Polycystic Ovary Syndrome

CONTEMPORARY ENDOCRINOLOGY

P. Michael Conn, SERIES EDITOR

Autoimmune Diseases in Endocrinology,edited by ANTHONY P. WEETMAN, 2008

Energy Metabolism and Obesity: Researchand Clinical Applications, edited byPATRICIA A. DONOHOUE, 2008

Polycystic Ovary Syndrome: CurrentControversies, from the Ovary to thePancreas, edited by ANDREA DUNAIF,

R. JEFFREY CHANG, STEPHEN FRANKS,

AND RICHARD S. LEGRO, 2008The Metabolic Syndrome: Epidemiology, Clinical

Treatment, and Underlying Mechanisms,edited by BARBARA CALEEN HANSEN

AND GEORGE A. BRAY, 2008Genomics in Endocrinology: DNA Microarray

Analysis in Endocrine Health and Disease,edited by STUART HANDWERGER

AND BRUCE ARONOW, 2008Controversies in Treating Diabetes: Clinical

and Research Aspects, edited byDEREK LEROITH AND AARON I. VINIK, 2008

Endocrine-Disrupting Chemicals: From BasicResearch to Clinical Practice, edited byANDREA C. GORE, 2007

When Puberty is Precocious: Scientificand Clinical Aspects, edited by ORA H.PESCOVITZ AND EMILY C. WALVOORD,2007

Insulin Resistance and Polycystic OvarianSyndrome: Pathogenesis, Evaluationand Treatment, edited by EVANTHIA

DIAMANTI-KANDARAKIS, JOHN E. NESTLER,

D. PANIDIS, AND RENATO PASQUALI, 2007Hypertension and Hormone Mechanisms, edited

by ROBERT M. CAREY, 2007The Leydig Cell in Health and Disease, edited by

ANITA H. PAYNE AND MATTHEW PHILLIP HARDY,2007

Treatment of the Obese Patient, edited byROBERT F. KUSHNER AND DANIEL H. BESSESEN,2007

Androgen Excess Disorders in Women:Polycystic Ovary Syndrome and OtherDisorders, Second Edition, edited byRICARDO AZZIS, JOHN E. NESTLER, AND DIDIER

DEWAILLY, 2006Evidence-Based Endocrinology, edited by

VICTOR M. MONTORI, 2006

Stem Cells in Endocrinology, edited by LINDA B.LESTER, 2005

Office Andrology, edited by PHILLIP E. PATTON

AND DAVID E. BATTAGLIA, 2005Male Hypogonadism: Basic, Clinical,

and Therapeutic Principles, edited bySTEPHEN J. WINTERS, 2004

Androgens in Health and Disease, edited by CARRIE

J. BAGATELL AND WILLIAM J. BREMNER, 2003Endocrine Replacement Therapy in Clinical

Practice, edited by A. WAYNE MEIKLE, 2003Early Diagnosis of Endocrine Diseases, edited by

ROBERT S. BAR, 2003Type I Diabetes: Etiology and Treatment, edited

by MARK A. SPERLING, 2003Handbook of Diagnostic Endocrinology, edited by

JANET E. HALL AND LYNNETTE K. NNIEMAN, 2003Pediatric Endocrinology: A Practical Clinical

Guide, edited by SALLY RADOVICK AND

MARGARET H. MACGILLIVRAY, 2003Diseases of the Thyroid, 2nd ed., edited by

LEWIS E. BRAVERMAN, 2003Developmental Endocrinology: From Research

to Clinical Practice, edited by ERICA A.EUGSTER AND ORA HIRSCH PESCOVITZ, 2002

Osteoporosis: Pathophysiology and ClinicalManagement, edited by ERIC S. ORWOLL AND

MICHAEL BLIZIOTES, 2002Challenging Cases in Endocrinology, edited by

MARK E. MOLITCH, 2002Selective Estrogen Receptor Modulators: Research

and Clinical Applications, edited by ANDREA

MANNI AND MICHAEL F. VERDERAME, 2002Transgenics in Endocrinology, edited by MARTIN

MATZUK, CHESTER W. BROWN, AND T. RAJENDRA

KUMAR, 2001Assisted Fertilization and Nuclear Transfer

in Mammals, edited by DON P. WOLF AND

MARY ZELINSKI-WOOTEN, 2001Adrenal Disorders, edited by ANDREW N. MARGIORIS

AND GEORGE C. CHROUSOS, 2001Endocrine Oncology, edited by STEPHEN P. ETHIER,

2000Endocrinology of the Lung: Development

and Surfactant Synthesis, edited by CAROLE

R. MENDELSON, 2000Sports Endocrinology, edited by MICHELLE P.

WARREN AND NAAMA W. CONSTANTINI, 2000

Polycystic Ovary

Syndrome

Current Controversies,

from the Ovary to the

Pancreas

Edited by

Andrea Dunaif, md

Division of Endocrinology, Metabolism and Molecular Medicine,Northwestern University, Chicago, IL

R. Jeffrey Chang, md

Department of Reproductive Medicine,University of California, San Diego School of Medicine, La Jolla, CA

Stephen Franks, md, fmedsci

Institute of Reproductive and Developmental Biology,Imperial College London, London, UK

Richard S. Legro, mdDepartment of Ob/Gyn, Penn State College of Medicine, Hershey, PA

EditorsAndrea Dunaif, MD R. Jeffrey Chang, MDDivision of Endocrinology, Metabolism Department of Reproductive Medicine,and Molecular Medicine, University of California, San DiegoNorthwestern University School of Medicine,Chicago, IL La Jolla, CA

Stephen Franks, MD, FMedSci Richard S. Legro, MDInstitute of Reproductive and Department of Ob/Gyn,Developmental Biology, Penn State College of Medicine,Imperial College London, Hershey, PALondon, UK

Series EditorP. Michael ConnOregon Health & Science University,Beaverton, OR

ISBN: 978-1-58829-831-7 e-ISBN: 978-1-59745-108-6

Library of Congress Control Number: 2007933472

©2008 Humana Press, a part of Springer Science+Business Media, LLCAll rights reserved. This work may not be translated or copied in whole or in part without the written permission ofthe publisher (Humana Press, 999 Riverview Drive, Suite 208, Totowa, NJ 07512 USA), except for brief excerpts inconnection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval,electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developedis forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identifiedas such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.While the advice and information in this book are believed to be true and accurate at the date of going to press,neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions thatmay be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Cover illustration: Figure 1, Chapter 21, “Impact of Diagnostic Criteria: NICHD Versus Rotterdam,” by Bulent O.Yildiz.

Printed on acid-free paper

9 8 7 6 5 4 3 2 1

springer.com

This book is dedicated to the memory of Samuel S. C. Yen, MD, DSc, one of thepreeminent reproductive endocrinologists of the latter half of the 20th century and afounding member of the Peacocks. Among his many contributions to the field were

his pioneering studies on the pathogenesis and treatment of PCOS. We will miss notonly his keen intellect but also his joie de vivre.

Preface

This volume is based on the proceedings of the first annual Peacocks polycystic ovarysyndrome (PCOS) Forum on Disease Mechanisms and Therapeutic Strategies, October6–9, 2005, Chateau de Vault de Lugny, Avallon, France. The Peacocks was foundedby R. Jeffrey Chang, Andrea Dunaif, Stephen Franks, Richard S. Legro, and SamuelS. C. Yen. The name is based on PCOS when it is pronounced as a word “pcos” ratherthan as individual letters. The purpose of the Peacocks is to organize biannual meetingsof experts to review the latest developments in the field. The second annual Peacocksmeeting was held September 27–30, 2007, Castello di Spaltenna, Spaltenna, Italy.

It has become increasingly clear over the past several years that PCOS is a complexgenetic disease resulting from the interaction of susceptibility genes and environmentalfactors. The insight that prenatal exposure to androgens can reproduce most of thefeatures of the human syndrome in primates has led to a paradigm shift in conceptsabout the pathogenesis of the disorder. The evidence for the fetal origins of PCOS willbe reviewed in animal models as well as in human studies. The novel mechanisms bywhich androgens may play a major role in the pathogenesis of the disorder will bepresented. Other emerging areas of PCOS will also be discussed, such as prepubertalprecursors of PCOS and the association between PCOS, epilepsy, and antiseizuremedications. State-of-the-art treatment of the reproductive and metabolic consequencesof the disorder will be reviewed. Finally, the impact of the differing diagnostic criteriafor PCOS will be reviewed.

vii

viii Preface

Participants’ First Annual Peacock Forum. First row, from left to right: Richard S. Legro, AndreaDunaif, and R. Jeffrey Chang. Second row, from left to right: Silva A. Arslanian, Eva Dahlgren,Evanthia Diamanti-Kandarakis, David H. Abbott, and Antoni J. Duleba. Third row, from left to right:Renato Pasquali, Bulent O. Yildiz, Ricardo Azziz, Enrico Carmina, Daniel A. Dumesic, and MichelPugeat. Fourth row, from left to right: John C. Marshall, Adam Balen, Juha S. Tapanainen, andRoy Homburg. Not present: Stephen Franks, Didier Dewailly, and Robert J. Norman. Photographby Antoni J. Duleba with permission.

Photograph by Antoni J. Duleba with permission.

Contents

Preface................................................................................................................................ viiContributors ....................................................................................................................... xiList of Color Plates............................................................................................................ xv

1 Folliculogenesis in Polycystic OvariesStephen Franks and Kate Hardy............................................................................... 1

2 Accounting for the Follicle Population in the Polycystic OvaryDaniel A. Dumesic and David H. Abbott ................................................................. 9

3 What Is the Appropriate Imaging of the Polycystic OvarySophie Jonard, Yann Robert, Yves Ardaens and Didier Dewailly ............................ 25

4 Polycystic Ovary Versus Polycystic Ovary Syndrome: A Necessary DistinctionAdam Balen............................................................................................................... 37

5 Genetic Analyses of Polycystic Ovary SyndromeMargrit Urbanek....................................................................................................... 51

6 Fetal Origins of Polycystic Ovary SyndromeDavid H. Abbott, Cristin M. Bruns, Deborah K. Barnett, Alice F. Tarantal,

Sarah M. Hoffmann, Rao Zhou, Jon E. Levine and Daniel A. Dumesic.............. 87

7 Pubertal Precursors of the Polycystic Ovarian SyndromeJohn C. Marshall, Christopher R. McCartney, Susan K. Blank and Quirine

Lamberts Okonkwo............................................................................................... 107

8 Variations in the Expression of the Polycystic Ovary Syndrome PhenotypeEnrico Carmina ........................................................................................................ 123

9 Acquired Polycystic Ovary Syndrome: Epilepsy, Bipolar Disorder, and the Role ofAnti-Epileptic Drugs

Richard S. Legro and Elizabeth A. Winans .............................................................. 133

10 Recommendations for the Early Recognition and Prevention of Polycystic OvarySyndrome

R. Jeffrey Chang ........................................................................................................ 147

11 Insulin Action and Secretion in Polycystic Ovary SyndromeJulia Warren-Ulanch and Silva A. Arslanian........................................................... 159

ix

x Contents

12 Polycystic Ovary Syndrome and the Metabolic Syndrome Long-Term RisksEva Dahlgren and Per Olof Janson .......................................................................... 185

13 Insulin Sensitizers Targeting Metabolic and Reproductive Consequences in PolycysticOvary Syndrome

Evanthia Diamanti-Kandarakis ............................................................................... 197

14 Mechanisms and Treatment of Obesity in Polycystic Ovary SyndromeRenato Pasquali and Alessandra Gambineri ............................................................ 217

15 Metabolic and Endocrine Effects of Statins in Polycystic Ovary SyndromePinar H. Kodaman and Antoni J. Duleba................................................................ 241

16 Recommended Therapies for Metabolic Defects in Polycystic Ovary SyndromeRobert J. Norman, Anneloes E. Ruifrok, Lisa J. Moran and Rebecca L. Robker ...... 259

17 Pathogenesis of Hyperandrogenism in Polycystic Ovary SyndromeWendy Y. Chang and Ricardo Azziz......................................................................... 281

18 Recommended Treatment Modalities for HyperandrogenismMichel Pugeat, Nisrin Kaddar and Véronique Raverot ............................................ 295

19 Effective Regimens for Ovulation Induction in Polycystic Ovary SyndromeJuha S. Tapanainen and Laure Morin-Papunen...................................................... 307

20 Pregnancy in Polycystic Ovary SyndromeRoy Homburg ............................................................................................................ 321

21 Impact of Diagnostic Criteria: NICHD Versus RotterdamBulent O. Yildiz ........................................................................................................ 333

Subject Index ..................................................................................................................... 345

Contributors

David H. Abbott, phd, National Primate Research Center and Department ofObstetrics and Gynecology, University of Wisconsin, Madison, WI

Yves Ardaens, md, Department of Radiology, Hopital Jeanne de Flandre, CentreHospitalier et Universitaire de Lille, France

Silva A. Arslanian, md, Division of Pediatric Endocrinology, Metabolism andDiabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, PA

Ricardo Azziz, md, mph, Department of Obstetrics and Gynecology, Cedars-SinaiMedical Center, Los Angeles, CA, and Departments of Obstetrics and Gynecologyand Medicine, The David Geffen School of Medicine, UCLA, Los Angeles, CA

Adam Balen, md, frcog, Reproductive Medicine and Surgery, Leeds TeachingHospitals, Clarendon Wing, Leeds General Infirmary, Leeds, UK

Deborah K. Barnett, phd, National Primate Research Center, University ofWisconsin, Madison, WI, and Department of Biology, University ofAlaska-Southeast, Sitka, Alaska

Susan K. Blank, md, Center for Research in Reproduction, University of VirginiaHealth System, Charlottesville, VA

Cristin M. Bruns, md, National Primate Research Center and Department ofMedicine, University of Wisconsin, Madison, WI

Enrico Carmina, md, Endocrine Unit, Department of Clinical Medicine, Universityof Palermo, Palermo, Italy

R. Jeffrey Chang, md, Department of Reproductive Medicine, University ofCalifornia, San Diego School of Medicine, La Jolla, CA

Wendy Y. Chang, md, Department of Obstetrics and Gynecology, Cedars-SinaiMedical Center, Los Angeles, CA, and Department of Obstetrics and Gynecology,The David Geffen School of Medicine, UCLA, Los Angeles, CA

Eva Dahlgren, md, phd, Department of Obstetrics and Gynecology, Institute ofClinical Sciences, The Sahlgrenska Academy, Göteborg University, Göteborg,Sweden

Didier Dewailly, md, Department of Endocrine Gynaecology and ReproductiveMedecine, Hopital Jeanne de Flandre, Centre Hospitalier et Universitaire de Lille,Lille, France

Evanthia Diamanti-Kandarakis, md, Medical School, University of Athens,Athens, Greece

Antoni J. Duleba, md, Department of Obstetrics/Gynecology, Yale UniversitySchool of Medicine, New Haven, CT

Daniel A. Dumesic, md, National Primate Research Center, University of Wisconsin,Madison, WI, and Reproductive Medicine & Infertility Associates, Woodbury, MN

Andrea Dunaif, md, Division of Endocrinology, Metabolism and MolecularMedicine, Northwestern University, Chicago, IL

xi

xii Contributors

Stephen Franks, md, fmedsci, Institute of Reproductive and DevelopmentalBiology, Imperial College London, London, UK

Alessandra Gambineri, md, Department of Internal Medicine, Division ofEndocrinology, University Alma Mater Studiorum, S. Orsola-Malpighi Hospital,Bologna, Italy

Kate Hardy, phd, Institute of Reproductive and Developmental Biology, ImperialCollege London, Hammersmith Hospital, London, UK

Sarah M. Hoffmann, md, National Primate Research Center, University ofWisconsin, Madison, WI

Roy Homburg, frcog, VU University Medical Centre, The Netherlands and IVF,Department of Obstetrics and Gynecology, Barzilai Medical Center, Ashkelon,Israel

Sophie Jonard, md, Department of Endocrine Gynaecology and ReproductiveMedecine, Hopital Jeanne de Flandre, Centre Hospitalier et Universitaire de Lille,Lille, France

Nisrin Kaddar, phd, Federation of Endocrinology and Diabetology, East Center,Lyon Hospital Board, Lyon, and INSERM Unit-M 0322, Lyon, France

Pinar H. Kodaman, md, phd, Department of Obstetrics/Gynecology, YaleUniversity School of Medicine, New Haven, CT

Richard S. Legro, md, Department of Ob/Gyn, Penn State College of Medicine,Hershey, PA

Jon E. Levine, md, Departments of Neurobiology and Physiology, NorthwesternUniversity, Evanston, IL

John C. Marshall, md, phd, Center for Research in Reproduction, University ofVirginia Health System, Charlottesville, VA

Christopher R. McCartney, md, Center for Research in Reproduction, Universityof Virginia Health System, Charlottesville, VA

Lisa J. Moran, phd, Research Centre for Reproductive Health, Discipline ofObstetrics & Gynaecology, University of Adelaide, The Queen Elizabeth Hospital,Woodville, South Australia, Australia

Laure Morin-Papunen, md, phd, Department of Obstetrics and Gynecology, OuluUniversity Hospital, University of Oulu, Oulu, Finland

Per Olof Janson, md, phd, Department of Obstetrics and Gynecology, Institute ofClinical Sciences, The Sahlgrenska Academy, Göteborg University, Göteborg,Sweden

Quirine Lamberts Okonkwo, md, Center for Research in Reproduction, Universityof Virginia Health System, Charlottesville, VA

Robert J. Norman, md, phd, Research Centre for Reproductive Health, Disciplineof Obstetrics & Gynaecology, University of Adelaide, The Queen ElizabethHospital, Woodville, South Australia, Australia

Renato Pasquali, md, Department of Internal Medicine, Division of Endocrinology,University Alma Mater Studiorum, S. Orsola-Malpighi Hospital, Bologna, Italy

Michel Pugeat, md, phd, Federation of Endocrinology and Diabetology, EastCenter, Lyon Hospital Board, Lyon, and INSERM Unit-M 0322, Lyon, France

Véronique Raverot, phd, Federation of Endocrinology and Diabetology, EastCenter, Lyon Hospital Board, Lyon, and INSERM Unit-M 0322, Lyon, France

Contributors xiii

Yann Robert, md, Department of Radiology, Hopital Jeanne de Flandre, CentreHospitalier et Universitaire de Lille, Lille, France

Rebecca L. Robker, phd, Research Centre for Reproductive Health, Discipline ofObstetrics & Gynaecology, University of Adelaide, The Queen Elizabeth Hospital,Woodville, South Australia, Australia

Anneloes E. Ruifrok, Medical Student, Universitair Medisch Centrum Groningen(UMCG), Discipline of Obstrics & Gynaecology, Groningen, the Netherlands

Juha S. Tapanainen, md, phd, Department of Obstetrics and Gynecology, OuluUniversity Hospital, University of Oulu, Oulu, Finland

Alice F. Tarantal, phd, Departments of Pediatrics, Cell Biology and HumanAnatomy, California National Primate Research Center, University of California,Davis, CA

Margrit Urbanek, phd, Division of Endocrinology, Metabolism and MolecularMedicine, Northwestern University Medical School, Chicago, IL

Julia Warren-Ulanch, md, Division of Weight Management and Wellness,Children’s Hospital of Pittsburgh, Pittsburgh, PA

Elizabeth A. Winans, pharmd, bcpp, College of Pharmacy, University of Illinoisat Chicago, Chicago, IL, and The Psychiatric Clinical Research Center, RushUniversity Medical Center, Chicago, IL

Bulent O. Yildiz, md, Department of Internal Medicine, Endocrinology andMetabolism Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey

Rao Zhou, md, National Primate Research Center and Endocrinology-ReproductivePhysiology Program, University of Wisconsin, Madison, WI

List of Color Plates

The images listed below appear in the color insert that follows page 184.

Color Plate 1. Fig. 2, Chapter 7: Overnight changes in ovarian steroids innormal early pubertal girls (Tanner stages I-III).

Color Plate 2. Fig. 1, Chapter 8: Distribution of body weight in US and Italianwomen with the classic polycystic ovary syndrome (PCOS)phenotype.

Color Plate 3. Fig. 2, Chapter 8: Prevalence of the metabolic syndrome inItalian normal woman aged 20–39 years and in Italian polycysticovary syndrome (PCOS) patients with the classic or ovulatoryhyperandrogenic phenotype.

Color Plate 4. Fig. 3, Chapter 8: Prevalence of the finding of at least one alteredcardiovascular risk factor in Italian polycystic ovary syndrome(PCOS) patients with classic or ovulatory hyperandrogenicphenotype.

Color Plate 5. Fig. 4, Chapter 8: Distribution of body weight in Italianpolycystic ovary syndrome (PCOS) patients with classic orovulatory hyperandrogenic phenotype.

Color Plate 6. Fig. 5, Chapter 8: Insulin serum levels and insulin sensitivity (byQUICKI) in Italian normal women and in Italian PCOS patientswith classic hyperandrogenic or with normoandrogenic phenotype.

Color Plate 7. Fig. 1, Chapter 11: Upper panel: insulin-stimulated glucosedisposal during a hyperinsulinemic euglycemic clamp in obesePCOS girls vs matched obese control girls. Lower panel: insulinsensitivity in PCOS versus obese control girls. (See completecaption on p. 163.)

Color Plate 8. Fig. 3, Chapter 11: First-phase and second-phase insulin secretionduring a hyperglycemic clamp (upper panel), insulin sensitivity(left lower panel), and glucose disposition index (GDI) (rightlower panel) in PCOS adolescents with impaired (IGT) versusnormal (NGT) glucose tolerance. (See complete caption onp. 165.)

Color Plate 9. Fig. 4, Chapter 11: Change in (�) hormone levels (30-min valueminus 0-min value) in response to ACTH stimulation pre- andpost-metformin treatment in adolescents with PCOS. (Seecomplete caption on p. 173.)

xv