多囊性卵巢症候群患者手术协助诱导排卵新策略

多囊性卵巢症候群患者

施行人工协助生殖技术时之

药物及手术协助诱导排卵新策略

PCO(S)多囊性卵巢(症候群)DiagnosisPCO:ReadilybasedonovarianmorphologyPolycysticovaries:

tenormorecysts2-8mmindiameter,arrangedaroundadensestromaorscatteredthroughoutanincreasedamountofstroma

Prevalenceofpolycysticovaries:20-25%inyoungadultsPCOS:polycysticovariesfoundinassociationwithmenstrualdisturbance,thecomplicationsofhyperandrogenandobesity.PCOS诊断之演进LaparotomyandhistologicalconfirmationofPCOSteinandLeventhal1935Biochemicalcriteria

RaisedLHorLH/FSHRaisedTestosterone,androstenedioneAbnormalestrogensecretionClinicalpresentation

MenstrualcycledisturbanceObesityHyperandrogenism(hirsutism,acne,androgen-dependentalopecia)USconsensusonthediagnosisofPCOS美国定义-NIH1990Twocriteria:Chronicoligo-/anovulationHyperandrogenism

Hirsutism

HyperandrogenTotaltestosterone>89ng/dlFreetestosterone>0.66ng/dlAndrostenedione>2.97ng/mlSHBGExcluding:Hyperprolactinemia,Thyroiddysfunction,LOCAH,Cushing’s,AndrogensecretingtumorUKdefinitionofthediagnosisofPCOS英国定义Polycysticovaries(PCO)

Ovarianarea>5.5cm2Ovarianvolume>11ml

12Follicles:2-9mm(meanofbothovaries)AssociatedclinicalorbiochemicalfeaturesOligo-/amenorrheaHyperandrogenismObesityElevatedserumtestosteroneElevatedserumLHPCOwithoutPCOS如何重要Incidence:around20%

NormallyovulatorywomenwithPCO

IncreasedincidenceofsubfertilityandmiscarriageFrequentlydeveloptypicalsymptomsaftergainingsignificantweightExaggeratedresponsetogonadotropinDegreeofinsulinresistancerankedbetweenPCOSandnormal

Proposedprotocol流程forthediagnosisofPCOSHomburg2002HR1.Symptomsmenstrualdisturbance,hirsutism,acneanovulatoryinfertility

2.Ultrasoundexamination:If(+)Dxconfirmed

>8follicles(<10mm)inoneplanestroma>25%volumeor>34%area

If(-):proceedto

3.Biochemicalexamination

elevatedserumtestosterone,elevatedLH,elevatedfreeandrogen,

fastingglucose:insulin<4.5Ifanyone(+):Dxconfirmed

NewconsensusondiagnosisofPCOS2003最新诊断共识

Atleasttwooutofthefollowingthreecriteria(1)Chronicoligo-/anovulation(2)Hyperandrogenism(3)PolycysticovariesSubsets:(1)+(2);(3)+(2);(3)+(1);(1)+(2)+(3)Excludinghyperprolactinemia,thyroiddysfunction,LOCAH,Cushing’s,androgensecretingtumorPCOS多囊性卵巢症候群TreatmentpolicyPCOS:elevatedLH,chronichyperandrogen,insulinresistance(hyperinsulinemia)CCremainsthefirst-linetherapy,ovulation70~85%,PR40~50%Standard(conventional)OI:CC,Gn(hMG,u-FSH,r-FSH),pulsatileGnRHIffail(refractorytoOIinvivo)

IVF-ETOrhavecoexistinginfertilityfactorsPrevalence盛行率ofPCO(S)inARTPolycysticovaries87%inoligomenorrhea,26%inamenorrhea,22%in‘normal’population(Polson,1988)PCOreferredforIVF:notsowellknown33%to50%inIVFcycles:commonfindingwithorwithoutclinicalsymptoms

(MacDougall,1994)Ifthereisnoothercauseforinfertility,tryovulationinductionfirst.OIforpurePCOSandIVFforothercausesorafterOIhasfailed

(>=6ovulatorycycles)Relevance关联性ofPCOStofertilityImplicationofPCOStofertilityCauseofinfertility:anovulationandhypersecretionofLHElevatedbasal(follicularphase)LH.Debate:Adverseeffect(Regan,Lancet:1990)-MidfollicularphaseLH>10IU/Lvsnormal:droppedPR(67%vs88%),increasedSAR(65%vs12%)Nodeleteriouseffect(Thomas,BJOG:1989)-LHabove75percentile:noadverseeffectonFRPrematureendogenousLHsurgeLHsurgeidentifiedatitsinitiation:abandonedoraugmentedwithHCGLHsurgeisestablished:cancelledCancelingcycleswithspontaneoussurge,unlessitiscaughtwithin12honset,intensivemonitoringrequired

COS控制性诱导排卵inPCO(S)Responsetostimulation

OIforunifolliculardevelopment:slowresponse,riskofhyperstimulation&cystformationOIformultifollicularrecruitment:explosivefollicleproductionIncreasednumberoffollicles,oocytes,andestrogenwithdecreasedFRPronetoOHSSART人工协助生殖技术inPCOSEfficacy/OutcomeofIVF-ETtherapyinPCOShigherpeakE2,lowerhMGrequirement,greaternumberoffollicles,oocytesreducedFR(57.3%vs65.7%),CR,comparablePR/aspiration,PR/ET(22.6~25.4%vs26.5~23%),orLBRwithotherdiagnosismoreMPR,increasedmiscarriage(SAB)rate,noincreasedcongenitalabnormalities10.5%OHSS(moderate~severe)Preconceptionalcounseling孕前咨询ImportanceofthediagnosisofPCOmorphologypriortoCOS

PreconceptionalcounselingExplanationthebehavioranddrugschosenAdviceaboutpotentialproblems–OHSSandmultiplepregnanciesMiscarriagerateincreased.CongenitalabnormalitiesnotincreasedReducingtheriskofpregnancylossbyweightreductionbeforeARTPreconceptionalcounselingHyperinsulin(obesity)associatedwithhypertension,pre-eclampsiaandGDM(prevalence8.1%).AttainidealBWbeforeconceptiontoavoidpre-eclampsiaScreeningwomenwithPCOSforglucoseintoleranceObesityleadstoincreasedUTI,malpresentation,dystocia,PPH,thromboembolism,PNMIncreasedriskofHT,NIDDMandCVD,endometrialhyperplasiainlaterlifeThemosteffectivemanagementisadviceondietandweightloss(Obesebecomeslim,non-obesestayslim)COSStrategyforARTinPCOSCOSinPCOSforIVF:multifolliculardevelopment

withoutcausingOHSSCCwithhMG/FSH:prematureluteinizationandprematureLHsurgemayoccurwithdeleteriouseffectondevelopingoocytesorovulationpriortoOR,theseproblemsaremorecommoninPCOSCOSresultingincollectionoflargenumberofoocytes(>10)resultsinpoorprognosis-theoptimumnumberbeingbetween7and9MovetowardpituitarydesensitizationwithaGnRH-a

suppressionofendogenousLHbyGnRH-aisofparticularrelevanceandadvantagetowomenwithPCOSCOSStrategyforARTinPCOS壹：InfluenceofaddingGnRH-ainCOSTrendstowardreducedcancellation(24%->15%),improvedcyclefecundity(16%->27%)(Dodson,1989)Longer(30Ds)desensitization:lowerandrogen,similarPR,SAB,OHSS(Salat-Baroux,1988)ReducedP,A,byGCcells,butnodifferenceinnumberofoocytes,FR,PR(Dor,1992)ImprovedFR(62vs51%),improvedPR(27vs16%),reducedSAB(18vs39%)inPCOS(Homburg,1993)GnRH-aforCOSinPCOSHughesE,Cochranereview(1996Feb):Gonadotrophin-releasinghormoneanalogueasanadjuncttogonadotropintherapyforclomiphene-resistantpolycysticovariansyndrome.SimilarconceptionratesweredemonstratedinwomenreceivingGnRHa/hMG/FSHversushMG/FSHalonecommonoddsratio1.50,(95%CI0.72–3.12)NosignificantdifferencewasnotedintheratesofOHSS:commonoddsratio1.40(95%CI0.5-3.92).GnRH-aforCOSinARTinPCOSBournHalldata1060preg/7623IVFcycles(6Ys)1984-1990Ongoing:68.3%(724/1060);Spontaneousmiscarriage26.6%;EP:5.1%Miscarriagerate

Nodifferenceinagegroup:20-24,25-29,30-34y/oincreasedsignificantlyin35-39y/oagegroup:31.9%normalovariesvsPCO:23.6%vs35.8%(p=0.0038)nodifferencebetweenhMGorFSHwithclomiphene(30.2%vs36.8%)shortbuserelin(28%),ultrashort(24.7%)nodifferencewithclomidhighlysignificantdecreasedbylongbuserelinregimen(19.1%)nodifferencebetweenhMGorFSHwithlongbuserelin(21%vs17%)GnRH-aforCOSinARTinPCOSGnRH-aforCOSinARTinPCOSHigherrateofmiscarriageinCCgroup:R/OdeleteriouseffectsofelevatedLHTheuseofshortorultrashortGnRHaexposesthepatienttothesameadverseeffectsasCCPituitarydesensitizationistheimportantfactorinreducingmiscarriagerateinPCO,ratherthantheCCbeingtheadversefactorThereappearstobenobeneficialeffectonmiscarriagerateforwomenwithnormalovaries.PretreatmentUSGisimportantinordertoselectthetreatmentregimentooptimizeoutcomeGnforCOSinARTinPCOShMGvsFSH没什么差别purifiedFSHdoesnotsubstantiallyimproveovulationratescomparedwithhMGincidenceofOHSSnotreducedwithFSHtherapydurationoftherapyoramountofgonadotropinrequired:nodifferencenodifferenceinduration,ampoules,oocytenumbers,%matureoocytes,FR,CR,PRandincidenceofOHSS(Tanbo,1990)GnforCOSinARTinPCOSDayaSCochranereview(1995Dec):Follicle-stimulatinghormoneandhumanmenopausalgonadotropinforovarianstimulationinassistedreproductioncycles.AmongtheGnRHastudies,therespectiveoveralloddsratiosforclinicalpregnancypercyclestarted,peroocyteretrievalprocedureandperembryotransferprocedurewere1.48(95%CI,0.93,2.34),1.51(95%CI,0.95,2.40)and1.54(95%CI,0.96,2.45)GnforCOSinPCOSNugentD

Cochranereview(2000May):Gonadotrophintherapyforovulationinductioninsubfertilityassociatedwithpolycysticovarysyndrome.ThebeneficialeffectofFSHversushMGforOHSSwasonlypresentwherenoanaloguewasused(OR0.20;95%CI0.08-0.46),halvingtheincidencefrom12%to6%.Higheroverstimulationrates(OR3.15;95%CI1.48-6.70)werefoundwiththeadditionofaGnRHawithoutasignificantlyhigherOHSSrate(OR1.41;95%CI0.50-3.95)althoughthedirectionofeffectremains.Insufficientdatawereavailabletodrawconclusionsonmiscarriageandmultiplepregnancyrates.COSStrategy(notforART)inPCOSPulsatileGnRHpump并不适合PoorresponseunlesspretreatmentwithGnRH-aProlongedsuppression8~12wksfollowedbypulsatileGnRHatdosageof5~20ugIV/SCat60~90minintervals

monofollicularovulation

Modificationfromhigh-dosestep-upregimenLow-dosestep-upregimenStep-downregimenStep-up-step-downregimenIntendtoallowselectionanddominancetooccur

COSStrategyforARTinPCOS贰：Dualsuppression(OCPandGnRH-a)

DualsuppressionimprovesIVFoutcomeinhighresponders(mostlyPCOS)DamarioHR1997:2359OCPtakenfor25daysfollowedbySCLeuprolideacetate1mg/day,overlappedwiththefinal5daysofOCP.hMGorFSH150IU/daysinceDOC3.

99cycles(73patientsin5Ys)Cancellation13.1%CPR/initiatedcycle46.5%OGPR/initiatedcycle40.4%(Miscarriage13.1%)OHSS:mild-moderate8/99ImprovementinFR,IR,CPR,OGPR

Dualsuppression(OCPandGnRH-a)

Dualsuppression(OCPandGnRH-a)COSStrategyforARTinPCOS

PreventionofOHSS风险规避计划FrequentcomplicationinCOSforPCOSOocyteaspirationimpartspartialprotectionRecognizingtheriskfactors:youngageandPCOSetcandclinicalprofileIndividualizethemedicationregimen,startatlowestStddose,closemonitoring,evenlowdoseofhMGmaybeassociatedwithsevereOHSSGnRH-asuppressionconfersnoprotectionbutriskforOHSS,notnecessarytodeviateinPCOSAtrisksign:decreasemedicationormid-cyclecoastingPreventionofOHSS

WithholdingGnfor1~8days(controlleddriftperiod)-IncidenceofOHSS:2.5%,PR:25%/cycle(~1996)TriggerovulationwithGnRH-ainlieuofHCG(cycleswithoutpriordesensitization)-Buserelinacetate250~500ugINatQ12Hfor2doses-LA500ugSCAdministrationofalbuminatthetimeofOR-25ghumanalbuminIVst+25gmatrecoveryroomor-Singledoseof50gmhumanalbumindilutedin500mlcrystalloidst

UseofexogenousPasopposedtohCGforLPSCryopreservationofallembryos-re-administrationofGnRH-atillsubsequentmenstruationAdministrationofalbuminDebate:Ben-ChetritRCTHR2001:1880OHSSincidencenodifference:relativerisk(RR)=1.49,95%CI=0.59-3.73Conceptionratesnodifference:RR=0.78,95%CI=0.44-1.39)AlbuminappearstohavenopositiveeffectonOHSSorconceptionrates,whileitsusecarriestheriskofundesirablesideeffects,includingexacerbationofascitesinOHSS,nausea,vomiting,febrilereaction,allergicreaction,anaphylacticshockandriskofvirusandpriontransmission.WesuggestthatthisformoftreatmentshouldnotbeincludedinthepreventionofOHSS.COSStrategyforARTinPCOS参：Coasting靠岸策略

HR2003:937,Levinsohn-TavorCoasting:withdrawingexogenousGn/postponinghCG

FirstdescribedbyRabinviciin1987,firstappliedinIVFbySher1993Variableapplication,heterogeneouscriteria,inconsistentefficacyWhatisthebestformula/recommendedprotocol?-Shouldbeinitiatedwhen?-Butnotunlesstheleadingfolliclesreach?-Durationshouldbelimitedto?-AdministrationofhCGwithheldtillserumE2fallsto?-IncidenceofsevereOHSS?,FR:?,PR:?COSStrategyforARTinPCOS参：Coasting靠岸策略

Whatisthebestformula/recommendedprotocol?-ShouldbeinitiatedwhenserumE2>3000pg/ml-Butnotunlesstheleadingfolliclesreach15-18mm-Durationshouldbelimitedto<4days

-AdministrationofhCGwithheldtillserumE2falls<3000pg/dl-IncidenceofsevereOHSS:<2%,FR:55-71%,PR:37-63%CoastingCoasting何时该靠岸休息呢？When?Excessiveresponse,atriskofsevereOHSS~Sizeofactivegranulosacellpopulation

SerumE2>3000pg/ml;morethan30folliclesSerumE2>6000pg/ml:38%;Fs>30:23%;Both:80%SOH(Asch,1991)CoastingWhentoinitiate/terminate?

Factors:serumE2,numberoffollicles,diameterofleadingfollicleE2:2500-3000pg/ml;highcut-offassociatedwithhigherOHSS/longercoastingAdditionalsubsequentrisehCGadministrationwithE2<2500-3000,-notbeallowedtofalltoolowbelowitwhenleadingF>=15mm,folliculargrowthcontinuedtoasizeof>18mm-oocytesinsmallerfollicles->maturationarrestandatresia-toomanylargerfollicle->cysticfolliclesandpoorqualityoocytes

Coasting该休息多久呢？Duration?

>=4daysreducestheIRandPR(Ulug,2002;Isaza2002)<=4daysdidnotinfluenceoutcome(Waldenstrom,1999)IntervalofcoastingmainlyaffectsEMreceptivity!?Prolongedcoasting:reductionofORrateandembryoquality!?CoastingisinitiatedwhenFnotmorethan17-18mm,E2notmorethan6000pg/ml,periodof>4dayscanbeavoided(Egbase2000)CoastingHowsuccessful?

SevereOHSS0.5-2%inIVF<2%inhigh-riskpatientsmanagedwithcoasting20%iftooearlyhCG/toolatecoasting80%ifnon-coastingNosignificantdifferenceinoocytematurity/quality,fertilizability,cleavageembryoquality(Isaza,2002)andPR(37~63%).Morespecificmarkerforprediction?Earlycoasting

早点休息吧！HR2002:1212,EgbaseEarlycoasting:consistentwithgoodclinicaloutcome102obesePCOSFixedperiodof3daysLeadingfollicle15mm

>10folliclesperovaryE2>1500but<3000pg/mlMeanhpFSH:23.2ampoulesE2coastingD1:1943,hCGday:2169FR73.9%,CR:87.7%CPR:45.1%

NosevereOHSS

ModifiedCoastingStrategy有些复杂！HR2001:24,Al-Shawaf:basedonultrasoundandE2E2<3000pmol/l(817pg/ml),theGndosemaintained;E2>3000pmol/lbut<13200pmol/l(3595pg/ml)and25%ofthefollicleshadadiameterof13mm,theGndosehalved;E2>13200pmol/land25%ofthefollicleshadadiameterof15mm,patientswerecoasted,hCG10000IUwasadministeredwhenatleastthreefollicles18mmandE2<10000pmol/l(2724pg/ml)MOH0.7%,SOH0.2%PR:39.6-40%;IR:30.7-25.6%(reduced-coastinggroup)AuxiliaryStrategyforARTinPCOS肆：早期(?)单侧滤泡抽吸术〈EUFA〉EgbaseHR,1999:1421EUFAvscoastingE2>6000pg/mland>15Fs(>=18mm)eachovaryEUFA10-12hoursafterhCGvscoasting4.9DstillE2<3000pg/mlSimilarE2&Fsatstarting:9911vs10055&43.3vs41.4Higheroocytesretrieved:15.4vs9.6Higher%OR/F:91.4%vs28.3%SimilarFRandCRSimilarCPR:40%vs33%SimilarOHSS:26.6%vs20%

早期单侧滤泡抽吸术〈EUFA〉COSStrategyforARTinPCOS伍：有限度卵巢刺激策略〈LOS〉LimitedovarianstimulationwithoutIVMEl-Sheikh,EJOGRB2001:245LOSpreventSOHinPCOD(EJOGRB1999:81LOSpreliminaryreport5patients)20patientswithpriorSOHLongprotocol(Suprefact,nasal)withdailyhMG(150IU)injectionhCG10000IUadministeredwhentheleadingFreachedadiameterof12mm

OR36hourslater(120mmHg,15G,noflushing)followedbyICSIandET

-HMGampoulesdecreased(21.5vs28.4);Durationdecreased(10.4vs13.9Ds)-E2decreased(1978vs2754);Fsdecreased(27.6vs34.3)-Oocytesretrieveddecreased(15.7vs25.5);MIIoocytes:12.3+6.3(4-25)**!!-FR:70.5%byICSI;8clinicalpregnancies(40%)andnonerecurrentSOH

NoneedtobestimulateduntilleadingFreaches18mm!!

COSStrategyforARTinPCOS陆：体外培育成熟之策略

(IVM)Cha1991-2000FS2000:978IVMinPCOSOocyteswereretrievedbyaUS-guidedoocyteaspirationtechniqueeither10–13daysafterspontaneousmensesorwithdrawalbleedinginducedbyIMinjectionofP

64patients,94cycles13.6oocytesperpatients89%morphologicallynormal62.2%maturedinvitro68%FRafterICSI(62.2%x68%=42%)PR27.1%(23/94cycles)IR:6.9%COSStrategyforARTinPCOS陆：体外培育成熟之策略

(IVMafterpriming)Lin&HwangHR2003:163260PCOS68IVMcyclesrFSH75IUfor6DsthenhCG(35cycles)vshCGalone(33cycles)hCG10000IU,OR(usualneedlewithflush)->IVM->ICSI->D2orD3ETE2level:377.2pmol/lvs143.8pmol/l(102.7pg/mlvs39.2pg/ml)Oocytesretrieved:21.9vs23.1Maturationrate74.2%(48hours):76.5%vs71.9%Fertilizationrate72.8%:75.8%vs69.5%(74.2%x72.8%=54%)PR33.8%:31.4%vs36.4%IR:9.7%vs11.3%ConfirmthebeneficialeffectofhCGprimingFSHpriminghasnoadditionalbeneficialeffectonIVMIVMforPCOSisafeasibletreatment体外培育成熟策略(LOS/priming+IVM)

Lin&HwangHR2003:1632好棒！体外培育成熟之策略

(priming+IVM)

Son(Korea)HR2002:134BCdevelopmentandpregnanciesafterIVM-ICSI/IVFfromunstimulatedPCOSwithin-vivoHCGpriming

Maturationmedium:YSmediumwith30%hFF+1IU/mlrFSH+10IU/mlhCG+10ng/mlrhEGFSonHR2002:2963OngoingtwinpregnancyaftervitrificationofBCsproducedbyIVMforPCOSCoculturewithcumuluscellwithabovematurationmediumsystemBagele(Austria)HR2002:373SuccessfulpregnancyresultingfromIVMoocytesretrievedatLSCsurgeryinPCOSDOC1210000IUhCGgiven,CombinedLSCretrievalofimmatureoocytesandovarianelectrocautery(usingmonopolarneedle40WatthepuncturesitesofOR有点麻烦有些复杂

AuxiliaryStrategyforARTinPCOS柒：经阴道卵巢钻孔术(TVOD)TranvaginalovariandrillingFeraretti,FS2001:812TVODimprovesoutcomeofARTinPCOSTVODwasperformedunderanesthesiawithPropofolusinga17-gauge,35-cmlongneedle.Eachovarywasrepeatedlypuncturedfromdifferentangles,andallthesmallfolliclesvisiblebyUSwereaspiratedandscraped.Patientsweredischargedafter2–3hoursandfollowedupwithbyUS,HigherFSHrequired52.2vs33.5ampoulesHigherFR(66%vs27%)&CR(72%vs54%)CPR58%andIR26%TVODiseffectiveindifficultPCOSTVODlessinvasiveandexpensiveascomparedtoLOD柒：经阴道卵巢钻孔术(TVOD)AuxiliaryStrat