Table Of ContentA E D W
NDROGEN XCESS ISORDERS IN OMEN
C E
ONTEMPORARY NDOCRINOLOGY
P. Michael Conn, S E
ERIES DITOR
Treatment of the Obese Patient,edited byROBERT Assisted Fertilization and Nuclear Transfer
F. KUSHNERAND DANIEL H. BESSESEN,2007 in Mammals, edited by DON P. WOLF
Androgen Excess Disorders in Women: Polycystic AND MARY ZELINSKI-WOOTEN, 2001
Ovary Syndrome and Other Disorders, Adrenal Disorders, edited by ANDREW N. MARGIORIS
Second Edition,edited by RICARDO AZZIZ, AND GEORGE P. CHROUSOS, 2001
JOHN E. NESTLER,AND DIDIER DEWAILLY, Endocrine Oncology, edited by STEPHEN P. ETHIER,
2006 2000
Endocrinology of the Lung: Development
Evidence-Based Endocrinology, edited by VICTOR
and Surfactant Synthesis, edited by
M. MONTORI,2006
Stem Cells in Endocrinology, edited by LINDA B. CAROLE R. MENDELSON, 2000
LESTER,2005 Sports Endocrinology, edited by MICHELLE P.
Office Andrology, edited by PHILLIP E. PATTON WARRENAND NAAMA W. CONSTANTINI, 2000
Gene Engineering in Endocrinology, edited by
AND DAVID E. BATTAGLIA,2005
MARGARET A. SHUPNIK, 2000
Male Hypogonadism: Basic, Clinical, and
Endocrinology of Aging, edited by JOHN E.
Therapeutic Principles,edited by
MORLEYAND LUCRETIAVANDEN BERG, 2000
STEPHEN J. WINTERS,2004 Human Growth Hormone: Research
Androgens in Health and Disease, edited by
and Clinical Practice, edited by
CARRIE BAGATELLAND WILLIAM J. BREMNER, ROY G. SMITHAND MICHAEL O. THORNER,
2003
2000
Endocrine Replacement Therapy in Clinical
Hormones and the Heart in Health and Disease,
Practice, edited by A. WAYNE MEIKLE,2003 edited by LEONARD SHARE, 1999
Early Diagnosis of Endocrine Diseases, edited
Menopause: Endocrinology and Management,
byROBERT S. BAR, 2003 edited by DAVID B. SEIFER
Type I Diabetes: Etiology and Treatment, edited
AND ELIZABETH A. KENNARD, 1999
byMARK A. SPERLING, 2003 The IGF System: Molecular Biology,
Handbook of Diagnostic Endocrinology, edited Physiology, and Clinical Applications,
byJANET E. HALLAND LYNNETTE K. NIEMAN, edited by RON G. ROSENFELD
2003 AND CHARLES T. ROBERTS, JR., 1999
Pediatric Endocrinology: A Practical Clinical Neurosteroids: A New Regulatory Function
Guide, edited by SALLY RADOVICK in the Nervous System, edited by
AND MARGARET H. MACGILLIVRAY, 2003 ETIENNE-EMILE BAULIEU, MICHAEL
Diseases of the Thyroid, 2nd ed., edited by SCHUMACHER,
LEWIS E. BRAVERMAN,2003 AND PAUL ROBEL, 1999
Developmental Endocrinology: From Research Autoimmune Endocrinopathies, edited by
to Clinical Practice, edited by ERICA A. ROBERT VOLPÉ, 1999
EUGSTERAND ORA HIRSCH PESCOVITZ, 2002 Hormone Resistance Syndromes, edited by
Osteoporosis: Pathophysiology and Clinical J. LARRY JAMESON, 1999
Management, edited by ERIC S. ORWOLL Hormone Replacement Therapy, edited by
AND MICHAEL BLIZIOTES, 2002 A. WAYNE MEIKLE, 1999
Challenging Cases in Endocrinology, edited by Insulin Resistance: The Metabolic Syndrome X,
MARK E. MOLITCH, 2002 edited by GERALD M. REAVENAND AMI LAWS,
Selective Estrogen Receptor Modulators: 1999
Research and Clinical Applications, Endocrinology of Breast Cancer, edited by
edited by ANDREA MANNIAND MICHAEL F. ANDREA MANNI, 1999
VERDERAME, 2002 Molecular and Cellular Pediatric Endocrinology,
Transgenics in Endocrinology, edited by edited by STUART HANDWERGER, 1999
MARTIN MATZUK, CHESTER W. BROWN, Gastrointestinal Endocrinology, edited by
AND T. RAJENDRA KUMAR, 2001 GEORGE H. GREELEY, JR.,1999
A E
NDROGEN XCESS
D
ISORDERS
W
IN OMEN
P O S
OLYCYSTIC VARY YNDROME
O D
AND THER ISORDERS
S E
ECOND DITION
Edited by
R A , , ,
ICARDO ZZIZ MD MPH MBA
Center for Androgen Related Disorders, Cedars-Sinai Medical Center;
and Department of Obstetrics and Gynecology, and Department of Medicine,
The David Geffen School of Medicine at UCLA, Los Angeles, CA
J E. N ,
OHN ESTLER MD
Department of Internal Medicine, Virginia Commonwealth University,
Richmond, VA
D D ,
IDIER EWAILLY MD
Department of Endocrine Gynaecology and Reproductive Medicine,
Lille University Hospital, Lille, France
© 2006 Humana Press Inc.
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Library of Congress Cataloging-in-Publication Data
Androgen excess disorders in women : polycystic ovary syndrome and other disorders / edited
by Ricardo Azziz, John E. Nestler, Didier Dewailly.-- 2nd ed.
p. ; cm. -- (Contemporary endocrinology)
Includes bibliographical references and index.
ISBN 1-58829-663-6 (alk. paper)
1. Adrenal glands--Diseases. 2. Androgens--Metabolism. 3. Androgens--Physiological effect.
4. Polycystic ovary syndrome.
[DNLM: 1. Adrenocortical Hyperfunction. 2. Hyperandrogenism. 3. Androgens.
4. Polycystic Ovary Syndrome. WK 770 A573 2006] I. Azziz, Ricardo. II. Nestler, John E.
III. Dewailly, Didier. IV. Series: Contemporary endocrinology (Totowa, N.J.)
RG207.5.A53 2006
618.1--dc22
2006003453
D
EDICATION
To Cindy, Ashlee, Jonathon, and Mallory, for their loving and patient
support and encouragement.
—RA
To my brother, Gregory, whose love, encouragement, and sense of humor
were always a source of comfort.
—JEN
To my family and friends, with love and fondness.
—DD
v
P
REFACE
The field of androgen excess disorders has advanced substantially since the original
publication of this book. The Androgen Excess Society (AES) was founded to bring
together investigators in the field. A better understanding of the screening, progression,
and molecular genetics of nonclassic adrenal hyperplasia (NCAH) has improved the
clinical care and diagnostic accuracy of these patients. New criteria for the diagnosis of
the polycystic ovary syndrome (PCOS) were proposed in Rotterdam, criteria that have
resulted in controversy and, hopefully, initiation of new studies. The association of
insulin resistance with PCOS has been strengthened, and the role of metformin in treat-
ing the infertility of the PCOS has been validated. Risks for diabetes and, more contro-
versially, cardiovascular disease in women with PCOS have received substantial
investigation. Our understanding of the epidemiology and economic impact of these
disorders has expanded, emphasizing their critical importance. These are but a few
highlights of how the terrain has changed in a relatively brief period of time.
In keeping with these advances, the title of this book has been revised to reflect the
growing importance of PCOS as the most prevalent androgen excess disorder in women,
and arguably, as the one that might have the most serious adverse consequences for
general health. There are fewer chapters to provide a more focused elucidation of the
area. Several chapters were penned by new (and young) authors who are conducting
cutting-edge research in the field. The time line for publication of the book was inten-
tionally kept tight, so that the information would be fresh and current. Although the
editors have grown grayer, and not necessarily wiser, we nonetheless hope that this
second edition of Androgen Excess Disorders in Women: Polycystic Ovary Syndrome
and Other Disorders will prove to be a helpful guide and resource for all clinicians and
researchers in the field of androgen excess.
Ricardo Azziz, MD,MPH,MBA
John E. Nestler, MD
Didier Dewailly, MD
vii
A
CKNOWLEDGMENTS
A text of this size and depth cannot be created by only a dedicated few and the authors
must, out of fairness, acknowledge the support and assistance of many. We would like
to thank our staff who helped in the preparation and formatting of the many drafts
involved, particularly acknowledging the expert administrative assistance of Lois Dollar
and April Moore. We also greatly appreciate the support, patience, and guidance offered
to us by the editorial staff at Humana Press, notably Richard Lansing, Executive Director
for Continuing Medical Education and New Project Development; Patrick Marton,
Acquisitons Editor; and Robin B. Weisberg, Director of Editorial Services. Our young
collaborators, and past and present fellows, deserve special thanks for their generous and
enthusiastic intellectual contributions; a notable example is Dr. Daniela Jakubowicz
who has played a significant role in furthering our understanding of the therapeutic value
of metformin in the polycystic ovary syndrome. We are also deeply indebted to the many
authors who gave freely of their time and effort, and who endured our frequent requests
for revisions under a tight and unforgiving timeline. Finally, we acknowledge with
profound gratitude our many patients who suffer from androgen excess disorders, and
who trusted us to care for them, teaching us so much about these disorders and about
living gracefully despite their disability.
Ricardo Azziz, MD,MPH,MBA
John E. Nestler, MD
Didier Dewailly, MD
ix
C
ONTENTS
Dedication............................................................................................
Preface..................................................................................................
Acknowledgments ...............................................................................
Contributors.........................................................................................
I. Introduction
1 A Brief History of Androgen Excess
Ricardo Azziz....................................................................................3
II. Physiology of Androgens
2 Ovarian and Adrenal Androgen Biosynthesis and Metabolism
Walter L. Miller, David H. Geller, and Mitchell Rosen ..............19
3 Androgens Throughout the Life of Women
C. Richard Parker, Jr. ...................................................................35
4 Physiological Effects of Androgens in Women
T. Keta Hodgson and Glenn D. Braunstein.................................49
5 Androgen Measurements: Methods, Interpretation,
and Limitations
Frank Z. Stanczyk..........................................................................63
III. Uncommon Causes of Androgen Excess
6 Androgen-Secreting Adrenal and Ovarian Neoplasms
Michel Pugeat, Gérald Raverot, Ingrid Plotton, Aude Brac
de la Perrière, Pascale Mirakian, Henri Déchaud,
Nicole Berger, and Jean Louis Peix........................................75
7 Cushing’s Syndrome, Acromegaly, and Androgen Excess
Anne-Céline Reyss and Didier Dewailly.......................................85
8 The Nonclassic Adrenal Hyperplasias
Didier Dewailly and Ricardo Azziz ...............................................91
9 Pregnancy-Related Androgen Excess
Howard D. McClamrock..............................................................107
10 Drug-Induced Hyperandrogenism
Barbara Neraud and Didier Dewailly.........................................121
11 Severe Insulin-Resistant Hyperandrogenic Syndromes
David E. Moller, Antonio Vidal-Puig, and Ricardo Azziz.........129
12 Idiopathic Hirutism
Enrico Carmina............................................................................139
xi
xii Contents
IV. The Polycystic Ovary Syndrome
13 Definition and Epidemiology of the Polycystic
Ovary Syndrome
Ricardo Azziz................................................................................145
14 Clinical Features of the Polycystic Ovary Syndrome
Walter Futterweit, Evanthia Diamanti-Kandarakis,
and Ricardo Azziz ....................................................................155
15 Biochemical Features of the Polycystic Ovary Syndrome
Adam H. Balen.............................................................................169
16 Ovarian Histology, Morphology, and Ultrasonography
in the Polycystic Ovary Syndrome
Sophie Jonard, Yann Robert, Yves Ardaens,
and Didier Dewailly.................................................................183
17 Hypothalamic–Pituitary–Gonadotrophic Dysfunction
in the Polycystic Ovary Syndrome
R. Jeffrey Chang and Rinku V. Mehta.......................................195
18 Ovarian Steroidogenic Abnormalities in the Polycystic Ovary
Syndrome
Denis A. Magoffin........................................................................203
19 Hypothalamic–Pituitary–Adrenal Dysfunction
in the Polycystic Ovary Syndrome
Bulent O. Yildiz, Enrico Carmina, and Ricardo Azziz ..............213
20 The Genetic Basis of the Polycystic Ovary Syndrome
Mark O. Goodarzi ........................................................................223
21 Pediatric Hyperandrogenism and the Polycystic Ovary
Syndrome in Adolescence
Kathleen M. Hoeger.....................................................................235
22 Environmental Factors in the Polycystic Ovary Syndrome
Marie-France Hivert and Jean-Patrice Baillargeon.................247
23 Animal Models and Fetal Programming of the Polycystic
Ovary Syndrome
David H. Abbott, Daniel A. Dumesic, Jon E. Levine,
Andrea Dunaif, and Vasantha Padmanabhan ......................259
24 Insulin Resistance and Hyperinsulinism in the Polycystic
Ovary Syndrome
Paulina A. Essah and John E. Nestler.......................................273
25 The Endocrine Impact of Obesity and Body Habitus
in the Polycystic Ovary Syndrome
Renato Pasquali and Alessandra Gambineri.............................283
26 Molecular Mechanisms of Insulin Resistance
in the Polycystic Ovary Syndrome
Theodore P. Ciaraldi....................................................................293
