北医三院生殖医学中心 讲义

FactorsinfluencingIVFoutcomesPekingUniversityThirdHospitalQiaoJieFactorsAffectingConceptionProductionofhealthyspermHealthyeggsbythewomanUnblockedfallopiantubesTheabilityforthespermtofertilizetheeggTheabilityfortheembryotoimplantintheuterusIVFsuccessrateDespitetheprogressinIVF,peopleundertakingIVFoftenfaceaconsiderableriskoffailure.--Pregnancyratepertransferremained30%-35%in2006.--DeliveryratebyOPUwas15%-30%infreshcyclein2005.

DatafromESHREFactorsaffectingIVFresultsAgeCausesofinfertilityResponsivenesstoovulationinductionDifferentstimulationprotocolsEmbryo

qualitySpermqualityEmbryotransfertechniqueLutealphasesupport

FactorsaffectingIVFresultsAgeCausesofinfertilityResponsivenesstoovulationinductionDifferentstimulationprotocolsEmbryo

qualitySpermqualityEmbryotransfertechniqueLutealphasesupport

EndometriosisandIVFLowerpregnancyrates

(Barnhartetal.,2002,P.Kuivasaarietal.2005,DeHondtA,etal,2005;AzemFetal,1999)

Reducedfertilizationrate

(Bergendaletal.1998,Azemetal.,1999,YamashitaY,etal,2002,Al-FadhliR,etal,2006;BarnhartK,etal,2002

)

Decreasedimplantationrates

(Azemetal.,1999;Barnhartetal.,2002;Kuivasaarietal.,2005;KumbakBetal,2008)Alowernumberofoocytesretrieved

(Bergendaletal.1998,Azemetal.,1999,SuzukiT,etal,2005;KumbakBetal,2008;BarnhartK,etal,2002;NakaharaKetal,1998)Alowerovarianresponsetogonadotrophins

(Azemetal,1999;Al-Azemietal,2000;Aboulghar,2003;Barnhartetal,2002;Kuivasaarietal,2005;Al-FadhliR,etal,2006;KumbakBetal,2008)EndometriosisandIVFPoorembryoquality

(Barnhartetal.,2002;Kuivasaarietal.,2005;KumbakBetal,2008)Higherrateofearlypregnancyloss

(YanushpolskyEHetal,1998)Reducedbirthratepercycle

(AzemFetal,1999)Pregnancyratesforwomenwithsevereendometriosisweresignificantlylowerthanforwomenwithmilddisease

(BarnhartK,etal,2002)EndometriosisandIVFLowerVEGFgeneexpressioningranulosacellsmayadverselyaffectoocytedevelopmentandmaturation

(YamashitaY,etal,2002)

Alteredfolliculogenesis

(TummonIS,etal,1988)Embryotoxicity

(DamewoodMDetal,1990;SimonCetal,1992)Increasedapoptosisingranulosacells

(NakaharaKetal,1998)EndometriosisandIVFDecreasedexpressionofbiomarkersofimplantation

--decreasedexpressionofHOXA10

(WeiQetal,2009;TaylorHSetal,1999;BrowneHetal,2006)--decreasedexpressionofglycodelinA

(KaoLC,2003;WeiQetal,2009;BurneyROetal,2007)--decreasedexpressionofosteopontin(BurneyROetal,2007;WeiQetal,2009)

--decreasedexpressionoflysophosphatidicacidreceptor3

(WeiQetal,2009)--decreasedexpressionofintegrin

(LesseyBAetal,1994;KhorramOetal,2002)

Alterationsinendometrialapoptosis

(GebelHMetal,1998;BergqvistAetal,1993)HydrosalpinxandIVFReducedclinicalpregnancyrate

(Simsetal.1993;Vejtorpetal,1995;Katzetal,1996;Andersenetal,1994;ZeynelogluHBetal,1998)

Highermiscarriagerate

(Simsetal.1993;Strandelletal,1994;Andersenetal,1994;ZeynelogluHBetal,1998)Lowerongoingpregnancyrate

(Simsetal,1993)HydrosalpinxandIVFReducedimplantationrate

(Strandelletal,1994;Katzetal,1996;Andersenetal,1994;Freemanetal,1996;ZeynelogluHBetal,1998)Fewerblastocystsdeveloping

(Freemanetal,1996)Improvedpregnancy,implantationanddeliveryratesaftersalpingectomyforhydrosalpingesbeforeIVF

(StrandellA,etal2001;JohnsonNP.etal,2002;FlemingandHull1996;MurrayDL,etal,1998;Johnsonetal.,2004)HydrosalpinxandIVFHydrosalpinxfluidmaycontaincytokines,prostaglandinsorotherinflammatorycompounds.Thesecompoundsmayhaveeitherdirectembryo-toxicityoradverselyaffecttheendometrium.(Meyeretal.,1997)Simplemechanicalflushingofembryosfromtheuterinecavity.

(MansourRT,etal,1991)HydrosalpinxandIVFEmbryotoxiceffects

--lowerrateofoftheembryosreachingthemorulastageandtheblastocyststage

(Schenketal.1996;SachdevR,Etal,1997;KoongMK,etal,1998)--higherfragmentationanddegenerationrateoftheembryos

(Schenketal.1996;MukherjeeT.etal,1996)--poorcavitationrates(MukherjeeT.etal.1996)--retardationofmouseembryodevelopment

(Beyleretal,1996;MukherjeeT.etal,1996)HydrosalpinxandIVFReduceendometrialreceptivity--lowerlevelsofintegrinsαVβ3intheendometrium

(Lesseyetal.1994;MeyerWetal,1997)

--

diminishedexpressionofHOXA10

intheendometrium

(DaftaryGSetal,2002;DaftaryGSetal,2007)

--

reducedLIFlevelintheendometrium

(SeliEetal,2005)

--increaseofintegrinαVβ3expressionaftersurgicalcorrectionofhydrosalpinx

(MeyerWetal,1997)HydrosalpinxandIVFChangesinendometrialpatternandendometrialbloodflow

--

patientswithhydrosalpinxhadasignificantlyhigherproportionofthenon-multilayeredendometrialpatternandsignificantlylowerendometrialandsubendometrialbloodflowsNgEHY.etal,2006Intra-ovarianFactorsinPolycysticOvarySyndrome(PCOS):

ImpactonOocyteMaturationandEmbryoDevelopmentalCompetencePCOSpatients’typicalcharacterization

InIVF

IncreasednumberofoocytesLowerfertilization,cleavageratesLowerimplantationratesHighermiscarriageratesPoorqualityofoocytesandembryosHumanReproductionUpdate,Vol.12,No.1pp.13–21,2006PCOS

duringfolliculogenesisandfolliclematurationabnormalendocrine/paracrinefactorsmetabolicdysfunctionintrafollicularmicroenvironmentalterations

ImpairedoocytematurationandembryonicdevelopmentalcompetenceSeminarReprodMed2008;26:53-61

Transforminggrowthfactors(TGF-β)Anti-Müllerianhormone(AMH)Growthdifferentiationfactor(GDF9)InhibinsActivitinsBonemorphological

protein-15(BMP15)TGF-β——AMHserumAMHlevelsreducesthroughoutreproductivelifeSerumAMHlevelsstablethroughoutthemenstrualcycleHumanReproductionUpdate,Vol.16,No.2pp.113–130,2010MeanAMHserumlevelssignificantlyhigherinPCOSpatientsassociatedwithincreaseddevelopmentofantralfolliclesandfolliculararrestinPCOSpatientslowerinPOFpatientsTrendsinEndocrinologyandMetabolismVol.19No.9PCOS-IVF——AMH

PCOSpatients:higherlevelsoffollicularMISfollicularMISlevelcorrelatingwithagreaternumberofimmatureoocytesretrievedFertilSteril.1997May;67(5):962-5PCOSinIVF:SerumandFFAMHsignificantlyhigherTheAMHlevelssignificantlylowerpatientswhobeganapregnancy(22.0vs.50.5pMol/L,P=0.018)anegativelinkbetweenAMHandfinaloocytematuration，possiblybecauseofimpairedaccessofFSHtofolliclesFertilSteril.2010Jun;94(1):198-204TGF-β——InhibinsInhibinsproducedbythedominantfolliclestimulatethecacellandrogenproductionforE2synthesisInIVFpatients,higherFFinhibinAandBlevels(measuredonthedayofoocyteretrieval)betteroocytematurityandfertilizationrateshigherpregnancyratesEuropJObstetGynecolReprodBiol2004;115:194–199

PCOS——InhibinsFFinhibinAandinhibinBconcentrationsaresignificantlyreducedinPCOScomparedwiththoseinsize-matchedfolliclesfromnormalwomen(JClinEndocrinolMetab.2005Oct;90(10):5582-7）

FFinhibinBlevelsaresignificantlycorrelatedtoembryoquality(HumReprod.2002Jul;17(7):1724-8)TGF-β——GDF9GDF9,anoocyte-secretedfactorpromotesgranulosacellproliferationandpreantralfolliclegrowthitsdeficiencyimpairsgranulosacellproliferationandcausesfolliculararrestattheprimaryfolliclestageSeminReprodMed.2008January;26(1):53–61PCOS——GDF9PCOSoocytesGDF9mRNAlevelsreducedImpairedfolliclegrowthLeadtoprematureluteinizationDecreaselutealgenerationMaybealteredgranulosacell-oocytesignalingJClinEndocrinolMetab2002;87:1337-1344Insulin-likegrowthfactorsmultifunctionalpolypeptideswithinsulin-likeactivitytworeceptorligands(IGF-IandIGF-II)twosurface-receptors(IGF1RandIGF2R)sixhigh-affinityIGFbindingproteins(IGFBP1-6)

PCOSIGF-IlevelsinimmaturefolliclesisdecreasedIGF-IIandIGFBP-1levelslowerlowerIGFBP-1leadingtofolliculararrestExpertRevEndocrinolMetab2007;2(2):215-223

IGFserumandfollicularfluidIGF-I/IGFBP-1higherinwomenwhobecamepregnantTheratioIGF-I/IGFBP-1mayreflectoocytequalityJAssistReprodGenet2003;20:167-176

PCOS——IGFIGF-IplaysakeyroleinoocytematurationinPCOSpatientsAlterationsinIGFBP-3concentrationduringstimulationmaybeacriticalmechanisminmodulatingIGF-IactivityPCOSpatients:

MeanserumIGF-IandIGFBP-3levelsincreasedduringstimulationSerumIGF-Ilevelsdecreasedhighermeannumberofimmatureoocytesretrieved(4.8±1.1vs.2.4±0.4;P.02)SerumIGFBP-3levelsincreasegreaterpregnant(P.03)ongoingpregnancy(P.02)FertilSteril2007;88:139–44CytokineFamilyalargefamilyofsolublepolypeptideregulatorsinterleukins(IL1~35)LeukemiaInhibitoryFactor(LIF)Tumornecrosisfactor-alpha(TNFα)SolubleFas(sFas)SolubleFasligand(sFasL)regulatingovarianfunctionexertinganinfluenceonproliferation,differentiation,follicularmaturation,steroidogenesisandapoptosisBestPracticeandResClinicalObsteandGynaecology.2004;18:755-771

PCOSundergoingIVF1)higherserumandFFinterleukin-6andTNF-α2)cytokineconcentrations:FF＞serum3)FFTNF-αconcentrationswereinverselycorrelatedtotheestradiollevels，indicativepoorqualityoocytesandembryosObstetGynecol2003;101:1177–82

CK——TNFα

ExposureofporcineoocytestoanelevatedTNF-aareductionintheirmaturationfromGVstagetoMIIstageincreasedtheproportionofoocyteswithabnormalchromosomealignmentandcytoskeletonstructurePCOSpatientstreatedwithpioglitazoneduringCOSFFTNF-aandIL-6levelssignificantlylowerThe