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Assistedreproductiontechniques Challengesandmanagementoptions

Tomymotherandfather,Zena,OmarandAbdallah(KS)

ToDukaydah,Abdea,Tara,Leela,Amma,Appa,Poongoaunti andDharini(AC)

Assistedreproduction techniques Challengesandmanagement options

EDITEDBY

KhaldounSharif MBBCh,MD,FRCOG,MFFP

ConsultantinReproductiveMedicineandSurgery

ClinicalDirector

IstishariFertilityCenter

IstishariHospital

Amman Jordan

ArriCoomarasamy MBChB,MD,MRCOG ProfessorofGynaecology

SubspecialistinReproductiveMedicineandSurgery

UniversityofBirminghamandBirminghamWomen’sHospital Birmingham UK

A John Wiley & Sons, Ltd., Publication

Thiseditionfirstpublished2012 C 2012byBlackwellPublishing

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LibraryofCongressCataloging-in-PublicationData

Assistedreproductiontechniques:challengesandmanagementoptions/editedbyKhaldounSharif, ArriCoomarasamy. p.;cm. Includesbibliographicalreferencesandindex.

ISBN-13:978-1-4443-3555-2(hardcover:alk.paper)

ISBN-10:1-4443-3555-3(hardcover:alk.paper)1.Humanreproductivetechnology–Case studies.I.Sharif,KhaldounW. II.Coomarasamy,Arri.

[DNLM:1.ReproductiveTechniques,Assisted–CaseReports.2.Infertility–complications–Case Reports.3.Pregnancy–physiology–CaseReports.4.ReproductiveHealthServices–manpower–Case Reports.5.RiskAssessment–CaseReports.WQ208] RG133.5.A78572012

618.1 7806–dc23

2011017803

AcataloguerecordforthisbookisavailablefromtheBritishLibrary. Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprint maynotbeavailableinelectronicbooks.

Setin9/11.5ptSabonbyAptara R Inc.,NewDelhi,India

012012

Contents

Contributors,xi

Preface,xxii

Howtousethisbook,xxiii

Section1:Counselingandpreparationphase

1Riskofcancerfromovarianstimulation,3 NikosKanakas,MiltiadisPitsosandThemisMantzavinos

2RiskofearlymenopausefollowingIVFtreatment,7 SeshKamalSunkara

3TheHIVpositivefemale,9 JoshuaU.KleinandMarkV.Sauer

4TheHIVpositivemale,13 MarkV.SauerandJoshuaU.Klein

5ThehepatitisB/Ccarrierpatient,17 SuzanneP.M.Lutgens,I.H.M.VanLoo,E.C.M.Nelissenand G.A.J.Dunselman

6Thepatientwithcysticfibrosis,21 TarekEl-Toukhy

7Thepatientonmedication,25 ArriCoomarasamy

8Thepatientwiththrombophilia,29 YingC.CheongandN.S.Macklon

9Thepatientwithautoimmunedisorders,34 Jos ´ eBellver

10Thepatientwithmalignantdisease:fertilitypreservation,38 ArriCoomarasamy

11Thepatientwithheartdisease,43 NatashaThorogoodandCatherineNelson-Piercy

12Thepatientwithdiabetes,48 NeelamPotdarandJustinC.Konje

13Thepatientwiththyroiddisease,51 ShiaoChan

14Thepatientwithhyperprolactinemia,56 JohnAyuk

15Thepatientwithpolycysticovaries,61 AdamH.Balen

16TherenaltransplantpatientandIVF,65 LynneRobinsonandClaraDay

17Thepatientwithpreviouspelvicirradiation,69 VishvanathC.Karande

18Fertilityafterchemotherapy,73 NiveditaReddy

19Thepatientwithabnormalcervicalcytology,77 MahmoodI.Shafi

20Thepatientwithpreviousborderlineovariantumor,80 ArriCoomarasamyandKavitaSingh

21Thepatientwithanendometrioma,83 LucianoG.NardoandOybekRustamov

22Thepatientwithcervicalstenosis,86 KhaldounSharif

23VaccinationandART,90

ArriCoomarasamyandDukaydahvanderBerg

24Thepatientwithhydrosalpinx,95 AnnikaStrandell

25Thepatientwithpoorovarianreserve,99 ScottM.Nelson

26Thepatientwithcongenitaluterineanomalies,105 SarahCreightonandLinaMichala

27Thepatientwithcongenitalcervico-vaginalanomalies,109 SarahCreightonandLinaMichala

28Thepatientwithuterinefibroids,112 HaithamHamodaandYakoubKhalaf

29ThepatientwithpreviousEssure® sterilization,115 T.JustinClark

30Thepatientwithpreviousendometrialablation,119 T.JustinClark

31Thecouplewithrecurrentimplantationfailure,124 TarekEl-Toukhy

32Thepatientwithpreviousuterinearteryembolization,128 HaithamHamodaandYakoubKhalaf

33EndometrialpolypdetectedduringARTtreatment,131 ArriCoomarasamy

34Theobesepatient,135

MostafaMetwallyandBolarindeOla

35Ashermansyndrome,139 DanYu,EnlanXiaandT.C.Li

36Theolderpatient,142 WilliamLedger

37RequestsformildornaturalcycleIVFtreatment,146 BradB.SwelstadandSuheilJ.Muasher

38TheARTpatientwithpsychosexualproblems,150 SueElkin

39Thepatientneedingthird-partyreproduction,153 MadhurimaRajkhowa

40Requestfor“socialeggfreezing”,159 ValerieL.PeddieandSiladityaBhattacharya

41Thepatientwithbariatricsurgery,165 ZaherO.MerhiandHarryJ.Lieman

Section2:Pituitarysuppressionandovarian stimulationphase

42Poorresponseduringovarianstimulation,171 LynneRobinsonandArriCoomarasamy

43OvarianstimulationforIVFinapatientwithprevioussevereovarian hyperstimulationsyndrome,175 KhaldounSharif

44Unabletoachievepituitarydown-regulation,178 K.JayaprakasanandNickRaine-Fenning

45Thepatientdiscoveredpregnantduringpituitarydown-regulation,184 MohammedKhairyMahmoudandArriCoomarasamy

46Ovariancystsfollowingpituitarydown-regulation,188 AlisonTaylor

47Poorendometrialdevelopment,192 LynneRobinsonandArriCoomarasamy

48MissedIVFmedications,201 LynneRobinsonandArriCoomarasamy

49Thepatientwithahistoryofestrogen-receptorpositivecancer,205 MuratSonmezerandKutlukOktay

50Thepatientover-respondingtocontrolledovarianstimulationduringIVF,208 KhaldounSharif

Section3:Oocyteretrieval

51Generalanesthesiaorsedationforoocyteretrieval?,215 AndrewF.Malins

52Delayedoocyteretrieval,219 KhaldounSharif

53Emptyfolliclesyndrome,223 GeorgeNdukwe

54Bleedingfollowingoocyteretrieval,227 AnnikaK.LudwigandBarbaraSonntag

55Toflushornottoflushfolliclesatoocyteretrieval?,232 MicahJ.HillandEricD.Levens

56Inaccessibleovariesatoocyteretrieval,236 HazemAl-Rumaih

57Endometrioticcystsatoocyteretrieval,239 GracielaKohlsandJuanA.Garc´ıa-Velasco

Section4:Embryotransfer

58Couplesplittingwhileembryosareinstorage,245 MasoudAfnan

59EndometrialcavityfluididentifiedduringIVFtreatment,249 ArriCoomarasamy

60Difficultembryotransfer,252 KhaldounSharif

61Excessivecervicalmucusandretainedembryoatembryotransfer,257 HassanN.Sallam,AhmedF.GalalandFadyS.Moeity

62Lifeafterembryotransfer,261 KeltonTremellen

Section5:Thelutealphase

63VaginalbleedinginthelutealphaseafterIVF,267 CarolCoughlanandBolarindeOla

64PelvicinfectionafterIVF,271 MuhammadFaisalAslam

65Thepatientpresentingwithovarianhyperstimulationsyndrome,274 KhaldounSharif

66AdnexaltorsionafterIVF,279 SaioaTorrealdayandBethW.Rackow

67ExposuretoinfectioninthelutealphaseofIVF,283 LithaPepasandArriCoomarasamy

Section6:TheARTlaboratory

68TotalfailureoffertilizationafterconventionalIVF-rescueICSI,291 A.AlbertYuzpe

69CouplesnotwishingtocreatesurplusembryosinIVF,296 HossamMohamed

70AneuploidyscreeningforadvancedmaternalageorrepeatedIVFfailure,300 HaithamHamodaandYacoubKhalaf

71Choosinganembryofortransfer,304 DennySakkas

72Globozoospermia,308

StevenMansell,AnneRice,CatherineBeatonandChristopher L.R.Barratt

73TotalfailureoffertilizationafterICSI,313 KaoruYanagida

74Refreezingofembryos,317 JeromeH.Check

75Infectioninembryoculturemedium,320 PeterM.M.Kastrop

76ICSIorIVFinnonmale-factorinfertility?,324 MohamedAboulghar

77TheARTprogramduringanaturalorhuman-madedisaster,328 RichardP.DickeyandCarlaWhite

78UsingthewrongspermorembryosinIVF,331 KhaldounSharifandMutazAl-Ahmad

Section7:Themalepatient

79Unexpectedinabilitytoproduceasemensampleonthedayof oocyteretrieval,337 KhaldounSharif

80Theazoospermicpatient,340 KhaldounSharif

81ARTinmenwithKlinefeltersyndrome,344 RonnieG.FineandDariusA.Paduch

82ARTinmenwith100%immotilesperm,349 CarolinaOrtega-Hrepich,DominiqueRaickandHermanTournaye

83Requestforposthumousfatherhoodwithperimortemsurgical spermretrieval,353 ZamipP.Patel,HeatherE.RossandLawrenceS.Ross

84Retrogradeejaculationandanejaculation,360 AsifMuneerandAnthonyHirsh

85Spermretrievalincanceroustestes,364 SaadAldousariandArmandZini

86LeukocytospermiaandART,367 GiuseppeRicci

87Theinfertilemalepatientwithageneticcause,371 KatherineL.O’FlynnO’BrienandAshokAgarwal 88YchromosomemicrodeletionsandART,376 ShermanJ.Silber

Section8:TheARTpregnancy

89UnexpectednumberorgenderofbabiesafterIVF,383 KhaldounSharif

90SuspectedectopicpregnancyafterIVF,387 VishvanathC.Karande

91CervicalectopicpregnancyafterIVF,391 UshaVerma

92HeterotopicpregnancyafterIVF,396 Abdel-MaguidRamzy

93Multi-fetalpregnancyreductionafterART,400 R.KatieMorrisandMarkD.Kilby

94MultiplepregnancyafterIVF:tocerclageornottocerclage?405 HaroldGee

95HyperreactioluteinalisafterIVF,409 MohammadEbrahimParsanezhad,LeilaForooghiniaand MaryamParsa-Nezhad

96Lactationbyacommissioningmotherinsurrogacy,412 FrankP.BiervlietandStephenL.Atkin

Section9:Generalissues

97DealingwiththeemotionaldistressfollowingfailedIVF,417 LindaHammerBurns

98IVFwhentheprognosisisverypoororfutile,421 KhaldounSharif

99UnexpecteddropintheARTclinicpregnancyrate,425 BulentUrmanandKayhanYakin

100NaturalfertilityafterIVF,430 FrankNawrothandAnnikaK.Ludwig

Index,433

Contributors

MohamedAboulghar MD

Professor,FacultyofMedicine CairoUniversity; ClinicalDirector,TheEgyptianIVFCenter Maadi,Cairo

Egypt

MasoudAfnan MBBS,FRCOG DepartmentChair DepartmentofObstetricsandGynecology

BeijingUnitedFamilyHospital Beijing People’sRepublicofChina

AshokAgarwal PhD Professor,LernerCollegeofMedicine ClevelandClinic Cleveland,OH

USA

MutazAl-Ahmad BSc DirectorofIVFLaboratory IstishariFertilityCenter IstishariHospital Amman

Jordan

SaadAldousari MD ChiefResident DivisionofUrology DepartmentofSurgery McGillUniversity Montreal,QC

Canada

HazemAl-Rumaih MRCOG,MD ConsultantObstetricianandGynecologist, ReproductiveMedicineandSurgery;Directorof IVFUnit MaternityHospital MinistryofHealth

Kuwait

MuhammadFaisalAslam MD,MRCOG AttendingPhysician DepartmentofObstetricsandGynecology

VirginiaRegionalMedicalCenter

Virginia,MN

USA

StephenL.Atkin MBBS,PhD,FRCP Head,AcademicEndocrinology,Diabetesand Metabolism

HullYorkMedicalSchool

MichaelWhiteDiabetesCentre

Hull UK

JohnAyuk MD,MRCP ConsultantEndocrinologist DepartmentofEndocrinology QueenElizabethHospital Birmingham UK

AdamH.Balen MD,DSc,FRCOG ProfessorofReproductiveMedicineandSurgery LeedsTeachingHospitalsNHSTrust Leeds UK

ChristopherL.R.Barratt PhD Professor,ReproductiveandDevelopmentalBiology, MaternalandChildHealthSciencesLaboratories CentreforOncologyandMolecularMedicine UniversityofDundee,NinewellsHopital Dundee

UK

CatherineBeaton BSc

MScStudent

ReproductiveandDevelopmentalBiology,Maternal andChildHealthSciencesLaboratories

CentreforOncologyandMolecularMedicine UniversityofDundee,NinewellsHopital Dundee UK

Jos ´ eBellver MD,PhD Gynecologist,DepartmentofHumanReproduction InstitutoValencianodeInfertilidad; AssociateProfessor DepartmentofPediatrics,ObstetricsandGynecology FacultyofMedicine UniversityofValencia Valencia Spain

SiladityaBhattacharya MD,FRCOG ProfessorofReproductiveMedicineandHonorary Consultant

DivisionofAppliedHealthSciences,Schoolof MedicineandDentistry UniversityofAberdeen AberdeenMaternityHospital Aberdeen UK

FrankP.Biervliet MRCOG ConsultantinObstetricsandGynaecology HullandEastYorkshireWomenandChildren’s Hospital Hull UK

LindaHammerBurns PhD AssociateProfessor DepartmentofObstetrics,Gynecologyand Women’sHealth UniversityofMinnesotaMedicalSchool DirectorofCounselingServices

ReproductiveMedicineCenter Minneapolis,MN USA

ShiaoChan PhD,MRCOG SeniorClinicalLecturer SchoolofClinicalandExperimentalMedicine UniversityofBirmingham Birmingham UK

JeromeH.Check MD,PhD Professor,ObstetricsandGynecology DivisionHeadofReproductiveEndocrinologyand Infertility

RobertWoodJohnsonMedicalSchoolatCamden Camden,NJ USA

YingC.Cheong MBChB,BAO,MA,MD,MRCOG SeniorLecturerandHonoraryConsultantin ObstetricsandGynaecology,Subspecialistin ReproductiveMedicineandSurgery

AcademicUnitofHumanDevelopmentandHealth FacultyofMedicine UniversityofSouthampton; ClinicalDirector CompleteFertilityCentre PrincessAnneHospital Southampton UK

T.JustinClark MBChB,MD,MRCOG ConsultantinObstetricsandGynaecology BirminghamWomen’sHospital Birmingham UK

ArriCoomarasamy MBChB,MD,MRCOG ProfessorofGynaecology

SubspecialistinReproductiveMedicineandSurgery UniversityofBirminghamand BirminghamWomen’sHospital Birmingham UK

CarolCoughlan MRCOG,MRCPI

SubspecialtyTraineeinReproductiveMedicineand Surgery

DepartmentofReproductiveMedicine JessopWing,RoyalHallamshireHospital Sheffield

UK

SarahM.Creighton MD,FRCOG ConsultantGynaecologist UniversityCollegeLondonHospitals London UK

ClaraDay BMBCh,MRCP,PhD ConsultantNephrologist DepartmentofRenalMedicine QueenElizabethHospital Birmingham UK

RichardP.Dickey MD,PhD MedicalDirector,FertilityInstituteofNewOrleans Mandeville,LA; Chairman,SectionofReproductiveEndocrinology andInfertility DepartmentofObstetricsandGynecology

LouisianaStateUniversitySchoolofMedicine NewOrleans,LA

USA

G.A.J.Dunselman MD,PhD Gynecologist DepartmentofObstetricsandGynecology ResearchInstituteGrowthandDevelopment MaastrichtUniversityMedicalCenter Maastricht TheNetherlands

SueElkin

GynaecologyNurseCounsellor BirminghamWomen’sHospital Birmingham UK

TarekEl-Toukhy MBBChMScMDMRCOG ConsultantinReproductiveMedicineandSurgery AssistedConceptionUnitandPGDCentre Guy’sandStThomas’HospitalNHSFoundation Trust

London

UK

RonnieG.Fine MD ChiefResident DepartmentofUrology

NewYorkPresbyterianHospital/WeillCornell MedicalCenter NewYork,NY

USA

LeilaForooghinia AssistantProfessor

DepartmentofObstetricsandGynecology

ShirazUniversityofMedicalSciences

Shiraz

Iran

AhmedF.Galal MD SeniorLecturer DepartmentofObstetricsandGynecology UniversityofAlexandria

Alexandria

Egypt

JuanA.Garc´ıa-Velasco MD,PhD AssociateProfessorofObstetricsandGynecology DepartmentofHumanReproduction ReyJuanCarlosUniversity; Director,IVIMadrid

Madrid

Spain

HaroldGee MD,FRCOG FormerMedicalDirector BirminghamWomen’sHospital Birmingham UK

HaithamHamoda MD,MRCOG ConsultantGynaecologist,Subspecialistin

ReproductiveMedicineandSurgery

TheAssistedConceptionUnit King’sCollegeHospital

London UK

MicahJ.Hill DO ClinicalFellow,PrograminReproductiveandAdult Endocrinology

EuniceKennedyShriverNationalInstituteofChild HealthandHumanDevelopment NationalInstitutesofHealth Bethesda,MD

USA

AnthonyHirsh MBBS,DRCOG,FRCS

ConsultantinAndrology,WhippsCrossUniversity Hospital

Hon.SeniorLecturerinAndrology,Guy’sand StThomas’Hospital,andTheLondon MedicalCentre

London UK

KannamannadiarJayaprakasan MBBS, MRCOG,PhD

AssociateProfessorandSubspecialistin ReproductiveMedicineandSurgery DivisionofObstetricsandGynaecology SchoolofClinicalSciences

Queen’sMedicalCentre UniversityofNottingham

Nottingham UK

NikosKanakas MD,PhD ConsultantinObstetricsandGynecology

Embryoland–CenterforAssistedReproduction

Athens Greece

VishvanathC.Karande MD President,MedicalDirector,DirectorIVFProgram DepartmentofReproductiveEndocrinologyand Infertility

InViaFertilitySpecialists HoffmanEstates,IL

USA

PeterM.M.Kastrop PhD ClinicalEmbryologist DepartmentofReproductiveMedicineand Gynecology UniversityMedicalCenterUtrecht Utrecht

TheNetherlands

MarkD.Kilby MD,FRCOG ProfessorofFetalMedicine SchoolofClinicalandExperimentalMedicine CollegeofMedicalandDentalSciences UniversityofBirmingham Birmingham UK

YakoubKhalaf MD,FRCOG ConsultantGynaecologist,Subspecialistin ReproductiveMedicineandSurgery Director,TheAssistedConceptionUnitandCentre forPreimplantationGeneticDiagnosis Guy’sandStThomas’Hospital London UK

JoshuaU.Klein MD Fellow,ReproductiveEndocrinologyandInfertility DepartmentofObstetricsandGynecology

ColumbiaUniversityMedicalCenter NewYork,NY

USA

GracielaKohls MD Gynecologist DepartmentofHumanReproduction IVIMadrid

Madrid Spain

JustinC.Konje MD,FRCOG

ProfessorofObstetricsandGynaecology

ReproductiveSciencesSection UniversityofLeicesterandUniversityHospitals ofLeicester Leicester UK

WilliamLedger MA,DPhil,BMBCh,FRCOG, FRANZCOG

ProfessorandHeadofDepartmentofObstetricsand GynaecologySchoolofWomen’sandChildren’s Health UniversityofNewSouthWales Randwick,NSW

Australia

EricD.Levens MD AttendingPhysician

PrograminReproductiveandAdultEndocrinology EuniceKennedyShriverNationalInstituteofChild HealthandHumanDevelopment NationalInstitutesofHealth Bethesda,MD; ShadyGroveFertilityReproductiveScienceCenter Rockville,MD

USA

T.C.Li MD,PhD,FRCOG,FRCP(Glasgow)

ConsultantinObstetricsandGynaecology

HonoraryProfessorofReproductiveMedicineand Surgery

SheffieldTeachingHospitals

Sheffield

UK

HarryJ.Lieman MD

AssociateProfessorandInterimDirectorofthe DivisionofReproductiveEndocrinologyand Infertility

AlbertEinsteinCollegeofMedicine; MedicalDirectorMontefiore’sInstitutefor ReproductiveMedicineandHealth MontefioreMedicalCenter Bronx,NY USA

AnnikaK.Ludwig MD,PhD ProfessorofObstetricsandGynecology ZentrumfurEndokrinologie,Kinderwunschund PranataleMedizin Hamburg Germany

SuzanneP.M.Lutgens MD,PhD TraineeMedicalMicrobiologist DepartmentofMedicalMicrobiology ResearchInstituteGrowthandDevelopment MaastrichtUniversityMedicalCenter Maastricht TheNetherlands

N.S.Macklon MBChB,MD,MNVOG,FRCOG ProfessorofObstetricsandGynaecology DivisionofHumanDevelopmentandHealth UniversityofSouthampton; Director,CompleteFertilityCentreSouthampton PrincessAnneHospital Southampton UK

MohammedKhairyMahmoud MD, MRCOG SpecialistRegistrarinObstetricsandGynaecology StJohnHospital Livingston UK

AndrewF.Malins MBChB,FRCA ConsultantAnaesthetist DepartmentofAnaesthetics BirminghamWomen’sHospital Birmingham UK

StevenMansell BSc ReproductiveandDevelopmentalBiology,Maternal andChildHealthSciencesLaboratories CentreforOncologyandMolecularMedicine UniversityofDundee,NinewellsHopital Dundee UK

ThemisMantzavinos MD,PhD Professor,ObstetricsandGynecology

Embryoland–CenterforAssistedReproduction AretaieioHospital

Athens

Greece

ZaherO.Merhi MD ClinicalFellow

DepartmentofObstetricsandGynecologyand Women’sHealth DivisionofReproductiveEndocrinology andInfertility

MontefioreMedicalCenter/AlbertEinsteinCollege ofMedicine

Bronx,NY

USA

MostafaMetwally MRCOG,MD

ConsultantGynaecologistandSubspecialistin ReproductiveMedicineandSurgery NinewellsHospitalandMedicalSchool

Dundee

UK

LinaMichala MRCOG LecturerinPediatricandAdolescentGynecology UniversityofAthens

Athens

Greece

FadyS.Moeity MD SeniorLecturer DepartmentofObstetricsandGynecology UniversityofAlexandria

Alexandria

Egypt

HossamMohamed MBBCh,MD,FRCOG ConsultantinGynaecologyandReproductive Medicine

JamesCookUniversityHospital Middlesbrough

UK

R.KatieMorris PhD,MRCOG

NIHRClinicalLecturerandSubspecialtyTraineein MaternalandFetalMedicine SchoolofClinicalandExperimentalMedicine CollegeofMedicalandDentalSciences UniversityofBirmingham

Birmingham

UK

SuheilJ.Muasher MD AssociateProfessor DepartmentofGynecologyandObstetrics DivisionofReproductiveEndocrinologyand Infertility

JohnsHopkinsSchoolofMedicine

Baltimore,MD

USA

AsifMuneer BSc,MBChB,FRCSEd,FRCS(Eng), FRCS(Urol),MD ConsultantinUrologicalSurgeryandAndrology UniversityCollegeLondonHospital,andTheHarley StreetClinic

London

UK

LucianoG.Nardo MD,MRCOG Director,ConsultantGynaecologistand ReproductiveSurgeon DepartmentofGynaecologyandReproductive Medicine

GyneHealth

Manchester

UK

FrankNawroth MD,PhD ProfessorofObstetricsandGynecology ZentrumfurEndokrinologie,Kinderwunschund PranataleMedizin

Hamburg

Germany

GeorgeNdukwe FWACS,FRCOG MedicalDirectorandConsultantinReproductive Medicine

ZitaWestAssistedFertilityClinics

London

UK

EwkaC.M.Nelissen MD TraineeGynecologist

DepartmentofObstetricsandGynecology ResearchInstituteGrowthandDevelopment

MaastrichtUniversityMedicalCenter Maastricht

TheNetherlands

ScottM.Nelson BSc,MBChB,PhD,MRCOG MuirheadChairinObstetricsandGynaecology SchoolofMedicine UniversityofGlasgow Glasgow UK

CatherineNelson-Piercy MBBAS,FRCP, FRCOG ProfessorofObstetricMedicineandConsultant ObstetricPhysician

DepartmentofWomen’sHealth Guy’sandStThomas’FoundationTrustand ImperialCollegeHealthcareTrust

London

UK

KatherineL.O’FlynnO’Brien BA ResearchAssistant

CenterforReproductiveMedicine ClevelandClinic Cleveland,OH USA

KutlukOktay

Director,DivisionofReproductiveMedicine, LaboratoryofMolecularReproductionand FertilityPreservation

DepartmentofObstetricsandGynecology InstituteforFertilityPreservationandReproductive Medicine

NewYorkMedicalCollege

NewYork,NY USA

BolarindeOla MBBS,FWACS,FRCOG,MD

ConsultantandHonorarySeniorLecturerin ObstetricsandGynaecology

SubspecialistandTrainingProgrammeDirectorfor ReproductiveMedicineandSurgery

SheffieldTeachingHospitalsNHSFoundationTrust

Sheffield

UK

CarolinaOrtega-Hrepich MD SpecialistinObstetricsandGynecology

SubspecialistinReproductiveMedicine

VisitingClinicalFellow DepartmentofReproductiveMedicine UniversityHospital Dutch-speakingBrusselsFreeUniversity Brussels Belgium

DariusA.Paduch MD,PhD

AssistantProfessorofUrologyandReproductive Medicine

DepartmentofUrologyandReproductiveMedicine

NewYorkPresbyterianHospital/WeillCornell MedicalCenter NewYork,NY USA

M.EbrahimParsanezhad

ProfessorofGynecologyandObstetrics Chairman,DepartmentofGynecologyandObstetrics MedicalSchool

ShirazUniversityofMedicalSciences

Shiraz Iran

MaryamParsa-Nezhad

RoyalCollegeofSurgeonsinIreland–Medical UniversityofBahrain KingdomofBahrain

ZamipP.Patel MD

FellowinReproductiveUrology DepartmentofUrology UniversityofIllinoisatChicago Chicago,IL USA

ValerieL.Peddie RGN,RM,ADM,BA,MSc

ClinicalResearchMidwifeandFertilitySpecialist

ObstetricsandGynaecology,SchoolofMedicine andDentistry

DivisionofAppliedHealthSciences

UniversityofAberdeen

AberdeenMaternityHospital

Aberdeen UK

LithaPepas MBBS,BSc,MRCOG

SubspecialityTraineeinReproductiveMedicine

StBartholomew’sHospital London UK

MiltiadisPitsos MD,PhD

ConsultantinObstetricsandGynecology

Embryoland–CenterforAssistedReproduction

Athens

Greece

NeelamPotdar MD,MRCOG

ClinicalLecturerandSubspecialistTrainee ReproductiveMedicine

ReproductiveSciencesSection UniversityofLeicesterandUniversityHospitals ofLeicester

Leicester UK

BethW.Rackow MD

AssistantProfessor

DepartmentofObstetrics,Gynecologyand ReproductiveSciences

YaleUniversitySchoolofMedicine

NewHaven,CT USA

DominiqueRaick PhD

HeadoftheARTLaboratory ClinicSaint-Vincent

Rocourt

Belgium

NicholasRaine-Fenning MBChBMRCOGPhD

AssociateProfessorandReaderofReproductive MedicineandSurgery

DirectorofResearchNottinghamUniversity ResearchandTreatmentUnitinReproduction DivisionofObstetricsandGynaecology,Schoolof ClinicalSciences

Queen’sMedicalCentre UniversityofNottingham

Nottingham

UK

MadhurimaRajkhowa MD,FRCOG ConsultantGynaecologist,Subspecialistin ReproductiveMedicine

DepartmentofObstetricsandGynaecology

BirminghamWomen’sHospital Birmingham UK

Abdel-MaguidRamzy MBBCh,MSc,MD Professor,DepartmentofObstetricsandGynecology KasrAl-AiniFacultyofMedicine

CairoUniversity; ConsultantinReproductiveMedicineandSurgery, DirectorofResearchandTrainingAssisted ConceptionUnit,CairoUniversity

Cairo

Egypt

NiveditaReddy MRCOG AssociateSpecialist,ReproductiveMedicine AssistedConceptionUnit

Guy’sHospital

London

UK

AnneRice BSc

ReproductiveandDevelopmentalBiology,Maternal andChildHealthSciencesLaboratories CentreforOncologyandMolecularMedicine UniversityofDundee,NinewellsHospital

Dundee

UK

GiuseppeRicci MD

AssociateProfessorofObstetricsandGynecology DepartmentofMedicalSciences UniversityofTrieste; Director,AssistedReproductionUnit InstituteforMaternalandChildHealth

IRCCSBurloGarofolo Trieste Italy

LynneRobinson MBChB,MD,MRCOG SubspecialityRegistrarinReproductiveMedicine BirminghamWomen’sHospital Birmingham UK

HeatherE.Ross JD SpecialistinReproductiveLaw FoundingPartner,RossandZuckerman,LLP Chicago,IL

USA

LawrenceS.Ross MD PastPresidentAmericanUrologicalAssociation ClarenceC.SaelhofProfessorEmeritus DepartmentofUrology UniversityofIllinoisatChicago Chicago,IL

USA

OybekRustamov MBBS,MRCOG ClinicalResearchFellowinReproductiveMedicine StMary’sHospital CentralManchesterUniversityHospitalsNHS FoundationTrust Manchester UK

DennySakkas PhD ChiefScientificOfficer MolecularBiometricsInc. Norwood,MA USA

HassanN.Sallam MD,FRCOG,PhD ProfessorinObstetricsandGynecology UniversityofAlexandria Alexandria Egypt

MarkV.Sauer MD ProfessorandViceChairman,Departmentof ObstetricsandGynecology Chief,DivisionofReproductiveEndocrinologyand Infertility

ColumbiaUniversity,CollegeofPhysiciansand Surgeons

ColumbiaUniversityMedicalCenter NewYork,NY

USA

MahmoodI.Shafi, MBBCh,MD,DA,FRCOG ConsultantGynaecologicalSurgeonandOncologist DepartmentofGynaecologicalOncology

Addenbrooke’sHospital CambridgeUniversityHospitalsNHSFoundation Trust

Cambridge UK

KhaldounSharif MBBCh,MD,FRCOG,MFFP ConsultantinReproductiveMedicineandSurgery ClinicalDirector

IstishariFertilityCenter IstishariHospital Amman

Jordan

ShermanJ.Silber MD Director InfertilityCenterofStLouis StLuke’sHospital StLouis,MO USA; ProfessorofReproductiveMedicine UniversityofAmsterdamFacultyofMedicine Amsterdam

TheNetherlands

KavitaSingh MD,MRCOG ConsultantGynaecologist

Pan-BirminghamWomen’sGynaecological CancerCentre CityHospital

Birmingham UK

MuratS ¨ onmezer MD

AssociateProfessor

DepartmentofObstetricsandGynecologyand CenterforResearchonHumanReproduction

AnkaraUniversitySchoolofMedicine

Ankara

Turkey

BarbaraSonntag MD,PhD ZentrumfurEndokrinologie,Kinderwunschund PranataleMedizin

Hamburg Germany

AnnikaStrandell MD,PhD

AssociateProfessor

DepartmentofObstetricsandGynecology SahlgrenskaAcademy UniversityofGothenburg Gothenburg

Sweden

SeshKamalSunkara MBBS,MRCOG

SeniorRegistrarinObstetrics,Gynaecologyand ReproductiveMedicine

AssistedConceptionUnit DepartmentofWomen’sHealth Guy’sandStThomas’NHS FoundationTrust

King’sCollegeLondon

London UK

BradB.Swelstad MD ClinicalandResearchFellow DepartmentofGynecologyandObstetrics DivisionofReproductiveEndocrinologyand Infertility

JohnsHopkinsSchoolofMedicine Baltimore,MD

USA

AlisonTaylor MD,MRCOG ConsultantGynaecologistandSpecialistin

ReproductiveMedicine

TheListerFertilityClinic

London

UK

NataliaThorogood MBBS,BA Consultant

DepartmentofDiabetesandEndocrinology

BristolRoyalInfirmary UniversityHospitalsBristolNHSFoundationTrust

Bristol

UK

SaioaTorrealday MD ClinicalInstructor

DepartmentofObstetrics,Gynecologyand ReproductiveSciences

YaleUniversitySchoolofMedicine

NewHaven,CT

USA

HermanTournaye SeniorMedicalDirector CenterforReproductiveMedicine UniversityHospital

Dutch-speakingBrusselsFreeUniversity

Brussels

Belgium

KeltonTremellen MBBS,PhD,FRANZCOG,CREI MedicalDirector,Repromed AssociateProfessorSchoolofPharmacyandMedical Sciences UniversityofSouthAustralia

Adelaide

Australia

BulentUrman MD AssociateProfessor DepartmentofObstetricsandGynecology KocUniversityFacultyofMedicine

Istanbul

Turkey

DukaydahvanderBerg MBChB,DFFP, DRCOG GeneralPractitioner FrankleyHealthCentre

Birmingham

UK

IngeH.M.vanLoo MD,PhD MedicalMicrobiologist DepartmentofMedicalMicrobiology ResearchInstituteGrowthandDevelopment MaastrichtUniversityMedicalCenter Maastricht TheNetherlands

UshaVerma MD AssociateProfessorofObstetricsandGynecology Director,GynecologicalUltrasoundDivision UniversityofMiamiMillerSchoolofMedicine Miami,FL USA

CarlaWhite Administrator FertilityInstituteofNewOrleans Mandeville,LA USA

EnlanXia MD ProfessorandDirectorofHysteroscopicCenter DepartmentofObstetricsandGynecology FuxingHospital AffiliateofCapitalUniversityofMedicalSciences Beijing China

KayhanYakin MD AssociateProfessor AssistedReproductionUnit AmericanHospital Guzelbahce Istanbul Turkey

KaoruYanagida MD,PhD ProfessorandDirector,CenterforInfertilityandIVF InternationalUniversityofHealthand WelfareHospital Tochigi Japan

DanYu MBBS,MMed SpecialistGynecologist HysteroscopicCenter FuxingHospital

AffiliateofCapitalUniversityofMedicalSciences Beijing China

A.AlbertYuzpe MD,MSc,FRCS(C) EmeritusProfessorofObstetricsandGynecology UniversityofWesternOntario,London,Ontario, Canada; Co-Director,GenesisFertilityCenter Vancouver,BritishColumbia Canada

ArmandZini MD,FRCSC Head,DivisionofUrology DepartmentofSurgery StMary’sHospital Montreal,QC; AssociateProfessorofUrology McGillUniversity,Montreal,QC Canada

Preface

LouiseBrown,theworld’sfirstbabyconceived through invitro fertilization(IVF),wasbornonJuly 25,1978inOldham,England.Sincethen,inarelativelyshorttimeintermsofscientificevolution,over 4millionbabieshavebeenbornworldwidefromIVF treatment.

IVFandotherassistedreproductiontechniques (ART)involvecounseling,medical,surgicalandlaboratorysteps,allcontributingtotheeventualpotential successoftheprocess.Assureasnightfollowsday, ateachstepvariouschallengescouldbeencountered.

TheaimofthisbookistostimulateresourcefulthinkingintheARTpractitionerwhendealingwiththose challenges,byoutliningvariousmanagementoptions, thereasoningbehindthem,andtheevidenceonwhich theyarebased.Thepractitionerwouldthenbebetter equippedtochoosethemostsuitablesolutionthatbest fitstheneedsofeachparticularpatient.

ArriCoomarasamy,Birmingham,UK 2012

Howtousethisbook

Thisisintendedtobeahighlypracticalmanual,providingviablesolutionstoreal-lifeARTproblems.To thisend,themajorsectionsofthebookhavebeen writtenmirroringthepatient’sjourneyintheART process.Inaddition,eachchapterhasbeenwritten concisely,startingwithoneormorecasehistoriesoutliningtheproblem,followedbyadiscussiononhow theproblemoccurred,howitcouldhavebeenprevented,whatmanagementoptionsareavailable,and thereasoningandevidencebehindthem.

Howwillyougetthemostoutofthisbook?We suggestyoureadthecasehistory,andworkoutsome managementsolutionsyourselfbeforereadingtherest ofthechapter.Compareandcontrastyoursolutions withtheoptionsprovidedinthebook.Discusswith yourcolleagues–seniorsandjuniors.Ifyouhavea betteroptionthanwhatisoutlinedinthebook,please letusknow;ifweagreewithyou,wewillacknowledge yourcontributioninthenextedition.

SECTIONONE

Counselingand preparationphase

1

Riskofcancerfromovarian stimulation

NikosKanakas,MiltiadisPitsosandThemisMantzavinos Embryoland–CenterforAssistedReproduction,Athens,Greece

CaseHistory: A36-year-oldwomanhadcontrolledovarianstimulationaspartofIVF treatment,resultinginatermpregnancy2yearspreviously.Followingthat,hermother developedbreastcancerattheageof61years.Nowthepatientdesiresanotherpregnancy butsheisconcernedabouttheriskofcancerduetoovarianstimulation.Howshouldthis patientbecounseled?

Background

Womenwhoundergoovarianstimulationareoften concernedaboutthesafetyofthedrugsandtherisk ofcancer.Oneissuetonoteisthatnulliparityitself isariskfactorfordevelopingbreast[1],ovarian[2] orendometrial[3]cancers.Furthermore,infertilityby itselfisassociatedwithcancerrisks.Ovarianstimulationdrugshavebeenprescribedonlyforafewdecades now,indifferentdosesandduration,andtheirlongtermeffectsarenotyetwellstudied.

Apopulation-basedcohortstudyofwomenwho gavebirthin1974–1976showedthatwomenwhoreceivedanytypeofovulationinductiontreatmenthad increasedriskofdevelopingcanceroverallcompared withwomenwhodidnotreceivetherapy[4].However,itisimportanttonotethatthisstudycompared womenwithinfertilitywithwomenwhoconceived naturally,andthusanydifferenceobservedcouldbe becauseofthefertilitydrugsorinfertilityitself.This ‘comparatorproblem’iscommoninepidemiologic studiesofassistedreproductiontechniques(ART)and cancerrisk.

Managementoptions

Breastcancer

Breastcancerisahormone-relatedcancer;manystudieshaveinvestigatedtheassociationbetweenfertility drugsandbreastcancer.OneDanishcohortstudy includedapproximately54,000womenwithinfertilityfrom1963to1998[5].Inthisstudy,thetreatmentwithinfertilitydrugswasnotassociatedwith breastcancerrisk.Neitherwasthereanassociationwiththenumberofcycles,lengthoffollowup orhistologictypeofmalignancy.Theonlyassociationwasbetweengonadotropinsandbreastcancer inwomenwhoremainednulliparous[5].However, intheJerusalemPerinatalstudy,womenwhounderwentovulationinductionhadanincreasedriskfor developingbreastcancerthoughtheriskdisappeared aftercontrollingforotherfactors,withtheincreased riskremainingonlywhenovulationinductionwas usedforover12months[4].Prolongedexposureto gonadotropinsforsixormorecycleswasassociated withincreasedriskofbreastcancercomparedwith thegeneralpopulationinanotherstudy[6].Acohort

studywhichincluded29,700patientswitharelatively shortfollowupof7yearsfoundatransientincrease intheincidenceofbreastcancertheyearfollowing IVFbutnooverallincreaseintheincidenceduring thefollow-upperiod[7].AgeatthefirstIVFcycle mightbeafactorrelatedwithincreasedriskofbreast cancer,withageover30yearshavinganincreased risk[8],orageover40yearsasshowninanother study[9].Inastudythatconsistedofasmallnumberofpatients,fertilitymedicationsdidnotalterthe breastcancerriskinwomenwith BRCA1 or BRCA2 mutations[10].

Ovariancancer

Infertilityitselfmayincreasetheriskofovariancancer inthosepatientswhodonotsubsequentlyconceive [11].Thereisevidencefroman invitro studythat follicle-stimulatinghormone(FSH)stimulatesovarian cancercellgrowth[12].Alargeretrospectivestudy whichincludedabout12,000patientswithamedianfollowupof18yearsshowedthatinfertilepatientshadahigherriskfordevelopingovariancancer thanthegeneralpopulation;however,therewasno differencebetweeninfertilepatientswhoeitherused orneverusedinfertilitydrugs[13].Ameta-analysis whichincludedbothcase–controlandcohortstudiesfoundthattheincidenceofexposuretoinfertility medicationswassignificantlyhigherinovariancancerpatientsthanthegeneralpopulation[14].However,whenthecomparisonwasbetweenfertilitydrug treatedinfertilepatientsanduntreatedinfertilepatientstherewasatrendtowardslowerovariancancerincidenceinthetreatedgroup[14].Thus,the increaseinovariancancerriskappearsattributable toinfertilityitselfthanovarianstimulationdrugs. Thismeta-analysishighlightedtheimportanceofan appropriatecomparatorgroup(i.e.anuntreatedinfertilegroupratherthanthegeneralpopulation).A studyofpatientswhoweretreatedforinfertilityin the1960sand1970sinSwedendidnotshowany significantriskforovariancancerafterfollowup foralmost30years[15].Acase–controlstudyin theUSAofmorethan3000womenshowedthat womenwhousedclomiphenecitrateforoverayear hadahigherriskofdevelopingovarianmalignancy thanthoseinfertilewomenwhohadneverusedthe drug[16].Apooledanalysisofeightcase–control

studiesshowedthatamongsubfertilenulliparous women,ovariancancerwasnotassociatedwithfertilitydrugusenorlengthofuse[17].Therewas noincreaseofovariancancerincidenceinwomen treatedwithIVFcomparedwiththegeneralpopulationinacohortstudywithashortfollowupof 7years[7].

Endometrialcancer

Endometrialcancerisassociatedwithanovulation andwiththeunopposedeffectofestrogensonthe endometrium[18].Acohortstudyof2496infertile womenwithameanfollowupof21.4yearsshowed anincreasedincidenceofendometrialcancerwhen comparedwiththegeneralpopulation.However,this riskdisappearedwhentreatedinfertilewomenwere comparedwithuntreatedones.Theincreasedriskwas attributedtotheunopposedactionofestrogenswhen researchersstudiedthehormonalstatusofwomen [19].Arecentlypublishedcohortstudywhichincluded54,362infertilewomenreportedthattheuse ofgonadotropinsincreasedtheriskforuterinecancer aftera10-yearfollowup.Theriskofuterinecancerwasalsoincreasedwiththenumberofcyclesof clomiphenecitrateuse[20].IntheJerusalemPerinatalStudy,womenwhoweretreatedwithanovulation inductionmedicationhadahigherriskofdeveloping uterinecancerthanwomenwhoconceivedwithout treatment.Theriskwasevenhigherwhenthetreatmentwaslongerthan12months[4].Aswithbreast cancer,inthesamecohortofwomenwhounderwent IVFwithashortfollowupof7years,therewasa transientincreaseintheincidenceofuterinecancer theyearfollowingIVFwithoutobservingoverallincreaseintheincidenceofuterinecancerduringthe follow-upperiod[7].

Manyofthecurrentstudiesarebasedonepidemiologicdataandfollowupatthetimewhenclomiphene citratewasthemostcommondrugandthemethods ofIVFwithsuperovulationwereeithernotavailable orwereoflimiteduse.Prospectivestudieswillanswer thequestionwhetherovarianstimulationincreasesthe riskofcancer.Atthistime,weknowthatinfertility andnulliparityareriskfactorsforgynecologiccancersandthereisnoproofthatthemedicationsusedin thepastdecadeshavehadasubstantialimpactonthe cancerrisk.

Keypoints

Challenge:Counselingwomenabouttherisksof cancerfromovarianstimulation.

Background:

Nulliparityisariskfactorforbreast,ovarianand endometrialcancers.

Infertilityitselfmayalsobeariskfactorformany gynecologiccancers.

Polycysticovarysyndrome(PCOS),acondition associatedwithinfertility,islinkedtoendometrial cancer.

Itisdifficulttoseparatethecancerrisks attributabletoinfertilityfromthatoffertility drugs.

Mostepidemiologicstudiesthathaveexamined theassociationbetweenfertilitydrugsandcancer riskshaveemployedthegeneralpopulationas thecomparator.Amoreappropriatecomparator isuntreatedinfertilepopulationasthiswould allowbetterassessmentofthecancerrisk attributabletofertilitydrugs.

Managementoptions:

Womenshouldbecounseledaboutthe uncertainlyintheavailableevidence.

Womenmaybecounseledthatthereisnoclear evidencethatshort-termuseoffertilitydrugs increasestheriskofgynecologiccancers.Short termmaybedefinedas:

❜ lessthan12cyclesforclomiphene,and

❜ lessthansixcyclesforgonadotropins

References

1.KeyTJ,VerkasaloPK,BanksE.(2001)Epidemiology ofbreastcancer. LancetOncol 2(3),133–40.

2.ModugnoF,NessRB,WheelerJE.(2001)Reproductive riskfactorsforepithelialovariancanceraccordingto histologictypeandinvasiveness. AnnEpidemiol 11(8), 568–74.

3.BrintonLA,BermanML,MortelR,TwiggsLB,BarrettRJ,WilbanksGD,etal.(1992)Reproductive,menstrual,andmedicalriskfactorsforendometrialcancer: resultsfromacase–controlstudy. AmJObstetGynecol 167(5),1317–25.

4.Calderon-MargalitR,FriedlanderY,YanetzR,KleinhausK,PerrinMC,ManorO,etal.(2009)Cancerrisk

afterexposuretotreatmentsforovulationinduction. AmJEpidemiol 169(3),365–75.

5.JensenA,SharifH,SvareEI,FrederiksenK,KjaerSK. (2007)Riskofbreastcancerafterexposuretofertility drugs:resultsfromalargeDanishcohortstudy. Cancer EpidemiolBiomarkersPrev 16(7),1400–7.

6.BurkmanRT,TangMT,MaloneKE,MarchbanksPA, McDonaldJA,FolgerSG,etal.(2003)Infertilitydrugs andtheriskofbreastcancer:findingsfromtheNationalInstituteofChildHealthandHumanDevelopmentWomen’sContraceptiveandReproductiveExperiencesStudy. FertilSteril 79(4),844–51.

7.VennA,WatsonL,BruinsmaF,GilesG,HealyD. (1999)Riskofcancerafteruseoffertilitydrugswith in-vitrofertilisation. Lancet 354(9190),1586–90.

8.KatzD,PaltielO,PeretzT,RevelA,SharonN,MalyB, etal.(2008)BeginningIVFtreatmentsafterage30increasestheriskofbreastcancer:resultsofacase–control study. BreastJ 14(6),517–22.

9.PappoI,Lerner-GevaL,HalevyA,OlmerL,FriedlerS, RazielA,etal.(2008)Thepossibleassociationbetween IVFandbreastcancerincidence. AnnSurgOncol 15(4), 1048–55.

10.KotsopoulosJ,LibrachCL,LubinskiJ,GronwaldJ, Kim-SingC,GhadirianP,etal.;HereditaryBreastCancerClinicalStudyGroup.(2008)Infertility,treatmentof infertility,andtheriskofbreastcanceramongwomen withBRCA1andBRCA2mutations:acase–control study. CancerCausesControl 19(10),1111–9.

11.MosgaardBJ,LidegaardO,AndersenAN.(1997)The impactofparity,infertility,andtreatmentwithfertility drugsontheriskofovariancancer. ActaObstetGynecolScand 76,89–95.

12.LiY,GantaS,ChengC,CraigR,GantaRR,Freeman LC.(2007)FSHstimulatesovariancancercellgrowth byactionongrowthfactorvariantreceptor. MolCell Endocrinol 267(1–2),26–37.

13.BrintonLA,LambEJ,MoghissiKS,ScocciaB,Althuis MD,MabieJE,etal.(2004)Ovariancancerriskafter theuseofovulation-stimulatingdrugs. ObstetGynecol 103(6),1194–203.

14.KashyapS,MoherD,FungMF,RosenwaksZ.(2004) Assistedreproductivetechnologyandtheincidenceof ovariancancer:ameta-analysis. ObstetGynecol 103(4), 785–94.

15.SannerK,ConnerP,BergfeldtK,DickmanP,Sundfeldt K,BerghT,etal.(2009)Ovarianepithelialneoplasia afterhormonalinfertilitytreatment:long-termfollowupofahistoricalcohortinSweden. FertilSteril 91(4), 1152–8.

16.RossingMA,DalingJR,WeissNS,MooreDE,SelfSG. (1994)Ovariantumorsinacohortofinfertilewomen. NEnglJMed 331(12),771–6.

17.NessRB,CramerDW,GoodmanMT,KjaerSK,Mallin K,MosgaardBJ,etal.(2002)Infertility,fertilitydrugs, andovariancancer:apooledanalysisofcase–control studies. AmJEpidemiol 155(3),217–24.

18.NavaratnarajahR,PillayOC,HardimanP.(2008)Polycysticovarysyndromeandendometrialcancer. Semin ReprodMed 26(1),62–71.

19.ModanB,RonE,Lerner-GevaL,BlumsteinT,Menczer J,RabinoviciJ,etal.(1998)Cancerincidenceinacohort ofinfertilewomen. AmJEpidemiol 147(11),1038–42.

20.JensenA,SharifH,KjaerSK.(2009)Useoffertility drugsandriskofuterinecancer:resultsfromalarge Danishpopulation-basedcohortstudy. AmJEpidemiol 170(11),1408–14.

2

Riskofearlymenopause followingIVFtreatment

AssistedConceptionUnit,DepartmentofWomen’sHealth,Guy’sandStThomas’NHS FoundationTrust,King’sCollegeLondon,London,UK

CaseHistory1: A34-year-oldwomenduetocommenceintracytoplasmicsperminjection(ICSI)treatmentformalefactorinfertilityisconcernedabouttheriskofpremature menopausefromovarianstimulation.Shehasregularmenstrualcyclesandnormalfollicularphasefolliclestimulatinghormone(FSH),luteinizinghormone(LH)andestradiol levels.Apelvicultrasoundscanshowedanormalsizeduterusandbothovarieswereof normalmorphologyandvolumewithatotalantralfolliclecountof16.Sheisfitandwell withnosignificantmedicalhistory.

CaseHistory2: Awomanwhoisnow43yearsofagehadIVFtreatment5yearsago whichwasunsuccessful.Shehadonlythreeoocytesretrievedfollowingovarianstimulation withgonadotropins.Herperiodshadbecomeirregular2yearsfollowingtheIVFtreatment cycleandtheystoppedayearago.

Background

Inwomen,theovariesagewithtimeandfinallylose theirfunction,withthemenopausemarkingthedefiniteendoffemalereproductivelife.Theovarianconceptofreproductiveagingassumesthattheage-related lossinfemalefertilityisdictatedbythedeclineofboth thequantityandqualityofthefollicles[1].Women withregularmenstrualcycles(premenopausal),have ovarianfolliclecounts10timesgreaterthaninperimenopausalwomenofsimilarage,whilefolliclesare virtuallyabsentinpostmenopausalwomen[2].

Bothfertilityandtheageatmenopausevarysubstantiallybetweenwomen[3].Resultsfromalarge cohortstudy,thepopulationofwhichwasselected

fromtheProspect-EPIC(EuropeanProspectiveInvestigationintoCancerandNutrition)projectwhichinvolvedaquestionnairesurveyofwomenaged50–69yearsfromthecityofUtrechtintheNetherlands, showedthatfertilityproblemsarefrequentlyfollowed byearlymenopause[4],supportingtheviewthatboth areanexpressionofacceleratedovarianaging.

Questionshavebeenraisedonwhethergonadotropinstimulationusedinassistedreproductive technologytreatmentshasanimpactonovarianaging andmenopause.Arecentretrospectivecohortstudy investigatingwhethermenopausalageisinverselyrelatedtothenumberofassistedreproductioncycles foundnosuchcorrelation[5],supportingtheview thatgonadotropinstimulationinwomendoesnot Assistedreproductiontechniques:Challengesandmanagementoptions,FirstEdition.EditedbyKhaldounSharifandArriCoomarasamy. c 2012BlackwellPublishingLtd.Published2012byBlackwellPublishingLtd.

acceleratefolliculardepletion,anobservationconsistentwithexperimentalstudiesthatshowedprimordial folliclerecruitmenttobeindependentofgonadotropin stimulation.

Inthiscontextitisalsoimportanttoaddressthe associationbetweenpoorovarianresponsetogonadotropinstimulationandearlymenopause.Alarge questionnairesurveyofwomenselectedfromparticipantsofanationwidecohortstudy(theOMEGA Project)of19,840womenwhounderwentIVFtreatmentintheNetherlandsfrom1983to1995indicated thatalownumberofretrievedoocytesatthefirst IVFtreatmentwasanimportantpredictorofearly menopausaltransition[6].Theresultsofthisstudy wereinlinewithanearlierfindingthatanticipated poorrespondersareatagreaterriskofbecoming postmenopausalattheageof46yearsorbeforethan normalresponders[7].

Managmentoptions

AquestionnotinfrequentlyaskedbywomenembarkingoncontrolledovarianhyperstimulationforIVF treatmentiswhetherthiswouldleadtoadepletion oftheprimordialfolliclesintheovariesandthereby anincreasedriskofearlymenopause.Itisimportant tocounselwomen,explainingthevariousstepsinvolvedinIVFtreatmentandimplicationstheyare likelytohaveforthewomanintheshortandlong term.WomenshouldbereassuredthatthereissubstantialevidencetosuggestthatgonadotropinstimulationtoinducemultifollicularrecruitmentandoptimizetheoutcomeofIVFtreatmentdoesnotresultin adepletionoftheovarianprimordialfollicles.

Womenshouldbeinformedthatthoseencounteringfertilityproblemsmayhaveanincreasedbackgroundriskofreachingearlymenopausethanfertilewomen,butgonadotropinstimulationduringIVF treatmentdoesnotincreasetheirriskofattainingearly menopause.Womenwhohaverespondedpoorlyto controlledovarianhyperstimulationduringIVFtreatmentindicatedbyalownumberofretrievedoocytes haveacompromisedovarianreserveandareatriskof becomingmenopausalearlier(CaseHistory2)than womenwhohavehadanormalresponse.Women shouldbeinformedthatallproceduresinvolvedinthe IVFtreatmentprocessaregenerallysafeanddonot putthewomanatriskofprematureovarianfailure.

Keypoints

Challenge: IVFtreatmentandtheriskofearly menopause.

Background:

Thequestionisfrequentlyraisedbywomen undergoingIVFtreatment.

Womenwithfertilityproblemshaveahigher backgroundriskofreachingmenopauseearlier thanfertilewomen.

Gonadotropinstimulationdoesnotcause depletionofprimordialfollicles.

Womenwithacompromisedovarianreserve (indicatingovarianaging)areatriskofbecoming menopausalearlierthanwomenwithagood ovarianreserve.

Managementoptions:

Reassurewomenthattheproceduresinvolvedin theIVFtreatmentcycledonotputthematarisk ofreachingearliermenopause.

Thereisnoassociationbetweenthenumberof attemptsatIVFtreatmentandtheageat menopause.

References

1.TeVeldeER,PearsonPL.(2002)Thevariabilityoffemale reproductiveageing. HumReprodUpdate 8,141–54.

2.RichardsonSJ,SenikasV,NelsonJF.(1987)Folliculardepletionduringthemenopausaltransition:evidenceforacceleratedlossandultimateexhaustion. JClinEndocrinol Metab 65,1231–7.

3.TeVeldeER,DorlandM,BroekmansFJ.(1998)Ageat menopauseasamarkerofreproductiveageing. Maturitas 30,119–25.

4.KokHS,VanAsseltKM,vanderSchouwYT,Grobbee DE,teVeldeER,PearsonPL,etal.(2003)Subfertilityreflectsacceleratedovarianageing. HumReprod 18,644–8.

5.ElderK,MathewsT,KutnerE,KimE,EspenbergE,Faddy M,etal.(2008)Impactofgonadotrophinstimulationfor assistedreproductivetechnologyonovarianageingand menopause. ReprodBiomedOnline 16,611–16.

6.deBoerEJ,DenTonkelaarI,TeVeldeER,BurgerCW, vanLeeuwenFE;OMEGAProjectGroup.(2003)Increasedriskofearlymenopausaltransitionandnatural menopauseafterpoorresponseatfirstIVFtreatment. HumReprod 18,1544–52.

7.deBoerEJ,DenTonkelaarI,TeVeldeER,BurgerCW, KlipH,vanLeeuwenFE.(2002)Lownumberofretrieved oocytesatIVFtreatmentispredictiveofearlymenopause. FertilSteril 77,978–85.

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Universe] which is contrary to the fundamental principles of our religion, and leads to “speaking words that turn away from God.”

You must rather have suspicion against your own reason, and accept the theory taught by two prophets who have bid the foundation for the existing order in the religious and social relations of mankind. Only demonstrative proof should be able to make you abandon the theory of the Creation; but such a proof does not exist in Nature.

You will not find it strange that I introduce into this discussion historical matter in support of the theory of the Creation, seeing that Aristotle, the greatest philosopher, in his principal works, introduces histories in support of the theory of the Eternity of the Universe. In this regard we may justly quote the saying: “Should not our perfect Law be as good as their gossip?” (B. T. Baba batra, 115 b). When he supports his view by quoting Sabean stories, why should we not support our view by that which Moses and Abraham said, and that which follows from their words?

I have before promised to describe in a separate chapter the strong objections which must occur to him who thinks that human wisdom comprehends fully the nature of the spheres and their motions; that these are subject to fixed laws, and capable of being comprehended as regards order and relation. I will now explain this. [196]

[Contents]

CHAPTER XXIV

You know of Astronomy as much as you have studied with me, and learnt from the book Almagest; we had not sufficient time to go beyond this. The theory that [the spheres] move regularly, and that the assumed courses of the stars are in harmony with observation, depends, as you are aware, on two hypotheses: we must assume either epicycles, or excentric spheres, or a combination of both. Now I will show that each of these two hypotheses is irregular, and totally contrary to the results of Natural Science. Let us first consider an epicycle, such as has been assumed in the spheres of the moon and the five planets, rotating on a sphere, but not round the centre of the sphere that carries it. This arrangement would necessarily produce a revolving motion; the epicycle would then revolve, and entirely change its place; but that anything in the spheres should change its place is exactly what Aristotle considers impossible. For that reason Abu-bekr ibn-Alzaig, in an astronomical treatise which he wrote, rejects the existence of epicycles. Besides this impossibility, he mentions others, showing that the theory of epicycles implies other absurd notions. I will here explain them:—(1) It is absurd to assume that the revolution of a cycle has not the centre of the Universe for its centre; for it is a fundamental principle in the order of the Universe that there are only three kinds of motion—from the centre, towards the centre, and round the centre; but an epicycle does not move away from the centre, nor towards it, nor round it. (2) Again, according to what Aristotle explains in Natural Science, there must be something fixed round which the motion takes place; this is the reason why the earth remains stationary. But the epicycle would move round a centre which is not stationary. I have heard that Abu-bekr discovered a system in which no epicycles occur; but excentric spheres are not excluded by him. I have not heard it from

his pupils; and even if it be correct that he discovered such a system, he has not gained much by it; for excentricity is likewise as contrary as possible to the principles laid down by Aristotle. For it seems to me that an excentric sphere does not move round the centre of the Universe, but round an imaginary point distant from the centre, and therefore round a point which is not fixed. A person ignorant of astronomy might think that the motion of the excentric spheres may still be considered as taking place round something fixed, since their centre is apparently within the sphere of the moon. I would admit this if the centre were situated in the region of fire or air, although the spheres would not move round a stable point. But I will show that the amount of excentricity has, in a certain way, been described in the Almagest; and later scholars have calculated the exact amount of excentricity in terms of radii of the earth, and have proved the result. The same measure has been used in astronomy in describing all distances and magnitudes. It has thus been shown that the point round which the sun moves lies undoubtedly beyond the sphere of the moon, and below the superficies of the sphere of Mercury. The centre for the circuit of Mars, that is, the centre of the excentric sphere of Mars, is beyond the sphere of Mercury, and below the sphere of Venus. The centre of Jupiter has the same distance; it lies between the sphere of Venus and that of Mercury, whilst the centre of Saturn lies between the spheres of Mars and Jupiter. Now, consider how improbable all this appears according to the laws of Natural Science. You will [197]find it out when you consider the known distances and magnitudes of each sphere and each star, all expressed in terms of the radii of the earth. There is a uniform measure for all, and the excentricity of each sphere is not determined by units proportionate to its own magnitude.

It is still more improbable and more objectionable to assume that there are two spheres, the one within the other; that these are closely joined from all sides, and have, nevertheless, different

centres. For in this case the smaller sphere might move whilst the larger be at rest; but the smaller cannot be at rest when the larger moves, and must move with the larger when the latter rotates round any other axis than that which passes through the two centres. Now we have this proposition which can be proved; and, further, the established theory that there is no vacuum, and also the assumed excentricity of the spheres; from all this it follows that in every two spheres the motion of the upper one should cause the lower sphere to move in the same way, and round the same centre. But this is not the case; the outer and the inner spheres do not move in the same way, and not round the same centre or the same axis; each of them has its peculiar motion. For this reason it has been assumed that between every two spheres there are substances different from those of the spheres. It may be very much doubted whether this is the case; for where should the centres of these intermediate substances be placed? have these substances likewise their own peculiar motion? Thabith has explained the above-mentioned theory in one of his treatises, and proved that we must assume a substance of a spherical form intermediate between one sphere and the other. All this is part of that which I have not explained to you when you studied with me, for I was afraid you might become confused and would not understand even those things which I wished to show you. But as to the inclination and the deviation assumed in respect to the latitude of the paths of Venus and Mercury, I have already clearly shown you vivâvocethat it is impossible to imagine material beings under such conditions. You have seen that Ptolemy has already pointed out this difficulty. He says as follows: “Let no one think that these and similar principles are improbable. If any one considers what we have here expounded in the same light as he considers things produced by skill and subtle work, he will find it improbable; but it is not right to compare human things to divine things.” This is, as you know, what Ptolemy says, and I have already pointed out to you the passages by which you can verify all I said,

except what I stated about the position of the centres of the excentric spheres; for I have not heard that any one has paid attention to this question. But you will understand it when you know the length of the diameter of each sphere, and the extent of its excentricity in terms of radii of the earth, according to the facts which Kabici has established in his treatise on the distances. When you notice these distances you will confirm my words.

Consider, therefore, how many difficulties arise if we accept the theory which Aristotle expounds in Physics. For, according to that theory, there are no epicycles, and no excentric spheres, but all spheres rotate round the centre of the earth! How then can the different courses of the stars be explained? how is it possible to assume a uniform perfect rotation with the phenomena which we perceive, except by admitting one of the two hypotheses [198]or both of them? The difficulty is still more apparent when we find that admitting what Ptolemy said as regards the epicycle of the moon, and its inclination towards a point different both from the centre of the Universe and from its own centre, the calculations according to these hypotheses are perfectly correct, within one minute; that their correctness is confirmed by the most accurate calculation of the time, duration, and extent of the eclipses, which is always based on these hypotheses. Furthermore, how can we reconcile, without assuming the existence of epicycles, the apparent retrogression of a star with its other motions? How can rotation or motion take place round a point which is not fixed? These are real difficulties.

I have explained to you already vivâvoce, that these difficulties do not concern the astronomer; for he does not profess to tell us the existing properties of the spheres, but to suggest, whether correctly or not, a theory in which the motion of the stars is circular and uniform, and yet in agreement with our observation. You know that Abu-bekr al-Zaig, in his treatise on Physics, expresses a doubt

whether Aristotle knew the excentricity of the sun but ignored it, and only discussed the effect of the inclination, because he saw that the effect of the excentricity was identical with that of the inclination; or whether he did not perceive it. The truth is that he did not notice it or hear of it; the science was not perfect in his age. If he had heard of it, he would have strongly opposed it; if he had been convinced of its correctness, he would have been greatly embarrassed as regards all that he said on the question. What I said before (ch. xxii.) I will repeat now, namely, that the theory of Aristotle, in explaining the phenomena in the sublunary world, is in accordance with logical inference; here we know the causal relation between one phenomenon and another; we see how far science can investigate them, and the management of nature is clear and intelligible. But of the things in the heavens man knows nothing except a few mathematical calculations, and you see how far these go. I say in the words of the poet, “The heavens are the Lord’s, but the earth He hath given to the sons of man” (Ps. cxv. 16); that is to say, God alone has a perfect and true knowledge of the heavens, their nature, their essence, their form, their motions, and their causes; but He gave man power to know the things which are under the heavens; here is man’s world, here is his home, into which he has been placed, and of which he is himself a portion. This is in reality the truth. For the facts which we require in proving the existence of heavenly beings are withheld from us; the heavens are too far from us, and too exalted in place and rank. Man’s faculties are too deficient to comprehend even the general proof the heavens contain for the existence of Him who sets them in motion. It is in fact ignorance or a kind of madness to weary our minds with finding out things which are beyond our reach, without having the means of approaching them. We must content ourselves with that which is within our reach, and that which cannot be approached by logical inference let us leave to him who has been endowed with that great

and divine influence, expressed in the words: “Mouth to mouth do I speak with Him” (Num. xii. 8).

This is all I can say on this question; another person may perhaps be able to establish by proof what appears doubtful to me. It is on account of my great love of truth that I have shown my embarrassment in these matters, [199]and I have not heard, nor do I know that any of these theories have been established by proof.

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CHAPTER XXV

We do not reject the Eternity of the Universe, because certain passages in Scripture confirm the Creation; for such passages are not more numerous than those in which God is represented as a corporeal being; nor is it impossible or difficult to find for them a suitable interpretation. We might have explained them in the same manner as we did in respect to the Incorporeality of God. We should perhaps have had an easier task in showing that the Scriptural passages referred to are in harmony with the theory of the Eternity of the Universe if we accepted the latter, than we had in explaining the anthropomorphisms in the Bible when we rejected the idea that God is corporeal. For two reasons, however, we have not done so, and have not accepted the Eternity of the Universe. First, the Incorporeality of God has been demonstrated by proof; those passages in the Bible, which in their literal sense contain statements that can be refuted by proof, must and can be interpreted otherwise. But the Eternity of the Universe has not been proved; a mere argument in favour of a certain theory is not sufficient reason for rejecting the literal meaning of a Biblical text, and explaining it figuratively, when the opposite theory can be supported by an equally good argument.

Secondly, our belief in the Incorporeality of God is not contrary to any of the fundamental principles of our religion; it is not contrary to the words of any prophet. Only ignorant people believe that it is contrary to the teaching of Scripture; but we have shown that this is not the case; on the contrary, Scripture teaches the Incorporeality of God. If we were to accept the Eternity of the Universe as taught by Aristotle, that everything in the Universe is the result of fixed laws, that Nature does not change, and that there is nothing supernatural,

we should necessarily be in opposition to the foundation of our religion, we should disbelieve all miracles and signs, and certainly reject all hopes and fears derived from Scripture, unless the miracles are also explained figuratively. The Allegorists amongst the Mohammedans have done this, and have thereby arrived at absurd conclusions. If, however, we accepted the Eternity of the Universe in accordance with the second of the theories which we have expounded above (ch. xxiii.), and assumed, with Plato, that the heavens are likewise transient, we should not be in opposition to the fundamental principles of our religion; this theory would not imply the rejection of miracles, but, on the contrary, would admit them as possible. The Scriptural text might have been explained accordingly, and many expressions might have been found in the Bible and in other writings that would confirm and support this theory. But there is no necessity for this expedient, so long as the theory has not been proved. As there is no proof sufficient to convince us, this theory need not be taken into consideration, nor the other one; we take the text of the Bible literally, and say that it teaches us a truth which we cannot prove; and the miracles are evidence for the correctness of our view.

Accepting the Creation, we find that miracles are possible, that Revelation [200]is possible, and that every difficulty in this question is removed. We might be asked, Why has God inspired a certain person and not another? why has He revealed the Law to one particular nation, and at one particular time? why has He commanded this, and forbidden that? why has He shown through a prophet certain particular miracles? what is the object of these laws? and why has He not made the commandments and the prohibitions part of our nature, if it was His object that we should live in accordance with them? We answer to all these questions: He willed it so; or, His wisdom decided so. Just as He created the world according to His will, at a certain time, in a certain form, and as we

do not understand why His will or His wisdom decided upon that peculiar form, and upon that peculiar time, so we do not know why His will or wisdom determined any of the things mentioned in the preceding questions. But if we assume that the Universe has the present form as the result of fixed laws, there is occasion for the above questions; and these could only be answered in an objectionable way, implying denial and rejection of the Biblical texts, the correctness of which no intelligent person doubts. Owing to the absence of all proof, we reject the theory of the Eternity of the Universe; and it is for this very reason that the noblest minds spent and will spend their days in research. For if the Creation had been demonstrated by proof, even if only according to the Platonic hypothesis, all arguments of the philosophers against us would be of no avail. If, on the other hand, Aristotle had a proof for his theory, the whole teaching of Scripture would be rejected, and we should be forced to other opinions. I have thus shown that all depends on this question. Note it.

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