DIAGNOSIS AND MANAGEMENT OF POLYCYSTIC OVARY SYNDROME · Nadir R. Farid Evanthia Diamanti-Kandarakis Editors DIAGNOSIS AND MANAGEMENT OF POLYCYSTIC OVARY SYNDROME 123 Editors NadirR.Farid EvanthiaDiamanti-Kandarakis TheLondonEndocrineClinic UniversityofAthensMedicalSchool 21WimpoleStreet Athens,Greece LondonWIG8GG [email protected] [email protected] ISBN978-0-387-09717-6 e-ISBN978-0-387-09718-3 DOI10.1007/978-0-387-09718-3 LibraryofCongressControlNumber:2008934726 (cid:2)c SpringerScience+BusinessMedia,LLC2009 Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewrittenpermissionofthepublisher(Springer Science+BusinessMedia,LLC.,233SpringStreet,NewYork,NY10013,USA),exceptforbriefexcerptsinconnectionwithreviewsor scholarlyanalysis.Useinconnectionwithanyformofinformationstorageandretrieval,electronicadaptation,computersoftware,orby similarordissimilarmethodologynowknownorhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,eveniftheyarenotidentifiedassuch,isnottobe takenasanexpressionofopinionastowhetherornottheyaresubjecttoproprietaryrights. Whiletheadviceandinformationinthisbookarebelievedtobetrueandaccurateatthedateofgoingtopress,neithertheauthorsnorthe editorsnorthepublishercanacceptanylegalresponsibilityforanyerrorsoromissionsthatmaybemade.Thepublishermakesnowarranty, expressorimplied,withrespecttothematerialcontainedherein. Printedonacid-freepaper springer.com Preface ConsultingcitationtrendsinPubMedforkeywordsorphrasesisinstructiveastotheinterestofthescientific communityinthesubjectandbyinferenceitscurrencyandlikelyimportance.Inthe5yearsbetween1985and 1989therewere91papersonPCOS.Therateescalatedrapidlyinthenexthalf-decadesto727,1642,and4355, 2005–July 2008. Insulin resistance was more topical and references reference to the term increased rapidly: 1995–1999,8517,2000–2004,21,828andin2005–July2008onlyroseto48,914. TheobservationthatmostwomenwithPCOSareinsulinresistanthasbeenanimportantturningpoint.From beingpredominantlythedomainofgynaecologistsasanovariandisorder,PCOSwasthereafterrecognizedas aheterogeneous metabolic disorderwithpolycystic ovaries aspartofitsmanifestations.Wehave sincelearnt thatnotallwomenwithPCOSareinsulinresistant,apparentlythispredominatesinthosewhosufferfromboth hyperandrogenismandanovultion.SomewomenwithPCOSwhohaveapparentlynormalseruminsulinlevels areneverthelessshowincreasedovarianandrogenssecretionatthoselevelsofinsulin. Withthemountingepidemicofinsulinresistance,manydoctorsinpracticeencounterwomenwhoaresymp- tomatic,havemoreorlessregularcycles,aresub-fertile,areatmostslightlyhyperandrogenemic andwithout PCOSovarianmorphology.Thereisnoconsensusonhowtomanagethesewomen.Wealsodonotknowthe rateatwhichuntreatedmildPCOSbecomesmoresevereorthatatwhichwomensatisfyingthecriteriaofThe AndrogenExcessSociety(AES)whoarenotanovulatorybecomesoandapparentlyacquireinsulinresistance. PCOS,acomplexmultigenicdisorder,canhavemajorimpactonqualityoflifewithdepressivetendencies, infertility, obesity, manifestations of hyperandrogenism as well as long term increased risks for diabetes, the metabolic syndrome non-alcoholic fatty liver and cardiovascular disease. These and other issues are expertly laid out in the pages of this book, as is their management. The intuitive expectation that PCOS is associated with increased risk for cardiovascular disease is supported by strong surrogate evidence, although outcome studies are lacking. And for now at least an increased risk for women who had PCOS and have entered the menopauseistentative. Theauthors,allinternationalexpertsintheirareasofcontribution,clearlayouttheproblem,offerpractical advice in the management of various aspects of the syndrome and raise question where current knowledge is incompleteornewdataisnecessary. Theideaofthisbookaroseoutofaconsensusamongthecontributingauthorsandmanyothersweconsulted with that knowledge about the diagnosis, health implications and up-to-date management of PCOS among communitydoctorsandtraineesisatbestincompleteandatmostspotty.Thisbookisanefforttoredressthat deficit. That this book has materialized at all is thanks to the efforts of Ms Laura Walsh who worked hard to find anicheforthisbookintheranksofwhatnowbecomeoneofthelargestpublishinghousesintheworld.Mrs MaureenTobinkeptusallontrack,andhasdoneawonderfulorganizationaljob...allveryquietly. ItwasanimmensepleasureformetoworkagainwithMaureenandLauraonanewsuccessfulproject. NadirR.Farid v Contents PartI TheSyndrome 1 ClinicalManifestationsofPCOS........................................................ 3 PasqualiRenato 2 TheMenstrualCycleinPCOS.......................................................... 15 SabrinaGillandJanetE.Hall 3 TheRadiologyofPolycysticOvaries..................................................... 23 SusanJ.Barter PartII Origins 4 InsulinResistanceinPCOS ............................................................ 35 EvanthiaDiamanti-KandarakisandCharikleiaD.Christakou 5 GeneticsofMetabolicSyndromeandGeneticLipodystrophies ............................. 63 TishaR.JoyandRobertA.Hegele 6 TheGeneticsofPolycysticOvarySyndrome.............................................. 83 BradEilerman,MarziehSalehi,andYaronTomer 7 UterineOriginsandEvolutioninChildhood.............................................. 93 AgathoclesTsatsoulisandNectariaXita PartIII Consequences 8 HyperandrogenisminPCOS ........................................................... 105 NeoklisA.Georgopoulos,EleniKandaraki,andDimitriosPanidis 9 TheRiskofDiabetesandMetabolicSyndromeinPCOS................................... 111 ThomasM.Barber 10 TheRisksofCardiovascularDiseaseandDiabetes inthePolycysticOvarySyndrome....................................................... 121 SusmeetaT.SharmaandJohnE.Nestler vii viii Contents 11 PregnancyComplicationsinPCOS...................................................... 135 RoyHomburg 12 PolycysticOvarySyndrome,SleepApnea,andDaytimeSleepinessandFatigue .............. 143 AlexandrosN.VgontzasandSusanCalhoun 13 PolycysticOvarianSyndromeandGynaecologicalCancer ................................. 155 AlexandraLawrenceandW.PeterMason 14 PCOS,Depression,andAlzheimer’sDisease.............................................. 167 PascaleG.Stemmle,HeatherA.Kenna,andNatalieL.Rasgon 15 PsychologicalIssuesandTheirTreatment................................................ 181 MelissaJ.HimeleinandSamuelS.Thatcher PartIV Management 16 DietaryManagementofPCOS.......................................................... 191 KateMarsh 17 ExerciseintheTreatmentofPCOS...................................................... 203 EmmaStevenson 18 MedicalTreatment .................................................................... 209 Jean-PatriceBaillargeonandNadirR.Farid 19 TherapyofHirsutism.................................................................. 233 SalvatoreBenvenga 20 OvulationInductioninPCOS .......................................................... 243 EvertJ.P.vanSantbrink 21 IVFinPolycysticOvarySyndrome...................................................... 253 RehanSalimandPaulSerhal 22 TheSurgicalManagementofPolycysticOvarianSyndrome................................ 259 ColinJ.Davis 23 WhenPeriodsStop:Long-TermConsequencesofPCOS................................... 265 EnricoCarmina,EttoreGuastella,andManfrediRizzo Index .................................................................................... 271 Contributors Jean-PatriceBaillargeon Associate Professor, Departments of Medicine and Physiology/Biophysics, Director, Program of Endocrinology and Metabolism, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada, Jean- [email protected] ThomasM.Barber,MA(Hons),MBBS,MRCP(UK) Research Fellow and Specialist Registrar, Department of Endocrinology, Oxford Centre for Diabetes, EndocrinologyandMetabolism,UniversityofOxford,Oxford,UK,[email protected] SusanJ.Barter,MBBS,MRCP,DMRD,FRCR Consultant Radiologist, Addenbrookes Hospital University Trust, Hills Road, Cambridge CB2 2QQ, UK, [email protected] SalvatoreBenvenga,MD Master on Childhood, Adolescent and Women’s Endocrine Health, University of Messina, Programma di EndocrinologiaMolecolareClinica,A.O.U.PoliclinicoG.Martino,PadiglioneH,4piano,98125Messina, Italy,[email protected] SusanCalhoun,PhD SleepResearchandTreatmentCenter,DepartmentofPsychiatry,PennsylvaniaStateUniversityCollegeof Medicine,Hershey,PA,USA,[email protected] EnricoCarmina,MD,PhD Professor of Medicine, Professor of Endocrinology and Head of Endocrine Unit, Department of Clinical Medicine,UniversityofPalermo,ViadelleCroci4790139Palermo,Italy,[email protected] CharikleiaD.Christakou,MD EndocrineSectionofthe1stDepartmentofMedicine,UniversityofAthens,MedicalSchool,Athens,Greece, [email protected] ColinJDavis ConsultantObstetricianandGynaecologist,StBartholomewsHospitalLondon,London,UK, [email protected] EvanthiaDiamanti-Kandarakis,MD EndocrineSectionofthe1stDepartmentofMedicine,UniversityofAthens,MedicalSchool,Athens,Greece, [email protected] BradEilerman,MD DivisionofEndocrinology,DepartmentofMedicine,UniversityofCincinnatiCollegeofMedicine,TheVontz CenterforMolecularStudies,Cincinnati,OH45267,USA NadirR.Farid,MD TheLondonEndocrineClinic,21WimpoleStreet,LondonWIG8GG,[email protected] ix x Contributors NeoklisA.Georgopoulos,MD DepartmentofObstetricsandGynecology,DivisionofReproductiveEndocrinology,PatrasMedicalSchool, Greece,[email protected] SabrinaGill,MD DivisionofEndocrinology&Metabolism,St.Paul’sHospitalandUniversityofBritishColumbia,Vancouver, BC,Canada,[email protected] EttoreGuastella DepartmentofObstetricsandGynecology,UniversityofPalermo,Palermo,Italy,ettore [email protected] JanetE.Hall,MD Reproductive Endocrine Unit,Massachusetts GeneralHospitaland Harvard MedicalSchool, Boston, MA, USA,[email protected] RobertA.Hegele,MD Director,BlackburnCardiovascularGeneticsLaboratory,Scientist,VascularBiologyResearchGroup,Robarts ResearchInstitute,406-100PerthDrive,London,Ontario,CanadaN6A5K8,[email protected] MelissaJ.Himelein,PhD ProfessorofPsychology,UniversityofNorthCarolinaatAsheville,LicensedPsychologist,CenterforApplied ReproductiveScience,JohnsonCity,TN,&Asheville,NC,USA,[email protected] RoyHomburg,FRCOG ProfessorofReproductiveMedicine,VUUniversityMedicalCentre,1007MBAmsterdam,theNetherlands; IVF,DepartmentofObstetricsandGynecology,BarzilaiMedicalCenter,Ashkelon,Israel,[email protected] TishaR.Joy RobartsResearchInstitute,406–100PerthDrive,London,Ontario,CanadaN6A5K8,[email protected] EleniKandaraki,MD SecondDepartmentofObstetricsandGynecology,DivisionofHumanReproduction,AristotleUniversityof Thessaloniki,Greece,[email protected] HeatherA.Kenna,MA DepartmentofPsychiatryandBehavioralSciences,StanfordUniversity,SchoolofMedicine,Stanford,CA, USA,[email protected] AlexandraLawrence,MD,MRCOG SubspecialityTraineeinGynaecologicalOncology,HammersmithHospital,DuCaneRoad,London,W12 0HS,UK,[email protected] KateMarsh,BSc,MNutrDiet,GradCertDiabEdn&Mgt AdvancedAccreditedPractisingDietitian(AdvAPD)andCredentialledDiabetesEducator(CDE),ThePCOS Health&NutritionCentre,Sydney,Australia,[email protected] W.PeterMason,MD Gynaecological Oncologist, Chairman North West London Network, Hammersmith Hospital NHS Trust, London,UK,[email protected] JohnE.Nestler,MD DivisionofEndocrinologyandMetabolism,VirginiaCommonwealthUniversity,Richmond,VA23298-0111, USA,[email protected] DimitriosPanidis SecondDepartmentofObstetricsandGynecology,DivisionofHumanReproduction,AristotleUniversityof Thessaloniki,Greece,[email protected] Contributors xi NatalieL.Rasgon,MD,PhD DepartmentofPsychiatryandBehavioralSciencesStanfordUniversity,SchoolofMedicine,Stanford,CA, USA,[email protected] PasqualiRenato DivisionofEndocrinology,DepartmentofInternalMedicine,S.Orsola-MalpighiHospital,UniversityAlma MaterStudiorum,ViaMassarenti9,40138,Bologna,Italy,[email protected] ManfrediRizzo Department of Clinical Medicine, University of Palermo, Via delle Croci 47, 90139 Palermo, Italy, [email protected] MarziehSalehi,MD DivisionofEndocrinology,DepartmentofMedicine,UniversityofCincinnatiCollegeofMedicine,Cincinnati, OH,USA,[email protected] RehanSalim,MD,MRCOG AssistedConceptionUnit,UniversityCollegeLondon,London,UK,[email protected] PaulSerhal,MBBS,MRCOG AssistedConceptionUnit,UniversityCollegeLondon,LondonWC1X8LD,[email protected] SusmeetaT.Sharma,MBBS DepartmentofInternalMedicine,UniversityofFlorida,Gainesville,FL,USA,[email protected] PascaleG.Stemmle,BS DepartmentofPsychiatryandBehavioralSciences,StanfordUniversity,SchoolofMedicine,Stanford,CA, USA,[email protected] EmmaStevenson,MD SchoolofPsychologyandSportsSciences,NorthumbriaUniversity,NewcastleUponTyne,NE18ST,UK, [email protected] SamuelS.Thatcher,MD,PhD Director,CenterforAppliedReproductiveScience,JohnsonCity,TNandAsheville,NC,USA YaronTomer,MD,FACP DivisionofEndocrinology,UniversityofCincinnatiCollegeofMedicine,TheVontzCenterforMolecular Studies,Cincinnati,OH45267,USA,[email protected] AgathoclesTsatsoulis,MD,PhD,FRCP ProfessorofMedicine/Endocrinology,DepartmentofEndocrinology,UniversityofIoannina,Ioannina,45110, Greece,[email protected] EvertJPvanSantbrink,MD,PhD SeniorconsultantinReproductiveMedicine,DivisionofReproductiveMedicine,DepartmentofObstetrics andGynecology,ErasmusMedicalCenter,Rotterdam,theNetherlands,[email protected] AlexandrosN.Vgontzas,MD SleepResearchandTreatmentCenter,DepartmentofPsychiatry,PennsylvaniaStateUniversityCollegeof Medicine,Hershey,PA17033,USA,[email protected] NectariaXita,MD DepartmentofEndocrinology,UniversityofIoannina,Ioannina,45110,Greece,[email protected]