing patterns in the United States. Obstet Gynecol 2004;104: 1042-1050. 54. Majumdar SR, Almasi EA, Stafford RS. Promotion and prescribing of hormone therapy after report of harm by the Women's Health Initiative, WHI. JAMA 2004;1983-1988. 55. Slattery ML, Anderson K, Samowitz W, et al. Hormone replacement therapy and improved survival among postmenopausal women diagnosed with colon cancer (USA). Cancer Causes Control 1999;10: 467-473. 56. Mandelson MT, Miglioretti D, Newcomb PA, Harrison R, Potter JD. Hormone replacement therapy in relation to survival in women diagnosed with colon cancer. Cancer Causes Control2003;14:979-984. 57. Newcomb PA, Storer BE. Postmenopausal hormone use and risk of large-bowel cancer. J Natl CancerInst 1995;87:1067-1071. 58. Persson I, Yuen J, Bergkvist L, et al. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy-long-term follow-up of a Swedish cohort. IntJ Cancer 1996; 67:327-332.
608 59. Csizmadi I, Collet J-P, Benedetti A, Boivin J-F, HanleyJA. The effects of transdermal and oral oestrogen replacement therapy on colorectal cancer risk in postmenopausal women. BrJ Cancer 2004;90:76-81. 60. Curtin K, Bigler J, Slattery ML, et al. MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer. CancerEpidemiol Biomarkers Prev 2004;13:285-292. 61. Fernandez E, La Vecchia C, Braga C, et al. Hormone replacement therapy and risk of colon and rectal cancer. CancerEpidemiol Biomarkers Prev 1998;7:329-333. 62. Grodstein F, Martinez E, Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med 1998;128:705-712. 63. Calle EE, Miracle-McMahill HL, Thun MJ, et al. Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. JNatl Cancer Inst 1995;87:517- 523. 64. Day NE. Epidemiology: the role of multi-stage models. Cancer Surv 1983;2:579-593. 65. Sturgeon SR, Schairer C, Brinton LA, et al. Evidence of a healthy estrogen user survivor effect. Epidemiology 1995;6:227-231. 66. Barrett-Connor E. Postmenopausal estrogen and prevention bias. _~Inn Intern Med 1991;115:455-456. 67. Hemminki E, Kennedy DL, Baum C, et al. Prescribing of noncontraceptive estrogens and progestins in the United States, 1974-86. Am J Public Health 1988;78:1479-1481. 68. Parazzini F, La Vecchia C, Negri E, et al. Determinants of estrogen replacement therapy use in northern Italy. Rev Epidem et Santg Publ 1993;41:53-58. 69. Chiaffarino F, Parazzini F, La Vecchia C, et al. Correlates of hormone replacement therapy use in Italian women, 1992-1996. Maturitas 1999;33:107-115. 70. Csizmadi I, Collett J-P, Boivin J-F, Hanley JA, Benedetti A. Healthrelated behavior and the use of hormone replacement therapy. Pharmacoepidemiol Drug Saf2004;13:65- 71. 71. La Vecchia C, Franceschi S. Hormone replacement therapy and cancer: an update. EurJ Cancer Prev 2003;12:3-4. 72. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N EnglJ Med 2004;350:991 - 1004. 73. Borras JM, Fernandez E, Gonzalez JR, et al. Lung cancer mortality in European regions (1955-1997). Ann Onco12003;14:159-161. 74. Adami H-O, Persson I, Hoover R, et al. Risk of cancer in women receiving hormone replacement therapy. IntJ Cancer 1989;44:833-839. 75. Taioli E, Wynder EL. Re: Endocrine factors and adenocarcinoma of the lung in women.JNatl CancerInst 1994;86:869-870. 76. Wu AH, Yu MC, Thomas D e , et al. Personal and family history of lung disease as risk factors for adenocarcinoma of the lung. CancerRes 1988;48:7279- 7284. 77. Blackman JA, Coogan PF, Rosenberg L, et al. Estrogen replacement therapy and risk of lung cancer. Pharmacoepidemiol Drug Saf 2002; 11:561-567. 78. Kreuzer M, Gerken M, Heinrich J, Kreienbrock L, Wichmann HE. Hormonal factors and risk of lung cancer among women? IntJEpidemiol 2003;32:263-271. 79. Olsson H, Bladstrom A, Ingvar C. Are smoking-associated cancers prevented or postponed in women using hormone replacement therapy? Obstet Gyneco12003;102:565-570. 80. Schabath MB, Wu X, Vassilopoulou-Sellin R, Vaporciyan AA, Spitz MR. Hormone replacement therapy and lung cancer risk: a case-control analysis. Clin CancerRes 2004;10:113-123. 81. Bain C, Feskanich D, Speizer FE, et al. Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst 2004;96:826- 834. 82. Blot WJ, McLaughlin JK. Are women more susceptible to lung cancer? J Natl Cancer Inst 2004;96:812-813.
CARLO LA VECCHIA 83. Wu AH, Paganini-Hill A, Ross RK, et al. Alcohol, physical activity and other risk factors for colorectal cancer: a prospective study. BrJ Cancer 1987;55:687-694. 84. Chute CG, Willett WC, Colditz GA, et al. A prospective study of reproductive history and exogenous estrogens on the risk of colorectal cancer in women. Epidemiology 1991;2:201-207. 85. Bostick RM, Potter JD, Kushi LH, et al. Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States). Cancer Causes Control 1994;5:38-52. 86. Folsom AR, Mink PJ, Sellers TA, et al. Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women. Am J Public Health 1995;85:1128 - 1132. 87. Risch HA, Howe GR. Menopausal hormone use and colorectal cancer in Saskatchewan: a record linkage cohort study. CancerEpidemiol Biomarkers Prev 1995;4:21-28. 88. Troisi R, Schairer C, Chow W-H, et al. A prospective study of menopausal hormones and risk of colorectal cancer (United States). Cancer Causes Control 1997;8:130-138. 89. Paganini-Hill A. Estrogen replacement therapy and colorectal cancer risk in elderly women. Dis Colon Rectum 1999;42:1300-1305. 90. Pukkala E, Tulenheimo-Silfvast A, Leminen A. Incidence of cancer among women using long versus monthly cycle hormonal replacement therapy, Finland 1994-1997. Cancer Causes Control 2001;12: 111-115. 91. Weiss NS, Daling JR, Chow WH. Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors. J Natl CancerInst 1981;67:57-60. 92. Potter JD, McMichael AJ. Large bowel cancer in women in relation to reproductive and hormonal factors: a case-control study. J Natl Cancer Inst 1983;71:703- 709. 93. Davis FG, Furner SE, Persky V, et al. The influence of parity and exogenous female hormones on the risk of colorectal cancer. Int J Cancer 1989;43:587-590. 94. Furner SE, Davis FG, Nelson RL, et al. A case-control study of large bowel cancer and hormone exposure in women. Cancer Res 1989;49: 4936-4940. 95. Fernandez E, La Vecchia C, D'Avanzo B, et al. Oral contraceptives, hormone replacement therapy and the risk of colorectal cancer. BrJ Cancer 1996;73:1431-1435. 96. Peters RK, Pike MC, Chang WWL, et al. Reproductive factors and colon cancers. BrJ Cancer 1990;61:741 - 778. 97. Wu-WiUiams AH, Lee M, Whittemore AS, et al. Reproductive factors and colorectal cancer risk among Chinese females. Cancer Res 1991;51:2307- 2311. 98. Gerhardsson de Verdier M, London S. Reproductive factors, exogenous female hormones, and colorectal cancer by subsite. Cancer Causes Control 1992;3:355-360. 99. Kampman E, Potter JD, Slattery ML, et al. Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, casecontrol study in the United States. Cancer Causes Control 1997; 8:146-158. 100. Yood SM, Ulcickas Yood M, McCarthy B. A case-control study of hormone replacement therapy and colorectal cancer. Ann Epidemiol 1998;8:133. 101. Jacobs EJ, White E, Weiss NS, et al. Hormone replacement therapy and colon cancer among members of a health maintenance organization. Epidemiology 1999;10:445-451. 102. Prihartono N, Palmer JR, Louik C, Shapiro S, Rosenberg L. A casecontrol study of use of postmenopausal female hormone supplements in relation to the risk of large bowel cancer. Cancer Epid Biomarkers Prey 2000;9:443-447.
SECTION IX
Clinical Trials and Observational Data This section deals with differences between randomized clinical trial (RCT) data and those derived from observational studies such as the Nurse's Health Study (NHS), the Leisure World Cohort, and so on. In so doing a discussion emanates on the overall risk-benefit equation for the use of hormones after menopause. In previous editions of this book a specific chapter was written on the cost-benefit analysis of hormonal therapy. Because the field is still somewhat unsettled after the publication of the recent randomized controlled trials (RCTs), and there is no clear consensus regarding who should be treated with hormones after menopause, that chapter has been omitted from this section. As will be pointed out in this section, there is remarkable agreement between the results of the observational data and the various RCTs. Only in two areas are the data discrepant; namely, coronary disease and dementia. The latter differences may be explained by the ages of the patients when treated, as pointed out by many authors in this book. (See the Section VII, on cardiovascular disease, and Section V, on brain function.) Nevertheless, there is no denying that certain intrinsic biases occur in observational studies that may affect the results to a varying degree. It is important, however, to point out that a good study is a good study and there is no reason to "trash" all studies that are not RCTs. Indeed, it has been shown that the results of RCTs and observational trials are largely in full agreement (1,2). Further, RCTs themselves also have intrinsic biases and problems. These concerns include problems of blinding (particularly hormonal studies in women where bleeding may occur), unique characteristics of women willing to be randomized in long trials, the socioeconomic status of many trial participants seeking "free care," and an overrepresentation of obese subjects in such trials. Perhaps for me the greatest concern regarding RCTs is the issue of poor external validity. It is very difficult and potentially erroneous in my view to extrapolate the findings of any given RCT, in one population and with one treatment regimen, to the entire population of women and to other potential treatment regimens within the same class. It has been said many times before, but first by the late Trudy Bush, "No single study has a monopoly on the truth." In this section, Margery L.S. Gass, a W H I investigator, reviews the recent findings in the various W H I trials. Next, Karin B. Michels and JoAnn E. Manson, who was an investigator in both W H I and the NHS, point out differences between observational data and RCTs, and offer possible explanations for the discrepancy. Finally, Annlia Paganini-Hill, who represents the rich experience of the Leisure World cohort study, discusses this issue and expands the discussion to an overall risk-benefit assessment.
References 1. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342: 1878-1886. 2. ConcatoJ, Shah N, Horwitz RI. Randomized,controlled trials, observationalstudies, and the hierarchy of research designs. N EnglJ Med 2000;342:1887-1892.
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~ H A P T E R 4_
The Women's Health Data nlt atlve and Discussion 9
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MARGERY L.S. GASS ClinicalObstetrics and Gynecology,University of Cincinnati College of Medicine, Cincinnati, OH 45267
I. B A C K G R O U N D
II. W H I H O R M O N E T H E R A P Y TRIAL
The Women's Health Initiative is a large, intricately designed multisite study sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health. The overarching purpose of the Women's Health Initiative (WHI) was to evaluate the efficacy and safety of three commonly used preventive health interventions: postmenopausal hormone therapy, low-fat diet, and calcium plus vitamin D supplementation (Fig. 45.1). All three W H I trial interventions were potentially beneficial for the majority of postmenopausal women regardless of age. Further, because all major outcomes of the study are more common with aging, it was important to include the older, more susceptible population for greater power in the data analysis. Healthy women ages 50 to 79 were enrolled. Women thought likely to discontinue the study (e.g., poor health, severe vasomotor symptoms, or likely to move from the area) were excluded. A detailed explanation of the rationale for the study design has been published (1). T R E A T M E N T OF T H E P O S T M E N O P A U S A L W O M A N
The trend in hormone therapy (HT) use at the time the W H I was designed in 1991 was to recommend H T for an expanding list of potential health benefits. The United States Food and Drug Administration (FDA) approved many estrogen products for the treatment of vasomotor symptoms, vulvovaginal atrophy, and the prevention of osteoporosis. There were recommendations for long-term use of H T for bone protection (2). Well-designed clinical trials demonstrated efficacy for the treatment of vasomotor symptoms and vulvovaginal atrophy and for preservation of bone mineral density. In the absence of fracture data, however, the FDA withdrew the indication for treatment of osteoporosis. A variety of trials and studies suggested that H T might protect against cardiac disease and dementia, as well as improve bone mineral density in older women who already had osteoporosis (3-8). See other chapters in this book for the scientific data that accumulated on the use of H T for these health conditions after the W H I had been designed. 611
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161,809women age 50-79 ] [ H0rm0neTria127,347] f ~ w F a t D i e t ] Estrogen+Progestin 16,608 1 | Trial EstrogenAlone 10,739,J l, 48,836
Calcium Vitamin D Trial Enrolled at Years 1 and
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information to the medical community, the participants, and the public as promptly as possible (10,11). This rapid publication necessitated using the database before health outcomes from the last few months of the trial had been entered. Subsequent publications focused more narrowly on specific endpoints and took advantage of the completed database. The different databases account for slightly different figures in the later papers.
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FIGURE 45.1 Overviewof the Women's Health Initiative.Total clinical trial (CT) included 68,133 subjects; 11.8% of the CT enrolled in both the Hormone Therapy (HT) and Dietary Modification (DM) Trials; 37% of the CT enrolled in the DM and Calcium Vitamin D (CAD)Trials; 23.6% of the CT enrolled in the HT and CaD Trials; 7.3% of the CT enrolled in all three arms of the CT.
To assess the role of hormone therapy as a preventive health measure, the most widely prescribed hormones in the United States were selected: conjugated equine estrogens 0.625 mg (CEE) and medroxyprogesterone acetate (MPA). A daily regimen of 2.5 mg of MPA was chosen over the higher cyclic dose in an effort to reduce the amount of uterine bleeding, the most common reason for discontinuing HT, especially in older women (9). Another consideration in selecting the regimen was the concern that the new onset of cyclic bleeding would unblind the participants to the fact that they had received the active study drug. The doubleblind aspect of the study would have been undermined with a cyclic regimen. The H T trial had two arms with different treatment regimens: estrogen therapy (ET) for women who had undergone hysterectomy and estrogen plus progestogen therapy (EPT) for those who had not undergone hysterectomy. The primary endpoints for the two H T arms were coronary heart disease and breast cancer. Secondary endpoints included hip and other osteoporotic fractures, other cardiovascular events, and other cancers. A data and safety monitoring board of independent experts who were not involved in the trial met every 6 months to review the accumulated data and to determine if either the benefits or the risks were of sufficient magnitude to stop the trial before the designated 8.5 years were completed. The E P T and the E T intervention phases were both stopped earlier than planned, albeit at different times and for different reasons. The E P T intervention was discontinued in July 2002 because an elevated occurrence of breast cancer reached a predetermined safety stopping point. The intervention phase of the E T arm was stopped in February 2004 because of an elevated risk of stroke along with evidence that there was no cardiac benefit. A summary of key findings for each trial was published at the time the trial was stopped in order to transmit the
A. Osteoporosis Results from the two H T arms were not congruent on all primary endpoints (Fig. 45.2). The one statistically significant beneficial finding in both arms of the Hormone Trial was the decreased risk of hip fracture. In the E P T arm, the hazard ratio (HR) was 0.67; 95% confidence interval (CI), 0.47-0.96 (12). In the E T arm, the H R was 0.61; 95% CI, 0.41-0.91 (11). The number of total fractures was also reduced in both arms. The H T trial was the first randomized, placebo-controlled hormone trial to demonstrate a statistically significant reduction in hip fractures and other osteoporotic fractures. The finding is notable because unlike
FIGURE 45.2 Annualized incidence of events per 10,000 women per year. EPT, estrogen-progestin therapy; ET, estrogen therapy; Hip Fx, hip fracture; CHD, coronary heart disease events; Breast CA, breast cancer; Colon CA, colon cancer; VTE, venous thrombosis events. See references 10, 11, 13, 14, 15, 19, 20.
CHAPTER 45 The Women's Health Initiative--Data and Discussion TABLE 45.1
Global Index of Risk Associated with Tertile of Fracture Risk.
Tertile of fracture risk
Global index 1.20 (95% CI 0.93-1.58) 1.23 (95% CI 1.04-1.46) 1.03 (95% CI 0.88-1.24)
Lowest Tertile Middle Tertile Highest Tertile See reference 12.
most osteoporosis drug trials, W H I participants were not required to have osteoporosis or a history of vertebral fracture to enroll in the study. Because of the growing number of elderly women in the population and the association of osteoporosis with aging, it is important to consider whether H T should be used on a widespread basis for prevention of osteoporosis. Cauley et al. addressed that question using the E P T data. Taking into consideration the documented side effects and stratifying study participants according to their risk of fracture, the authors found that even in the highest fracture risk category, the risk/benefit ratio of E P T was neutral, indicating that the fracture-prevention benefit was not outweighing the risks of E P T (Table 45.1)(12).
B. Cardiovascular Disease A key finding in the E P T and ET arms was the failure of either hormone regimen to demonstrate prevention of coronary heart disease, the major endpoint of the Hormone Trial (10,11,13,14). An increase in cardiac events (myocardial infarction [MI] or coronary death) occurred in the first year in the E P T arm (HR 1.81; 95% CI, 1.09-3.01) but was no longer statistically significant by the time the study was stopped (HR 1.24; 95% CI, 1.00-1.54). Mean follow-up was 5.6 years (13). Unlike EPT, ET did not produce a statistically significant increase in coronary events in the first year (HR 1.11; 95% CI, 0.64-1.94) (14). However, after a mean follow-up of 7.1 years, there was no significant benefit with regard to the primary coronary endpoints (HR 0.95; 95% CI, 0.79-1.16). Additional analyses of the effect of H T on cardiovascular disease (CVD) by subgroup failed to demonstrate prevention of MI or coronary death according to age decade with either E P T or ET. Among participants ages 50 to 59 at baseline, analysis by composite coronary outcomes suggested a benefit for those participants assigned to ET. The H R for a combination of MI, coronary death, revascularization procedures, and confirmed angina was 0.66 (95% CI, 0.45-0.96); however, the test for interaction of treatment effect by age was not significant (14). Secondary coronary events did not differ among the older ET and placebo participants in the ET arm. The expected effects
613 of oral ET on lipids were observed, and it was noted that the effect of ET did not vary by baseline lipoprotein levels. This finding was in contrast to findings in the E P T arm, where the risk of C H D increased with higher levels of L D L cholesterol. Elevated C-reactive protein at baseline was associated with an increased risk of C H D among those assigned to ET but not to EPT. On the other hand, women assigned to ET who had coronary disease or multiple risk factors for coronary disease at baseline were not found to be at increased risk for cardiac events on treatment. In totality, these data, while not proving a benefit of H T for CVD prevention, do suggest relative safety of H T in regard to C H D for the younger symptomatic postmenopausal woman interested in using HT.
C. Stroke and Venous Thrombosis Another area of similarity between the two H T arms was the finding of an increased risk of stroke. Both E P T and ET resulted in an increased risk of stroke by the second year that persisted over the course of the study (HR 1.31; 95% CI, 1.02-1.68, and H R 1.39; 95% CI, 1.10-1.77, respectively) (11,15). Both H T arms also demonstrated an increased risk of venous thrombosis (VT), confirming previous reports on hormone therapy (16-18). The risk of thrombosis was highest in the first year of the E P T trial (HR 4.01), declined thereafter, but remained above average throughout the study (HR 2.06, 95% CI, 1.57-2.70) (19). In the ET arm the hazard ratio of thrombotic events was less (HR 1.33; 95% CI, 0.99-1.79) (11). The rate of pulmonary emboli was statistically significant in the E P T arm (HR 2.13; 95% CI, 1.45-3.11), but not in the ET arm (HR 1.34; 95% CI, 0.87-2.06) (11,19). Other factors can increase the baseline risk of thrombosis and thereby increase the absolute number of events seen with HT. Both older age and greater body mass index (BMI) increased the risk of venous thrombosis in W H I . Compared with women ages 50 to 59 on placebo, women ages 70 to 79 on E P T had a hazard ratio of 7.46 (95% CI, 4.32-14.38). Women on E P T with a BMI greater than 30 had a hazard ratio of 5.61 (95% CI, 3.12-10.11) compared with women on placebo with a BMI less than 25. Among E P T users no protective effect was seen with statins or aspirin (19).
D. Cancer Two areas of disagreement between the two hormone arms were the main cancer outcomes, colorectal and breast. Invasive breast cancer was increased in the E P T arm
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(HR 1.24; 95% CI,1.01-1.54), whereas there was an insignificant decrease in breast cancer in the ET arm (HR 0.80; 95% CI, 0.62-1.04) (20,21). In both trials the tumors in the active arm were larger and more likely to have spread to the lymph nodes, raising a possible role for diagnostic delay due to a masking effect of H T on breast density or consistency. Further analyses of the breast cancer data across the entire W H I cohort revealed that the incidence rates and types of breast cancer differed among racial and ethnic groups (22). Age-adjusted incidence of breast cancer was lowest in African Americans (HR 0.75; 95% CI, 0.61-0.92), but the mortality rate was higher compared with Caucasian women (HR 1.79; 95% CI, 1.05-3.05). African Americans were more likely to have tumors with an unfavorable prognosis, such as high-grade and estrogen-receptor-negative tumors (adjusted odds ratio [OR] 4.70; 95% CI, 3.12-7.09). Colorectal cancer was decreased among women randomized to EPT compared with placebo (HR 0.56; 95% CI, 0.38-0.81; p = 0.003) (23). The percentage of invasive tumors with regional or metastatic disease was higher in the EPT group compared with placebo (76.2% versus 48.5%; p = 0.004). There was no statistically significant difference in the incidence of colorectal cancer in the ET arm (HR 1.08; 95% CI, 0.75-1.55) (11).
E. C o g n i t i v e D e c l i n e The W H I Memory Study (WHIMS) is a W H I ancillary study that published key findings soon after each H T arm was stopped (24-27). Women in this ancillary study were required to be age 65 or older to participate because the younger age group was unlikely to be diagnosed with dementia during the time course of the study. Neither EPT nor ET prevented cognitive decline or dementia. The analysis of the pooled EPT and ET data, as was originally planned, suggested harm rather than benefit with regard to probable dementia (HR 1.76; 95% CI, 1.19-2.60; ? = 0.006)(26).
F. M e n o p a u s a l S y m p t o m s Vasomotor symptoms were not the focus of the WHI. Women with severe vasomotor symptoms (VMS) were discouraged from participating in the randomized controlled hormone trials because it was thought they would be likely to discontinue the study if randomized to the placebo arm. Nonetheless, 2046 women with moderate to severe VMS did enroll in the EPT trial, and W H I confirmed a statistically significant benefit for VMS as well as small benefits for sleep, physical functioning, and body pain at the 1-year visit. Health-related quality of life was reported in several papers (28-30). Vaginal dryness was significantly improved
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for hormone users, as was the occurrence of joint pain and general aches and pains. W H I is the first trial to document H T benefit for aches and pains. In a subgroup analysis over a 3-year period of women 50 to 59 who were asymptomatic at baseline, fewer women developed vaginal dryness (OR 0.22, 95% CI, 0.08-0.59) and fewer women developed joint aches and pains (OR 0.54; 95% CI, 0.29-0.98) (30). The benefits of H T for menopausal symptoms have been the mainstay of the list of reasons for using H T as far as the Food and Drug Administration is concerned. These benefits, however, are sometimes offset by the side effects. The serious side effects were incorporated as major endpoints of the study and are listed earlier in the key findings. Less serious side effects play a role through their negative effect on quality of life as well as their effect on cost of medical care, including the need for repeat mammograms and breast biopsies. Justification for the concern about bleeding in the choice of hormone regimens is evident in the reasons participants gave for discontinuing therapy. In the EPT trial, 234 women mentioned vaginal bleeding as one of the reasons they discontinued therapy, compared with 8 in the placebo group, a 29-fold difference (30). Throughout the course of the EPT trial, 66.7% of the hormone users reported bleeding at some point despite being on continuous HT, compared with only 13.8% of the placebo users. Of the 875 endometrial aspirations and 217 transvaginal ultrasounds performed for uterine bleeding in the first year of the EPT trial, 91.3% and 86.2%, respectively, were performed in the active hormone group. Dilation and curettage procedures, as well as hysterectomies, were more common in the hormone users (30). The effect of H T on the breast was manifested in several ways: (1) an effect on breast cancer incidence as described earlier; (2) changes in mammographic density and incidence of abnormal mammogram; (3) symptoms of breast tenderness. A statistically significant increase in breast tenderness was seen at year 1 in the EPT 50- to 59-year-old group who were asymptomatic at baseline (OR 4.26; 95% CI, 3.59- 5.04) (30). An increase in the incidence of abnormal mammograms was noted in the first year (EPT 9.4% versus placebo 5.4%; p < 0.001). Over the course of the study the incidence of abnormal mammograms in the EPT group was 31.5% versus 21.2% in the placebo group (p < 0.001) (20). The Mammogram Density Ancillary Study involved 17 of the 40 W H I clinical centers. An analysis of mammographic density and abnormal mammograms was performed centrally over 1- and 2-year intervals. At year 1, mammographic percent density increased by 6% in the EPT group and declined by 0.9% in the placebo group, for an absolute difference of 6.9% (11.6% in the 70- to-79year-old group). At year 2, the absolute difference was 5.7%. Findings were similar across racial and ethnic groups. The relative risk of an abnormal mammogram report was 3.9 (95% CI, 1.5-10.2) and was not explained by the
CHAPTER 45 The Women's Health Initiative m Data and Discussion increase in density. At year 2, the relative risk for an abnormal mammogram in the EPT group was 1.8 (95% CI, 0.68-4.9) (31). Pre-WHI information on the subject of urinary incontinence generally taught that hormone therapy had a beneficial effect on incontinence (32). A combined analysis of the two W H I hormone arms revealed that women who were continent at baseline were more likely to develop incontinence when randomized to hormone therapy compared with those who were randomized to placebo (RR 1.87 [95% CI, 1.61-2.18] and 2.15 [95% CI, 1.77-2.62] for EPT and ET respectively compared to placebo) (33). Among those women who reported incontinence at baseline, the amount and frequency of incontinence increased on HT. Estrogen alone increased the incidence of urge incontinence (RR 1.32; 95% CI, 1.10-1.58). These findings do not support prescribing ET or EPT for either prevention or treatment of incontinence. The report from the H T trials on incontinence does not address the issue of recurrent cystitis in older women, a condition that some have thought benefits from topical estrogen (34).
III. WHI DIETARY MODIFICATION TRIAL The W H I Low-Fat Dietary Modification (DM) study was designed to test the hypothesis that lowering total fat intake would reduce the risk of breast and colorectal cancer in postmenopausal women. A secondary endpoint was the effect of low-fat diet on cardiovascular disease. The goal of the dietary intervention was to decrease the total fat consumption to 20% of energy intake while increasing the intake of fruits and vegetables to 5 servings a day and grains to 6 servings per day. To accomplish the dietary modification, specially trained nutritionists met with the women in the active intervention group 18 times in the first year and quarterly thereafter. Numerous strategies, including self-monitoring programs and motivational techniques, were employed in the effort to achieve and maintain the desired outcome. Despite intense efforts to effect dietary change, only 31% of the participants achieved the 20% fat goal at year 1 and only 14% at year 6.
A. Breast and Colorectal Cancers The hazard ratio for breast cancer was 0.91 (95% CI, 0.83-1.01). It was noted, however, that the women in the intervention arm with the highest baseline fat intake had a greater reduction in breast cancer (P for trend = 0.04) (35). The low-fat diet group had a statistically significant increase in sex-hormone-binding globulin as well as lower levels of serum estradiol.
615 Although there was no statistically significant reduction in colorectal cancer among women on the low-fat diet, the active intervention women did report fewer colorectal polyps (HR 0.91; 95% CI, 0.87-0.95) (36). Whether this will result in fewer cases of colorectal cancer in the years to come is unknown. The 5-year extension of the W H I may contribute to a better understanding of the long-term effects of the lowfat dietary intervention.
B. Cardiovascular The effect of the low-fat intervention on cardiovascular disease was a modest reduction in some of the known cardiac risk factors that did not lead to a statistically significant reduction in cardiovascular events (37). The intervention was not intended to be a weight loss diet, although the intervention group did weigh a statistically significant 1.29 kg less than the control group at year 3, a difference that dwindled to 0.4 kg by the end of the study.
IV. WHI CALCIUM VITAMIN D TRIAL In the Calcium Vitamin D (CAD) Trial, participants were randomized to 1000 mg/day of elemental calcium given in divided doses as calcium carbonate, plus 400 IU vitamin D3 or placebo. At 3 of the 40 W H I research sites bone mineral density was measured at years 1 (baseline for this trial), 3, 6, and 9. The primary endpoint of the CaD Trial was the effect of calcium and vitamin D supplementation on hip and other fractures. The secondary endpoint was the effect of CaD supplements on colorectal cancer.
A. Osteoporosis There was a 12% decrease in hip fractures in the CaD group that was not statistically significant (38). Subgroup analyses determined that women who were adherent to the supplements (defined as taking 80% or more of the tablets) had a statistically significant 29% decrease in hip fracture (HR 0.71; 95% CI, 0.52-0.97). Those women 60 years and older experienced a 21% decrease in hip fracture (HR 0.79; 95% CI, 0.64-0.98). Bone mineral density (BMD) increased from the baseline BMD to one year later at the hip for both the intervention and control group and then declined thereafter. BMD in the intervention group revealed a statistically significant increase compared with the control group at all time points after baseline. Bone mineral density at the hip was 1.06% higher in the intervention group (P < 0.01), but the 12% reduction in hip fractures and the 10% reduction in clinical spine fractures were not statistically significant (38).
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B. Colorectal Cancer The CaD arm of the W H I did not confirm the hypothesis of a reduced rate of colorectal cancer with calcium and vitamin D supplementation (39). Unlike the low-fat diet trial, there was no finding of a decrease in colorectal polyps. Women should not be advised to use CaD supplements for prevention of colorectal cancer. Bone mineral density at the hip was 1.06% higher in the intervention group (P < 0.01), but the 12% reduction in hip fractures and the 10% reduction in clinical spine fractures were not statistically significant. A statistically significant adverse event associated with the CaD Trial was the increased rate of renal calculi (HR 1.17; 95% CI, 1.02-1.34). The finding was unrelated to a high calcium intake at baseline (38). Confounding the study results from the CaD Trial is the fact that the control group was allowed to take calcium and vitamin D. It was considered unethical to proscribe these supplements in an older population of women at risk for osteoporosis. As a result very few of the women in the placebo arm were calcium deficient or insufficient. Mean intakes at baseline in the control group for calcium and vitamin D were 1154 mg/day and 368 IU/day, respectively (38).
V. WHI OBSERVATION TRIAL The W H I Observation Trial is comprised of 93,676 women. It is yet another extensive source of biospecimens for the study of disease markers (1).
VI. CHALLENGES Most H T products reached the market by demonstrating relatively short-term effective and safe treatment of vasomotor symptoms and vulvovaginal atrophy. Clinicians are now in a position of translating risks and benefits found in a chronic disease prevention trial conducted across a wide age range to their predominantly younger (i.e., 45 to 55 year old) patients seeking treatment for specific symptoms. Some have approached this challenge by using qualitative phrases such as "small increase" in risks. Others discuss the smaller absolute risk in the youngest age decade of WHI. While not designed to address this particular situation, W H I does provide more specific risk and benefit information than previously existed for the 50- to-59-year-old age group. Some of the unexpected outcomes from the W H I present scientific challenges because they defy simple explanations. The cardiac and cognitive findings from W H I and W H I M S were unexpected. Much effort has been spent trying to understand the discrepancy between the observational data and the randomized controlled W H I and
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W H I M S data. Potential explanations for the conflicting findings have included the following topics. 1. The hormone regimens used in the W H I differed from what most women were using in the earlier observational studies. H T users from earlier decades often used conjugated equine estrogens alone. When a progestogen was used, it was typically used in an intermittent, cyclic fashion. It has been variously proposed that in the W H I the progestogen offset the potential benefits of estrogen; that a cyclic rather than the continuous combined regimen of EPT might have resulted in more benefit; or that bioidenfical estradiol and progesterone should have been used. 2. The beneficial effect seen in observational studies may have been the result of selection bias; healthy user effect; and failure to capture the early adverse events such as thrombosis, pulmonary emboli, myocardial infarction, and stroke among users. 3. The W H I H T Trial may have failed to find cardiac and cognitive benefits because H T was not initiated in all participants at the time of menopause. This theory holds that in order to see benefit in these two domains, one must begin H T prior to the development of atherosclerosis in the coronary and cerebral vasculature as well as prior to neurologic aging in the brain. These hypotheses have been explored elsewhere (40). Although there is evidence of no harm in the 50- to-59year-old women in the ET arm and a suggestion of benefit in some combinations of various cardiac outcomes, there was no statistically significant difference in the hazard ratios across age groups (11,14). Another scientific challenge lies in the different results seen in the two H T arms (see Fig. 45.2). An obvious difference between the two arms is the progestogen that was given along with estrogen to women who still had a uterus. However, progestogen was not the only difference between the groups. All the ET participants had undergone hysterectomy, and in some of them one or both ovaries had been removed. Furthermore, there were a number of differences between the ET and EPT groups at baseline (Table 45.3) (41). It is clear from the baseline
TABLE 45.2 Event Rates in Placebo Group of the ET and EPT Arms of the W H I Hormone Trial Event Stroke CHD rate CHD death Death Global index From references 10 and 11.
ET (5429)
EPT (8102)
0.32 0.54 0.16 0.78 1.90
0.21 0.30 0.06 0.53 1.51
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CHAPTER 45 The Women's Health Initiative m Data and Discussion
TABLE 45.3 Baseline Characteristics of Participants in the ET and EPT Arms of the W H I Hormone Trial Characteristic Mean age (yrs) BMI (kg/m 2) 1st birth at age < 20 (%) Black (%) W h i t e (%)
E T (5310)
E P T (8506)
63.6 30.1 27.3 15.1 75.3
63.3 28.5 16.4 6.8 84.0
From reference 41.
data that the ET women were less healthy at baseline. During the course of the study, ET placebo group participants had higher rates of clinical events compared to the EPT placebo group (Table 45.2). Further research and analysis may be needed to address the different outcomes regarding invasive breast cancer from the EPT and ET arms. Ongoing data collection and in-depth analyses may provide better understanding of the findings from all three trials. The high retention rate over the 10 years of the original study is a tribute to the commitment of the participants to advancing the science of women's health.
VII. F U T U R E W H I REPORTS The principal papers for each arm of the W H I (10, 11,35-39) presented a summary of the primary and secondary endpoints for each trial. Subsequent publications have elaborated those findings and presented additional information. Data published to date represent a small fraction of the health information stored in the W H I database. The extensive demographic and health outcomes data for various ethnic groups make W H I a rich source of information on women's health. The repository of biospecimens provides opportunity for genomic and proteomic research that could lead to earlier identification of disease and disease risk factors. The 5-year WHI Extension Study (2005-2010) enhances the original study by providing long-term follow-up of participants with a unique opportunity to track the duration of benefits and risks associated with each intervention once the intervention is discontinued. Ongoing and new ancillary studies further expand the dividends from this program. The WHI database can be accessed via the Internet at www.whiscience.org or www.nhlbi.nih.gov/whi/index.html. The database is open to other scientists to further the research in women's health.
References 1. The Women's Health Initiative Study Group. Design of the Women's Health Initiative Clinical Trial and Observational Study. Controlled Clin Trials 1998;19:61-109. 2. Lufldn EG, Carpenter PC, Ory SJ, Malkasian GD, Edmonson JH. Estrogen replacement therapy: current recommendations. Mayo Clin Proc 1988;63:453-460. 3. Bush TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the lipid research clinics program follow-up study. Circulation 1987;75: 1102-1109. 4. Sullivan JM, Vander Zwaag R, Hughes JP, et al. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Arch Intern Med 1990;150:2557-2562. 5. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses' Health Study. NEnglJMed 1991;325:756-762. 6. Fillit H, Weinreb H, Cholst I, et al. (1986). Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer's type. Psychoneuroendocrinology 1986;11:337- 345. 7. Honjo H, Ogino Y, Naitoh K, et al. In vivo effects by estrone sulfate on the central nervous system-senile dementia (Alzheimer's type). J Steroid Biochem 1989;34:521-525. 8. Christiansen C, Riis BJ. 17 Beta-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women. J Clin Endocrinol Metab 1990;71:836- 841. 9. Ettinger B, Pressman A, Silver E Effect of age on reasons for discontinuation of hormone replacement therapy. Menopause 1999;7: 282-289. 10. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;321- 333. 11. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative Randomized Controlled Trial. JAMA 2004;291:1701-1712. 12. Cauley JA, Robbins J, Chen Z, et al., for the Women's Health Initiative Investigators. Effects of estrogen plus progestin on the risk of fracture and bone mineral density: The Women's Health Initiative Randomized Trial. JAMA 2003;290:1729-1738. 13. Manson JE, Hsia J, Johnson KC, et al., for the Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N EnglJ Med 2003;349:523-534. 14. Hsia J, Langer R, Manson JE, et al., for the Women's Health Initiative Investigators. Conjugated equine estrogens and coronary heart disease. The Women's Health Initiative. Arch Intern Med 2006;166:357-365. 15. Wassertheil-Smoller S, Hen&ix SL, Limacher M, et al., for the WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women. JACMA2003;289:2673-2684. 16. Hulley S, Grady D, Bush T, et al., for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAM,4 1998;280:605-613. 17. Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348: 977-980. 18. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981-983. 19. Cushman M, Kuller LH, Prentice R, et al., for the Women's Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573-1580.
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20. Chlebowski RT, Hendrix SL, Langer RD, et al., for the Women's Health Initiative Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAM,4 2003;289:3243-3253. 21. Stefanick ML, Anderson GL, Margolis KL, et al., for the WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295;1647-1657. 22. Chlebowski RT, Chen Z, Anderson GL, et al. Ethnicity and breast cancer: Factors influencing differences in incidence and outcome. J Natl CancerInst 2005;97:439-448. 23. Chlebowski R, Wactawski-Wende J, Ritenbaugh C, et al., for the Women's Health Initiative Investigators. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Eng! J Med 2004; 350:991-1004. 24. Rapp SR, Espeland MA, Shumaker SA, et al., for the WHIMS Investigators. Effect of estrogen plus progestin treatment on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study. A randomized controlled trial. JAMA 2003;289:2663-2672. 25. Shumaker SA, Legault C, Rapp SR, et al., for the WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003 ;289:2651 - 2662. 26. Shumaker SA, Legault C, Kuller L, et al., for the Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: WHIMS. JAMA 2004;291:2947-2958. 27. Espeland MA, Rapp SR, Shumaker SA, et al., for the Women's Health Initiative Memory Study. Conjugated equine estrogens and global cognitive function in postmenopausal women: The Women's Health Initiative Memory Study. JAMA 2004;291:2959-2968. 28. Hays J, Ockene JK, Brunner RL, for the Women's Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N EnglJ Med 2003;348:1839-1854. 29. Brunner RL, Gass M, Aragaki A, et al., for the Women's Health Initiative Investigators. Effects of conjugated equine estrogen on healthrelated quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative randomized clinical trial. Arch Intern Med 2005;165:1976-1986.
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30. Barnabei VM, Cochrane BB, Aragaki AK, for the Women's Health Initiative Investigators. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gyneco12005;105:1063-1073. 31. McTiernan A, Martin CF, Peck JD, et al., for the Women's Health Initiative Mammogram Density Study Investigators. Estrogen plus progestin influence on mammogram density in healthy postmenopausal women in the Women's Health Initiative. J Natl Cancer Inst 2005;97:1366-1376. 32. McCully KS, Jackson S. Hormone replacement therapy and the bladder. J BR Menopause Soc 2004;10:30-32. 33. Hen&ix SL, Cochrane BB, Nygaard IE, et al., Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005;293: 935-948. 34. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N EnglJ Med 1993;329:753-756. 35. Prentice RL, Caan B, Chlebowsld RT, et al., Low-fat dietary pattern and risk of invasive breast cancer: The Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006;295;629-642. 36. Beresford SA, Johnson KC, Ritenbaugh C, et al., Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006;295:643-654. 37. Howard BV, Van Horn L, Hsia J, et al., Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006;295:655-666. 38. Jackson RE), LaCroix AZ, Gass M, et al., for the Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. NEnglJ Med 2006;354:669-683. 39. Wactawski-Wende J, Kotchen JM, Anderson GL, et al., for the Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N EnglJMed 2006;354:684-696. 40. Prentice RL, Langer R, Stefanick ML, et al., for the Women's Health Initiative Investigators. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. Am J Epidemio12005;162:404- 414. 41. Stefanick ML, Cochrane BB, Hsia J, et al. The Women's Health Initiative Postmenopausal Hormone Trials: overview and baseline characteristics of participants. Ann Epidemio12003;13:$78- $86.
2HAPTER 4(
Postmenopausal Hormone Therapy in the 21st Century: Reconciling Findings from Observational Studies and Randomized Clinical Trials KARIN B. M I C H E L S
Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
JOANN E.
Divisionof Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215
MANSON
I. INTRODUCTION
disease (CVD), and breast cancer (1-3). In this chapter we discuss the current state of knowledge regarding effects of H T and try to elucidate apparent discrepancies in results from observational studies and randomized clinical trials (RCTs), taking into account differences in methodology between the studies as well as biologic differences in the populations and drug regimens studied.
Recent years have seen a wealth of new data on possible effects of postmenopausal hormone therapy (HT). Some of these data appear inconsistent and contradictory, which has rendered clinical decision making more difficult. For decades, H T was thought to be beneficial not only to treat menopausal symptoms and to counter osteoporosis, but potentially to prevent cardiovascular disease. After the release of results from the Women's Health Initiative (WHI), physicians and patients became more reluctant to use HT. The weight of evidence appeared to shift to a negative balance for HT, particularly for the combination of estrogen and progestin: an increase in the risk of thromboembolic events, cardiovascular TREATMENT OF THE POSTMENOPAUSAL WOMAN
II. EFFECTS OF HT H T was introduced in the mid-20th century as an estrogen-only formulation. The sales of exogenous oral estrogen to counter menopausal symptoms was spurred by 619
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publication of the bestseller F e m i n i n e F o r e v e r in 1968, which advertised H T as a designer drug promising "extended youth, .... femininity," and beauty (4). Despite the undisputed effectiveness of H T in treating the symptoms of menopause, enthusiasm for the use of H T dampened when it was found to substantially increase the risk of endometrial cancer. Opposing estrogen with progesterone eliminated this unwanted effect. Estrogen receptors can be found in many tissues, in particular in the endometrium, breast, and ovary. Exogenous estrogen promotes cell proliferation and increases the risk of endometrial cancer, breast cancer, and probably ovarian cancer. Although progesterone counters the proliferative effect of estrogen in the endometrium, it may enhance proliferation in the breast. Given the higher absolute risk of breast cancer than endometrial cancer, there is a greater increase in the incidence of both cancers combined with the estrogen plus progesterone combination therapy than with estrogen alone among women with a uterus (5). Exogenous estrogen also has several vascular and metabolic effects, including reducing plasma low-density lipoprotein (LDL) cholesterol levels and raising high-density lipoprotein (HDL) levels, lowering lipoprotein (a) levels and reversing postmenopausal increases in fibrinogen and plasminogen-activator inhibitor type 1 (6). Estrogen also improves glucose metabolism (7), boosts endothelial vascular function (6), and reduces plasma homocysteine levels (8). These effects of estrogen would predict a decrease in the risk of coronary heart disease (CHD) associated with H T use. However, exogenous estrogen also has adverse effects on related biomarkers, including increasing triglyceride levels; promoting coagulation through increases in factor VII, prothrombin fragments 1 and 2, and fibrinopeptide A; raising levels of the inflammatory marker C-reactive protein (6); and promoting the production of metalloproteinases, degradative enzymes important in the destabilization and rupture of plaques (9). Thus, estrogen's effects on vascular function are diverse and complex.
III. THE EFFECT OF HT ON CARDIOVASCULAR DISEASE INCIDENCE A. Data from Observational Studies Results from dozens of observational studies conducted during the past three decades have fairly consistently suggested a substantially lower risk of coronary heart disease (CHD) events among women using H T compared with those who do not use HT. A meta-analysis of 40 epidemiologic studies suggested a 50% reduction in the risk of CHD associated with current estrogen use (10). Because combination therapy with
estrogen and progestin has become prevalent only in the past two decades, most data from long-term observational studies are based on unopposed estrogen use. Data on the effects of opposed estrogen use from observational studies are limited. The Nurses' Health Study, with a 30-year follow-up, is one of the largest prospective cohorts for which information on HT use was collected. Among 70,533 postmenopausal women with no history of CVD, the relative risk (RR) for CHD was 0.55 (95% CI 0.45-0.68) among women taking oral conjugated estrogen alone during 808,825 person-years of follow-up after adjusting for coronary risk factors and 0.64 (95% CI 0.52-0.71) among women using estrogen plus progestin compared with never users (11). Among 2489 postmenopausal women with prior CHD, the RR for a second coronary event was 1.25 (95% CI 0.78-2.00) during the first year of H T use and 0.65 (95% CI 0.45-0.95) during the total follow-up period of 20 years compared with never users of l i T (12).
B. Randomized Clinical Trials on Secondary Prevention Six randomized clinical trials have addressed the question whether HT use may confer CHD benefits among women with prior heart disease (Table 46.1). Although clinical events data are not available from all these secondary prevention trials, these studies have generally not confirmed the inverse association between H T use and CHD reported in observational studies. In the Heart and Estrogen/Progestin Replacement Study (HERS), including 2763 women with documented CHD, the RR for a secondary CHD event was 0.97 (95% CI 0.82-1.14) among women using 0.625 mg of oral conjugated equine estrogen (CEE) plus 2.5 mg of medroxyprogesterone (MPA) compared with placebo (13). Participants randomized to HT experienced a 50% higher incidence of secondary CHD events during the first year of the trial compared with women receiving placebo, but this difference was offset in later years (13,14). The Estrogen Replacement and Atherosclerosis Trial (ERA) and the Women's EstrogenProgestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) were three-arm trials comparing the effects of estrogen, estrogen plus MPA, and placebo on atherosclerotic progression. No differences were found between groups in the rates of angiographically determined progression ofstenoses (15,16). Similarly, the Papworth Hormone Replacement Therapy Atherosclerosis Study, which evaluated the effects of transdermal estradiol with and without norethindrone compared with placebo, found no significant difference in secondary CHD events in the three groups (17). In the Women's Angiographic Vitamin and Estrogen Trial (WAVE), which tested CEE, CEE plus MPA, and placebo, and in the Estrogen in the Prevention of Reinfarction Trial (ESPRIT), which tested estradiol valerate and
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CHAPTER 46 Postmenopausal Hormone Therapy in the 21st Century TABLE 46.1
Results of Randomized Clinical Trials of Postmenopausal Hormone Therapy and Coronary Heart Disease
Trial
Study group
Age range at entry (mean) in years
Treatment
Mean duration in years
Results
Secondary Prevention Heart and Estrogen/ Progestin Replacement Study 13
2763 women with documented CHD
44-79 (66.7)
0.625 mg of oral CEE plus 2.5 mg of MPA or placebo
6.8
Primary CHD events: RR = 0.97 (95% CI 0.82-1.14)
Estrogen Replacement and Atherosclerosis Trial 15
309 women with CHD
42-80 (65.8)
3.2
No significant differences in rates of angiographic stenoses or clinical events
Women's EstrogenProgestin LipidLowering Hormone Atherosclerosis Regression Trial 16
226 women with at least one coronary-artery lesion
15 years duration 3.31 (p < 0.001) -> 15 years since last use 10 (p < 0.0001) ever (17) 20 (7.2-54) -> 15 years duration 5.8 (2.0-17) --- 15 years since last use 0.93 (NS) recent (22)
0.66 (0.44-0.98) recent (21)
1.02 0.80 1.08 1.02 0.95 0.82 0.95 0.60
1.05 (NS) ever (23) 0.95 (NS) recent
0.65 0.44 0.80 0.64 0.90 0.84 0.84
NHS
(0.49-0.88 ever (20) (0.26-0.75) 15+ years (0.70-0.87) ever (18) (0.52-0.78) recent (0.85-0.94) ever (25) (0.78-0.92) recent (0.77-0.91) 20+ years
Meta-analyses
2.3 (2.1-2.5) ever (37) 9.5 (7.4-12.3) > 10 years duration 2.3 (1.8-3.1) >- 5 years since last use
1.32 1.41 1.05 1.37 1.49 0.65
(1.14-1.54) (1.15-1.74) (0.92-1.20) (1.18-1.59) (1.29-1.74) (0.50-0.83)
current ET (27) current C H T past HT (35) current < 5 years HT current --- 5 years HT current H T (31)
(0.81-1.27) ever (19) (0.53-1.21) recent (NS) ever (24) (NS) recent (NS) ever (24) (NS) recent (NS) ever (24) (0.42-0.84) recent
0.72 (0.53-0.97) ever (15) a
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1.21 (2p = 0.00002) current H T (42) 1.023 (1.011 - 1.036) increase per year
0.67 (0.59-0.77) recent H T (50) 0.66 (0.59-0.74) current H T (51) 0.75 (0.68-084) ever (55)
0.66 (0.41-1.07) current (54)
0.60 (0.43-0.83) current ET (28) 0.39 (0.19-0.78) current C H T 0.55 (0.45-0.68) current ET (33) 0.64 (0.49-0.85) current C H T 1.27 (0.95-1.69) current ET (28) 1.09 (0.66-1.80) current C H T 1.18 (0.95-1.45) current ET (33) 1.45 (1.10-1.92) current C H T 2.1 (1.2- 3.8) current HT (34) b 1.3 (0.7-2.4) past HT
0.64 0.50 0.70 0.66 1.12
(0.59-0.68) ever ET (63) (0.45-0.59) current ET (0.65-0.75) ever ET (64) (0.53-0.84) ever C H T (1.01-123) ever HT (69)
2.14 (1.64-2.81) current H T (72) 3.49 (2.33-5.59) first year H T 0.66 (0.53-0.82) (76)
0.63 (0.56-0.70) current (32) 1.03 (0.94-1.12) past 0.80 (0.67-0.96) 10+ years
C. The Nurses' Health Study T h e Nurses' Health Study ( N H S ) began in 1976 when questionnaires were mailed to all female, married, registered nurses, ages 30 to 55 years, who were living in one of 11 large U.S. cities. A total of 121,700 women
completed the survey, which included information on menopause and use of postmenopausal hormones. Being registered nurses, participants are quite homogenous with respect to occupation, education, and health awareness. Biennial follow-up questionnaires update the information originally obtained and inquire about the development of
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new illnesses and death. This cohort has been analyzed for the effect of C H T and ET on morbidity and mortality in postmenopausal women.
II. T H E O U T C O M E S A. Endometrial Cancer Endometrial cancer is the fourth most common cancer in U.S. women, with an annual incidence of 40,880 cases and 7310 deaths each year (36). More than three dozen observational studies have confirmed the strong association between endometrial cancer and ET (17,22,37-40). Women who have used unopposed estrogen are at greater risk of endometrial cancer than neverusers. Risk increases with higher doses and longer durations of ET and persists for several years after discontinuation of estrogen. Women using ET for more than 10 years have nearly a tenfold increased risk. Five years or more after stopping estrogen, risk is still increased more than twofold. The substantial increase in risk of endometrial cancer with unopposed estrogen led physicians to add progestin to the treatment regimen for women with an intact uterus. More recent studies have shown that combined estrogen-progestin regimens (with progestin given sequentially for 10 or more days or continuously) do not increase the risk of endometrial cancer compared with nonusers (39-41). The W H I clinical trial confirmed the finding of no increased risk of endometrial cancer in women receiving continuous C H T therapy (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.48-1.36) (3). However, it also found an increased frequency of uterine bleeding leading to more frequent biopsies, ultrasounds, and hysterectomies in treated women.
type nor dose markedly affects the results. In contrast to the preponderance of observational study results, including those of recent studies (43-46), the ET trial of W H I found no increased risk of breast cancer among treated women (2). Although current ET may increase breast cancer risk slightly, observational studies found that adding progestin to estrogen therapy adds substantially to the risk (relative risk [RR] = 1.24-2.00) (27,43-47). Similarly, W H I found C H T increased risk (RR = 1.24; 95% CI 1.01-1.54) (4). Also, more women in the estrogen plus progestin group than in the placebo group had abnormal mammograms requiring additional medical evaluation. C H T decreases both the sensitivity and specificity ofmammography because of increased radiographic breast density (48,49).
C. Colorectal Cancer Colorectal cancer is the third most common cancer in incidence among U.S. women. Each year 73,470 women are diagnosed with colorectal cancer and 27,750 die of the disease (36). More than two dozen observational studies, including LWCS (21) and NHS (31), have explored the relationship of H T and colorectal cancer. Meta-analyses indicate a 10% to 20% reduction among ever-users compared with never-users and a 35% reduction among current users (50,51). The relation appears to be similar for cancers of the colon and rectum. The W H I clinical trial of C H T reported similar outcomes (5). The risks were 0.56 (95% CI 0.38-0.81) for colorectal, 0.54 (95% CI 0.36-0.82) for colon, and 0.66 (95% CI 0.26-1.64) for rectal cancers, though the number of rectal cancers (n = 19) was small. The W H I trial of ET found no difference in rates of colorectal cancer between treatment and placebo groups.
D. Osteoporosis and Fracture B. Breast Cancer As the most common cancer in U.S. women, breast cancer will affect one in seven women in their lifetime. In 2005, 211,240 new cases will develop, and 40,410 women will die of breast cancer (36). The magnitude of the risk of breast associated with H T has been clarified in recent years. A reanalysis of 90% of the worldwide epidemiologic evidence of primarily unopposed estrogen included 51 studies in 21 countries (42). The two main findings are based on more than 53,000 postmenopausal women with known age at menopause, of whom 33% had used HT. First, while women are using H T and in the 5 years after they cease use, breast cancer risk increases 2.3% per year of use. Among women who use estrogen for 5 years or more, the relative risk is 1.35. Second, 5 years or more after ceasing use, no excess risk persists. Neither estrogen
Osteoporosis is common among elderly women and predisposes to fractures of the hip, vertebrae, distal forearm, and other less common sites (52). Nearly half of the 40 million women in the United States over age 50 have or will develop osteoporosis, and 1.5 million per year endure fractures (53). In addition to the enormous economic costs, these fractures often cause permanent disabili~, dependency, and premature death. Hip fractures, the most serious consequence of osteoporosis, occur in 300,000 each year and kill 20% in the first year. A wealth of data from randomized trials indicates that estrogen use prevents or greatly retards bone loss at the menopause and thereafter (53,54). Findings are similar for opposed and unopposed regimens, oral and transdermal routes of administration, and types of progestins. Bone density increases at lumbar spine, femoral neck, and forearm sites are greater with higher estrogen doses. Rapid bone loss follows estrogen
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CHAPTER 47 Morbidity and Mortality Changes with Hormone Therapy discontinuation, so that within a few years, bone mass in treated patients approaches that in untreated controls. Likewise, evidence from prospective cohort studies (19,55-58) and randomized clinical trials (including WHI) (1,2,6,53,54,59) support the antifracture efficacy of estrogen therapy in postmenopausal women. Randomized clinical trials show a decrease in hip, vertebral, and wrist fracture frequency of about 25% to 35%. In WHI, ET decreased fractures by 30% (RR = 0.70; 95% CI 0.63-0.79) (2) and C H T by nearly a quarter (RR = 0.76; 95% CI 0.69-0.83) (6). The degree of protection against fractures afforded by estrogen is greater among current or recent users, with previous use appearing to give little protection (19,56-58). In addition, some studies suggest that elderly women who use estrogen are not protected against fracture to the extent of younger women (59-61).
E. Coronary Heart Disease Coronary heart disease (CHD) is the most common and deadly disease of women. An American woman's lifetime risk of developing C H D is 32%, and it kills 242,000 each year (62). Women are more likely than men to die within one year after a heart attack (38% versus 25%) and have higher rates of disability. Early evidence from observational studies suggested a 30% to 50% lower risk of C H D among estrogen users (15,18,26,28,33,55,63,64), consistent with randomized trials of H T on intermediate markers (lipids, lipoproteins, fibrinogen, carotid intimal medial thickness) that showed beneficial changes (65,66). However, NHS showed an increased C H D risk in the first year among hormone users with a previous myocardial infarction or atherosclerosis (34). The randomized clinical trials of W H I provide no support for cardioprotection and some suggestion of harm by H T (1,2,8). Unopposed estrogen appeared not to affect incidence of C H D (RR = 0.91; 95% CI 0.75-1.12) (2). Among women assigned to CHT, the risk for C H D (myocardial infarction and coronary death) was increased (RR = 1.24; 95% CI 1.00-1.54), but not for coronary revascularization, angina, acute coronary syndrome, or congestive heart failure (8). Risk of C H D was substantially increased in the C H T group in year 1 (RR = 1.81; 95% CI 1.09-3.01) but tended to decrease over time, with no elevation past year 5.
E Stroke Stroke ranks as the third leading cause of death (behind heart disease and cancer) in U.S. women (62). Not only does stroke kill, it is the major cause of serious, long-term disability (62) and is the second leading cause of dementia (after Alzheimer's disease) (67). Stroke is a heterogeneous
group of diseases that can be classified by the pathology as ischemic (70-88%), hemorrhagic (12-27%), and other etiologies (62,68). Over the past 25 years, epidemiologic studies have produced no conclusive evidence of a beneficial effect of H T on stroke (55,68). However, a recent meta-analysis of nine selected observational studies found increased risk of incident stroke among ever-users (RR = 1.12; 95% CI 1.01-1.23) with no difference between ever-, current, or past users (69). Risk was increased for ischemic stroke (RR = 1.20; 95% CI 1.01-1.40) but not subarachnoid hemorrhage (RR = 0.80; 95% CI 0.57-1.04) or intracerebral hemorrhage (RR = 0.71; 95% CI 0.25-1.29). The NHS reported a significant dose-response relationship with risks of 0.54, 1.35, and 1.63 for doses of 0.3, 0.625, and 1.25+ mg, respectively (33), as did a recent casecontrol study in a health maintenance organization (70). The NHS also found that risk among C H T users was 45% higher compared with never-users of HT, whereas the risk among ET users was increased 18% but not statistically significant. Some observational data indicate that estrogen users have a moderately reduced risk of fatal stroke (16,68,69). A meta-analysis of nine studies estimated a 20% lower risk for stroke mortality (RR = 0.81; 95% CI 0.71-0.92) (69). Both ET and C H T increased stroke risk in W H I (1,2,9). In the ET trial, risk of stroke was 1.39 (95% CI 1.10-1.77) (2). Similar results were found in the C H T trial: The risk was 1.31 (95% CI 1.02-1.68) for all stroke subtypes. Most of the elevation occurred for ischemic stroke (RR = 1.44; 95% CI 1.09-1.90) versus hemorrhagic stroke (RR = 0.82; 95% CI 0.43-1.56) and for nonfatal events (9).
G. Venous Thromboembolism Venous thromboembolic events (deep vein thrombosis and pulmonary embolism) contribute to 200,000 deaths per year (71 ). Case-control, cohort (29), and randomized clinical trials have consistently found risk of venous thromboembolic events greater than 1.0 among H T users. A meta-analysis of 12 studies found a twofold increase in risk among current users, with risk highest (more than a threefold increase) in the first years of use (72). The W H I also reported significant doubling in risk among C H T users (RR = 2.06; 95% CI 1.57-2.70) (7) and a 30% higher risk in ET users (RR = 1.33; 95% CI 0.99-1.79) compared with placebo (2). However, a recent case-control study found that CEE, but not esterified estrogen, was associated with venous thrombolic risk (73). Among CEE users, risk increased with increasing dosage. Risk was also higher with current use of estrogen plus progestin compared with use of estrogen alone.
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H. Cognition and Dementia Although nearly all cognitive functions decline, on average, with age, the variability ranges from successful aging to dementia. More than one-third of women aged 65 and older will develop dementia, of which three-quarters will be Alzheimer's disease (AD) (74). Today AD affects 4.5 million Americans, and it is expected to claim 13 million by 2050 (75). Although observational studies provide little support for the hypothesis that H T preserves overall cognitive function, a few found improvement in selected aspects of cognition such as verbal fluency, verbal memory, and reasoning (32,76-78). A review of 15 double-blind, randomized controlled trials of H T on cognitive function over a treatment period of 2 weeks to 9 months in healthy postmenopausal women also found little evidence of an effect of estrogen on overall cognitive function (78). The Women's Health Initiative Memory Study (WHIMS) was an ancillary study to W H I designed to assess, in women ages 65 and older, whether H T can decrease risk of dementia. W H I M S involved 7510 women in the CHT/placebo trial and 4532 in the ET/placebo trial (10-13). With an average of 4 to 5 years of follow-up, both ET or C H T were found to have a small adverse effect on a measure of global cognitive function, the Modified Mini-Mental State Exam (3MMSE) (11,13). Several observational studies with dementia outcomes (generally AD) have suggested that H T is associated with a 29% to 44% decreased risk for dementia (20,76-78). In a meta-analysis of cohort and prospective case-control studies, H T was associated with a 34% reduction in risk of dementia (RR = 0.66; 95% 0.53-0.82) (76). In WHIMS, the only randomized controlled trial to examine the effects of l i T on dementia risk, women assigned to C H T had a twofold increased risk of developing dementia compared with the placebo group (RR -- 2.05; 95% CI 1.21-3.48) (10). Although the increased risk of dementia was not statistically significant in the ET trial, estrogen alone increased risk of mild cognitive impairment or dementia combined (RR = 1.38; 95% CI 1.01-1.89) (12).
I. Mortality Prospective studies have consistently shown a 20% to 50% decrease in mortality among users of estrogens (18,25,30,55). Grady et al. (55) calculated that the life expectancy for a 50-year old woman choosing long-term ET was nearly a year greater than nonusers. The association with reduced mortality was related to both duration and recency of estrogen use (25,30). In WHI, H T was unrelated to mortality. In the C H T trial, the numbers of overall deaths in the estrogen/progestin
and placebo groups were statistically and clinically similar in this short-duration (5-year) study (RR = 0.98; 95% CI 0.82-1.18) (1). Likewise, in the ET trial, overall death rates did not differ between the estrogen and placebo arms (RR = 1.04; 95% CI 0.88-1.22) (2).
III. WHY RESULTS DIFFER Overall, the results of the W H I study are consistent with the growing body of literature, including observational studies, on the effects of liT. The increasing risk of breast cancer with duration of use and the reductions in risk of colon cancer and fracture are in the expected direction and magnitude. As with observational studies, risk of venous thromboembolism was greatest in year 1 but continued throughout the 5 years of therapy. W H I also found greater risk of stroke as suggested by recent observational studies. In contrast with observational studies, in W H I the risk of C H D was elevated, especially in the first years, and in older women, risk of dementia was increased. Commentaries addressing the differences in findings between observational studies, which found a beneficial effect on C H D and dementia, and the randomized trials, which found none, continue. Some suggest that the divergent findings may be partially due to differences in the clinical characteristics of the study populations, including differences in age, years since menopause, and risk factors for CHD. Others have pointed out the methodologic limitations of both types of studies.
A. Confounding A major concern in observational studies is the possibility that unrecognized confounders or bias account for the observed results. In general populations, women taking H T may have other health-promoting habits and may differ from nonusers in unmeasured ways that influence longevity--the healthy user effect (79-81). However, the Leisure World cohort is a relatively homogeneous group of mostly white, highly educated, upper-middle class women with access to health care. Likewise, all participants in NHS are registered nurses, with similar education and health care knowledge. Thus, both studies controlled for the potential confounders of education and social class by focusing on populations with uniform education, income, and/or occupation. In addition, differences in lifestyle practices and cardiovascular risk factors between estrogen users and nonusers in these studies were not great and adjustment was made for these potentially confounding factors. Nonetheless, uncontrolled confounding cannot be ruled out in any observational study. Observational studies (including LWCS and NHS) have yielded relative risks for fracture, breast cancer, colon cancer, venous thromboembolism, and stroke that were similar to
CHAPTER47 Morbidity and Mortality Changes with Hormone Therapy those reported by WHI. Because confounding would be expected to alter the findings for these disease endpoints as well, perhaps other factors explain the different findings for C H D and dementia between observational studies and WHI.
B. A g e at S t a r t i n g T r e a t m e n t a n d P r e - e x i s t i n g Disease A major difference between participants in the observational studies and those in W H I trials is the age at initiation of HT. In WHI, most of the women were at ages that are, on average, substantially older than those at which most women in the general population initiate HT. In the observational studies, most hormone use began at menopause. In both LWCS and NHS, 80% of women initiated H T within 2 years of menopause. In contrast, W H I women were on average age 63 years, two-thirds were over age 60, and most had been postmenopausal for more than 10 years at enrollment (1,2). This is especially true in WHIMS, where all women took H T after age 65 years. This difference in age at starting treatment raises concern that W H I trial results may not apply to treatment begun early in menopause. The W H I found a trend toward lower risk of C H D with decreasing time since menopause; the relative risk was 0.89, 1.22, and 1.71 among women whose time since menopause was less than 10, 10 to 19, and 20 or more years, respectively (8). In addition, the W H I ET trial found that women in the youngest age group (ages 50 to 59 years) responded more favorably than older postmenopausal women for many outcomes (2). Even though the W H I subjects were designated healthy, many had pre-existing disease or other cardiovascular risk factors (older, obese, smoking, hypertensive, diabetic) and the process of atherosclerosis may have been active. In these women, the trial may have been more similar to a secondary (than a primary) prevention trial of cardiovascular disease. In the first year of WHI, more cardiac events occurred in the C H T group consistent with the findings of HERS (82), other secondary prevention trials, and NHS (34). Some researchers have speculated that estrogen's cardioprotective properties may depend on maintenance of a healthy endotheliummthe healthy endothelium concept (83,84). Here the favorable effects of estrogen on atherosclerosis, inflammation, hemostatis, and coronary flow reserve depend on the integrity of the endothelium and the estrogen receptor populations in endothelial and vascular smooth muscle cells. These would likely be seen only in younger women before the development of substantial atherosclerotic plaques. In older women with pre-existing disease, H T may not inhibit progression from later stages of atherosclerosis to coronary events but may cause prothombotic plaque &stabilization and result in an early harmful effect. This is consistent with studies in rabbits showing the estrogen benefits were reversed in the presence of endothelial dysfunction (85) and in
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monkeys showing that a 2-year (equivalent to a 6-year in women) delay in H T is enough to reduce the protective actions of H T (86). Likewise, H T may not have been protective against dementia in W H I M S because it was not taken during the critical early menopausal years or for long duration (87,88). In addition, only 50% of the dementia cases in W H I M S were classified as AD, less than the 60% to 70% in the general population (74). This could suggest that H T increases the risk of vascular dementia more than the risk of AD and is consistent with the twofold increased risk of stroke in hormone-treated women in WHI.
C. S h o r t - t e r m a n d L o n g - t e r m Effects o f H T By design, most observational studies have sparse numbers concerning the first years of H T and therefore limited ability to capture acute short-term effects, including the increase in C H D events observed in the initial years of the W H I trial. This effect probably led to a modest overestimate of the apparent benefit of hormones for C H D and an underestimate of the apparent risk for stroke and venous thromboembolism in the observational studies. However, several observational studies provided hints of early CHD, stroke, venous thromboembolism, and mortality risk elevations with H T (25,29,34,89,90). Although the risk estimates from observational study are heavily weighted by longer-term use, clinical trial data are comparably sparse after 5 years' duration and their risk estimates reflect shorter-term use. Long-term treatment and follow-up in the context of a randomized clinical trial like W H I is unlikely. Thus, LWCS, NHS, and other long-term observational studies will continue to contribute valuable data about long-term use of l i T that complement those of clinical trials. Comparing the W H I observational study with the W H I clinical trial, Prentice and colleagues found that the relative risks for CHD, stroke, and venous thromboembolism tended to decrease with increasing time from initiation of C H T and that following control for time from initiation the estimates were rather similar for the trial participants and observational cohort (91).
D. Specific R e g i m e n The W H I evaluated only two drug regimens (0.625 mg CEE with or without 2.5 mg MPA daily) and therefore cannot answer questions regarding risks associated with other hormones, doses, schedules, or routes of administration. Whether other regimens carry similar risks to those studied in W H I is unclear. However, one review of clinical studies that investigated different types and regimens of estrogens in combination with progestins concluded that the risk/ benefit analysis reported by the W H I can be generalized to
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other estrogens (e.g., oral ethinyl estradiol, 17[3-estradiol, estradiol valerate, piperazine estrone sulfate, estriol, or transdermal 17[3-estradiol) and other progestins (e.g., oral NETA; levonorgestrel, norgestrel, or transdermal norethisterone; and dydrogesterone) (92). Although recent findings with lower doses of H T have suggested that some benefits (osteoporosis, fracture, colorectal cancer) are maintained, whether lower doses will minimize the risks seen with standard doses remains to be determined.
E. D r o p o u t a n d D r o p - i n Rates Another limitation in W H I is the relatively high rate of discontinuation of hormone therapy. Over the course of the trial, 42% of the women in the C H T group and 38% in the placebo groups stopped taking their medications and 6.2% and 10.7%, respectively, initiated HT. Likewise, more than 50% of the women in the ET trial had stopped therapy by the time the study was terminated. With this substantial crossover, the intention-to-treat analysis may have underestimated the true effects of hormones. Also, if duration of treatment is important, as with breast cancer risk, and if compliance decreases over time, 5-year results may underestimate longer-term treatment effects.
IV. THE RISKS AND BENEFITS OF HORMONE
THERAPY
The purpose of healthy women taking longer-term H T is to preserve health and prevent disease. The results of W H I studies provide strong evidence of significant risks with such therapy. Although population and biologic differences offer plausible explanations for the divergent findings between observational studies and WHI, clinically it may not matter. Risk of breast cancer increases with longer duration of HT, especially CHT. Even if l i T were cardioprotective in younger menopausal women, it does not balance the excess risk of breast cancer. Safe options are available for reducing C H D risk as well as for preventing osteoporosis and fractures. Like all drug therapy, H T has benefits and risks. 9 H T is the most effective treatment for moderate to severe menopausal symptoms (hot flashes, night sweats, vaginal dryness, urogenital atrophy) (93,94). 9 ET increases risk of endometrial cancer in women with an intact uterus. 9 C H T increases frequency of uterine bleeding, leading to more biopsies, ultrasounds, and hysterectomies. 9 H T increases risk of breast cancer during use and several years after. The risk disappears several years after discontinuing therapy. C H T increases risk over that seen with ET.
9 H T (current or recent use) reduces risk of colorectal cancer. 9 H T reduces risk of osteoporotic fractures of the hip, vertebrae, and other sites. H T is not warranted solely for fracture prevention. Alternative therapies are available. 9 H T is not indicated for the prevention of cardiovascular disease. Alternative health strategies (proper diet, exercise, refrain from smoking) and, if needed, pharmaceutical agents (for maintenance of low LDL cholesterol levels and normal blood pressure) with established value should be used. 9 H T increases risk of ischemic stroke. 9 H T increases risk of venous thromboembolism especially in the first years of use. 9 H T in older women (more than 65 years) does not enhance cognition or prevent the development of dementia. H T is appropriate for the relief of menopausal symptoms, as long as a woman has weighed the risks and benefits with her health care provider (95). The lower absolute risk for many adverse outcomes at ages 50 to 59 and the possibility of more favorable findings in this age group both suggest that use of H T to treat menopausal symptoms for a limited duration early in menopause is reasonable. If chosen, a woman should take the lowest dose possible for the shortest time possible and without a progestin if feasible. She should review the decision to take H T annually. However, H T should not be initiated or continued for the prevention of cardiovascular disease.
References 1. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321- 333. 2. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701 - 1712. 3. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures. The Women's Health Initiative randomized trial. JAMA 2003;290: 1739-1748. 4. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. The Women's Health Initiative randomized trial. JAM,q 2003;289:3243- 3253. 5. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. NEngl J Med 2004;350:991-1004. 6. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density. The Women's Health Initiative randomized trial. JAMA 2003;290:1729-1738. 7. Cushman M, KuUer LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573-1580.
CHAPTER 47 Morbidity and Mortality Changes with H o r m o n e Therapy 8. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N EnglJ Med 2003;349:523- 534. 9. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women. The Women's Health Initiative: a randomized trial. JAMA 2003;289: 2673-2684. 10. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651 - 2662. 11. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women. The Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2663-2672. 12. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. Women's Health Initiative Memory Study. JAMA 2004;291:2947-2958. 13. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women. Women's Health Initiative Memory Study. JAMA 2004;291:2959-2968. 14. Barnabei VM, Cochrane BB, Aragaki AK, et al. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gyneco12005;105:1063-1073. 15. Henderson BE, Paganini-Hill A, Ross RK. Estrogen replacement therapy and protection from acute myocardial infarction. Am J Obstet Gyneco11988;159:312-317. 16. Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: a prospective study. Brit Med J 1988;297: 519-522. 17. Paganini-Hill A, Ross RK, Henderson BE. Endometrial cancer and patterns of use of oestrogen replacement therapy: a cohort study. BrJ Cancer 1989;59:445-447. 18. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991;151: 75-78. 19. Paganini-Hill A, Chao A, Ross RK, Henderson BE. Exercise and other factors in the prevention of hip fracture: the Leisure World Study. Epiderniology 1991;2:16-25. 20. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer's disease. Arch Intern Med 1996;156:2213-2217. 21. Paganini-Hill A. Estrogen replacement therapy and colorectal cancer risk in elderly women. Dis Colon Rectum 1999;42:1300-1305. 22. Paganini-Hill A. Morbidity and morality changes with estrogen replacement therapy. In: Lobo RA, ed. In: The treatment of the postmenopausal woman." basic and clinical aspects, 2nd ed. New York: Lippincott Williams &Wilkins, 1999:549-555. 23. Paganini-Hill A, Perez Barreto M. Stroke risk in older men and women: aspirin, estrogen, vitamins, and other factors.J Gend SpecifMed 2001;4:18-28. 24. Paganini-Hill A, Atchison KA, Gornbein JA, et al. Menstrual and reproductive factors and fracture risk: the Leisure World Cohort Study. J Women's Health 2005;14:773-784. 25. Paganini-Hill A, Corrada MM, Kawas CH. Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study. Menopause 2006;13:12-18. 26. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses' Health Study. N EnglJ Med 1991;325:756- 762. 27. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. NEnglJMed 1995;332:1589-1593. 28. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N EnglJ ivied 1996;335:453-461; erratum, 1406.
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29. Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983 - 987. 30. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N EnglJ Med 1997;336:1769-1775. 31. Grodstein F, Martinez ME, Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Int Med 1998;128:705-712. 32. Grodstein F, Chen J, Pollen DA, et al. Postmenopausal hormone therapy and cognitive function in healthy older women. J A m Geriatr Soc 2000;48:746-752. 33. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933-941. 34. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the Nurses' Health Study. Arch Intern Med 2001;135:1-8. 35. Chen WY, Coldtiz GA, Rosner B, et al. Use of postmenopausal hormones, alcohol, and risk of invasive breast cancer. Ann Intern Med 2002;137:798- 804. 36. American Cancer Society. Cancer facts and figures 2005. Atlanta: American Cancer Society, 2005. 37. Grady D, Gebretsadik T, Kerlikowske K, et al. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gyneco!1995; 85:304-313. 38. Cushing KL, Weiss NS, Voigt LF, et al. Risk of endometrial cancer in relation to low-dose, unopposed estrogens. Obstet Gyneco! 1998; 91:35-39. 39. Pike MC, Peters RK, Cozen W, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Nat/Cancer Inst 1997;89: 1110-1116. 40. Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Nat/ Cancer Inst 1999;91:1131-1137. 41. Hill DA, Weiss NS, Beresford SA, et al. Continuous combined hormone replacement therapy and risk of endometrial cancer. Am J Obstet Gyneco! 2000;183:1456-1461. 42. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-1059. 43. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Nat/Cancer Inst 2000;92:328- 332. 44. Million Women Study Collaborators. Breast cancer and hormonereplacement therapy in the Million Women Study. Lancet 2003;362: 419-427. 45. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogenprogestin replacement therapy and breast cancer risk. JAMA 2000;283: 485-491. 46. Chen C-L, Weiss NS, Newcomb P, et al. Hormone replacement therapy in relation to breast cancer. JAMA 2002;287:734-741. 47. Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA 2003;289:3254- 3263. 48. Carney PA, Miglioretti DL, Yankaskas BC, et al. Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med 2003;138:168-175. 49. Greendale GA, Reboussin BA, Slone S, et al. Postmenopausal hormone therapy and change in mammographic density. J Nat/ CancerInst 2003;95:30-37. 50. Nanda K, Bastian LA, Hasselband V, Simel DL. Hormone replacement therapy and the risk of colorectal cancer: a meta-analysis. Obstet Gyneco11999;93:880- 888.
636 51. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999;106:574- 582. 52. Cummings SR, Melton LJ III. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002;359:1761 - 1767. 53. American College of Obstetricians and Gynecologists. Osteoporosis. Obstet Gyneco12004;104(suppl):66S- 76S. 54. Wells G, Tugwell P, Shea B, et al. Meta-analysis of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23:529-539. 55. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Internal Med 1992;117:1016-1037. 56. Cauley JA, Seeley DG, Ensrud K, et al., for the Study of Osteoporotic Fractures Research Group. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995;122:9-16. 57. Yates J, Barrett-Connor E, Barlas S, et al. Rapid loss of hip fracture protection after estrogen cessation: evidence from the National Osteoporosis Risk Assessment. Obstet Gyneco12004;103:440-446. 58. Barrett-Connor E, Wehren LE, Siris ES, et al. Recency and duration of postmenopausal hormone therapy: effects on bone mineral density and fracture risk in the National Osteoporosis Assessment (NORA) study. Menopause 2003;10:412-419. 59. Torgerson DJ, Bell-Syer SEM. Hormone replacement therapy and prevention of nonvertebral fractures. A meta-analysis of randomized trials. JAMA 2001;285:2891 - 2897. 60. Naesstn T, Persson I, Adami H-O, Bergstrtm R, Bergksvist L. Hormone replacement therapy and the risk for first hip fracture. A prospective, population-based cohort study. Ann Intern Med 1990;11:95-103. 61. Kanis JA, Johnell O, Gullberg B, et al. Evidence for efficacy of drugs affecting bone metabolism in preventing hip fracture BMJ 1992;305: 1124-1128. 62. American Heart Association. Heart disease and stroke statistics--2005 update. Dallas: American Heart Association, 2005. 63. Grodstein F, Stampfer M. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovascular Diseases 1995;38:199-210. 64. Barrett-Connor E, Grady D. Hormone replacement therapy; heart disease, and other considerations. Annu Rev Public Health 1998;19:55- 72. 65. Writing Group for the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208. 66. Mendelson ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N EnglJ Med 1999;340:1801 - 1811. 67. Skoog I, Nilsson L, Palmertz B, Andreasson L-A, Svanborg A. A population-based study of dementia in 85 year-olds. N EnglJ Med 1993;328:153-158. 68. Paganini-Hill A. Hormone replacement therapy and stroke: risk, protection or no effect? Maturitas 2001;38:243-261. 69. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy. Scientific review.JAMe12002;288:872- 881. 70. Lemaitre RN, Heckbert SR, Psaty BM, et al. Hormone replacement therapy and associated risk of stroke in postmenopausal women. Arch Intern Med 2002;162:1954-1960. 71. American College of Obstetricians and Gynecologists. Venous thromboembolic disease. Obstet Gyneco12004;104(suppl):118S- 127S. 72. Miller J, Chan B KS, Nelson HD. Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2002;136:680-690. 73. Smith NL, Heckbert SR, Lemaitre RN, et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMel 2004;292:1581-1587.
ANNLIA PAGANINI-HILL 74. Ott A, Breteler MMB, van Harskamp F, et al. Incidence and risk of dementia. The Rotterdam Study. Am J Epidemiol 1998;147: 574-580. 75. Hebert LE, Scherr PA, Bienias JL, et al. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003 ;60:1119 - 1122. 76. LeBlanc ES, Janowsky J, Chan BKS, Nelson HD. Hormone replacement therapy and cognition. Systematic review and meta-analysis.JAMA 2001 ;285:1489-1499. 77. American College of Obstetricians and Gynecologists. Cognition and dementia. Obstet Gyneco12004;104(suppl):25 S - 40S. 78. Hogervorst E, Yaffe K, Richards M, Huppert F. Hormone replacement therapy for cognitive function in postmenopausal women (review). Cochrane System Rev 2002;2:CD003122. 79. Humphrey LL, Chan BKS, Sox HC (2002). Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern ivied 2002;137:273-284. 80. MacMahon S, Collins R. Reliable assessment of the effects of treatment on mortality and major morbidity. II. Observation studies. Lancet 2001;357:455-462. 81. Petitti DB. Hormone replacement therapy and heart disease prevention. Experimentation trumps observation. JAMA 1998;280:650-652. 82. Hulley S, Grady D, Bush T, et al., for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMd 1998;280:605-613. 83. Koh KK. Can a healthy endothelium influence the cardiovascular effects of hormone replacement therapy? IntlJ Cardio12003;87:1- 8. 84. Phillips LS, Langer RD. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertility and Sterility 2005;83:558-566. 85. Holm P, Andersen HL, Andersen MR, et al. The direct antiatherogenic effect of estrogen is present, absent, or reversed, depending on the state of the arterial endothelium. A time course study in cholesterolclamped rabbits. Circulation 1999;100:1727-1733. 86. Mikkola TS, Clarkson TB, Notelovitz M. Postmenopausal hormone therapy before and after the women's health initiative study: what consequences? Ann Med 2004;36:402-413. 87. Zandi PP, Carlson MC, Plassman BL, et al. (2002). Hormone replacement therapy and incidence of Alzheimer disease in older women. The Cache County Study. JAMA 2002;288:2123-2129. 88. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease. A critical time. JAMA 2002;288:2170- 2172. 89. Heckbert SR, Kaplan RC, Weiss NS, et al. Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy. Arch Intern Med 2001;161:1709-1713. 90. Alexander KP, Newby LK, Hellkamp AS, et al. Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up. JAm Coll Cardio12001;38:1- 7. 91. Prentice RL, Langer R, Stefanick ML, et al. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative Clinical Trial. Am J Epidemio12005;162: 404-414. 92. Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gyneco12004;190: 1141-1167. 93. American College of Obstetricians and Gynecologists. Vasomotor symptoms. Obstet Gyneco12004;104(suppl):106S- 117S. 94. Cardozo L, Bachmann G, McClish D, et al. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenpausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gyneco11998;92:722-727. 95. Peterson HB, Thacker SB, Corso PS, et al. Hormone therapy. Making decisions in the face of uncertainty. Arch Intern Med 2004;164: 2308-2312.
SECTION X
Life Cycle and Q OL Only in more recent years has there been a real focus aimed at understanding the full impact of a given treatment on the life of the patient. It is often said in the cancer field that improved quality-of-life years is more important than total longevity. Part of the problem here is that it has been difficult to accurately assess quality of life. The validity of various instruments has come into question in the past. This section deals with lifestyle and quality-of-life issues in postmenopausal women. Included here is a chapter by Adriane Fugh-Berman on complementary medicine, including the use of herbs and phytoestrogens, but also discussing choices such as the use of acupuncture. A valid argument may be made that this chapter belongs in Section XIII, Some Alternative Medical Therapies. Whether taking herbs and nutraceuticals should be considered a treatment or is part of a lifestyle management choice is a matter of debate. This section begins with an in-depth discussion of quality of life and the various instruments used to assess this. When evaluating studies on this point, it is important to know the validity of the instrument used and also the characteristics of the patient population studied. For example, in my view, regardless of the instrument used, Q.OL is improved across the board in postmenopausal women receiving hormones for symptoms. However, this may not be the case in asymptomatic and older women. Next, Michelle Warren discusses the important lifestyle variables of exercise and nutrition. As noted earlier, the final chapter in this section reviews the most current information we have on the effect of certain complementary approaches on various menopausal problems.
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2 H A P T E R 41
Issues Relating to O..uality of Life in Postmenopausal Women and Their Measurement HERMANN
P. G . S C H N E I D E R
Department of Obstetrics & Gynecology, University of Muenster, 48149 Muenster, Germany
I. I N T R O D U C T I O N
Those years of life in which a woman passes through a transition from the reproductive stage of life to the menopausal years form a period marked by waning ovarian function, best referred to as the climacteric. According to the Massachusetts Women's Health Study, which provided data from 2570 women, the median age for the onset of menopause is 51.3 years and the range of menopause is approximately 48 to 55 (3). The perimenopausal transition, for most women, lasts for approximately 4 years. Thinner women experience a slightly earlier menopause (4), obviously related to the contribution of body fat to estrogen production. Factors of little influence are race, income, geography, parity, or height (3,4). The cessation of menses by most women is perceived to have almost no impact on subsequent physical and mental health (3). The Massachusetts Women's Health Study has provided information that women would express either positive or neutral feelings about menopause with the exception of those who experience surgical menopause. By that token, the majority of women feel healthy and happy and do not seek contact with physicians. Medical intervention at this point of life should rather be regarded as an
Health-related quality of @ refers to the effects of an individual's physical state on all aspects of psychosocial functioning. In a more broad sense, quality of life may also be defined as "the extent to which our hopes and ambitions are matched by experience" (1). Health status and quality of life are not linearly related. In recent years, there has been a growing awareness of the aspects of quality of life and aging. Q.uality of life is a subjective parameter, and direct questioning is therefore a simple and appropriate way of accruing information about how patients feel and function. Accordingly, measures of quality of life (Q_OL) attempt to gauge the effect ill health has across a number of physical, psychologic, and social parameters. Menopause is a transition in life and therefore differs from illness. Moreover, menopause challenges self-identity, which may be determined by age-related changes, illness cognitions, and symptom attributions. These need to be taken into account when assessing changes that affect quality of life during the menopausal transition (2). TREATMENT OF THE POSTMENOPAUSAL WOMAN
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640 opportunity to provide and reinforce a program of preventive health care. These issues of preventive health care for women include family planning, cessation of smoking, control of body weight and alcohol consumption, prevention of heart disease and osteoporosis, maintenance of mental wellbeing (including sexuality), cancer screening, and treatment of neurologic problems. Menopause has also been looked at as a wonderful signal occurring at the right time of life when preventive health care is especially critical (5). This way, menopause is considered a normal stage in development, incorporating biology, psychology, society, and culture. Fries summoned up three eras in health and disease (6). The first era, which extended into the early 1900s, was characterized by acute infectious diseases. The second era, highlighted by cardiovascular disease and cancer, is now beginning to move into the third era, marked by problems of frailty (fading eyesight and hearing, impaired memory and cognitive function, decreased strength and reserve). Chronic disease in an aging population is incremental in nature. The best health strategy would be to change the rate at which illness develops and thus postpone the clinical illness; in the end, if it is postponed long enough, it might be prevented effectively. This postponement of illness has been termed compression of morbidity (7,8). The target is to lead a relatively healthy life and compress illness into a short period just before death. Thus, disease is something not necessarily best treated by medication or surgery, but by prevention or, more accurately, by postponement. Improvement of quality of life is a primary purpose of health promotion. This can be achieved by preventive health programs, with their greater impact on morbidity rather than mortality (8). The aim is maximal vigor in life rather than accepting linear senescence. Some linear decline is unavoidable, but the slope can be changed by effort and practice.
II. H O W T O ASSESS MENOPAUSAL SYMPTOMS AND QUALITY OF LIFE The first widely accepted attempt to document the severity of menopausal complaints in women was the Kupperman Index (9,10), a listing of the relevant symptomatology in this age span. This questionnaire focused primarily on symptomatic relief, assessed on the basis of the physician'ssummary of the severity of the climacteric complaints, and assisted by a weighting index, rather than letting women assess their perceived symptoms. This is an example for a simple symptoms inventory without attempts to standardize it or to apply psychometric methodology. Some decades later, time had come for the development of more specific symptom fists or other questionnaires as instruments to measure changes and to validate them in a scientific manner. Psychometric methods
HERMANN P. G. SCHNEIDER
were more frequently applied in the 1950s and 1960s; this knowledge, however, was greatly restricted to psychology and social science and not yet common in medicine. Test theory and test construction developed rapidly in the 1960s also, spreading to the medical field. It was the period when social scientists had to acknowledge the differences between "objective hard data" and "subjective soft data," as different degrees of proos In particular, increased awareness emanated of subjectively perceived quality of life to best serve the description of treatment benefits. Attention focused on instruments with applied psychometrics to develop a scale and evaluate their basic properties such as dimensions (domains) of a scale to measure complex human characteristics. This would, for example, require to analyze the structure of a construct such as menopausal complaints. By analyzing the possible intercorrelations of all symptom combinations, it was found that symptoms would cluster into "factors," which allow to assess variation. This is the simple basis of factor analysis. The factors represent the "domains or subscales" of a complex construct such as menopause. There is a recent trend of increasing recognition among clinicians and researchers of the role of patient-reported data as outcome measure for clinical and drug research. Health authorities are in support of this growing interest. As a result, multiple attempts have been undertaken for a state-of-the-art development of health-related qualityof-life scales applicable to women in their menopausal transition.
A. Methodologic Considerations The standard method used for collecting information on the prevalence and severity of menopausal symptoms has been a checklist of symptoms. Symptoms are defined as "an indication of a disease or a disorder noticed by the patient himself. A presenting symptom is one that leaves a patient to consult a doctor" (11). This way, symptoms represent a subjective expression or manifestation of some underlying physical, psychologic, or social dysfunction. Symptoms are, in effect, evidence of disease (12). Why do women seek medical assistance? Most of the time, for any of the following symptoms: 9 Vasomotor instability, resulting in the leading symptoms of menopause--the hot flushes and sweating 9 Atrophic conditions of estrogen-sensitive tissues-among these, atrophy of the vaginal epithelium; atrophic urethritis with a formation of urethral carbuncles; and dyspareunia and pruritus due to vulvar, introital, and vaginal atrophy 9 Urinary difficulties, such as stress incontinence, urgency, and abacterial urethritis and cystitis.
CHAPTER48 Issues Relating to Q.uality of Life in Postmenopausal Women and Their Measurement In addition, psychologic symptoms, such as anxiety, depressive mood, irritability, insomnia, and decreased libido are extremely common. Although the menopause is blamed for many of these problems, it is associated with a multiplicity of symptoms, some of which are similar to psychiatric disturbances. A deleterious effect of the menopause per se on mental health is not supported by the psychiatric literature. In addition, there is no proof for a specific psychiatric disorder such as involutional melancholia. Even depression is less common, not more common, among middle-aged women (13). Menopause, however, may increase minor so-caUed psychologic complaints. Becoming forgetful in the advanced years is a concern of many, and differentiation of the aging process and pathologic memory loss has a major clinical impact. Research on gender differences in cognition during the aging process and in the course of dementia is in its early stages. Many women become anxious or otherwise disturbed by aspects of a normal aging process in conjunction with a lessening of energy level compared with younger years, changes in sleeping patterns, and changes in the frequency and intensity of sexual desire. Coronary risk factors are highly prevalent among older women. About one-third of middle-aged women have hypertension. More than one-fourth of these are cigarette smokers; more than one-fourth are also overweight. Coronary risk factors tend to predominate in populations of lower socioeconomic class as well as lower educational levels. Relative coronary risk is imparted by gender. The relative risk (RR) of hypertension is comparable for women and men, about 1.5; the gender risk for hypercholesterolemia is 1.1 and 1.4, respectively; for diabetes 2.4 and 1.9, respectively; for overweight 1.4 and 1.3, respectively; and for smoking 1.8 and 1.6, respectively (14). Other long-standing metabolic consequences of the climacteric include osteoporosis and osteoporotic fractures, skin changes, weight gain, and obesity, as well as degenerative disease of the central nervous system (CNS). There is still much to be discovered about the action of estrogen and other sex steroids on the vascular system, immunity, CNS function, and musculoskeletal disease, with special emphasis on the cellular level. A knowledge of symptoms in particular, however, and their effect on the daily lives of women, will assist the caregiver in providing competent care and providing women with long-standing professional assistance during the aging process. In fact, it will be very helpful to provide objective information about an individual's climacteric symptoms that may affect her quality of life.
1. THE CONSTRUCTION OF SCALES AND SUBScALES
As indicated earlier, reliable and valid measures of multisymptom conditions generally come in the form of scales and subscales, developed on the basis of principles of test construction and scaling (15). In the field of psychology, the
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techniques developed to construct such measures became known as psychometrics. The first experimental psychology laboratory was founded by Wilhelm Wundt at the University of Leipzig in 1870. The interest was to establish the general principles of psychologic expression. However, it was very quickly realized that there is a wide variation in individual expression. The assessment of differences between individuals required the construction of measures sensitive enough to distinguish between subjects and the various items under investigation. This, in turn, led to attempts to construct "scales." Scales, by definition, are instruments that measure phenomena on a continuum using ordinal scaling (12). Scales measuring more complex human characteristics, such as intelligence or personality traits, invariably consist of a number of items that are summated to give an overall score for each person. They usually consist of a number of symptoms, yielding a total score that reflects the degree of severity of a condition along a graded continuum for each individual. Moreover, each symptom is usually rated in terms of its frequency of occurrence or severity. Scales for measuring a complex phenomenon or multifaceted syndromes are generally made up of a number of subscales, each measuring a different facet of the syndrome. Very often, summating symptoms from apparently different domains is meaningless. Greene, in his methodologic evaluation, has compared this to adding a person's height and waist measurement to give an overall measure of "size." Such a measure would fail to distinguish tall, thin people from small, obese people, because both would tend to have a similar overall "size" score (12). Similarly, the common practice of reporting symptoms indMdually is bound to fail because such a measure will not assess a condition comprehensively. Scales for measuring human characteristics or conditions can be categorized into two types, general scales and conditionspecific scales. Thus, the types of questionnaire developed focus on either generic or disease- and treatment-specific aspects. The contents of the different generic scales show many similarities, assessing the ability of patients to cope with their condition physically, emotionally, and socially, as well as their general performance at work and in daily life (16). Among the more commonly used instruments are the Sickness Impact Profile (17), Nottingham Health Profile (18), Q.gality of Well-Being Scale (19), and Short Form-36 (SF-36) Health Survey (20). The generic measures cover the multidimensional aspects of quality of life over a wide range of health problems. The scales may be less responsive to treatment-induced changes and could be considered lengthy and time consuming. The disease-specific measures are more likely to be responsive and make sense to clinicians as well as to patients. Their specific measures relate to concepts and domains in patient populations, diagnostic groups or diseases. One of the very first was the Women's Health Q.uestionnaire (WH Q) (21), a menopause-specific instrument. The W H Q_ consists of 37 items, including nine scales, and it assesses, in
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addition to vasomotor symptoms, important areas such as other somatic symptoms, mood, sleeping problems, cognitive difficulties, and sexual functioning. Other test systems and questionnaires refer to psychiatric problems, such as the Beck Depression Index (22), which was designed to assess clinical depression in psychiatric patients. This index proved to be much less sensitive to change than were other nonpsychiatric measures. The depressed mood experienced by climacteric women obviously may not be less severe than that of psychiatric patients, but it has different origins and may have a different context from that of psychiatric depression. Other test systems include pain scores, sleep disturbances, and the assessment of sexual dysfunction, mental and cognitive function. The description of the merits and shortcomings of the different tools is presented elsewhere in this chapter (23). 2. MERITS OF FACTORANALYSIS
Factor analysis is a multivariant mathematical technique traditionally used in psychometrics to construct measures of psychologic and behavioral characteristics, such as intellectual abilities or personality traits (12). Theoretically, it addresses the problem of how to analyze the structure of the interrelationship (correlations) among a large number of variables (test scores, questionnaire responses, behavior, symptoms) by identifying a set of underlying dimensions known as factors. The overall objective of factor analysis is data summarization and data reduction. A central aim of factor analysis is the orderly simplification of a number of interrelated measures. Factor analysis describes the data using many fewer dimensions than original variables. It aims to order and give structure to observed variables and, by virtue of that, allows for the construction of instruments in the form of scales and subscales. The relationship between a symptom and a factor is measured by a correlation coefficient known as a factor loading. This wa~4 an instrument can be constructed that consists of several separate subscales and will measure different aspects of the symptom picture, based on the way symptoms cluster together within factors and on the size of the factor loadings. This results in a scale that yields a symptom profile for each subject (12). In the end, by identifying symptoms that cluster together or form groups of factors, one may be able to delineate facets of the symptom picture and identify those symptoms that are an essential part of a syndrome and those that are not.
B. Currently Employed Menopause-Specific Quality-of-Life Scales There has been a lack of standardized menopausespecific instruments for measuring the symptoms of climacteric women. Currently there are at least seven standardized
HERMANN P. G. SCHNEIDER
menopause-specific scales that satisfy the following four criteria formulated by Gerald Greene (12): 1. They have been constructed on the basis of a factor analysis. 2. They consist of several subscales, each measuring a different aspect of climacteric symptomatology. 3. The scales possess sound psychometric properties. 4. They have been standardized using populations of climacteric women. Of the instruments which fulfill these criteria and include self-report by the patients, the following eight are currently dominating. Although some of them do not necessarily need the criterion to be considered health-related quality-of-life (HRQoL) instruments, they are preferred because of their extensive clinical usage and the large amount of statistical information collected. A definition of HRQoL was developed by the PRO-Harmonization Group (24): "HRQoL represents the patients' evaluation of the impact of health condition and its treatment on daily life." According to their chronologic order of construction, the scales are: 9 Greene Climacteric Scale 9 Women's Health Q.uestionnaire (WHO.) 9 Q.ualifemme 9 Menopause-Specific Q OL Q.uestionnaire (MENQ_OL) 9 Menopausal Symptom List (MSL) 9 Menopause Rating Scale (MRS) 9 Menopausal Quality of Life Scale (MQOL) 9 Utian Menopause Q~ality of Life Scale (UQ_OL)
1. GREENE CLIMACTERIC SCALE
The first properly analyzed climacteric symptom scale was the Greene Climacteric Scale. In 1976, J. G. Greene developed his original 30-item self-administered scale (25). In essence, it was derived from an earlier study by Neugarten and Kraines (26). Gerald Greene recognized endocrine and emotional factors underlying the etiology and dynamics of menopause. Based on this theory, he investigated the relationship between menopausal symptoms. Climacteric symptoms factor analysis was used to establish independent domains such as vasomotor and physical. Originally, the symptoms of 50 women ages 40 to 55 years were scored on a four-point Likert scale (0 to 3). The results were intercorrelated using product-moment coefficients with a resulting matrix being submitted to principal component analysis. The final scale yielded three independent symptom groups or factors, equivalent to subscales. These were psychologic, somatic, and vasomotor symptoms. Items with factor loadings greater than +0.40 on one factor and less than 0.30 on the other two factors were included in the questionnaire. The resulting 21 items from
CHAPTER 48 Issues Relating to Q.uality of Life in Postmenopausal Women and Their Measurement an initial list of 30 were included in the scale. Those items with factor loading above +0.50 were given a weighting factor of 2. Gerald Greene's tool represents a pioneering piece of work. The original Greene Climacteric Scale, however, was never designed to be a genuine HRQpL instrument as it is defined today. It first applied quantitative techniques to questionnaire construction and marked the beginning of the use of factor analysis in clinical studies with "patientreported" outcomes as the endpoint in the field of women's health. Factor analysis has since been applied to samples for various size and characteristics in order to generate new menopausal scales. In order to reconcile the findings of seven such factor analytic studies and meet the demand for a "communal and comprehensive measure" of climacteric symptoms, Greene based his new tool on a sample of 200 rather than 50 women. His 1998 report (27) looked at the optimal number of factors or domains to be established with resultant "communal" scales of psychologic, somatic, and vasomotor symptoms. By only selecting symptoms found to have a factor loading of more than 0.35 in three or more studies, he also determined which symptoms should be included. Greene's new study replaced four items from the original 1976 scale with four new ones. Four other symptoms underwent a change in the wording. An additional item on loss of sexual interest was added, and the psychologic symptoms domain was broken down into an anxiety and a depressed mood subscale. The result is a 21-item, four-level questionnaire. This "standardized" Greene Climacteric Scale of 1998 was employed in a trial of Kliogest, a continuous-combined regimen with 2 mg 1713-estradiol and 1 mg NETA (28). In his detailed analysis of HRQgL instruments, ZSllner (29) classified the Greene Climacteric Scale as a valid instrument for the use in clinical trials. The impact of adverse effects of menopausal hormone therapy, however, is not adequately addressed, resulting in the need for a more comprehensive instrument. Table 48.1 presents an overview of currently employed menopause-specific quality-of-life scales. 2. WOMEN'S HEALTH QUESTIONNAIRE
The Women's Health Q.uestionnaire ( W H Q ) was developed by Myra Hunter in 1986 to assess a wide range of physical and emotional symptoms and to study possible health changes in women ages 45 to 65 years (21). It is composed of 36 items, which cover mood states, physical sensation and experience, sexual behavior, and vasomotor symptoms. A clinical sample of 682 women attending a routine ovarian screening program in London hospitals served as the basis. Self-reported symptoms were scored on a fivepoint Likert scale (values 0 to 4), which was reduced to a binary scale for factor analysis. None of the original 36 items
643
were excluded after factor analysis, but rather grouped into nine subscales or factors (see Table 48.1). Psychometric properties with respect to test-retest reliability, internal consistency, and validity are listed in Table 48.2. Subscale 9 (attractiveness) accounted for a small proportion of the variance and may be omitted, depending on the needs of research. Some interdependence between subscales cannot be denied. The WHQ_was used both in epidemiologic and intervention studies. It was employed in the Adelphi Women's Health Program in 1998, with subsequent publications (30-32). A double-blind, randomized, placebo-controlled multicenter clinical study was performed in 1995 (33). This trial examined 223 volunteering Swedish postmenopausal women with mild to severe climacteric symptoms at baseline in terms of their HRQgL response to transdermal estradiol or placebo patches, respectively. The W H Q . i s a valid and well-documented instrument for use in clinical trials. According to ZSllner (29), potentially MHT-driven adverse effects are difficult to delineate. Therefore, a more comprehensive instrument for HRQgL assessment of postmenopausal hormone therapy is required. 3.
QUALIFEMME
The Qualifemme instrument was developed in France to measure the impact of menopausal hormone deficiency on a woman's quality of life. The first version consisted of 32 items delineated from several other validated and accepted H R Q g L questionnaires. These items were translated and linguistically validated for use in France (34). The Qualifemme instrument is scored using a visual analog scale. Item weighting was achieved by a group of menopausal experts contributing their clinical experience. Initially, a subject pool of 351 women ages 51 to 68 was investigated. A principal component analysis resulted in the identification of five domains with 32 items: general (9), psychologic (12), vasomotor (2), urogenital (6), and a final domain covering pain and problems with hair and skin (3). Cronbach's c~ coefficient of 0.87 demonstrated internal consistency. The original instrument underwent a reduction process and 17 items were removed, resulting in the current 15-item instrument. The reduction was achieved while maintaining the instrument's quality psychometric standards (35). For details of test-retest reliability, internal consistency, and validity, see Table 48.2. The Qualifemme was applied in a multicenter trial in France during the years 1996 and 1998 with 36 centers comparing HRQoL before and after sequential versus continuous application of 1713-estradiol percutaneous gel and nomegestrol acetate in a total of 141 postmenopausal women. The Qualifemme proved sensitive by demonstrating a 44.6% increase in the global quality-of-life score for those on sequential treatment and 38.3% in the continuous-combined
644
HERMANNP. G. SCHNEIDER TABLE 48.1
Instrument
Currently Employed Menopause-Specific Q.uality-of-Life Scales Author
Greene Climacteric Scale
Greene (1976, 1998)
Women's Health Q.uestionnaire (WHO.)
Hunter (1992)
Qualifemme
Floch (1994)
The Menopause-Specific Q.OL Q.uestionnaire (MENQ_OL)
Hilditch (1996)
Menopause Rating Scale (MRS)
Schneider (1996, 2000)
Menopausal Symptom List (MSL)
Perz (1997)
Menopause Q.uality of Life Scale (MQOL)
Jacobs (2000)
Utian Q.uality of Life Scale (UQOL)
Ufian WH (2002)
treatment group (36). Thus, Q.ualifemme appears to be a valid instrument and attempts to include side effects of menopausal hormone therapy such as androgenic skin effects.
4. MENOPAUSE-SPECIFICQUALITY OF LIFE QUESTIONNAIRE The Menopause-Specific Q.uality of Life Q.uestionnaire (MENQ.OL) was developed by a group of researchers from Canada during the mid-1990s (37). A list of symptoms or problems that could be experienced by postmenopausal women was created using the menopause and quality-of-life literature and existing menopause and quality-of-life questionnaires plus the clinical experience of the investigators. The final item-reduction questionnaire had 106 items. From the original five domains, physical, vasomotor, psychosocial and sexual, and working
Domains covered 9 Psychologic 9 Somatic 9 Vasomotor 9 Depressed mood 9 Somatic symptoms 9 Vasomotor 9 Anxiety/fears 9 Sexual behavior 9 Sleep problems 9 Menstrual symptoms 9 Memory/concentration 9 Attractiveness 9 Climacteric 9 Psychosocial 9 Somatic 9 Urogenital 9 Vasomotor 9 Psychosocial 9 Physical 9 Sexual 9 Psychologic symptoms 9 Somatovegetative symptoms 9 Urogenital symptoms 9 Psychologic 9 Vasosomatic 9 General somatic 9 Physical 9 Vasomotor 9 Psychosocial 9 Sexual 9 Occupational quality of life 9 Health-related quality of life 9 Emotional quality of life 9 Sexual quality of life
Items List of symptoms
Fully phrased statements (symptoms and feelings)
List of symptoms
List of symptoms, signs, feelings
List of symptoms
List of symptoms
Fully phrased statements (symptoms and feelings)
Fully phrased statements (symptoms and feelings)
life, upon completion of the study, the domain "working life" was finally omitted. A 32-item menopause-specific H R Q p L instrument resulted. It encompasses four subscales (physical, vasomotor, psychosocial, and sexual) plus one overall HRQ.gL item (see Table 48.2). Each domain is scored separately within a possible range from 1 (not experiencing a problem) to 8 (extremely bothered). The mean of the subscale is taken as the overall subscale score. In analogy to the W H Q ~ no overall score can be obtained from this questionnaire, as the relative contribution of each domain to an overall score is unknown. Reliability, responsiveness, and construct validity of the M E N Q O L instrument (see Table 48.2) were determined within a randomized, parallel-group design trial of conjugated versus transdermal estrogen, both supplemented with medroxyprogesterone acetate (MPA) in a sequential fashion.
645
CHAPTER 48 Issues Relating to Quality of Life in Postmenopausal Women and Their Measurement TABLE 48.2 Scale Greene Climacteric Scale
WHO..
Qualifemme
Structure Psychologic (P) scale 11 items: 1 to 11 (anxiety I to 6; depression: 7 to 11): 1. Tachycardia 2. Nervousness 3. Insomnia 4. Being excitable 5. Panic attacks 6. Difficulty concentrating 7. Tired, lack of energy 8. Lost interest in most things 9. Unhappy or depressed 10. Crying spells 11. Irritability Somatic (S) scale 7 items: 12 to 18: 12. Dizzy or faint feelings 13. Pressure, tightness in head, body 14. Paresthesia 15. Headaches 16. Arthralgia, myalgia 17. Loss of feeling in hands, feet 18. Breathing difficulties Vasomotor (V) scale 2 items: 19 and 20: 19. Hot flushes 20. Sweating at night "Probe" for sexual dysfunction: 21. Loss of interest in sex 9 Depressed mood 9 Somatic symptoms 9 Vasomotor 9 Anxiety/fears 9 Sexual behavior 9 Sleep problems 9 Menstrual symptoms 9 Memory/concentration 9 Attractiveness NB: Symptoms are not listed in blockwise manner to complete one domain and proceed to the next; rather, items from all domains are shuffled across the questionnaire
15-item questionnaire 9 Climacteric (2) 9 Psychosocial (5) 9 Somatic (4) 9 Urogenital (4) 9 Item weighting was determined by a group of menopausal experts adding clinical experience to the instrument
Characteristics of the Scales Scoring 4-point scale Patient asked to indicate degree to which she is bothered "at the moment" by listed symptoms 0: not at all 1: a little 2: quite a bit 3: extremely
4-point scale Patient asked to indicate her agreement with statements as listed: Yes, definitely Yes, sometimes No, not much No, not at all NB: Scoring had to be reversed for some items, as these were phrased positively rather than negatively
Visual analog scale 100 mm
Psychometric properties
Reliability Reliability coefficients: P scale: 0.87 S scale: 0.84 V scale: 0.83 Validity Content validity: Only symptoms with statistically significant factor loading (confirmed by other factorial studies in the latest version) have been included Construct validity: Has been demonstrated in relation to 9 Life stress 9 Bereavement 9 Psychologic 9 Treatment 9 HRT
Reliability Test-retest (2 weeks): Correlation between factor scores (scores of same factor at two different times) ranged between 0.69 and 0.96 across factors Internal consistency: Assessment not deemed necessary as underlying factor analysis provides sufficient information about item to scale relationship Validity Concurrent validity of psychologic scales was estimated by comparison with the 30-item GHQ_, which correlated 0.81 with the depression scale and 0.46 with the anxiety scale
Reliability Test-retest (4 weeks): Pearson's correlation coefficient ranged from 0.84-0.98 Internal consistency: Cronbach's o~ coefficient of 0.73 Validity PCA resulted in five distinct factors explaining 71.8% of variance
Continued
646
HERMANN R G. SCHNEIDER TABLE 48.2
Scale MENQ_OL
MSL
MRS
MQOL
Characteristics of the Scales - - cont'd
Structure Physical (16 items) Vasomotor (3 items) Psychosocial (10 items) Sexual (3 items) Plus general Q_OL question, which was not included in analysis
Total of 25 items covering three domains 9 Psychologic symptoms 9 Vasosomatic symptoms 9 General-somatic symptoms Total of 11 items covering three domains 9 Psychologic symptoms 9 Somatovegetative symptoms 9 Urogenital symptoms
9 Energy (10 items) 9 Sleep (3 items) 9 Appetite (1 item) 9 Cognition (5 items) 9 Feelings (12 items) 9 Interactions (7 items) 9 Symptoms impact (10 items)
Scoring 7-point scale Patient asked to indicate how strongly she is bothered by symptoms listed: 0: not at all 1
2 3 4 5 6: extremely Intermediate levels do not carry any description NB: Scoring had to be reversed for some items, as these were phrased positively rather than negatively
6-point scale to indicate severity and frequency
5-point scale Patient asked to indicate the severity of symptoms 0: no symptoms 1: mild 2: moderate 3: marked 4: severe
6-point scale Patient asked to rate the degree to which the following statements apply to you 1: I am never like this 2 3 4 5 6: I am always like this In addition, a global item included, in which patients are asked to score their overall quality of life on a 100 point scale
Psychometric properties Reliability Test-retest (1 month): Correlation between factor scores (scores of same factor at two different points in time) ranged between 0.55 and 0.85 across factors Internal consistency: Cronbach's ot ranged between 0.81 and 0.89, indicative of fairly high internal consistency
Validity Construct validity: Correlation coefficients are computed for both evaluative and discriminative validity and oscillate between 0.40 and 0.65 (discriminative), or 0.28 and 0.60 (evaluative) (global Q OL item excluded) Test-retest reliability with satisfactory coefficients Validity of limited experience
Reliability Test-retest (1.5 years): Correlation between factor scores (scores of same factor at two different points in time) for severity of scores: K = 0.25 P = 0.000 Somatic symptoms: K = 0.25 P - 0.000 Psychological symptoms: K - 0.30 P - 0.000 Urogenital symptoms: K = 0.19 P = 0.000 Comparison with SF-36 Reliability Internal consistency: Cronbach's oLranged from 0.92 for the total MQ.OL scale, and from 0.91 to 0.69 for each of the menopausal Q OL domains demonstrating a good level of internal consistency
CHAPTER 48 Issues Relating to Quality of Life in Postmenopausal Women and Their Measurement TABLE 48.2 Scale
UQOL
Characteristics of the Scalesmcont'd
Structure
9 Occupational (7 items) 9 Health (7 items) 9 Emotional (6 items) 9 Sexual (3 items)
647
Scoring Named end points: "Perfect quality of life," "Might as well be dead," as well as seven additional quantifiers along the scale 5-point scale Patient asked to rate the degree to which the following statements, apply to you 1: Not true for me 2 3: Moderately true 4: 5: Very true of me Negative item: Scores reversed Missing values: Single missing value scored at the mean of the remaining domain values, second missing score resulted in missing domain score
Improvement was observed in all domains; however, there were significant differences between groups (38). Poor discriminative power was observed in the vasomotor domain, but it was good in other domains. Evaluative performance was fair in the vasomotor and libido, poor in the global subscale. In addition to such identified shortcomings, the lack of factor analysis is another disadvantage, as it withholds correlation patterns of data variants. M E N Q O L also does not address the full picture of potential side effects of menopausal hormone therapy (29). 5. MENOPAUSALSYMPTOM LIST The Menopausal Symptom List (MSL) was developed in 1997 to measure the severity of symptoms commonly associated with menopause. The theoretical symptom checklist was sent to 40 women ages 45 to 55 years living in Australia. Following completion of two principal component analyses, 25 significant items emerged in three domains, labeled psychologic, vasosomatic, and general somatic (39). The latter combines the anxiety and depression subscales of the Greene Climacteric Scale and the Women's Health Questionnaire. The vasomotor subscale, besides two vasomotor symptoms, also includes other somatic symptoms for reasons not quite apparent. The items are scored on a six-point Likert scale of both frequency and severity. The MSL is a symptom inventory in terms of the selection, wording of items, and its scoring. Test-retest reliability coefficients are satisfactory. Validation experience is limited.
Psychometric properties
Reliability Internal consistency: Cronbach's oLvalue of 0.83 indicative of fairly high internal consistency
Validity
Comparison with SF-36 resulting in Pearson correlations demonstrating scale validity
Standard hormone replacement therapy will significantly reduce both frequency and severity of classical menopausal symptoms. In 2002, Hogervorst et al. (40) systematically reviewed the effect of menopausal hormone therapy on cognitive function. Their study included 15 publications with a total of 566 postmenopausal women. This meta-analysis did not report any favorable effect of M H T on cognitive functions (verbal measures, spatial measures, speed of reading, or memory). In the W H I Study, no favorable effect on cognitive function associated with the use of M H T was found (41). Overall, randomized data systematically report that H R T improves quality of life when it is hampered by the presence of climacteric symptoms. W h e n symptoms are not present, M H T does not improve quality of life and would not do so in elderly women. Therefore, clinical practice would foster the application of menopause-specific questionnaires and their validated association with quality of life in women of transient menopausal age. A globally validated and short symptom scale would optimally serve such practical purposes. The Menopause Rating Scale (MRS) is the prototype (42).
6. MENOPAUSERATING SCALE The first version of the Menopause Rating Scale has been used since 1992 (43,44). It was initially developed to provide the physician with a tool to document specific climacteric symptoms and their changes during treatment and was seen as an improvement over the commonly applied Kupperman Index.
648 A critical assessment of this new scale, however, disclosed methodologic deficiencies, which both in theory and practice limited its use. This resulted in proposals to improve the physician-based scale: 9 Application of the scale in a representative sample of women after questionnaire revision. 9 Revision of the questionnaire such that women will complete it themselves; first of all because self-assessment is more sensitive, and second, a self-administered questionnaire would not limit future application. 9 Modification of the wording of items to a simple, laymen-appropriate form. 9 Proper psychometric evaluation of the revised scale based on a representative sample and development of simple-to-use standardized items with clear dimensions. 9 Classification of the severity of complaints based on a normal population sample. 9 Provision of normative data, representative for the climacteric age in the female population. In early 1996, the MRS questionnaire was standardized using a representative random sample of 689 German women ages 40 to 60 years in order to obtain a new and standardized Menopause Rating Scale (45). The first revision of the questionnaire mainly concerned the layout, including some adjustments regarding the number, structure, and wording of items; these were made to support applicability as self-administered questionnaire. The MRS was formally standardized following up-to-date psychometric rules. The revised scale consists of a list of 11 items to be answered: The respondent has a choice among five categories: no symptom, mild, moderate, marked, or severe complaints/symptoms (see Table 48.2). Factor analysis of the standardized l 1-item version encompassed three domains: psychologic, somatovegetative, and urogenital dimension. Scoring is based on a five-point Likert scale ranging from no symptoms to severe symptoms. A follow-up investigation was performed from August to October 1997 on 306 women from the original study. The retest reliability of scores between the two points was evaluated using Pearson's correlation coefficient. The results of the follow-up survey demonstrate stability of the individual scores. The total score and scores of the three defined factors have significant agreement as demonstrated using K statistics (46). The validity of the MRS to measure HRQoL in postmenopausal women was determined by comparing the instrument to both the Kupperman Index (1,2) and the SF-36 (47). In the Kupperman Index, weighting factors are based on the intuition of the developers. The criterion of assignment of a weighting factor based on "prevalence and consequence" is not explicit and merges distinct concepts into one coefficient. No quantitative research or psychometric validation has ever been given to this simple symptom questionnaire of the late 1950s. The MRS proved to be a much more
HERMANN E G. SCHNEIDER
sound and accurate instrument than the Kupperman Index; the differences between scores could easily be explained by the domains resulting from factor analysis. Kendall's T-b coefficient and Pearson's correlation coefficient both demonstrated a high degree of association between the results of both instruments (47). Truly more significant were the results of comparing the MRS to SF-36. When comparing the psychologic and somatovegetative MRS subscales to the eight domains of the SF-36, they did not correlate equally well across all domains. However, the pattern of correlation was understandable, as the highest degree of correlation occurred in the domains of the SF-36 that are most relevant to women during the menopausal transition (48). Thus, the MRS is a reliable, well-defined instrument for measuring the impact of climacteric symptoms on quality of life (49,50). It should be regarded as a brief and compact instrument, easy to complete and to score, and suitable for routine controls. It covers the key complaints of women during and after menopause. This type of scale is not tailored to detail specific therapies to the needs of each individual woman. The MRS had an excellent international response and acceptance. The first translation was into English (51). Other translations followed (52), this way applying international methodologic recommendations. Currently, the following versions are available: Brazilian, Bulgarian, Belgium-French, Belgium-Dutch, Chilean, Chinese, Croatian, English, French, German, Greek, Indonesian, Mexican/Argentinean, Polish, Spanish, Swedish, Rumanian, Russian, South African Engfish, South African Afrikaans, Turkish, Ukrainian (Russia), Ukrainian (Ukraine). Some of these versions are available in a published form (52), and all--including the unpublished-can be downloaded in PDF format from the internet (see ref. 48 and www.menopause-rating-scale.info). Details of compatibility of the MRS scores among countries are given elsewhere (53). 7. MENOPAUSALQUALITY OF LIFE SCALE
The Menopausal Q.uality of Life Scale (MQOL) was developed in 2000 (54). It was intended to create a condition-specific questionnaire that examines the effects of menopause on HRQoL, as well as the impact of employment, age, and medical history; in addition, cross-sectional information on differences in HRO_gL was obtained in a community-based sample of women consequent to a self-rated change in menopausal status. Hnally, the effects of M H T in the early postmenopause were investigated. Subject pools of 32 and later another 29 women were interviewed, and the results of such preliminary information served to develop a pilot questionnaire containing 63 items divided into seven domains. These were energ~ sleep, appetite, cognition, feelings, interactions, and symptoms impact. Each of these items is reported using a six-point Likert scale. Of the total of 191 distributed questionnaires, 99 were returned. The following psychometric analysis resulted in a
CHAPTER 48 Issues Relating to Q.uality of Life in Postmenopausal Women and Their Measurement 48-item questionnaire, as well as a global HRQoL question to rate the overall quality of life. A second analysis using oblimin rotation was performed resulting in a seven-factor hierarchical structure, which accounted for 57% of the data variance. This structure proved unstable across subsamples. As a result, the MQ_OL questionnaire was scored by an overall score instead of seven subscale scores for each of the seven domains. Reliability data are presented in Table 48.2. Strong correlations of interdependence between domains could be shown. Consequently, the global quality-of-life index was disregarded as a single factor, indicating that all the items were evaluated with the same importance and were added in a total score. The attempts to circumvent or mask the psychometric shortcomings of this instrument both undermine the empirical foundation of this questionnaire construction. 8. UTIAN QUALITYOF LIFE SCORE
The Utian Q.uality of Life Score is a modification of the original Utian questionnaire from the 1970s. The UQ_OL was systematically developed from the old questionnaire designed to assess the sense of well-being of participants in a treatment study comparing estrogen to placebo (55). The UQ_OL is focused on general quality of life rather than Q_OL in menopausal women. It was developed with twostage application of factor analysis. The 23-item instrument with a five-point rating scar for each item has four subscales (occupational, health, emotional, and sexual). A field study was conducted on 327 women recruited from 11 separate communities throughout the East and Midwest of the United States. Subjects ranged from 46 to 65 years of age. The resulting 23-item instrument was subsequently administered to a second sample of 270 menopausal women and then readministered to determine test-retest validity. The SF-36 was concurrently administered to determine scale validity. This scale can measure severity of Q.OL burden. Only limited data on reliability and validity are as yet available. The relatively low number of menopausal symptom-specific items may require a parallel application of another more menopausal symptom-related scale for the most widely practiced application of such scales, which is during the menopausal transition. Reliability and validity properties are documented in Table 48.2.
C. Health-related Quality of Life in Postmenopausal Women In order to document the practice of assessing quality of life in postmenopausal women, a few pertinent studies shall be referred to.
649
1. THE BERLIN STUDY
As a basic instrument for quantification of menopausal symptoms, the Menopause Rating Scale was applied in a Berlin Study in 1994 with 230 women with psychosocial determinants of menopausal symptoms. The latter included lack of social support, deficit in self-esteem, and stressful reorientation. For personality identification in this Berlin sample, the Freiburg Personality Inventory (FPI), widely acknowledged and evaluated in Germany, and a projective sentence-accomplishing technique, were applied. The returns were analyzed as material for the evaluations of wellbeing in menopausal women. Attitudes of the women toward menopause could be transformed into items and scales of well-defined diagnostic quality. Scales of this Berlin Menopause Q.uestionnaire have been factor-analyzed and evaluated on a large (n = 603) nationwide German representative sample (56). A questionnaire applied in the Berlin Study was based on results of a pilot investigation and contained 90 items within 13 psychosocial domains. Eight scales were characterized as a result of a factor analysis (Table 48.3). The first four scales relate to complaints such as depressive mood, sleeping disorders, irritability, and exhaustion. Furthermore, the instrument records women's self-confidence, quality of partner relationship, reorientation initiated by menopause, and the absence of menopause-related problems. Based on this information, a validated test instrument consisting of 32 items was developed creating individual profiles of coping and quality of life in menopause conditions. According to their own appraisals, menopause is inconspicuous in 80% of women, who experience no apparent loss in quality of fife. Two out of five women emphasize the physical relief of the menopause, with a resultant general improvement in well-being (Fig. 48.1). Instead of focusing on detailed climacteric complaints, the test asks about the joy of riving and quality of fife. A total of 62% of our probands reported positive attributions to the menopause itself. Altogether, 78% of women took the interview experience as a means to further organize fife in a more conscious manner. TABLE 48.3 Subscales to the Berlin Menopause Q.uestionnaire Depressive moods: "I live in constant worry." Reorientation: "A new life period starts for me." Sleeping disorders: "At night, I lay awake." Irritability: "When I get frustrated, I cannot control myself." Problem-free: "I have no problems with menopause." Self-esteem: "I am happy with myself." Exhaustion: "I have no energy." Q.uality of relationship: "My partner relationship is trustful." Reproduced from res 49.
650
HERMANN E G. SCHNEIDER
TABLE 48.4
Age-Related Perception of Personal Image Percentage of postmenopausal women ages 50-70 years
Feature
FIGURE 48.1 Individualperception of positive effects of menopausal
age. (Reproducedfrom res 49.)
In public opinion, menopausal transition relates to biologic changes co-occurring with social and psychologic alterations during midlife. Very often, psychosocial relief is not encountered and does not contribute positively to perimenopausal age. The fact that children often leave home around mother's menopause is predominantly associated with a loss ("empty nest syndrome"). The psychoanalytic literature on menopause stresses the "empty nest syndrome," mental depression, and the offense of not being in command of reproduction any longer. In contrast to this general attitude, women in the Berlin Study pointed to the advantages of greater personal independence. Only 20% of all participants complained of empty nest symptoms, pointing to different attitudes in the younger generation; they also feel strong relief from menstrual problems, premenstrual complaints, contraceptional obligations, and pregnancy complications of older age (see Fig. 48.1). With increasing age, the quality of sexual life is of growing importance. Tender loving care is a dominant issue in 75% of the interrogated women. In a cluster analysis of this Berlin Study, three types of menopausal coping styles were identified. The first cluster identifies pragmatic women, a more or less problem-free group of 37% with discrete menopausal complaints but with a good level of self-esteem, regarding themselves as attractive. They deny being seriously affected by menopausal changes. Possibly, this pragmatic group has a repressor coping strategy and shields the occurring symptoms with self-discipline. The majority of women (75%) stated no loss in their attractiveness. Women who judged themselves attractive showed fewer menopausal symptoms. With increasing age this individual positive body image seems to modify. Individual features, as seen from our study in 1997 (56) with 1000 postmenopausal women ages 50 to 70, are depicted in Table 48.4 (49). Women with low self-esteem score much higher in the MRS in all our studies (Fig. 48.2). A very important finding is the high correlation between personal professional activity and a quantified low degree of menopausal complaints. The positive feedback of health-promoting behavior needs to be emphasized. Regular exercise correlated signifi-
Drop in efficiency Figure changes Gain in weight Skin slackness Get wrinkles Decrease in attraction
(~ = 1038)
49 39 35 35 30 13
Reproduced from ref. 49. cantly with high self-confidence and with fewer menopausal complaints. Another factor analyzed was reorientation in life. The Berlin Study revealed that 50% of women experienced a reorientation process in their life that was initiated by menopause and that had the consequence of rearranging their lifestyle. A trend toward a creative form of reorientation dominates. Those subjects presenting with a high level of positive reorientational motives in the questionnaire were the ones with a low level of psychologic complaints in the MRS. This group of women look forward to new perspectives in their individual fives. Another group considers themselves as being forced into a form of reorientation that is not at all dominated by the women's own intentions. Here we found a correlation with high levels of psychologic complaints (Fig. 48.3). A further predictor for a rather problem-free menopausal coping is a satisfactory partner relationship. The impact of satisfactory interpersonal relationships and of a secure social net is clearly evident. The personal relationship and its quality grow in importance during midlife. Women without partners score both low and high levels of menopausal complaints in the MRS. Looking at women with partners, when asked about the quality of their partnership, those who were dissatisfied were those who suffered more complaints (Fig. 48.4). What is the overall message of this Berlin Study? Important sequelae for the understanding of well-being in menopausal women are women's self-confidence, the quality of their
FIGURE 48.2 Self-confidenceand well-being in menopausal women.
(Reproduced from ref. 49.)
CHAPTER 48 Issues Relating to Q.uality of Life in Postmenopausal Women and Their Measurement
FIGURE 48.3 Reorientation and well-being in menopausal women. (Reproduced from ref. 49.)
partner relationship, and the reorientation process initiated by menopause or by their psychosocial condition. Good selfconfidence is a predictor for successful coping. A satisfying relationship and social network improves quality of life. Employment is confirmed as a protective factor. Furthermore, several types of physical and psychosocial relief have to be considered in the assessment of well-being in menopausal women. Introducing these variables into the interaction between a woman and her counseling doctor will allow for better cooperation and a higher degree of compliance with treatment.
651
The absolute improvement of the symptoms during treatment was 9.3 points of the MRS total score on average. An important aspect is whether or not a scale like the MRS is good enough to detect even treatment-related changes in women with only few or mild symptoms. This question seems even more important when referring to a metaanalysis of HRT and cognitive function (40). One of Hogervorst's conclusions from this study was: "When symptoms are not present, H R T does not impress Q OL and would not do so in elderly women." Our MRS experience is documented in Fig. 48.5. The relative improvement of complaints or quality of life increases with the degree of severity of symptoms at baseline, which is consistent with the general expectation. It is, however, important to underscore that the MRS scale apparently detects a positive treatment effect also in women with few complaints (57). The MRS-assisted assessments of menopausal hormone therapy and the meta-analysis of Eva Hogervorst both would explain why the W H I investigationmwith menopausal complaints as exclusion criterionmdid not produce major benefits in terms of quality-of-life outcomes except improved vasomotor symptoms and a small benefit in terms of sleep disturbance (40,58).
3. THE PAN-ASIA MENOPAUSE (PAM) STUDY 2. THE MENOPAUSE RATING SCALE AS OUTCOME MEASURE FOR HORMONE TREATMENT
An open, uncontrolled postmarketing study with more than 9000 women with pretreatment and posttreatment data of the MRS scale was organized to evaluate the capacity of the scale to measure the health-related effects of hormone treatment independent from the severity of complaints at baseline. Hormone therapy consisted of a combination of 2 mg estradiol valerate continuously and 1 mg cyproterone acetate in a sequential addition (Climen). The mean age was 49.8 years (SD 6.4); about half the women participating were still perimenopausal (51.9%), the others already in the postmenopausal period (48.1%). The mean body mass index was 24.7 (SD 3.7).
FIGURE 48.4 Relationshipwith partner and well-being in menopausal women. (Reproduced from ref. 49.)
A group of Asian colleagues has organized a prospective, randomized, double-blind multinational clinical trial in 1028 healthy postmenopausal women of nine ethnic groups from eleven Asian countries or regions (59). Following 2 weeks of basal observation, the women received one of three conjugated estrogens and medroxyprogesterone acetate doses. At baseline and at the end of 1, 3, and 6 months following the start of therapy, the study participants were asked to record on a M E N Q O L questionnaire 29 menopausal symptoms, as experienced during the preceding month. The symptoms were categorized into four domains: vasomotor,
FIGURE 48.5 HRT: relative change of the MRS. Mean values (SD) in four categories of severity at baseline. (From ref. 49.)
652
HERMANN R G. SCHNEIDER
psychosocial, physical, and sexual. The results are shown in Table 48.5. Overall, Vietnamese and Pakistani women had the highest baseline scores--that is, were most afflicted by each set of symptoms in a given d o m a i n ~ a n d Indonesian, Malay, Taiwanese, and Thai women were least afflicted. In the overall population, intervention resulted in statistically significant decreases in the scores of all four domains within 1 month of intervention. It is of special interest to observe that the prevalence of four domains of menopausal symptoms, representative of quality of life as recorded on a MENQ_OL questionnaire, vary considerably among ethnic groups of Asian women. Consequently, multinational studies across ethnic groups need to consider such variation.
performed in North America, Europe, and Australia. The PFSF is reliable and valid for use in women with hypoactive sexual disorder and was demonstrated to have robust psychometric properties across numerous geographies (61). Sexuality certainly has great bearing on quality of life. Recent European questionnaires in four to six different countries agree to reduced sex drive concerning a good third of women ages 50 to 60 years. Of these, only small proportions of up to 10% ever seek treatment. In a scale of 1 (extremely unhappy) to 10 (extremely happy), sexual satisfaction of the average European woman was rated around 6, vaginal pain being the leading symptom. These women also admit that an "increased sex life would make me feel more feminine and helps confidence and selfesteem" (62). A detailed report is in preparation (63).
4. ASPECTS OF SEXUALITY All these mentioned questionnaires and inventories more or less consider sexual behavior a separate domain or item. More specific treatment options as well as considerable variation across populations urged clinical scientists to develop broader profiles of female sexual function and appropriate ways of assessment. Hypoactive sexual desire disorder (HSDD) is defined as a persistent deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty (60). Women who have undergone menopause, whether natural or surgical, may experience a significant reduction in sexual desire. The Profile of Female Sexual Function (PFSF) is a new, self-reported multinational instrument designed to measure sexual desire and associated symptoms in women with H S D D following menopause. Specifically, this instrument, which contains 37 items in seven separate domains and an overall sexual satisfaction question, has been developed to reflect the clinical phenomenology of this disorder and its effects on the patients' thoughts, feelings, behaviors, and emotions. The initial development of the PFSF was
TABLE 48.5
Ethnic origin Chinese Filipino Indonesian Korean Malay Pakistani Taiwanese Thai Vietnamese SD, standard deviation. Data from ref. 60.
No. of women 249 199 60 97 24 60 81 150 100
III. CONCLUSION In recent years, there has been a growing awareness among clinicians of the importance of learning all about how patients cope with symptoms of the climacteric. Healthrelated quality of life is a subjective parameter commonly used to assess the views of the patients in terms of the physical, social, and emotional aspects of living with their condition. Direct questioning is a simple and appropriate way of accruing information about how patients feel and function. Using standardized questionnaires ensures welldocumented psychometric properties. For routine application in clinical practice or in clinical trials, it is essential that the instruments employed are simple and comparatively short. The majority of patients or probands welcome the opportunity to report how symptoms and their subsequent treatment affect daily life. Psychometrically evaluated questionnaires allow uniform administration and unbiased quantification of data because the response options are predetermined and thus equal for all respondents. A core set of
PAM Study: Baseline Domain Scores by Ethnic Group Vasomotor
MENQ_OL (29) domain (mean _+ SD) Psychosocial Physical
3.13 (1.67) 3.17 (1.60) 2.28 (0.87) 2.21 (1.40) 3.02 (1.56) 4.96 (2.41) 2.29 (1.39) 2.87 (1.61) 5.71 (1.59)
2.84 (1.37) 3.33 (1.41) 2.40 (0.68) 3.06 (1.46) 2.78 (1.11) 4.24 (1.64) 2.37 (1.32) 3.10 (1.22) 5.96 (1.48)
3.21 (1.15) 3.20 (1.23) 2.66 (0.63) 3.29 (1.24) 2.93 (1.08) 4.84 (1.61) 2.84 (1.23) 3.28 (1.08) 5.39 (1.20)
Sexual 4.04 (2.20) 3.03 (2.03) 2.63 (1.18) 3.55 (2.29) 3.14 (1.78) 2.90 (1.70) 2.11 (1.32) 2.89 (1.90) 6.55 (1.67)
CHAPTER 48 Issues Relating to Q.uality of Life in Postmenopausal Women and Their Measurement questionnaires would allow the comparison of study results in patient populations. The growing awareness of an interest in the subjective aspects of quality-of-life outcomes is evident by the increasing number of publications in this area. A growing emphasis has been on self-administered questionnaires. Unless conventional variables are supplemented with self-assessment measures, a limited picture of the impact of symptoms and the effect of treatment is obtained. Certain difficulties, however, introduce bias into the interpretation of data. These include the experiences of some interviewed individuals, particularly of older age who might have difficulty with reading or writing, or who have been exposed to less experienced interviewers, or simply the expenses involved in gathering quality-of-life data. Standardization, compatibility, eradication of possible bias, and economy are therefore important variables for the validity of any type of quality-of-life assessment. The application of healthrelated quality-of-life instruments requires the same scrutiny and intention as the measurement of physiologic outcomes. Random and representative samples of the population should be investigated in sufficient numbers and over prolonged periods. In terms of statistics, quality of life is, by definition, an assessment of multiple variables. The use of many measures and multiple statistical tests reduces the statistical power of the analysis. Health-related quality of life certainly is a multidimensional concept; there is a continuing debate as to whether or not the aggregation of several dimensions into a summary index is appropriate. A summary score may falsely suggest improvement in one vital area and conceal deterioration in another. Indices, however, are practical and are a convenient method of information transfer. Q O L measures are increasingly used for measuring health outcomes in evaluative research. There is evidence of a lack of consistency in the selection of measures for clinical trials which hinders comparison among studies. Concurrent evaluation and professional consensus will assist to determine the most suitable measure for a particular application. There may be a need for combining general with disease- or populationspecific measures of Q OL, as they complement each other. In a larger representative Berlin Study, important sequelae for the understanding of well-being in menopausal women were found to be women's self-confidence, the quality of their partner relationship, and the reorientation process initiated by menopause and their psychosocial condition. Employment is considered to be a protective factor. The experience of relief from several physical and psychosocial conditions has to be considered in the assessment of well-being in menopausal women. Other examples of application document the prevalence of individual menopausal symptoms to differ among ethnic groups of Asian women. Within each ethnic group, the percentage of women reporting each symptom varies substantially. A hypoactive sexual desire disorder causes marked distress or interpersonal difficulty with severe impact on quality of life. In addition to the menopause-related questionnaires and inventories,
653
which more or less consider sexual behavior a separate domain, a more specific evaluation has emanated. H u m a n beings are social individuals. If one changes the health status or quality of life of an aging person, the partner might also be affected, sometimes strongly and with positive or negative interaction. This is rarely considered in the development of tools to measure treatment. A well-defined menopausal complaint rating scale may serve as a less troublesome, less time-consuming, and therefore rather practical instrument to address the impact of treatment on various aspects of quality of life and at the same time avoid a wide-ranging battery of questionnaires with their practical drawbacks.
References 1. Calman KC. Quality of life in cancer patients--an hypothesis.J ivied Ethics 1984;10:124-127. 2. Alder B. How to assess quality of life--aspects of methodology. In: Schneider HPG, ed. Hormone replacement therapy and quality of life. Carnforth, New York: Parthenon Publishing, 2002:11- 22. 3. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14:103-115. 4. MacMahon B, WorcesterJ. Age at menopause.United States 1960-62. Vital Health Stat 1966;11:1-20. 5. Speroff L. A signal for the future. In: Lobo R, ed. Treatment of the postmenopausal woman. New York: Raven Press, 1994:1-8. 6. FriesJE Aging, illness, and health policy: implications of the compression of morbidity. Perspect Biol Med 1988;31:407-428. 7. Fries JE Aging, natural death and the compression of morbidity. N E n g l J M e d 1980;303:130-135. 8. FriesJF, Green LW, Levine S. Health promotion and the compression of morbidity. Lancet 1989;1:481-483. 9. KuppermanHS, Blatt MHG, Wiesbader H, et al. Comparative clinical evaluation of estrogen preparations by the menopausal and amenorrhoea indices.J Clin Endocrino11953;13:688-703. 10. Kupperman HS, Wetchler BB, Blatt MHG. Contemporary therapy of the menopausal syndrome.JdMd 1959;171:1627-1637. 11. Martin EA. The Oxford medical dictionary. Oxford, UK: Oxford University Press, 1994. 12. Greene JG. Generic score assessment of quality of life and climacteric subscales. In: Schneider HPG, ed. Hormone replacement therapy and quality of life. Carnforth, NY: Parthenon Publishing, 2002:35-44. 13. Hiillstr6m T, Samuelsson S. Mental health in the climacteric. The longitudinal study of women in Gothenburg.Acta Obstet Gynecol &and 1985;130(suppl):13 - 18. 14. Anda RF, Waller MN, Wooten KG, et al. Behavioral risk factor surveillance, 1988. M M W R CDC Surveill Summ 1991;39:1-22. 15. Peck D, Shapiro C. Measuring human problems." a practical guide. Chichester, UK: Wiley, 1990. 16. Fitzpatrick R, Fletcher A, Gose S, et al. Q.uality of life measures in health care. I: Applications and issues in assessment. Br MedJ 1992; 305:1074-1077. 17. BergnerM. Development,use and testing of the sickness impact profile. In: Walker S, Rosser M, eds. Quality of life assessment."key issues in the 1990s. Dordrecht, Netherlands: KluwerAcademic Press, 1993:201-209. 18. Hunt SM, McKenna SP, McEwen J, et al. The Nottingham Health Profile: subjective health and medical consultations. Soc Sc Med 1981; 15A:221-229. 19. Kaplan RM, Anderson JP, Ganiats T. The Quality of Wellbeing Scale: rationale for a single quality of life index. In: Walker S, Rosser M, eds: Quality of life assessment." key issues in the 1990s. Dordrecht, Netherlands: KluwerAcademic Press, 1993:65ff.
654 20. McHorney CA, Ware JE, Raczek AE. The MOS 36-item short-form health status survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31:247-263. 21. Hunter M. The Women's Health Q.uestionnaire (WHO.J: a measure of mid-aged women's perceptions of their emotional and physical health. Psychol Health 1992;7:45-54. 22. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression.Arch Gen Psychiatry 1962;4:561-574. 23. Wiklund I, Dimen~is E, Wahl M. Factors of importance when evaluating quality of life in clinical trials. ControlClin Trials 1990;11:169-179. 24. Acquadro C, Berzon R, Dubois D, et al. Incorporating the patient's perspective into drug development and communication: an ad hoc task force report of the patient-reported outcomes (PRO) harmonization group meeting at the Food and Drug Administration, February 16, 2001. ValHealth 2003;5:522-531. 25. Greene JG. A factor analytic study of climacteric symptoms.JPsychosom Res 1976;20:425-430. 26. Neugarten BL, Kraines RJ. Menopausal symptoms in women of various ages. Psychom Med 1965;27:266-273. 27. Greene JG. Constructing a standard climacteric scale. Maturitas 1998;29:25-31. 28. Ulrich LG, Barlow DH, Sturdee DW, et al., for the UK continuous combined HRT study investigators. Q.ualityof life and patient preference for sequential versus continuous combined HRT: the UK Kliofem multicenter study experience, lntJ GynaecolObstet 1997;59(suppl 1):11-17. 29. Z611nerYF, Acquadro C, Schaefer M. Literature review of instruments to assess health-related quality of life during and after menopause. Qual Life Res 2005;14:309-327. 30. Z6llner Y, Piercy J, Alt J. Mental health aspects of peri- and postmenopausal women, attitudes, quality of life, and the role of HRT (poster). Arch Women Mental Health 2001;3(suppl 2):68. 31. Z6llner Y, Kay S, Abetz L, et al. La qualit6 de vie sexuelle des europtennes. Gyn Info 2001;51:9-11. 32. Piercy J, Z6llner Y, Kay S, et al. Q.uality of life in postmenopausal women in five European countries (poster). ValHealth 2001;4:168. 33. Karlberg J, Mattsson LA, Wiklund I. A quality of life perspective on who benefits from estradiol replacement therapy. Acta Obstet Gynecol Scand 1995;74:367-372. 34. Le Floch JP, Colau JCI, Zartarian M. Validation d'une mtthode d'dvaluation de la qualit6 de vie en mtnopause. Refs en Gyn~colObst~tr 1994;2:179-188. 35. Le Floch JP, Colau JCI, Zartarian M, Gelas B. Rtduction d'un questionnaire d'tvaluation de la qualit6 de vie en mtnopause. Contracept Fertil Sex 1996; 24:238-245. 36. Le Floch JP, Chevalier T, Gelas B, et al. Q.uality of life improvement and hormonal replacement therapy: comparison of sequential versus continuous combined schedules with 1713-estradiol percutaneous gel and nomegestrol acetate. Menopause Rev 1999;4:87-96. 37. Hilditch JR, Lewis J, Peter A, et al. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas 1996;24:161-175. 38. Hilditch JR, Lewis JE, Ross AH, et al. A comparison of the effects of oral conjugated equine estrogen and transdermal estradiol-17[3 combined with an oral progestin on the quality of life in postmenopausal women. Maturitas 1996;24:177-184. 39. Perz JM. Development of the menopause symptom fist: a factor analytic study of menopause associated symptoms. WomensHealth 1997;25:53-69. 40. Hogervorst E, Yaffe K, Richards M, et al. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev 2002;CD003122. 41. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-2662.
HERMANN P. G. SCHNEIDER 42. Schneider HPG, Behre HM. Contemporary evaluation of climacteric complaints: its impact on quality of life. In: Schneider HPG, ed: Hormone replacementtherapy and quality of life. New Yorlc Parthenon, 2002:45-61. 43. Hauser GA, Huber IC, Keller PJ, et al. Evaluation der klimakterischen Beschwerden (Menopause Rating Scale [MRS]). Zentralbl Gynakol 1994;116:16-23. 44. Schneider HPG, Hauser GA. The Menopause Rating Scale (MRS II) m clusters of menopausal symptoms.Maturitas 1996;27(suppl. 1):201. 45. Potthoff P, Heinemann LAJ, Schneider HPG, et al. MenopauseRating-Skala (MRS II): Methodische Standardisierung in der deutschen Bevoelkerung. Zentralbl Gynako12000;122:280-286. 46. Schneider HPG, Heinemann LAJ, Rosemeier HP, et al. The Menopause Rating Scale (MRS): reliability of scores of menopausal complaints. Climacteric2000;3:59- 64. 47. Schneider HPG, Heinemann LAJ, Rosemeier HP, et al. The Menopause Rating Scale (MRS): comparison with Kupperman index and quality-of-life scale SF-36. Climacteric2000;3:50- 58. 48. Greene JG. Measuring the symptoms dimension of quality of life: general and menopause specific scales and their subscale structure. In: Schneider HPG, ed. Hormone replacement therapy and quality of life. Carnforth, NY: Parthenon 2002:35-45. 49. Schneider HPG, Schultz-Zehden B, Rosemeier HP, et al. Assessing well-being in menopausal women. In: Studd J, ed. The management of the menopausemthe millennium review 2000. New York: Parthenon Publishing, 2000:11 - 19. 50. Wiklund I. Methods of assessing the impact of climacteric complaints on quality of life. Maturitas 1998;29:41-50. 51. Schneider HPG, Heinemann LAJ, Thiele K. The Menopause Rating Scale (MRS): cultural and linguistic validation into English. Life Med Sc Online 2002;3: DOI:10.1072/LO0305326. 52. Heinemann LAJ, PotthoffP, Schneider HPG. International versions of the Menopause Rating Scale (MRS). Health Qual Life Outcomes 2003;1:28. 53. Heinemann LAJ, Schneider HPG. Q.uality of life assessment in the menopause. In: Eskin B, ed. The menopause." endocrinologic basis and management options, 5 ed. Oxon: Informa Healthcare, 2007:79-85. 54. Jacobs P, Hyland ME, Ley A. Self rated menopausal status and quality of life in women aged 40- 63 years. BrJ Health Psych2000;5:395- 411. 55. Utian WH. The mental tonic effect of oestrogens administered to oophorectomised females. S Afr MedJ 1972;46:1079-1082. 56. Schultz-Zehden B. FrauenGesundheit in und nach den Wechseljahren.Die 1000 Frauenstudie. Gladenbach: Verlag Kempkes, 1998. 57. Heinemann LAJ, DoMinh T, Strelow F, et al. The Menopause Rating Scale (MRS) as outcome measure for hormone treatment? A validation study. Health Qual Life Outcomes2004;2:67. 58. Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. NEnglJMed 2002;348:1839-1854. 59. Limpaphayom KK, Darmasetiawan MS, Hussain RI, et al. Differential prevalence of quality of life categories (domains) in Asian women and changes after therapy with three doses of conjugated estrogens/ medroxyprogesterone acetate: the Pan-Asia Menopause (PAM) study. Climacteric 2006;9:204- 214. 60. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4 ed. Washington, DC: APA, 1994. 61. Derogatis L, Rust J, Golombok S, et al. Validation of the Profile of Female Sexual Function (PFSF) in surgically and naturally menopausal women. J Sex Marital Ther 2004;30:25-36. 62. Strothmann A, Schneider HPG. Hormone replacement therapy: the European women's perspective. Climacteric2003;6:337- 346. 63. Genazzani AR, Schneider HPG, Nijland E. The European Menopause Survey 2005. What do women think right now about menopause and HRT? Climacteric2005;8 (suppl 2):96.
( ; H A P T E R 4~
Role of Exercise and Nutrition MICHELLE P. WARREN
Departmentof Obstetrics/Gynecology,Columbia University,New York, NY 10032
CECILIA ARTACHO
Departmentof Obstetrics/Gynecology,Columbia University,New York, NY 10032
ALLISON R.
HAGEY Departmentof Obstetrics/Gynecology,Columbia University,New York, NY 10032
I. ROLE OF EXERCISE AND NUTRITION The effects of menopause and the aging process itself cause many physiologic changes, which explain the increased prevalence of chronic diseases observed in postmenopausal women. Exercise and nutrition play important roles in the prevention and treatment of cardiovascular disease, cancer, obesity, diabetes, osteoporosis, and depression, which are some of the major health problems seen in postmenopausal women. Clinicians caring for older women should stress the relevance of these two lifestyle factors to overall health and advise their patients about adequate exercise prescriptions and nutrition.
II. CARDIOVASCULAR DISEASE A N D T H E ROLE OF N U T R I T I O N Cardiovascular disease (CVD) incidence increases with advancing age in women, with a notable increase after menopause, possibly as a result of estrogen deficiency. Coronary heart disease (CHD) is the leading cause of death among postmenopausal women (1,2). It is believed that the T R E A T M E N T OF T H E POSTMENOPAUSAL W O M A N
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atherosclerotic process is attenuated in women until perimenopause because circulating estrogen prevents the incorporation of low-density lipoprotein cholesterol (LDLc) into atherosclerotic plaques (3). By the year 2015, one-half of all women in the United States will be more than 45 years old (3), and primary prevention of CVD in this group is becoming increasingly important. Smoking, hypertension, hypercholesterolemia, obesity, diabetes mellitus, a sedentary lifestyle, and estrogen deficiency all increase the risk of atherosclerotic plaque formation (4,5). Changes that take place during menopause, including atherogenic changes in serum cholesterol profiles and weight gain, contribute to the increased risk of CHD after menopause (7). CVD causes other diseases, besides heart disease and stroke, that result in significant morbidity in women. As many as 25% of women ages 55 to 74 years suffer from lower extremity atherosclerosis (8). Although these CVD and CHD risk factors become more pronounced during menopause, they, in turn, are affected by nutrition and physical activity. Cardiovascular disease risk factors, such as lipid changes, become more pronounced during menopause. In a large cohort of premenopausal and postmenopausal French women, menopause was associated with higher levels of serum cholesterol, triglycerides, apolipoprotein (apo) B, and Copyright 9 2007 by Elsevier,Inc. All rights of reproduction in any form reserved.
656 apo A-I, and also with elevated diastolic blood pressure (9). Lipoprotein profiles change with age, and LDLc increases in women after age 50 (10). Postmenopausal women not only have higher total LDLc plasma levels, but also the L D L particle itself becomes more dense (11). This smaller, denser form of L D L is linked to C H D risk (12). The highdensity lipoprotein cholesterol (HDLc) plasma level declines with the onset of menopause, and the H D L particle itself is altered. The relative proportions of its two subfractions change, and the more dense H D L 3 C increases and the less dense H D L 2 C decreases (13). The HDL3b subclass is usually present in individuals with C H D (14). Serum ferritin, total cholesterol, and L D L cholesterol all increase in postmenopausal women, and their parallel rise may be partly responsible for the increased risk of C H D in this population (15). The Framingham Offspring/Spouse Study, which examined the relationship between diet and plasma total and L D L cholesterol levels in a large sample set of premenopausal and postmenopausal women, showed that cholesterol levels were directly related to consumption of saturated fat and inversely related to total caloric intake, but that dietary cholesterol was not a predictor of cholesterol levels (16). Another study of the same cohort showed that plasma triglycerides were inversely related to protein, fiber, and polyunsaturated fat and directly related to saturated fat and oleic acid (17). High triglyceride levels are better predictors of C H D risk in women than in men, and triglycerides are strongly related to HDLc, which is an important predictor of C H D risk in women (18,19). High triglyceride levels are an important risk factor for C H D in women, but the effect of high triglycerides is most pronounced when they are present in conjunction with low H D L c levels. Patients who have both high triglyceride levels and low HDLc levels have an increased incidence of CVD (20). A low HDLc appears to be the strongest predictor of C H D in women (20,21). An association of H D L c with cardiovascular disease in women was also found in the 20-year follow-up of the Donolo-Tel Aviv cohort (21). The importance of HDLc and triglycerides as risk factors for CVD in women was also apparent in the Lipid Research Clinics Follow-up Study (20), which found that H D L c levels of less than 1.3 mmol/L (50 mg/ dL) and triglyceride levels of 2.25 to 4.49 mmol/L (200-399 mg/dL) were independent predictors of death from CVD. A low H D L c level places women at a greater risk for C H D than a high LDLc level (20). The Framingham, Donolo-Tel Aviv, and Lipid Research Clinics studies all indicate that low H D L c levels in women are stronger predictors of cardiovascular disease mortality than total cholesterol levels (20-22). C H D in women is also more strongly related to the total cholesterol H D L c ratio than to either total cholesterol or to LDLc (23). An age-related increase exists in the ratio of total to HDLc, and when the ratio is greater than 7.5, women have the same C H D risk as men (24).
WARREN ET AL.
The entire lipid profile should be assessed yearly, and dietary and exercise interventions should be prescribed to women who are not within the range of optimal cholesterol and lipoprotein profile (Table 49.1). Only one-half of the women in the Framingham study met the 1996 National Cholesterol Education Program (NCEP) guidelines for a desirable blood level of LDLc (130 mg/dL) (5,25). In 2001 the N C E P updated these cholesterol designations to more rigorous standards and now suggests that people at low or
TABLE 49.1 Adult Treatment Plan (ATP) III Classification of LDL, Total, and H D L Cholesterol (mg/dL) L D L cholesterol < 100 100-129 130-159 160-189 -> 190
Optimal Near optimal/above optimal Borderline high High Very high
Total cholesterol < 200 200-239 >- 240
Desirable Borderline high High
H D L cholesterol < 40 -> 60
Low High
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol and Adults (AdultTreatment Plan III). Executive summary.AccessedMay 2001, from http://www.nhlbi.nih.gov/guidelines/ cholesterol/index.htm.
TABLE 49.1A Major Risk Factors (Exclusive of L D L Cholesterol) that Modify L D L Goals a Cigarette smoking Hypertension (blood pressure -> 140/90 mm Hg or an antihypertensive medication) Low HDL cholesterol (< 40 mg/dL) b Family history of premature CHD (CHD in male first-degree relative < 55 years; CHD in female first-degree relative < 65 years) Age (men -> 45 years; women -> 55 years)a aln ATP Ill, diabetes is regarded as a CHD risk equivalent. bHDL cholesterol -> 60 mg/dL counts as a "negative"risk factor; its presence removesone risk factor from the total count. From Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol and Adults (AdultTreatment Plan III). Executive summary.AccessedMay 2001, from http://www.nhlbi.nih.gov/guidelines/ cholesterol/index.htm.
CHAPTER 49 Role of Exercise and Nutrition TABLE 49.1B
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Three Categories of Risk that Modify L D L Cholesterol Goals LDL level at which to initiate therapeutic lifestyle changes (TLC)
Risk category
LDL goal (mg/dL)
CHD and CHD risk equivalents Multiple (2 +) risk factors a
< 100 mg/dL
-> 100 mg/dL
< 130 mg/dL
-> 130 mg/dL
< 160 mg/dL
-> 160 mg/dL
Zero to one risk factor
LDL level at which to consider drug therapy -> 130 mg/dL (100-129 mg/dL: drug optional) b 10-year risk 10-20%: -> 130 mg/dL 10-year risk < 10%: -> 160 mg/dL -> 190 mg/dL (160-189 mg/dL: LDL-lowering drug optional)
~Risk factors that modify the LDL goal are listed in Table 49.1a. bSome authorities recommend use of LDL-lowering drugs in this categoryif an LDL cholesterol < 100 mg/dL cannot be achievedby therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL, such as nicotinic acid or fibrate. Clinicaljudgment also may call for deferring drug therapy in this subcategory. From Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol and Adults (Adult Treatment Plan III). Executive summary.Accessed May 2001, from http:llwww.nhlbi.nih.gov/guidelineslcholesterol/ index.htm.
moderate risk of coronary heart disease maintain LDLc levels less than 100 mg/dL (26). Although women in the Framingham cohort were adhering to a moderate cholesterol intake of no more than 300 mg/day, their average fat intake constituted 38% of calories (22). Only one-fifth of the women adhered to the recommended upper limit for fat intake of no more than 30% of calories (22). In light of these findings, it is important for postmenopausal women to receive adequate counseling about ways to reduce their saturated fat, total fat, oleic acid from animal sources, and total caloric intake and to increase their intake of fiber and polyunsaturated fat in order to improve their lipoprotein profile and reduce their risk for CVD. Dietary change resulting in lowered blood cholesterol correlates with a reduction in C H D rates among women in the United States (3). For each 1% decrease in serum cholesterol, a corresponding 2% to 3% reduction is seen in CVD risk in U.S. adults, (27) and dietary intervention can lower cholesterol concentrations by approximately 10% (28). One of the important steps in the primary prevention of C H D should be a nutritional intervention aimed at the many women who still consume diets that place them at increased risk for CHD. Women with hypercholesterolemia clearly benefit from a reduction in dietary fat and cholesterol (3). Healthy women with only slightly elevated cholesterol levels may or may not benefit from a dietary intervention because such a lipid-lowering intervention can also reduce H D L c (3). Because a low H D L c level places women at increased risk of C H D , dietary interventions should be geared toward raising H D L and lowering L D L (3). The American Heart Association (AHA) recommends that total fat intake be
reduced to 30% of calories, that saturated fat intake be decreased below 10% of calories, and that dietary cholesterol be lowered to less than 300 mg/day for healthy people and less than 200 mg/day for at-risk individuals. Other L D L lowering enhancers include plant stanols/sterols (2 g/day), increased viscous (soluble) fiber (10-25 g/day), protein approximating 15% of total calories, and moderate physical activity (29). This A H A Phase I diet (30) should be followed by all nonobese, normocholesterolemic women (31). Women who have a higher CVD risk profile should follow the A H A Phase II or the A H A Phase II1 diets. Both the A H A step I diet and the A H A step II diet have proven to be equally effective in reducing total serum cholesterol and LDLc in men and women (Fig. 49.1) (32). Reducing fat intake may have additional protective effects. Data from the Iowa Women's health study also indicated that a high fat intake is associated with decreased survival of postmenopausal women with breast cancer (33). A 5-year randomized trial designed to determine whether increases in LDLc and body weight during menopause can be prevented through changes in diet and physical activity showed that a dietary and behavioral intervention was successful during the first 6 months in a cohort of premenopausal women (7). The risk of CAD can be reduced through dietary intervention, which can improve the lipid profile and lower blood pressure (34). The A H A encourages reaching an optimal blood pressure of less than 120/80 mm H G through diet and exercise modifications. For individuals with blood pressure ranges greater than 140/90 mm H G with related target-organ damage or diabetes, the A H A recommends pharmacology such as thiazide diuretics (25). Diet and other nonpharmacologic interventions should,
658 0
WARREN ~.v aT..
Per 9
-2 -4 -6 -8 -10
-12 -14 -16
I
1
Low
Mid Men
~
High Women
FIGURE 49.1 Low-density lipoprotein cholesterol responses in women and men following the American Heart Association step I diet for an 8-week period. Subjects are grouped by tertile based on initial serum cholesterol level. Women had the following serum cholesterol responses: highest titer, initial values 295 (7.6 mmol/L) _+ 6 mg/dL,-12.8% (p < 0.0001); middle titer, initial values 253 (6.5 mmol/L) _+ 2 mg/dL,-9.0% (p < 0.0001); lowest titer, initial values 224 (5.8 mmol/L) _+ 3 mg/dL,-1.9% (p = 0.34). (From ref. 32, with permission.)
however, be the first step in management of both hypercholesterolemia and hypertension (35). Lower caloric intake, decreased total, saturated fat, and cholesterol intake, weight loss, sodium restriction, and abstinence from alcohol are effective dietary interventions used to lower blood pressure (34,35). In terms of dietary profiles that can affect blood pressure, increased potassium consumption has been shown to significantly lower it (36), and hypertensive patients may benefit from potassium supplements. Complex carbohydrates and soluble fiber have also been shown to lower blood pressure (37). Thus, women should actively attempt to improve unfavorable lipid profiles by restricting caloric intake, losing excess weight, consuming the recommended quantities and types oflipids, consuming sufficient complex carbohydrates and soluble fiber, and exercising. Evidence shows that 100 mg of aspirin taken every other day has little or no effect on all-cause mortality, but it does reduce the risk for stroke in healthy middle-aged and older women (38). Evidence of aspirin's effect on heart disease remains unclear (38). Although aspirin use may benefit women older than 65 with a higher baseline risk for cardiovascular disease, the A H A suggests that routine use of aspirin in lower-risk women under the age of 65 be delayed pending the results of ongoing trials (38,39). Aspirin recommendations are currently challenging because most data from primary prevention trials lack female patients and data on men may not necessarily be extrapolated to women. Further, aspirin therapy may increase the risk of hemorrhagic stroke in women with uncontrolled hypertension and may also cause gastrointestinal bleeding. Nonsteroidal anti-inflammatory medications should not be substituted for aspirin for CVD prevention. ~3-blockers are recommended for women who have
had a myocardial infarction or who have chronic ischemic syndromes, and angiotensin-converting enzyme (ACE) inhibitors should be prescribed for high-risk women. Angiotensin II receptor blockers (ARBs) should be used for high-risk women with clinical evidence of heart failure or an ejection fraction, of which 40% are intolerant to ACE inhibitors (25). Oxidative stress, which is defined as an imbalance between prooxidative factors and the antioxidative defense mechanisms, has been linked with the development of early stages of arteriosclerosis and cancer (40-43). Epidemiologic studies have shown that diets rich in antioxidants from fruit, vegetable, and vegetable oil sources reduce the relative risk of premature death from CVD and cancer (44). It is believed that an optimal antioxidant status is necessary for optimal health. Threshold antioxidant plasma levels associated with minimal relative risk of premature death by CVD and cancermin other words, desirable optimal levels--can tentatively be established from available consistent data (41-43,45). At these optimal antioxidant plasma levels, relative risks seem to disappear (44). Most middle-aged persons can obtain optimal plasma levels by consuming antioxidants at levels close to or only slightly above the current recommended daily allowances (RDAs) (46): 75 mg vitamin C in nonsmokers, 125 to 130 mg in smokers; 2 to 3 mg ~3-carotene in nonsmokers, and 15 mg or more for females over the age of 50 (44,47). The risk for CVD and cancer is twice as high at levels 25% to 35% below these levels. Suboptimal levels of a single antioxidant may increase relative risk, and suboptimal levels of several antioxidants further increase relative risk (44). The First U.S. National Health and Nutrition Examination Survey showed that habitual consumption of a vitamin C-containing multivitamin by the general middle-aged U.S. population reduced the mortality rate from CVD by approximately 42% in men and by about 25% in women (48). The effects of vitamin C consumed as a multivitamin did not have a significant effect in terms of lower cancer mortality (48). The U.S. Health Professionals Study and the U.S. Nurses' Health Study showed a protective effect against coronary risk for f3-carotene supplements in smokers but not in nonsmokers, probably because nonsmokers had above optimal levels of ~3-carotene even without the use of supplements, but smokers had low levels and they have an increased requirement (44). A low intake of vitamin A may increase the relative risk of breast cancer; thus, any benefit of vitamin A supplements may be limited to women with diets already low in vitamin A (49). Randomized antioxidant intervention trials conducted in China and Finland in middle-aged and elderly subjects over a 5- to 6-year period were successful in preventing the earlier stages of CV-D and cancer by rectifying previously poor antioxidant levels (50-52). However, antioxidant supplementation did not have an effect on irreversible precancerous lesions, clinically established common cancers, and vascular lesions in chronic smokers (44). It is therefore important for
CHAPTER 49 Role of Exercise and Nutrition women to start consuming a diet rich in antioxidants as a preventive measure before menopause, when the risk of CVD and cancer begins to escalate with advancing age. Some studies report no association between intake of antioxidant vitamins and relative risk of breast cancer (53), but because of the protective effects of some antioxidants on CVD and possible protective effects against breast cancer and other types of cancers, increasing dietary antioxidant intake seems like a prudent preventive measure. Studies have shown that antioxidant supplementation aimed at preventing or correcting previously poor levels may protect from both CVD and cancer. No evidence indicates that megadoses of antioxidants have an additional protective effect. Practitioners should discourage self-prescribed overconsumption of antioxidant supplements, especially because overdoses of the fat-soluble vitamin A can be extremely toxic. Antioxidants are most effective when overall nutritional status is optimized. The AHA guidelines recently stated that antioxidant vitamin supplements should not be used to prevent CVD pending the results of ongoing trials. In fact, the AHA recognizes that while the use of antioxidant supplements may have some benefits, currently there is evidence that certain levels may be harmful. Additional large-scale randomized trials of antioxidants in the primary and secondary prevention of CVD should be conducted to prove their effectiveness in reducing CVD risk before advising patients to take antioxidant supplements (25,54). Oxidative modification of LDLc may accelerate atherosclerotic plaque formation, and dietary antioxidant vitamins may play an important role in preventing CHD. However, intake of the antioxidant vitamins, vitamins A and C, was not correlated with decreased risk of death from C H D (25). Antioxidant vitamins exert an antioxidant effect on LDL and may also preserve the endogenous antioxidants of LDL (55). Preliminary data indicate that H R T can preserve the LDL particle content of two antioxidants, c~-tocopherol and [3-carotene, and keep the LDL in a reduced antioxidant state (55). However, the A H A states that estrogen plus progestin hormone therapy should not be initiated or continued to prevent CVD in postmenopausal women, and other forms of H R T such as unopposed estrogen, should not be initiated or continued pending ongoing trials. Overall, the A H A recommends a conservative approach in HRT use but suggests health care providers weigh the risks of therapy against the potential benefits for menopausal symptom control (25). Nutrition can play a role, not only in the primary prevention of CVD through the effects of the antioxidant vitamins, but also in the treatment of premature arteriosclerotic disease. Mild hyperhomocysteinemia, which is often present in patients with premature arteriosclerotic disease, can be corrected by treatment with compounds involved in folic acid metabolism, such as vitamin B6, folic acid, and betaine (25,56). The U.S. Food and Nutrition Board recommends
659 that women over the age of 50 consume 1.7 mg of vitamin B6 and 400 Ixg of folate (47). The A H A has concluded that the intake of omega-3 fatty acids in the form of fish has been associated with a reduced risk of CVD. However, the A H A encourages women of childbearing age and pregnant women to avoid shark, swordfish, king mackerel, and tilefish because the high mercury levels in these fish impair fetal neurologic development (25). Increased fruit and vegetable consumption lowers the risk of ischemic heart disease by almost 15% for those in the 90th percentile of fruit consumption compared with those in the 10th percentile of fruit consumption. Although the mechanism responsible for the protective effect on heart disease of fruit and vegetables is not well understood, the positive effect is commensurate with the estimated protective effects of the potassium and folate in these fruits and vegetables (57). The 2005 U.S. Department of Health and Human Services and the U.S. Department of Agriculture 2005 Dietary Guidelines recommend that people over the age of 50 meet their recommended dietary allowance (RDA) for vitamin B12 (2.4 Ixg/day) by eating foods fortified with vitamin 812 such as fortified cereals, or by taking the crystalline form of vitamin B12 supplements (58). Also of recent interest are studies indicating that moderate alcohol consumption may lower the risk factors for cardiovascular disease in postmenopausal women on a controlled diet (59). However, further studies should be conducted before moderate alcohol consumption is recommended to women. Because CVD is one of the main health problems of postmenopausal women, adequate dietary habits should be initiated as early as childhood or adolescence and maintained throughout life, especially during menopause and in the postmenopausal years.
III. CARDIOVASCULAR DISEASE: THE ROLE OF EXERCISE In recent years many studies have shown that increased physical activity plays an independent role in the primary prevention of CHD, the most serious and common form of CVD. Physically active individuals are at lower risk for C H D than those who have a sedentary lifestyle. Physical inactivity is a high risk factor for CVD, but it can also exert its effects by contributing to the physiologic changes associated with atherogenesis, such as hypertension, obesity, diabetes, and hypercholesterolemia. Exercise favorably affects plasma lipids and lipoproteins and thus may have protective effects against CVD and C H D mortality (60,61). Exercise increases the levels of the less dense HDL2 cholesterol subfraction, which normally decreases during menopause, by causing an increase in lipoprotein lipase, the enzyme that catabolizes triglyceride-rich lipoproteins (31). Higher concentrations of
660 lipoprotein lipase are found in the slow-twitch skeletal muscle fibers of endurance athletes (31). Exercise also lowers triglyceride levels. Population studies such as the Framingham Study have shown that age, total cholesterol, H D L cholesterol, systolic blood pressure, treatment for hypertension, cigarette smoking, and triglyceride levels (25,62,63) are the best predictors of C H D in women, and dietary or exercise interventions that can alter these lipids can decrease C H D risk. Thirty of forty studies conducted between 1985 and 1995 suggest that exercise can reduce cardiovascular risk between 10% and 50% (64). However, research on C H D risk and exercise has been conducted mostly in men. Few studies have examined the effects of exercise on CHD in women, and data from available studies are often inconsistent, possibly because the number of individuals in the high activity category is too small. Most cross-sectional studies examining the effects of exercise in women show a positive correlation between exercise and HDLc in both premenopausal and postmenopausal women (62). Longitudinal studies on the effects of exercise in women have given inconsistent results because of methodologic problems; nevertheless, about half the studies showed that exercise increases HDLc (62). HDLc can be expected to increase by approximately 10% in both men and women as a result of training (62). Large-scale prospective studies have consistently shown exercise to be effective in reducing heart disease (65-67). A meta-analysis of 27 cohort studies comparing sedentary and physically active individuals indicates an association between lack of physical actMty and increased risk of CHD (68). This study also found that the association is stronger when a high activity group is compared with a sedentary group, rather than when the active group only has a moderate activity level, indicating that a dose response relationship exists between physical activity and protection from C H D (68). Exercise was found to have a protective effect in terms of preventing major cardiovascular events in this study, but not in terms of reducing the severity of such events (68). Cardiovascular disease risk occurs less in women who exercise than it does in nonexercisers (69). One mechanism that may account for the decreased risk seen in active women is that these women may have more favorable blood pressure-related risk factors than do sedentary women (69). Physically active postmenopausal women in their mid-50s have more favorable systolic blood pressure-related CVD risk factors than do sedentary healthy women in their late 50s (69). The observed decrease in risk may result from the lower levels of abdominal adiposity found in the more active women. The study group was small (active women n = 18; less-active control subjects n = 34). Prospective studies need to be conducted with a larger group to establish more definitively the effects of exercise on blood pressure. In light of these findings, however, it would be prudent to advise patients to increase their level of physical activity because of its potential beneficial effects on blood pressure and consequent
WARREN ET AL.
reduction of CVD risk. Exercise therapy may be particularly appropriate for postmenopausal women, in whom LDLc levels rise sharply with increasing age, because antihypertensive medication, thiazide diuretics, and [3-adrenergic blockers all tend to increase blood cholesterol levels (3). Before prescribing antihypertensive medication, a patient's overall C H D risk profile should be evaluated and, in some patients, exercise and weight loss may be a safer alternative. Exercise improves cardiovascular fitness, which has been linked to decreased mortality in prospective studies. Longitudinal studies on cardiovascular disease indicate threshold levels of approximately 20 minutes per day of moderate physical activity or 2 to 3 hours per week (70). One study of 3120 women found that those with the lowest fitness level, as measured by maximal treadmill test, had a relative risk of death almost fivefold greater than those with the highest fitness level (60). Being in the lowest fitness level was associated with greater risk of death but slightly lower than the risk from having an elevated systolic blood pressure (> 140 mm Hg) or an elevated serum glucose (6.7 mmol/L). The risk associated with cigarette smoking was approximately equal to the risk associated with being in the lowest fitness category (60). A study in an Australian cohort showed that previously sedentary women who improved their fitness level over a 4-year period had significantly improved blood lipid profiles and systolic blood pressure (61). Similar benefits were not reported for the men in this study. Exercise appears to have many protective effects that can improve the C H D risk profile. In a cross-sectional study of premenopausal and postmenopausal runners and joggers, HDLc was higher in the women who exercised than in the inactive control subjects (71). The rise in HDLc was the same for premenopausal and postmenopausal women exercisers. In premenopausal women, exercise did not affect the HDLc/LDLc ratio, but in postmenopausal women exercise had a favorable effect on the ratio, which increased significantly from 0.57 mg/dL in the inactive women to 0.85 mg/dL in runners (71). Postmenopausal women may exhibit a greater response to exercise (72). In a crosssectional study of premenopausal and postmenopausal trained runners, the postmenopausal exercise group had a higher HDLc (74 mg/dL vs. 56 mg/dL), a lower LDLc (141 mgldL vs. 185 mgldL), and a higher HDLc/LDLc ratio (0.57 mg/dL vs. 0.32 mg/dL) than the sedentary postmenopausal control group (73). In the premenopausal group, only LDL changed significantly with exercise. In these two studies, exercise blunted the age-dependent increase in LDLc and prevented the age-dependent decrease in HDLc experienced by menopausal women. Both premenopausal and postmenopausal women who exercise can improve their lipoprotein profile and thereby reduce their risk of developing CHD. In prospective studies, sedentary women had a greater risk of developing hypertension
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CHAPTER 49 Role of Exercise and Nutrition independent of body weight (74). In a large study of perimenopausal women, those who increased their exercise participation over the course of 3 years gained less weight and had a smaller decrease in H D L 2 c (75). The activity levels in this study were moderate and seem to indicate that even slight increases in exercise at the time of menopause can help prevent the atherogenic changes in lipid profiles and the weight gain experienced by menopausal women. Thus, moderate exercise seems to lead to improved weight and blood pressure and to more favorable lipid profiles in both premenopausal and postmenopausal women. Controversy exists regarding the frequency and intensity of exercise that must be maintained to observe the beneficial rise in HDLc. Few studies have been conducted in postmenopausal women. At least 4 months of fairly strenuous activity, such as running 16 to 24 km per week, may be needed to obtain a significant increase in H D L c (31). More moderate activities, such as walking 48 km per week, require 3 months to observe a significant rise in H D L c (31). Walking can lower CVD risk because of its effects on cardiorespiratory function and on body fat. Walking 3 or 5 days per week increased peak volume of oxygen utilization (VO2
peak) and decreased body fat, but it did not alter serum lipids of nonobese, normolipidemic postmenopausal women (76). A case-control study of postmenopausal women found that the risk of myocardial infarction in this population is decreased by 50% with energy expenditures corresponding to 30 to 45 minutes of walking three times per week (77). In a large cross-sectional study of male runners participating in the National Runners Health Study, substantial increases in H D L c were observed in women who exercised at levels exceeding current guidelines (78). Official guidelines from the Centers for Disease Control and Prevention (CDC) state that most health benefits from physical activity can be achieved by walking 2 miles (3.2 km) briskly most days, which is the energy equivalent of running 8 to 12 km per week (79). However, the study conducted in runners demonstrated that women obtain additional health benefits from exercise at levels higher than currently recommended, because plasma H D L c concentrations increased for every additional kilometer run per week (Fig. 49.2). A 2-year randomized trial testing the effects of different intensities and formats of exercise on participation rates, fitness and plasma H D L c levels in older men and in
FIGURE 49.2 Plasma high-density lipoprotein (HDL) cholesterol concentrations according to weekly distance run. Menstrual periods were reported by 1390 women; the absence of periods was reported by 447. A total of 236 women reported using oral contraceptives and 176 reported using postmenopausal estrogen-replacementtherapy.The p-values shown in the figure are for the regression slope of HDL cholesterol plotted against distance run, with adjustment for age, education, progesterone use, and intake of red meat, fish, fruit, and vitamins C and E. (From ref. 78, with permission.)
662 postmenopausal women showed that moderate-intensity exercise improved cardiorespiratory fitness levels and improved HDLc levels (Fig. 49.3) (80). Two years were required to observe a change in HDLc. Frequency of participation played an important role in influencing HDLc in this age group (80). This finding differs from previous reports that exercise intensity is the determining factor affecting H D L c levels. In summary, most studies have shown that exercise causes an increase in HDLc, which may be related to the amount, frequency, and intensity of exercise, and that as many as 2 years may be required to produce this increase in HDLc. The effects of exercise, exercise intensi~, and hormone replacement therapy (HRT) on lipid and lipoprotein profiles are controversial. Some studies in women on HRT indicate that exercisers have higher HDLc levels than nonexercisers (62). In a cross-sectional study of postmenopausal women, regular exercise was associated with significantly greater HDLc concentrations, especially in women using exogenous estrogens (81). In the group of women who were not taking estrogen, the most significant increase in HDLc was observed for the sedentary versus the fight activity categories. Increasing activity levels from fight to moderate or heavy did not produce an incremental change in HDLc in this study (81). However, other investigators studying the effects of HRT and exercise on fipid metabolism had conflicting results. In a study assessing the independent effects of a moderate exercise program, with and without oral estrogen replacement, on lipids and lipoproteins in a group of postmenopausal women, estrogen therapy alone had the greatest beneficial effect on the lipid and lipoprotein profile (82). Exercise alone also favorably altered lipid and lipoprotein levels, resulting in a significant reduction in
FmORE 49.3 Bar graph shows mean change (with standard error bars) in high-density lipoprotein cholesterol based on the average number of exercise sessions per week completed across 2 years by exercise training condition (higher-intensity, group-based exercise; higher-intensity, homebased exercise; and lower-intensity, home-based exercise). (Adapted from ref. 80, with permission.)
WARREN ET AL.
cholesterol, triglycerides, and LDLc and in an increase in the H D L / L D L ratio. The combination of oral estrogen and exercise did not produce additional improvements in lipid metabolism (82). In a controlled, prospective 2-month clinical trial in postmenopausal women who participated in a 2-month, lowintensity exercise regimen followed by a 9-month period of high-intensity exercise for 45 minutes per day, three or more days per week, those in the exercise group had lower total cholesterol and LDLc levels, but HDLc and triglycerides were unaffected by the exercise regimen (83). Those in the exercise plus HRT group had decreased total cholesterol and LDLc and increased HDLc levels. Exercise was found to be protective against the HRT-related increase in triglycerides observed in the HRT group (83). However, recent studies examining H R T therapy on postmenopausal women indicate further risks from hormones. In March 2004 the National Institutes of Health (NIH) instructed participants in the Women's Health Initiative (WHI) to stop taking the estrogen study pills because of an increased stroke risk (84). The W H I study was established to assess the effects of long-term use of hormone therapy in healthy postmenopausal women on the prevention of heart disease and hip fractures as well as breast cancer. In early 2004, the NIH concluded that estrogen alone does not affect heart disease or b r e a s t cancer and that estrogen alone appears to increase the risk of stroke and decrease the risk of hip fracture. The increased risk of stroke in the estrogen-alone study is similar to the findings in the estrogen plus progestin study, which was discontinued in July 2002. The NIH follows the FDA guidelines, which recommend that postmenopausal women considering using estrogen or estrogen with progestin discuss the risks and benefits with their physicians. Estrogen and estrogen with progestin are still approved therapies for relief from moderate to severe hot flashes and symptoms of vulvar and vaginal atrophy (84). Hormone therapy is also approved for treatment of osteoporosis; however, the NIH advises that hormone therapy should only be administered to women at significant risk of osteoporosis who cannot take nonestrogen medications (84). The W H I study found a 24% reduction in all fractures and a 33% reduction in hip fractures in women assigned to estrogen plus progestin (85). In addition, the estrogen plus progestin trial was discontinued after 5.6 years of follow-up because the increased risk of breast cancer, coronary heart disease, stroke, and blood clots outweighed the benefits on hip fracture and colorectal cancer (84). The increased risk of breast cancer due to estrogen plus progestin was 8 additional cases of breast cancer for every 10,000 women over 1 year, and there was a 24% overall increase in breast cancer due to the estrogen plus progestin therapy (86). The breast cancer tumors in the estrogen plus progestin group tended to be larger and with more local spread as compared with women taking a placebo (86). Even 1 year after the study was discontinued, quite a few women
663
CHAPTER 49 Role of Exercise and Nutrition had abnormal mammograms in the estrogen plus progestin group (9.4%) as compared with the placebo group (5.4%) (86). The relative risk of coronary heart disease was 1.24 (6 more heart attacks annually per 10,000 women using estrogen plus progestin) with most of the events occurring in the first year (87). The relative risk of stroke was 1.31 (8 more cases per 10,000 per year) (88). Most of the strokes were ischemic rather than hemorrhagic (88). The estrogen studied in the estrogen alone trial was conjugated equine estrogens (CEE; Premarin) at a dose of 0.625 mg/day. There was no effect on heart disease or breast cancer; however, stroke risk was increased by 12 excess cases per 10,000 women per year and tended to increase deep vein thrombosis by 6 per 10,000 (89). The latter was much lower than the estrogen plus progestin arm of the study, which reported an excess incidence of 18 per 10,000. The study did find that CEE had no effect on pulmonary embolisms and decreased hip fractures at a rate of 6 fewer cases per 10,000 women per year and total bone fractures by 30%. These numbers are similar to those found by the W H I combined estrogen-progestin study (89). Although HRT remains controversial, all women should be encouraged to engage in physical activity starting at a young age so that they can enter menopause with improved CVD risk factors. Exercise is especially important during menopause and in the postmenopausal years as a means of attenuating the development of CVD risk factors that become more pronounced at this time. Evidence suggests that exercise, initiated sufficiently early in a woman's life, also protects against breast cancer, cancers of the reproductive system, non-reproductive system cancers, diabetes, and obesity (90-94). In fact, one study examining 74,171 W H I participants found that physical activity plays a protective role in women who engage in strenuous activity at the ages of 35 and 50 years, with the greatest associations observed for the lightest-weight women. Moderately overweight women, however, did also benefit from increased total physical activity (95). The study found that increasing physical activity (5.1-10.0 metabolic equivalent [MET] hours per week, which is equivalent to 1.25-2.5 hours per week of brisk walking) reduces the risk of breast cancer by 18%. And increasing the intensity of the physical activity more than 40 M E T hours per week further reduces the risk of breast cancer by 22% as compared with sedentary women (95). Women who engaged in strenuous exercise at least three or more times per week at the age of 35 had a 14% reduction in breast cancer risk compared with women who did not exercise at this level (95). Likewise, women over the age of 50 who engaged in strenuous exercise at least three or more times per week had a slight, though not statistically significant reduction in risk in breast cancer (95). The study also found that physical activity reduces risk among women who are using hormone therapy; a group that is at increased risk for developing breast cancer. Physical activity also helps women maintain a health body mass index, which is a risk factor for breast cancer. A
study of 85,917 W H I participants found that generalized obesity is an important risk factor for postmenopausal breast cancer, but only among women who have never taken HRT (96). For women of average size or less who exercised regularly and are taking or have taken HRT, there is no association between anthropometrics and breast cancer risk (96). Women above average size (body mass index [BMI] >-- 28.4) did not increase their risk of breast cancer with HRT use; however, exercise did not decrease their risk (96). Among HRT nonusers, their weight at the time of enrollment was the strongest predictor of breast cancer risk (96). For the HRT nonusers, heavier women (BMI > 31.1) had a greater relative risk of postmenopausal breast cancer compared with slimmer women (BMI -< 22.6); however, this effect was more pronounced in younger women (50-69 years of age) compared with older postmenopausal women (96). Exercise is also important for maintaining cardiorespiratory fitness, which decreases as a result of the aging process. Sedentary individuals have a 1% loss of VO2 max per year with age, particularly after age 50 (31). Physical activity can slow the natural age-related decline in aerobic power. The age-associated decline in muscle mass, strength, and flexibility can largely be prevented by regular exercise participation. Paradoxically, lowering body fat can adversely affect lipids. Exercise at an intensity that results in reduction in body fat and in a consequent drop in endogenous estrogen can cause atherogenic changes in lipoprotein profiles (3). Heavier postmenopausal women tend to have higher endogenous levels of estrone, because of increased aromatization of androstenedione to estrone. Higher estrone levels are related to higher HDLc and lower LDLc levels in perimenopausal women. Both men and women, but especially women, experience an age-related loss of muscle strength. Before beginning an exercise regimen, all women would probably benefit from a strength training program, especially those women who have been inactive for extended periods. Few studies have examined whether exercise can effectively prevent CVD. Lack of compliance has been a problem in many studies. Randomized clinical trials should be conducted to prove that exercise reduces cardiovascular risk and to establish the level of intensity, frequency, and exercise duration that produces maximal protective effects in postmenopausal women. These studies are hard to do because of lack of blinding, long-term intervention, and compliance issues. The combined effects of exercise, diet, and HRT on CV-D risk remain controversial.
IV. OBESITY Obesity is characterized by excess body fat or an excess storage of triglycerides in adipose tissue that results from consumption of a high-fat, high-calorie diet and a sedentary lifestyle. Obesity is a condition that has become more prevalent in
664 the United States and one that is often resistant to treatment. Women make up a greater percentage of the obese population than do men (97). The levels of central and total adiposi~, which increase with age, contribute to the development of cardiovascular and metabolic disease. The incidence of obesity increases threefold in adult women until age 65 (98). Individuals who are above the 85th percentile of BMI, which is the weight in kilograms divided by the height in meters squared, are usually classified as obese. Obesity is a risk factor for diabetes, low HDLc level, hypertension, degenerative arthritis, lipid disorders, gallbladder disease, renal disease, cirrhosis of the fiver, and several forms of cancer (24). Obesity places people at increased risk for CVD, because it is associated with four major risk factors for atherosclerosis: hypertension, diabetes, hypercholesterolemia, and hypertriglyceridemia (24). The waist/hip ratio is used to estimate the relative proportions of upper body or android obesity and lower body or gynoid obesity. A waist/hip ratio greater than 0.85 is indicative of android obesity and a ratio of less than 0.75 is indicative of gynoid obesity. The waist/hip ratio is the index of obesity most strongly associated with C H D (24). Android obesity is associated with increased risk of CVD. Central body fat is metabolically active: It is sensitive to catecholamines and insensitive to insulin. Gynoid adiposity is a store of fat that does not exhibit significant fatty acid fluxes because, unlike android obesity, it is resistant to catecholamines and sensitive to insulin. Women with gynoid obesity are less likely to develop diabetes mellims and C H D than are women with android obesity. Body fat in women tends to be distributed superficially on the body frame, whereas men are prone to central obesity (97). A significant increase in waist/hip ratio, which is indicative of central obesity, is observed in menopausal women, and this increase places women at greater risk for coronary artery disease, whereas lower-body or appendicular adiposity appears less harmful and is more favorably associated with serum triglyceride and HDLc levels and markers of insulin resistance (97,99). It is more difficult for the obese woman to lose weight than it is for the obese man; therefore, it is important for women to avoid gaining excessive amounts of weight during middle age. Men are able to maintain HDLc levels and lose central obesity by diet alone, whereas women must reduce their caloric intake and exercise to obtain the same results (97). A body mass index greater than 27 or more in late middle age, or approximately 65 years old, is associated with increased risk of coronary heart disease in late life (100). Women with a BMI greater than 27 would probably benefit from initiating a dietary and exercise regimen, and those with a BMI of 28 or more should definitely be treated (24). Increased mortality is seen at a BMI of 30, which corresponds to roughly 30% excess body weight (24). The American Heart Association (AHA) recommends women maintain a BMI between 18.5 and 24.9 kg/m 2 and a waist circumference less than 35 inches (25).
WARREN ET AL.
Central obesity is associated with an androgenic hormonal stares, hypertension, and irregularities in lipid and carbohydrate metabolism in middle-aged women (63), and it places women at an increased risk of C H D (101). Abdominal fat is associated with an atherogenic lipid profile in women that is influenced by insulin and estrogen (102). A direct relationship exists between central adiposity and increased total cholesterol, triglycerides, and LDLc in women and an inverse relationship between central fat and HDLc (103). The waist/hip ratio is the variable that is most strongly and inversely associated with the level of the HDL2 cholesterol subfraction (104). The HDL2 cholesterol subfraction is strongly related to protection from CVD. Women with large waist/hip ratios, which are indicative of android obesity, will have low HDL2 cholesterol levels, and they will therefore be at increased risk of developing CV-D. The amount of weight gained during menopause is strongly correlated with the degree to which cardiovascular risk factors such as changes in the lipid profile, blood pressure, and insulin levels become more pronounced (105). Blood insulin levels are elevated in obesity because excess body fat affects insulin secretion and sensitivity, resulting in insulin resistance. In both men and women, insulin resistance is influenced by total adipose tissue content, daily caloric intake, carbohydrate content of the diet, and daily exercise participation (24). In obese individuals, the observed increase in insulin secretion causes downregulation of insulin receptors, which in turn leads to insulin resistance. Carbohydrate, fat, and protein metabolism are all adversely affected by insulin resistance, and inadequate insulin suppression of fat cells leads to increases in circulating free fatty acids. HDLc levels decrease and LDLc levels increase because of the reduced catabolism of triglycerides caused by the insulin resistance (24). The atherogenic changes in lipid profiles caused by insulin resistance result in increased risk of CVD. High insulin levels can also contribute to the development of hypertension. Although hyperinsulinemia in obese individuals significantly increases their CVD risk profile, it is responsive to diet and exercise. Hyperinsulinemia is reversible with weight loss. Exercise promotes a more sensitive insulin response (94), and long-term athletic training is associated with a lower risk of developing diabetes (93). The resting metabolic rate decreases about 2% per decade after age 18, resulting in progressive weight gain over the years if no change occurs in caloric intake or exercise level (24). A study examining the effects of age and gender on energy expenditure independent of differences in body composition found no gender effect and no linear decrease in energy expenditure with increasing age; however, the middle-aged subjects had a lower basal metabolic rate (BMR) than did the younger ones (106). This effect on BMR is independent of body size, body composition, and level of activity (106).
665
CHAPTER49 Role of Exercise and Nutrition Dietary and exercise interventions to prevent weight gain during menopause may also have a protective effect in terms of breast cancer risk (107). Several studies have shown that a history of weight gain in early adult life is associated with increased breast cancer risk in Western women (107). Obesity also seems to be associated with increased breast cancer risk in Asian women. In a prospective case-control study of 1086 Singaporean Chinese women, central obesity was associated with the highest risk for breast carcinoma (107). Excessive weight gain in early adult life can lead to the development of hyperinsulinemia in women who are genetically susceptible to insulin resistance (107). The metabolic relationship between weight gain and breast cancer risk in Western women has been supported by evidence of insulin resistance in these women (107). Some studies have found that hyperinsulinemia is related to overall obesity in postmenopausal women; however, in premenopausal women it is related to abdominal adiposity (107). This finding could be the reason why a high BMI is a risk factor for breast cancer in postmenopausal but not in premenopausal women (107). It is believed that overnutrition and insufficient exercise can promote the development of hyperinsulinemia and increase breast cancer risk in genetically susceptible women, but this hypothesis has not been tested in intervention studies (107). Overweight and obese postmenopausal women should follow a weight reduction program to reduce their risk for CVD, hypertension, diabetes, and cancer. At the time of menopause, the rise in LDLc, triglycerides, and insulin levels is most pronounced in women who put on the most weight (105). The Nurses' Health Study demonstrated the importance of weight reduction in preventing CVD. The study found that women with a BMI of 29 or greater had a threefold increase in risk for CVD (109). In this study, 40% of coronary events were caused by excess body weight. Women who are mildly overweight have a substantial increase in coronary risk, and women who are very overweight have an even higher risk. In the Nurses' Health Study, 70% of coronary events were the result of excess body weight. Physicians should prescribe a diet and actively oversee the management of a realistic weight loss program to which the patient will adhere. In the first month, patients should lose 4 to 5 pounds, and in the next 4 to 5 months they should lose 20 to 30 pounds (24). An appropriate rate of weight loss can be achieved when energy expenditure exceeds energy intake by 500 to 1000 calories (110). As patients lose weight they should decrease their energy intake, because their energy requirements will be lower than they were before. For patients wishing to maintain their current weight, women over the age of 51 who are sedentary should consume approximately 1600 calories a day, women who are moderately active should consume 1800 calories a day, and women who are active should consume between 2000 and 2200 calories a day (58). The optimal diet for weight loss should be composed of 50% carbohydrates, 15% to 20% protein, and less than 30% fat.
Less than 10% of calories should be from saturated fatty acids, and the consumption of cholesterol should be less than 300 mg/day (58). This diet will not compromise vitamin and mineral status, but further caloric restriction has an adverse effect on overall nutritional status. The majority of fats should be from polyunsaturated and monounsaturated fatty acids, such as fish, nuts, and vegetable oils. Trans fatty acid consumption should be as low as possible. Reducing fat intake is the most successful method of weight loss, because fat has twice as many calories per gram than either carbohydrate or protein. Successful weight loss programs set realistic goals that can be reached by gradual weight loss through diet and exercise, and they teach patients behavior modification strategies. Weight loss and increased physical activity have been shown to reduce LDLc levels and to increase HDLc (111). In overweight and obese women, exercise alone or exercise combined with a low-fat diet was found to independently raise HDLc (112,113). Strenuous or prolonged physical activity inhibits appetite for an extended period and increases the resting metabolic rate for 24 to 48 hours. Obese individuals must incorporate increased physical activity into their lifestyles, because exercise is necessary to increase caloric expenditure significantly and to lose weight. It is important for the patient and the physician to design a weight loss program that encourages compliance, because repeated dieting and recidivism have a negative impact on metabolism. With successive diets the body can become more calorically efficient, resulting in difficulty in achieving and maintaining weight loss.
V. DIABETES The metabolic syndrome in women is characterized by risk factors including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance or glucose intolerance, prothrombotic state, and proinflammatory state (Fig. 49.4) (114). People with metabolic syndrome are at increased risk of coronary heart disease and other disease relating to plaque buildup in artery walls, as well as type 2 diabetes (114). Physical inactivity is often associated with the syndrome. Studies show that adoption of regular exercise by older adults (over the age of 67) is associated with reduced development of metabolic risk factors for cardiovascular disease, fewer exercise-induced cardiac abnormalities, and reduced comorbidity (115). A recent study by researchers at Johns Hopkins determined that in people age 55 to 75, a moderate program of physical exercise can significantly offset the metabolic syndrome risk factors causing heart disease and diabetes (116). In the Johns Hopkins study, exercise improved overall fitness, but the 23% fewer cases were more strongly linked to reductions in total and abdominal body fat and increases in muscle leanness, rather than improved fitness.
666
WARREN ET AL.
Diabetes mellitus is a chronic metabolic syndrome characterized by glucose intolerance, hyperglycemia, absolute or relative insulin availability, and insulin resistance. The alterations in carbohydrate, protein, and lipid metabolism in diabetics produce atherosclerosis and microvascular complications. Type 2, or non-insulin dependent diabetes mellitus (NIDDM), occurs more frequently with advancing age, and it is one of the major chronic disorders of older women. It is characterized by insulin resistance. A family history of diabetes, obesity, and age are the major risk factors for diabetes (117). An increased prevalence of diabetes is seen in women with advancing age, because women have a high tendency toward weight gain. Diabetes is a more important risk factor for CVD in women than in men, possibly because of its effects on lipoprotein profiles (8). Exercise and weight reduction are effective in the primary prevention of diabetes meUitus in most older women. Type 2 diabetics are insulin resistant and thus have hyperinsulinemia. Insulin resistance appears to be caused by decreased insulin receptor numbers and to postreceptor abnormalities, both of which cause alterations in the insulin action system. Genetic predisposition, aging, physical inactivity, and weight gain, especially android obesity, affect the development of insulin resistance. Certain patterns of fat distribution in middle-aged adults may confer additional risks for metabolic syndromes such as diabetes mellitus. The Health, Aging and Body Composition Study found that visceral
....R i s k
facs
"~ominal
........... Obesity
Defining--level '.......W.a i s t
cirCumferenCe
Men
> 102 cm (> 40 in)
Women
> 88 cm (> 35 in)
...T....r...i....g...l ....y....c...e....r....i...d....e....s...........................................z........1....5....0... m g / ~
................
HDL cholesterol Men
< 40 mg/dL
Women
< 50 mg/
B l o o d pressure
.....F a s s
-~ 1301185 ~ g
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giueose ............. e ~ l0 m g / ~
FmURE49.4 Clinicalidentificationof the metabolicsyndrome.The ATP III paneldid not find adequateevidenceto recommendroutine measurement of insulin resistance (e.g. plasma insulin), proinflammatorystate (e.g. highsensitivity C-reactive protein), or prothrombotic state (e.g. fibrinogen or PAI-1) in the diagnosis of metabolic syndrome.FromThird Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol and Adults (Adult Treatment Plan III). Executivesummary.AccessedMay 2001, from
http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.
abdominal adipose tissue (AT) and muscle-associated AT are related to insulin resistance in older subjects of normal weight, and that accumulation of these regional AT depots is characteristic of older people with type 2 diabetes and impaired glucose tolerance (118,119). Metabolic syndromes should therefore not be discounted on the basis of body composition, including body weight and BMI (118). Hyperinsulinemia in postmenopausal women is related to overall obesity, whereas in premenopausal women hyperinsulinemia is related to abdominal adiposity (107). Type 2 diabetics have a high incidence of complications caused by atherosclerosis, such as CHD, cerebrovascular disease, peripheral vascular disease, and premature and severe coronary artery disease (CAD). Type 2 diabetes also produces multiple lipid disorders, which place patients at increased risk of developing CHD. Elevated LDLc, elevated triglycerides, oxidized LDLc, and decreased HDLc are commonly seen in patients with poorly controlled type 2 diabetes. Both diet and exercise can prevent many of these complications. Improved diet and exercise are also protective against breast cancer. The incidence of breast cancer is high in societies with a sedentary lifestyle and with diets rich in fat, saturated fat, and refined carbohydrates (120). Exercise is considered an important intervention, because it increases insulin sensitivity and decreases triglycerides and total cholesterol. Exercise also improves glucose tolerance in both lean and obese type 2 diabetics under age 55; however, in those older than age 55, this effect is only seen in obese patients (121). Women who are obese, who have a family history of diabetes, or who have a history of gestational diabetes should periodically monitor their fasting plasma glucose levels, and they should initiate an exercise and weight reduction program for the primary prevention of diabetes mellitus (24). A sedentary individual who initiates an exercise program consisting of walking approximately 5 km per day or swimming, running, or biking 30 to 60 minutes per day is 50% less likely to develop diabetes (24). Long-term athletic training in premenopausal women is associated with a lower risk of developing diabetes (93). Preventing weight gain and possibly losing weight also decrease the likelihood of developing diabetes (93). A group of women ages 34 to 59 years who initiated a once a week exercise program had a 16% decrease in the relative risk of diabetes during an 8-year follow-up (122). Women in this cohort who lost weight and exercised showed a 33% decrease in their relative risk. Primary prevention of type 2 diabetes mellitus should be initiated at an early age in high-risk women. All women more than 30 years old who are overweight, hypertensive, or who have a family history of diabetes should exercise at least once a week to lose weight and thereby prevent type 2 diabetes. Therapy for type 2 diabetes consists of relieving symptoms and decreasing the risk of vascular complications, which are a common problem in these patients. Based on observations in
667
CHAPTER 49 Role of Exercise and Nutrition type I diabetics (123,124), it has been hypothesized that lowering glucose levels can reduce microvascular complications in type 2 diabetics; however, this has not been supported by data in type 2 diabetics (24). Type 2 diabetics should attempt to obtain good control of blood glucose through diet and exercise. The American Diabetes Association (ADA) and the World Health Organization diagnosis diabetes mellitus at random plasma glucose measurements greater than 200 mg/ dL with associated diabetes symptoms, at fasting plasma glucose levels greater than 126 mg/dL, or with 2-hour plasma glucose levels greater than 200 mg/dL (125). The ADA targets fasting glucose measurements less than 120 mg/dL (125). Patients without diabetes mellims may still demonstrate impaired glucose tolerance, with fasting plasma glucose levels less than 126 mg/dL and 2-hour postglucose load levels greater than 140 mg/dL (125). Dietary therapy for diabetes focuses on weight loss and reduced consumption of refined carbohydrates (126). Weight gain and overeating should be prevented because they increase insulin resistance (127). Simple carbohydrates such as sucrose should be avoided because they produce sharp increases in blood glucose. Complex carbohydrates such as starch do not cause drastic fluctuations in blood glucose. Women should restrict caloric intake to 34 kcal/kg of ideal body weight (24). Obese patients require a more severe caloric restriction to achieve weight loss. The diet should consist of 60% or less carbohydrates (mostly complex carbohydrates and dietary fiber); approximately 5% refined sugar; 12% to 20% protein; less than 30% total fat, 10% saturated fat, 10% unsaturated fat, and 10% monounsaturated fat; and 300 mg or less cholesterol per day (126). Dietary fiber has been shown to reduce serum cholesterol and to decrease the postprandial rise in blood glucose (128,129). The ADA initially recommended a total of 40 g of crude and soluble fiber intake per day (126) but subsequently found that such a high fiber intake interferes with the absorption of some vitamins and minerals. It now recommends an intake of 20 to 35 g of fiber per day for healthy adults (130). A low protein intake is essential to prevent the renal complications associated with high-protein diets. Type 2 diabetics will benefit from strict adherence to a fixed diet consisting of three meals a day with no snacks, because such a diet will improve plasma glucose levels when insulin levels are limited. Patients should be introduced to the Exchange Listsfor Meal Planning (126) to ensure proper nutritional balance. A nutrition assessment and an annual dietary history should be conducted in diabetic patients to determine compliance with the prescribed meal plan (131). Nutritional needs of diabetic patients require particular attention because complications associated with diabetes can affect these requirements (131). Vitamin and mineral requirements in diabetics may exceed the RDAs, and micronutrient imbalances or deficiencies can result (131). Vitamin and mineral deficiencies may play a role in decreased insulin secretion and
increased insulin resistance (131). Patients with poor control can lose large amounts of water-soluble vitamins and minerals (131). Careful dietary monitoring and supplementation may be useful in patients at risk of developing deficiencies; however, routine vitamin and mineral supplementation is not indicated in the management of most patients (131).
VI. OSTEOPOROSIS In the United States, approximately 15% of women age 50 or older have osteoporosis and 35% to 50% have low bone mass (135). Prevention of osteoporosis is extremely important, because compromised bone strength predisposes women to an increased risk of fracture. Bone strength is reflected in bone mass, bone density, bone architecture, bone size, and bone mineral quality (135). More than 40% of women in the United States over the age of 50 will suffer an osteoporotic fracture, typically in the vertebrae, hip, pelvis, ribs, distal forearm, and other limb bones (135). Further, there is a high association of hip fractures with increased mortality and decreased independence, with women suffering from a hip fracture showing 20% mortality in the first year; 50% of these patients will have some long-term decrease in mobility and independence, and 25% of these women will require long-term care (135). Osteoporosis is a multifaceted disease in which genetics, endocrine function, exercise, and nutrition play important roles. Once the disease becomes established, treatment options are not highly effective. Therefore, preventative strategies aim at preventing fractures by slowing or preventing bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to falls. Preventive strategies attempt to achieve and maintain peak bone mass through diet, exercise, HRT, and avoiding behaviors such as smoking that have adverse effects on bone (132). Parathyroid hormones used as a therapeutic agent may be available for some patients wishing to stimulate new bone formation (135). Risk factors for osteoporosis include menopause, smoking, poor vitamin D and calcium nutrition, lack of weight-bearing exercise, high alcohol intake, and a family history of the disease (132,133). The contribution of dietary factors, most notably calcium intake, and exercise to peak bone development has recently been under increased scrutiny. Improved diet and exercise during childhood are essential to reach adulthood with optimal bone mass. Bone mass accumulation until the age of 20 is determined largely by hereditary factors (134). Heredity accounts for 50% to 70% of the accumulated bone mass, but the remaining 30% to 50% is likely determined by dietary and other lifestyle factors until early adulthood (134). After age 20, lifestyle factors such as diet and physical activity become increasingly important in promoting an increase in bone mass. Attainment of peak
668 bone mass (PBM) and peak bone density (PBD) during the adolescent and early adult years and reducing bone loss after menopause are factors believed to be most important in preventing osteopenia and osteoporotic fractures during the postmenopausal years. Adequate calcium along with vitamin D intake prevents bone loss and reduces the risk of spine, hip, and other fractures in perimenopausal and postmenopausal women (135,136,138). Proper calcium nutrition increases bone mineral density (BMD) during periods of skeletal growth and prevents loss of bone and osteoporotic fractures in the elderly (137). During menopause, calcium requirements increase because bone resorption rate increases and bone mass declines (135). This increase in calcium needs results from the fall in ovarian estrogen production and the resulting decrease in efficiency of utilization of dietary calcium (135). At menopause, calcium absorption efficiency is typically 50% below that of adolescent peak absorption and is believed to be associated with a lack of vitamin D resulting from age-related declines in ingestion, dermal synthesis (139), renal enzymatic activity (140), and intestinal responsiveness (135,141). Total BMD decrease in the spine is approximately 15%, beginning 1.5 years after the last menstrual period and continuing at a rate of 3% for about 5 years (135). Hip BMD declines at a rate of approximately 0.5% per year before and after menopause and loses approximately 5% to 7% across the menopause transition period (135,142). Calcium supplementation slows the rate of postmenopausal bone loss by 30% to 50% (143). A review of more than 20 comprehensive studies indicates a bone loss of 0.014% per year in postmenopausal women receiving calcium supplementation compared with a bone loss of 1.0% per year in untreated women (144). The smaller decrease in bone loss was maintained for up to 4 years in longer-term trials (145-147). A 3-year study of older women (65 years and older) given 500 mg/day supplemental calcium (with vitamin D) demonstrated significant reduction in the loss of total BMD compared with a placebo after 1 and 3 years of therapy (148). The North American Menopause Society recommends at least 1200 mg/day of calcium for most women, with levels not exceeding 2500 mg/day (135). In postmenopausal women, loss of bone density in the forearm is significantly attenuated by daily calcium supplementation with 1000 to 2000 mg (149-151). Several studies indicate that calcium supplementation does not have a beneficial effect on spinal bone loss in early postmenopausal women (149,152,153). One study in immediately postmenopausal women reports a beneficial effect on cortical bone from calcium supplements (154). Calcium supplementation in women 3 to 6 years postmenopausal significantly reduced the rate of total body and femoral neck bone loss (155). In late postmenopausal women with low dietary calcium intakes (400 mg/day), a 500 mg/day
WARREN ET AL.
calcium supplement resulted in improvements in bone density of the spine, proximal femur, and radius as compared with the control group; however, the supplementation did not benefit women with higher initial calcium intakes (153). A 4-year randomized, placebo-controlled trial of 1 g/day calcium supplements in late postmenopausal women found significant reductions in the rate of bone loss from the total body, lumbar spine, and proximal femur (156,157). In the second half of the study, the group receiving calcium supplementation showed statistically significantly less bone loss in the total body. Based on evidence from this study, it can be concluded that the long-term use of calcium supplements produce small but significant cumulative benefits at baseline calcium intakes of 750 mg, which are typical of postmenopausal women in Western countries (143,157). A further study found that vitamin K1 supplementation in conjunction with calcium, magnesium and vitamin D over a 3-year period reduced bone loss of the femoral neck (158). Calcium appears to augment the effect of exercise on improving BMD in postmenopausal women; however, the benefits of exercise plus calcium were only observed with doses of calcium above 1000 mg (159). A 2-year randomized, placebo-controlled study examining the effects of calcium supplementation (1 g/day) and weight-bearing exercise in women who were more than 10 years postmenopausal found that calcium supplementation resulted in cessation of bone loss at the hip and in a significant reduction in the rate of bone loss at the tibia (160). Exercise plus calcium supplementation resulted in less bone loss at the femoral neck than calcium supplementation alone. Bone loss in elderly women may be attenuated by calcium in conjunction with vitamin D supplementation (133). In elderly women who are vitamin D deficient, rectification of the deficiency has been associated with a significant decline in hip fractures (161,162). In fact, a large 18-year prospective study found that adequate vitamin D intake is associated with a lower risk of osteoporotic hip fractures in postmenopausal women, whereas milk and high-calcium diets do not appear to reduce the risk (163). A large trial with elderly women with low vitamin D levels and low calcium intake who received supplemental vitamin D (800 IU/day) and calcium (1200 mg/day) for 18 months had significantly fewer nonvertebral fractures (32%) and hip fractures (43%) than placebo recipients (164). A recent study of daily calcium and vitamin D supplementation in men and women more than 65 years old found that 500 mg of calcium and 700 IU of vitamin D3 moderately reduced bone loss in the femoral neck, spine, and total body during the 3-year study period (165). The supplementation program also reduced the incidence of nonvertebral fractures. Optimal calcium absorption is dependent on proper vitamin D nutrition (166). A fall in intestinal calcium absorption causes an increase in parathyroid hormone secretion leading to mobilization of calcium from the skeleton and bone loss. This process is reversed by vitamin D therapy, which
669
CHAPTER 49 Role of Exercise and Nutrition improves calcium absorption from the bowel by 20% of the level of insufficiency (167). Elderly patients are at increased risk of vitamin D deficiency (levels less than 10 n g / m L of 25-hydroxyvitamin D [25OH]D]), and their vitamin D status should consequently be monitored. T h e level of insufficiency is the level of 2 5 ( O H ) D at which there appears to be an inadequate absorption of calcium to maintain necessary physiologic levels of circulating calcium levels. A parathyroid hormone increase is triggered, which occurs at the expense o f b o n e - - a level at about 30 ng/mL. One study of 78 hospitalized patients with
TABLE 49.2
M e a n intake of vitamin D (Ixg) from food and food plus dietary supplements. CSFI a
Sex/age category Both sexes, 1-3 years Both sexes, 4 - 8 years Males, 9-13 years Males, 14-18 years Males, 19-30 years Males, 31-50 years Males, 51-70 years Males, -> 71 years Females, 9-13 years Females, 14-18 years Females, 19-30 years Females, 31-50 years Females, 51-70 years Females, - 71 years
Sample size
osteoporotic fractures (76 were hip fractures) reported that 97% had vitamin D levels less than 30 ng/ml (168). T h e National Health and Nutrition Examination Survey ( N H A N E S ) III report showed that 70% of women between 50 to 70 had inadequate vitamin intake as well as 90% of women over 70 (Table 49.2) (169). Another study recently showed that more than 50% of women over 50 in North America have low levels of vitamin D, and the proportion increases with age (170). Daily supplementation with 600 to 800 IU of vitamin D in institutionalized elderly patients improves calcium balance and reduces
Vitamin D from food (mg/d 6 IU/d) c
NHANES III b
Sample size
Vitamin D from food (mg/d 6 IU/d) d
Vitamin D from food and supplements (mg/d 6 IU/d) d
Percent using vitamin D-containing supplements
3777
6.0 _+ 0.05 (242)
3309
5.7 + 0.09 (228)
9.8 _+ 0.32 (393)
39.3
3769
5.9 + 0.08 (235)
3448
6.0 _+ 0.10 (240)
9.4 _+ 0.22 (376)
36.0
569
6.6 _ 0.19 (265)
1219
6.6 _+ 0.27 (264)
8.7 _+ 0.33 (346)
22.0
446
6.9 _ 0.28 (274)
909
7.0 _+ 0.40 (280)
7.7 +_ 0.40 (310)
11.0
854
4.0 _+ 0.18 (190)
1902
5.5 _+ 0.21 (220)
8.0 _ 0.53 (320)
20.4
1684
5.2 _+ 0.11 (210)
2533
5.7 _+ 0.25 (230)
7.9 _ 0.35 (315)
23.7
1606
5.2 _+ 0.10 (207)
1942
5.7 _+ 0.18 (227)
8.0 _ 0.27 (320)
25.4
674
5.5 _+ 0.15 (220)
1255
5.9 +_ 0.16 (236)
8.3 __ 0.24 (332)
26.0
580
5.2 _+ 0.15 (206)
1238
5.2 _+ 0.24 (210)
7.3 __ 0.31 (291)
24.1
436
3.9 ___0.14 (154)
974
4.3 _+ 0.20 (172)
5.3 +_ 0.23 (210)
14.9
760
3.5 _+ 0.15 (140)
1919
3.9 _ 0.18 (156)
6.1 _+ 0.23 (244)
25.2
1614
3.7 _+ 0.09 (148)
2953
3.9 _+ 0.13 (158)
7.1 _+ 0.35 (283)
30.4
1539
4.0 _+ 0.14 (160)
2076
4.5 _+ 0.16 (178)
7.8 _+ 0.29 (312)
31.0
623
4.3 _ 0.12 (172)
1368
4.5 _ 0.12 (180)
8.1 _ 0.56 (325)
29.7
Two-day average estimates based on data from the U.S. Department of Agriculture, Agricultural Research Service, Continuing Survey of Food Intakes by Individuals (CSFIII), 1994-1996, 1998, and ENVIRON Health Sciences Institute Vitamin D database. Error terms for the CSFII data were calculated with WesVar Complex Samples 3.0 software (Westat, 1998). bDay 1 estimates based on data from U.S. Department of Health and Human Services, National Center for Health Statistics, Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Standard errors for the NHANES data were estimated by the Taylor linearization method utilizing Software for Statistical Analysis of Correlated Data (SUDAAN User's Manual, Release 7.5, Research Triangle Institute, 1997). cl Ixg vitamin D = 40 International Unites (IU). dContinuing Survey of Food intakes by individuals (CSFII) and the Third National Health and Nutrition Examination Survey (NHANES III). Excludes breastfeeding infants and pregnant and lactating females. Reprinted with permission from Moore C, Murphy MM, Keast DR, Holick ME Vitamin D intake in the United States.JAm Diet Assoc 2004;104:980-983. a
670 fracture risk (171). The supplementation program also reduced the incidence of nonvertebral fractures. In studies of calcium supplementation without concomitant vitamin D, fracture rates were reduced in postmenopausal women with prior spine fractures and low calcium intakes; however, there was no reduction in fracture rates in women with a history of fractures (172). A recent study reports that vitamin D levels are a better predictor of calcium absorption than calcium intake (173-176). Vitamin D also appears to have other beneficial actions, including antiproliferative effects, which may decrease cancer risk, including colon breast and prostate, and effects on muscle and the cardiovascular system and enhance immunity. Vitamin D can be acquired via sunlight alone or by diet. Sunlight is the most effective source of vitamin D, with a slight sunburn yielding the equivalent of 10,000 to 25,000 IU of oral vitamin D (177). A randomized trial found that a group of stroke patients exposed to sunlight over a 1-year period had a higher mean level (25[OH]D), higher bone mineral density, and a lower incidence of hip fracture than a group of patients not exposed to sunlight (177,178). The provision of vitamin D by sunlight can be hampered by sunscreen use, melanin in darkly pigmented people, winter months in northern latitudes, and increased age. Dietary sources of vitamin D include oily fish and fish liver oil; it is found commonly in fortified milk, cereals, and bread products. However, because milk also contains vitamin A, which does not support bone health, it is recommended that women obtain vitamin D through supplements or consumption of dark fish (163). In addition, recent studies indicate that increased milk and calcium consumption are not associated with a lower risk of osteoporotic hip fracture (55,177). Based on current studies, the Food and Nutrition Board recently set the adequate daily intake of vitamin D at 10 ~g for women 51 to 70 years of age and 15 ~tg for women greater than 70 years of age (163,179). A recent study of 2310 adults found that as long as vitamin D intake is adequate, calcium intake levels of more than 800 mg/day may be unnecessary in maintaining calcium metabolism (180). Studies examining the effect of calcium supplementation on fracture number in postmenopausal women indicate that calcium supplements may be effective in preventing fractures despite only a modest 1% to 4% difference in BMD between the treated and placebo groups (157,181). A 4-year follow-up study of elderly women found that calcium supplementation is associated with a 45% reduction in the incidence of vertebral fractures in women with a pre-existing fracture but had no effect on women who were fracture free at the beginning of the study (182). The difference in BMD in the two groups in this study was less than 2%. Small effects on BMD may thus result in significant protective effects on fracture risk, especially in high-risk women who have already suffered a fracture. Calcium supplements cause decreases in bone turnover rates, which result in the preservation of trabecular connectivity
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(143). Supplements improve neuromuscular function and therefore may prevent falls, ultimately resulting in fewer fractures. Long-term studies are needed to definitively assess whether the small benefit on BMD in postmenopausal women is protective against fractures. In most studies, calcium supplementation produced small but significant benefits on axial bone density in women more than 5 years after the menopause. Calcium supplementation is probably most effective when given in several doses, because divided doses will prevent saturation of the calcium-active transport system and will result in its increased absorption (143). Calcium-active transport is also stimulated by the major vitamin D metabolite, 1,25dihydroxyvitamin D. Consuming supplements with meals allows food acids to contribute to the dissolution of insoluble calcium salts and lengthens its transit time in the small bowel, also resulting in improved absorption (143). It is important to have calcium available at night, when bone resorption rates are greatest. Ideally, patients should consume small amounts of calcium with meals and at bedtime. Consuming 500 mg of calcium carbonate after breakfast and after dinner or 1000 mg of calcium lactate-gluconate at night is probably easier for most patients (143). All women older than 51 years should consume 1200 mg/day of calcium (47). Calcium-rich foods such as dairy products should constitute the primary source of daily calcium intake, but supplements can be used by patients who cannot consume adequate amounts of calcium through diet alone. In addition to proper calcium and vitamin D intake, a recent study demonstrated that elderly women with higher protein intakes, approximately 71 g/day as a percentage of energy, had higher BMDs when daily calcium intake exceeded 408 mg/day (183). Bone mass density was significantly higher in the spine (7%), midradius (6%) and total body (5%), but no significant difference was observed in hip BMD (184). The study did not observe any significant difference between dairy and nondairy protein consumption. On the other hand, studies of young adult women show that low-protein diets depresses intestinal calcium absorption and were often accompanied by secondary hyperparathyroidism (184,185). Although the exact repercussions of a low-protein diet are not fully understood, there definitely exists a potential to affect bone health (184,185). The type, duration, and frequency of physical activity needed to result in observable beneficial effects on bone remains controversial. Regular exercise including resistance training and high-impact activity contributes to the development of high peak bone mass and may reduce the risk of falls in older women (138). In a study of female college athletes, activities that involve high skeletal impacts, such as gymnastics, were found to be especially osteotropic for young women (186). Bone mineral density at the lumbar spine and femoral neck was found to respond dramatically to the mechanical loading exercises typical of gymnastics training, whereas running and swimming did not have pronounced effects on
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CHAPTER 49 Role of Exercise and Nutrition BMD. Muscle strengthening activity did not seem to have a significant effect on BMD in gymnasts (186). A study of mature female athletes had similar findings, namely that women who regularly engage in high-impact physical activity in the premenopausal years have higher BMD than nonathletic control subjects (187). Amenorrhea in premenopausal women, particularly in competitive athletes, can adversely affect bone mass (188). Increasing physical activity can slow bone loss in postmenopausal women, even if exercise produces no significant increase in BMD (189). Studies indicate that moderate levels of physical activity provide protection against later hip fracture, whereas decline in physical activity level over time is an important risk factor for hip fracture (70,190). Longitudinal studies examining the effects of walking interventions show that walking, which is frequently prescribed to postmenopausal women, does not prevent bone loss (191-194). Higher intensity exercises may be required to attenuate menopausal bone loss. A randomized, controlled trial of high-intensity strength training exercises two days per week
conducted in postmenopausal women ages 50 to 70 years showed that the exercises preserved bone density and improved muscle mass, strength, and balance (195). No evidence indicates that exercise alone can replace bone loss during menopause (189). A 12-month study investigating the effects of aerobic training conducted three times a week at 70% to 85% of maximal heart rate (Fig. 49.5) for 30 to 45 minutes and calcium supplementation did not find significant increases in forearm or lumbar BMD, but the training did attenuate lumbar BMD loss in early postmenopausal women (approximately 6 years of the onset of menopause) (196). The exercise program produced significant gain in aerobic power. Prospective studies of strength-training, muscle loading, and aerobic exercise programs in postmenopausal women are difficult to compare because they differ in terms of exercise prescription, length of follow-up, subject age hormonal status, and method and site of BMD measurement. Nevertheless, the literature seems to indicate that exercise increases forces on bone and may thereby attenuate loss of bone mass (197).
FIGURE 49.5 Aerobictraining guide. Exercise performed at 70% to 85% of the maximal heart rate was found to be protective againstlumbar bone loss in earlypostmenopausalwomen and to produce significantgain in aerobicpower.(From ref. 24, with permission.)
672 It is important to understand the influence of behavioral and genetic factors on BMD in premenopausal and postmenopausal women to assess adequately the effectiveness of interventions aimed at increasing or maintaining BMD. A study conducted on 25 elderly women, whose mean age was 72 years, and on their premenopausal daughters, whose mean age was 41 years, investigated the associations between lifetime milk consumption, calcium intake from supplements, lifetime weight-bearing exercise, premenopausal and postmenopausal hormone use, and BMD to determine the relative importance of lifestyle factors, such as calcium intake and physical activity, and genetic contributions (198). In the older women, multiple regression analyses showed that total and peripheral BMD were positively related to calcium intake from supplements after age 60, body weight, current ERT, and past oral contraceptive (OC) use. Axial BMD in this group was positively associated with body weight and past OC use. By contrast, in the premenopausal women, total and peripheral BMD were found to be determined by lifetime weight-bearing exercise, and axial BMD was found to be determined by total lean body mass. Mothers and daughters had similar lifetime milk consumption patterns (198). The results of this study indicate that supplemental calcium intake and exogenous estrogen have a positive effect on bone mass in postmenopausal women and that physical actMty is effective in preventing osteoporosis. Behavioral and hormonal factors had a stronger effect on BMD than did familial similarity in the premenopausal and postmenopausal women studied. Women, therefore, are capable of increasing their genetically determined bone mass by engaging in weight-bearing physical activity, following a postmenopausal ERT regimen, and consuming an adequate amount of calcium (198). Calcium alone does not prevent menopause associated bone loss as effectively as when combined with estrogen replacement therapy (ERT)/HRT, selective estrogen receptor modulators (SERMs), or bisphosphonates (135,199). Although calcium plus vitamin D can reduce the risk of fracture, it is no substitute for an antiresorptive agent in early postmenopausal women. The Multiple Outcomes of Raloxifene Evaluation (MORE) study of 7705 postmenopausal women with osteoporosis showed a reduced risk of vertebral fractures (200). In addition, the bisphosphonates alendronate and risedronate have also shown a reduction in vertebral and hip fractures in women with low bone density, although their effectiveness was dependent on the women's fracture status at the entry into the clinical trial (201-204). Vitamin D deficiency results in secondary hyperparathyroidism and increased rates of bone catabolism. The effects of the potent vitamin D metabolites such as calcitriol and alphacalcidol on postmenopausal bone density remain controversial (143). HRT or the potent bisphosphonates produce greater increases in BMD than the vitamin D metabolites (143). HRT
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is routinely used to prevent and treat osteoporosis. In fact, the 2004 Position Statement issued by The North American Menopause Society recognizes that ET and combined estrogen-progestogen therapy (EPT) are effective in reducing the risk for postmenopausal osteoporosis fractures; however, it is suggested that ET/EPT use must be balanced against the risks (204). Studies of early postmenopausal women indicate that calcium alone was not as effective as ERT/HRT alone in reducing estrogen-withdrawal bone loss, but supplemental calcium did improve the efficacy of ERT/HRT (206). Several studies investigating whether calcium supplementation is beneficial to women on HRT seem to indicate that it is, but more study is needed in this area (152,207,208). Estrogen, when used as an antiresorptive agent, can be prescribed alone as estrogen replacement therapy or as hormone replacement therapy (135). The effects of HRT and exercise on bone have been found to be synergistic in many studies; however, some studies have not found a complementary effect. A placebocontrolled, 2-year prospective trial of two estrogen-progestin regimens in healthy postmenopausal women investigating the effects of HRT and exercise on bone density, muscle strength, and lipid metabolism found that exercise exerted a positive effect on BMD in the placebo group, however, in the HRT group no synergistic effect of exercise and estrogen on BMD was observed (209). Exercise cannot substitute for HRT, which clearly has the most significant impact on BMD. Estrogen therapy is effective in the prevention of osteoporosis and in treatment of established osteoporosis (210). A doubleblind, placebo-controlled randomized study conducted in 120 postmenopausal women (mean age 56 years) with low forearm bone density examined the effects of an exercise regimen, exercise combined with 1000 mg of supplemental calcium, and exercise plus estrogen and progesterone (Fig. 49.6) (150). The control group, which consisted of women with normal bone density, had a 2.7% decrease in distal forearm bone density per year. The exercise group showed a similar 2.6% decrease. The exercise-calcium group had significantly reduced bone loss (-0.5% of the baseline value per year). Bone density actually increased by 2.7% over the baseline value per year in the exercise-estrogen group. Similar patterns of bone loss and accrual were observed in the median forearm. In postmenopausal women with low BMD, bone loss can be slowed or prevented by a combined regimen of HRT and exercise or by calcium supplementation plus exercise (150). An exerciseestrogen regimen was more effective in increasing bone mass than calcium plus exercise. The exercise regimen used in this study, a 1-hour low-impact aerobics session per week with 30% of the time devoted to arm exercises, and two 30-minute brisk walks per week, was fairly moderate. A more significant exercise effect might have been observed at a higher training intensity. Nevertheless, the results of this study seem to indicate that both exercise and nutrition play important roles in the prevention and treatment of osteoporosis. In addition, a study administering estrogen and high amounts of calcium
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for the proper development and maintenance of the skeleton, and sedentary women can slightly increase their bone mass and prevent further bone loss by becoming more active (189). Exercise programs for older women should aim to improve muscle tone, strength, flexibility, and coordination, which may reduce falls in older women and prevent osteoporotic fractures (133,189). Many postmenopausal women are inactive. Clinicians should help their patients design an indMdualized moderate exercise program that is both safe and encourages compliance. The osteogenic effects of such a program may be modest, but the long-term effects on cardiorespiratory fitness, strength, and agility will improve the overall health and quality of life of postmenopausal women well into old age.
VII. TRACE ELEMENTS
FIGURE 49.6 How various treatments affect bone density. Effects of exercise only, calcium with exercise, and estrogen with exercise in postmenopausal women. (Adapted from ref. 150,with permission.)
(1183 mg/day through diet and supplements) demonstrated a significant increase in BMD at various skeletal sites in comparison to estrogen therapy combined with low calcium intakes (563 mg/day)(206). Body weight also contributes to BMD. Obesity and N I D D M are associated with increased bone mineral density. In a study of 559 women, fasting insulin levels were significantly and positively associated with bone density in the radius and in the spine (211). This study indicates that hyperinsulinemia may partly explain the association of diabetes and obesity with BMD in women (211). Weight loss in postmenopausal women can lead to decreased BMD. The number of pregnancies and a BMI of less than 20 kg/m 2 also had an adverse effect on BMD in a group of Mexican women (212). Increasing age and lack of exercise were found to be significant predictors of bone demineralization in this group. In summary, women with established osteoporosis can be treated with estrogen, or with estrogen and progestin, calcium, and vitamin D (133). Although HRT has the most significant impact on bone, its use remains controversial because of the side effects. Neither calcium supplementation nor exercise can substitute for HRT at the time of menopause, but their importance should not be overlooked. Estrogen-related bone loss usually takes place 3 to 6 years postmenopause, but loss caused by calcium deficiency results in continued bone loss until the nutritional inadequacy is corrected (213). Many postmenopausal women have low calcium intakes. Absorption efficiency decreases with age, exacerbating the existing nutritional inadequacy. Supplementation is therefore important in this population. Weight-bearing exercise is essential
Although the role of trace minerals in osteoporosis is still controversial, increasing evidence indicates that trace minerals are important for adequate bone formation and maintenance. Calcium, vitamin D, fluoride, magnesium, and trace elements such as copper, manganese, and zinc are essential for optimal bone matrix development and the maintenance of bone mineral density (214). These trace elements are necessary because they serve as cofactors for certain enzymes. A study investigating the role of copper, manganese, and zinc in bone metabolism in a rat model found that female rats placed on diets low in manganese or in copper and manganese for a period of 12 to 24 months had significantly lower BMD than those placed on a trace mineral-sufficient diet (215). The trace element-deficient groups had higher serum calcium concentrations. Serum and femur calcium content were inversely correlated; examination of isolated femurs showed an increase in femur porosity. Based on this observation, the authors concluded that trace mineral deficiency can result in changes in bone crystal composition and alteration of calcium control at the level of the bone (manifested as decreased mineralization or increased bone resorption), intestine, or kidney (215). Another group investigated the effects of dietary copper or manganese restriction on serum levels of calcium, copper, and manganese and on body mass density of the right femoral shaft in male rats kept on one of four diets for 12 weeks (216). By 8 weeks, BMD in the femoral shaft was significantly lower in the rats that were copper and manganese deficient than in the controls; rats placed on diets deficient in only one of the two trace minerals had intermediate BMD (216). Subcutaneous implants of demineralized bone powder (DBP) and bone powder (BP) were used to determine the effects of long-term dietary deficiencies in manganese and copper on the cellular activity of bone formation and bone resorption in vivo (217). This study found that osteoblast activity is compromised more than osteoclast activity,
674 resulting in increased bone resorption. Both bone formation and resorption are impaired by long-term dietary manganese and copper deficiency (215). Manganese deficiency in rats also resulted in lowered proteoglycan content in the organic matrix of bone (214). Evidence from animal studies for the importance of trace elements in bone formation and maintenance led investigators to study the role of trace elements in humans. A retrospective study in normal and osteoporotic women showed that bone integrity correlates with serum manganese levels (218). The osteoporotic women had low trabecular bone volume, low bone mineral content, low BMD, and significantly lower serum manganese levels than the control group. Cross-sectional studies in a group ofpostmenopausal women showed a strong correlation between low BMD and low dietary calcium intake and serum copper levels (219). A 2-year prospective, double-blind, placebo-controlled clinical trial evaluating the effect of supplementary calcium with and without a combination of copper, manganese, and zinc found a significant association between BMD and supplementation with calcium and trace minerals (220,221). Dietary calcium, copper, manganese, and zinc supplements could significantly decrease the loss of BMD in postmenopausal women (220,221). A recent study of postmenopausal women found that iron was associated with greater BMD at all sites (222). The study uncovered a complex calcium-iron relationship in which women who consumed 800 to 1200 mg of calcium had significantly higher BMD with increasing levels of iron intake. However, women with lower or higher intakes of calcium did not demonstrate the same association of iron and BMD. Although the exact relationship of iron to BMD is not fully understood, it is known that iron is essential for the synthesis of collagen structure upon which bone mineralization occurs (223). Iron is also involved in the conversion ofhydroxyvitamin D to 1,25-dihydroxyvitamin D, the active form of vitamin D (222,224). Animal studies have confirmed the association of iron to BMD. In one study on iron deficient rats it was found that the iron deficient rats had decreased bone mechanical strength in their femurs as compared to normal rats with similar BMD, BMC and dietary levels of calcium (222,225). Other studies found that iron deficiency resulted in low bone mass and bone volume (222,226,227). However, it appears that limitations to iron supplementation exist and iron overload has been associated with low bone density (222,228,239). Further studies of iron intake and the biologic mechanisms of iron and bone mass density are warranted. These studies suggest that trace elements are needed for optimal bone development and for maintaining bone density. Postmenopausal women who consume a balanced diet can significantly reduce the incidence ofosteoporosis. The amount of calcium used in the clinical trial was 1000 mg/day and the amount of zinc used was 15 mg. The current U.S. RDA for
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calcium is 1200 mg/day for women over the age of 51 and 8 mg/day of zinc and 1.8 mg/day of manganese (46). The amount of copper used was 5 mg and 2.5 mg. The U.S. RDA of copper is 900 p~g/day (46,220,221). Many multivitamin supplements with minerals contain similar amounts of copper, zinc, and manganese. It therefore might be prudent for postmenopausal women to take a daily multivitamin with minerals in addition to consuming at least 1200 mg of calcium through the diet or by the use of supplements.
VIII. DEPRESSION The incidence of psychiatric disorders increases with each decade of life (230), and depression is more prevalent in women than in men. Many women deny they are suffering from depression and often refuse to see psychiatrists. Women have a 20% to 25% lifetime risk of suffering from a major depression (231). Many women and some clinicians share the misconception that women are likely to become depressed or irritable during menopause. Cross-sectional and longitudinal analyses of 2565 women ages 45 to 55 years participating in the Massachusetts Women's Health Study (MWHS) found no association between menopause status or change in menopause status and depression (231,232). Prior depression was found to be highly predictive of increased depression. A lengthy perimenopausal period was associated with increased depression (232). Depression typically manifests itself as depressed mood; however, older women more often have other symptoms such as loss of appetite, weight loss, decreased energy levels, decreased motivation, and sleep disturbances (24). Physicians should prescribe a suitable course of antidepressant medication and psychotherapy for treatment of depression, but the potentially adverse impact of a depressive disorder on a woman's nutritional status should be carefully monitored. No hard data exist on the role of nutrition in the management of depression. Nevertheless, the use of nutritional supplements, which provide a good balance of essential nutrients, might prove helpful in the depressed patient who may not have the appetite or the motivation to consume regular meals. Health professionals and regular exercisers share the belief that exercise produces psychologic benefits (233). The effects of exercise on anxiety, depression, personality, cognition, fatigue, socialization, and work performance have been extensively investigated, but most of the studies were not carefully designed or controlled (233,234). One study reviewed randomized, controlled experiments conducted mostly in male populations of all age groups on the psychologic effects of habitual aerobic exercise on mood, personality, and cognition (233). The study found evidence that exercise improves self-concept; however, it did not find significant evidence to substantiate claims that exercise
CHAPTER 49 Role of Exercise and Nutrition improves anxiety, depression, body image, personality, or cognition (233). An earlier review of the literature found suggestion that physical fitness results in improved mood, self-concept, and work behavior, and that improvements in physical fitness have an effect on self-concept but not on other personality traits in male and female cohorts of various age groups (234). A popular belief that does not appear to be supported by the scientific literature is the concept of the runner's high, a feeling of euphoria believed to result from release of [3-endorphin. A study examined the effect of running on plasma [3-endorphin in 6 female and 20 male trained long distance runners (235). Although running did produce increases in plasma [3-endorphin that were more pronounced at higher training intensities, the authors caution that the decrease in anxiety reported after running, the other mood changes, and the runner's high cannot be caused by the small changes that occurred in peripheral plasma [3-endorphin concentration (235). Most studies of the effects of exercise on psychologic health have been conducted in men. A clear need exists for well-designed studies in women, especially because preliminary evidence indicates that postmenopausal women will derive benefits from exercise in terms of fitness, psychologic well-being, and overall health (236). A randomized, controlled trial studying the impact of a 12-month exercise program on the physical and psychologic health in 124 postmenopausal, osteopenic women ages 50 to 70 years found that exercise produced significant increases in functional fitness, psychologic well-being, and self-perceived health (236). The exercise program consisted of weight-bearing exercises, aerobic dancing, and flexibility exercises performed for 60 minutes three times per week. This program was tailored for osteopenic women, who also benefited from decreased back pain and a stabilization of spinal BMD, but similar programs suited to all postmenopausal women should be studied in controlled, randomized trials. All women should be encouraged to exercise because of the potential physical and psychologic benefits they can derive from exercise. Even if future studies do not find a scientific basis for a psychologic benefit from exercise, the placebo effect can be beneficial and possibly more effective in motivating women to exercise.
IX. PHYTOESTROGENS Natural estrogen-like substances called phytogens found in plants are attracting increasing attention, particularly with reference to their role in menopause. Epidemiologic data from Asian countries, where the diet naturally contains large amounts of these products, suggest that they may behave like estrogen by modifying symptoms such as hot flashes and thus attenuating menopausal symptoms. This diet may offer an intriguing alternative treatment in the menopause
675 and may explain why some countries appear to have a lower incidence of menopausal symptoms. Phytoestrogens are naturally occurring compounds that are structurally or functionally similar to estradiol (E2). They consist of a number of classes, including isoflavones, lignans, coumestrans, and resorcyclic acid lactones. They are biologically active, and this biologic activity has been shown in animals (237). In general the human diet provides precursors for mammalian lignans and isoflavones. Even more intriguing is that the metabolism of the precursors to the phytoestrogens may be highly variable, suggesting that the production of the phytoestrogens can vary from individual to individual. The major components of isoflavones, genistein and daidzein, are found in chickpeas, lentils, soybeans, bluegrass, and red clover. Most of the metabolism occurs as a result of fermentation by gut flora, but the liver may also be involved (238). In humans, 30% to 70% of dietary isoflavones are converted into various metabolites (239,240). Four isoflavones m formononetin, biochanin, daidzein, and genisteinmappear to have a wide range of biologic effects on human cells, including activating the steroid receptor. In countries where soy and legumes are a major part of the diet, they can provide 30 to 100 mg of the four isoflavones daily. Unfortunately, current studies are inconclusive as to the efficacy of phytoestrogens in treating menopausal symptoms (241). A meta-analysis evaluating the effect of phytoestrogens from soy found an average of 9.3% decrease in total cholesterol, a 12.9% decrease in LDL cholesterol, a 10.5% decrease in triglycerides, and a 2.4% increase in HDL; however, these changes were not significant (242). One study did find a significantly lower Lp(a) levels with higher habitual isoflavone intake (242). It is believed that Lp(a) is a strong risk factor for atherosclerotic heart disease and has been associated with premature cardiovascular disease (242). In addition to their effect on the menopause, some studies show that the excretion of phytoestrogen is associated with a substantial reduction in breast cancer risk. Thus, the action of these phytoestrogens may be different in some respects from estradiol, which has been associated with a slight increase in breast cancer risk (243). This suggests that the phytoestrogens may act selectively on some estrogen receptors and not on others, in particular on the estrogen receptor beta. This receptor is expressed more prominently in the brain, prostrate, and urinary tract and only weakly in the breast cells, where the classic estrogen receptor alpha is prominent.
X. SUMMARYAND CONCLUSIONS Physicians should encourage their patients to initiate or continue a program of regular physical activity and improved nutrition. A better diet and regular exercise can help prevent
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the development of the chronic diseases of older women. In patients with established disease, exercise and nutrition may delay its progression, help reverse the disease, and improve prognosis. Aerobic exercise has beneficial effects on cardiovascular disease, cancer, obesity, diabetes, and, possibly, on depression; it specifically improves lipid profiles and insulin resistance and lowers body fat. Strength training and flexibility exercises can reduce bone loss and prevent osteoporotic fractures, respectively. Trace minerals may be important in the management of osteoporosis. Phytoestrogens may improve menopausal symptoms and reduce breast cancer risk. Healthy women can safely initiate an exercise program or change their diet with adequate counseling. Exercise and changes in diet, however, may pose serious health risks in women with certain conditions. These patients should be carefully evaluated to determine the safety of a dietary and exercise regimen, and they should be monitored on a regular basis. Exercise frequency and intensity should be prescribed according to the ability and motivation of each patient. Frequent, relatively high intensity exercise might be more beneficial, but such a regimen is less likely to encourage compliance, may result in increased injury rates, and thus may not have lasting effects on overall health. Exercise performed at 70% to 75% of the maximal heart rate at least three times per week for 50 to 60 minutes is protective against cardiovascular disease and osteoporosis (24). A brief period of warm-up and cool-down is important. Jumping, bouncing, and quick bending of the spine should be avoided. Compelling evidence suggests that improved nutritional and activity profiles can significantly affect the development of chronic diseases that accelerate after menopause. Diet composition should be altered in specific conditions such as CHD and diabetes and appropriate exercise programs prescribed. At-risk patients should also be aware of nutritional and exercise interventions that can significantly attenuate the development of such conditions as osteoporosis.
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CHAPTER 49 Role of Exercise and Nutrition 196. Martin P, Notelovitz M. Effects of aerobic training on bone mineral density of postmenopausal women. J Bone Miner Res 1993;8:931-936. 197. Snow CM, Shaw JM, Matkin CC. Physical activity and risk for osteoporosis. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. New York: Academic Press, 1996:511-528. 198. Ulrich CM, Georgiou CC, Snow-Harter CM, Gillis DE. Bone mineral density in mother-daughter pairs: relations to lifetime exercise, lifetime milk consumption, and calcium supplements. Am J Clin Nutr 1996;63:72-79. 199. Heaney RE Calcium, dairy products and osteoporosis.JAm CollNutr 2000;19:83S-99S. 200. Ettinger B, Black DM, Mitlak BH, et al., for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637-645. 201. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;282:637-645. 202. Harris ST, Watts NB, Genant HK, et al., for the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Effects of rise&onate treatment on vertebral and nonvertebral factures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 1999;282:1344-1352. 203. Liberman UA, Weiss SR, Broll J, et al., for the Alendronate Phase III Osteoporosis Treatment Study Group. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N EnglJ Med 1995;333:1437-1443. 204. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. OsteoporosInt 2000;11:83 - 91. 205. The North American Menopause Society. Recommendations for estrogen and progestogen use in peri- and postmenopausal women: October 2004 position statement of the North American Menopause Society. Menopause 11;6:589-600. 206. Nieves JW, Komar L, Cosman F, Lindsay R. Calcium potentiates the effect of estrogen and calcitonin on bone mass: review and analysis. A m J Clin Nutr 1998;67:18-24. 207. Haines CJ, Chung TKH, Leung PC, Hsu SY, Leung DHY. Calcium supplementation and bone mineral density in postmenopausal women using estrogen replacement therapy. Bone 1995;16:529-531. 208. Davis JW, Ross PD, Johnson NE, Wasnich RD. Estrogen and calcium supplement use among Japanese-American women: effects on bone loss when used singly and in combination. Bone 1995;17:369-373. 209. Heikkinen J, Kyllonen E, Kurttila-Matero E, et al. HRT and exercise: effects on bone density, muscle strength and lipid metabolism. A placebo controlled 2-year prospective trial on two estrogen-progestin regimens in healthy postmenopausal women. Maturitas 1997;26:139-149. 210. Lindsay R. Hormone replacement therapy for prevention and treatment of osteoporosis. Am J Med 1993;95:37S- 39S. 211. Barret-Connor E, Kritz-Silverstein D. Does hyperinsulinemia preserve bone? Diabetes Care 1996;19:1388-1392. 212. Parra-Cabrera S, Hernandez-Avila M, Tamayo-y-Orozco J, LopezCarrillo L, Meneses-Gonzalez E. Exercise and reproductive factors as predictors of bone density among osteoporotic women in Mexico City. Calcif Tissue Int 1996;59:89-94. 213. Heaney RE Nutrition and risk for osteoporosis. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. New York: Academic Press, 1996:483-509. 214. Saltman PD, Strause LG. The role of trace minerals in osteoporosis. JAm Call Nutr 1993;12:384-389. 215. Strause L, Saltman P. The role of manganese in bone metabolism. Washington, DC: American Chemical Society, 1987:45-55.
681 216. Andon M, Luhrsen K, Kanerva R, Chatzidakis C. Effects of dietary copper and manganese restriction on serum mineral concentrations and femoral shaft bone density in rats.JAm CollNutr 1992;11:600. 217. Strause L, Saltman P, Glowacki I. The effect of deficiencies of manganese and copper on resorption of bone particles in rats. ClacifTissue Int 1987;41:145-150. 218. Reginster JY, Strause LG, Saltman P, Franchimont E Trace elements and postmenopausal osteoporosis: a preliminary study of decreased serum manganese. Med Sci Res 1988;16:337-338. 219. Howard G, Andon M, Bracker M, Saltman P, Strause L. Serum trace mineral concentrations, dietary calcium intake and spine bone mineral density in postmenopausal women. J Trace Elem Med Bid 1992;5:23-31. 220. Strause L, Saltman P, Smith K, Andon M. Calcium, copper, manganese arid zinc supplementation sustains bone density in postmenopausal women. In: Burckhardt P, Heaney RP, eds. Nutritional aspects ofosteoporosis. New York: Raven Press, 1991:223-232. 221. Strause L, Saltman P, Smith KT, Bracker M, Andon ME. Spinal bone loss in postmenopausal women supplemented with calcium and trace minerals. J Nutr 1994;124:1060-1064. 222. Harris MM, Houtkooper LB, Stanford VA, et al. Dietary iron is associated with bone mineral density in healthy postmenopausal women. J Nutr 2003;133:3598-602. 223. Propckop DJ. Role of iron in the synthesis of collagen in connective tissue. Fed Proc 1971;30:984-990. 224. Deluca HE Metabolism of vitamin D: current status. Am J Clin Nutr 1976;29:1258-1270. 225. Medeiros DM, Ilich J, Ireton J, et al. Femurs from rats fed diets deficient in copper or iron have decreased mechanical strength and altered mineral composition. J Trace Elem Exp Med 1997;10:197-203. 226. Kipp D, Pinero D, Beard JL. Low bone mass and volume in irondeficient rats. FASEB J 1998;12:A508. [Abstract.] 227. Kipp D, Beard J, Lees C. Mild iron deficiency results in altered bone mass and histomorphometry in growing female rats. FASEBJ2002;16: A273. [Abstract.] 228. Schnitzer CM, Macphail AP, Shires R, et al. Osteoporosis in African hemosiderosis: role of alcohol and iron. J Bone Miner Res 1994;9: 1865-1873. 229. Diamond T, Stiel D, Posen S. Osteoporosis in hemochromatosis: iron excess, gonadal deficiency or other factors? Ann Intern Med 1989;110: 430-436. 230. Buffer RN. The geriatric patient. In: Usdin G, Lewis JM, eds. Psychiatry in generalmedicalpractice. New York: McGraw-Hill, 1979. 231. McKinlay JB, McKinlay SM, Brambilla D. The relative contributions of endocrine changes and social circumstances to depression in middleaged women. J Health Soc Behav 1987;28:345- 363. 232. Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women's Health Study. Ann Epidemiol 1994;4: 214-220. 233. Hughes JR. Psychological effects of habitual aerobic exercise: a critical review. Prev Med 1984;13:66-78. 234. Folkins CH, Sime WE. Physical fitness training and mental health. Am Psycho11981;36:373-389. 235. Colt EWD, Wardlaw SL, Frantz AG. The effect of running on plasma beta-endorphin. Life Sci 1981;28:1637-1640. 236. Bravo G, Gauthier P, Roy PM, et al. Impact of a 12-month exercise program on the physical and psychological health of osteopenic women.JAm Geriatr Soc 1996;44:756-762. 237. Kaldas R, Hughes CL Jr. Reproductive and general metabolic effects of soy extracts in mammals. Reprod Toxico11989;25:1917-1925. 238. Nilsson A. Demethylation of the plant oestrogen biochanin A in the rat. Nature 1961;192:358.
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-IAPTER 5(
Herbs, Phytoestrogens, and Other CAM Therapies ADRIANE FUGH-BERMAN
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC 20057
I. P H Y T O E S T R O G E N S
Complementary and alternative medicine (CAM), sometimes called unconventional, natural, integrative, traditional, or non-traditional medicine, is quite popular in the United States. An analysis of 2002 National Health Interview Survey (NHIS) data found that 62% of American adults used CAM in that year (1). In the Study of Women's Health Across the Nation (SWAN), almost half of midlife women had used CAM in the past year (2). An analysis of the 1999 NHIS found that one-third of American women used CAM in the previous year, with spiritual healing/prayer and herbal medicine being the most popular (3). A national survey that oversampled minority women found that 43% of 812 African-American women reported using religion/ spirituality in the past 12 months for health reasons (4). (It bears noting that estimates of use are higher when prayer is included as a CAM therapy; in the Barnes study, excluding prayer specifically for health dropped the percentage of CAM users from 62% to 36%.) The well-delineated risks of menopausal hormone therapy may increase the utilization of CAM therapies by consumers. It is important for physicians to familiarize themselves with complementary therapies in order to counsel patients effectively.
Many food plants contain phytoestrogens, or plant estrogens, primarily phenolic compounds that include isoflavones and lignans. Phytoestrogens can occupy estrogen receptors but are less than 1% as potent as endogenous estrogens (5). Soybeans (Glycine max) are rich in the conjugated isoflavones genistein and daidzin, but many other beans, including Anasasi, brown, black, navy, pinto, and turtle beans (all Phaseolus vulgaris), have as much or more genistin as soybeans (6). Gut bacteria convert conjugated isoflavones to the unconjugated (aglycone) active isoflavones, primarily genistein, daidzein, and equol. It is unclear whether aglycone or glucoside forms of isoflavones are more bioavailable. The isoflavones in cooked soybeans, textured vegetable protein (TVP), and soy milk contain 95% glycosides, whereas isoflavones in tofu (soybean curd) and tempeh (fermented soybean curd) contain 20% to 40% aglycones. It has been suggested that differences in gut bacteria could affect bioavailability of isoflavones. One study compared the bioavailability of daidzein and genistein in American women and found no difference in bioavailability (7). Lignan precursors are found in whole grains, seeds, fruits, and vegetables, especially flaxseed (linseed), rye, millet, and legumes. Gut bacteria convert plant lignans to mammalian lignans (enterolactone and enterodiol).
The author acknowledges Jenna Bythrow for contributing to this update. TREATMENT OF THE POSTMENOPAUSAL WOMAN
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A. Hot Flushes Evidence is mixed on whether phytoestrogen supplementation can help hot flushes. Only two (8,9) of nine controlled trials found a clear benefit of dietary soy for hot flushes; six studies were negative (10-15) and one was mixed (16). Phytoestrogen supplements have also been tested in eight trials, which have been evenly split between positive (17-20) and negative (21-24) results. A crossover study of pure genistein 90 mg/day in 100 postmenopausal women for 6 weeks found that the treatment significantly reduced hot flushes compared with placebo but that the effect was mild (25). Both dietary and supplemental phytoestrogens appear to be safe; however, long-term studies have not been performed with concentrated phytoestrogen supplements or purified isoflavones.
B. Vaginal Epithelium It is not clear how changes in vaginal epithelium correlate with discomfort during sex. Of four studies that looked at phytoestrogen supplemention and vaginal epithelium, two studies found an estrogenic effect and two did not. A study of 45 g soy flour daily in 25 women found significant improvements in the vaginal maturation index (26). The Brzezinski study (9) also found improvements in vaginal cytology. Negative studies include the Murkies study (12) and another study of soy foods 165 mg isoflavones/day in 97 women (91 completed)(27).
C. Breast Cancer Risk Until recently, dietary intake of phytoestrogens has been primarily determined by cultural differences in diet. Although breast cancer patients excrete lower amounts of phytoestrogens than other women do, and breast cancer risk is low in areas of the world where excretion of phytoestrogens is high, observational studies are insufficient evidence for benefit because other differences between populations exist. For example, Japanese women who eat traditional foods have lower breast cancer rates than those who eat a Western diet (28); however, phytoestrogens are not the only difference in these two diets. Among other factors, a traditional diet is lower in meat and fat and higher in fiber and vegetable intake, including seaweed. Although breast cancer rates in Asia are lower at all ages than breast cancer rates in the West, it is unclear to what extent phytoestrogens contribute to this disparity. No randomized controlled trials have tested the effect of phytoestrogens on breast cancer risk. The following are observational studies, which can never prove benefit.
A case control study among Chinese, Japanese, and Filipino women in Los Angeles County (501 breast cancer patients and 594 controls) found that women who reported soy intake at least once weekly during adolescence had a reduced risk of breast cancer. There was also a significant trend of decreasing risk with increasing soy intake during adult life (29). Phytoestrogen intake among non-Asian women had no effect on breast cancer risk in a case-control study of almost 3000 African-American, Latina, and Caucasian women aged 35 to 79 years (30). A case-control study of 117 postmenopausal women in Shanghai found that an inverse association between urinary phytoestrogen excretion and breast cancer risk was more evident among women with a high body mass index or waist-to-hip ratio; the inverse association was also more pronounced among women with high blood concentrations of estradiol or low levels of estrone sulfate or sex hormone binding globulin (SHBG) (31). An earlier study of Chinese women in Singapore found that soy product intake was associated with lower rates of breast cancer in premenopausal, but not postmenopausal, women (32). There is no evidence that merely adding phytoestrogens to a Western diet would decrease breast cancer risk. Dosage, formulation, duration, and timing may all have an effect. It has been theorized, for example, that phytoestrogens may affect terminal end bud differentiation and that the most important period for phytoestrogen intake is around puberty. This effect would not be possible to extract from epidemiologic data on lifelong consumption of soy foods. On the other hand, there is no evidence that soy foods increase risk of breast cancer or any other disease. Soy foods have been consumed for thousands of years and are not dangerous. However, concentrated phytoestrogen products and purified isoflavones are now readily available, and there are no long-term safety data on these food-free phytoestrogens.
D. Endometrial Cancer Soy foods do not increase endometrial cancer rates. A case-control study of 332 endometrial cancer cases and 511 controls among a multiethnic population in Hawaii found that high soy intake appears to protect against endometrial cancer in both premenopausal and postmenopausal women (33). A study of soy cereal containing 82 mg isoflavones/day for 6 months caused no changes in endometrial biopsies (34). Although isoflavones may have a selective estrogen receptor modulator (SERM) effect, it is not enough to counteract estrogen; soy protein isolate (containing 120 mg aglycone isoflavones) over 6 months did not prevent estradiol-induced endometrial hyperplasia (35).
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CHAPTER 50 Herbs, Phytoestrogens, and Other CAM Therapies
E. Cardiovascular Disease Risk Factors Soybeans may have a beneficial effect on cardiovascular disease risk factors. In a meta-analysis of 38 controlled clinical trials on the effect of soy intake on serum lipids, ingestion of an average of 47 grams of soy protein daily was associated with reduced cholesterol (23.2 mg/dL, or 9.3%), reduced low-density-lipoprotein (LDL) cholesterol (21.7 mg/dL, or 12.9%), and reduced triglycerides (13.3 mg/dL, or 10.5%) (36). High-density-lipoprotein (HDL) cholesterol was unaffected. In most studies, intake of fat, saturated fat, and cholesterol was similar between the control group and soy group, thus lipid changes cannot be attributed to the lower fat content in soy products compared with animal products.
E Osteoporosis In a double-blind trial of 66 postmenopausal, hypercholesterolemic women aged 49 to 73 (37), subjects were randomly assigned to 40 g protein per day from one of three sources: milk (nonfat dried milk and casein), soy protein with medium isoflavone content (equivalent to 55.6 mg isoflavones daily), or isolated soy protein with high isoflavone content (equivalent to 90 mg isoflavones daily). All women also followed a low-fat, low-cholesterol diet. Dualenergy x-ray absorptiometry (DXA) bone density studies of the lumbar spine, proximal femur, and total body were done at the beginning of the study (after a 2-week lead-in) and at the end of the 6-month study. No differences were seen among the three groups in bone density studies of the hip or total body, but subjects receiving the high-isoflavone preparation experienced a significant increase in lumbar bone density and mineral content (2%) compared with the milk protein group.
G. Risks Although consumption of subterranean clover (Trifolium reDens) and other phytoestrogen-rich forage or feed has caused lower conception rates in several animal species, the implicated plant species are not consumed in the human diet. Soy foods, on the other hand, are consumed in large quantities in China, Japan, and Korea and have not been associated with fertility problems or other adverse effects. In North America, soy infant formula has been used for more than 30 years; formula contains primarily the glycosides genistin and daidzin. A retrospective cohort study of adults aged 20 to 34 fed soy milk or cow milk as infants in a controlled feeding study found no significant differences between groups in pubertal maturation, reproductive history,
menstrual history, hormonal disorders, height, weight, or current health. Women fed soy as infants reported slightly longer duration of menstrual bleeding and greater discomfort with menstruation (38). Soybeans are quite high in oxalates, containing 0.67 to 3.5 grams oxalates per 100 grams of dry weight. Commercial soy foods contain between 16 and 638 mg oxalates per serving, comparable to peanut butter, reffied beans, and lentils (39). The oxalate content of soy foods may be of concern in patients who are avoiding oxalates because of nephrolithiasis (most kidney stones are composed of calcium oxalate). Some women with vulvodynia also choose to minimize dietary oxalates, which may aggravate symptoms. There is much misinformation on the Internet about the putative adverse effects of soy on the thyroid. Genestin does inactivate thyroid peroxidase, and soy consumption may be linked to thyroid dysfunction if iodine is deficient. Iodine deficiency is a serious problem in many developing countries, but it is rare in North America due to iodine fortification of table salt. Soy supplementation does not appear to affect thyroid function in most iodine-replete women (40). It is possible, however, that soy interferes with the absorption of thyroid medication. In one case, a 45-year-old woman with hypothyroidism who required high doses of levothyroxine was able to reduce her dose by separating ingestion of a soy drink from ingestion of levothyroxine (41). Although consumption of soy or other beans is probably benign, the safety of concentrated extracts or high doses of purified isoflavones has not been established. This is an issue because pure genistein or isoflavone mixtures are available at heath food stores.
II. HERBS Ginseng (Panax ginseng), chaste-tree berry (Vitex agnus castus), Dong quai (Angelica sinensis), black cohosh (Actaea racemosa), and licorice (Glycyrrbiza glabra) are a few of the herbs commonly used to treat hot flushes and other symptoms associated with menopause. However, there are few clinical studies on these therapies, and little information is available on the long-term effects of medicinal herbs.
A. Black Cohosh
(Actaea racemosa)
Black cohosh is the most studied herb for hot flashes; at least nine controlled studies have been performed. The most recent, methodologically sound placebo-controlled studies have been largely negative. Studies performed in the United States have been largely negative, while those performed in
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Germany have been more positive. An NIH-funded, yearlong, placebo- and treatment-controlled trial found no benefit of black cohosh (160 mg/day 2.5% triterpene glycosides, 70% ethanol extract) or a multibotanical preparation containing 200 mg black cohosh over placebo; conjugated equine estrogens 0.625 mg/day was effective (42). A crossover study in 132 women found no benefit of Remifemin (a standardized product that has changed formulation over time) 20 mg twice daily over placebo for four weeks (43). Another U.S. study found that Remifemin (40 mg/day 3< 2 months) had no effect over placebo for hot flashes in 85 breast cancer survivors (59 taking tamoxifen) (44). A German study in 304 women found a benefit of black cohosh over placebo on several subscores, including hot flashes, of the Menopause Rating Scale 1 (45). Recent treatment-controlled trials comparing black cohosh treatments to estrogens have been negative. An Italian study found no difference between Remifemin 40 mg extract/day and a transdermal estradiol patch (25 mcg/week plus dihydrogesterone 10 mg/day for 12 days over the three-month trial) (46). A randomized controlled trial found no significant effect of the standardized black cohosh preparation BNO1055 (Klimadynon/Menofem) over conjugated estrogens or placebo on hot flashes in 62 women, although a menopausal symptom score improved in women who completed the trial, and both conjugated estrogens and black cohosh improved vaginal epithelium (47). Older studies have found previous formulations of Remifemin equivalent to estrogens in reducing symptoms (48-50). The effects of long-term use of black cohosh are unknown. No clinical trials of black cohosh have been longer than six months in duration. Recently, several cases of hepatitis have been linked to black cohosh (51-53).
B. D o n g Q v a i
(Angelica sinensis)
Dong quai was tested in a randomized, double-blind, placebo-controlled clinical trial in 71 women. 4.5 grams of dong quai root/day 3< 6 months was not superior to placebo for hot flashes (54). Traditionally, dong quai is almost always used as part of a mixture. Dong quai can cause bleeding when administered concurrently with warfarin (55); the furocoumarins it contains can cause photosensitization.
C. E v e n i n g Primrose
(Oenethera biennis)
Evening primrose oil, a good source of linoleic and gamma linolenic acid, has been evaluated in a double-blind controlled trial of 56 women and found to be no more effective than placebo for hot flashes (56).
D. Kava
(Piper metbysticum)
Widely used in Polynesia, rhizomes of the kava shrub, a psychoactive member of the pepper family, are used medicinaUy for anxiety and insomnia. Active constituents in kava are the kavapyrones (also called kavalactones).Two doubleblind studies of kava for climacteric symptoms have been performed by the same investigator. A study in 40 women using doses of 30 to 60 mg/day for 56 to 84 days found significant improvements in the Kupperman index (57). A trial utilizing a higher dose (equivalent to 210 kavapyrones/ day) in 40 menopausal women also found improvements in menopausal symptoms (Kupperman index), and mood (assessed with the Hamilton Anxiety Scale [HAMA] and the Depression Status Inventory) (58). Extremely heavy, chronic recreational use of kava results in yellowing of the skin and an ichthyosiform eruption known as kava dermopathy,sometimes accompanied by eye irritation (59). Kava should not be recommended because of numerous case reports of hepatotoxicity (60,61). E. G i n s e n g
quinquefolius,
(Panax ginseng, Panax or Panax notoginseng)
The most common types of ginseng are Chinese ginseng (Panaxginseng), American ginseng (Panax quinquefolius), and Siberian "ginseng" (Eleutherococcussenticosus), which is not ginseng at all, although it is in the same family. Ginseng contains terpenoids, especially a group of compounds called ginsenosides. One randomized, doubleblind, placebo-controlled clinical trial in 384 menopausal women found no effect of ginseng (Panaxginseng; in this case Ginsana, containing 100 mg standardized extract Gl15 x 14 weeks) on hot flushes, endometrial thickness, or the vaginal maturation index (62). Although case reports have associated ginseng with postmenopausal bleeding (63,64), implicated products were not examined for hormone adulterants.
E Licorice
(Glycyrrhiza glabra)
Licorice is the most common herb in Chinese medicine products. In Chinese medicine, licorice is always used as part of a mixture, and the synergistic effects of mixtures as well as perhaps dose limitations may prevent problems. It bears noting that not all of the reported cases of licorice-induced problems were from licorice-containing candies, gum, laxatives, or chewing tobacco, and not from the use of licorice as herbal medicine (most "licorice" candies manufactured in the United States are actually flavored with anise; imported candies usually contain real licorice). However, licorice tinctures and extracts, capsules, lozenges, and such are available
CHAPTER50 Herbs, Phytoestrogens, and Other CAM Therapies in the United States, so it is useful to know about possible side effects. Glycyrrhizinic acid and its derivatives affect the metabolism of cortisol, apparently by inhibiting the 11 betahydroxysteroid dehydrogenase system that converts cortisol to cortisone (65). Large chronic doses may result in a pseudoprimary aldosteronism with symptoms that may include edema, hypertension, and hypokalemia (66,67). Cardiac arrhythmias and cardiac arrest, including two deaths, have occurred in users of licorice products. Cardiomyopathy has been reported (68) and pulmonary edema (69).
G. Sage
(Salvia officinalis)
Sage is reputed to help hot flushes and night sweats but should not be recommended because it contains thujone, a neurotoxin. Long-term use can cause seizures or other neurologic symptoms (70). Although thujone is inactivated by heat, sage products may not be heat-treated.
H. Vitex or Chaste-Tree Berry (Vitex agnus-castus)
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j. Chinese Herbs A randomized, double-blind, placebo-controlled clinical trial in 78 menopausal women found no benefit of a Chinese herb mixture for 3 months (75). Chinese herbs are usually individualized; in this study all subjects received the same mixture.
K. Yam and Progesterone Creams A double-blind, placebo-controlled, 3-month crossover trial in 23 menopausal women with hot flushes found no benefit of wild yam (Dioscorea villosa) topical cream over placebo (76) on hot flushes or night sweats. Wild yam contains diosgenin, a precursor to progesterone; however, this conversion is not known to occur endogenously. Topical progesterone cream (20 mg progesterone/day) reduced hot flushes in a 1-year study of 102 healthy postmenopausal women with a primary endpoint of bone mineral density (77). Another study, however, found no effect (78).
L. Bioidentical Hormones Vitex contains flavonoids and an alkaloid called viticin. There have been no clinical studies on vitex for menopausal symptoms, but it is commonly used for irregular or heavy menstrual bleeding. Vitex can cause an acneiform rash but has not been linked to serious adverse effects.
I. Red Clover
(Trifolium pratense)
Red Clover contains the isoflavones formononetin, biochanin A, daidzein, and genistein. Red clover is currently being marketed as a long-term phytoestrogen source and natural hormone therapy. The largest randomized controlled trial to date, the Isoflavone Clover Extract study, found no advantage of Promensil or another red clover preparation, Rimostil, on hot flashes in 252 symptomatic women over three months (71). Two 3-month randomized, double-blind, placebocontrolled clinical trials of Promensil (containing 40 mg total isoflavones) conducted in Australia (one with 37 postmenopausal women, one with 51 postmenopausal women) reported no significant benefit of red clover extract for hot flushes (72,73). A randomized, double-blind, placebocontrolled trial in 30 menopausal women reported that Promensil 80 mg/day • 12 weeks reduced hot flushes and improved Greene scores, based on the difference in proportion of patients above and below the mean at 8 and 12 weeks (74). Only median percentage changes in hot flushes were provided.
Bioidentical or "natural" hormones, including estriol, estradiol, estrone, and progesterone, are being promoted to consumers as safe alternatives to conventional menopausal hormone therapy. No data support the claim that bioidentical hormones are safer than other hormones (79). Commercial or compounded estrogen preparations may be effective for treating hot flushes or vaginal dryness. If estriol is used to treat menopausal symptoms, it should be opposed with an oral progestin. Although some progesterone creams may provide some endometrial protection in some women, studies have been inconsistent and not reassuring. Serum levels of progesterone after application of transdermal creams are insufficient to prevent estrogenic stimulation of the endometrium, and it is inappropriate to prescribe topical progestin cream as the progestin component of hormone therapy. Any menopausal hormone therapy should be reserved for women with bothersome symptoms and used in the lowest effective dose for as brief a period as possible.
M. Vitamin E Several poorly controlled trials of vitamin E as a menopause treatment were done as early as the 1940s. In 1953, a double-blind, 3-year study compared vitamin E (50 to 100 mg/day) with two estrogen preparations, phenobarbital, and a placebo in 658 women (80). On an 11-symptom menopause index (hot flushes were not analyzed separately,
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ADRIANE FUGH-BERMAN
vitamin E was no more effective than placebo. A recent randomized, placebo-controlled crossover study tested 400 IU vitamin E succinate twice daily on 125 breast cancer survivors with hot flushes. After 4 weeks, vitamin E was statisticaUy superior to placebo, but the difference between phases (one hot flush a day) was not considered clinically significant; subjects did not prefer vitamin E to placebo. Vitamin E is benign. It is a common misperception among clinicians that vitamin E may cause bleeding, but studies designed to assess bleeding risk have found no effect of vitamin E (81), even in those on warfarin (82).
N. A c u p u n c t u r e A study of acupuncture for hot flushes randomized 24 menopausal women either to electroacupuncture (electrical stimulation of acupuncture needles) at standardized points or to control (shallow acupuncture needle insertion) at the same points (83). Both groups improved, with no difference between groups. Shallow needle insertion at correct acupuncture points should have some effect, so the chosen control may have been suboptimal. Acupuncture occasionally causes tissue trauma and rarely, serious complications, including pneumothorax and cardiac tamponade. The most common complication has been hepatitis or other infections from inadequately sterilized needles (84). Disposable needles, the standard of care in the United States, obviate this
be other differences between exercisers and the general population. Some women report that exercise triggers hot flushes.
III. SUMMARY In summary, most CAM therapies for menopausal symptoms are benign. Because CAM therapies are widely used, studies should be done to delineate both benefits and risks. The current evidence on the use of phytoestrogens and herbs for hot flushes and other menopausal symptoms is unimpressive; most studies of herbs found them no better than placebo. Hot flushes are notoriously placebo-responsive. Among herbs tested for hot flushes, limited evidence supports a beneficial effect only for black cohosh (and long-term safety questions remain). Red clover has been shown ineffective in two of three trials. Single trials show no effect of dong quai, wild yam, evening primrose oil, ginseng, and a Chinese herb mixture. Although some trials of herbs were quite small and may have been underpowered, it is clear that the herbs tested to date lack a dramatic effect. Behavioral techniques, including relaxation and biofeedback, may be helpful for some women. Because of the wellestablished risks of hormone therapy, interest in CAM therapies for menopausal symptoms may increase. A variety of complementary therapies deserve further research.
concern.
References O. Paced Respiration and Relaxation A 4-month study compared paced respiration (slow, deep breathing) with progressive muscle relaxation or alpha electroencephalogram (EEG) biofeedback (control) in 33 postmenopausal women with hot flushes (85). Only paced respiration training significantly reduced hot flush frequency. In another trial by the same investigators, only paced respiration decreased hot flushes significantly in 24 menopausal women randomized to either paced respiration or control biofeedback (86). A randomized, controlled, 7-week study in 45 women with hot flushes compared 20 minutes daily of trained relaxation, reading, or symptom-charting (87). Hot flush frequency did not improve in any group; hot flush intensity decreased significantly only in the relaxation group. No adverse effects of paced respiration or relaxation have been reported.
E Exercise Although women who exercise regularly appear to have fewer hot flushes than women in the general population (88), this cannot be considered proof of benefit, as there may
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689 31. Dai Q_, Franke AA, Yu H, et al. Urinary phytoestrogen excretion and breast cancer risk: evaluating potential effect modifiers endogenous estrogens and anthropometrics. Cancer Epidemiol Biomarkers Prev 2003;12:497-502. 32. Lee HP, Gourley L, Duffy SW, et al. Dietary effects on breast cancer risk in Singapore. Lancet 1991;337:1197-1200. 33. Goodman MT, Wilkems LR, Hankin JH, et al. Association of soy and fiber consumption with the risk of endometrial cancer, d m J E p i 1997; 146:294-306. 34. Balk JL, Whiteside DA, Naus G, DeFerrari E, Roberts JM. A pilot study of the effects of phytoestrogen supplementation on postmenopausal endometrium. J Soc GynecolInvestig 2002;9:238-242. 35. Murray MJ, Meyer WR, Lessey BA, et al. Soy protein isolate with isoflavones does not prevent estradiol-induced endometrial hyperplasia in postmenopausal women: a pilot trial. Menopause 2003;10:456-464. 36. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N EnglJ Med 1995; 33:276-282. 37. Potter SM, Baum JA, Teng H, et al. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women.Am J Clin Nutr 1998;68:1375S- 1379S. 38. Strom BL, Schinnar R, Ziegler EE, et al. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAm MedAssoc 2001;286:2402-2403. 39. Massey LK, Palmer RG, Homer HTJ. Oxalate content of soybean seeds (Glycine max: Leguminosae), soyfoods, and other edible legumes. Agric Food Chem 2001;49:4262-4266. 40. Messina M, Redmond G. Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: a review of the relevant literature. Thyroid 2006;16:249-258. 41. Bell DS, Ovalle E Use of soy protein supplement and resultant need for increased dose of levothyroxine. Endocr Pract 2001;7:193-194. 42. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern IVied 2006;145:869-879. 43. Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol 2006 ;24:2836 - 2841. 44. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Onco12001;19:2739-2745. 45. Osmers R, Friede M, Liske E, et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol 2005;105:1074-1083. 46. Nappi R, Malavasi B, Brundu B, Facchinetti E Efficacy of Cimicifuga racemosa on climacteric complaints: a randomized study versus low dose transdermal estradiol. GynecolEndocrino 2005;20:30-35. 47. Wuttke W, Sedlova-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebocontrolled study: effects on menopause symptoms and bone markers. Maturitas 2003;$67- $77. 48. Warnecke G. Beeinflussung ldimakterischer Beschwerden durch ein Phytotherapeutikum: Erfolgreiche therapie mit Cim#ifuga-Monoextrakt (Influence of phytotherapy on menopausal syndrome: successful treatments with monoextract of cimicifuga). Medizinische Welt 1985;36: 871-874. 49. Stoll W. Phytotherapeutikum beeinflusst atrophisches Vaginalepithel: Doppelblindversuch Cimicifuga vs. Ostrogenpr~iparat (Phytotherapy influences atrophic vaginal epithelium--double-blind studymCimicifuga vs. estrogenic substances). Therapeutikon 1987;1:23 - 31.
690 50. Lehmann-Willenbrock E, Riedel H. Klinische und endokrinologische Untersuchengen zur Therapie ovarieller Ausfallserscheinungen nach Hysterektomie unter Belassung der Adnexe (Clinical and endocrinological examinations concerning therapy of climacteric symptoms following hysterectomy with remaining ovaries). Zentralblatt fur Gynakologie 1988;110:611-618. 51. Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure associated with the use of black cohosh: a case report. Liver Transpl 2006;12:989- 992. 52. Cohen S, O'Connor AM, Hart J, Merel NH, Te Hs. Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause 2004;11:575-577. 53. Whiting P, Clouston A, Kerlin P. Black Cohosh and other herbal remedies associated with acute hepatitis. MJA 2002;177:440-443. 54. Hirata JD, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steri11997;68:981-986. 55. Fugh-Berman A. Herb-drug interactions. Lancet 2000;355:134-138. 56. Chenoy R, Hussain S, Tayob Y, et al. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ 1994;308:501-503. 57. Warnecke G, Pfaender H, Gerster G, Gracza E. Wirksamkeit yon Kava- Kava- Extrakt beim klimakterischen Syndrom. Z Phytother 1990; 11:81-86. 58. Warnecke G. Psychosomatic dysfunctions in the female climacteric. Clinical effectiveness and tolerance of Kava Extract WS 1490]. Fortschr Med 1991;109(4):119-122. 59. Norton SA, Ruze P. Kava dermopathy. J Am Acad Derm 1994;31: 89-97. 60. Tickel F, Baumuller HM, Seitz K, et al. Hepatitis induced by Kava (Piper methysticum rhizoma). J Hepato12003;39:62-67. 61. Humberston CL, Akhtar J, Krenzelok EP. Acute hepatitis induced by kava kava. J Toxicol Clin Toxico12003;41:109 - 113. 62. Wiklund IK, Mattsson L-A, Lindgren R, Limoni C. Effects of a standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebocontrolled trial. IntJ Clin Pharm Res 1999;XIX:89-99. 63. Greenspan EM. Ginseng and vaginal bleeding. J Am Med Assoc 1983;249:2018. 64. Hopkins MO, Androff L, Benninghoff AS. Ginseng face cream and unexplained vaginal bleeding. Am J Ob Gyn 1988;159:1121-1122. 65. Farese RV, Biglieri EG, Shackleton CHL, et al. Licorice-induced hypermineralocorticoidism. N EnglJ Med 1991;325:1223-1227. 66. Epstein MT, Espiner EA, Donald RA, Hughes H. Effect of eating liquorice on the renin-angiotensin aldosterone axis in normal subjects. BMJ 1977;1:488-490. 67. Chandler RF. Glycyrrhiza glabra. In De Smet PAGM, Keller K, Hansel R, Chandler RF. Adverse effectsof herbaldrugs, vol 1. Berlin:Springer-Verlag, 1992. 68. Shintani S, Murase H, Tsukagoshi H, Shiigai T. Glycyrrhizin (Licorice)induced hypokalemic myopathy. Eur Neuro11992;32:44-51. 69. Chamberlain JJ, Abolnik IZ. Pulmonary edema following a licorice binge. WesternJ Med 1997;167:184-185. 70. Wichtl M. Herbal drugs andphytopharmaceuticals. Stuttgart: Medpharm Scientific Publishers, 1994.
ADRIANE FUGH-BERMAN 71. Tice JA, Ettinger B, Ensrud K, et al. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. JANM 2003;290:207-214. 72. Barber RJ, Templeman C, Morton T, Kelly GE, West L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85- 92. 73. Knight DC, Howes JB, Eden JA. The effect of Promensil, an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79-84. 74. van de Weijer PH, Barentsen R. lsoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 2002;42:187-193. 75. Davis SR, Briganti EM, Chen RQ~ et al. The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women. A randomised controlled trial. MedJAust 2001;174:68-71. 76. Komesaroff PA, Black CV, Cable V, Sudhir K. Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women. Climacteric2001;4:144-150. 77. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225-228. 78. Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women. Menopause 2003;10:13-18. 79. Fugh-Berman A, Bythrow J. Bioidentical hormones for menopausal therapy: variation on a theme. J Gen Int Med 2007; published online March 7, 2007. http://www.springerlink.com/content/ q4772464371784g2/. 80. Blatt MHG, Wiesbader H, Kupperman HS. Vitamin E and climacteric syndrome. Arch Intern Med 1953;91:792-796. 81. Meydani SN, Meydani M, Blumberg JB, et al. Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults. Am J Clin Nutr 1998;68:311 - 318. 82. Kim JM, White RH. Effect of vitamin E on the anticoagulant response to warfarin. Am J Cardio11996;77:545-546. 83. Wyon Y, Lindgren R, Lundeberg T, Hammar M. Effects of acupuncture on climacteric vasomotor symptoms, quality of fife, and urinary excretion of neuropeptides among postmenopausal women. Menopause 1995;2:3-12. 84. Ernst E, White A. Life-threatening adverse reactions after acupuncture? A systematic review. Pain 1997;71:123-126. 85. Freedman RR, Woodward S. Behavioral treatment of menopausal hot flashes:evaluation by ambulatory monitoring. Am J Obstet Gynecol 1992;167:436-439. 86. Freedman RR, Woodward S, Brown B, Javaid JI, Pandey GN. Biochemical and thermoregulatory effects of behavioral treatment for menopausal hot flashes. Menopause 1995;2:211-218. 87. Irvin JH, Domar AD, Clark C, Zuttermeister PC, Friedman R. The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynaeco11996;17:202-207. 88. Hammar M, Berg G, Lindgren R. Does physical exercise influence the frequency of postmenopausal hot flushes? Acta Obstet Gynecol Scand 1990;69:409-412.
SECTION XI
Urinary Symptoms and Pelvic Support The total population of older women in the world is increasing. It has been estimated that there will be approximately 38 million women over the age of 55 in the United States by 2010. With aging, and particularly after menopause, a larger percentage of women will experience problems of pelvic support. These symptoms include a variety of urinary complaints, uterine and vaginal prolapse (including cystocele, rectocele, and enterocele), and rectal and anal problems. A recent survey of more than 4000 women in Southern California reported that the prevalence of urinary incontinence and overactive bladder was 28%, and 7% of women had uterine prolapse (1). Thirty-seven percent of women had various combinations of pelvic support problems. In an Australian survey the prevalence of urinary problems was 35.3% (2). These numbers are similar to a survey of women attending a gynecology clinic in the United Kingdom, where the prevalence of urinary problems was estimated to be 26.8%, and 8.4% of women had mixed urinary and anal incontinence (3). Thus, many millions of women worldwide suffer from pelvic support problems. In order to address some of the needs of this growing problem, a subspecialty of obstetrics and gynecology was developed to establish an advanced training fellowship program directed by the American Board of Obstetrics and Gynecology. The American Board of Urology has a similar program and, indeed, these two specialties may have a joint fellowship program. This section, therefore, attempts to provide the reader with up-to-date information on pelvic floor problems in postmenopausal women. There is a little overlap in the chapter of urinary incontinence in this section and an earlier chapter by Goran Samsioe (Chapter 18) where the intent was to bring this issue to light as a major change that occurs after menopause and may adversely affect quality of life. Both chapters have been written by Mat H. Ho and Narender N. Bhatia, who are involved in the advanced training of this subspecialty area. This new section has been added to this third edition of the book because of its immense importance in the care of postmenopausal women.
References 1. Lukacz ES, Lawrence JM, Contreras R, Nager CW, Luber KM. Parity, mode of delivery, and pelvic floor disorders. Obstet
Gyneco12006;107:1253-1260. 2. MacLennan AH, Taylor AW, Wilson DH, Wilson D. The prevalence of pelvic floor disorders and their relationship to gender, age, parity and mode of delivery. BJOG 2000;107:1460-1470. 3. Griffiths AN, Makam A, Edwards GJ. Should we actively screen for urinary and anal incontinence in the general gynaecology outpatients setting?--A prospective observational study.J Obstet Gynaeco12006;26:442-444.
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-IAPTER 5
Lower Urinary Tract Disorders in Postmenopausal Women MAT H. H o
Divisionof Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Torrance, CA 90509
NARENDER N. B HATIA Division of Female Pelvic Medicine and Reconstructive Surgery,Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Torrance, CA 90509
I. INTRODUCTION
This chapter focuses on the pathophysiology, diagnosis, and management of urinary incontinence, interstitial cystitis, and urinary tract infections in postmenopausal women.
During the past century, life expectancy has been increased, and this trend will continue, particularly in the industrialized countries. Women will, therefore, spend a significant part of their life in the postmenopausal years. In the United States, postmenopausal women now comprise more than 15% of the population, with a growth rate of 1.5% predicted until the year 2020 (1). The incidence of lower urinary tract disorders increases in these women, which is probably due to estrogen deficiency, hormonal alterations, muscular and neuronal damages secondary to previous childbirths, and other age-related physiologic changes (2,3). Disturbances in the lower urinary tract produce a wide variety of symptoms in postmenopausal women and account for a significant number of medical visits. Although not life threatening, lower urinary tract disorders can have a severe impact on quality of life. Patients with these problems may suffer from a loss of self-esteem, loss of independence, decrease in sexual actMty, social isolation, and depression (4). In addition to the medical impact and psychologic burden, disorders of the lower urinary tract are also associated with significant medical costs (5). T R E A T M E N T OF T H E POSTMENOPAUSAL W O M A N
II. ANATOMY O F T H E LOWER URINARY TRACT In order to understand the evaluation and treatment of lower urinary tract disorders in postmenopausal women, the anatomy of these structures is briefly discussed.
A. Anatomy of the Pelvic Floor and Lower Urinary Tract 1. THE PELVIC FLOOR
The pelvic floor, which consists of levator ani muscles and their associated connective tissue attachments, prevents pelvic organ displacement and help to maintain urinary continence. The levator ani is a broad term that consists of two parts: the diaphragmatic part (coccygeus and 693
Copyright 9 2007 by Elsevier, Inc. All rights of reproduction in any form reserved.
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iliococcygeus muscles) and the pubovisceral part (pubococcygeus and puborectalis muscles) (6,7). These are bilaterally paired muscles (Fig. 51.1). The coccygeus muscles attach anteriorly to the ischial spines, then fan out medially to attach to the lateral surface of coccyx. The iliococcygeus muscles arise from the lateral wall of the pelvis, run over the obturator internus to attach to the arcus tendineus, and then insert into a midline raphe behind the rectum. The pubococcygeus fibers run from the pubis and the fascia covering the obturator internus and meet in the midline behind the rectum to form the levator plate. Because the iliococcygeus merges together with the pubococcygeus, the distinction between these two muscles is arbitrary. The puborectalis provides muscular sling that pulls the rectum toward the pubic bones when the muscle contracts. The pelvic floor is a dynamic support system, with constant muscle tones and tension adjustments in response to pressure changes, rather than a rigid structure. The levator ani contains both type I (slow-twitch) fibers, which maintain muscle tone over a long period, and type II (fast-twitch) fibers, which increase muscle tone quickly to compensate for any increased abdominal pressure. Reflex contractions of both types of muscle fibers are important in supporting the pelvic contents and keeping urinary and fecal continence. When pubococcygeus and puborectalis muscles contract, they pull the rectum, vagina, and urethra anteriorly toward the pubic bone and constrict the openings of these organs. The anterior movement of the vagina and the contraction of the levator ani also produce strongly occlusive forces on the urethra. These actions help to maintain urinary continence. The pelvic floor is discussed in more detail in Chapter 52.
AND BHATIA
2. THE LOWERURINARYTRACT a. The Bladder The bladder's role is to store and empty urine under voluntary control. The bladder lining consists of transitional epithelium and has a rugose appearance formed by mucosal folds. The bladder neck has three layers of muscles: inner longitudinal, middle circular, and outer longitudinal (8). The remainder of the bladder musculature consists of smooth muscles that run in many directions and can expand to accommodate increasing volume without an appreciable rise in pressure. The trigone is a triangular area in the bladder base, and its three corners are formed by the paired ureteral orifices and the internal urethral opening. The trigone has superficial and deep muscle layers. The superficial layer is continuous with muscle fibers of the ureters and the urethra, and the deep layer fuses with the detrusor fibers. The deep muscle innervation is identical to that of the detrusor, with predominant cholinergic nerves and sparse noradrenergic fibers (6). The superficial layer has greater numbers of noradrenergic nerves and only few cholinergic activities. b. The Urethra In the adult female, the urethra is a muscular tube 3 to 4 cm in length and about 6 mm in diameter (6,8). Throughout its length, the urethra is embedded in the adventitia of the anterior vaginal wall. It is lined proximally with transitional epithelium that becomes striated squamous epithelium distally. The urethra is surrounded by smooth muscle that is primarily composed of oblique and longitudinal fibers and has extensive cholinergic innervations with few
FIGURE51.1 Superiorviewof the pelvicfloor structures. (Reproducedfrom RetzkySS, Rogers RM Jr, RichardsonAC. Anatomyof femalesupport.In: BrubakerLT, SaclaridesTJ, eds. Thefemale pelvicfloor." disordersoffunction and support. Philadelphia:FA Davis Company,1996:11.
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CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women noradrenergic nerves (6). The striated muscular urethral sphincter, which surrounds the proximal two-thirds of the urethra, contributes about 50% of the total urethral resistance and serves as a defense mechanism against incontinence. It is also responsible for the interruption of urinary flow at the end of micturition. The two posterior pubourethral ligaments provide a strong suspensory mechanism for the urethra and serve to hold it forward and in close proximity to the pubic bone under conditions of stress (Fig. 51.2). They extend from the lower part of the pubis to the urethra at the junction of its middle and distal third. The anterior vaginal
wall also provides a slinglike support to the proximal urethra and bladder base through its attachment to the levator ani muscles and the arcus tendineus fascia pelvis. The urethral functions are maintained by intrinsic and extrinsic factors. The intrinsic factors include the tones, contractions, and elasticity of the urethral muscles and the coaptation of the urethral mucosa. The tones and contractions are mediated by alpha-adrenergic receptors of the sympathetic nervous system. The extrinsic factors include the levator ani muscles, the endopelvic fascia, and their attachments. These structures form a hammock beneath the urethra to provide a backboard for its compression when intra-abdominal pressures are increased. Hypermobility of the urethra and bladder neck secondary to the loss of their support can occur with the muscular weakening and endopelvic fascia detachment, resulting in stress urinary incontinence.
B. Innervation of the Lower Urinary Tract 1. SYMPATHETIC AND PARASYMPATHETIC INNERVATION S
FIGURE 51.2 The components of bladder and urethral supports and periurethral structures. A. Interrelationships of these structures. B. Sphincter urethrae, urethrovaginal sphincter, and compressor urethrae are all parts of striated urogenital sphincter muscle. LA: levator ani muscles; VLA: vaginal levator attachment; D: detrusor muscle; AT: arcus tendineus fasciae pelvis; PUL: pubourethral ligament; US: urethral sphincter (or sphincter urethrae); CU: compressor urethrae; UVS: urethrovaginal sphincter; IC: ischiocavernosus muscle; BC: bulbocavernosus muscle. (A, From Mishell DR Jr, Stenchever MA, Droegemueller W, Herbst AL. Comprehensive gynecology. St. Louis, Mosby, 1997:576; B, From DeLancey JOL, Richardson AC. Anatomy of genital support. In: Hurt WG, ed. Urogynecologicsurgery. New York, Raven Press, 1992,:27.)
The lower urinary tract is under the control of both sympathetic and parasympathetic nerves (9). Although the parasympathetic system seems to control primarily bladder emptying while the sympathetic system controls bladder storage, the mechanism of micturition involves the interplay of both these systems (Fig. 51.3). Furthermore, a variety of nonadrenergic and noncholinergic neurotransmitters as well as neuropeptides are also involved in the modulation of these activities at the spinal cord and higher levels of the central nervous system. The sympathetic nerves originate from thoracolumbar segments (T10 through L2) of the spinal cord. These nerves have alpha- and beta-adrenergic components. The alpha fibers terminate primarily in the urethra and bladder neck, whereas the beta fibers terminate primarily in the detrusor muscle. Alpha-adrenergic stimulation contracts the bladder neck and urethra, and beta-adrenergic stimulation relaxes the detrusor muscle. The parasympathetic fibers originate in the sacral spinal cord segments $2 through $4. The main neurotransmitter is acetylcholine, which acts on muscarinic receptors. Stimulation of the pelvic parasympathetic nerves causes the detrusor muscle to contract, while administration of anticholinergic drugs controls detrusor overactivity, reduces the vesicle pressure, and increases the bladder capacity.
2. SOMATIC MOTOR CONTROL
The pudendal nerve ($2 through $4) provides motor innervation to the striated urethral sphincter. At the perineal membrane, this nerve divides into the inferior rectal nerve, the dorsal nerve to the clitoris, and the perineal nerve. Although there is considerable variation with the
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Ho ANDBHATIA sacral reflex arc. Later, connections to the higher centers become established, and by training and conditioning, this spinal reflex becomes socially influenced so that voiding can be voluntarily accomplished.
III. U R I N A R Y I N C O N T I N E N C E A. Classification and Definition Urinary incontinence was recently redefined by the International Continence Society (ICS) as the complaint of any involuntary leakage of urine, and it can be classified into six different types: stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, nocturnal enuresis, continuous urinary incontinence, and other types of urinary incontinence (10). This new definition and classification reflect the recent advances in the field. Although this classification system is not perfect, it assists the clinicians in the evaluation and treatment of urinary incontinence.
1. STRESS URINARY INCONTINENCE
FIGURE 51.3 Innervations of the female lower urinary tract and mechanism of micturition. A. Innervations of the lower urinary tract. B. Actions of the autonomic and somatic nervous systems during bladder filling/storage and voiding. (Reproduction from Benson JT, Waiters MD. Neurophysiology of the lower urinary tract. In: Waiters MD, Karram MM, eds. Urogynecology and reconstructive pelvic surgery, ed. 2. St. Louis, Mosby, 1999:16-17.)
branching, the perineal nerve divides into a superficial branch that goes to the labia and a deep branch that innervates the periurethral striated muscles. The involved neurotransmitters are acetylcholine, and receptors are nicotinic type. The somatic efferent branches of the pelvic nerve may also innervate the proximal striated sphincter muscle (9). 3. SENSORY INNERVATIONS
Sensory afferents can be found in the pelvic, hypogastric, and pudendal nerves. Afferent impulses from the bladder, trigone, and proximal urethra pass to the spinal cord. Urethral sensation is carried out primarily by the pudendal nerve. It has been postulated that the loss of the sensory receptors at the trigone, which are different from the stretch receptors in the rest of the bladder, may lead to urge incontinence (9). In infancy, the storage and expulsion of urine is automatic and controlled at the level of the
Stress urinary incontinence (SUI) is the complaint of involuntary leakage of urine on effort or exertion, or with sneezing or coughing (10). SUI can also occur with lifting, running, or any activities that increase the intra-abdominal pressure. The urine leakage can range from a few drops to large volumes. The detrusor contraction should be absent. SUI is caused by ineffective urethral closure, which is related to the deficiencies in extrinsic urethral support or intrinsic urethral integrity, during times of increased intra-abdominal pressure. SUI therefore can be classified further into bladder neck hypermobility and intrinsic sphincter deficiency (ISD). Although bladder neck hypermobility is the major cause of SUI, many women with this condition do not have urinary incontinence if their urethral sphincters are strong and well functioning. Bladder neck hypermobility and ISD can occur together, and the classification in this case is based on the predominated mechanism of incontinence. This decision will guide the type of treatment, which will be discussed later. Genuine stress incontinence (GSI) is used for patients who have undergone urodynamic testing and met the diagnostic criteria. These criteria include the demonstrable urinary leakage when intravesical pressure exceeds the maximal urethral closure pressure and the absence of detrusor contractions. The term GSI is referred to as urodynamic stress incontinence in the new ICS terminology (10).
2. URGE URINARY INCONTINENCE
Urge urinary incontinence (UUI) is defined as the complaint of involuntary leakage of urine accompanied or immediately preceded by urgency (10). The symptom of
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urgency is defined as the complaint of a sudden compelling desire to pass urine that is difficult to defer (10). Several other terminologies need to be clarified. Detrusor overactivity (DO) is a urodynamic observation characterized by involuntary detrusor contractions during the filling phase (10). These detrusor contractions may be spontaneous or provoked. The older terms "detrusor instability" and "unstable bladder" are now replaced by DO. Detrusor overactivity incontinence is a new term to describe urinary incontinence due to DO. The difference between UUI and detrusor overactivity incontinence is that the former is characterized by the symptom of urgency and the latter is characterized by the sign of DO. DO can be divided into neurogenic detrusor overactivity (NDO) and idiopathic detrusor overactivity (IDO). N D O is used when there is a relevant neurologic condition that causes the detrusor overactivity. N D O replaced the older term "detrusor hyperreflexia." However, in the majority of patients the cause of involuntary bladder contractions is unknown, and this condition is referred to as IDO. This type of DO can be triggered by specific events similar to UUI or can occur in the absence of any identifiable event and without any feeling of urgency. Overactive bladder (OAB), or overactive bladder syndrome, is the condition whereby a patient has symptoms of urgency, with or without urge incontinence, in the absence of infection or other proven etiologies (10). These patients may also have urinary frequency and nocturia. OAB is a symptomatic diagnosis and therefore does not require urodynamic testing for confirmation. 3. MIXED URINARY INCONTINENCE
Mixed urinary incontinence (MUI) is defined as the complaint of involuntary leakage of urine associated with urgency and also with exertion, effort, sneezing, or coughing (10). MUI is, therefore, a coexistence of SUI and UUI. However, the degree to which each component contributes to the patient's symptoms varies, and one type of incontinence often predominates the other. Patients with MUI tend to have more incontinent episodes and leak larger volume of urine than those with either SUI or UUI alone (11). 4. NOCTURNALENURESIS
Nocturnal enuresk is the complaint of urinary loss occurring during sleep (10). It should be distinguished from the complaint of waking up at night one or more times to void, which is nocturia, and from waking with urgency and then leaking before arriving at the toilet, which is UUI. Nocturnal enuresis can be primary or secondary. Primary nocturnal enuresis starts in childhood and can persist into adulthood, and secondary nocturnal enuresis starts in adulthood.
5. CONTINUOUS URINARY INCONTINENCE
Continuous urinary incontinence is the complaint of continuous leakage of urine. Nonfunctioning urethra caused by partial urethral resection secondary to vulvar cancer or by scarring and fibrosis from previous surgeries can be the etiologies. Urethral sphincter paralysis secondary to lower motor neuron diseases can also cause continuous incontinence. Other causes include urogenital fistulas, noncompliance bladder secondary to pelvic radiation and fibrosis, and congenital malformations of the urogenital tract, such as bladder exstrophy and ectopic ureters. 6. OTHER TYPES OF URINARY INCONTINENCE
a. Overflow Urinary Incontinence
Ove~flozo incontinence
can occur with underactive detrusor and/or overactive urethra. This type of incontinence is commonly related to neurogenic bladder and outlet obstruction (12). Several medical conditions such as diabetes mellitus, multiple sclerosis, meningomyelocele, lumbosacral tumors, high spinal cord injuries, and prolapsed vertebral disks can result in bladder neuropathy and overflow incontinence. When detrusor muscle becomes acontractile, bladder emptying is not effective and incontinence can occur as an overflow of urine. In the early stage of diabetic bladder neuropathy, the detrusot functioning may wax and wane between hypoactivity and overactivity.
b. Transient Urinary Incontinence Transient incontinence (or functional incontinence) is caused by reasons other than neurologic, anatomic, or other urinary tract dysfunctions. The detrusor and urethra are normal. The common causing factors are described in the mnemonic DL/IPERS (delirium and psychiatric disorders, infection of the urinary tract, atrophic urethritis or vaginitis, pharmacologic agents, excessive urine production, reduced mobility, and stool impaction). Delirium and psychiatric disorders may cause disorientation that result in incontinence. Urinary tract infection may lead to bladder irritation and DO. Atrophic urethritis and vaginitis in postmenopausal women can cause urinary urgency, frequency, and incontinence. Several pharmacologic agents (as described in the section on incontinence evaluation) can induce urinary leakage. Excessive urine production from diabetes, hypercalcemia, or excessive fluid intake as well as restricted mobility and stool impaction can also lead to urinary incontinence. Bowel disorders are usually associated with lower urinary tract disorders because these structures share the innervation. Because these conditions are reversible, thorough medical history and evaluations are important components of the work-up of patients with urinary incontinence, particularly for older women.
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c. Potential Urinary Incontinence Potential incontinence (or masked incontinence) refers to the SUI that is revealed only after reduction of the pelvic organ prolapse. The prolapse may kink the urethra and mask the presence of SUI. Typically, the patient has a history of SUI with some improvement as the pelvic organ prolapse progressed, and finally the SUI resolved coincidently with worsening of the prolapse. The diagnosis can be made with the stress test or urodynamics after reduction of the prolapse with a pessary in the vagina. In the evaluation of patients with pelvic organ prolapse for surgical treatment, the potential incontinence must always be ruled out in order to avoid the new-onset incontinence that follows the surgical correction of the prolapse. In the patients with both pelvic organ prolapse and potential incontinence, anti-incontinence surgery should be performed concomitantly with the antiprolapse procedure. Other types of incontinence such as coital incontinence, which occurs during sexual intercourse, or giggle incontinence, which occurs when a women laughs, are usually reversible and poorly reproducible.
B. Epidemiology Urinary incontinence in postmenopausal women may be under-reported because only one-quarter of incontinent women in the United States and one-third in the European countries seek medical attention for this problem (13). Many postmenopausal women may be embarrassed about their symptoms, think that urinary incontinence is normal as they get older, and delay the seeking of treatment until the condition is severe (4). The precise prevalence of urinary incontinence in these women is difficult to estimate because most studies are questionnaire based and only few are comprehensive, standardized epidemiologic investigations (13,14). Furthermore, many clinicians have misconceptions about urinary incontinence. An earlier study in 1989 reported that 70% of primary care physicians and 80% of nursing home physicians failed to acknowledge this problem in their patients (15). Although this number has improved in recent years, a study published in 2001 still showed that 46% of patients seeking help for urinary incontinence were untreated (16). When compared with men, women have twice the prevalence and are more likely to suffer moderate to severe urinary incontinence (4,13,17). The prevalence of urinary incontinence increases with age, and this increase was demonstrated in a review of 21 epidemiologic studies in which the pooled mean prevalence of urinary incontinence among women at age of 50 or older was 34% versus 25% among middle-aged and younger women (14). Urinary incontinence has been reported to affect more than 50% of nursing home residents (4). Genitourinary atrophy due to hypoestrogenism, weakening of connective tissue, increasing in
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medical comorbidity, decreasing in cognitive functions, impairments in mobility, and increasing in nocturnal diuresis are contributing factors to this age-related increase in urinary incontinence. The prevalence of postmenopausal incontinence in the community is thought to be between 16% and 29% (18-20). Of the group of perimenopausal and postmenopausal women who attended a menopause clinic, however, 20% complained of severe urinary urgency and nearly 50% complained of stress incontinence (18). Recent data on the distribution of urinary incontinence by type reported that 33.8%, 31.8%, and 34.4% of women with incontinence disorders have SUI, UUI, and MUI, respectively (21,22). SUI tends to be more common among younger women, whereas older women have more UUI and MUI (14). The data on prevalence of urinary incontinence in racial and ethnic groups are somewhat limited. One study reported that the prevalence rates among Caucasian women and African-American women are similar (13), whereas another study found higher prevalence among Caucasian women (23). In a study of older women, urinary incontinence was found in 23% of Caucasian women and in 16% of African-American women (22). Recently, Thorn and coworkers (24) reported that the risk of SUI is lower, while the risk of UUI was similar, in African-American and Asian-American women when compared with Caucasian women.
C. Pathophysiology Urinary incontinence is a complex, multifactorial disorder, and the etiologies are diverse and, in many cases, incompletely understood. It usually involves more than one anatomic structure. Contributing factors include structural and functional disorders of the urethra, bladder, ureters, and surrounding supporting elements. At the urethral level, urinary incontinence can be caused by intrinsic etiologies, extrinsic factors, or obstruction. Intrinsic urethral etiologies can be anatomic, such as urethral fistula and diverticula, or functional, such as ISD and urethral instability. Extrinsic factors refer to the loss of anatomic support to the proximal urethra and urethrovesical ]unction causing urinary incontinence. At the bladder level, urinary incontinence can be caused by idiopathic or neurogenic detrusor overactivities as well as other conditions such as urinary tract infection, bladder calculi, foreign bodies, bladder neoplasms, radiation exposure, bladder overdistention, and outlet obstruction. Damage to the bladder anatomic integrity, including vesicovaginal fistula, vesicocutaneous fistula, and untreated exstrophy, can also result in incontinence. At the ureteral level, the causes of incontinence are very rare and include congenital abnormalities such as ectopic ureter or anatomic injuries such as ureterovaginal fistula.
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women It should also be noted that urinary incontinence can have a spontaneous remission. In a 5-year follow-up of 90 women who were incontinent at baseline, 28% of these women became continent, which corresponds to an annual remission rate of 5.6% (25). Women in the remission group tended to be younger, and the highest remission rate (10.6%) was in the 20- to 29-year-old group. Women with SUI at baseline had a higher annual remission rate than those with UUI or MUI. In order to understand the pathophysiology of different types of urinary incontinence, brief discussions of the mechanism of micturition and continence are warranted.
1. MECHANISM OF MICTURITION AND CONTINENCE
During the filling phase, the detrusor muscle relaxes to allow gradual expansion of the bladder while the urethral sphincter closes to prevent urine leaking. Normally, there is little or no increase in intravesical pressure despite a large increase in urine volume. This process is coordinated by the parasympathetic and sympathetic nervous systems, pelvic nerve, spinal cord, and brain (9). The bladder is controlled by neural impulses from both afferent and efferent pathways. As the bladder volume increases during the filling phase, tension-stretch receptors on the bladder wall become activated, leading to a desire to void. However, normal women are able to suppress this micturition reflex until an appropriate time. These activities seem to be mediated primarily by the sympathetic nervous system. In the bladder-emptying phase, cholinergic signal from the pelvic nerves coordinates the detrusor contraction and urethral sphincter relaxation (9). The voiding occurs with voluntary relaxation of the urethral sphincter and the pelvic floor as well as the contraction of the detrusor muscle. The bladder-emptying phase is mediated by the parasympathetic nervous system. In order for these mechanisms to work properly, thus maintaining continence, the anatomic and functional properties of the involved structures and their innervations should be intact.
2. STRESS URINARY INCONTINENCE
a. Bladder Neck Hypermobility SUI occurs when the rise in the intravesical pressure, which is caused by an increase in intra-abdominal pressure, overcomes the urethral resistance, resulting in urinary leakage. For continent women, the bladder and proximal urethra are located retropubically within the sphere of intra-abdominal pressure. The urethral sphincter and urethra have a higher pressure than the bladder, and this pressure gradient is preserved during period of physical stress because the changes in intra-abdominal pressures are transmitted equally to the bladder and proximal urethra. The commonly accepted theory for the pathogenesis of SUI is
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that the bladder neck and proximal urethra drop below the pelvic floor because of the loss of anatomic support. This condition is often referred as bladder neck hypermobility (17,26). The increase in intra-abdominal pressures during strenuous activities or coughing is, therefore, not transmitted equally to the bladder and proximal urethra. As a result, intraurethral pressure falls below bladder pressure and urinary leakage occurs. The anterior vaginal wall and the endopelvic fascia that attaches bilaterally to the arcus tendineus and levator ani muscles provide support to the bladder neck and urethra. The attachment of suburethral endopelvic fascia to the pubococcygeus further limits bladder neck descent during physical stress (6,8). Damages to these structures and to the nerves, muscles, and connective tissues of the pelvic floor are thought to be the main culprits. Trauma from childbirth has been shown to predispose women to SUI (17). b. Suburethral Hammock Support In continent women, the urethra is firmly supported by the anterior vaginal wall and endopelvic fascia that are attached laterally to the arcus tendineus and levator ani muscles. These tissues provide a "hammock" of supporting structure, not only for the urethra but also for the urethrovesical junction (6,8,27). Any increase in intra-abdominal pressure will transmit a downward force to the anterior urethral wall and compress it against the firm, supported posterior urethral wall, thus occluding the urinary flow. If the anterior vaginal wall is damaged or weakened, or if the endopelvic connective tissue is detached from its normal lateral fixation, the optimal urethral compression does not occur, and urinary leakage results. With the success of tension-free suburethral sling procedures, it is now recognized that both of the hypermobility and loss of support to the bladder neck and urethra are important mechanisms of SUI. It has also been postulated that the integrity of the suburethral hammock is more important for continence than the location of the urethra relative to the pelvic floor (27). c. Intrinsic Sphincter Deficiency ISD, in which the urethral sphincter fails to close appropriately during period of stress, is another cause of SUI (26). Several factors such as childbearing and delivery, hypoestrogenism, periurethral vascular damage, neurologic diseases, radiation exposure, scarring secondary to previous surgery, or certain medications (i.e., alpha-adrenergic antagonists) can contribute to the development of ISD. Mucosal atrophy and hypovascularity of the urethral wall as well as neuromuscular damage to the urethral sphincter can also decrease urethral tone and cause ISD. This condition may result from myelomeningocele or epispadias or may be acquired after trauma or a sacral cord lesion. ISD is also common in women who had multiple anti-incontinence surgeries. Urine leakage in this
700 condition can occur with little exertion or with minimal activity such as throat-clearing or lifting a light weight (17). SUI secondary to ISD is less common but more challenging to diagnose and treat. It has been shown that suburethral sling procedures can effectively restore long-term continence in 76% to 96% of lSD patients (28). 3. URGE URINARY INCONTINENCE
UUI can be quite debilitating, and its pathophysiology is not completely understood. This type of incontinence can be triggered by some events such as water running, handwashing, orgasm, changes in posture or position, changes in temperature, or opening the front door. Neurologic diseases, outflow obstruction, local bladder and urethral irritants, and medications must be considered as etiologies. Neurologic disorders such as multiple sclerosis (MS), cerebrovascular diseases, Parkinson's disease, spinal cord injuries, and neoplasms of the central nervous system or spinal cord can cause N D O and UUI (17,26). Approximately 90% of patients with MS have lower urinary tract dysfunction during the course of the disease. Any hemorrhage, infarction, or vascular diseases in the areas of the cerebral cortex, internal capsule, brainstem, and cerebellum can result in N D O and UUI. Spinal cord injuries interrupt the sacral reflex and other pathways that are responsible for the voluntary and involuntary inhibition of detrusor contractions. Although the bladder is areflexic during the initial phase of injury that results in overflow incontinence, detrusor muscle eventually becomes hyperreflexic in the later phase. Bladder outlet obstruction due to advanced pelvic organ prolapse, such as severe cystocele or vaginal vault prolapse, is another cause of UUI (17,26). Local bladder and urethral irritants such as foreign bodies, permanent sutures, stones, and neoplasms as well as cystitis and medications such as parasympathomimetics must also be considered as etiologies in the work-up of UUI. However, in the majority of patients the cause of UUI is unknown. Theories regarding the intrinsic bladder abnormalities in UUI include disorders of bladder ganglia, disorders of pacemaker cells, increased activity of sensory nerves, and deficiency in prostaglandin production (29). The common final pathway of these mechanisms is probably the myogenic dysfunction of the detrusor muscle with increased capacity for spontaneous contractions. Damage to the detrusor muscle caused by trauma, aging, atrophy, or loss of innervation as well as disruption in the neurochemical pathways are responsible for this condition. UUI and OAB can also be caused by changes at the cellular level of the detrusor muscle (29). With an increased ratio of abnormal-to-normal cell junctions, the detrusor can spread these uninhibitory contractions. In a small subgroup of patients with UUI, the leakage of urine into a funneled and incompetent proximal urethra may trigger the micturition reflex, causing involuntary bladder contraction (30).
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UUI or OAB that occurs after anti-incontinence procedures in patients who preoperatively had only GSI is referred as de novo U U I or de novo OAB. It was hypothesized that elevation of the bladder neck in anti-incontinence procedures could cause urethral compression and outflow obstruction resulting in de novo U U I or OAB. However, this theory has been challenged (31). It was also proposed that repeat surgeries at the bladder neck may interfere with the autonomic nerve supply of the bladder and result in de novo 13151 or OAB. The incidence of de novo O A B ranges from 5% to 18% in two series (32,33) and from 5% to 27% in another series (34). 4. MIXED URINARY INCONTINENCE
MUI is a coexistence of both SUI and UUI, and the degree to which each component contributes to the patient's incontinence varies. It has been shown that 33% of women with SUI may have coexistent DO (35). These patients represent a therapeutic challenge, and whether coexistence of DO decreases the surgical cure rate of SUI is controversial. Currently, the exact etiology of MUI is not clear, and this condition often responds poorly to treatment, either pharmacologic or surgical. A better understanding of its pathophysiology is needed to target the treatment more effectively.
D. E v a l u a t i o n Initial evaluation of urinary incontinence in postmenopausal women requires a systemic approach that includes a detailed history, the bladder diaries, the quality of life questionnaires, the physical examinations, a cotton swab Qztip test, a stress test, a urinalysis (with urine culture and cytology if indicated), and a postvoid residual volume. For at least 90% of patients with urinary incontinence, these steps in combination with a simple cystometry are adequate investigations (36,37). They can be carried out in the office, and noninvasive empirical therapy such as pelvic floor muscle exercises, behavioral modification, or pharmacologic therapy can be initiated following these evaluations. Additional multichannel urodynamic, uroflowmetric, cystourethroscopic, electromyographic, electrophysiologic, or imaging studies may be necessary in patients with a history of multiple previous surgeries for urinary incontinence and for patients with associated neurologic diseases. They are also indicated for patients who failed the empiric therapy and are being considered for surgical intervention. 1. MEDICAL HISTORY
A thorough medical history should include the presenting symptoms, the degree to which these symptoms are bothersome, the onset and frequency of incontinence, and the amount of urine loss. Triggering events causing urine
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women loss, character of urine loss as constant or .intermittent, associated symptoms of dysuria or bladder pain, and other concomitant symptoms are also essential. Medical history of chronic cough, chronic obstructive pulmonary disease (which can lead to SUI due to chronic coughing), diabetes mellitus (which can produce osmotic diuresis if glucose control is poor), vascular insufficiency (which can mobilize fluid from peripheral edema into the vascular system at night, resulting in diuresis), cancer treatment (adverse effects of radiotherapy or chemotherapy on the urinary tract), and renal disorders should be obtained. Neurologic conditions that especially affect the bladder and urethral sphincter functions, such as MS, stroke, Parkinson's disease, spinal cord injury or neoplasm, and myelodysplasia, should be included. Symptoms suggesting neuropathy, such as muscle weakness, paralysis or poor coordination, gait disturbance, tremor, tingling sensation, numbness, and double vision, are also important in the medical history. Surgical histories of the pelvic, urologic, and central nervous systems are essential. Radical hysterectomy for uterine or cervical cancer may cause detrusor denervation, and surgeries involving the spine and brain can affect bladder function. Obstetric histories, such as the number of pregnancies, spontaneous deliveries, cesarean deliveries, and instrumental deliveries, are important because they may have significant effects on the pelvic support and lower urinary tract structures. Modifiable risk factors such as diet, smoking, alcohol and caffeine intake, mobility problems, and other transient causes of urinary incontinence (DIAPERS causes, as described earlier) should be obtained. All medications that may affect the lower urinary tract should be carefully reviewed. Antihypertensive medications, such as alpha blockers and calcium channel blockers, may decrease detrusor contractility or relax the bladder neck and urethra, leading to incontinence and voiding problems. The increased urine volume produced by diuretic therapy can be a challenge to older patients because of their decreased bladder capacity. Anticholinergic drugs, such as antihistamines, antidepressants, antipsychotics, antispasmodics, opiates, and anti-Parkinson's disease medications, may impair detrusor contractility and cause voiding difficulty or overflow incontinence. Over-the-counter cold medications that contain sympathomimetics or antihistamines with significant anticholinergic effects can adversely affect the detrusor and urethral sphincter functions. Tricyclic antidepressants, neuroleptics, narcotic analgesics, sedatives (e.g., benzodiazepines), and alcohol can be detrimental to cognition and, therefore, incontinence, especially in older patients. The presentation of urinary incontinence can range from a simple complaint to a combination of symptoms. The medical history may not accurately identify the type of urinary incontinence, and attempting to diagnose this disorder with medical history alone frequently leads to mistakes. A recent meta-analysis reported that the symptoms of urine
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loss only with coughing, sneezing, laughing, running, or Valsalva maneuvers have a false-positive rate of 23% and a positive predictive value of 56% for the diagnosis of GSI (38). For the UUI, the reported symptom (i.e., urine loss only following a strong desire to void) has a sensitivity of 77% and a specificity of 34% (38). In patients with MUI, the described symptoms of both stress and urge incontinences have a false-positive rate of 36% and a positive predictive value of 79% (38). Although the patient's presenting symptoms may not be reliable in the determination of the type of incontinence, her perceptions of the severity of these symptoms are important in the evaluation and treatment. The decision on surgical procedures should not be based on medical history alone because these procedures are more likely to fail if the diagnosis is incorrect or incomplete. 2. VOIDINGDIARY
Although a voiding diary can be a valuable aid in the evaluation of patients with urinary incontinence, its use is often neglected. There is no standardized format for the voiding diary; however, any of the published forms (37,39) can be employed because they are similar and provide adequate information. Because studies have demonstrated that a 3-day diary is as reliable as a 7-day diary, recording for 3 continuous days is a common approach. The volumes of each void can be obtained with a plastic measuring "hat" that fits over the patient's toilet bowl. The voiding diary should record the time and volume of each void, the type and volume of fluid intake, the frequency and volume of incontinence, and the associated activities and symptoms with incontinence. Many types of fluid intake, such as caffeinated or alcoholic drinks, carbonated beverages, and certain food ingredients, can act as bladder irritants. Initial management in these patients is to eliminate or minimize these irritants. The voiding diary also helps the clinician to confirm complaints and to determine whether the incontinence is in part due to an abnormally high or low urinary output. For example, in diabetic patients with urinary incontinence secondary to osmotic diuresis (high urine output), the first step is to control blood sugar in order to decrease the urine output, rather than pharmacologic or surgical interventions. On the other hand, patients who limit the fluid intake dramatically in an attempt to control their incontinence will make highly concentrated urine (low urine output), which can irritate the bladder and cause UUI. Increase fluid intake will help these patients. The voiding diary can also help to determine the initial interval in the timed voiding technique for the treatment of UUI. Generally, a functional bladder capacity of 400 to 600 mL, an average voided volume of approximately 250 mL, a voiding frequency of six to eight times per day, and a daily urine output of 1500 to 2500 mL are considered normal (39,40). Although this recorded information can provide a
702 reliable voiding pattern and severity of the incontinence over a given period, it cannot differentiate stress from urge or mixed incontinences. Voiding diaries are shown to be reproducible in the setting of stress incontinence; however, data regarding its reproducibility in urge and mixed incontinences are lacking (3 9). 3. QUALITY OF LIFE QUESTIONNAIRES Validated instruments such as the Urogenital Distress Inventory (UDI) and Incontinence Impact Q.uestionnaire (IIQ] were developed to assess the impact of incontinence on quality of life (41,42). The UDI and IIQ instruments provide a multiple-component quantification of the severity of incontinence and its effects on the daily activities. These questionnaires allow the inclusion of the patient's perception of incontinence into the overall assessment. They can be easily administered in the clinic. 4. PHYSICALAND PELVIC EXAMINATIONS
General, focused neurologic, and detailed pelvic examinations should be parts of the evaluation. When the patient arrived with a full bladder, the voided volume is measured and the bladder is then catheterized to obtain the postvoid residual volume as well as samples for urinalysis and urine culture. If urodynamics are a part of the evaluation, these volumes can be obtained more conveniently at that time. a. GeneralExamination The generalexamination should include the vital signs, height, and weight as well as the specific cardiac, pulmonary, abdominal, and extremity evaluations. The body mass index should be calculated because obesity is a contributing factor to SUI. The examination should also include detection of medical conditions, such as cardiovascular insufficiency, pulmonary disease, and neurologic disorders, that may affect the lower urinary tract. The abdomen should be examined for surgical scars, hernia, masses, and bladder distention. The presence of hernias may indicate inherent connective tissue weakness, a possible contributor to the incontinence. b. Neurologic Examination Neurologic disorders can cause or exacerbate urinary incontinence (43). The patient's mental status and gait should be observed, and any abnormalities should prompt more in depth investigations such as examination of the cranial nerves, extremity function, and reflexes. Neurologic examination should also focus on the motor, sensory, and proprioceptive functions of the lumbosacral nerve roots by evaluating the strength, sensation to dull and sharp stimuli, and deep tendon reflexes of the lower extremities (43,44). Two reflexes may help in the evaluation of
Ho AND BHATIA sacral integrity. The anal wink reflex, or sensation of the perianal areas, can be detected by stroking laterally to the anal canal with a cotton swab and observing the reflex contraction of the external anal sphincter muscle. The bulbocavernosus reflex, which reflects the integrity of the $2 to $4 levels of the sacral cord, is elicited by gently tapping the clitoris with a cotton swab and observing the contraction of the bulbocavernosus and ischiocavernosus muscles. Although the presence of these reflexes may rule out any significant sacral cord problem, their absence does not indicate neuropathy. Up to 30% of neurologically intact women do not demonstrate these reflexes (43). c. Pelvic Examination For the pelvic examination, the external genitalia, urethral meatus, and vagina should be inspected for evidences of atrophy and hypoestrogenism, such as pallor and thinness of tissues, loss of rugae, fleshy lesion, and caruncle. Because the distal urethra is estrogen dependent, the patient with atrophic vaginitis may also have atrophic urethritis. The urethra should be palpated for suburethral masses, which raise the suspicion for a urethral diverticulum. If tenderness and watery or purulent discharge occur with compression of the urethra, diverticulum or urethritis may be present. Tenderness with the urethral and trigonal palpations may also indicate urethral syndrome or interstitial cystitis. Skin irritation suggests the presence of prolonged incontinence. Pelvic floor relaxation usually coexists with incontinence and should be carefully evaluated because surgical treatments for both of these conditions can be carried out simultaneously. Pelvic examination should be performed systematicaUy for the apical, anterior, and posterior vaginal wall defects. The presence of uterine or apical prolapse, cystocele, urethrocele, rectocele, enterocele, and perineal laxity should be noted. Details of these examinations are described in Chapter 52. In the digital examination, the uterus and adnexa are palpated for masses or tenderness. The urethra should be carefully palpate against the pubic symphysis to rule out suburethral masses and diverticula. The bladder should also be palpated for tenderness that may represent urinary tract infection, interstitial cystitis, or bladder stone. The levator ani muscles are palpated and their strength is appreciated while the patient squeezes the examining fingers. The perineal body should also be carefully inspected for its length and tissue thickness. A short perineal body with mostly skin and little or no underlying muscle indicates a damaged or compromised structure. The thickness of the rectovaginal septum is determined by a rectovaginal examination. Internal and external rectal sphincter tones should also be noted. With fingers in the vagina and rectum, any sliding down of tissue while the patient is in maximal straining may suggest enterocele.
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women
5. STRESSTEST
The stress test can be carried out during the pelvic examination or urodynamic study. Because the test must be done with full bladder, many clinicians prefer to perform it following the urodynamic procedure when the bladder is filled with fluid. While the physician observes the urethral meatus, the patient is asked to perform provocative maneuvers such as coughing or straining in the supine position. SUI is suggested if short spurts of urine escape simultaneously with each cough or straining. Generally, the patient with SUI displays immediate urine loss of relatively short duration. A delayed leakage, or loss of large volumes of urine, suggests uninhibited bladder contractions. If loss of urine is not demonstrated in the supine position, the test should be repeated with the patient in a standing position. If more than mild pelvic organ prolapse is present, the prolapse should be reduced (with a pessary or a single-blade speculum) during the stress test because the prolapse may mask the urine leakage. Care must be taken not to compress the urethra while reducing the prolapse. If the stress test is positive with a relatively empty bladder, in supine position, and with minimally increased intra-abdominal pressure, ISD is suspected and urodynamic testing is indicated. The stress test must be done with a full bladder, the urine loss should be visualized with each coughing or straining maneuver, and the urine loss should cease between the tests for it to be reliable (36,37). If the history strongly suggests SUI but stress test findings are negative and DI is ruled out, the pyridium pad test (45) can be employed. 6. THE Q2TIP TEST The Qztip test determines the mobility and descent of the urethrovesical junction on straining (36). With the patient in the lithotomy position, a sterile and lubricated cotton swab Qztip is inserted into the urethra to the level of the urethrovesical junction, and the angle between the Qztip and the horizontal is measured. Another simple way is to place the Qztip all the way into the bladder and then pull back until increased resistance is met, which indicates that the cotton tip is at the urethrovesical junction. The patient then asked to strain maximally, which produces a descent of the urethrovesical junction. Along with this descent, the Q:tip moves, producing a new angle with the horizontal. The resting and straining angles are measured with a simple goniometer. The normal change in these angles is up to 30 degrees. Hypermobility of the bladder neck is defined as a deflection angle with straining of greater than 30 degrees from the resting angle or greater than 30 degrees from the horizontal. In patients with pelvic relaxation and SUI, the change in Qztip angles can be in the range of 50 to 60 degrees or more.
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The Qztip test does not establish the diagnosis of SUI and is not essential for patients in whom noninvasive treatment is intended (36). However, it may be valuable in differentiating SUI caused by bladder neck hypermobility from that caused by ISD and in predicting the failure of incontinence surgery. This test is useful if surgical intervention is planned because those with SUI and a well-supported bladder neck and urethra (the Qztip test is negative) may have ISD and should be treated with periurethral bulking agents or suburethral sling procedure rather than with bladder neck suspension. 7. POSTVOIDRESIDUALVOLUME
Although the Agency for Health Care Policy and Research (AHCPR) guidelines recommend that postvoid residual volume should be included in the initial evaluation (36), its value is limited except in patients suspected of having obstructional or neuropathic causes for their incontinence, and in postoperative patients. As compared with men, obstructive voiding is rare in women. Furthermore, the postvoid residual volumes have a poor test/retest reliability (44). The postvoid residual volume less than 50 mL is considered normal, and the volumes greater than 100 mL is generally considered abnormal (17,44). Volumes of greater than 100 mL but less than 200 mL should be repeated and correlated clinically. Volumes of greater than 200 mL should be referred for evaluation by a specialist. Patients with a large postvoid residual volume may have a diminished functional bladder or outlet obstruction. Incontinence can occur in these patients as a result of irritation from urinary tract infection (UTI) or overflowing from an overdistended bladder. Bladder overdistention may also provoke uninhibited contractions in the detrusor muscle, leading to incontinence. In these patients, bladder emptying with intermittent self-catheterization can eliminate recurrent UTI and correct the incontinence. 8. URINALYSIS
Urinary tract infection (UTI) can cause urinary urgency, frequency, and incontinence. A simple urine dip or analysis in the office can diagnose the absence of infection with a specificity of 97% to 99% (36). There is no need for urine culture and sensitivity in the patients with negative urinalysis. However, in those patients with high clinical suspicion, urine culture and sensitivity should be obtained regardless of the urinalysis results. Although urinalysis is excellent at ruling out UTI, its positive predictive value for diagnosing the presence of infection is poor. Patients with positive urinalysis should, therefore, have urine culture and sensitivity results before diagnosing infection as a cause of incontinence.
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Although urine cytology is not obtained routinely, it is useful as a screening test for urinary tract malignancy. Microscopic or macroscopic hematuria should be followed with cytology and cystoscopy. 9. PAD TEST
Pad test can be used to quantify the amount of urine loss; however, it is not always required for the diagnosis of incontinence, except in the evaluation of the efficacy of therapy. Patients are given pre-weighted pads and plastic bags and instructed to wear these pads for 24 hours, change them whenever necessary, and immediately place the wet pads into the zip-top bag. These pads and bags are returned to the office after completion of the 24-hour period for reweighing. A gain of up to 8 grams is within the normal range (44,45). 10. URODYNAMICS
In general, urodynamic studies involve a variety of procedures that together evaluate the structure and function of the lower urinary tract. In this sense, obtaining voiding diary and measurements of voided and postvoid residual volumes are parts of the urodynamic studies. The urodynamic methods range from simple cystometry (or singlechannel urodynamics) to complex multichannel urodynamics and videoradiographic studies (40,46-50). The findings in urodynamics should correlate with clinical observations and reproduce the patient's symptoms; if not, further evaluation is necessary. For example, if the stress test during urodynamic study demonstrates only scant urine loss after several repeated deep coughs while the patient complaints of continuous urine loss in large amounts with any provocative maneuver, the finding is not correlated with the patient's symptoms. Further evaluation of this patient, either to validate the complaint or to look
for other causes, is necessary. For most primary care physicians, the ability to employ and interpret simple cystometry and stress test is important in the management of urinary incontinence. Patients with complicated incontinence or who require multichannel urodynamics and/or cystourethroscopy can be referred to specialists.
a. Single Channel Cystometry Single channel cystometry involves distending the bladder with known volumes of sterile water or normal saline and observing the changes in the bladder function during the filling (40,46). A simple ofrice cystometry consists of a bladder catheter, a large syringe with the plunger removed, and a 500-mL bag of normal saline or sterile water (Fig. 51.4). After the patient voided, the residual volume can be measured by draining it through a 10 or 12 French rubber catheter. The bladder catheterization should be performed in a sterile fashion. The patient's bladder is then gradually refilled with the fluid at a rate of 60-80 mL/min until her functional bladder capacity is reached. During bladder filling, the patient is asked to report her first bladder sensation, initial urge to void, and maximal bladder capacity. Detrusor contraction is indicated by a rise in the meniscus of the fluid in the syringe. The most important observation is the presence of a detrusor reflex and the patient's ability to control or inhibit this reflex. For the normal female bladder, the first sensation of bladder filling occurs at volumes of 150 to 200 mL, and the strong desire to void occurs at 400 to 600 mL (40,46). During filling, an initial rise in detrusor pressure between 2 and 8 cm H20 usually occurs. The maximal cystometric capacity (usually 400 to 600 mL) is the volume that the bladder musculature can tolerate before the patient experiences a strong, uncontrollable desire to urinate. At this point, if the patient is asked to void, a terminal contraction may appear and is seen as a sudden rise in intravesical pressure. At the peak of the contraction, the patient is instructed to inhibit this reflex. A normal person should be able to inhibit this detrusor
FIGURE 51.4 Single channel cystometry. Pves = bladder pressure. (Reproduction from Karram MM. Urodynamics: cystometry. In: Walters MD, Karram MM, eds. Urogynecology and reconstructivepelvic surgery, ed. 2. St. Louis, Mosby, 1999:57.)
CHAPTER51 Lower Urinary Tract Disorders in Postmenopausal Women reflex and thereby bring down intravesical pressure. In urologically or neurologically abnormal patients, the detrusor reflex may appear without the specific instruction to void, and the patients cannot inhibit it; this observation is referred to as an uninhibited detrusor contraction or detrusor overactivity (40,46). These cystometric procedures allow differentiation between patients who are incontinent as a result of uninhibited detrusor contraction and those who have SUI. Conversely, the hypotonic bladder accommodates excessive amounts of fluid medium with little increase in intravesical pressure, and the terminal detrusor contraction is absent when the patient is asked to void. Single channel cystometry is not sensitive, with a poor negative predictive value, in the diagnosis of DO as compared with multichannel urodynamics (47). However, simple cystometry can be combined with a stress test to provide useful tools for the determination of incontinence type in the typical uncomplicated patients (48). If the patient experiences urgency with accompanying urine loss and detrusor contraction during bladder filling (positive cystometrogram) while the stress test is negative, she is likely to have UUI due to DO. If the patient has urine leakage with each time she coughs or strains (positive stress test) and there is no associated detrusor contraction, she has SUI. If both cystometric and stress tests are positive, the patient may have either MUI or UUI. In patients with UUI, a cough can induce detrusor contraction that will lead to urinary leakage with the subsequent cough, mimicking a positive stress test. Thus, in a patient who has strong detrusor contractions followed by a positive cough stress test, further studies are warranted prior to the treatment because this patient may only have UUI rather than MUI. Patients who have complaints that cannot be verified, who exhibit prolonged urine leakage with coughing that suggests a cough-induced detrusor contraction, and who exhibit both stress and urge incontinence require further evaluation with multichannel urodynamics. Patients in whom the cystometric findings do not reproduce their symptoms and in whom cystometric and stress tests do not provide a clear diagnosis also need multichannel urodynamic studies.
b. Multichannd Urodynamics In the single channel cystometry, only intravesical pressure is measured. Changes in the intravesical pressure can be caused by a detrusor contraction, an increase in the abdominal pressure, or both. In order to obtain the bladder pressure exerted only by detrusor activities (Pdet), the intra-abdominal pressure (Pabd) is measured and then subtracted from the total intravesical pressure (Pves) in the multichannel urodynamics (Fig. 51.5). The pressures of the bladder, urethra, and abdomen are recorded simultaneously by using microtransducers, which are incorporated in a small catheter (usually 8 French or less). The intravesical and urethral pressures are measured directly with a sensor-equipped catheter placed in both the
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bladder and urethra. The intra-abdominal pressure is approximated by measuring either vaginal or rectal pressure. The detrusor pressure (Pdet = Pves - Pabd) is obtained by subtracting the intra-abdominal pressure from the intravesical pressure using electronic equipment. This procedure sometimes described as subtracting cystometry. Urodynamic studies are helpful if the results are interpreted with reference to the findings in patient's history and physical examination. The investigation includes assessment of filling and emptying, urethral pressure profile, leak point pressure, and uroflowmetry (40,46). Assessment of Filling and Emptying: Usually sterile water or normal saline is used to fill the bladder at a rate of 50-100 mL/min. The study can be carried out in the supine, modified lithotomy, sitting, or standing position; however, standing position is preferable because most patients experience incontinence when they are erect. During the filling phase, patients are asked to report the first sensation, strong desire to void, urgency, and maximal bladder capacity as in the single channel cystometry. The stress test is also performed. Provocative maneuvers, such as straining, coughing, heel-bouncing, fast filling of fluid, or listening to running water, are performed in an attempt to produce any urine leakage or uninhibited detrusor contractions. In normally continent patients, the detrusor does not contract even though the patient may have an urge to urinate. The bladder compliance is obtained by dividing the change bladder volume (in mL) by the change in detrusor pressure (in cm H20) (40). Urethral Pressure Profile and Leak Point Pressure: Because continence requires the pressure in the bladder to be lower than the pressure in the urethra, measuring the differences between these two pressures may provide useful clinical information. The urethral pressure profile is obtained by slowly pulling a pressure-sensitive catheter through the urethra, from the urethrovesical ]unction to the urethral meatus. Although the pulling can be performed manually, urodynamic instruments can carry out this procedure automatically with high precision. The urethral pressure profile is a graphic record of pressure along the length of the urethra (Fig. 51.6). From this profile the functional length and anatomic length of the urethra can be calculated (40,49). The maximum urethral closure pressure is obtained by subtracting the intravesical pressure (Pves) from the maximum urethral pressure (Pure). A low urethral closure pressure (Pucp = Pure - Pves) may be found in patients with SUI, whereas an abnormally high urethral closure pressure may be associated with voiding difficulties, hesitancy, and urinary retention. The urethral closure pressure normally varies between 50 and 100 cm H20 (40,49). The leak point pressure is the intravesical pressure, or sometimes intra-abdominal pressure, at the moment when stress incontinence occurs (40,49). The patient is asked to strain in order to increase intravesical pressure gradually, and the lowest pressure at which urine leakage occurs is the
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FIGURE 51.5 Multichannel urodynamics. A. Instrumentation. Abdominal pressure (Pabd), bladder pressure (Pves) and urethral pressure (Pure) are measured directly. Detrusor pressure (Pdet) and urethral closure pressure (Pucp) are electronically derived. Electromyography (EMG) and urine flow studies are also performed. B. Cystometrogram of a 70 year old multiparous woman with the complaint of stress urinary incontinence. She develops urgency at a volume of 70 ml and demonstrates leakage due to detrusor overactivity after several coughs. This patient has no urinary leakage without triggered detrusor spasms. (A, Reproduction from Karram MM. Urodynamics: cystometry. In: Waiters MD, Karram MM, eds. Urogynecologyand reconstructivepelvic surgery, ed. 2. St. Louis: Mosby, 1999:58; B, Reproduction from Theofrastous JP, Swift S. Urodynamic testing. In: Bent AE, Ostergard DR, Cundiff GW, Swift SE, eds. Ostergard's urogynecology and pelvicfloor dysfunction, ed. 5. Philadelphia: Lippincott Williams & Wilkins, 2003:122.)
Valsalva leakpoint pressure. Patients may cough, with gradually increasing intensity, until urine leakage occurs and the intravesical pressure, or intra-abdominal pressure, at this point is the cough leak point pressure. If urine leakage does not occur at the highest pressure obtainable, this pressure is a reasonable estimation of the urethral sphincteric strength.
An abdominal leak point pressure of less than 60 cm H20 or urethral closure pressure of less than 20 cm H20 is suggestive of the diagnosis of ISD (40,49). However, the clinical applications of urethral closure pressure and abdominal leak point pressure are controversial and should not be the sole determinant for important management issues such as surgical intervention.
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CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women
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tract anatomy and function (53). The bladder neck mobility, bladder neck funneling, and urethra or bladder diverticula can be observed simultaneously with the urodynamic profiles. Although this technique is useful in the investigation of obstructive voiding and can show the anatomic level of the obstruction, it adds little information to the uncomplicated patient. The cost and radiation exposure associated with voiding cystourethrogram and videoradiographic urodynamics also obviate their need in the incontinent evaluation of the typical female patient. These techniques are reserved for complicated cases of urinary incontinence.
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Urethral Length (cm) FIGURE 51.6 Urethral pressure profile. As the pressure sensor is withdrawn through the urethrovesical junction, urethral pressure rises to a maximum urethral closure pressure (MUCP) and then decreases to zero as it exits the urethra. FUL is the functional urethral length. (From Theofrastous JR Swift S. Urodynamic testing. In: Bent AE, Ostergard DR, Cundiff GW, Swift SE, eds. Ostergard's urogynecology and pelvic jToor dysfunction, ed. 5. Philadelphia: Lippincott, Williams & Wilkins, 2003:124.)
Uroflowmetry: Uroflowmetry records the rates of urine flow through the urethra when the patient is asked to void spontaneously. It is a simple test that can be used to document voiding dysfunction objectively. The urine flow rate and profile can be measured alone or concurrently with the detrusor pressure and urethral closure pressure to provide a better assessment of voiding function (50). In this way, poor bladder contraction that results in failure to empty can be identified. These pressure-flow studies help to differentiate voiding dysfunction secondary to obstruction from that secondary to an underactive detrusor. The high detrusor pressure and low flow rate of voiding indicate outlet obstruction as the cause of abnormal voiding. On the other hand, if a patient voids with a low flow rate and minimal or no rise in detrusor pressure, her voiding dysfunction is probably secondary to an acontractile or underactive detrusor.
11. VOIDING CYSTOURETHROGRAM AND VIDEORADIOGRAPHIC URODYNAMICS
In the voiding cystourethrogram, fluoroscopy is used to observe bladder filling, mobility of the urethra and bladder base, and anatomic changes during voiding (51,52). The procedure provides valuable information regarding bladder size and the competence of the bladder neck during increased intra-abdominal pressure with coughing or Valsalva maneuver. It also helps to determine the presence of bladder trabeculation and vesicoureteral reflux as well as the integrity of the urethral sphincter. Videoradiographic urodynamics incorporate fluoroscopy with simultaneous measurement of detrusor and urethral pressures to provide a comprehensive analysis of lower urinary
12. CYSTOURETHROSCOPY
Cystourethroscopy, which involves insertion of an endoscopic instrument into the urethra and bladder, allows the physician to examine inside the urethra, urethrovesical junction, bladder walls, and ureteral orifices (54). This procedure can detect bladder stones, tumors, diverticula, or suture from prior surgeries. Due to the discomfort associated with this procedure, cystourethroscopy is usually reserved for patients with confounding factors such as microscopic or macroscopic hematuria, bladder pain on palpation, suburethral mass, or persistent UTI despite adequate therapy or for patients with urge incontinence who failed the first-line therapy. Some clinicians also advocate cystourethroscopy and multichannel urodynamics in all patients with persistent incontinence prior to surgical treatment.
13. ELECTROPHYSIOLOGIC STUDIES
When the history, physical examination, and urodynamic findings suggest the possibility of nervous system impairment as the cause of incontinence, the adjunctive use of electrophysiologic testing is very helpful. Pelvic floor electrophysiologic testings include surface and needle electromyography, nerve conduction, terminal latency, evoked potential, and reflex response studies. It is beyond the scope of this chapter to discuss these techniques in details; their descriptions can be found elsewhere (55). 14. ULTRASONOGRAPHY
Employing real-time or sector ultrasonography, information can be obtained about the mobility and inclination of the urethra as well as the mobility and funneling of the urethrovesical junction, both at rest and with Valsalva maneuver (52,56). In addition to imaging these structures, bladder and urethral diverticula, periurethral cysts, and flatness of the bladder base can be identified. Ultrasound is also useful in the evaluation of postvoid residual volumes. Recently, the three-dimensional (3D) ultrasound, with its improved resolution, has provided another modality to capture the events related to the bladder, urethrovesical
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junction, and urethra. The simultaneous combination of real-time ultrasonography and urodynamics is under investigation. Ultrasound presents the advantages of low cost and no radiation exposure or reaction to contrast medium. 15. MAGNETIC RESONANCE IMAGING
Magnetic resonance imaging (MRI) is a relatively new and emerging technique for the study of pelvic floor dysfunction and urinary incontinence. It is useful for evaluating abnormalities not readily imaged with other modalities. Whereas fluoroscopic studies provide little information on the anatomic details of the bladder neck, urethra, pelvic floor, and surrounding tissues, MRI produces unsurpassed images of these structures (52). MRI can be useful in assessing urethrovesical junction and urethral abnormalities because the anatomy of these structures is well visualized. This imaging technique can also be employed in the assessment of the pelvic floor dysfunction and organ prolapse. Because of the cost associated with this imaging technique and because the information can also be obtained from clinical evaluation and multichannel urodynamics, the role of MRI in the diagnosis and management of typical female patients with urinary incontinence remains investigative. E. T r e a t m e n t 1. STRESS URINARY INCONTINENCE
Stress urinary incontinence is almost always treatable with nonsurgical or surgical interventions. Nonsurgical therapy can be initiated without urodynamic testing, and primary care physicians should be able to treat a large number of patients. Referrals to specialists should be reserved for patient with severe incontinence, complicated medical or surgical history, unclear diagnosis, or treatment failure and those contemplating surgery. a. Conservative Management
Treatment of Medical Comorbidities and Transient Causes: Conservative management and behavioral intervention are generally recommended as a first step in the treatment of urinary incontinence. Medical conditions such as chronic cough, chronic obstructive pulmonary disease (COPD), and diabetes mellitus should be controlled. All medications that may affect the lower urinary tract functions are carefully reviewed and modified if possible. These medications were discussed in the medical history section. The transient causes of urinary incontinence, as described earlier in the mnemonic DIAPERS, should be identified and treated. These issues are important in the postmenopausal female and elderly populations. Fluid management and dietary modification are also important. Generally, the fluid intake of 6 to 8 glasses, or 2 to 3 liters, per 24-hour period is
adequate. Bladder irritants such as caffeine, tea, carbonated drink, alcohol, chocolate, and certain food ingredients should be minimized or avoided. Absorbent Products: Absorbent pads are the most commonly used product in the elderly population for treatment of urinary incontinence. Although they do not cure or improve the incontinence, these pads are simple and noninvasive to use. Improved products featuring better absorbency, smaller size, greater comfort, and reusable undergarments are now used by younger women as an alternative approach to deal with urinary incontinence (57). Prosthetic Devices: There are two types of prosthetic devices that can be used for anti-incontinence: intravaginal devices and urethral occlusion devices (57). For intravaginal devices, large diaphragms, tampons, and various types of pessaries have been used to elevate and support the bladder neck and urethra. Although ring-type pessaries are traditionally employed for this purpose, the bladder neck support prosthesis (Introl) is very useful. This specially designed pessary consists of two arms at the end that help to support and elevate the bladder neck to the pubic bone in order to prevent urine leakage. Urethral occlusive devices can be inserted into the urethral meatus to achieve mechanical occlusion of the urethra, thus preventing urinary leakage. Placement of these urethral plugs may also stimulate the pelvic floor muscles, which contributes to the therapeutic effects of the devices (57). Other devices such as adhesive patch (Miniguard), urethral cup (Fern-Assist), and urethral catheter (Reliance) have been marketed with suboptimal outcomes. Mthough the prosthetic devices are not very effective, they may provide an acceptable alternative for patients who are unfit for surgery, for elderly women who have difficulty with behavioral and medical therapies, or for younger patients who are awaiting surgery. b. Behavioral Intervention The behavioral therapy includes bladder training, pelvic floor exercises, and biofeedback techniques. Bladder training, which will be discussed in detail later in this chapter, has been shown to be effective in patients with SUI without the presence oflSD (57). Pelvic Floor Exercises: Pelvic floor exercises (Kegel exercises) are known to improve or cure mild forms of SUI. These exercises supposedly increase the strength of periurethral and perivaginal muscles, thus improving anatomic support to the bladder neck and urethra (58,59). Strengthening the striated urogenital sphincter also enhances its ability to compress the urethra. The aim of this physical therapy is to train women to identify their pelvic floor muscles and to contract these muscles in anticipation of increased abdominal pressure during coughing, sneezing, lifting, or physical activities. For the pelvic floor exercises to be effective, they must be supervised, performed regularly, and aided by some form of
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women feedback so that the progress can be followed. The majority of patients are unlikely to benefit from written instruction alone. During the pelvic examination, the patient can learn to correctly isolate her levator ani muscles by contracting around the examiner's fingers. Patient can also insert her own finger into the vagina to detect these muscle contractions. Other adjunct approaches such as electromyography or electrical stimulation are useful in identifying the corrected muscles. After identifying the pelvic floor muscles, patients are instructed to "pull your pelvic in and up" or "squeeze as if you were trying to stop your urine." These contractions should be hold as long as possible and gradually increased up to 10 seconds. Typically, the exercises are performed three to five times per day in sets of 15 to 20 contractions each time. These numbers can be further increased each week. In addition to these exercises, which will strengthen slow-twitch muscle fibers, patients should be instructed to perform a similar exercise with rapid contractions to strengthen the fast-twitch fibers. For those who are unmotivated or have poor strength of contractions, the help of a physical therapist is beneficial. Improvement in incontinence typically takes at least 4 to 6 weeks and sometimes as long as 6 months of continuous exercises (58-60). Pelvic floor muscle exercises are recommended for all women with mild to moderate incontinence, for women who choose not to pursue surgical options, for young women who have not completed childbearing, and for elderly patients who are unfit for surgery. These exercises should also be incorporated into routine health maintenance for postmenopausal women because they are noninvasive, are virtually without side effects, and may prevent the development of pelvic organ prolapse. In general, exercises alone can result in a 56% to 95% reduction in incontinence episodes (60). In an intensive program of pelvic floor exercises for 3 months, Benvenuti and coworkers (61) reported that 32% of patients with G SI were cured and 68% had marked improvement in symptoms. Improvements of bladder neck support and contractility of the pubococcygeus muscle were observed with urodynamic and radiologic evaluations. This study also showed that at 12 to 36 months post-treatment follow-up, 77% of patients still maintained the functional level they had attained at the end of treatment. Pelvic floor exercises before and after delivery may help patients with postpartum urinary incontinence. Pelvic floor exercises require diligence and willingness to practice at home and at work, particularly in incontinenceprovoking situations and daily activities. They require a high level of motivation and compliance. The success of pelvic floor exercises can be enhanced by the use of adjunctive techniques such as vaginal cones, biofeedback, or electrical stimulation. Vaginal Cones: Vaginal cones are a useful adjunction to the pelvic floor exercises. These tampon-shaped devices can be inserted into the vagina for 15 to 30 minutes while the
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patient is going about her normal activities. The patients are instructed to contract her pelvic floor muscles to keep the cones from falling out. After the lightest cone can be retained, the weights are then increased progressively from 20 to 100 grams. The feeling that the cone is slipping out of the vagina forms a sensory biofeedback to increase contraction of the pelvic floor muscles. Vaginal cones are reported to improve the symptoms of stress incontinence in 60% to 90% of patients (57,59). In a study of 30 postmenopausal women with GSI, Peattie and coworkers (62) reported that 70% of patients were either cured or had significant improvement of symptoms and only 37% had subsequently undergone surgical intervention. Biofeedback Techniques: Other biofeedback techniques can also be used in combination with the pelvic floor exercises. The two most commonly employed devices are vaginal perineometer and electromyographic units (57-59). The perineometer is a probe that can be inserted into the vagina to measure the pressure changes during pelvic muscle contractions. The electromyography helps patients to identify and contract appropriate pelvic muscles in their pelvic floor exercises in response to auditory or visual feedback (57,58). The data on using biofeedback in conjunction with pelvic floor exercises for SUI are conflicting. One meta-analysis showed that combining pelvic floor exercise with biofeedback was more effective than exercise alone (63), whereas another review of randomized trials indicated that the combination was no more effective than pelvic floor exercise alone (64).
c. Electrical Stimulation Therapy Electrical stimulation therapy is another adjunction to pelvic floor exercises. This technique involves the use of vaginal or rectal probes to deriver a low-level electrical current to the muscles and nerves of the pelvic floor (59). Stimulation of the afferent fibers of the pudendal nerve can produce contractions of the pelvic floor and periurethral skeletal muscles, which augment their tone in women with SUI. Simultaneously, the electrical current also causes a reflex inhibition of detrusor activity and improves UUI. Electrical stimulation can be used to increase pelvic floor muscle strength or to identify these muscles for voluntary control in Kegel exercises. Improvement rates of 60% to 90% and cure rates of 10% to 30% were reported in patients with stress, urge, or mixed incontinence (57). Although this mode of therapy remains an option for the treatment of urinary incontinence, patient acceptance of the technique is often poor. Furthermore, the effectiveness of electrical stimulation therapy in SUI has not been formally evaluated. d. Pharmacologic Therapy Estrogen Treatment: Although estrogen can improve vaginal epithelium thickness and vascularity, and possibly urethral function, in the postmenopausal women with urogenital atrophy, the role of estrogen in the treatment of SUI is
710 controversial. Some earlier studies reported promising results; however, they were poorly designed and were not randomized, controlled, and blinded. A meta-analysis of several studies of estrogen therapy showed significant subjective improvements for all patients, including those with SUI (65). These subjective improvements were probably due to the effects of estrogen on the feeling ofweU-being by the subjects. Another study also reported that estrogen was not effective in the treatment of SUI but might be useful for associated symptoms of urgency and frequency (66). Other studies of estrogen for the treatment of GUI in hypoestrogenic and postmenopausal women reported no significant changes in quality of life or objective outcomes (19,67). Recently, the effects of hormone therapy on the symptoms of SUI, UUI, and MUI in healthy postmenopausal women were investigated in a large study (68). The results showed that conjugated equine estrogen, either alone or in combination with medroxyprogesterone, increases the risks of urinary incontinence among continent women and worsens the characteristics of incontinence among symptomatic women after 1 year. A1pha-adrenergics: Alpha-adrenergic activities from the sympathetic nervous system help to maintain continence by increasing the tone of the urethra and bladder neck. Alphaadrenergic stimulants such as ephedrine, pseudoephedrine, or phenylpropanolamine are useful for treatment of SUI. However, they are not uroselective and are associated with systemic side effects, particularly hypertension, a condition that affects many postmenopausal women. Ephedrine and its stereoisomer, pseudoephedrine, can produce anxiety, headaches, and insomnia. Although phenylpropanolamine causes less central nervous stimulation, it can produce hypertension, cardiac arrhythmias, and anxiety. A review of eight randomized controlled trials of phenylpropanolamine demonstrated a low cure rate (0% to 14%) and a wide range in improving SUI symptoms (19% to 60%) (57,69). These data indicate that the effectiveness of phenylpropanolamine in the treatment of SUI is questionable. Duloxefine: Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor. This drug has been shown to enhance the external urethral sphincter contraction and is currently in clinical trials for treatment of SUI. Early results of duloxetine uses in SUI have been encouraging (70-72); however, long-term data are not yet available. Duloxetine also appears to be safe and tolerable; adverse effects are common but not serious (71,72). e. Surgical Treatment
General Considerations: Surgery is the most common type of treatment in SUI because it offers the potential for effective and long-term results. When behavioral and pharmacologic managements fail to improve symptoms of SUI, surgical treatment is the next step. However, in patients with severe SUI or those unable to comply with nonsurgical interventions, surgery may be considered as a first-line treat-
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ment. The aim of all surgical procedures is to correct the pelvic relaxation as well as to stabilize and restore the normal position of the bladder neck and urethra and provide adequate support to these structures. Another goal of surgical treatment is to improve the patient's quality of life. The first surgical procedure for SUI treatment is critical because the cure rate may decline with subsequent operations. Every effort should be made for a proper preoperative evaluation before embarking on any kind of surgical procedure for incontinence. A thorough medical history, physical examination, and urodynamic investigation should be performed to determine the cause and type of incontinence. Based on these findings, the choice of surgical procedure should be formalized and discussed with patients. The potential benefits should be weighed against the potential risks of surgery, and the decision resides ultimately with the patient because SUI is not a life-threatening condition and the ability to cope with the incontinence is subjective. Surgical treatment for GSI is not contraindicated in patients with coexistent DO. However, these patients should be counseled that the surgery may cure, may not have any effect, or may worsen the urge incontinence. In patients with both pelvic organ prolapse and potential stress incontinence (masked incontinence), the antiincontinence procedure should be performed concomitantly with the anti-prolapse procedure. A prospective study demonstrated that potential incontinence occurred in 58% of patients with severe pelvic organ prolapse (73). For those patients with potential incontinence who underwent concomitant anti-prolapse and anti-incontinence procedures, 86% had no postoperative stress incontinence. For those patients without demonstrable potential incontinence who underwent only anti-prolapse procedure, no postoperative SUI was observed. The mean follow-up of this study was 44 to 47 months. These data demonstrated that the antiincontinence surgery may not be needed if potential incontinence has been ruled out. Surgical treatment for SUI can be performed vaginally, abdominally or laparoscopically. Vaginal Approach: Vaginal approaches are as follows: Anterior Colporrhaphy with Suburethral Plication: Anterior colporrhaphy (Kelly's plication) is an excellent procedure for correction of cystocele but is less effective for correction of SUI. Anterior colporrhaphy for SUI includes simple plication of the bladder neck, plication of the fascia under the urethra to elevate the bladder neck, or both (Fig. 51.7). This procedure does not hold up well over time, and most of the studies have shown long-term success rates of only 37% to 75% (74), which are quite low compared with other surgical procedures. One series on the revised technique of anterior colporrhaphy showed a success rate of 91% (75). Needle Suspension Procedures: A needle suspension procedure was first described by Pereyra in the 1950s, and since then it has been modified to better anchor the sutures
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women
FIGURE 51.7 Anterior colporrhaphy with suburethral plication. A. Plication of the urethrovesical junction with one to three sutures. B. The plication sutures at the urethrovesical junction are tied. C. A cystocele is reduced with pursestring sutures incorporating vaginal muscularis. D. Completion of the repair and vaginal epithelium is trimmed before closure. (From Weber AM. Surgical correction of anterior vaginal wall prolapse. In: Waiters MD, Karram MM, eds. Urogynecology and reconstructive pelvic surgery, ed. 2. St. Louis: Mosby, 1999:215.)
(74). These procedures involve passage of sutures through the periurethral tissue, near the bladder neck, and then to the suprapubic space and rectus fascia using a specially designed long needle carrier. After these steps are carried out on both sides of the urethra, the sutures are tied over the rectus fascia to suspend the proximal urethra and bladder neck. These procedures have fallen into disfavor due to their poor long-term success rates. In a review of the longterm outcomes (more than 48 months), the needle suspension procedure was found to have 67% success rate whereas retropubic suspension and the midurethral sling have 84% and 83% success rates, respectively (76). In several other studies, the reported 5-year success rates of needle suspension procedures were considerable lower than retropubic approaches or suburethral slings (74). This procedure is simple and takes less time to perform; however, complications such as perforation of the bladder or urethra by the long needle, infections, formation of granulation tissue around the sutures, and nerve entrapment syndrome have been reported (74,76). Suburethral Sting Procedures: The best approach for SUI patients with ISD dysfunction is the suburethral sling procedure. In these patients, the sling supports and compresses the urethra when abdominal pressure is increased,
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thus compensating for a faulty urethral closure mechanism and preventing incontinence (77). The suburethral sling procedures are suitable for patients who failed retropubic suspension (MMK or Burch) or needle suspension, and, recently, for all types of SUI (78,79). Sling procedures are also recommended for patients with SUI who engage in heavy occupational lifting, who have COPD or chronic cough, and who have post-hysterectomy vaginal vault eversion, because these patients seem to have higher failure rates with other procedures (79). The traditional procedure involves placement of a sling under the bladder neck and urethra and fixation of its both ends to the anterior rectus fascia or other abdominal sites. The sling is adjusted for appropriate tension, under the direct visualization of a cystoscope, to cradle the urethra in a supporting hammock (Fig. 51.8). The sling materials can be autologous tissue (fascia lata or rectus fascia), allografts (cadaveric fascia or dermal graft), xenografts (porcine dermis or porcine intestine), or synthetic meshes (Mersilene, Marlex, Prolene, Gore-Tex, Silastic band) (78,79). Autografts can eliminate the risks of tissue reactions and erosions; however, tissue harvesting increases the operative time and morbidity. Tissue failure can also occur over time with autografts. Allografts and xenografts are associated with durability and tissue reaction problems. Synthetic materials offer better uniformity, consistency, and durability than biomaterials; however, they are more prone to infection and can have significant complications, such as erosion into the vagina, urethra, or bladder. The selection of sling materials remains controversial, and currently there is no ideal graft material. Long-term cure rates for suburethral sling procedures are reported to be 73% to 90% (74,79,80). These cure rates are comparable to the Burch procedure. Although obstructed voiding after the sling placement can occur, this problem usually resolves over time. However, some patients may require long-term bladder drainage with suprapubic catheter or clean intermittent self-catheterization. Tension-Free Mid-Urethral Sling Procedures: Recently, tension-free support of the mid-urethra has quickly gained popularity in the treatment of SUI (81-84). There are two different techniques for the mid-urethral sling procedures: the tension-free vaginal tape (TVT) and the tension-free transobturator tape (TOT). The TVT approach has been gaining wide acceptance as an effective and minimally invasive procedure for treatment of SUI (81,82). Following a small sagittal incision in the vaginal mucosa, a synthetic polypropylene tape is placed at the level of the mid-urethra and extended bilaterally, behind the pubic symphysis, into two separated small suprapubic incisions (Fig. 51.9). There should be a visible space between the tape and the urethra in order to ensure that the urethral support is free of tension. The data accumulated for the past 6 to 8 years showed that the TVT procedure has cure rates of 85% to 90% (81,82). The TVT procedure is less
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FIGURE 51.8 Suburethral sling procedure. A. Placement of suburethral sling. B. Attachment of the mini sling to endopelvic fascia or pubic rami bilaterally. C. Attachment of the mini sling to anterior rectus fascia by permanent sutures. D. Attachment of the full length sling to anterior rectus fascia. (A, From Chaikin DC, Blaivas JG. Sling procedures-organic. In: Cardozo L, Staskin D. Textbook offemale urology and urogynaecology. London: Isis Medical Media, 2001:540; B, C, D, From Kohli N, Karram MM. Surgery for genuine stress incontinence. In: Waiters MD, Karram MM, eds. Urogynecology and reconstructive pelvic surgery, ed. 2. St. Louis, Mosby, 1999:183.)
invasive and requires less time than retropubic suspension; however, it can expose patients to a number of possible complications. The blind passage of the trocar and tape using the retropubic route has been associated with several intraoperative complications resulting from penetration into the bladder, urethra, bowels, nerves and vessels, although the rates of these complications are low (81,82). To minimize these complications, a TOT procedure using the prepubic approach has been developed (83,84). This technique takes the full advantages of the tension-free sling in the TVT approach but spares the retropubic space (Fig. 51.10). In general, a 1.5- to 2-cm vertical incision is made in the vaginal wall at the middle third of the urethra. A polypropylene tape is passed from the vaginal incision, through the obturator foramen, and toward the thigh fold to provide a tension-free sling under the mid-urethra. Although no long-term data are available, the effectiveness and safety of this approach during the past 5 years are promising, and the TOT procedure has now become a popular surgical treatment for female SUI. The continent rates obtained with the TOT procedure have been similar to those of the retropubic TVT at least on the shortterm follow-up (83,84). These data also suggest that complication rates can be decreased with the obturator approach.
Abdominal Approach: Abdominal approaches include the following:
Retropubic Suspension: The MarshaU-MarchettiKrantz Vesicourethral Suspension: Most of the abdominal retropubic procedures for suspension of the bladder neck are modifications of the Marshall-Marchetti-Krantz (MMK) vesicourethral suspension or Burch retropubic urethropexy (85,86). The MMK procedure, which was described in 1949, begins with an abdominal incision to gain access to the retropubic space (space of Retzius) and to identify the vesicourethral junction and proximal urethra (Fig. 51.11). Two pairs of nonabsorbable sutures are then placed through the endopelvic fascia on each side of the urethrovesical junction and the proximal urethra and attached to the fibrocartilage of the pubic symphysis. The sutures are adjusted to provide suspension of the bladder neck into their normal intra-abdominal position. Occasionally, the patient may develop osteitis pubis after the MMK procedure. The Burch Retropubic Urethropexy: The Burch retropubic urethropexy, which was described in 1961, is also performed extraperitoneally in the space of Retzius and is similar to the MMK procedure. The retropubic space is entered through an abdominal incision, and sutures are
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal W o m e n
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FIGURE 51.9 Tension-free transvaginal tape (TVT) procedure. The polypropylene tape is placed under the mid-urethra and without any tension. The tape is then cut just under the skin line. (Courtesy of CR Bard, Inc., Covington, GA.)
FIGURE 51.11 MMK vescicourethral suspension and Burch urethropexy. A. In the MMK procedure, the sutures are placed through a full thickness of vaginal wall, excluding the epithelium, on each side of the bladder neck and then into the pubic symphysis. B. In the Burch procedure, the sutures are placed into the Cooper's (pectineal) ligament. Usually two sutures are placed on each side of the bladder neck. (A, From Mishell DR Jr, Stenchever MA, DroegemueUer W, Herbst AL. Comprehensivegynecology. St. Louis: Mosby, 1997:587; B, From Waiters MD. Retropubic operations for genuine stress incontinence. In: Waiters MD, Karram MM, eds. Urogynecologyand reconstructivepdvic surgery, ed. 2. St. Louis: Mosby, 1999:161.)
FIGURE 51.10 Tension-free transobturator tape (TOT) procedure. The polypropylene tape passed through the obsturator foramen and toward the thigh fold to provide a tension-free sling under the mid-urethra. (From Karram M, Blaivas J, Waiters M. Which sling for which patient? OBG Management 2005;17:68.)
placed in the fascia lateral to and on each side of the bladder neck and proximal urethra. The Burch procedure differs from the MMK procedure in that it involves attachment to the Cooper's ligament (iliopectineal ligament) rather than the pubic symphysis. The advantages of the Burch procedure include easier suture placement, eliminating the risk of pubic osteitis and allowing the correction of small cystourethroceles (85,86).
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Abdominal retropubic urethropexy has a long-term success rate of 82% to 90% (85,86). The cure rates for the MMK procedure are similar to the Burch retropubic urethropexy. Both procedures are associated with complications including urethral and bladder injuries, intraoperative bleeding, and postoperative retropubic hematoma. Postoperative urinary tract infection and retention can occur. Although rare, long-term complications such as detrusor instability, de novo UUI, bladder pain, pelvic organ prolapse, and retropubic abscess can also occur. Laparoscopic Approaches: Recent advances in the technique combined with the popularity of operative laparoscopy for various gynecologic procedures have stimulated the use of laparoscopic approaches for retropubic suspension of the bladder neck. The Burch procedure and paravaginal repairs have been successfully performed by laparoscopy (86,87). The advantages of the laparoscopic approach include short hospitalization and minimal invasiveness. However, many surgeons are not skillfully trained for these procedures, and long-term success rates have been disappointing. On the other hand, some reports demonstrated that laparoscopic Burch urethropexy and paravaginal repairs are associated with less patient morbidity and a cure rate similar to traditional procedures (77,86,87). These results are usually from experienced laparoscopists.
f Periurethral Bulking Injections Conventional surgical procedures for SUI sometimes fail in patients with diagnosis of ISD. These patients may be treated by suburethral sling procedures, periurethral bulking injections, or placement of an artificial urinary sphincter. For patients with ISD and a hypermobile bladder neck, suburethral or mid-urethral slings are ideal choices. For ISD without bladder neck hypermobility, use of periurethral bulking injection or an artificial sphincter are recommended. Injection of bulking agent is an attractive alternative to invasive operations for elderly patients who are unsuitable
for surgery or for women who have undergone prior surgery that has failed (74,88). The aim of this procedure is to inject bulking agents into the periurethral space to provide urethral coaptation, thus preventing urinary incontinence under conditions of increased intra-abdominal pressure. Several bulking agents, such as polytetrafluoroethylene (Teflon), glutaraldehyde cross-linked bovine collagen (Contigen), and carbon-coated microbeads (Durasphere), have been employed (74,88). Teflon is hard to inject and has been shown to migrate to other parts of the body under some circumstances. Contigen is easier to inject but requires skin testing for possible allergic reactions before the injection. Recently, ethylene vinyl alcohol copolymer suspended in a dimethyl sulfoxide carrier (Tegress, Uryx) has been developed and has shown to be a promising bulking agent (88); however, clinical trials are currently in progress and no published data are yet available. There are two different techniques for the injection. The transurethral technique involves injecting a bulking agent into the submucosa of the proximal urethra, under the direct visualization of a cystoscope (Fig. 51.12). Usually, the injection is carried out at 3:00 and 9:00 positions. For the periurethral injection technique, the needle is advanced in the submucosa, parallel to the urethra, to the area near the bladder neck. Bulking agent is injected under direct visualization until occlusion of the urethrovesical junction is observed. The injection is usually carried out at 3:00 and 9:00, similar to the transurethral technique. Bulking agent injections are a reasonable alternative to a suburethral sling procedure in women with a well-supported but poorly functioning urethra. Patient satisfaction rates up to 80%, marked improvement rates of 50% to 60%, shortterm cure rates up to 70%, and long-term cure rates of 20% to 30% with collagen injections have been reported (74,77,88). These procedures may be associated with complications, such as injury to the bladder or urethral wall, bleeding from the injection site, urinary retention, voiding dysfunction, urge
FIGURE 51.12 Periurethral bulking injection. (From Kohli N, Karram MM. Surgery for genuine stress incontinence. In: Walters MD, Karram MM, eds. Urogynecology and reconstructive felvic surgery, ed. 2. St. Louis: Mosby, 1999:187.)
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women incontinence, and urinary tract infection. The dissolution of the collagen agent requires repeat applications, usually 2 to 3 months apart. It has been reported that after two injections, the effects can last from 3 months to a few years (77).
g. Artificial Urinary Sphincter Although rare, some patients with severe incontinence may have a scarred, fibrotic, and nonfunctional urethra that is very difficult to treat. These patients may benefit from periurethral bulking injection, placement of a deliberately obstructive sling, or implantation of an artificial urinary sphincter. Periurethral injections often fail in these cases, and an obstructive sling requires lifetime self-catheterization. Artificial urinary sphincter implantation is an attractive mode of therapy for these patients because the device allows urethral obstruction to prevent urinary leakage. This obstruction can be voluntarily relieved at the time of voiding. As reported in two series of 66 patients, the success rates for incontinence were 91% to 100% (74). Mechanical failure with the device can occur and requires surgical repair. 2. URGE URINARYINCONTINENCE
In treating urge incontinence, it is important to exclude significant outflow obstruction that may precipitate DO. Although the majority of women with UUI have IDO, treatable conditions such as bladder inflammation or irritation due to infection, calculi, or foreign bodies should be identified and managed properly. In addition to the attention to medical comorbidities and transient causes of urinary incontinence, as described earlier, the treatment of UUI includes behavioral modifications, pharmacologic therapy, electrical stimulation, intravesical therapy, and surgical intervention. Among these options, behavioral therapy and pharmacologic treatment are the main approaches.
a. Behavioral Therapy Behavioral therapy was recommended as a first-line treatment for UUI (57,60). The best approach is to incorporate behavioral therapy into the longterm management because most of the drugs used in treating UUI have unpleasant anticholinergic side effects and patients will likely discontinue these medications over time. Behavioral therapy also has good successful rates and can help to enhance the effects of pharmacologic treatments. The therapy includes fluid management and bladder training. Fluid management: Depending on the patient condition, fluid management may involve restriction or increase in fluid intake. It is generally recommended that the fluid intake should be about 6 to 8 glasses, but not exceeding 2 to 3 liters, in a 24-hour period (60). However, too much restriction in fluid intake can produce highly concentrated urine and constipation, which subsequently irritate the bladder and aggravate the symptoms of UUI. Bladder irritants such as caffeine, tea, carbonated drinks, and chocolate should be avoided.
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Bladder Training: Bladder training involves deferred voiding, timed voiding, and desensitization programs. The aim of these techniques is to increase functional capacity of the bladder and control urgency. Bladder training represents a behavioral modification designed to repeat the process of toilet training. It is based on the assumption that DO is caused by the loss of cortical control over the detrusor muscle. In the deferred voiding technique, the patient delays urination for as long as possible when a feeling of urge occurs. This can be achieved with various distraction methods such as deep breathing, changing posture, or quick and repeated contractions of the pelvic floor muscles to inhibit detrusor activities (57,60). Timed voiding is another technique that can benefit patients with DO and urge symptoms. The essential aim is to increase bladder capacity week by week and to prolong the intervals between voids. Based on the voiding diaries, the shortest interval is selected and the patient is asked to void at this fixed interval, regardless of whether she has the urge feeling. For example, if the interval is 1 hour, then the patient has to void every hour even she does not feel the need to void. If the patient is desperate to urinate before the scheduled time, she must wait even if urinary leakage occurs. The objective of this bladder retraining is to make the patient's bladder do what she wants it to do. This fixed interval is gradually increased by 15 minutes every week to achieve a period of 3 hours between voids and with less urgency. At night, the patient is allowed to void only when she is awakened from sleep by the problem. Compliance is critical for the success of timed voiding method. N D O does not respond well to this behavioral therapy. The desensitization technique is useful for patients with urgency that is triggered by an event such as water running or rising from a seated position. The patient is asked to delay voiding while gradually exposed to these events. b. Pharmacologic Treatment Medications employed in the treatment of UUI involve those that decrease contraction of the detrusor muscle and those that act on both the detrusor and the urethral sphincter together. It is best to start with a low dose, particularly in older patients. It is also reasonable to try several drugs, one at a time, and/or to increase the dose up to the maximal tolerable level, in order to find the most effective drug and its optimal dose for each patient. In general, patients with N D O require more medication than those with IDO. Anticholinergic Drugs: Anticholinergic medications are useful in the treatment of UUI because ace@choline is the primary neurotransmitter involved in the contraction of the detrusor muscle. These medications act by inhibiting the cholinergically innervated detrusor to reduce its hyperactivities. The systemic side effects of these drugs, such as dry mouth, constipation, blurred vision, increased heart rate, and
716 drowsiness, may limit their uses. These medications are contraindicated in patients with untreated narrow-angle glaucoma. The most frequently employed agents are oxybutynin chloride (Ditropan, Ditropan XL) and tolterodine tartrate (Detrol, Detro LA). Recently, darifenacin (Enablex), solifenacin (Vesicare), and trospium chloride (Sanctura) have been approved for the treatment of UUI and OAB. Hyoscyamine sulfate (Levsin), propantheline (Pro-Banthine), and dicyclomine (Bentyl) are also used for the treatment of UUI. Oxybutynin reduces detrusor hyperactivity by its antispasmodic activities, and in randomized and placebo-controlled trials, the cure or reduction of UUI was reported in 9% to 56% of patients (69,89). Similar to other anticholinergic agents, its use is frequently associated with central nervous effects and dry mouth. Ditropan XL, a slow-release formulation for single dose daily, was reported to produce a better pharmacokinetic profile and fewer systemic side effects than the immediaterelease formulation (69,89). The transdermal delivery oxybutynin formulation is also available for twice-weekly applications. In a randomized and placebo-controlled study, this formulation was shown to be effective in the treatment of UUI or MUI but with fewer systemic side effects, except for local skin irritation (90). Tolterodine is another anticholinergic agent that is more selective for the bladder. In a meta-analysis of randomized trials, tolterodine was shown to be less effective but to have a better side effect profile than oxybutynin (91). Patients who received tolterodine were better tolerated, had less dry mouth, and were less likely to withdraw from the studies due to side effects than those given oxybutynin. However, oxybutynin produced a greater increase in voiding volume and a lesser number of incontinence episodes per 24 hours than tolterodine. The long-acting tolterodine (Detrol LA) is a single-dose daily formulation and provides better patient compliance. A comparative study of the efficacy and safety of Detrol LA and transdermal oxybutynin showed that both formulations are effective treatments for patients with UUI or MUI. However, transdermal oxybutynin formulation was associated with fewer systemic side effects (90). Solifenacin, darifenacin, and trospium chloride are three new anticholinergic agents for the treatment of UUI and AOB (89). Solifenacin and darifenacin seem to have high selectivity for the M3 receptors in the bladder, whereas trospium may involve multiple subtypes of muscarinic receptors, including M2 and M3. Although solifenacin is marginally more effective than tolterodine, it is well tolerated and has a better side effect profile. In clinical trials, solifenacin treatment has been associated with statistically significant reductions in all key symptoms of OAB, while adverse effects are few and usually mild in nature (89). Darifenacin is also effective for the treatment of OAB; however, its uroselective properties have not yet been confirmed in clinical studies. Trospium chloride, which is a quaternary amine, has the lowest ability to penetrate the blood-brain barrier
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among anticholinergic agents and, therefore, produces favorable CNS tolerability. In addition, trospium is not metabolized extensively by the liver but excreted largely as an active compound in the urine, thus minimizing the systemic effects. In clinical investigations, this medication significantly improved the symptoms of UUI and showed minimal adverse effects, except for dry mouth, constipation and headache, when compared with placebo. The reported side effects of hyoscyamine sulfate are conflicting, with some authors promoting its use as an initial agent, whereas others rarely use it because of adverse systemic effects (69). There are no studies that adequately compare its effects with placebo. Two studies reported that propantheline produces a 13% to 17% reduction of UUI symptoms over placebo (29). TricyclicAntidepressants:Tricyclic antidepressants, such as imipramine (Tofranil) and doxepin (Sinequan), relax the detrusor muscle by virtue of their anticholinergic action and increase bladder outlet resistance by their action on the alpha-adrenergic receptors. These drugs are, therefore, useful in patients with MUI. For treatment of UUI, the reported cure rate of these drugs was 31% and the improvement rates were 20% to 77% (69). Randomized and placebo-controlled studies also revealed the effectiveness of doxepin and imipramine in reducing nocturnal enuresis in patients with UUI (92,93). The side effects of these agents include fatigue, dizziness, blurred vision, nausea, and insomnia. Imipramine may cause orthostatic hypotension and cardiac arrhythmias. Other Pharmacologic Agents: Beta-sympathomimetic agonists have also been employed in the treatment of UUI. The detrusor-relaxing action of beta-sympathomimetics forms the basis for the use of drugs such as metaproterenol (Alupent). They also enhance the effect of propantheline (69). Musculotropic drugs, such as flavoxate (Urispas), act by causing direct relaxation of the detrusor muscle (29,69). Diazepam (Valium) acts by a combination of direct smooth muscle relaxation, anticholinergic effect, and central nervous system sedation (69). c. Sacral Neuromodulation and Electrical Stimulation Therapy Recently, implantable sacral neuromodulation
has been employed in refractory cases of UUI with good success (94). The reported cure rates range from 47% to 56%, although potential bias may exist in these studies. These cure rates seems to be low; however, it should be noted that the patients have failed other therapies and sacral neuromodulation is the only available option. This mode of therapy may cause detrusor relaxation through its activation of the afferent fibers, which inhibits the spinal and supraspinal signals. Sacral neuromodulation may also cause a reflex relaxation in the detrusor muscle by activation of the efferent fibers to the striated urethral sphincter. However, the exact mechanism of neuromodulation in the treatment of UUI is not known. Sacral neuromodulation
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women has been shown to be an effective mode of therapy for the patient with UUI who has a history of poor response to other therapies (94-96). Detailed description of the sacral modulation and implanting technique can be found elsewhere (94). Other techniques of electrical stimulation, such as transcutaneous electrical nerve stimulation (TENS) and percutaneous posterior tibial nerve stimulation (PTNS), offer additional alternatives to the treatment of UUI. They are less invasive and have been shown to improve the symptoms of UUI (29).
d. Intravesical Injection of Botulinum Toxin Botulinum toxin has been investigated for the treatment of DO. When injected into the bladder wall, botulinum toxin prevents the release of acetylcholine and, therefore, inhibits detrusor contractions. Botulinum toxins A and B have been used for N D O and IDO with varying success (97). Although this mode of therapy is not yet an approved treatment for UUI, available data suggest that intravesical injection ofbotulinum toxin can be a therapeutic option in patients with N D O and IDO who are refractory to anticholinergic medications. e. Surgical Treatment Generally, surgery is not a treatment option for UUI or OAB, except in the patients who are refractory to pharmaceutical, behavioral, or other nonsurgical management. In these patients, surgical procedures such as bladder denervation, bladder augmentation, and urinary diversion can be tried (29). These procedures are associated with significant morbidity, and their usefulness remains controversial. They should be considered the last resort in the treatment ofUUI or OAB.
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treatment for MUI patients with predominant stress incontinence (22). Tolterodine, an anticholinergic agent, has been shown to significantly reduce urge incontinence, but not the stress component, in patients with MUI (22). The transdermal formulation of oxybutynin and the long-acting form of tolterodine (Detrol LA) are also effective in the treatment of MUI patients who have predominant urge symptoms (90).
b. Surgical Treatment In some patients, surgery to suspend the bladder neck cures not only stress but also the urge component of MUI (22). In other patients, surgical treatment for the stress component of MUI does not have any effect or may even worsen the urge component (22). Considerable debate also exists regarding the role of suburethral sling procedures in women with MUI (79). However, there is some evidence that surgical treatment may relieve symptoms of DO and provide a better prognosis if stress symptoms predominate and predate urge symptoms (98,99). For patients with pure DO, bladder neck suspension and sling placement are contraindicated. A comprehensive clinical and urodynamic evaluation is, therefore, essential before making the decision for the surgical intervention. Recently, tension-flee suburethral sling procedures, such as TVT, have been proposed for the treatment of MUI, and cure rates of 66% to 85% were reported (22,100). However, a retrospective study on the long-term results of the TVT procedure for MUI reported that the cure rates continued to maintain at 60% for 4 years postoperatively and then declined to 30% at 8 years after the surgery (101). The decline in cure rates was due to the increases of urgency symptoms.
IV. INTERSTITIAL CYSTITIS 3. MIXED URINARYINCONTINENCE
MUI is a coexistence with both SUI and UUI. The treatment of MUI is challenging, and controversy exists regarding the best approach. Some authors advocate the use of conservative therapy first because surgery for MUI is not as effective as for pure stress symptoms, whereas others recommend that treatment be based on the predominated symptoms.
a. Nonsurgical Therapy Because pelvic floor exercises are recommended for both SUI and UUI, these exercises can be employed in MUI. Some vaginal support devices designed to treat SUI have modest efficacy in the treatment of MUI (57). Electrical stimulation can also be used to treat MUI, and improvement rates of 60% to 90% and cure rates of 10% to 30% have been reported (57). Pharmacologic approaches to the treatment of MUI include serotoninnorepinephrine reuptake inhibitors and anticholinergic agents. Duloxetine, a combined serotonin-norepinephrine reuptake inhibitor, is currently in clinical trials as a potential
Interstitial cystitis (IC) is a poorly defined clinical syndrome that manifests as urinary frequency, urinary urgency, nocturia, and bladder pain without an identifiable etiology. Until recently, most of the women with these symptoms were presumed to have UTI, overactive bladder, or chronic pelvic pain and were often treated accordingly. IC is now gaining recognition, and the diagnostic methods as well as treatment modalities are emerging.
A. Epidemiology Despite recent advances, the epidemiology of IC remains incompletely understood. IC affects mainly women, with a female to male ratio of approximately 10:1 (102). Reports on the prevalence of IC are conflicted depending on the criteria used for the diagnosis and method of study. In a population-based study, the estimated prevalence o f l C was 66 per 100,000 adult American females (103). Using the validated questionnaires, other studies demonstrated
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that the estimated prevalence of IC may range from 0.23% to 12.6% (104,105). Parsons and coworkers suggested that the prevalence of IC may be as high as 20% (106). Using potassium sensitive test as a diagnostic method, IC prevalence rates of 81% to 85% in gynecologic patients with complaints of pelvic pain were also reported (107,108). Although prevalence estimates vary greatly, IC is obviously much more common than traditionally believed.
B. Pathophysiology Currently, there are no proven etiologies for IC, and the pathophysiology of this disease is not completely understood. The etiology of IC is probably multifactorial rather than a single entity because a variety of etiologies have been proposed, but none adequately explains the variable presentations, clinical courses, or responses to therapies. It is also possible that different patients may have different etiologies. Recently, several studies reported the associations between IC and other disorders, such as endometriosis, vulvodynia, chronic pelvic pain, irritable bowel syndrome, inflammatory bowel disease, fibromyalgia, chronic fatigue syndrome, systemic lupus erythematous, Sj6rgen's syndrome, and allergies (109). These associations suggest that IC may be a systemic syndrome or a genetically predisposed disease. The suggested genetic predisposition to I C is further supported by the observation that the concordance rate of IC among monozygotic twins was greater than among dizygotic twins (110). One of the earliest theories suggested that IC is a result of a "leaky" urothelium in the bladder caused by the deficiency of the glycosaminoglycan (GAG) layer. The presence of a GAG layer in the urothelium helps to protect the bladder against both bacteria and urinary toxins (111). When urothelium in the bladder becomes more permeable to these bacteria and toxins, IC can develop. This theory, which forms a basis for potassium chloride test and pentosan polysulfate therapy in IC, was derived from several studies in animal models and humans that used protamine to induce an increased permeability in urothelium by stripping the GAG layer (112). However, whether there is an increase in the permeability of the IC urothelium and whether the penetration of bacteria and urinary toxins can be prevented by the GAG layer are still debatable (113). Another proposed etiology is the augmentation of the sensory function in the urothelium of IC patients (114). This theory was based on the findings that the bladder urothelium may have a sensory function in addition to providing a protective barrier. Altering the production of peptide growth factors, such as antiproliferative factors (APF) and heparin-binding epidermal growth factor, in the urothelium was also proposed to explain the etiology of IC (115). These factors may inhibit the growth or the regeneration of normal bladder urothelium. Although much
more investigation is needed to elucidate the mechanism, these growth factors may provide the basis to develop a urinary test for IC. The degranulation of mast cells causing the release of neuroactive and vasoactive agents in the bladder is also believed to play an important role in IC (116). This proposed mechanism forms a basis for the use of antihistamines such as hydroxyzine in the treatment of IC. Other proposed theories include neurogenic hypersensitivity or inflammation mediated locally at the bladder or spinal cord level, release of substance P leading to inflammation and pain, and chronic bladder infection with a poorly characterized agent (116). C. Evaluation 1. CLINICAL PRESENTATION
The symptoms of IC, such as urinary frequency, urinary urgency, and bladder pain, overlap with the symptoms of overactive bladder or chronic pelvic pain. The main differences between these conditions are that overactive bladder does not have bladder pain and chronic pelvic pain may not have urinary frequency and urgency. The presentation of IC symptoms is highly variable from one patient to another and does not necessarily follow a set pattern. Generally, IC patients complain of urinary urgency, urinary frequency, nocturia, and pelvic pain that do not have identifiable etiologies. Other patients may complain of vague symptoms of pain and incomplete bladder emptying or a constant sensation to void. These symptoms can wax and wane during the course of the disease, and one symptomatic component may predominate over the others. IC is characterized by periods of exacerbation followed by variable periods of remission, and the spontaneous remissions, although temporarily, occur in as many as 50% of patients at a mean of 8 months (116). The pain component of IC is nonspecific because the bladder is autonomic innervated and patients often have difficulty in locating or describing the pain. The typical pain over the bladder (suprapubic) area that can be relieved by voiding is described only by a small number of patients, whereas the majority of the women with IC may complain of referral pains such as urethral pain, back pain, vulvar pain, rectal pain, dyspareunia, dysuria, constant burning sensation, or general pelvic pain. Nocturia and urinary frequency and urgency are other components of IC. These symptoms are difficult to separate from each other and from the pain complaint because urinary frequency can be a result of urgency or bladder pain. IC patients may also have a constantly strong urge to void, despite low bladder volume, which is often described as pain. The typical patient voids 16 times a day and 2 or more times at night; however, in severe cases, the patient may urinate as often as 60 times a day and every half hour at night (106). Voided volumes are usually small. Q.uality of life is severely
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women impaired in these women. The patient may be anxious, depressed, angry, and sleep deprived, which can exacerbate the pain and urinary symptoms. 2. DIAGNOSIS
The ability to diagnose IC definitely does not exist because the proven etiology, typical physical examination findings, and conclusive tests or markers are not available. Furthermore, the symptoms are highly variable and can wax and wane. The key to diagnosis is to have highly clinical suspicion, exclude other identifiable conditions, and quantify the symptoms as objectively as possible. Currently, the clinical diagnosis o f l C is made primarily by the combination of symptomatic features and exclusionary criteria. Although the dilemma still exists in the diagnosis of IC, the investigation described in this section can be employed together with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) exclusionary criteria and questionnaire instruments to guide the evaluation and treatment while awaiting further studies on the pathophysiology of lC.
a. The N I D D K Criteria In 1988 a list of criteria was formulated by the N I D D K to standardize subject selections for the research purposes (117). These criteria are summarized in Table 51.1. Although these criteria were not designed as a diagnosis tool, they can provide the clinicians with a useful guideline. However, recent studies showed that 60% of IC cases were missed if the diagnosis relied only on these criteria (118). Furthermore, the early IC may not show a reduction in bladder capacity and glomerulation, thus excluding these cases from the N I D D K criteria. The challenge to clinicians is to diagnose and treat IC early because some authors have reported that the more severe and advanced stages of I C are more resistant to current therapies (109,116). The usefulness of the N I D D K criteria in clinical practice is, therefore, limited. b. Physical Examination and Laboratory Studies General and pelvic examinations are performed to rule out other diseases and pelvic pathologies. Typically, the pelvic examination is negative in the IC patients, except for suprapubic and/or trigonal tenderness. Sexually transmitted diseases, urinary tract infections, urethral diverticulum, and pelvic masses should be ruled out. During the pelvic examination, specimens are collected for the determination of sexually transmitted diseases if clinically indicated. Urinalysis and urine culture are warranted, although the results are usually negative. Urine cytology should be obtained if microscopic hematuria is present or if the patient has other risk factors such as a history of smoking and is more than 40 years old.
719 TABLE 51.1 NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) Diagnostic Criteria for Interstitial Cystitis
Inclusion criteria 9 Symptoms of urinary frequency/urgency or bladder pain 9 Presence of glomerulations (in at least 3 quadrants with at least 10 glomerulations per quadrant) and/or Hunner's ulcers on cystoscopy and hydrodistention Exclusion criteria 9 Maximal bladder capacity greater than 350 ml on cystometry while patient is awake 9Absence of an intense urge to void with the bladder filled to 150 ml of water during cystometry using a fill rate of 30 to 100 ml/min 9 Demonstration of phasic involuntary bladder contractions on cystometry using the fill rate of 30 to 100 ml/min 9 Duration of symptoms less than 9 months 9Absence of nocturia 9 Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics 9 Frequency of urination while awake of less than 8 times a day 9 Diagnosis of bacterial cystitis in the past 3 months 9 Bladder, ureteral or urethral calculi 9Active genital herpes 9 Uterine, cervical, vaginal, or urethral cancer 9 Urethral diverticulum 9 Cyclophosphamide or any type of chemical cystitis 9Tuberculous cystitis 9 Radiation cystitis 9 Benign or malignant bladder tumors 9Active vaginitis 9 Age less than 18 years
c. Voiding Diary and Symptoms Scale A voiding diary, as described earlier for urinary incontinence, is very helpful in establishing baseline frequency, urgency, and bladder capacity in IC patients. These patients should also keep a voiding diary before and after treatment, as well as during any flare-up, to document the improvements and identify the triggers. Several patient symptom scales have been developed and validated for IC symptom quantification. These instruments include the O'Leary IC Indices (Table 51.2), the University of Wisconsin IC Scale (UW-ICS), and the Pelvic Pain and Urinary Urgency and Frequency Scale (PUF). The O'Leary IC Indices have two components: the IC Symptom Index (ICSI), which quantifies the symptoms, and the IC Problem Index (ICPI), which quantifies the quality of life (120). Using the cystoscopic and hydrodistention findings, and NIDDK criteria as the objective diagnosis of IC, the sensitivity, specificity, positive predictive value, and negative predictive value of ICSI and ICPI were found to be 94%, 50%, 53%, and 93%, respectively (121). The [A/V-ICS (Table 51.3), which is based on how much the patients experienced the symptoms, has also been developed and validated for IC (122). Recently, PUF scale (Table 51.4) has become more
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Ho TABLE 51.2 The O'Leary-Sant Symptom Index and Problem Index for Interstitial Cystitis
Interstitial Cystitis Symptom Index (ICSI) 1. During the past month, how often have you felt the strong need to urinate with little or no warning? 0. not at all 1. less than 1 time in 5 2. less than half the time 3. about half the time 4. more than half the time 5. almost always 2. During the past month, have you had to urinate less than 2 hours after you finished urinating? 0. not at all 1. less than I time in 5 2. less than half the time 3. about half the time 4. more than half the time 5. almost always 3. During the past month, how often did you most typically get up at night to urinate? 0. none 1. once 2. 2 times 3. 3 times 4. 4 times 5. 5 or more times 4. During the past month, have you experienced pain or burning in your bladder? 0. not at all 1. a few times 2. almost always 3. fairly often 4. usually
Interstitial Cystitis Problem Index (ICPI) During the past month, how much has each of the following been a problem for you: 1. Frequent urination during the day? 0. no problem 1. very small problem 2. small problem 3. medium problem 4. big problem 2. Getting up at night to urinate? 0. no problem 1. very small problem 2. small problem 3. medium problem 4. big problem 3. Need to urinate with little warning? 0. no problem 1. very small problem 2. small problem 3. medium problem 4. big problem 4. Burning, pain, discomfort, or pressure in your bladder? 0. no problem 1. very small problem 2. small problem 3. medium problem 4. big problem Adapted from res 120.
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popular as a simple but reliable symptom index for I C screening (106). This scale has been validated, and the scores are strongly correlated with a positive PST. Consequently, a high PUT score (10 or above), in combination with a history and physical examination suggesting IC, is considered by many clinicians to be sufficient to make presumptive diagnosis (106). Any of these validated instruments can be used to quantify the patient symptoms and help in the evaluation and treatment of IC as well as in the following patient improvement as objectively as possible.
d. Cystoscopy and Hydrodistention Cystoscopy is generally recommended for ruling out bladder neoplasm and other pathologies. The bladder capacity under anesthesia can also be determined, and the reduction in this capacity suggests the presence of IC, although this criterion is not reliable because many IC patients may have normal anesthetic bladder capacity. The disadvantages of this procedure are its invasiveness and requirement of anesthesia. A number of investigators advocate bladder biopsies to confirm the presence of inflammation; however, the morbidity of the procedure outweighs any potential benefits because histologic findings are not specific for IC. Hydrodistention can be carried out at the time of cytoscopy under general or regional anesthesia. The bladder is fully examined first with cystoscopy to rule out any abnormal appearing or evidence of lesions. The bladder is then distended with sterile water or normal saline at a pressure of 80 to 100 cmH20 for 2 to 5 minutes. After that, the bladder is emptied, and bloody efflux of irrigant suggests the presence of IC. Repeat cystoscopy is performed to reexamine the bladder epithelium, and any glomerulation and/or Hunner's ulcers are noted. Bladder rupture can occur in these patients, so careful inspection during filling and avoiding overdistention are crucial. The presence of glomerulations and/or Hunner's ulcer in the bladder on hydrodistention is the specific N I D D K criteria for the diagnosis of IC. In the United States, Hunner's ulcers (ulcerative form) only occur in less than 10% o f l C patients, and some authors consider it to be more resistant to therapy (116). Although they are uncommon, the presence of Hunner's ulcers is thought to be a specific sign for IC. The appearance of glomerulation after hydrodistention is more common; however, its specificity for the diagnosis of IC is subject to debate because the incidences of glomerulation between IC patients and asymptomatic controls were not significantly different, as reported by one study (123). The sensitivity of glomerulation findings in the diagnosis of IC is also questionable (116). Hydrodistention may have a therapeutic effect on the IC symptoms, although a randomized trial to compare hydrodistention with a sham cystoscopy (without hydrodistention) has not been performed. Some patients may have a temporary worsening of symptoms after hydrodistention, before getting better. Chai and coworkers (124)
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women TABLE 51.3
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University of Wisconsin Interstitial Cystitis Scale
Interstitial Cystitis Items How much have you experienced the following symptoms today? (0: not at all; 6: a lot)
1. 2. 3. 4. 5. 6. 7.
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Bladder pain Bladder discomfort Getting up at night to go to the bathroom Going to the bathroom frequently in the day Urgency to urinate Difficulty sleeping because of bladder problems Burning sensation in the bladder
Reference Items How much have you experienced the following symptoms today? (0: not at all; 6: a lot)
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
Other pelvic discomfort Backache Abdominal cramps Dizziness Aches in joints Heart pounding Chest pain Headache Nausea Numbness, tingling Blind spots, blurry vision Sore throat Swollen ankles Nasal congestion Coughing Suffocation Ringing in ears Flu Adapted from res 122.
suggested that the bladder stretching during hydrodistention can normalize growth factors, which are abnormally expressed in the IC patients, resulting in improvement of symptoms. Hunner's ulcer may be treated at the time of cystoscopy by laser fulguration (125). e. Potassium Sensitive Test The potassium sensitive test (PST) is based on the theory that the bladder epithelium in IC patients is leaky because of the deficiency in the GAG layer (106,126). If potassium is present in the urine, it will cross the leaky urothelium to activate the sensory nerve endings in the suburothelium and cause pain. This test is performed while the patient is awake and without anesthesia. About 40 mL of sterile water is infused into the bladder at a rate of 15-20 mL/min, and 5 minutes after completion of the infusion, the patient rates her pain and urgency using a visual scale from 0 to 5, with 5 being the worst. The bladder is then emptied, and 40 mL of a solution of 0.4 M potassium chloride (KC1) is instilled into the bladder and kept for 5 minutes in the same fashion as with sterile water. The patient then rates her pain and urgency using the same visual scale before voiding. The test is considered positive if
the patient is asymptomatic with water instillation and has a score of ->2 in either pain or urgency with KC1 solution (106). This test is quite painful in IC patients, and the bladder should be emptied immediately after completion of the test. Subsequent irrigation with sterile water or rescue therapy may be necessary. The positive PST was obtained in 75% to 78% of patients with IC (based on N I D D K criteria) and in 4% of controls (106,126). However, a negative PST does not rule out IC because up to 46% of patients with a negative PST meet the N I D D K criteria for IC (127). In gynecologic patients with chronic pelvic pain, 81% to 85% had positive PST (107,108) whereas 38% had positive findings for IC with cystoscopy and hydrodistention (121). This observation suggests that PST is more sensitive for IC, and most gynecologic patients with chronic pelvic pain may have this condition. However, in another study on a population who had symptoms suggestive of IC, the positive predictive values of PST and cystoscopy with hydrodistention were not significantly different (56% and 66%, respectively) (127). A false-positive result can be caused by infection or prior exposure to radiation or chemotherapy. The PST may help
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Ho TABLE 51.4
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Pelvic Pain and Urgency/Frequency (PUF) Scale for Interstitial Cystitis
Please circle the answer that best describes how you feel for each question
How many times do you go to the bathroom during the day? 2 a. How many times do you go to the bathroom at night? b. If you get up at night to go the bathroom, does it bother you? 3 Are you sexually active? Yes No 4 a. If you are sexually active, do you now or have you ever had pain or symptoms during or after sexual intercourse? b. If you have pain, does it make you avoid sexual activity? 5 Do you have pain associated with your bladder or in your pelvis (vagina, labia, lower abdomen, urethra, perineum, testes, or scrotum)? 6 a. If you have pain, is it usually b. Does your pain bother you? 7 Do you still have urgency after going to the bathroom? 8 a. If you have urgency, is it usually b. Does your urgency bother you? Symptom Score (1, 2a, 4a, 5, 6, 7a, 8a) = B o t h e r Score (2b, 4b, 7b, 8b) = Total Score (Symptom Score + Bother Score) =
Score 0
Score 1
Score 2
Score 3
Score 4
3-6
7-10
11-14
15-19
20+
0
1
2
3
Never
Occasionally
Usually
Always
Never
Occasionally
Usually
Always
Never
Occasionally
Usually
Always
Never
Occasionally Mild Occasionally
Usually Moderate Usually
Always Severe Always
Never
Occasionally Mild
Usually Moderate
Always Severe
Never
Occasionally
Usually
Always
1
Never
4+
PUF Symptom Scale. 9 2000 C. LowellParsons,MD (From ref. 106).
to predict the response to pentosan polysulfate therapy. Patients with a positive PST seem to have a better response than those who have a negative PST (128). f Urodynamics In general, urodynamic studies are not necessary in the evaluation of IC because voiding diaries can provide adequate information. However, some investigators believe that urodynamics will allow determination of detrusor instability and urethral dysfunction that can be treated differently. If urinary incontinence is present, urodynamic investigations are recommended. g. Urinary Markers An attractive approach is to find a sensitive and specific maker in the urine that might serve as a noninvasive diagnostic tool for IC. Among many urinary substances that have been investigated, A P F (115) and glycoprotein-51 (GP-51) (129) are potentially useful. Both of these markers were evaluated, and there was no overlapping in the urinary levels of A P F and GP-51 in those who
met the N I D D K diagnostic criteria and in controls. The alteration of these markers in patients who do not fulfill the N I D D K criteria remains unknown (130). Although attractive, the usefulness of these urinary markers in the diagnosis of lC requires much more investigations.
D. Treatment Because the etiology of IC is not completely understood, effective treatment for this disease does not exist. Currently, there is no cure for this condition, and clinicians should carefully counsel patients on the best form of therapy and the realistic expectation of the outcomes. The current treatments of IC are empirical and can only alleviate symptoms. Most of the employed modalities have not been studied in prospective, randomized, and placebo-controlled trials. Currently, some ongoing prospective studies are being carried out by the National Institutes of Health (NIH)-sponsored Interstitial
CHAPTER51 Lower Urinary Tract Disorders in Postmenopausal Women Cystitis Clinical Trial Group, and the results are pending. In addition to the therapeutic effects of hydrodistention, the current treatments of IC include supportive management, oral therapy, intravesical instillation, and surgical approach. NSMDs can be used adjunctively to reduce pain and inflammation. It should be noted that anticholinergic and antispasmodic agents are ineffective in women with IC. Anticholinergics block the motor pathway, but IC is primarily a hypersensory condition. 1. SUPPORTIVEMANAGEMENT
Supportive management consists of dietary modification, stress management, pelvic floor exercises, bladder training programs, and other behavioral measures. Although the link between dietary factors and IC symptoms has not been fully established, some foods and beverages may exacerbate the symptoms. It has been shown that about 53% of IC patients associate symptom aggravation with acidic foods and beverages (131). Another study demonstrated that urinary levels of tryptophan metabolites were elevated in women with hypersensitive bladders as compared with the controls (132). This increase in the tryptophan metabolites may disrupt the GAG layer of the urothelium and thus predispose to the development of IC or exacerbate its symptoms. However, more studies are needed to investigate the role of dietary factors. Stress management and behavioral modification may play a role in the treatment of IC. Distraction techniques can be employed to increase the time between voids. Contracting the pelvic floor muscles and overriding the first urge to void are very helpful for this purpose. Pelvic floor exercises and bladder training programs, as described earlier for urinary incontinence, can be employed in IC patients. These are good initial or adjunctive interventions and have been used with some success. 2. ORALTHERAPY
a. Sodium Pentosan Polysulfate (Elmiron) Sodium pentosan polysulfate is a weak heparinoid that supposedly reverses the GAG layer deficiency in the urothelium and thus minimizes the permeation of urinary bacteria or toxins. This medication is approved by the U.S. Food and Drug Administration (FDA) for oral use in the treatment of 1C. Hanno (133) reported that pain relief occurred in approximately 40% to 60% of patients after 3 months of treatment with 100 mg, three times per day. In other prospective, randomized, and placebo-controlled trials, the improvement of certain IC symptoms was significant with pentosan polysulfate (28% of treated subjects versus 13% of placebo controls), although the degree of improvement was not dramatically from a clinical standpoint (134). A recent study showed that the response rates of pentosan polysulfate at 32 weeks of treatment range
723
from 45% to 49% and these responses are not dose dependent, but the duration of therapy appears to be more important (135). Because pentosan polysulfate may take 3 to 6 months to achieve maximal benefit (133), adequate time should be allowed for the treatment to become effective. Long-term efficacy studies demonstrated that the benefit was maintained for I to 2 years in those who responded to the therapy (133). Although this medication is well tolerated, gastrointestinal side effects and reversible alopecia occur in 4% of patients.
b. dmitriptyline (Elavil) This medication has been used to decrease the chronic pain component of IC (136,137). In addition to its inhibiting properties in the noradrenaline and serotonin reuptakes, amitriptyline also has analgesic, sedative, anticholinergic, and antihistaminic effects. Amitriptyline is usually given at night to obtain additional benefit of improving sleep disturbance and decreasing nocturia. The starting dose is 10 to 25 mg at bedtime, gradually increased to 75 mg or until the side effects are intolerable in order to achieve maximal benefit. Weight gain, sedation, and anticholinergic side effects such as dry mouth and constipation occur in 20% to 80% of patients (136). When compared with placebo, amitriptyline significantly improved pain and urgency in patients with IC, and a long-term efficacy study (mean of 17 months) revealed a 64% improvement rate using the global assessment questionnaire (137). When used in conjunction with pentosan polysulfate, amitriptyline can be tapered off once remission is attained. Other tricyclic antidepressants have not been studied in the treatment of IC. c. Hydroxyzine (Atarax) Hydroxyzine, which is an antihistamine that prevents mast cell &granulation, has been employed in the treatment of IC. The degranulation of mast cells causing the release of neuroactive and vasoactive agents is believed to be responsible for the symptoms of IC. For IC patients who have a history of allergies, or in whom mast cells were confirmed on bladder biopsy, an antihistamine such as hydroxyzine is a good choice. In an open-label investigation with hydroxyzine, 40% reductions in IC symptoms were reported (138). This improvement increased to 55% in patients with history of allergies. Hydroxyzine can be taken alone, or given together with pentosan polysulfate, at a dose of 10 to 25 mg at bedtime for 1 week, then gradually increased to 50 to 75 mg. Hydroxyzine also has sedative and anxiolytic side effects, which are beneficial for nocturia and other IC symptoms. d. Gabapentin (Neurontin) Gabapentin is an antileptic medication that can hyperpolarize the neurons involved in pain transduction and thus increase their sensory thresholds. Because of this action, gabapentin has been tried for chronic pelvic pain and IC patients with variable success (139).
7
2
4
H
3. INTRAVESICAL INSTILLATION As compared with oral therapy, intravesical instillation is an attractive approach in the treatment of IC for three reasons. First, the side effects can be minimized in the intravesical therapy because of the lack of systemic absorption. Second, the therapy should be more effective because it targets directly on the urothelium where the abnormalities are believed to occur. Third, a "cocktail" mixture of multiple medications can be employed in intravesical instillation to provide the synergic effects. Several agents, either alone or as a mixture, have been used; however, the selection of these agents is empiric, and data on the prospective and randomized studies of these agents are limited. These medications are instilled through a urethral catheter and left in the bladder for 20 to 30 minutes or as long as the patient can tolerate. Although the schedule of treatment varies with each agent, the instillation is usually carried out once per week for 6 weeks. After this initial treatment period, some patients may need a maintenance schedule of instillations, usually biweekly or monthly. Intravesical instillation can also be used as an adjunct to oral therapy. A potential risk for UTI via catheterization and a transient chemical cystitis that exacerbates the symptoms can occur.
a. Dimethyl Sulfoxide Besides pentosan polysulfate, dimethyl sulfoxide (DMSO) is the only other drug approved by the FDA for the treatment of IC. DMSO is thought to improve the IC symptoms through its anti-inflammatory actions, mast cell inhibitions, muscle relaxant effects, and sensory neuropeptide depletions of the afferent nerves. About 50 mL of a 50% DMSO solution is instilled into the bladder and held for 20 to 30 minutes before voiding. Instillations are performed every 1 to 2 weeks for a total of 4 to 8 treatments. Some patients may need a maintenance schedule of instillations because of relapsed symptoms. A garlic-like odor may occur in the skin or breath because DMSO is secreted through the skin and lungs. DMSO can induce remission in 35% to 60% of patients for up to 24 months (140). If patients do not respond to DMSO initially, the combination of DMSO with hydrocortisone, heparin, and sodium bicarbonate in the instilled solution has been recommended (116). b. Sodium Pentosan Polysulfate (Elmiron) The action of sodium pentosan polysulfate is to replenish the defected GAG layer in the urothelium of the bladder. Because sodium pentosan polysulfate is poorly excreted in the urine, intravesical application of this medication is expected to be more effective than the oral route. However, this effect was not observed clinically. This agent is administered as a solution of 300 mg in 50 ml of normal saline, twice weekly for 12 weeks. It has been shown that intravesical instillation of pentosan polysulfate increases the bladder capacity and improves the symptoms of IC (141). These improvements are similar to the oral route, but symptoms were relieved quicker with the instillation.
o
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c. Steroids Steroids such as hydrocortisone, methylprednisolone, or triamcinolone can be reconstituted in a small volume (10 to 15 mL) and instilled intravesically, either alone or in a mixture with other agents. Steroids are though to improve the IC symptoms through their immunosuppression and anti-inflammatory properties. d Heparin Heparin is thought to help replenish the GAG layer in the bladder's urothelium, thus improving the IC symptoms. In addition to this surface protective action, heparin is believed to have anti-inflammatory effects in the bladder. Heparin solution can be used alone or in a mixture with other agents. Because this medication has been shown to reduce relapses in patients who responded to DMSO, it is common for heparin and DMSO to be instilled together into the bladder. The instillation can be carried out 1 to 3 times per week, at a dose of 10,000-20,000 U each time. When administered 3 times per week for 3 months, remission of symptoms was reported in 56% of patients (142). The remission was maintained for up to 1 year in 80% to 90% of patients, if the treatment was continued at a maintenance level. Recently, bladder instillation of a mixture of 40,000 units heparin and 2% alkalinized lidocaine (lidocaine and bicarbonate) has been shown to produce immediate symptom relief in 94% of patients before heparin reaches its full effect (143). e. Local Anesthetics Local anesthetics, such as lidocaine (1%) or bupivacaine (Marcaine, 0.5%), can be used intravesically, either as a single solution or in a mixture with other agents (116,143). These agents are used in bicarbonate buffered solution. The responses of lidocaine and bupivacaine are significant; however, lidocaine requires frequent instillation due to its short duration of action. The longer-acting bupivacaine has been used in a variety of mixtures with other agents for bladder instillation. fi Hyaluronic Acid (Cystistat) Hyaluronic acid, which occurs namraUy in the human connective tissues, is another agent for intravesical therapy. When instiUed into the bladder, as a 40 mg in 40 ml normal saline solution, hyaluronic acid is believed to coat the lining of the bladder and protect it from irritating substances in the urine. Hyaluronic acid can be instilled weekly for 4 to 6 weeks, and then monthly for 6 months, or twice weekly and then monthly after improvement in symptoms occurs. In a small study involving 20 patients, weekly administration of hyaluronic acid decreased pain and nocturia in 30% and 40% of patients, respectively, while improving the IC symptoms in 65% of patients (144). g. Capsaicin/Resiniferatoxin Capsaicin is an extract of chili pepper that can reduce the activation of C-fiber. Symptoms oflC are thought to involve the C-fibers in the bladder (109,116). If the sensation of bladder pain mediated by these fibers can be blocked by capsaicin, then the symptoms of I C
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CHAPTER51 Lower Urinary Tract Disorders in Postmenopausal Women may be improved. Resiniferatoxin (RTX) is a potent analog of capsaicin that acts similarly by desensitizing the sensory nerves of the bladder. This agent has been shown to be effective in some studies with small numbers of patients (116). RTX has an advantage over capsaicin because it does not cause a burning sensation with instillation. However, a recent prospective, randomized, and placebo-controlled clinical trial involving 163 patients demonstrated that RTX is not effective for IC (145).
h. Bacillus Calmette Gugrin Bacillus Calmette Gu6rin (BCG) is currently approved by the FDA for bladder cancer treatment. The mechanism of BCG action in the treatment of IC is unknown, although the modulation of the host immune response by this agent has been proposed. This agent has been employed intravesically in a prospective study involving 30 patients and showed a 60% improvement in IC symptoms versus a 27% for placebo (146). However, another study was unable to reproduce these results (147). Recently, a prospective, randomized, and placebo-controlled study involving 248 patients showed a response rates (in global assessment) of 21% for BCG and 12% for placebo (148). Although the safety profile of BCG is acceptable and the effectiveness of this agent is confirmed, the response rate is not dramatic from a clinical standpoint. i. Mixture of Multiple Agents Several "cocktail" regimens, which are mixtures of different agents, have been employed empirically for bladder instillations (116). These solutions involve lidocaine (or bupivacaine), bicarbonate, hydrocortisone (or triamcinolone), heparin, and DMSO, in a variety of mixtures, to provide immediate symptom relief as well as long-term effects. The common "cocktail" solutions are: (a) a mixture of 50 ml of DMSO, 10,000 units of heparin, 10 mg of triamcinolone, and 44 mEq of bicarbonate that can be administered weekly for 6 weeks (116), and (b) a mixture of 40,000 units of heparin, 8 ml of 2% lidocaine, 3 ml of 8.4% bicarbonate, and 5 ml of sterile water that can be administered 3 times per week for 2-3 weeks (143). Alternatively, an oral medication can be added to a patient who has already started with intravesical therapy to enhance the effects. No data on the formal evaluation of these "cocktail" regimens are available. 4. SURGICALTHERAPY
a. Laser Therapy Neodymium:YAG laser can be used to fulgurate the Hunner's ulcers during cystoscopy. This method is effective in improving the IC symptoms but carries a high relapse rate. About 50% of the 24 studied patients required one to four re-treatments (125). The application of laser therapy is limited because most of the IC patients do not have Hunner's ulcers (116).
b. Sacral Neuromodulation Sacral neuromodulation is a long-term electrical stimulation of the $3 nerve root that has been approved by the FDA for the treatment of IDO, frequency-urgency syndrome, and idiopathic urinary retention. The mechanism of action of sacral neuromodulation in the treatment of IC is unclear, although this modality has been applied to a small number of patients who failed other modes of treatment, with promising results (94,149). Thus far, it has significantly reduced urinary frequency and urgency symptoms as well as the pain associated with IC. Recently, a multicenter clinical trial also showed significant improvements in urinary frequency, pain symptoms, and voided volumes (150). The neuromodulation is achieved with an implanted lead that is placed through $3 foramen and an implanted electrical pulse generator as described in detail elsewhere (94). c. Cystectomy and Bladder Augmentation Surgical therapies, particularly major surgical interventions with denervation procedures, cystectomy, and bladder augmentation, are the last resort in the treatment oflC. Cystectomy and bladder augmentation has been described in the treatment of IC in patients with a severely contracted bladder (116). Although cure rates ranging from 50% to 80% were reported in some series, other studies demonstrated that IC symptoms may persist despite of total cystectomy and urinary diversion, and repeat surgery is often required (116,119). For this reason, patients must be carefully selected and fully counseled. 5. OTHER THERAPIES
Transcutaneous electrical nerve stimulation has been described for the treatment of IC with some benefits (151). This treatment modality supposedly stimulates the afferent nerves, thereby activating the inhibitory circuits and decreasing the sensation of pain. However, its exact mechanism remains unclear. Other approaches under investigation include intravesical injection of botulinum toxin and gene therapy (152). Botulinum toxin has been shown some benefits in the treatment of IC (152); however, a recent report demonstrated that intravesical injection of botulinum toxin A is not effective in 8 patients who have refractory IC (153).
V. LOWER URINARY TRACT INFECTION UTI can be classified as involving the upper and the lower urinary tract. The discussion in this chapter focuses only on lower UTI, which occur much more commonly than upper tract infection, and the term UTI is used to indicate lower urinary tract infection. Although the diagnosis and management of UTI in postmenopausal women are often simple, new challenges have been occurred recently. These challenges
726
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include the recognition of additional pathogens such as Staphylococcus saprophyticus and Chlamydia trachomatis, the understanding that many cases of acute cystitis may have less than the standard 105 colony forming units (CFU)/mL in urine, the realization that many other conditions such as interstitial cystitis and urethral syndrome may present with UTI-like symptoms, and the awareness of recurrent and instrument-associated infections.
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pathology. Detrusor dysfunctions, UTI, urethral defects, and other anatomic and functional defects of the urinary tract should be ruled out before attempting to use this term. Pydonephritis is a bacterial infection of the renal parenchyma and the renal pelvicaliceal system. The discussion ofpyelonephritis is beyond the scope of this chapter.
B. Epidemiology A. Terminology The commonly used terminology surrounding UTI requires some definitions because it can be confusing. Bacteriuria means the presence of bacteria in the urine, including both renal and bladder bacteria. Asymptomatic bacteriuria is generally accepted as a bacterial colony count of 105 or more per mL of urine in at least two properly collected "clean catch" specimens in the absence of clinical UTI symptoms. These patients may or may not have pyuria. Lower colony counts, even as low as 102 CFU/mL of urine, may be accepted as bacteriuria in symptomatic patients. Persistent bacteriuria is the presence of microorganisms that were isolated at the start of treatment and continue to be isolated while the patient is receiving therapy. Persistence may be caused by several factors, including the presence of resistant organisms, inadequate drug therapy, and poor patient compliance. Superinfection is the appearance of a different organism while a patient is still receiving therapy. The new organism may be a different strain or a different serologic type. Relapse of infection occurs with the recurrence of significant bacteriuria with the same species and serologic strain of organism. Relapse usually appears within 2 to 3 weeks of completion of therapy and most likely represents perineal colonization by the infecting organism. Recurrent infection (or reinfection) is an infection occurring after cessation of therapy with a different strain of microorganism or a different serologic type of the original infecting strain. Typically, reinfection occurs 2 to 12 weeks after a previous episode of infection and indicates recurrent bladder bacteriuria. Cystitis is an inflammation of the urinary bladder, which may have infectious or noninfectious etiology. Infectious cystitis or bacterialcystitis may be classified as simple, complicated, or recurrent infection. Recurrent UTI is diagnosed with 2 infections within 6 months or 3 or more infections during 1 year in which the initial episode is resolved and subsequently followed by another UTI. Trigonitis refers to inflammation or localized hyperemia of the bladder's trigone, commonly seen by cystoscopy. Urethritis indicates inflammation of the urethra and is usually caused by Chlamydia trachomatis, Neisseria gonorrhea, genital herpes, or other nonspecific conditions. Urethral syndrome is a poorly defined condition in patients with urinary frequency and urgency, dysuria, voiding difficulty, and suprapubic discomfort without any discernible
UTI occur much more frequently in females than in males, with a female to male ratio of 10:1. The incidence of UTI increases with age, and the infection is more common in women who are sexually active and in those who use diaphragms and spermicides for contraception (154). Approximately 20% to 50% of women will have at least one episode of UTI during their lifetime (155). Although UTI can occur in women of all ages, its prevalence is higher in the postmenopausal women. Impairment of the bladder emptying and alterations in the vaginal flora after menopause are thought to place these women at an increased risk of UTI. Furthermore, poor perineal hygiene, urinary incontinence, and fecal incontinence in these women can contribute to the problem. The elderly are usually sicker and at greater risk of dying with UTI than younger women. Because the pH of the vaginal secretion is increased and the number of lactobacilli is decreased in postmenopausal women, Gram-negative bacteria can colonized the vagina and serve as the uropathogens. The increase in residual volume of urine in the bladder of postmenopausal women also promotes bacterial growth. However, the analysis of midstream urine showed that the proportion of positive infections increases with age in both men and women, with no specific changes in the rates of infection at or after the menopause (156). The exact role of the menopause in the development of UTI is, therefore, not clear, and more investigations are needed.
C. Pathophysiology 1. Pathogenesis The most common pathogen in UTI is Escherichia co& which accounts for about 80% of the community-acquired infections (157). The second most common pathogen is Staphylococcus saprophyticus, which presents in 5% to 15% of young women with acute cystitis. Klebsiella species were found in about 5%, Enterobacter species in about 2%, and Proteus species in another 2% of community-acquired UTI. Approximately 1% to 2% of UTI are caused by other Gram-positive organisms such as group B and group D streptococci. Staphylococcus epidermidis is a frequent cause of nosocomial UTI in catheterized patients (158). This organism is also frequently resistant to
CHAPTER51 Lower Urinary Tract Disorders in Postmenopausal Women antibiotics. Serratia marcescens and Pseudomonas aeruginosa are primarily hospital acquired and are responsible for the infection in hospitalized patients with urethral catheterization or manipulation (157,159). These pathogens may gain entry to the urinary tract by three pathways: the ascending route, the hematogenous route, and the lymphatic route. The ascending route appears to be the most important mechanism for organisms to enter the urinary tract. Normally, the urinary tract in women is sterile above the level of the distal urethra, and organisms that gain access to the bladder tend to do so from neighboring sites such as the perineum, vaginal vestibule, lower urethra, paraurethral tissues, and bowel. Women are more susceptible to UTI due to their short urethra and the decreased urethral resistance after menopause. Urinary infection via the hematogenous route is uncommon but is seen occasionally in elderly, debilitated, or immunosuppressed patients with overwhelming infections or in whom kidney infection is only part of the multisystemic involvement. Renal seeding of staphylococcal organisms and tuberculosis are almost always acquired via the hematogenous route. Large bacterial inoculums and virulent organisms are also spread through hematogenous dissemination. Although very rare, lymphatic route of infection can occur. Sexual intercourse and use of diaphragm increase the risk of UTI (154). Other risk factors in postmenopausal women include diabetes mellitus, history of UTI, and urinary incontinence (160). Additional sources of infections include vulvovaginitis, urethra] diverticula, poor hygiene, and indiscriminate urethral catheterization. Infrequent and incomplete voiding resulting in large bladder volumes also increases the susceptibility to UTI.
727
urine may also block bacterial adherence. The deficiency of the GAG layer in the bladder may play a role in recurrent bacterial cystitis (162). Because voiding tends to dilute and wash away the inoculated organisms, bladder infection depends on the residual volume of urine, rate of urine flow, and frequency of voiding. Voiding not only displaces infected urine with freshly sterile urine, but also flushes out bacteria attached to the urothelium. Furthermore, urine inhibits bacterial growth with its low pH, high organic acid concentration, and very low or high osmolarity. Anaerobes are rarely seen in UTI, although they are abundant in the feces, because oxygen tension in the urine prevents their growth.
D. Evaluation 1. CLINICALPRESENTATION Acute cystitis generally has an abrupt onset of severe urinary tract symptoms such as dysuria, frequency and urgency that are associated with suprapubic or low back pain. Systemic symptoms such as fever and chills are usually absent in lower UTI. Occasionally, mild urinary incontinence may occur. Physical examination reveals suprapubic tenderness. Infection is characterized by a large number of leukocytes and organisms in the urine. Microscopic hematuria may sometimes occur in urine analysis. The symptoms of urethritis are usually milder and the onset is more gradual than acute cystitis. Patients may have lower abdominal pain and abnormal vaginal discharge or bleeding related to concurrent cervicitis. In female patients, symptoms of urethritis may be difficult to distinguish from those of cystitis. 2. DIAGNOSTICTESTS
2. HOST DEFENSE MECHANISM
Susceptibility to UTI depends on the status of the host defense mechanisms, the virulence of microorganism, and the inoculum size. The host defense mechanisms can be found in the vagina, urinary tract, and urine. Normally, the vagina and periurethral areas provide important defense mechanisms to prevent the progression of microorgansims from the rectum to the urethra. The acidity of vaginal secretions promotes the growth of normal flora such as lactobacillus and prevents the growth of uropathogens such as E. coli. In the premenopausal woman, the vaginal pH is around 4. When the pH becomes less acidic, enterobacteria can colonize vaginal introitus and periurethral areas, thus predisposing to UTI. The normal urinary tract in the female is remarkably resistant to infection. The urinary tract secretes proteins, such as Tamm-Horsfall protein, that inhibit bacterial adherence and allow the bacteria to be flushed away (161). The presence of GAG in the bladder urothelium and immunoglobin in the
Diagnosis of cystitis is based on the clinical manifestations, microscopic examinations, urinalysis, and culture results. The method of urinary collection must be carefully performed to avoid contamination. Collecting a cleancatch and midstream specimen is widely employed; however, urine sample can be obtained by bladder catheterization or suprapubic aspiration in special cases. Bladder catheterization and suprapubic aspiration should only be used when it is impossible to obtain uncontaminated urine samples or in symptomatic patients who have very low bacterial counts. a. Urine Analysis In addition to presenting symptoms, urinalysis can provide important evidences of UTI. The pH and specific gravity of urine are usually not helpful, except in the case of Proteus mirabilis infection (pH 8). The presence of distinctive crystals in the urine is not sensitive or specific for acute cystitis. Dipstick tests for proteinuria also have a poor predictive value in detecting UTI. However, dipstick
728 tests for esterase, hematuria, and nitrite are very useful in the diagnosis of UTI. Although less accurate than microscopic examination, these rapid dipstick tests in the office are reasonable substitutions (163). The nitrite test is based on the conversion of urinary nitrate to nitrite by bacterial action. The esterase test is based on a substrate color change that is caused by the esterase found in leukocytes. The nitrite and esterase tests, which indicate the presence of bacteriuria and pyuria, respectively, depend on the bacterial counts for their sensitivities. With the bacterial counts of 105 CFU/mL or more, the sensitivities of these tests are 60%; whereas infections with 104 to 105 CFU/mL, the sensitivities are only 22% (164). False-negative results can occur with a poor sampling technique, an enterococci infection (because they do not convert nitrate to nitrite), and the presence ofbilirubin, methylene blue, or phenazopyridine that may interfere with the test. Other rapid tests are also available for detecting the presence of bacteria and leukocytes in the urine simultaneously (165). These tests are based on the staining of the bacteria and leukocytes in a concentrated sample and then comparison of the resulting colors with a reference. Their sensitivities are 79% to 85% with the bacterial counts of 105 CFU/ mL or greater, but only 34% to 65% with infections of 104 to 105 CFU/mL. These tests, which are more sensitive but less specific than the nitrite and esterase tests, can be a good screening method for UTI. b. Microscopic Examination Microscopic examination of bacteria, leukocytes, and red blood cells in urine is an easy and valuable method of evaluating UTI. Bacteria can be detected with microscopy and the presence of several organisms per high power field usually correlates with a culture count of 105 CUF/ml urine. Gram stain may further help in determining the organism. Yeast infection, such as Candida albicans, can also be detected with microscopy. The presence of leukocytes in the urine indicates host injuries from infectious or noninfectious causes. In patients with bacteriuria, leukocyte counts help to differentiate colonization (bacteriuria without evidence of tissue invasion) from UTI (bacteriuria with evidence of host injury). A leukocyte count of more than 5 leukocytes/high power field in a centrifuged urine sample is usually considered significant pyuria; however, this method has been shown to have a poor reproducibility (166). Studies have suggested the nonpathologic limit for pyuria is less than 10 leukocytes/ml of uncentrifuged urine. Stamm (166) reported that 96% of patients with symptomatic bacteriuria have 10 leukocytes/ml of urine or more, while less than 1% of asymptomatic and a bacteriuric subjects have this level of leukocyte counts. Examination for microscopic hematuria may be helpful because it can be found in about 50% of women with acute
Ho
AND BHATIA
UTI while it is rarely present in patients who have dysuria from other causes (166,167). The presence of red blood cells in the urine frequently occurs when there is an infection in the mucosa of the bladder. However, microscopic hematuria, that does not resolve with UTI treatment or occurs in asymptomatic patients, requires further diagnostic workup to rule out other pathologies. c. Urine Culture and Sensitivity In the uncomplicated patient, the diagnosis can be presumed with presenting symptoms and positive screening tests for bacteriuria, pyuria, or hematuria, and starting antibiotics without urine culture is a reasonable approach. If the screening tests are inconclusive in a symptomatic patient, or if persistent or recurrent infection occurs in a patient who has been treated with antibiotics, urine culture and sensitivity should be performed. Urine culture and sensitivity should also be performed in patients with signs and symptoms that are consistent with upper urinary tract infection (i.e., pyelonephritis). Positive urine culture traditionally requires a growth of bacteria at least 105 CFU/ mL; however, the application of this criterion may have some limitations. It has been shown that 20% to 24% of women with symptomatic urinary infection have less than 105 C F U / m L in urine (168). A diagnostic criterion of 102 CFU/mL, rather than 105 CFU/mL, has been proposed for young symptomatic women. The other limitation is the contamination from other bacteria on the perineum, which can occur in 18% of specimens (169). Therefore, urine specimen collection must be carried out with considerable care. d. Cystourethroscopy Cystourethroscopy is not routinely performed in the evaluation of female patients with UTI. However, it should be considered in women with asymptomatic hematuria or with recurrent or persistent UTI. In hematuria, cystoscopy should be performed to rule out malignancy or other noninfectious pathologies, whereas recurrent or persistent UTI may result from a fistula or diverticulum (170). e. Radiologic Studies Radiographic study is not routinely necessary. However, if urethral diverticulum is thought to be the cause of recurrent infection in the lower urinary tract, a voiding cystourethrogram or a double-balloon catheter study should be performed. Intravenous pyelography (IV-P) may be indicated in UTI patients who have a history of urinary stones or obstruction, history of recurrent infection caused by urea-splitting organisms such as Proteus mirabilis, history of previous upper urinary tract infection, history of childhood UTI, infection associated with painless hematuria, and infection suggesting the presence of an enterovesical fistula.
CHAPTER 51 Lower Urinary Tract Disorders in Postmenopausal Women
F. M a n a g e m e n t 1. GENERALMANAGEMENT
The bacteriuria may clear spontaneously without antibiotic therapy due to the host defense mechanisms. Two of the important protective factors are the washout effects cause by urination and the dilution of pathogenic organisms caused by the freshly sterile urine. Hydration is a simple way that may help to wash out and dilute the bacteria in the urinary tract. Cranberry juice may inhibit bacterial adherence and protect against the development of UTI (171). Pain and burning sensation with urination can be relieved with analgesic agents such as phenazopyridine hydrochloride (Pyridium). This agent is usually prescribed for 2 to 3 days along with the antibiotic treatment, and patients should be warned that their urine and contact lenses may turn an orange color. 2. ANTIBIOTICTREATMENT
Verifying the presence of complicated or recurrent infections and selecting the antimicrobial agent that is most likely to be effective are important tasks in the management of UTI. Two considerations should be kept in mind when prescribing antibiotic treatment for UTI. First, the treatment agent should ideally not alter the bacteria in the bowel because the fecal flora is the reservoir for most of the organisms causing infection. This alteration can occur if the drug has a high serum level or passes through the gastrointestinal tract without being absorbed. Second, the treatment agent should not disturb the vaginal flora in order to avoid yeast vaginitis. Disrupting the vaginal flora allows yeast to grow and causes vaginitis, which can subsequently lead to a vaginitis-cystitis cycle that may be difficult to treat. The spectra of antimicrobial activities against common pathogens in UTI are shown in Table 51.5. The combinations of trimethoprim and sulfamethoxazole (Bactrim, Septra) have become popular in the treatment of UTI. They provide a broad range of activity against uropathogens but have a low incidence of side effects and infrequent occurrence of bacterial resistance. These agents have moderate effects on the vaginal and bowel flora (157). Nitrofurantoin has excellent activity against E. coli but no significant changes in vaginal or bowel flora and low bacterial resistance. Fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, levofloxacin, and amifloxacin have also been introduced for the treatment of UTI. These agents offer excellent actMty against E. coli and other organisms such as Pseudomonas aeruginosa, staphylococci, and enterococci. Their adverse effects are infrequent; however, an increase in bacterial resistance, particularly by E. coli, has already occurred with ciprofloxacin due to its widespread use (157). These agents are also expensive and should be reserved for patients with persistent or recurrent infections, or as an
729
alternative to parenteral antibiotics in complicated infections. Amoxicillin or first-generation cephalosporins are generally avoided by many clinicians because of relatively high failure rates. Dosage and side effects of antibiotics commonly used in the treatment of UTI are shown in Table 51.6. 3. ASYMPTOMATICBACTERIURIA Asymptomatic bacteriuria can resolve spontaneously. It has been shown that 66% and 40% of elderly women with asymptomatic bacteriuria clear their bacteriuria when they are treated with antibiotics or placebo, respectively (172). Although the long-term effects of asymptomatic bacteriuria are not completely known, it is seldom associated with adverse outcomes. Except for pregnant women and for the preoperative evaluation before urologic or gynecologic surgeries, screening for asymptomatic bacteriuria in adults offers very little value. It has been shown that postoperative complications can be reduced by detecting and treating asymptomatic bacteriuria before urologic surgeries (173). There are no data to indicate that the routine treatment for asymptomatic bacteriuria is necessary in postmenopausal women.
4. SIMPLEINFECTION
In the uncomplicated patients with acute cystitis, treatment can be carried out without urine culture, and follow-up visit is unnecessary unless symptoms persist or recur. There are several regimens for the treatment of simple UTI. A single-dose therapy has been proposed; however, this approach had significantly higher treatment failure rate when compared with the 10-day course of trimethoprim (TMP)sulfamethoxazole (SMX) (174). However, a recent study demonstrated that a single dose of 500 mg of ciprofloxacin and a 3-day course of norfloxacin (400 mg twice a day) have the same efficacy (175). With most uncomplicated UTI, the 3-day regimens of TMP-SMX or nitrofurantoin are effective, but with less cost and fewer side effects than the 7-day regimens. Although a 3-day course of TMP-SMX is the current standard for empiric treatment of acute cystitis in uncomplicated patients, there has been a trend towards increasing resistance among uropathogens to this antimicrobial agent. The fluoroquinolones are highly effective and have low side effects, but they are more expensive. Prudent use of fluoroquinolones for the treatment of uncomplicated UTI is warranted because resistant organisms may develop with widespread use of these antibiotics. For patients with systemic diseases, such as diabetes meUitus, known structural abnormalities of the urinary tract, history of a treatment failure in the past 6 months, history of acute pyelonephritis, and history of childhood urinary tract infections, a 7- to 10-day course of therapy should be given. For patients whose UTI symptoms persist beyond the third day of
730
Ho AND BHATIA TABLE 51.5
Drug
Dosage and Adverse Reactions of C o m m o n Antibiotics Used in the Treatment of Lower Urinary Tract Infections Dosage
Common Adverse Reactions
TMP-SMX (160 mg/800 mg)
1 tablet PO q 12 h
Hypersensitivity, photosensitivity, skin reactions, GI upset, blood dyscrasia
Nitrofurantoin
100 mg PO q 6 h
GI upset, peripheral neuropathy, pulmonary hypersensitivity reactions, hemolysis in patients with G6PD deficiency
Nitrofurantoin, sustained release (Macrobid) Norfloxacin
100 mg PO q 12 h
Same as nitrofurantoin above
400 mg PO q 12 h
Nausea, vomiting, diarrhea, abdominal pain, skin rash, convulsions, psychoses, joint damage
Levofloxacin
500 mg PO q 24 h
Ciprofloxacin
500 mg PO q 12 h
Enoxacin
400 mg PO q 12 h
Lemofloxacin
400 mg PO q 24 h
Cephalexin
250-500 mg PO q 6 h
Ampicillin
500 mg PO/IV q 6 h
Gentamicin
1 mg/kg IM/IV q 8 h or 5-7 mg/kg IV q 24 h
Disturbance of blood glucose, allergic, photosensitivity, nausea, headache, allergic reactions, tendon rupture, pseudomembranous colitis Anosmia, taste loss, myalgia, dyspepsia, central nervous system effects, theophylline interactions, pseudomembranous colitis, anaphylactic reaction Mild GI effects, photosensitivity, CNS effects as other fluoroquinolones above Mild GI effects, photosensitivity, CNS effects as other fluoroquinolones above Allergic reactions (less than with penicillins), GI upset, pseudomembranous colitis Hypersensitivity, allergic reactions, diarrhea, GI upset, pseudomembranous colitis, decreased platelet aggregation, candidal overgrowth Ototoxicity, nephrotoxicity, neuromuscular blockade with high levels
Precautions Hematologic toxicity in AIDS patients, increased risk of hematologic effects in folateor G6PD-deficient patients, avoid in patients receiving warfarin Avoid concomitant use of magnesium or quinolones, which are antagonistic to nitrofurantoin, do not use in patients with low creatinine clearance ( estrone > estriol > catecholestrogens. The stilbene estrogens such as diethylstilbestrol have an affinity three to four times higher than that of estradiol, whereas the triphenylethylene estrogen agonist/antagonist vary, with 4-hydroxytamoxifen having almost twice the affinity of estradiol and clomiphene and tamoxifen having 25% or less affinity for the ER than does estradiol (38). The human ER-beta has 47% homology with ER-alpha (39,40), with 96% homology in the DNA binding domain and 58% in the ligand binding domain (41). In the presence of estradiol, both receptors bind to the same DNA estrogen
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CHAPTER53 Pharmacology of Estrogens response element with similar affinity (42). The affinity of ER-beta for natural and synthetic ligands is similar to that of ER-alpha, except that the ER-beta has a higher affinity for phytoestrogens (38). Tamoxifen is both an agonist and antagonist for ER-alpha but only an antagonist for ER-beta (43). In the human ER-beta mRNA is expressed in classic estrogen-sensitive tissues such as the uterus, breast, and bone (41,44,45). It is also expressed in human granulosa cells and spermatids, tissues devoid of ER-alpha (41). In addition to their role as classic DNA binding nuclear receptors, both ER-alpha and ER-beta are present in mitochondria. The mitochondrial genome contains potentially estrogen-responsive sequences, and estrogen increases mitochondrial DNA-encoded gene transcript levels (43). Like peptide growth factors that act on membrane-bound receptors, estrogens activate various protein kinases and increase levels of second messengers such as cyclic adenosine monophosphate (AMP) within minutes. Membrane-bound forms of ER-alpha and ER-beta cause these nontranscriptional effects (43). Thus, estrogens acting via two receptors and through both genomic and nongenomic pathways are able to effect an incredibly complex nexus of cellular regulation.
II. E S T R O G E N METABOLISM Irreversible metabolism of estrogen proceeds primarily in the liver by oxidation of estrone via two different pathways (21). Hydroxylation at the 16 position on the D ring results in the formation of estriol, a biologically weak estrogen, and its isomers, epiestriols. Obesity, hypothyroidism, and cirrhosis favor the metabolism of estrone to estriol. Hydroxylation at the 2 or 4 positions on the A ring results in the formation of catechol estrogens (see Fig. 53.1). Catechol estrogens are also produced in the hypothalamus, where they may have important central nervous systems effects. Catechol estrogens competitively inhibit the enzymes tyrosine hydroxylase and catechol-o-methyl transferase. Catechol estrogens can modulate synthesis and degradation of catecholamines, dopamine, and norepinephrine, neurotransmitters important in the control ofgonadotropinreleasing hormone (GnRH) release (46). Catechol estrogen formation by A ring metabolism is favored in states of weight loss, such as anorexia nervosa and hyperthyroidism. Estrogen metabolism proceeds in the liver and kidney by conjugation of estriol, epiestriols, and catechol estrogens to glucuronides and sulfates, which are highly water soluble and are rapidly excreted by the kidney. The principle urinary estrogens are the conjugates of estriol and 2-hydroxyestrone (47). In addition to urinary excretion, there is a significant enterohepatic circulation of estrogen metabolites. After labeled estrone or estradiol is injected, approximately one-half is present in the urine excreted during the first 24 hours while the remainder is found in bile (48). The conjugated
biliary estrogens undergo hydrolysis in the gut, and approximately 80% are reabsorbed. They are returned to the liver, where they may escape reconjugation and enter the systemic circulation, or they may be reconjugated and excreted in the urine or bile. Only about 10% of an injected estrogen will ultimately be lost in the feces. The enterohepatic circulation of estrogen metabolites may be an important factor in the prolonged effect of orally administered estrogens. All estrogens, conjugated and unconjugated, circulate in the blood either protein bound or unbound (physiologically free). Estrogens are specifically bound with high affinity to sex hormone-binding globulin (SHBG) or loosely (nonspecifically) bound to serum albumin. Serum binding affects the availability of estrogen to diffuse across cell membranes and express biologic activity. Thirty-eight percent of estradiol is bound to SHBG, 60% is loosely bound to albumin, and approximately 2% to 3% is free to diffuse across cell membranes (49). Estrone, estriol, and estrone sulfate all bind poorly to SHBG but have a greater affinity for albumin than does estradiol. Estrone sulfate has the highest affinity for albumin, with more than 90% of circulating estrone sulfate bound to albumin (50). Alterations in SHBG levels change the concentration of unbound estradiol altering bioavailability. Estrogen therapy, pregnancy, and hyperthyroidism increase SHBG, and hypothyroidism, androgen excess, hyperinsulinemia, and obesity lower SHBG levels (14,51,52). Obese women who are ->50 lb (23 kg) above ideal body weight have serum SHBG binding capacity reduced by 20% to 30% compared with normal-weight postmenopausal women, which results in a twofold to threefold increase in the free and albumin-bound fractions of estradiol (13). In summary, the liver plays the central role in the metabolism and excretion of estrogens and is, just as importantly, influenced by estrogen status. The liver is affected by estrogens absorbed from the gastrointestinal tract (first-pass effect) and by reabsorption of estrogens secreted in the bile (enterohepatic circulation). The liver is a principal site of metabolic interconversion of estrogens as well as conjugation of estrogens in preparation for excretion into bile and by the kidney. Bioavailability of estrogens is affected by SHBG and albumin, products of the liver. Estrogens in turn influence liver carbohydrate metabolism, lipid metabolism, bile production, and protein production (binding proteins, clotting factors, and renin substrate).
III. PHARMACOLOGY OF E S T R O G E N PREPARATIONS Estrogens for hormone therapy may be separated by chemical composition (natural or synthetic) or by route of administration (oral or parenteral) (Tables 53.1 and 53.2). Natural estrogens include estradiol, estrone, estriol, and
770
BARNES AND LEVRANT
TABLE 53.1
Estrogen Replacement Therapies Available in the United States
Generic name Oral Conjugated equine estrogens Synthetic conjugated estrogens Estropipate (Piperazine estrone sulfate) Micronized estradiol Estradiol acetate Raloxifene (selective estrogen receptor modulator) Oral combined Conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) Esterified estrogens and methyltestosterone Estradiol and norethindrone acetate Estradiol and norgestimate
Brand name
Daily dose
Premarin Cenestin
0.3, 0.45, 0.625, 0.9, 1.25 mg 0.3, 0.45, 0.625, 0.9, 1.25 mg
Estrace Femtrace Evista
0.75, 1.5, 3 mg 0.5, 1, 2 mg 0.45, 0.9, 1.8 mg 60 mg
Prempro Estratest, Estratest HS Activella Prefest
0.3/1.5, 0.45/1.5, 0.625/2.5, 0.625/5 mg (CEE/MPA) 1.25/2.5, 0.625 mg/1.25 mg esterified estrogen/methyltestosterone 1/0.5 mg estradiol/norethindrone acetate 1 mg estradiol for 3 days alternating with 1 mg estradiol/0.09 mg norgestimate for 3 days
Transdermal
Estradiol patch
Estradiol gel
Alora (twice weekly) Climara (weekly) Menostar (weekly) Vivelle (twice weekly) Vivelle-Dot (twice weekly) Estrogel (daily)
0.014 (Menostar), 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 mg
Climara Pro (weekly) CombiPatch (twice weekly)
0.045/0.015 mg estradiol/levonorgestrel 0.05/0.14, 0.05/0.25 mg estradiol/norethindrone acetate
Premarin vaginal cream Estrace vaginal cream
0.625 mg/gram 1.0 mg/gram
Estring (3 months) Femring (3 months)
0.0075 mg 0.05, 0.10 mg
Vagifem
0.025 mg
Transdermal combined
Estradiol and levonorgestrel Estradiol and norethindrone acetate Vaginal cream CEEs Micronized estradiol Vaginal ring Estradiol Estradiol acetate Vaginal tablet Estradiol
their conjugates as well as conjugated equine estrogens (CEEs). Synthetic estrogens include ethinyl estradiol, mestranol, quinestrol, diethylstilbestrol, and raloxifene. Parenteral routes of administration include injection, transvaginal (creams, tablets, and silastic rings), transdermal patches, subcutaneous pellets, intranasal, and percutaneous gel administration. No matter the type of estrogen or the route of administration, large intraindividual and interindividual variations of serum concentrations occur (53,54).
A. Synthetic Estrogens Synthetic estrogens that have been used for menopause estrogen replacement include ethinylestradiol; its C-3 methylated derivative, mestranol; its cyclophenyl ether, quinestrol;
1.25-gram gel containing 0.75 mg estradiol
and the stilbene derivative diethylstilbestrol. Ethinyl estradiol, the estrogen used in most oral contraceptives, is rapidly absorbed in the gastrointestinal tract after oral administration. Comparing oral and intravenous doses of ethinyl estradiol, the bioavailability of oral ethinyl estradiol is 59.0 _+ 13% (55). An oral dose of 50 mg of ethinyl estradiol results in a blood level of 400 pg/mL. The ethinyl group at position 17e~ on ethinyl estradiol prevents oxidation by 17[3-HSD. With D-ring metabolism impeded, the principal inactivation pathway is ring A 2-hydroxylation to catecholestrogens. Liver cytochrome P-450 enzymes, the chief site of oxidative transformation of ethinyl estradiol, can become irreversibly inactivated by the intermediate compounds of ethinyl estradiol metabolism (56). The strong potency and pronounced effects on hepatic metabolism of ethinyl estradiol compared with natural estrogens are a consequence of the relatively slow
CHAPTER 53 Pharmacology of Estrogens
771
TABLE 53.2 Approximate Serum Estradiol and Estrone Levels after Administration of Various Estrogen Preparations Preparation Oral Conjugated equine estrogens Estropipate
Micronized estradiol Vaginal Conjugated equine estrogen Micronized estradiol Transdermal Estradiol patch Estradiol gel
Daily dose (mg)
Estradiol (pg/mL)
Estrone (pg/mL)
0.625 1.25 0.625 1.25 2.5 1 2
30-50 40-60 35 30-50 125 30-50 50-180
150 120-200 125 150-300 360 150-300 300-850
1.25 0.5
25 - 40 250
65 - 80 130
0.05 0.1 1.5 3.0
30-65 50-90 40-100 60-140
40-45 30-65 90 45-155
ethinyl estradiol that has an extremely long half-life. The pharmacokinetics of mestranol and quinestrol correspond to those of ethinyl estradiol. Raloxifene, a nonsteroidal benzothiophene derivative initially developed as a therapy for breast cancer, is approved in the United States for the prevention of osteoporosis in postmenopausal women. Raloxifene is a selective estrogen receptor modulator (SERM) that acts as an estrogen agonist in bone and the liver but as an estrogen antagonist in the uterus and breast (60,61). It binds to recombinant human ER with an affinity similar to estradiol. Raloxifene treatment maintained bone mineral content in postmenopausal women over a period of 2 years (62) and decreased total and low-density lipoprotein (LDL) cholesterol. Although raloxifene had no overall effect on high-density-lipoprotein (HDL) cholesterol, it increased HDL-2 cholesterol but not to the same extent as with CEEs (63). After oral administration, raloxifene undergoes extensive first-pass metabolism to its glucuronide conjugates, which are its primary circulating forms in plasma. It is excreted mainly in the feces, with less than 6% of the dose eliminated in urine as glucuronide conjugates (Evista Package Insert).
B. Conjugated Equine Estrogens transformation into inactive metabolites in the hepatocytes and resultant high local concentrations during the first liver passage. Ethinyl estradiol is approximately 75 to 1000 times more potent on a per weight basis than CEEs, piperazine estrone sulfate, or micronized estradiol in terms of increasing the production of hepatic proteins (SHBG, renin substrate, corticosteroid binding globulin, and thyroid binding globulin) (57). Potencies of estrogens including ethinyl estradiol vary according to the site of action; for example 10 mg is required for the normalization of the urinary calcium/ creatinine ratio, while 5 mg produces elevations in hepatic protein production (58). As with natural estrogens, the major circulatory form of ethinyl estradiol is its 3-sulfate (56). Ethinyl estradiol is excreted in the urine and feces as glucuronides and sulfates and undergoes enterohepatic circulation. Ethinyl estradiol is almost exclusively bound to albumin. Vaginal administration of 50 mg ethinyl estradiol results in circulating ethinyl estradiol levels equivalent to those achieved after oral ingestion of 10 mg ethinyl estradiol. Equivalent serum levels of ethinyl estradiol achieved after oral or vaginal administration result in similar effects on hepatic proteins (59). This suggests that the hepatic effects of ethinyl estradiol are more related to the chemical property of ethinyl estradiol than merely first liver pass after oral ingestion. Mestranol is a pro-drug that must be converted to ethinyl estradiol before becoming active. Q.uinestrol is an ester of
One of the most commonly prescribed estrogen preparations for postmenopausal hormone replacement are CEEs. This preparation is extracted from the urine of pregnant mares and contains classical estrogens (estrone, estradiol, and estrone sulfate) and ring B unsaturated estrogens that are not native to humans. CEE contains approximately 45% estrone sulfate, 25% equilin sulfate, 15% 17~t-dihydroequilenin sulfate, and lesser amounts of the sulfate esters of equilenin, 1713-dihydroequilin, 17~idihydroequilenin, 1713-dihydroequilenin, estradiol, 17ciestradiol, and delta-8-estrone (64,65). The pharmacokinetics of CEE is complex due to the various estrogenic components that constitute the preparation. The conversion of equilin and equilenin to 1713-dihydroequilin and 1713-dihydroequilenin by reduction of the 17-ketosteroid correspond to the conversion between estrone and estradiol. As with estrone, the major ring B unsaturated estrogens circulate in the blood as sulfate esters. Ingestion of 10 mg of CEE, containing 4.5 mg estrone sulfate and 2.5 mg equilin sulfate, results in peak levels of 560 pg/mL equilin and 1400 pg/mL estrone within 3 and 5 hours, respectively. After 24 hours, hormone levels decrease to 125 pg/mL equilin and 280 pg/mL estrone (66). Intravenous administration results in peak levels of equilin and estrone by 20 minutes because equilin sulfate and estrone sulfate are rapidly hydrolyzed to the unconjugated steroids (67). Oral ingestion of 1.25 mg of CEE results in peak levels of 120 to 180 pg/mL estrone and 40 pg/mL
772 estradiol within 6 to 10 hours. Plasma estrone and estradiol values return to baseline within 48 hours (68). A significant portion of equilin sulfate and estrone sulfate are hydrolyzed to the unconjugated steroids prior to absorption from the gut (67). After absorption the unconjugated estrogens undergo reconjugation in the liver to their sulfate, the main circulatory form of these hormones. The sulfated estrogens are also excreted in the bile and undergo enterohepatic recirculation (67,69). Equilin sulfate binds to albumin (74% of total) in a similar fashion to estrone sulfate (up to 88% of total) and does not bind to SHBG. Equilin sulfate is metabolized to its 1713metabolites. 1713-dihydroequilin, like 17[3-estradiol, is more potent than its parent compound equilin and has a binding affinity to SHBG similar to that of 1713-estradiol (67). Equilin sulfate has an M C R of 176 +_ 44 L/day/m 2 (range 93-342) and a half-life of 3.2 hours compared with an M C R of 94.1 +_ 22 L/day/m 2 (range 39-141) and a half-life of 5.3 to 9 hours for estrone sulfate (67). 1713-dihydroequilin and 1713-dihydroequilin sulfate have MCRs of 1252 + 103 L/day/m 2 and 376 + 93 L/day/m 2, respectively, and half-lives (slow component) of 45 _+ 9 minutes and 135 + 17 minutes, respectively (70). The binding affinities for human ER for various components of CEE follows the following order: 17[3-dihydroequilin > 1713-estradiol > 17~3-dihydroequilenin > estrone = equilin > 17ta-dihydroequilin > 17~-estradiol > 17pdihydroequilenin > equilenin (64,67). The pharmacokinetics of equilin sulfate is similar to that of estrone sulfate, with equilin and 17J3-dihydroequilin being analogous to estrone and 1713-estradiol. About 25% of equilin sulfate is converted to equilin which is similar to the estrone to estrone sulfate conversion rate of 15% to 20%. However, 15% of equilin sulfate is converted to 1713-dihydroequilin which is much higher than the 1% to 3% conversion rate of estrone to 1713-estradiol (64). Metabolites of equilin sulfate are excreted in the urine mainly conjugated to glucuronic acid (69). The biologic effects of CEE are therefore a combination of primarily estrone sulfate and equilin sulfate and their respective metabolites. CEE vaginal cream results in serum levels approximately one-half to one-fourth of those obtained with comparable oral dosages (Fig. 53.2) (71-73). Each gram of vaginal cream contains 0.625 mg of CEE. Intravaginal application of 1.25 mg CEE results in peak estradiol level of 33 + 6.6 pg/mL in 6 hours and peak estrone level of 73 + 9.2 pg/mL in 8 hours (73). Twenty-four hours after vaginal CEE, estradiol levels did not differ significantly from baseline and estrone levels were 50 + 8.7 pg/mL, twice the baseline level (73). Vaginal CEE (0.3 mg) is equivalent to the effect of 1.25 mg oral CEE on vaginal cytology. However, vaginal CEE (0.3 mg) results in minimal increases in estrone and estradiol levels that are lower than those found in the early follicular phase (72). Vaginal CEE (2.5 mg) is comparable to
BARNES AND LEVRANT
150 140
130
(lo)
120 110
(4)
A
E
v
_1
tu
100
i
p65 years) is altered compared with adult women and younger postmenopausal women. Elderly women have increased oral bioavailability of drugs due to decreased hepatic cytochrome P450 content; this results in decreased hepatic first-pass metabolism. They also have a more extensive volume of distribution of lipidsoluble drugs and a less extensive volume of distribution of water-soluble drugs. Perhaps the most important cause for altered pharmacokinetics of drugs in the elderly is the decline in renal clearance of a drug.
A. Progesterone Crystalline progesterone is poorly absorbed. However, when it is broken down to minute particles by the process of micronization, its absorption is improved substantially. The micronization process gives rise to a greater surface area of the compound, allowing it to be dissolved in the aqueous medium of the intestine. Increased surface area of a water-insoluble compound such as progesterone can also be achieved by dispersing the compound in watersoluble carriers such as sterols. For example, oral administration of a mixture of progesterone with cholesterol
CHAPTER
785
54 Structure-Function Relationships, Pharmacoldnetics, and Potency of Progestogens TABLE 54.2
Average Bioavailabilities and Half-Lives of Progestogens
Progestogen
Dose ( m g )
Progesterone Medroxyprogesterone acetate Megestrol acetate Cyproterone acetate Chlormadinone acetate Medrogestone Dydrogesterone Trimegestone Norethindrone Levonorgestrel Desogestrel Gestodene Dienogest Drospirenone Nomegestrol acetate
100, 200, 300 10 160 2 2 5 10 0.5 1 0.15-0.25 0.15 0.075 4 3 5
Bioavailability (%)
Half-Life (Hrs)
--* m
16.2-18.3 24 22.3 54.0-78.6 80.1 34.9 14-17 15 8 9.9, 13.2 11.9,23.8 12-14 10.8, 11.6 31.1-32.5 40
~ 100 m ~-100 64 89, 99 62, 76 87, 99 96.2 66 63
*Dashed line indicates that no data were available. pivolate on a lactose carrier increases plasma progesterone levels. Although the processes just described allow progesterone to be readily absorbed, its bioavailability is also limited by the extensive hepatic first-pass metabolism that it undergoes (9). This is due to the presence of a double bond and two ketone groups on the progesterone molecule, making it highly vulnerable to enzymatic reduction by reductases and hydroxysteroid dehydrogenases. These transformations occur in the small intestine by enzymes in bacterial flora and intestinal mucosa, and to a greater extent by hepatic enzymes. The bioavailability of orally administered micronized progesterone is generally considered to be testosterone > androstenediol > estradiol > estrone (18). SHBG also weakly binds DHEA, but not DHEA-S (18). Therefore, variations in the plasma levels of SHBG have a significant impact on the amount of free or bioavailable testosterone. Elevations in
estradiol and thyroxine increase SHBG, whereas increases in testosterone, glucocorticosteroids, growth hormone, and insulin suppress SHBG production. In women, androgens may act directly via the androgen receptor or indirectly after conversion to estrogen. Androgens are the precursor hormones for estrogen production, not only in the ovaries but also in extragonadal tissues, including bone, adipose, and brain (19). Therefore, maintenance of physiologic circulating androgen levels in women ensures an adequate supply of substrate for estrogen biosynthesis in extragonadal sites, such as bone, in which high tissue estrogen concentrations may be required physiologically (for example, maintenance of bone mineralization and prevention of bone loss). That the primary source of estrogen in extragonadal sites is that produced locally from androgens also explains the apparent threshold dose of estrogen replacement postmenopausally below which bone loss continues, and the observation that whereas standard estrogen replacement therapy has little effect on libido (20,21), most parameters of sexuality improve when extremely high doses of estrogen are administered (22). Furthermore, this hypothesis may also explain the gender discrepancy between the development of osteoporosis and dementia, which occur much later in life in men than in women because men maintain adequate circulating testosterone levels for the extragonadal production of estrogen in bone and brain well into their later years.
III. PHYSIOLOGIC AND NONPHYSIOLOGIC CAUSES OF T E S T O S T E R O N E DEFICIENCY IN W O M E N The mean circulating levels of total and free testosterone decline continuously with increasing age from the early reproductive years, such that the levels of women in their forties are approximately half of those of women in their twenties (1,23). Androstenedione and DHEA-S levels also fall linearly with age (1), and this may contribute to the decline in the level of their main metabolite, testosterone. In the late reproductive years there is failure of the midcycle rise in free testosterone that characterizes the menstrual cycle in young ovulating women (11). This occurs despite preservation of normal free testosterone levels at other phases of the cycle. The mean plasma concentrations of testosterone in women transiting the menopause are also significantly lower than younger ovulating women sampled in the early follicular phase. Acutely, across the perimenopausal period, neither A, DHT, nor the ratio of total testosterone to SHBG (the free androgen index, or FAI) appear to change (1,24). Following menopause, direct ovarian secretion appears to account for up to 50% of testosterone production, with the
CHAPTER 55 Intervention: Androgens
adrenal gland being a less important source (25). Ovarian stromal hypertrophy and hyperplasia may persist or develop after menopause, probably secondary to elevated LH levels and individual sensitivity, resulting in increased testosterone production (20). Alternatively, the ovaries may become fibrotic and a poor source of sex steroids, and in such women the adrenal gland becomes the main androgen source following menopause (20). A sudden decline in androgens is a feature of ovariectomy, with both testosterone and A decreasing acutely by about 50% (25). Other iatrogenic causes of testosterone deficiency include chemical ovariectomy; for example, the use of gonadotropin-releasing hormone (GnRH) agonists and antagonists for the treatment of fibroids or endometriosis, postchemotherapy or radiotherapy, and the administration of exogenous estrogens or glucocorticosteroids. In general, circulating free testosterone is suppressed in women using either the combined oral contraceptive pill or oral estrogen replacement therapy (26,27). This is a result of an increase in SHGB combined with suppression of LH production by the pituitary and, hence, decreased stimulus for the ovarian stromal production of testosterone. These effects may be amplified in older women whose overall androgen production is declining. Treatment with oral glucocorticosteroids results in ACTH suppression and, hence, reduced adrenal androgen production (28). In the premenopausal years, other pathophysiologic states such as hypothalamic amenorrhea and hyperprolactinemia are characterized by low circulating testosterone levels and bone loss. Similarly, women with premature ovarian failure experience significant loss of bone that not uncommonly persists despite adequate standard dose estrogen-progestin therapy (29), and it is likely that young women with either ongoing hypothalamic amenorrhea or premature ovarian failure require testosterone replacement to prevent progressive bone resorption.
IV. CLINICAL CONSEQUENCES OF A N D R O G E N INSUFFICIENCY A N D EVIDENCE FOR BENEFITS OF TESTOSTERONE REPLACEMENT IN W O M E N
A. Sexual Dysfunction Multiple interacting factors influence libido and the frequency and enjoyment of sexual activity in women. These include general health stares, the physical and social environment, education, past experiences, current expectations, and the cultural milieu. Prevailing myths are that sexuality in women declines with increasing age and that older women mostly continue to be sexually active in order to
801 please their partner. However, one study of women in nursing homes reported that 25% percent of women over the age of 70 masturbate (30). Most women who have a natural menopause do not report loss of sexual desire, erotic pleasure, or orgasm. However, there is an age-related reduction in sexual frequency among women and lessening of coital frequency associated with the menopausal transition independent of age (31). Androgens appear to be important in female sexuality, with reduced androgen levels in the late reproductive years and beyond contributing to the decline in sexual interest experienced by a proportion of women. Compared with premenopausal women, women in their postmenopausal years report fewer sexual thoughts or fantasies, have less vaginal lubrication during coitus, and are less satisfied with their partners as lovers (31). A low testosterone level is most closely correlated with reduced coital frequency (32). In the Melbourne Women's Midlife Health Study, 62% of women aged 45 to 55 years reported no change in sexuality in the preceding year, although 31% reported a decrease (33). In the latter group, the decline was significantly and adversely associated with menopause rather than with age. In a study of sexagenarian women, the only hormone positively correlated with sexual desire was circulating free testosterone (34). Estradiol and testosterone are both present in the human female brain. The highest concentrations of estradiol have been reported in the hypothalamus and the preoptic area, and the highest concentrations of testosterone have been reported in the substantia nigra, hypothalamus, and preoptic area (35). The concentration of testosterone is several times higher than estradiol in each of these regions, with the highest ratio of testosterone to estradiol demonstrated in the hypothalamus and preoptic area. This distribution corresponds with high aromatase activity found in these regions in animals (36). Thus, androgen effects within the central nervous system may be mediated directly via androgen receptors and as a consequence of local aromatization of androgen precursors to estrogen. Support for specific direct androgen actions within the brain comes from cross-sex H T studies in transsexuals (37). In one such study, the administration of androgens to female-to-male transsexuals led to increases in sexual motivation and arousability, whereas the combination of antiandrogens and high-dose estrogen given to male-to-female transsexuals had the opposite effect (37). Androgen treatment of female-to-male transsexuals also resulted in improved visuospatial ability, lessened verbal fluency, and increased anger readiness, while the reverse, including an increased tendency to indirect angry behavior, was seen in the male-to-female subjects. We have recently reported in a randomized controlled trial that aromatase inhibition does not interfere with the favorable effects of exogenous testosterone on libido and well-being in postmenopausal women (38).
802 Research addressing the effect of women anticipating an adverse influence of menopause on their sexuality has shown a weak correlation between anticipated changes in sexuality and what actually occurs. The greatest predictor of postmenopausal sexual satisfaction is the quality of the sexual aspects of a woman's life in her premenopausal years, although having a satisfying sexual relationship prior to menopause does not preclude a woman from experiencing androgen-responsive sexual dysfunction subsequently. Undoubtedly, the availability of a sexual partner and the effects of age on the health and sexual interest of that person contribute to the apparent decline in sexuality among some women with increasing age. Estrogen replacement improves vasomotor symptoms, vaginal dryness, and possibly general well-being, but it has little effect on libido (39,40). Oral estrogen replacement therapy improves sexual satisfaction in women with atrophic vaginitis as a cause of their dyspareunia, but women lacking this symptom benefit little or not at all (41). In some cases, the commencement of estrogen replacement may suppress free testosterone levels and cause relative testosterone deficiency in the postmenopausal years, as described earlier, and hence precipitate a decline in sexual desire. Several randomized controlled trials have demonstrated improvements in several aspects of sexuality in postmenopausal women treated with exogenous testosterone, over and above the effects achieved with estrogen alone (4-6,22). Sustained improvements in intensity of sexual drive, arousal, frequency of sexual fantasies, satisfaction, pleasure, and relevancy were observed in these studies of postmenopausal women. In contrast to the consistently observed increases in sexual motivation, improvements in coital frequency and orgasm vary considerably among studies. The failure for testosterone supplementation to improve coital frequency may be attributed to the participants in these studies being women with very long-term relationships, with established sexual patterns, such that change is less likely. Frequency of sexual activity as a measure of efficacy of androgen therapy in women can also be misleading, as often this is more a measure of a male partner's sexual appetite rather than the woman's. The only study in which the addition of testosterone replacement did not show any benefit over estrogen alone was in women being treated for generalized menopausal symptoms rather than for low libido (42). Testosterone therapy should also be considered as part of the management of young women with premature menopause, particularly Turner syndrome. Women who are sexually active when they develop premature ovarian failure are often very disturbed by their diminished libido. Alternatively, young women who have not become sexually active and have either primary or secondary premature ovarian failure should be fully informed about the option of androgen replacement or perhaps in some instances
SUSAN R. DAvis
offered low-dose androgen replacement as a component of their hormone replacement regimen. Whether premenopausal women who complain of loss of libido and have low bioavailable testosterone levels should be offered testosterone therapy is controversial. We have shown in a randomized, placebo-controlled crossover study that testosterone therapy improves libido, mood, and wellbeing in women age 35 to 45 years who present with low libido (43). Furthermore, such women appear to be at greater risk of premenopausal bone loss (44). At present this is a subgroup of women for whom clear recommendations cannot be made but for whom research is ongoing. Testosterone replacement is unlikely to benefit women in whom other factors play a dominant role in their sexual dysfunction. Clinically discerning this may be quite straightforward (e.g., postovariectomy) but may be extremely difficult in some women, and therefore an insightful psychosocial and sexual history is essential when evaluating the appropriateness of testosterone therapy in a woman.
B. Androgens and Bone Androgenic steroids have an important physiologic role in the development and maintenance of bone mineralization in women and men, although the mechanisms of androgen action on bone are still a matter of debate. The skeletal effects of androgens appear to be mediated in part via the estrogen receptor after local aromatization of androgens to estrogen, and mutations in either the estrogen receptor gene or the aromatase gene are associated with osteoporosis (45,46). Abundant aromatase activity has been reported in fetal osteoblasts and cell lines of osteoblastic origin (47). There is also evidence that androgens act directly on bone. Androgen receptors have been demonstrated in human osteoblast-like cell lines, and androgens have been shown to directly stimulate bone cell proliferation and differentiation (48,49). D H T has been shown to increase alkaline phosphatase activity, type 1 procollagen synthesis, and insulin-like growth factor II messenger RNA in the SAOS2 cell line (50). Androgen receptor mRNA is expressed in human osteoblasts, osteocytes, hypertrophic chondrocytes, marrow mononuclear cells, and vascular endothelial cells within bone, but not in osteoclasts (51). The pattern and number of cells expressing the androgen receptor are similar in female and male tissues (51). In addition, androgen receptors are upregulated in osteoblastic cells by both testosterone and D H T in vitro (52). Total and bioavailable testosterone and DHEA-S, not estradiol, are the greatest predictors of bone mineral density (BMD) and bone loss in premenopausal women (44,53). Women who experience bone loss confined to the hip prior to menopause, a not uncommon occurrence, have lower total and free testosterone concentrations, by
CHAPTER 55 Intervention: Androgens 14% and 22%, respectively, than those who do not significantly lose bone (44). Consistent with these findings, hyperandrogenic women have higher BMD, after correction for body mass index, than their normal female counterparts (53). In the premenopausal years, BMD is also strongly positively correlated with body weight (54). In obesity, SHBG is suppressed with a resultant increase in free testosterone (55), and this may partially explain the relationships between obesity, free testosterone, and increased BMD, with the greater endogenous levels of biologically active free testosterone in more corpulent women directly enhancing bone mass. Androgen insufficiency may also be a factor underlying bone loss in young women with premature ovarian failure. Despite adequate standard dose estrogen-progestin therapy, two-thirds of such women have significantly reduced BMD to levels associated with an increased risk of hip fracture. Of these, 47% have reductions in BMD within 18 months of their diagnosis (29). In postmenopausal women, low circulating free testosterone is predictive of subsequent height loss (a surrogate measure of vertebral compression fractures) and hip fracture (56,57). Circulating D H E A and DHEA-S are positively correlated with BMD in aging women (58-60), and the progressive decline in D H E A with increasing age is believed to contribute to senile osteoporosis. It is unlikely that these adrenal pre-androgens directly influence bone metabolism; rather, their effects are mediated indirectly following conversion to estradiol, A, or testosterone. Suppression of adrenal production of D H E A and DHEA-S with chronic glucocorticosteroid therapy may also contribute to the pathogenesis of osteoporosis and osteopenia, which are known complications of this therapy in women and men. D H E A or testosterone administration may be effective in preventing and/or treating this common and serious side effect of glucocorticosteroid therapy. Women treated with oral D H E A have restoration of circulating A, DHT, and testosterone to premenopausal levels, as well as increases in D H E A and DHEA-S, with no changes in circulating levels of estrone or estradiol from baseline (61). Similarly, the daily percutaneous administration of 10 mL of a 20% D H E A solution results in an increase in circulating total testosterone of approximately 50%, with no consistent effect on estradiol or estrone (62). Circulating DHEA-S, but not estradiol, in postmenopausal women is positively correlated with BMD, and daily application of a 10% D H E A cream has been reported to increase hip BMD in older women (62). Thus, D H E A therapy may prove in time to be an alternative to administration of testosterone replacement to androgen-deficient women. Studies of both oral and parenteral estrogen and estrogen + testosterone therapy in postmenopausal women have shown beneficial effects of testosterone replacement on BMD (22,63,64). Oral esterified estrogen-methyltestosterone
803 treatment has been shown to increase spinal BMD over a 2-year period, in contrast to estrogen-only therapy, which prevented bone loss (63). The estrogen-methyltestosterone combination not only suppresses biochemical markers of bone reabsorption (as seen with estrogen alone) but is also associated with increases in markers of bone formation (65). Treatment of postmenopausal women with nandrolone decanoate has been shown to increase vertebral BMD and has been used successfully for many years to treat osteoporosis (66). Combined estradiol and testosterone replacement with subcutaneous implant pellets increases bone mass in postmenopausal women (64,67), with the effects in the hip and spine being greater than with estradiol implants alone (22) (Figs. 55.1 and 55.2). Thus, it appears that estradiol alone has an antireabsorptive effect on bone in postmenopausal women, whereas the addition of testosterone, either orally or parentally, enhances bone formation. This idea is further supported by the previously mentioned studies of men, either with a mutation of the gene encoding the aromatase enzyme (45,46,68,69) or a mutation of the estrogen receptor (45). Increasing BMD is only clinically important if it is associated with enhanced mechanical strength and a reduced fracture rate. As yet, no studies have addressed the impact of androgens on fracture incidence. However, the effects of androgens on the mechanical properties of bone have been studied in female cynomolgus monkeys (70). In this primate model, increases in intrinsic bone strength and resistance to mechanical stress were associated with increased BMD following testosterone therapy. Treatment also resulted in increased bone torsional rigidity and bending stiffness. In summary, current data indicate that androgen therapy, in the form of testosterone, and possibly DHEA, is potentially an effective alternative for the prevention of bone loss and the treatment of osteopenia and osteoporosis, and warrants further investigation. As prospective data confirming a reduction in fracture rate with androgen therapy are lacking, specific guidelines cannot be given for this sole indication. The addition of androgen to standard hormone replacement regimens may be necessary to prevent bone loss in young hypogonadal women in whom androgen insufficiency is aggravated by exogenous estrogen. The use of testosterone to prevent bone loss in individuals on long-term glucocorticosteroids has not been studied but also warrants further research.
C. Testosterone and Autoimmune Disease Although immunogenetic factors are the major determinants of the development of immune-mediated diseases, gender and age also play a role. Androgens appear to suppress both cell-mediated and humeral immune responses, and it has been proposed that higher testosterone levels in men may be protective against autoimmune disease (71-75).
804
SUSANR. DAVIS DHEA, DHEA-S, and testosterone. Further evaluation of potential beneficial effects of testosterone administration in women with rheumatoid arthritis and systemic lupus erythematosus is needed.
D. Effects on Body Composition
FIGURE 55.1 and 55.2 The effects of hormonal implants on bone mineral density (BMD) (g/cm2): lumbar spine (L1-L4), femoral trochanter (Troc), estradiol (E), and estradiol plus testosterone (E+Te). Error bars represent standard error of the differences between means (SED). Inner error bars are used to compare means between times for the same treatment. The comparison between the treatment groups is made with the outer error bars. If error bars do not overlap (i.e., differ by more than 2 SEDs), the means are significantly different by a p value of at least 0.05.
The direct administration of testosterone replacement has resulted in symptomatic improvement in postmenopausal women with rheumatoid arthritis (74), and both premenopausal and postmenopausal women have been observed to have reductions in disease activity with D H E A therapy associated with increases in levels of circulating
In postmenopausal women, neither measured nor estimated free testosterone is associated with waist-to-hip ratio measurements, and there does not appear to be a direct relationship between androgens and visceral adiposity in this population (76). Contrary to popular belief, neither oral nor parenteral hormone therapy significantly increases body weight (77,78). There is also no evidence that the addition of testosterone replacement causes weight gain (4,5,22). With increasing age, women tend to lose muscle mass and replace it with increased fat mass, coupled with an overall tendency for weight gain in most Western societies. Increases in fat-free mass and a reduced-fat mass/fat-free mass ratio have been reported in postmenopausal women treated with concurrent estrogen-testosterone therapy (79,80). Gain in fat-free mass probably reflects increased muscle mass. As aging is associated with loss of muscle mass, this is a beneficial effect of testosterone therapy in the older woman and may contribute to preservation of muscle strength and skeletal stability. However, the ethics of treating an older woman who participates in competitive (Master's) sports with testosterone replacement for medical indications has become a significant issue that needs to be resolved. Testosterone levels are frequently lower in HIV-positive premenopausal women. The effects of physiologic testosterone replacement using a transdermal patch on fat-free mass, muscle strength, and weight maintenance have been studied in HIV-infected women with relative androgen deficiency and weight loss. Administration of the 300-~tg patch was found to be safe and effective in raising testosterone levels into the mid- to high-normal range, but it did not significantly increase fat-free mass, body weight, or muscle performance in HIV-infected women with low testosterone levels and mild weight loss (81).
V. POTENTIAL RISKS OF TESTOSTERONE REPLACEMENT IN W O M E N
A. Cardiovascular Disease Risk The differences in cardiovascular disease (CVD) morbidity and mortality between men and women and the increase in incidence in CVD in women in later life have been partially attributed to gender differences in absolute and
CHAPTER 55 Intervention: Androgens relative amounts of estrogens and androgens and the shift to a less favorable hormonal milieu in women following menopause. However, whether androgen levels in women contribute to the increased CVD risk in older women remains contentious (82-85). The particular concerns are the potential adverse metabolic effects of androgens with respect to lipid and lipoprotein metabolism and vascular function. Low SHBG levels have been reported as related to elevated CVD risk, as has a higher free androgen index (FAI: total testosterone/SHBG ratio) (84,85). However, the significance of the latter findings in terms of a direct adverse androgen effect is limited by the possibility that FAI is a proxy risk factor for CVD risk, where the real risk factor is SHBG (85a). Recent studies have demonstrated that inflammatory mechanisms underlie the process of arterial thrombus formation following atheromatous plaque rupture (86). Populationbased studies have shown that circulating inflammatory markers are strongly associated with cardiovascular events, even in individuals with normal lipoprotein profiles (87-89). Of the inflammatory markers, C-reactive protein (CRP) provides the strongest risk prediction for CVD in women (90,91). Elevated levels of CRP are also associated with obesity and weight gain (92) and predict the risk of developing type 2 diabetes mellitus (93). However, determination of CRP contributes more prognostic information to CVI) risk in women than serum lipids or features of the metabolic syndrome alone (89,94). 1. TESTOSTERONE TREATMENT AND CARDIOVASCULARRISK MARKERS
Menopause, both natural and surgically induced, is associated with the development of a more adverse lipoprotein profile that is unrelated to endogenous testosterone levels (95). Postmenopausal estrogen therapy lowers total and low-density lipoprotein (LDL) cholesterol (77,78), and these favorable effects are not diminished with either oral or parenteral testosterone therapy (5,22,38). Parenteral testosterone replacement does not affect high-density lipoprotein (HDL) cholesterol (22,38); however, H D L cholesterol and apolipoprotein A1 decrease significantly when oral methyl testosterone is administered with oral estrogen (96-98).Whereas oral estrogen replacement is associated with increased triglyceride levels, concomitant administration of oral methyltestosterone has resulted in a reduction in triglycerides (98). Measurement of circulating lipids is a clinical surrogate for lipoprotein-lipid metabolism. A more direct measurement of lipid metabolism is probably a better indicator of the effects of exogenous steroid therapy on cardiovascular risk. Combined oral esterified estrogen and methyltestosterone therapy reduces arterial LDL degradation and cholesterol ester content in cynomolgus monkeys, which does not
805 differ from the effects observed when estrogen is given alone (99). Combined estrogen and methyltestosterone therapy is also associated with reduced plasma concentrations of apolipoprotein B, reduced LDL particle size, and increased total body LDL catabolism (99). Small LDL particles are more susceptible to oxidation and are hence considered to be more atherogenic. However, because estrogens appear to increase oxidative modification of LDL in the arterial wall, the reduction in LDL particle size observed with both oral estrogen and combined therapy may not be deleterious, but rather may merely reflect selective removal of large LDL particles from the circulation. In a recent randomized controlled trial, testosterone gel therapy was not associated with any changes in highsensitivity CRP or lipoprotein (a) in postmenopausal women receiving concurrent estrogen therapy (38). 2. EFFECTS OF ANDROGENS ON THE MYOCARDIUM AND VASCULARFUNCTION
The incidence of coronary heart disease in postmenopausal women is not correlated with levels of circulating testosterone or DHEA-S (100,101). Intracoronary testosterone administration to anesthetized male and female dogs induces increases in coronary artery cross-sectional area peak flow velocity and calculated volumetric blood flow, which is blocked by pretreatment with an inhibitor of nitric oxide synthesis (102). The beneficial effects of estrogen therapy on coronary artery reactivity in cynomolgus monkeys is not lost with the addition of oral methyltestosterone (103). In postmenopausal women using long-term estrogen therapy, exogenous testosterone implants improve both endothelial-dependent (flow mediated) and endotheliumindependent (glyceryl trinitrate [GTN]-mediated) brachial artery vasodilation (104). Cardiac myocytes and fibroblasts contain functional alpha and beta estrogen receptors, and cardiac myocytes express cyp450 aromatase (105). Incubation of cardiac myocytes with A or testosterone results in transactivation of an estrogen receptor-specific reporter, with A resulting in a significantly higher induction than testosterone (105,106). Furthermore, both A and testosterone upregulate inducible nitric oxide synthase in cardiac myocytes (106). The capacity for cardiac myocytes to synthesize estrogen from androgenic precursors and activate downstream target genes is greater in cells from female animals compared with male animals (106). Thus, evaluating the data at hand, the administration of testosterone to women does not appear to affect the key events in coronary artery lipid metabolism or coronary artery function. Parenteral testosterone replacement does not negate the favorable effects exerted by exogenous estrogen on lipid and lipoprotein levels, whereas oral methyltestosterone use not only opposes the HDL-cholesterol elevating effects of oral estrogen but also reduces HDL-cholesterol
806
SUSAN R.
levels below baseline values. It is not known whether this effect of oral methyltestosterone in the setting of concomitant lowering of total cholesterol, LDL-cholesterol, and triglyceride levels is detrimental. Certainly a high cardiac risk profile, which includes a low HDL-cholesterol level, central obesity, and low SHBG, should be considered a relative contraindication to testosterone therapy.
DAVIS
TABLE 55.2 Contraindications to Testosterone Therapy Relative
Severe acne Moderate to severe hirsutism Androgenic alopecia Circumstances in which enhanced libido would be undesirable Very low sex hormone globulin level Absolute
B. Androgens and Breast Cancer Studies of possible relationships between endogenous androgen levels and breast cancer have been extensively reviewed (107). In premenopausal women, there are inconsistent results from two cross-sectional studies (108,109), and two prospective case-control studies have found no association between breast cancer risk and total testosterone levels (110,111). The risk of breast cancer is also not increased in women with polycystic ovarian syndrome (PCOS) who have chronic estrogen exposure and androgen excess (107). Results are inconsistent in both cross-sectional studies and prospective studies of postmenopausal women (107). Most studies are limited by measurement of only total (not free) testosterone, use of insensitive assays, and failure to consider the diurnal variation of testosterone or oophorectomy status. In experimental studies, testosterone action is antiproliferative and pro-apoptotic and is mediated via the androgen receptor (AR), despite the potential for testosterone to be aromatized to estrogen (107). Animal studies suggest that testosterone may serve as a natural, endogenous protector of the breast and limit mitogenic and cancer-promoting effects of estrogen on mammary epithelium. Androgen receptors are found in more than 50% of breast tumors (112) and are associated with longer survival in women with operable breast cancer and a favorable response to hormone treatment in advanced disease. There is also evidence that the mechanism by which high-dose medroxyprogesterone acetate (MPA) exerts a negative effect on breast cancer growth is mediated via the androgen receptor (113). No studies of testosterone therapy have evaluated breast cancer risk.
C. Testosterone Replacement and Clinical Side Effects The potential masculinizing effects of androgen therapy include development of acne, hirsutism, deepening of the voice, and excessive libido. These cosmetic side effects are uncommon if supraphysiologic hormone levels are avoided. Other adverse metabolic effects are also uncommon with judicious therapy. Fluid retention appears to be more idiosyncratic than dose related. Hirsutism, androgenic alopecia, and/or acne are relatively strong contradictions to androgen
Pregnancy or lactation Known or suspected androgen-dependent neoplasia
therapy. Enhancement of libido is currently the most common indication for testosterone therapy; however, circumstances in which this would be an undesirable effect are a relative contraindication to therapy. Absolute contraindications include pregnancy and lactation, as well as known or suspected androgen-dependent neoplasia (Table 55.2). Hepatocellular damage has been reported with high-dose oral 1713-alkylandrogens, but not in currently used doses or other oral formulations (114).
D. Summary of the Potential Risks
of Testosterone Therapy Syndromes of endogenous androgen excess are clearly associated with increased cardiovascular risk, perturbations in lipid and carbohydrate metabolism, a more android weight distribution, and virilization. In contrast, clinical data at hand do not indicate testosterone maintained close to, or within, the normal female reproductive range has any adverse metabolic consequences (Table 55.3). With respect to breast cancer risk, whether women who have endogenously high testosterone levels are at increased risk is controversial, and there is no evidence that there is an increased in risk with so-called "physiologic" exogenous androgen replacement therapy after menopause. Physicians should
TABLE 55.3 Potential Dose-Related Side Effects of Androgen Therapy in Women Masculinizafion: hirsutism, acne, temporal balding, voice deepening, clitoromegaly Fluid retention (more often idiosyncratic) Lipids: Oral testosterone may adversely affect serum levels of HDL-cholesterol and apolipoprotein A1. Drug interactions: C17 substituted derivatives of oral testosterone may decrease anticoagulant requirements. Androgens may elevate serum levels of oxyphenbutazone and may rarely affect insulin requirements in diabetic patients. Hepatocellular damage has been associated with high-dose 17otalkylandrogens given orally.
CHAPTER 55 Intervention:
Androgens
always be cognizant of the anxiety most women have about breast cancer when prescribing any hormone therapy.
VI. W H I C H W O M E N ARE M O S T LIKELYTO BENEFIT FROM TESTOSTERONE? A list of potential indications for testosterone therapy is provided. However, indications for androgen therapy for a woman is most often low libido and diminished well-being, and hence based on clinical assessment, with evaluation of the outcome of treatment based on the subjective selfassessment of response and reporting by the patient. Biochemical measurements are of limited value, as there is no cut-off level for total or free testosterone that distinguishes women with low libido from other women (2). The clinical settings in which the administration of testosterone is most likely to enhance a woman's health and well-being are listed in Table 55.1. Future indications may also include the prevention or treatment of bone loss, particularly iatrogenic bone loss from glucocorticosteroid therapy or premenopausal bone loss. Some women present seeking clinical assistance for low libido and/or inadequate restoration of well-being despite apparently sufficient estrogen/progestogen therapy. Others may volunteer such problems while attending their physician for another reason. A significant proportion of women will not raise the issue of diminished libido because they find the topic awkward. Sadly, many young women who suffer low/absent libido following treatment of a malignancy express difficulty discussing the issue with their physician as they feel their problem will be perceived as trivial relative to their disease recovery or remission. Following treatment with chemotherapy or radiotherapy, the symptoms of the iatrogenic menopause and androgen deficiency, including fatigue, loss of well-being, depression, and reduced libido, can be difficult to distinguish from the overall physical toll of cancer treatment, and frequently premature menopause and associated androgen insufficiency go undiagnosed and untreated. Therefore, all "at-risk" women should be directly questioned about the symptoms of androgen deficiency and made aware of the therapeutic possibilities available. Testosterone therapy is becoming a more common component of hormone therapy for the restoration of sexual function in women who have undergone a surgical menopause. Testosterone therapy in women who have undergone natural menopause and especially in women who have premature ovarian failure continues to be a controversial therapeutic issue. It is essential that physicians offering this therapy be sensitive to the enormous variations in women's knowledge, expectations, sexual practices, and needs and always tailor treatment to the needs of the individual.
807 The management of young women with premature menopause, particularly those with primary amenorrhea (e.g., Turner syndrome) who have never been sexually active, is more difficult. Testosterone replacement should be considered for such women experiencing persistent fatigue, lack of well-being, and low libido despite adequate estrogen and progestogen replacement. However, it is obviously difficult for a woman to identify herself as having inadequate libido when she has never experienced what may be "normal." Alternatively, young women who have not been sexually active should have the option of testosterone replacement explained to them. Whether young women with premature ovarian failure should be recommended to use testosterone replacement to prevent bone loss, specifically from the neck of femur, is yet to be established.
VII. ASSESSMENT OF POTENTIAL CANDIDATES FOR A N D R O G E N THERAPY All women should be carefully screened for depression and relationship issues as a cause of their sexual difficulties. Similarly, the presence of chronic illness does not exclude a hormonal cause. Indeed, a hormonal cause may be more likely in women with illness or therapy that causes adrenal suppression. A complete gynecologic history should be taken. History should also identify possible iron deficiency, thyroid disease, and galactorrhea. A general physical examination should include assessment of thyroid status and presence of anemia or galactorrhea. Gynecologic examination should include a pelvic examination with attention to signs of vaginal atrophy, size of introitus, presence of discharge or evidence of infection, vulvodynia, and deep tenderness. Women presenting with low libido and fatigue should have routinely have the following measured: iron stores, thyroid-stimulating hormone to exclude subclinical thyroid disease, and, on clinical suspicion, a screen for autoimmune disease causing chronic fatigue. A history of treatment for hirsutism, acne, and androgenic alopecia should be sought as well as these features on physical examination. Measurement of total or free testosterone or DHEA-S does not distinguish patients who will benefit from treatment but does enable exclusion of women with biochemical androgen excess. Free or bioavailable (non-SHBG-bound) testosterone measures are the most reliable indicators of tissue testosterone exposure. Ideally blood should be drawn between 8:00 and 10:00 AM due to the diurnal variation of testosterone, which results in higher levels at this time. In premenopausal women, testosterone is at its nadir during the early follicular phase, with small but less significant variation across the rest of the cycle. Thus, blood should be
808
SUSAN R. DAvis
drawn after day 8 of the cycle, and preferably before day 20. A serum sample is preferred to plasma.
VIII. H O W SHOULD TESTOSTERONE REPLACEMENT BE PRESCRIBED? Currently no form of testosterone therapy is approved by the U.S. Food and Drug Administration (FDA) for the treatment of loss of libido in women; however, oral methyltestosterone can be prescribed for menopausal symptoms that do not respond to estrogen therapy alone. Testosterone implants have been approved for therapy for women in the United Kingdom. The current international therapeutic options in terms of androgen therapy are listed in Table 55.4. To achieve a good therapeutic response in terms of enhanced libido with parenteral testosterone, levels usually need to be restored to within the normal physiologic range for young ovulating women. The oral estrogen/androgen preparation available in the United States is in two strengths, esterified estrogen 0.625 mg plus methyltestosterone 1.25 mg, or esterified estrogen 1.25 mg plus methyltestosterone 2.5 mg. Methyltestosterone is not available in most other countries because liver damage has been reported with long-term, high-dose therapy. More recent data do not support any short-term (12 months) detrimental effects of the available doses of methyltestosterone combined with estrogen on hepatic enzymes or blood pressure. It has been observed that women who use esterified estrogens combined with methyltestosterone report a lower instance of nausea compared with women receiving conjugated equine estrogen (CEE) alone (114). Testosterone undecanoate is an oral androgen prescribed for replacement therapy in hypogonadal men. Its clinical use in women has been little studied, although in some countries it is quite widely prescribed for women. It is believed to be absorbed via the lymphatics; hence, for optimal absorption it is recommended that testosterone undecanoate be ingested
TABLE 55.4
with fat, such as a glass of milk. However, supraphysiologic peaks of total testosterone have been reported with a dose as low as 20 mg (115). At present, testosterone undecanoate use cannot be recommended. There has been considerable clinical experience with the administration of testosterone implants in postmenopausal women, particularly in the Commonwealth countries, and these are approved for use in women in the United Kingdom. These implants are fused crystalline implants, 4 to 5 mm in diameter, containing testosterone BP (British Pharmacopoeia) as the active ingredient. A dose of 50 mg is extremely effective and does not cause virilizing side effects. This dose can be obtained by bisecting a 100-mg implant under sterile conditions. The implant is inserted subcutaneously (under local anaesthesia), usually into the lower anterior abdominal wall, using a trocar and cannula. This therapy provides a slow release of testosterone with an approximate duration of effect of 3 to 6 months for a 50-mg implant. There is marked individual variation in this period; therefore, testosterone levels must be carefully monitored, with a testosterone level measured prior to the administration of each subsequent implant. The author recommends that additional testosterone implants should not be inserted unless total testosterone is below the normal range for young women. Rarely is a 100-mg testosterone implant necessary to achieve an adequate therapeutic effect. Mean circulating testosterone levels approximately three times the upper limit of normal have been reported 4 weeks following the administration of 100-mg testosterone pellets. In contrast, 6 weeks after the insertion of a 50-mg testosterone implant, the mean circulating testosterone levels in postmenopausal women are just above the upper limit of normal for young ovulating women. Mixed testosterone esters, 50 to 100 mg, are occasionally administered 4 to 6 weekly as an intramuscular injection to women with androgen deficiency symptoms. Clinically this therapy results in a more rapid onset of effects, such that women report enhanced libido within 2 to 3 days of treatment. Some women report a heightened sense of agitation with this
Androgen Replacement Therapy Formulations Used for Women Dose range
Frequency
Route
Methyltestosterone* (in combination with esterified estrogen) Testosterone undecanoate** Nandrolone decanoate** Mixed testosterone esters** Testosterone implants
1.25-2.5 mg 40-80 mg 25-50 mg 50-100 mg 50 mg
Oral Oral Intramuscular Intramuscular Subcutaneous
Transdermal testosterone patcht
300 tag
Daily Daily or alternate days Every 6-12 weeks Every 4-6 weeks 3-6 Monthly Every 3.5 days
*Currently availablein the United States. **MeansNOT recommendedfor generaluse. *Undergoing clinical trial.
Topical
809
CHAPTER 55 Intervention: Androgens therapy. The pharmacokinetics of mixed testosterone esters administered intramuscularly to women have not been studied; however, many women report increased acne and occasional clitoromegaly with this therapy. The recent development of a transdermal testosterone matrix patch, specifically for use in women, may provide a new option for women requiring testosterone replacement. The patch, which has now been evaluated in phase III clinical trials, has been shown to improve the number of self-reported satisfactory sexual events experienced by surgically menopausal women (3,5). The patch delivers 300 Ixg of testosterone per day over a 3- to 4-day period (twiceweekly application). This therapy has now been approved for marketing in Europe. Nandrolone decanoate, a weakly aromatizable androgen, is approved in some countries for the treatment of postmenopausal osteoporosis. The dose, administered intramuscularly, should not exceed 50 mg, and the frequency of treatment is best titrated against the patient's gross build. It is prudent that treatment not be given more than every 6 weeks, and as these women are usually elderly and not on estrogen therapy, they should be very carefully monitored for masculinization. In most women, treatment with nandrolone decanoate results in cessation of bone loss over time and, in some women, an increase in BMD. Alternatives that are not currently or generally available include transdermal testosterone as a patch, spray, cream, gel, or parenteral testosterone via a vaginal ring. Although the transdermal preparations may be regionally available with a specific prescription from compounding pharmacists, there are no pharmacokinetic data available or published clinical experience for their preparations. The contraindications to and side effects of testosterone replacement are listed in Tables 55.2 and 55.3. Again, it is emphasized that with judicious dosing and careful patient monitoring, side effects of testosterone replacement are rare. All postmenopausal women treated with testosterone should be using concurrent estrogen therapy until such time as data are available for the safety of testosterone alone. The only clinical situation in which androgen therapy has been used in postmenopausal women without concurrent estrogen is the administration of the anabolic steroid, nandrolone decanoate. Women treated with this steroid must be very carefully monitored for virilization, which may occur when this compound is given unopposed by estrogen.
IX. CONCLUSIONS Testosterone levels in women fall substantially during the reproductive years, with little further change at the time of spontaneous menopause. A major fall in circulating testosterone occurs following bilateral oophorectomy. The biologic availability of the hormone is determined by the levels of
SHBG, with factors that raise SHBG levels leading to a fall in bioavailable testosterone. There is increasing interest in the contribution of androgen insufficiency to low libido and a variety of other symptoms. A substantial body of evidence indicates that testosterone is an important determinant of female sexuality and that androgen therapy enhances certain aspects of sexual function, particularly in women who have undergone oophorectomy. Many women are uneasy discussing their loss of sexual desire, particularly those who have undergone chemotherapy, and they often comment that they feel the issue will be viewed by their physician as trivial relative to their recovery or remission. Also, the symptoms of iatrogenic menopause can easily be attributed to side effects of chemotherapy or to other psychosocial factors in premenopausal women or in those who have undergone a premature menopause. Therefore, it is the treating physician's responsibility to facilitate discussion of sexuality in all "at-risk" women. Potential etiologic factors such as depression, poor relationship, and stress as well as other medical conditions should be addressed. The possibility of low androgen production as an underlying cause might then be considered. Physiologic-range androgen therapy may also have a role in the maintenance or restoration of bone mass, both following menopause and after pharmacologic glucocorticoid therapy. Further research into the biologic actions of androgens in bone and clinical studies of testosterone and fracture is needed to define the appropriate clinical application of androgens in the prevention and treatment of bone loss in women. Mthough more controversial, premenopausal women with either spontaneous or iatrogenic androgen deficiency also warrant consideration for androgen therapy, as do women experiencing glucocorticosteroid-induced bone loss and possibly premenopausal bone loss. At levels within or just above the physiologic range, testosterone in women does not appear to have major adverse effects on cardiovascular risk factors or on vascular function. Its actions, if any, in breast cancer risk remain uncertain. The inclusion of testosterone therapy in postmenopausal hormone therapy regimens is increasing but still limited by the lack of availability of preparations and formulations designed specifically for use in women. Advances, particularly involving transdermal technologies, are occurring in the effort to optimize the methods of androgen therapy in women, as well as in men.
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811 68. Carani C, Qin K, Simoni M, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N E n g J M e d 1997;337:91. 69. Maffei L, Murata Y, Rochera V, et al. Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol. J Clin Endocrinol Metab 2004;89:61. 70. Kasra M, Grynpas MD. The effects of androgens on the mechanical properties of primate bone. Bone 1995;17:265. 71. Masi AT, Feigenbaum SL, Chatterton RT. Hormonal and pregnancy relationships to rheumatoid arthritis: convergent effects with immunological and microvascular systems. Semin Arthritis Rheum 1995;25:1. 72. Cutolo M, Seriolo B, Sulli A, Accardo S. Androgens in rheumatoid arthritis. In: Bijlsma JWJ, Linden S, van der Barnes CG, eds. Rheumatology highlights 1995. Rheumatol Eur. 1995;24:211. 73. Wilder RL. Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis. J Rheumatol Supp11996;44:10. 74. Booij A, Biewenga-Booij CM, Huber-Bruning O, et al. Androgens as adjuvant treatment in postmenopausal female patients with rheumatoid arthritis. Ann Rheum Dis 1996;55:811. 75. van Vollenhoven RE Dehydroepiandrosterone for the treatment of systemic lupus erythematosus. Expert Opin Pharmacother 2002;3:23. 76. Goodman-Gruen D, Barrett-Connor E. Total but not bioavailable testosterone is a predictor of central adiposity in postmenopausal women. IntJ Obes 1995;19:293. 77. Darling GM, Johns JA, McCloud PI, Davis SR. Estrogen and progestin compared with simvastatin for hypercholesterolemia postmenopausal women. N E n g J M e d 1997;337:595. 78. The Writing Group for the PT. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAm MedAssoc 1995;273:199. 79. Davis SR, Walker KZ, Strauss BJ. Effects ofestradiol with and without testosterone on body composition and relationships with lipids in postmenopausal women. Menopause 2000;7:395. 80. Dobs AS, Nguyen T, Pace C, Roberts CR Differential effects of oral estrogen versus estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin EndocrinolMetab 2002;87:1509. 81. Choi HH, Gray PB, Storer TW, et al. Effects of testosterone replacement in human immunodeficiency virus-infected women with weight loss. J Clin Endocrinol Metab 2005;90:1531-1541. 82. Tunstall-Pedoe H. Myth and paradox about coronary risk and the menopause. Lancet 1998;352:1425. 83. Colditz GA, Willett WC, Stampfer MJ, et al. Menopause and the risk of coronary heart disease in women. N E n g J M e d 1987;316:1105. 84. Golden SH, Ding J, Szklo M, et al. Glucose and insulin components of the metabolic syndrome are associated with hyperandrogenism in postmenopausal women: the atherosclerosis risk in communities study. Am J Epidemio12004;160:540. 85. Sutton-Tyrrell K, Wildman RP, Matthews KA, et al. Sex hormonebinding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN). Circulation 2005;111:1242. 85a. Bell RJ, Davison SL, Papalia MA, McKenzie DP, Davis SR. Endogenous androgen levels and cardiovascular risk profile in women across the adult life span. Menopause 2007. 86. Kaplan RC, Frishman WH. Systemic inflammation as a cardiovascular disease risk factor and as a potential target for drug therapy. Heart Dis 2001;3:326. 87. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98:731. 88. Ridker P, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral artery disease. JAm MedAssoc 2001;285:2481.
812 89. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14719 initially healthy American women. Circulation 2003;107:391. 90. Albert MA. The role of C-reactive protein in cardiovascular risk. Curr Cardiol Rep 2000;2:274. 91. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001;103:1813. 92. Barinas-Mitchell E, Cushman M, Meilahn EN, Tracy RP, Kuller LH. Serum levels of C-reactive protein are associated with obesity, weight gain, and hormone replacement therapy in healthy postmenopausal women. A m J Epidemio12001;15 3 :1094. 93. Pradham AD, Manson JE, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. J A m MedAssoc 2001;286:327. 94. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. J A m MedAssoc 2005;294:326-333. 95. Wakatsuki A, Sagara Y. Lipoprotein metabolism in postmenopausal and oophorectomized women. Obstet Gyneco11995;85:523. 96. Lobo R, Rosen RC, Yang HM, Block B, Van der Hoop RG. Comparative effects of oral esterified estrogens with and without methyl testosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 2003;79:1341. 97. Barrett-Connor E, Young R, Notelovitz M, et al. A two-year, doubleblind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles. J Reprod Med 1999;44:1012. 98. Chiuve SE, Martin LA, Campos H, Sacks FM. Effect of the combination of methyltestosterone and esterified estrogens compared with esterifled estrogens alone on apolipoprotein CIII and other apolipoproteins in very low densi~, low density, and high density lipoproteins in surgically postmenopausal women. J Clin EndocrinolMetab 2004;89:2207-2213. 99. Wagner JD, Zhang L, Williams JK, et al. Esterified estrogens with and without methyltesterone decrease arterial LDL metabolism in Cynomolgus monkeys, drteriosder Thromb VascBio11996;16:1473. 100. Barrett-Connor E, Goodman-Gruen D. Prospective study of endogenous sex hormones and fatal cardiovascular disease in postmenopausal women. BMJ 1995;311:1193. 101. Rexrode KM, Manson JE, Lee IM, et al. Sex hormone levels and risk of cardiovascular events in postmenopausal women. Circulation 2003; 108:1688-1693.
Susan R. DAVIS 102. Chou TM, Sudhir K, Hutchison SJ, et al. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation 1996;94:2614. 103. Honore EK, Williams JK, Adams MR, Ackerman DM, Wagner JD. Methyltestosterone does not diminish the beneficial effects of estrogen replacement therapy on coronary artery reactivity in cynomolgus monkeys. MenopauseJ North Am Menopause Soc 1996;3:20. 104. Worboys S, Kotsopoulos D, Teede H, McGrath BP, Davis SR. Parental testosterone improves endothelium-dependent and independent vasodilation in postmenopausal women already receiving estrogen. J Clin Endocrinol Metab 2001;86:158. 105. Grohe C, Kahlert S, Lobbert K, et al. Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett 1997;416:107. 106. Grohe C, Kahlert S, Lobbert K, Vetter H. Expression of oestrogen receptor alpha and beta in rat heart: role of local oestrogen synthesis. J Endocrino11998;156:R1. 107. Somboonporn W, Davis SR. Testosterone and the breast: therapeutic implications for women. Endocrine Rev 2004;25:374. 108. Secreto G, Toniolo P, Pisani P, et al. Androgens and breast cancer in premenopausal women. CancerResearch 1989;49:471. 109. Yu H, Harris RE, Gao YT, et al. Comparative epidemiology of cancers in the colon, rectum, prostate and breast in Shanghai, China versus the United States. IntJEpidemio11991;20:76. 110. Thomas HV, Key TJ, Allen DS, et al. A prospective study of endogenous serum hormone concentrations and breast cancer risk in premenopausal women on the island of Guernsey. BrJ Cancer 1997;75:1075. 111. Wysowski DK, Freiman JR Tourtelot JB, et al. Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Intern Med 1993;118:860. 112. Bryan RM, Mercer RJ, Rennie GC, Lie TH, Morgan FJ. Androgen receptors in breast cancer. Cancer 1984;54:2436. 113. Birrell SN, Roder DM, Horsfall DJ, Bentel JM, Tilley WD. Medroxyprogesterone acetate therapy in advanced breast cancer: the predictive value of androgen receptor expression.J Clin Onco11995;13:1572. 114. Barrett-Connor E, Timmons MC, Young R, Wiita B, Estratest Working Group. Interim safety analysis of a two-year study comparing oral estrogen-androgen and conjugated estrogens in surgically menopausal women. J I47omensHealth 1996;5:593. 115. Buckler HM, McElhone K, Durrington PN, et al. The effects of lowdose testosterone treatment on lipid metabolism, clotting factors and ultrasonographic ovarian morphology in women. Clin Endocrinol (Oxf) 1998;49:173.
; H A P T E R 5(
Future Strategies in
Climacteric
GORAN S A M
Medicine
SIOE
Department of Obstetrics & Gynecology, Lund University Hospital, 221 85 Lund, Sweden
MARTINA DOREN
Charit&Universit~itsmedizin Berlin, Campus Benjamin Franklin, Clinical Research Center of Women's Health, D-12200 Berlin, Germany
I. I N T R O D U C T I O N The various mechanisms of action of estrogen are still not fully understood, but major advances in our understanding of receptor-mediated effects have been achieved during the last decade. The discovery of a second estrogen receptor and an interaction between estrogen receptors and other steroid receptors, as well as the role of cytokines in modifying receptor responses, have been established. This research has led to an increased understanding as to why some substances could act as estrogen antagonists in some tissues and estrogen agonists in other tissues. With this knowledge it is possible to target the original molecular structure to create novel compounds with higher selectivity. These groups of substances, commonly referred to as selective steroid receptor modulators (SSRMs), have been developed to enhance desirable effects and avoid the drawbacks. For example, for corticosteroids, it would be ideal to have full corticosteroid effects without bone loss or the development of "moon face." Possible health hazards of long-term menopausal estrogen therapy, particularly of estrogen-progestogen therapy, have generated interest in developing alternatives to current regimens. The concept of pharmacotherapy, with the exception of the treatment of vasomotor and urogenital symptoms, has been questioned because of perceived health risks associated with short- and long-term use. Proposed alternatives include TREATMENT OF THE POSTMENOPAUSAL WOMAN
813
the use of naturally occurring compounds, many of which have estrogenic properties, often referred to as phytoestrogens. Several such agents have been introduced onto the market, but existing products are too "weak" to be a real alternative to menopausal hormone therapy for the treatment of hot flushes. Above all, there are virtually no long-term data available on efficacy and safety; this also applies for black cohosh, a substance which has been approved for the treatment of climacteric symptoms for many years in some countries. Many of the active substances in phytoestrogens have been classified based on their chemical structure, and "purified phytoestrogens" are under development. More than 100 plants, some of which are edible, which contain approximately 30 specific compounds, are known to exhibit estrogenic activity. Phytoestrogens consist of a number of classes: isoflavones, lignans, coumestans, and fungal estrogens. Various legumes contain the isoflavones daidzein, genistein, formononetin, biochanin A, and the coumestan coumestrol. It is possible to alter slightly the chemical structure of these compounds and thereby possibly change the pharmacokinetic and pharmacodynamic properties. It has become increasingly clear that the compulsory addition of progestogens to protect the endometrium from malignant transformations by estrogen stimulation is problematic. The addition of a progestogen increases the relative risk of breast cancer (1,2). Women may accept monthly Copyright 9 2007 by Elsevier,Inc. All rights of reproductionin any form reserved.
814 bleeds around the menopause and during the few years there after, but with advancing age, bleed-free regimens are clearly preferred in most cultures. Bleed-free regimens can be achieved in a great many women by using continuous combined regimens, but some women may bleed from an atrophic endometrium. Monitoring, surveillance, and treatment of bleeding from an atrophic endometrium remain a challenge because we do not fully understand the etiology behind these bleeding episodes, although much knowledge has been gained during the past few years. Whether endometrial ablation will alleviate or even abolish the problem of uterine bleeding remains to be proven in well-designed studies with appropriate long-term follow-up. The recent Women's Health Initiative (WHI) data augment an interest in finding a safe therapy and hence using estrogen alone avoiding progestogens. To induce endometrial atrophy and thereby a bleedfree regimen, the progestogen effect in combined therapy needs to be fairly high. This means that other progestogenic side effects are not uncommon in women using continuous combined regimens. Hence, we need to have more selective progestogens primarily designed as estrogen co-medications and also for the use in elderly postmenopausal woman. Unfortunately, it is still a fact that almost all data on pharmacokinetics and pharmacodynamics on estrogens, progestogens, and various estrogen/progestogen combinations, including the continuous combined regimens have been obtained in women around 50 years of age, and such data are probably not transferable to an older population. For these reasons, we have insufficient data to guide us in selecting the progestogen type, dose, or mode of administration for older postmenopausal women. Cost-benefit analyses seem to suggest that estrogens are cost-effective in women with symptoms and particularly in women without a uterus. That is to say that in the hysterectomized woman, estrogens can be given without a progestogen. This statement should not be used to encourage the medical community to perform hysterectomies around the time of the menopause. This type of surgery is performed too often worldwide for reasons which are not always convincing. However, the only proven positive effect of progestogen co-administration is its reduction of endometrial hyperplasia and the prevention of endometrial cancer.
II. DEVELOPMENT OF ESTROGEN COMPONENTS The predominant human natural estrogen during the fertile period is 17[3-estradiol. Hence, several hormone replacement therapies focus on the use of estradiol. Many of the same problems arise with natural estradiol as with natural progesterone. We need to know what the critical molecular structures are responsible for the positive effects on
SAMSIOE AND DOREN
symptoms and, thus, to avoid those molecular structures which may contribute to weight gain and influence breast tissues. Proliferation is thought to be involved in the development of breast cancer. Potentially, the estradiol molecule could be "tailored," in order to diminish or even abolish any interaction with breast tissue. Another feature to look at is the various components of conjugated equine estrogens (CEEs). Although the major components are estrone and estrone sulphate, CEE contains a variety of compounds that display different estrogenic activities. In particular, the so-called "alpha estrogens" contained in CEE are of interest as they possess qualifies different from the beta compounds. The further characterization of the various components of conjugated estrogens and their biologic effects should stimulate future research into estrogen pharmacokinefics and pharmacodynamics. It is also of pivotal importance to try to identify the type of molecular infrastructure that is responsible for the various cardiovascular effects, such as anfioxidative properties and vasodilatation, as well as the bone-sparing effects. New delivery systems have been introduced to improve the convenience of treatment and the potential for long-term use. A vaginal silicone ring that releases approximately 7.5 ~g estradiol per day constantly over a period of 3 months seems to be a valuable addition in the treatment of urogenital symptoms in estrogen-deprived women. Vaginal tablets containing 25 pg estradiol to be applied twice weekly are other alternatives to vaginal creams containing estriol or conjugated estrogens. Hormone-containing patches and gels are now established, but these need to be improved to avoid local skin irritation. Nasal spray continues to be an interesting line of development. Other forms of local treatment, although systemic absorption seems to be possible, include estradiol eye drops designed for the treatment of postmenopausal keratojunctivitis sicca. Long-acting delivery systems such as estradiol implants and intramuscular injections have been used for many years in various European countries. However, supraphysiologic blood levels are commonly encountered, sometimes associated with tachyphylaxis, and may therefore also carry health risks to a degree that is not well defined. Nonbiodegradable, silicone-based implants could improve this type of therapy by avoiding peak levels after insertion and maintaining lower, more constant hormonal levels that are in the range of the early to mid-follicular phase. An additional intriguing approach is the external regulation of body implants hormone-containing devices by a remote control. This can be achieved via the so-called "blue-tooth technique," which is under development in cooperation with the telecommunications industry. Many medical problems could benefit immensely from such techniques, including insulin administration in diabetics as well as sex steroids and anticoagulant therapy. The long-cycle therapy addresses a major problem, uterine bleeding, which is not accepted by most women. Although it is a very intriguing idea to space out the sequential administration of a progestogen to induce endometrial shedding, it
CHAPTER 56 Future Strategies in Climacteric Medicine
should be noted that the long-term endometrial safety of the few combinations tested remains to be demonstrated.
III. DEVELOPMENT OF P R O G E S T O G E N S AND PROGESTERONE An important task for future research is to try to delineate which structures in the progesterone molecule yield the different metabolic aspects. In other words, specific molecular structures influence the endometrium, and these molecular specifications give other potential negative effects such as premenstrual syndrome (PMS)-like effects and lowering of high-density lipoprotein (HDL) cholesterol? Thus far, progestogens have been developed mostly for use in contraception but also to treat various bleeding disorders in fertile life. More recently, progestogens to be used for postmenopausal women have become an important feature in the development of newer agents. The development of newer progestogens with fewer side effects and a more selective influence on the endometrium is an obvious goal in this respect. The patch administration of estrogens has been much in favor. However, there is less of an incentive to administer progestogens via the transdermal route because some of them have very little or no first-pass hepatic metabolism, as exemplified by levonorgestrel. Other progestogens including progesterone may show a first-pass metabolism. Natural progesterone displays a low oral bioavailability. Using newer microcrystallization techniques, it has become possible to achieve an acceptable bioavailability by the oral route. However, this needs to be substantially improved, as only a small fraction of orally administered progesterone is bioavailable. This means that progesterone has to be given in doses of approximately 200 mg per day to ensure endometrial protection. Work is underway to modify the molecule so that it may penetrate into the body, either via the skin or the oral route, and then rapidly degrade to natural progesterone. A vaginal progesterone gel, 45 mg, to be administered twice weekly for a period of I month, has been shown to induce a secretory endometrium in the presence of mean serum progesterone levels as low as some 2 mg/mL, which is suggestive of a so-called "first uterine pass" effect in women with premature ovarian failure and ovarian dysgenesis. The endometrial safety remains to be demonstrated in clinical trials of postmenopausal women subjected to treatment. Other developments to improve acceptance by women without compromising endometrial safety are to administer or use various progestogens in either implant form or as intrauterine devices (IUD). One approved IUD releases levonorgestrel 20 big daily for approximately 5 years. Two different IUDs with a release rate of 5 and 10 big/24 h were reported to induce acceptable bleeding patterns and showed no adverse effects on lipid and lipoprotein metabolism
815 when combined with 2 mg estradiol valerate orally administered (3). A disadvantage with this type of device is that the progestogen reservoir covered by the rate-limiting membrane could be too thick for insertion into the uterus of a postmenopausal woman. A smaller device with a thinner vertical arm is currently in clinical development for the use of postmenopausal women (4) (Table. 56.1). A release rate of 5 to 10 big/24 h is sufficient for endometrial protection. Another feature is the introduction of newer regimens in order to reduce the progestogen dosage. An example of this is the so-called "on-and-off therapy" in which estrogens are given continuously but progestogens are given 3 days on and 3 days off. In such clinical trials, bleeding discomforts were acceptable, but extensive clinical experience and controlled studies providing long-term efficacy and safety data are lacking. It is also disputable which type of progestogen should be preferred; in other words, one that has similar pharmacokinetics to the administered estrogens, such as medroxyprogesterone acetate (MPA), norethisterone, or dydrogesterone, or one that is longer acting, such as desogestrel, levonorgestrel, or norgestimate. Also under current investigation are combinations of estrogens and a variety of antihypertensive drugs to delineate perceived additive or even synergistic effects. This is particularly prudent because estrogen is about the only compound that has more effects (albeit small) on diastolic than systolic blood pressure. An angiotensin-converting enzyme (ACE)inhibiting effect and calcium channel blocking effects have been demonstrated for estrogens, and research that combines estrogens with different classes and compounds of antihypertensive drugs could improve the overall effect and possibly also decrease untoward effects by several of the compounds involved.
IV. FUTURE AVENUES FOR MIDLIFE WOMEN'S HEALTH For how long can women use hormones without adverse effects if vasomotor symptoms persist once therapy is discontinued and resumption of therapy is considered as an option? Whether the benefits of short-term use of hormones during TABLE 56.1
Intrauterine Menopausal Hormone Therapy
Levonorgestrel (LNG)-Intrauterine device 10 pg + 50 big E2 patch: Open, multicenter study of 294 postmenopausal women intended for 3 years First year results presented First insertion was 94% successful Bleeding and spotting mainly up to 2 months; decreased from 9 to 0 days at month 4 No adverse lipid effects (From ref. 4, with permission.)
816 the perimenopause and early menopausal period (5), the time with the highest likelihood of hot flushes, appear to outweigh the risks depends on available evidence, largely generated in trials including women well beyond 50 years old, and a personal benefit-risk assessment and perception. However, there are no such comprehensive controlled clinical trials results available to assess benefits and risks in women in the immediate perimenopausal period, during which vasomotor symptoms are most common. How should women be counseled if they seek medical advice once they experience health-related changes at midlife? Given that women (and men) face various physiologic changes as they age, evidence-based approaches to manage changes associated with midlife health are needed. At present, there is no clear, agreed-upon role for any natural or synthetic hormone with estrogenic properties in disease prevention, possibly except for osteoporosis in women at high risk, but this approach would be associated with accepting various health risks--and this does not seem to be prudent. Given the recent results of controlled studies with clinical end points as an outcome, the decreases in the risks of hip fracture and colon cancer do not appear to balance the increased risks of stroke, thromboembolic events, and breast cancer, not to mention the risks of cognitive impairment and urinary incontinence (6). Given the availability of other effective agents, the use of hormone therapy for the treatment or prevention of osteoporosis is not appropriate for most women. Until recently, it has been argued that many women, including (older) women who do not have vasomotor or urogenital symptoms, feel better when they take hormones, but the majority of placebocontrolled trials including W H I suggest that hormone therapy had no effect on measures of depression or cognition. However, there is no ultimate pharmacologic solution to meet the needs of symptom relief, particularly in women whose flushes may not disappear for many years. Nonhormonal medications for both vasomotor and urogenital symptoms are available, including a growing variety of soy products, black cohosh preparations, and vitamins, yet efficacy appears to be at least low (if existing) for many compounds, in particular for over-the-counter preparations (7,8); the exceptions (9) warrant further good-quality studies. Whether antidepressants such as serotonin and norepinephrine reuptake inhibitors provide relief from hot flushes (10,11) or are a "true" alternative to hormones remains to be established by carefully designed controlled trials that also provide data on longer-term safety. Also, there is no good (if any) evidence that nonpharmacologic approaches, including homeopathy or yoga, provide lasting benefits (7). In women with mild to moderate vasomotor symptoms, physical activity has repeatedly been shown to mitigate symptoms (12-14). Hence, we must increase our efforts to motivate and encourage physical activity in the community, including middle-aged women as well. To make people understand the importance of physical activity, it can be put on
SAMSIOE AND DOREN
prescription, such as in Sweden. The use of a drug prescription form to prescribe physical exercise augments the patient's comprehension and understanding that physical activity equates pharmacologic therapy. The annual increase in the risk of serious adverse events associated with postmenopausal hormone therapy is relatively small, but why should women be exposed at any risk? If the rates of diseases among 50-year-old women are estimated to be about half that reported for older women in the WHI, the net effect of hormone therapy in this age group will be about 1 serious adverse event per 1000 women treated per year. Hot flushes may be very disabling. Some women may choose to try other remedies or to live with their symptoms, whereas others will find the relief of symptoms afforded by hormone therapy worth the risk. Vasomotor symptoms resolve within several months in many women and within a few years in most women, so attempts should be made to taper the dose of hormones and to discontinue therapy. For women whose menopausal symptoms persist beyond the immediate postmenopausal period, estrogen (with or without a progestogen) may be an option, although it is associated with hazards given the inferiority of other currently available therapies. Women should be counseled that menopausal hormone therapy is only one option to improve certain aspects of midlife health. Evidence-based advice about smoking cessation, which may help with vasomotor symptoms (15), nutrition and weight control, physical exercise, management of stress, and possibilities to maintain cognitive abilities in old age in order to prevent diseases are the most essential cornerstones of preventive medicine. Regular (leisure time) physical activity can maintain cardiovascular health, diminishes the risk of osteoporosis, protects against obesity's many adverse health outcomes, and may protect against Alzheimer's disease (16). Moderate use of alcohol could be beneficial (17). However, data related to the consumption of alcohol and the onset of flashes are conflicting (18). Lung cancer in women, on the rise in many countries, may be targeted if women stop smoking and do not regard smoking as an expression of possessing equal rights of (smoking) men. Obesity appears to be one of the most challenging health problems for aging women and men. The prevalence of diabetes, which often accompanies obesity, appears to be associated with changing living conditions of women, who progressively often live alone in older age in Western societies (19). A balanced diet, not necessarily supplemented by calcium and vitamin D if daily nutrition provides amounts regarded as sufficient for bone protection, will help prevent osteoporosis and may reduce the risk of failing. Continued mental exercises appear to decrease the risk of Alzheimer's disease. Whether lowdose aspirin (50 mg/day) may have the potential to prevent strokes in women older than age 65 has been demonstrated in one large prospective trial (to date), yet this therapy also has side effects (20). However, all nonpharmaceufical approaches
CHAPTER 56 Future Strategies in Climacteric Medicine
are somewhat arduous and demand continuous, essentially lifelong, efforts, which are often not invested in maintenance of health by individuals and not often enough recommended and explained by doctors. The optimal prevention of disease remains a compelling, growing task given the demographic changes never before seen in history, with rapidly growing numbers of women and men at old and very old ages. Hormonal therapies to prevent symptoms and diseases with maximal benefits and minimal risks are one part of preventive health care yet to be optimized. In conclusion, there are several possibilities to address the age-dependent decrease of gonadal hormones in women, all of which need to offer more benefits than risks as a principle in order to be acceptable as a strategy to maintain or possibly improve (post)menopausal health. It is a challenge for today's clinical medicine to determine those women who have the most to gain from such therapy in order to make it cost-effective.
References 1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAm MedAssoc 2003;289:3243-3253. 2. Greiser C, Greiser EM, D6ren M. Menopausal hormone therapy and risk of breast cancer: a meta-analysis of epidemiological studies and randomized controlled trials. Hum Reprod Update 2005;11:561 - 573. 3. Wollter-Svensson LO Stadberg E, Andersson K, et al. Intrauterine administration of levonorgestrel 5 and 10 micrograms/24 hours in perimenopausal hormone replacement therapy. A randomized clinical study during one year. Acta Obstet GynecolScand 1997;76:449-454. 4. Sturdee DW, Rantala ML, Colau JC, Zahradnik H-P, Riphagen FE. The acceptability of a small intrauterine progestogens-releasing system for continuous combined hormone therapy in early postmenopausal women. Climacteric2004;7:404- 411. 5. MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. CochraneDatabase System Rev 2004;4(CD002978). 6. Farquhar CM, Marjoribanks J, Lethaby A, et al., for the Cochrane HT Study Group. Long term hormone therapy for perimenopausal and postmenopausal women. CochraneDatabase System Rev 2005;3(CD004143). 7. Balk E, Chung M, Chew P, et al. Effects of soy on health outcomes. Evidence Report/Technology Assessment No. 126. AHRQ_Publication No. 05-E024-2. Rockville, MD: Agency for Healthcare Research and Quality, Aug. 2005.
817 8. Krebs EL, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gyneco! 2004;104:824-836. 9. Wuttke W, Seidlova-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas 2003;44:$67- $77. 10. Sterns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomised controlled trial. JAm MedAssoc 2003;289:2827- 2834. 11. Evans ML, Pritts E, Vittinghoff E, et al. Management of postmenopausal hot flashes with venlaflaxine hydrochloride: a randomized, controlled trial. Obstet Gyneco12005;105:161-166. 12. Aiello EY, Yasui Y, Tworoger SS, et al. Effect of a year-long, moderate-intensity exercise intervention on the occurrence and severity of menopause symptoms in postmenopausal women. Menopause 2004;11:382-388. 13. Lindh-Astrand L, Nedstrand E, Wyon V, Hammar M. Vasomotor symptoms and quality of life in previously postmenopausal women randomised to physical activity or estrogen therapy. Maturitas 2004;48: 97-105. 14. Gold EB, Sternfeld B, Kelsey JL, et al. Relation of demographic and lifestyle factors to symptoms in a multiracial/ethnic population of women 40-55 years of age. Am Epidemio12000;152:463-473. 15. Nelson HD, Haney E, Humphrey L, et al. Management of menopauserelated symptoms. Evidence Report/Technology Assessment No. 120. AHRQ_ Publication No. 05-E016-2. Rockville, MD: Agency for Healthcare Research and Q.uality, March 2005. 16. Rovio S, K&eholt I, Helkala E-L, et al. Leisure-time physical actMty at midlife and the risk of dementia and Alzheimer's disease. Lancet Neuro12005;4:705- 711. 17. Schilling C, Gallicchio L, Miller SR, et al. Current alcohol use is associated with a reduced risk of hot flashes in midlife women. Alcohol Alcoholism 2005;40:563- 568. 18. Freeman EW, Sammel MD, Grisso JA, et al. Hot flashes in the late reproductive years: risk factors for African American and Caucasian women. J WomensHealth Gend Based Med 2001;10:67- 76. 19. Lidfeldt J, Nerbrand C, Samsioe G, Agardh C-D. Women living alone have an increased risk to develop diabetes, which is explained mainly by lifestyle factors. Diabetes Care 2005;28:2531-2536. 20. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N EnglJ Med 2005;352:1293-1304.
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SECTION XIII
Some Alternative Medical Therapies This section covers a variety of other therapies that may be considered by postmenopausal women. Use of herbs and phytoestrogens were covered in an earlier section on Lifestyle (see Section X). Although not all potential therapies will be covered here, some of the major alternatives to traditional hormonal therapy will be discussed. Some of these therapies in reality are forms of hormonal therapy; however, they are not the traditional forms of estrogen and progestogens. It is clear that women require various options when considering treatment, and it is anticipated that these discussions will be useful in this regard. In the first chapter in this section, John E. Buster reviews the use of dehydroepiandrosterone (DHEA). Although D H E A is a hormone, it is available without a prescription and is not regulated by the Food and Drug Administration. It has been popularized as an anti-aging medicine that affects immune function and body composition and improves hormonal status. John will tell the reader whether this is true. Next, Ralf C. Zimmermann discusses the use of melatonin. This, too, is an interesting hormone available over the counter. Does it help with sleep and mood? The next chapter by Felicia Cosman and Robert Lindsay discusses the use of selective estrogen reuptake modulators (SERMs). It is appropriate that this chapter is authored by two "bone heads" in that the major indication for these agents is osteoporosis. Several products are available now, and more are in the pipeline. Finally, David Archer and Chris Gallagher discuss tibolone. This interesting progestogen has unique estrogenic, androgenic, and progestogenic properties and has been coined a "STEAR" (Selective Tissue Estrogenic Activity Regulator). It is available in many countries and is quite widely prescribed around the world for the indications of vasomotor symptom control and osteoporosis prevention. However, to date it is not available in the United States.
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"m
t" J"
~ H A P T E R D,
Alternative Therapy: D e hydro ep i an dro s te ro n e for Menopausal Hormone Replacement PAUL S. DUDLEY Departmentof Obstetrics and Gynecology,Division of Reproductive Endocrinology and Infertility, Baylor College of Medicine, Houston, TX 77030 JOHN E. BUSTER Departmentof Obstetrics and Gynecology,Division of Reproductive Endocrinology and Infertility, Baylor College of Medicine, Houston, TX 77030
Dehydroepiandrosterone (DHEA) and its sulfoconjugate, dehydroepiandrosterone sulfate, DHEA(S), are androgen prohormones. Having no known receptors, these prohormones serve as precursors to downstream androgens such as testosterone (T) and dihydrotestosterone, both of which do have steroid receptors and are therefore biologically active. Because DHEA(S) production declines with advancing years, many aspects of aging have been attributed to waning DHEA(S) synthesis. Accordingly, DHEA is among the products touted by the supplement industry for its ability to defer many of ages' tyrannies. Statements trumpeting its potential are tempting: "Live better than ever. Maximize immunity. Stop stress in its tracks. Mend a broken heart." These assertions are not unfounded. As an androgen prohormone, DHEA(S) has the physiologic advantage of enhancing production of biologically active androgens within TREATMENT
OF T H E P O S T M E N O P A U S A L W O M A N
target tissues themselves. Because target tissues autoregulate their own intracellular production of bioactive androgens, replacement strategies involving DHEA are a tantalizingly natural method of restoring a youthful androgen milieu to postmenopausal women. DHEA as menopausal hormone replacement offers significant advantages over traditional estrogen and androgen therapy. A system employing such a strategy should approximate youthful D H E A production rates, allowing for a woman's natural physiology to produce downstream bioactive hormones at their site of action. Unfortunately, optimal development of a safe, effective DHEA delivery system remains elusive. This chapter reviews relevant literature on therapeutic DHEA and analyzes the rationale and controversies surrounding its clinical use as a menopausal hormone replacement. 821
Copyright 9 2007 by Elsevier, Inc. All rights of reproduction in any form reserved.
822
DUDLEY AND BUSTER
I. DHEA IN MENOPAUSE AND AGING DHEA and DHEA(S) are androgens, a class of C19 steroids produced by the adrenal glands and ovaries (1,2). Androgen syntheses proceed via two interrelated pathways invoMng five steroidogenic enzymes (Fig. 57.1). The preferred route entails cleavage of 17-OH pregnenolone to form DHEA. Within the highly specialized zona reticularis (ZR), or androgen cortex of the adrenal, DHEA is largely converted to and secreted as DHEA(S), which is secreted in considerable abundance. In young women, the production rate of DHEA(S) is 11 to 20 mg per day, an amount that considerably exceeds other steroids (2). Within the ovaries, DHEA is secreted, in far more modest amounts, as unconjugated DHEA. DHEA and DHEA(S) are extensively interconverted in peripheral tissues and secreted as various metabolites back into the circulation. Very high production rates of DHEA(S), combined with its slow clearance and long half-life, produce circulating concentrations of DHEA(S) that are 100 to 1000 times higher than any of the unconjugated steroids (3). DHEA(S) circulates in a pool with very slow turnover. This pool provides a large reservoir for peripheral conversion into biologically active androgens and estrogens in target tissue cells. Thus, steroids produced from DHEA(S) exert action inside the same cells in which their synthesis takes place ("intracrinology") (Fig. 57.2) (4). The quantitative importance of this mechanism is illustrated by estimates that approximately 50% of total androgens are derived from DHEA and DHEA(S) in adult men (5). In women, the intracrine contribution of DHEA and DHEA(S) to peripheral estrogen formation is even more substantial: approximately 75% before and close to 100% after menopause (Fig. 57.3) (6). CHOLESTEROL 20,22 hydroxylation 1
Side ChainCleavage (P450SCC) 17 Hydeoxylation PREONENOLONE- (P450 c17) ir 17-OHPREONENOLONE 17-20cleavagei (P450 c 17)
3/~-HSD
DHEA
