REVIEW Open Access GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer IVFET Raffaella Depalo K Jayakrishan Gabriella Garruti Ilaria Totaro Mariantonietta Panzarino - PDF document

REVIEW Open Access GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer IVFET Raffaella Depalo   K Jayakrishan  Gabriella Garruti  Ilaria Totaro  Mariantonietta Panzarino
REVIEW Open Access GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer IVFET Raffaella Depalo   K Jayakrishan  Gabriella Garruti  Ilaria Totaro  Mariantonietta Panzarino

REVIEW Open Access GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer IVFET Raffaella Depalo K Jayakrishan Gabriella Garruti Ilaria Totaro Mariantonietta Panzarino - Description


The review summarizes the main differences and the clinic characteristics of the protocols in use with GnRH agonists and GnRH antagonists by emphasizing the major outcomes and hormonal changes associated with each protocol The majority of randomized ID: 35863 Download Pdf

Tags

The review summarizes the

Embed / Share - REVIEW Open Access GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer IVFET Raffaella Depalo K Jayakrishan Gabriella Garruti Ilaria Totaro Mariantonietta Panzarino


Presentation on theme: "REVIEW Open Access GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer IVFET Raffaella Depalo K Jayakrishan Gabriella Garruti Ilaria Totaro Mariantonietta Panzarino"— Presentation transcript


REVIEWOpenAccess GnRHagonistversusGnRHantagonistin invitro fertilizationandembryotransfer(IVF/ET) RaffaellaDepalo 1* 2 ,GabriellaGarruti 3 ,IlariaTotaro 1 ,MariantoniettaPanzarino 1 , FrancescoGiorgino 3 andLuigiESelvaggi 1 Abstract Severalprotocolsareactuallyavailablefor inVitro FertilizationandEmbryoTransfer.Thereviewsummarizesthe maindifferencesandthecliniccharacteristicsoftheprotocolsinusewithGnRHagonistsandGnRHantagonistsby emphasizingthemajoroutcomesandhormonalchangesassociatedwitheachprotocol.Themajorityof randomizedclinicaltrialsclearlyshowsthatin “ inVitro ” FertilizationandEmbryoTransfer,thecombinationof exogenousGonadotropinplusaGonadotropinReleasingHormone(GnRH)agonist,whichisabletosuppress pituitaryFSHandLHsecretion,isassociatedwithincreasedpregnancyrateascomparedwiththeuseof gonadotropinswithoutaGnRHagonist.ProtocolswithGnRHantagonistsareeffectiveinpreventingapremature riseofLHandinduceashorterandmorecost-effectiveovarianstimulationcomparedtothelongagonistprotocol. However,adifferentsynchronizationoffollicularrecruitmentandgrowthoccurswithGnRHagoniststhanwith GnRHantagonists.FuturedevelopmentshavetobefocusedontimingoftheadministrationofGnRHantagonists, bygivingagreatattentiontonewstrategiesofstimulationinpatientsinwhichradio-chemotherapycyclesare needed. Keywords: ivf,GnRH,Oocytes,GnRHprotocols Review Severalrandomizedclinicaltrialsdemonstratethatin IVF-ET,thecombinationofexogenousgonadotropinplus GonadotropinReleasingHormoneagonist(GnRH-a),for thesuppressionofpituitaryFSHandLHsecretion,is associatedwithhigherpregnancyratesascomparedtothe useofgonadotropinswithoutGnRH-a.Themajorbenefits preventionofprematureLHsurgeandluteinisation[1], enhancementoffollicularrecruitment,allowingtherecov- eryofalargernumberofoocytes[2],andtheimprove- mentinroutinepatienttreatmentschedule[3].Thegold standardforovarianstimulationinyoungnormo- gonadotropicwomenisrecognizedasthelongprotocol, startingGnRH-ainthemidlutealphaseofthepreceding cycle(Figure1).Asystematicoverviewoftwenty-sixtrials comparingdifferentGnRH-aprotocolsforpituitary desensitizationin invitro fertilizationdemonstratedthe superiorityofthelongprotocolovertheshortandultra- shortprotocols(OR1.32forclinicalpregnancyrateper cyclestarted),withGnRHanaloguebeingcommencedei- therinfollicularphaseorinlutealphase[4].GnRH-along protocol,inducesprofoundsuppressionofendogenousre- leaseofgonadotropinsduringtheearlyfollicularphase, allowingtheearlyantralfolliclestogrowco-ordinatelyin responsetoexogenousgonadotropinstoaccomplishsim- ultaneousmaturation.Thisleadstoanextendedwidening oftheFSHwindow,anincreasednumberofrecruitedma- TwotypesofGnRH-aadministrationpatterncanbe usedtoleadtopituitarydesensitizationinthelong protocol;oneconsistingoflowdose(0.1mg)ofGnRH-a dailyandanotherconsistingoftheadministrationof higherdoses(3.75mg,depot)oflong-actinganalogues. Albuquerqueetal.[5],inameta-analysisofsixrando- mizedcontrolledtrials(RCTs),foundthatpregnancy ratesaresimilarinthelongprotocolusingdepotor dailyGnRHanalogues.However,theuseoflong-acting analoguesisassociatedwithanincreasingrequirement *Correspondence: ilariatotaro.it@libero.it 1 UnitofPhysiopathologyofHumanReproductionandGametes Cryopreservation,DepartmentofGynecology,ObstetricandNeonatolgy, UniversityofBari “ AldoMoro ” ,Bari,Italy Fulllistofauthorinformationisavailableattheendofthearticle ©2012Depaloetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited. Depalo etal.ReproductiveBiologyandEndocrinology 2012, 10 :26 http://www.rbej.com/content/10/1/26 forgonadotropinsandalongertimeofovarianstimula- tioncomparedtothedailyGnRH-alowdose.Inpatients withnormalBMIcomparedtoover-weightpatients,it wasdemonstratedthatlowdosesoftryptorelin (0.05mg,daily)areadequatetopreventaprematureLH rise,resultinginreducedgonadotropinlevelsand increasedclinicaloutcomes[6].SinceGnRHreceptors areexpressedinhumanovary,itwassuggestedthathigh dosesofGnRH-amayinducedesensitizationofovarian receptorsinnormalorunderweightpatients.Incontrast, inoverweightwomen,increasedfatmassmayaccount foreitherincreasedsteroidstorageorincreasedperiph- eralconversionofandrogenstoestradiol(E2),thuspro- vidingasourceforserumE2levelswhenovarian steroidogenesismightbesuppressed[6]. TheuseofGnRHagonistsinthelongprotocolischar- acterizedbysomedisadvantagesforthepatients:a)the drawbackofalongtreatmentperioduntildesensitization occurs[7];b)theincreasedriskoftheovarianhyperstimu- lationsyndrome(OHSS)[8];c)morefrequentoccurrence ofsideeffects(e.g.,hotflushes,headache,bleeding,and cystdevelopment)duringthedesensitizationperiod[9,10]. TheintroductionofGnRHantagonists(GnRH-ant)in AssistedReproductiveTechnologies(ART)toprevent LHsurge,seemedtoopenupanewwaytowardsamore “ friendlyIVF ” [11].Unliketheindirectpituitarysuppres- sioninducedbyGnRH-a,GnRH-antadministration causesimmediateanddose-relatedinhibitionofgonado- tropinsreleasebycompetitiveoccupancyoftheGnRH receptorsinthepituitary[12]. TheuseofGnRH-antleadstoasignificantreductionin thedurationofovarianstimulation.GnRHantagonistsare alsonotassociatedwithacuteinductionofgonadotropins, whichmayinducecystformation.Inaddition,nohot flushesareobservedwithGnRH-antbecausetheiruse doesnotresultintheprofoundhypo-oestrogenemia observedwithGnRH-a.Finally,areducedincidenceof moderateandsevereOHSSmayoccurwhileusing GnRH-ant.InaCochranereview,Al-Inanyetal.have shownthatwomenreceivingantagonists,haveasignifi- cantlylowerincidenceofOHSSwhentreatedwithGnRh antcomparedwithwomentreatedwithGnRhagonist (RD=  0.03,95%CI=  0.05to0.02,P 0.00001)[13] Inameta-analysiscomparingGnRH-aversusGnRH- antforcontrolledovarianstimulationinoocytedonors, Bodrietal.foundnosignificantdifferenceintheinci- denceofOHSSbycomparingprotocolswithGnRHago- nistsversusantagonists[RR0.61(95%)CI0.18to2.15, P=45,heterogeneityP=45,I20%fixedeffectsmodel] [14].Moreover,theGnRhantagonistprotocolmakesit possibletotriggerovulationwithGnRhagonistinstead ofhCG,minimizingtheriskofOHSSandsecuringthe appropriatematurationofoocytes. Inarecentreview,ithasbeendemonstratedthatin freshIVFcycleswithET,noOHSSwasreportedafter GnRHant[riskdifferenceof5%whencomparedwith GnRHagroup(with95%CI:-0.07to0.02)][15]. OvulationtriggeringwithGnRHagonist,inGnRHant protocolsisassociatedwiththestrategytofreezeall oocytesforfutureuse,andthiscouldbethetoolto- wardseradicationofOHSS[16].(Writteninformedcon- sentwasobtainedfromthepatientforpublicationof thisreport). Theaboveconsiderationsarecorroboratedbyrecent reportsindicatingaclassicGnRh-antprotocolwhere ovulationinductioniscarriedoutwithGnRhagonist, associatedwithdecreasedriskofpost-triggeroestradiol exposureaswellasOHSSriskinwomenwithbreast cancer[17-19]. Inourexperience,theavoidanceofanacutestimula- tionofendogenousgonadotropins,theshortdurationof treatment,andtheabilitytoinhibitdirectlytheprema- tureLHsurgemadeGnRH-antthemostappropriate regimenforovarianstimulation,forembryoorgamete Figure1 GnRHagonistprotocols. LongProtocol:GnRHagonist0.1mgstartinginfollicularphaseorlutealphase(CycleDay21)ofthepreviuos cycleuntilhCGadministration.ShortProtocol:GnRHagonist0.1mgstartingonday1or3ofstimulationuntilhCGadministration.Ultrashort Protocol:GnRHagonist0.1mgadministeredonday2 – 4ofstimulation. Depalo etal.ReproductiveBiologyandEndocrinology 2012, 10 :26Page2of8 http://www.rbej.com/content/10/1/26 cryopreservationincancerpatients,priortogonadotoxic therapy. TwoGnRH-antregimenshavebeendevelopedforcon- trolledovarianstimulation,involvingeithersingleadmin- istration[20]ormultipleadministrations[21].(Figure2). Inthesingledoseprotocol,theadministrationofa3mg doseofGnRH-antonday7oftheovarianstimulationwas showntopreventaprematureLHsurge[22].Inthemul- tipledoseprotocol,theGnRH-antwasadministeredcon- tinuouslyuntilthedayofhCG,andtheminimaleffective dosetopreventtheoccurrenceofaprematureLHrise wasidentifiedas0.25mgofCetrorelix[23,24].Nosignifi- cantdifferenceinpregnancyrateswasshowninarando- mizedcontrolledtrialwhichcomparedsingleinjectionsof cetrorelixacetate(3mg)andadailydoseofganirelix (0.25mg)intheinhibitionofprematureLHsurge.How- ever,thesingle-doseGnRH-antprotocolhastheadvan- tagetoreducethenumberofinjections,although additionaldailydosesofantagonistareneededin10%of cycles[25].Moreover,insomecasesa3mg-dosemayre- sultinexcessiveandpotentiallyharmfulsuppressionof endogenousLH[26]. Fixedversusflexibleregimen:Whichisthemosteffective? Definingthemostappropriatetimetostartcetrorelix administrationhasbeenthesubjectofseveralstudies. Fromthephysiologicalpointofview,GnRH-antadmin- istrationshouldstartwhenthereisfolliculardevelop- mentand/orproductionofE2bythedevelopingfollicles whichmaycauseaprematureelevationinpituitaryLH release,duetopositivefeedbackmechanisms. Themostcommontypeoftreatmentcalledfixedproto- colconsistsofgivingGnRH-ant5daysafterthestimula- tionwithgonadotropins.However,inordertoreducethe numberofantagonistinjectionsandthedurationof stimulation,theflexibleprotocolwasintroduced.Itcon- sistsinadministeringGnRHantagonistwhenthefollicles reachasizeof � 14mm[27,28]. Ameta-analysisbyAlInany[29]evaluatedfourRCTs [27,28,30,31]thatwereperformedtocomparefixedversus flexibleGnRH-antprotocols.Therewasnosignificantstat- isticaldifferenceinpregnancyrateperrandomizedwoman (OR=0.795%CI=0.47to1.05),andnosignificantdiffer- enceintheincidenceofprematureLHsurgeinboth protocols. Severalstudieshaveraisedconcernsregardinganun- favourableeffectoflateadministrationofGnRH-ant,either onday6ofstimulationorlaterinflexibleprotocols.With thismodeofadministration,LHlevelsremainunsup- pressedduringtheearlyfollicularphaseandenhanceE 2 production.Intheflexibleprotocol,highexposureofthe genitaltracttoLH,E2andprogesteronelevelsduringthe earlyfollicularphase,mightadverselyaffecttheimplant- ationratemainlybyalteringend ometrialreceptivity,lead- ingtoaworsereproductiveoutcome.Kolibianakisetal., [32],inarandomizedcontrolledtrial,showedthatstarting theGnRH-anteitheronstimulationday1oronstimula- tionday6resultedinequalfolliculardevelopment.In addition,itsusewassuggestedinPolycysticOvarianSyn- dromepatientswithhighLHlevels,duringthefollicular phase. Whenanalyzingfolliculardevelopmentandendocrine profileofpatientswhoreceivedtheirfirstGnRH-ant administrationonday8orlater,itwasnoticedthat thesepatientshadahighernumberoffollicles � 11and 15mmindiameterandhighE2andLHlevelscom- paredtopatientsinthefixedprotocolgroup.Thisdata suggeststhatinthisflexibleregimen,thecohortof Figure2 GnRHantagonistprotocols. Fixedday6protocol:0.25mgGnRHantagonist/dailyuntilhCGadministration (Albano etal. ,F&S1997) [23].Singledoseprotocol.3mgGnRHantagonistatday7ofstimulation (Olivennes etal. ,HR1998) [22] . Flexibledoseprotocol:0.25mgGnRH antagonistwhenfolliclesreach � 14mm (Diedrich etal. ,HR1994) [21]. Depalo etal.ReproductiveBiologyandEndocrinology 2012, 10 :26Page3of8 http://www.rbej.com/content/10/1/26 follicleshadmoretimetodevelopleadingtoahighernumberoffolliclesinmid-follicularphase[28]TheoptimallevelsofendogenousLHinGnRH-antcycles,arestillamatterofdebate.ItmaybeassumedthatthedeepsuppressionofLHsecretioninducedbyGnRH-aadministrationislikelytobedetrimentalforthefollicle-oocytecomplex.AlowresidualLHconcentrationsandimpairedE2secretionwithincreasingdosesofantagonistwereindeedassociatedwithlowimplantationrates[24].Ontheotherhand,atrendtowardslowerpregnancyrates,wasobservedinpatientswithLHdeficiency,documentedbylowE2:oocyteratio,whichcouldbeexplainedbytheendometrialimpactoflowLHlevels[33].Onthebasisoftheseobservations,thepossibilityofLHsupplementationinGnRH-antregimenswasexamined.Datafromtworan-domizedcontrolledtrialsshowedthattheadditionof75IUofrecombinantLHtorecombinantFSHatGnRH-antinitiation,orfrominitiationofstimulation,doesnotappeartoincreasepregnancyrates[34].Similarly,noim-provementinpregnancyratescouldbeshownbyincreas-ingthedoseofHMGby75IUatGnRH-antinitiation[35].Bothstudiesshownoevidence,thatlowendogenousLHlevelsafterGnRH-antinitiationareassociatedwithadecreasedprobabilityofpregnancyinIVFcycles[31,36].InathirdstudyofBaruffietal.,ametaanalysisoffiveRCT,significantlyhigherserumE2concentrationandnumberofMIIoocyteswereobservedinGnRhantcyclesupplementedwithLH,suggestingthatLHmaypreventanydecreaseinoestradiollevelsafterantagonistadminis-trationeveniftherewasnosignificantdifferenceinim-plantationandpregnancyrates[37].ItwassuggestedthatlowertheLHlevelsonday8ofstimulationforIVF,higherwastheprobabilityofpregnancy[32].HighserumLHlevelsatearlystageofstimulationmightberesponsibleforadvancedendometrialmaturationwhichinducesanearlyclosureoftheimplantationwindowthroughearlierexpressionofprogesteronereceptorsinthefollicularphaseanddownregulationofE2receptorsbytheexposuretosupraphysiologicalsteroidhormonelevels[30].Huirneetal.highlightedtheevidencethatduringGnRH-antadministration,verylargechanges(eitherin-creaseordecrease)inLHlevels,ratherthanabsoluteLHlevels,areassociatedwithadecreasedchanceofclinicalpregnancy[38].Theuseoforalcontraceptivepill(OCP)hasbeencon-sideredasameanforprogrammingIVFcyclesusingGnRH-ant[33],andithasbeenspeculatedthattheuseofOCPpre-treatmentmayresultinimprovedsynchron-izationoftherecruitablecohortofovarianfollicles.AstudybyKolibianakisetal.[39]showednosignificanteffectofOCPpre-treatmentontheprobabilityofpregnancyinGnRH-antcycles;howevereasierschedulingofthecycle,anincreaseofgonadotropinrequirement,andalongerdurationoftreatmentwasobservedwiththeuseofOCP.Howeverinarecentmeta-analysis,encompassing1343randomizedpatients,Griesingeretal.(2010)observedthattheprobabilityofanongoingpregnancyperrandomizedwomanwasfoundtobesignificantlylowerinpatientswhoreceivedOCpre-treatment.(RR0.80,95%CI:0.66to0.97,P=0.02)[40]FinallythepotentialbeneficialeffectofGnRH-antonpregnancyrateinintrauterineinsemination(IUI)cycles,hasbeenassessedinarecentmeta-analysisconductedbyKosmasonsixstudieswith521women[41].Higherpreg-nancyrateswerefound(16.9%intheantagonistgroupand11.5%inthecontrolgroup)whenGnRH-antwasadministered.MoreoveratrendformultiplepregnancieswasalsoobservedwhenGnRH-antwasadministered.IncreaseddurationforadministrationofgonadotropinswasobservedintheGnRH-antgroupcomparedwiththecontrol-group.GnRH-aversusGnRH-antregimensSeveralRCTshavebeendesignedtocomparetheeffi-cacyoftheGnRH-antwiththatofGnRH-alongproto-col,butthesestudiesoftenshowconflictingresults.SignificantlylessgonadotropinampouleconsumptionandstimulationdaysinGnRH-antregimeswithrespecttoGnRH-aregimen[28,42]wasobserved.Nosignificantdifferencewasobservedintheclinicalpregnancyratesandthelivebirthratesbetweenthetwodifferentregi-mens[28].Althoughasimilarnumberofgoodembryoswereobtainedandreplacedinbothgroups,theimplant-ationrateandclinicalandongoingpregnancyratestendedtobelowerinGnRH-antgroup.Themiscarriageratehoweverwascomparable[42].Moreover,alowermeannumberofcumulus-oocyte-complexes(COC)and2pronuclear(PN)oocyteswerefoundinGnRH-antgroupthaninGnRH-agroup[28,42].LHandE2concentrations,inearlyfollicularphase,werehigherinGnRH-antregimeascomparedwithGnRH-aregime,whereastheLHconcentrationsonthedayofhCGwerecomparableinbothprotocols[42].AprematureLHrisewasobservedin4.3%ofGnRH-antpatients[28]andin3%ofGnRH-apatients[42].OHSSgradeIIandIII(WHOclassification)wassignificantlyhigherinGnRH-agroup(1.1%P=0.03)andfinally,theinitiationofFSHadministrationinaGnRH-antregimenwasfoundtobecycle-dependent,makingtreatmentplanningandschedulingmoredifficult[38,43].Nowthatmorethan200papershavebeenpublishedwiththeaimtocomparetheefficacyofGnRH-antpro-tocolswithGnRH-alongprotocol,itmaybetimetotrytoclosethedebate.Recently,threemeta-analysishavebeenpublishedwiththeaimtocomparetheGnRH-antregimenswiththeGnRH-alongprotocol.Themeta-analysisbyAlInany[13]examinesthefirstfivecom-parativestudiesoffixedGnRH-antprotocolwiththeetal.ReproductiveBiologyandEndocrinology:26Page4of8http://www.rbej.com/content/10/1/26 standardGnRH-alongprotocol.TheORforclinical pregnancyrate(PR)perrandomizedwomanwas0.78 (95%CI0.62-0.97)infavourofagonistregimen,andthe absolutetreatmenteffectwas5%,thusmeaningthat5% lowerPRwasobservedwithGnRH-antregimen. AsecondstudybyKolibianakisetal.,[39]isameta- analyticreviewof22RCTspublishedasfullpapersin peerreviewedjournalsanalysingatotalof3,100patients. Theprimaryoutcomewaslivebirth.Thestudyshowed thattheprobabilityoflivebirthbetweenGnRH-antand GnRH-awasnotsignificantlydifferent(OR0.86,95%CI 0.72to1.02,P=0.085),meaningthatonecouldnot identifysignificantdifferenceswithrespecttotheprob- abilityoflivebirthindependentlyofthepopulationstud- ied,typeofgonadotropinusedforstimulation,ortypeof agonistprotocol(fixedorflexibleGnRH-antregimen). Thethirdstudyisanadditionalupdatedmeta-analysis byAlInany.Thisstudyshowedthattherewasnosig- nificantdifferencefollowingGnRhantcomparedwith GnRhagonistregimens(OR0.86,95%CI=0.69to1.08, P=0.20)inthelivebirthrateandintheongoingpreg- nancyrateperwomanrandomized(OR=0.88,95%CI= 0.77to1.00,P=0.05). Conclusionsofmetaanalysis Overall,thesestudiesnowdem onstratecomparableefficacy andbettersafetyofGnRHantprotocolthanGnRhagonist protocol.Previousstudieshaveshownalowerclinicaland ongoingpregnancyratesforth eGnRhantagonistprotocols. Infact,thesestudiesshowsomeconfoundingvariables fromamethodologicalpointofview:1.datawerepooled frompatientswithpreviouslyfailedIVFattempts;2.basal FSH,BMI,anddurationoffertilitywerenotstated;3.three typeofantagonistprotocol(singledose,flexibleandfixed administrationprotocols),4 .GnRH-atreatmentbyeither dailyintranasalorsubcutaneusadministration,and5.dif- ferentstartingdoseofFSHwereconsidered. MoreoverGnRH-antwereoftenusedincycleswithan unfavourableprioroutcomes,i.e.patientswithadvanced ageandwithahighernumberofpreviouslyunfavour- ablecycles,therebycarryingapossibleriskofintrodu- cingconfoundingfactors. Asofnow,weemphasizewhathasbeensuggestedby Griesinger,that, “ PerhapsGnRHantagonistisusedas drugofsecondchoiceinIVFpractice? ” ThisAuthor, evaluatingthedatafromtheGermanyIVFregistryand stratifyingtheresultsbycyclesrank,observedthatthe proportionofGnRH-antcyclesincreasesfrom23%infirst treatmentto35%infifthtreatmentandto48%intenth treatment.Engelsetal.,analyzingthedataretrievedfrom theNationalGermanyIVFregistrydemonstratedthat GnRH-antarecomparativelymoreoftenemployedin higherranksoftreatmentandthattheproportionofolder womeniscomparativelyhigherinantagonistcycles.Thus, theyconcludedthatGnRH-antarecurrentlyoftenusedas asecondlinemedicationorasfirstlinetreatmentforpa- tientwithlowerchancesforpregnancy. Sub-analysisofpatientswithequaldemographicand clinicalfeaturesresultedinsimilarpregnancyratesinde- pendentofwhetherGnRHagonistorantagonistwasused Figure3 Linearregressionanalysisbetweenpatient ’ sageandnumberofoocytesintheGnRHagonistgroup(A)andtheGnRH antagonistgroup(B). InGnRHantagonistprotocolitwasobservedapositivecorrelationbetweennumberofoocytesandpatient ’ sage:the luteo-folliculartransitioninducesFSHlevelsabovethetresholdforashort-perioduntilhormonalfeedbackoccurs,leadingtotheinitiationof folliculargrowthofafewleadingfollicle.AfterexogenousFSHadministration,FSHlevelsariseabovethresholdagainandwillinitiateseveral additionalfolliclestogrow,leadingtoalesssynchronizationofthefollicularcohort,andamorenaturalrecruitmentoffollicles.InGnRH antagonistprotocolnocorrelationwasobservedbetweennumberoffolliclesandpatient ’ sage.InGnRHagonistprotocol,FSHlevelsremain abovethethresholdfollowingpituitarydownregulationandFSHexogenousadministration,resultinginamoresynchronizedfollicular recruitment (Depalo etal. ,GynecolEndocrinol.2009) [45]. Depalo etal.ReproductiveBiologyandEndocrinology 2012, 10 :26Page5of8 http://www.rbej.com/content/10/1/26 [44].Thus,aftercriticalappraisalofcurrentlyavailablestudiesusingGnRH-antitseems,thatthedifferencesinreportedoutcomemeasurementscouldbetheconse-quenceofthelargevariationofpopulationincludedinthestudies.InaRCTbyourgroup,inwhichastrictin-clusioncriteriaofpatientswasapplied,itwasshownthatImplantationrate,clinicalPregnancyrateandmis-carriageratesweresimilarintheGnRH-antagregimensaswellinGnRH-alongprotocol.Howeverasignifi-cantlyhighernumberofoocytesandhigherproportionofmatureMIIoocyteswasretrievedperpatientrando-mized,intheGnRHagonistgroupcomparedtotheGnRHantgroup.MoreoverasignificantlyrelationshipwasobservedbetweenpatientsageandnumberofoocytesretrievedinantagonistgroupmeaningthatGnRHantagallowsamorenaturalrecruitmentoffolli-clesinthefollicularphaseinanovarythathasnotbeensuppressed,whereasabettersynchronizationofthefol-licularcohortisobservedinagonisttreatment(Figure3)[45](Table1).Morerecently,aretrospectivecohortreviewoffirst-timeIVFcyclesingoodresponders,hasdemon-stratedthatclinicalpregnancyratesandlivebirthratesaresimilarutilizingeitherGnRhagonistorGnRhantagonist[46].ConclusionsGnRH-antregimeniseffectiveinpreventingaprema-tureriseofLHandthereforeresultsinashorterandmorecost-effectiveovarianstimulationprotocolcom-paredtothelongagonistprotocol.However,thereisdif-ferenceinthesynchronizationoffollicularrecruitmentandgrowthintheGnRH-aandGnRH-antregimens,withbetterfolliculargrowthandoocytematurationseenwithGnRH-atreatment[45].TheeffectofelevatedLHlevelsinfollicularphasebe-foreGnRH-antadministration,hastobefocusedon.AnoptimizationofthecurrentlyusedstimulationprotocolisneededwithregardtotimingofGnRH-antadminis-tration,takingintoaccountstrategiesformildovarianstimulation,makingmorepatientfriendlyIVFprotocolsforpatientswhohavetoinitiateradio-chemotherapyprocedures.Finally,severalaspectsoftheGnRH-antuseneedstobefurtherexploredsuchasthedirecteffectsofGnRH-antonextra-pituitarytissues(i.e.,corpusluteum,endo-metrium,ovary,embryo),andpotentialpharmacologicaldifferencesamongtheexistingcompounds.CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests. Table1AdvantagesanddisadvantagesofGnRHagonistprotocolsandGnRHantagonistprotocolsGnRHAgonistlongGnRHAntagonistfixedGnRHAntagonistflexibleGnRHagonistshortandAdvantages.StableandlowLHandPlevelsthroughoutthestimulationphaseSuppressionofendogenousFSHlevelsleadingtoafollicularcohortofallsmallfollilclesattheinitiationofFSHstimulationresultinginasynchronizedfollicular.Immediate,reversiblesuppressionofgonadotropinsecretionwhichavoidseffectsrelatedtotheinitialflareupandsubsequentdown.InitiationoftheIVFtreatmentinanormalmenstrualcycleEndogenousinter-cycleFSHriseratherthanFSHsuppression,thusresultinginasignificantreductionintheeffectivedosageandshortertreatment,thanwithGnRHa.Reduceddoseoftheantagonistisneeded.Thecohortoffollicleshavemoretimetodevelopthusleadingtoahighernumberoffolliclesinmid-follicularphase.TheovariansuppressionisnotexcessiveTheinitialstimulationoftheGnRHreceptorsandconsequentsecretionofendogenousgonadotropinsenhancetheeffectsoftheexogenouslyadministeredgonadotropinsDisadvantagess.Moretimecounsumingandcomplexstimulation.Acutestimulationofgonadotropinsandsteroidhormonesduetotheflareup.Profoundhypoestrogenemiaduetodownregulation.Riskofcomplications(OHSS)HighintercycleendogenousFSHconcentrationsinducingsecondaryfolliclerecruitmentandleadingtoanasynchronousfollicularLHlevelsremainunsuppressedduringtheearlyfollicularphaseandenhanceproductionFlareupeffectsinmid-follicularphasecomments.Increasednumberofoocytescollected.Additionalpregnancychancesfromcryo-preservedembryosImprovementinroutinepatienttreatmentschedule.MoreIVFcyclestobecarriedoutinagivenStartingstimulationinpatientscheduledforantineoplastictreatments(oocytecryopreservation)ItmakesfeasibletotailorstimulationtopatientsAmicrodoseGnRHaflareprotocolisusefulinpoor.SeveralmicrodosesofGnRHaintheflareupprotocolshavebeentestedtoachievegonadotropinreleaseandavoidside-effectsoftheclassicflareupprotocoletal.ReproductiveBiologyandEndocrinology:26Page6of8http://www.rbej.com/content/10/1/26 Allauthorshaveparticipatedequallyinthedraftingofthemanuscript.Allauthorshavereadandapprovedthefinalmanuscript.AcknowledgementsWethankdrKJayakrishanforthecorrectionofEnglishlanguage.AuthordetailsUnitofPhysiopathologyofHumanReproductionandGametesCryopreservation,DepartmentofGynecology,ObstetricandNeonatolgy,UniversityofBariAldoMoro,Bari,Italy.KJKHospital,FertilityResearchCentre,Nalanchira-Trivandrum,Kerala,India.SectionofInternalMedicine,Endocrinology,AndrologyandMetabolicDiseases,DepartmentofEmergencyandOrganTransplantation(DETO),UniversityofBariAldoMoroBari,Italy.Received:18September2011Accepted:13March2012Published:13April20121.CaspiE,Ron-ElR,GolanA,NachumH,HermanA,SofferY,WeinraubZ:Resultsofinvitrofertilizationandembryotransferbycombinedlong-actinggonadotropin-releasinghormoneanalogD-Trp-6-luteinizinghormone-releasinghormoneandgonadotropins.FertilSteril2.LiuHC,LaiYM,DavisO,BerkeleyAS,GrafM,GrifoJ,CohenJ,RosenwaksZ:Improvedpregnancyoutcomewithgonadotropinreleasinghormoneagonist(GnRH-a)stimulationisduetotheimprovementinoocytequantityratherthanquality.JAssistReprodGenet3.ZornJR,BoyerP,GuichardA:NeveronaSunday:programmingforIVF-ETandGIFT.4.DayaS:GonadotropinreleasinghormoneagonistprotocolsforpituitarydesensitizationininvitrofertilizationandgameteintrafallopiantransferCochraneDatabaseSystRev5.AlbuquerqueLE,SaconatoH,MacielMC:Depotversusdailyadministrationofgonadotrophinreleasinghormoneagonistprotocolsforpituitarydesensitizationinassistedreproductioncycles.DatabaseSystRev6.LorussoF,DepaloR,SelvaggiL:Relationshipbetweengonadotropinreleasinghormoneagonistdosageandinvitrofertilizationoutcome.GynecolEndocrinol7.ConnPM,StaleyD,HarrisC,AndrewsWV,GorospeWC,McArdleCA:Mechanismofactionofgonadotropinreleasinghormone.8.RizkB,SmitzJ:OvarianhyperstimulationsyndromeaftersuperovulationusingGnRHagonistsforIVFandrelatedprocedures.HumReprod9.Ben-RafaelZ,LipitzS,BiderD,MashiachS:Ovarianhyporesponsivenessincombinedgonadotropin-releasinghormoneagonistandmenotropintherapyisassociatedwithlowserumfollicle-stimulatinghormonelevels.FertilSteril10.Ron-ElR,HermanA,GolanA,RazielA,SofferY,CaspiE:Folliclecystformationfollowinglong-actinggonadotropin-releasinghormoneanalogadministration.FertilSteril11.OlivennesF,FrydmanR:FriendlyIVF:thewayofthefuture?.HumReprod12.HuirneJA,HomburgR,LambalkCB:AreGnRHantagonistscomparabletoagonistsforuseinIVF?.HumReprod13.Al-InanyHG,YoussefMAFM,AboulgharM,BroekmansFJ,SterenburgMD,SmitJG,Abou-SettaAM:Gonadotrophin-releasinghormoneantagonistsforassistedreproductivetechnology.CochraneDatabaseofSystematic14.BodriD,SunkaraSK,CoomarasamyA:Gonadotropin-releasinghormoneagonistsversusantagonistsforcontrolledovarianhyperstimulationinoocytedonors:asystematicreviewandmeta-analysis.FertilSteril15.HumaidanP,KolS,PapanikolaouEG:CopenhagenGnRHAgonistTriggeringWorkshopGroup:GnRHagonistfortriggeringoffinaloocytematuration:timeforachangeofpractice?.HumReprodUpdate524.Review.16.DevroeyP,PolyzosNP,BlockeelC:AnOHSS-FreeClinicbysegmentationofIVFtreatment.HumReprod17.OktayK,TürkçüoluI,Rodriguez-WallbergKA:GnRHagonisttriggerforwomenwithbreastcancerundergoingfertilitypreservationbyaromataseinhibitor/FSHstimulation.ReprodBiomedOnline2010,(6):78318.CavagnaM,DzikA:DepotGnRH-agonisttriggerforbreast-cancerpatientundergoingovarianstimulationresultedinmatureoocytesforcryopreservation:acasereport.ReprodBiomedOnline19.vonWolffM,MontagM,DittrichR,DenschlagD,NawrothF,LawrenzB:Fertilitypreservationinwomenapracticalguidetopreservationtechniquesandtherapeuticstrategiesinbreastcancer,HodgkinlymphomaandborderlineovariantumoursbythefertilitypreservationnetworkFertiPROTEKT.ArchGynecolObstet20.OlivennesF,FanchinR,BouchardP,deZieglerD,TaiebJ,SelvaJ:Thesingleordualadministrationofthegonadotropin-releasinghormoneantagonistCetrorelixinaninvitrofertilization-embryotransferprogram.FertilSteril1994,(3):46821.DiedrichK,DiedrichC,SantosE,ZollC,al-HasaniS,ReissmannT,KrebsD,KlingmüllerD:Suppressionoftheendogenousluteinizinghormonesurgebythegonadotrophin-releasinghormoneantagonistCetrorelixduringovarianstimulation.HumReprod22.OlivennesF,AlvarezS,BouchardP,FanchinR,Salat-BarouxJ,FrydmanR:TheuseofaGnRHantagonist(Cetrorelix)inasingledoseprotocolinIVF-embryotransfer:adosefindingstudyof3versus2mg.HumReprod23.AlbanoC,SmitzJ,CamusM,Riethmüller-WinzenH,VanSteirteghemA,DevroeyP:Comparisonofdifferentdosesofgonadotropin-releasinghormoneantagonistCetrorelixduringcontrolledovarianFertilSteril24.Theganirelixdose-findingstudygroup:Adouble-blind,randomized,dose-findingstudytoassesstheefficacyofthegonadotrophin-releasinghormoneantagonistganirelix(Org37462)topreventprematureluteinizinghormonesurgesinwomenundergoingovarianstimulationwithrecombinantfolliclestimulatinghormone(Puregon).HumReprod25.WilcoxJ,PotterD,MooreM,FerrandeL,KellyE:CAPIVInvestigatorGroup:Prospective,randomizedtrialcomparingcetrorelixacetateandganirelixacetateinaprogrammed,flexibleprotocolforprematureluteinizinghormonesurgepreventioninassistedreproductivetechnologies.Fertil26.OlivennesF,Belaisch-AllartJ,EmperaireJC,DechaudH,AlvarezS,MoreauL:Prospective,randomized,controlledstudyofinvitrofertilization-embryotransferwithasingledoseofaluteinizinghormone-releasinghormone(LH-RH)antagonist(cetrorelix)oradepotformulaofanLH-RHagonistFertilSteril27.LudwigM,KatalinicA,BanzC,SchröderAK,LöningM,WeissJM,DiedrichK:TailoringtheGnRHantagonistcetrorelixacetatetoindividualpatientsneedsinovarianstimulationforIVF:resultsofaprospective,randomizedstudy.HumReprod28.MochtarMH,DutchGanirelixStudyGroup:TheeffectofanindividualizedGnRHantagonistprotocolonfolliculogenesisinIVF/ICSI.HumReprod29.Al-InanyH,AboulgharMA,MansourRT,SerourGI:OptimizingGnRHantagonistadministration:meta-analysisoffixedversusflexibleprotocol.ReprodBiomedOnline30.KolibianakisEM,AlbanoC,CamusM,TournayeH,VanSteirteghemAC,DevroeyP:Initiationofgonadotropin-releasinghormoneantagonistonday1ascomparedtoday6ofstimulation:effectonhormonallevelsandfolliculardevelopmentininvitrofertilizationcycles.JClinEndocrinol31.EscuderoE,BoschE,CrespoJ,SimónC,RemohíJ,Pellicer:AComparisonoftwodifferentstartingmultipledosegonadotropin-releasinghormoneantagonistprotocolsinaselectedgroupofinvitrofertilization-embryotransferpatients.FertilSteril32.KolibianakisEM,ZikopoulosK,SmitzJ,CamusM,TournayeH,VanSteirteghemAC:Administrationofgonadotropin-releasinghormoneantagonistfromday1ofstimulationininvitrofertilization.FertilSteril33.Cédrin-DurnerinI:Antagonistprotocols:residualLHlevelsandthevalueofexogenousLHsupplementation.JGynecolObstetBiolReprod(Paris)(6Pt2):3S29etal.ReproductiveBiologyandEndocrinology:26Page7of8http://www.rbej.com/content/10/1/26 34.Cédrin-DurnerinI,Grange-DujardinD,LaffyA,ParneixI,MassinN,GaleyJ, ThéronL,WolfJP,ConordC,ClémentP,JayotS,HuguesJN: Recombinant humanLHsupplementationduringGnRHantagonistadministrationin IVF/ICSIcycles:aprospectiverandomizedstudy. HumReprod 2004, 19 (9):1979 – 1984. 35.AboulgharMA,MansourRT,SerourGI,Al-InanyHG,AminYM,Aboulghar MM: Increasingthedoseofhumanmenopausalgonadotrophinsonday ofGnRHantagonistadministration:randomizedcontrolledtrial. Reprod BiomedOnline 2004, 8 (5):524 – 527. 36.MervielP,AntoineJM,MathieuE,MillotF,MandelbaumJ,UzanS: Luteinizinghormoneconcentrationsaftergonadotropin-releasing hormoneantagonistadministrationdonotinfluencepregnancyratesin invitrofertilization-embryotransfer. FertilSteril 2004, 82 (1):119 – 125. 37.BaruffiRL,MauriAL,PetersenCG,FelipeV,MartinsAM,CornicelliJ,Cavagna M,OliveiraJB,FrancoJGJr: RecombinantLHsupplementationto recombinantFSHduringinducedovarianstimulationinthe GnRH-antagonistprotocol:ameta-analysis. ReprodBiomedOnline 2007, 14 (1):14 – 25. 38.HuirneJA,vanLoenenAC,SchatsR,McDonnellJ,HompesPG,Schoemaker J,HomburgR,LambalkCB: Dose-findingstudyofdailyGnRHantagonist forthepreventionofprematureLHsurgesinIVF/ICSIpatients:optimal changesinLHandprogesteroneforclinicalpregnancy. HumReprod 2005, 20 (2):359 – 367. 39.KolibianakisEM,CollinsJ,TarlatzisBC,DevroeyP,DiedrichK,GriesingerG: AmongpatientstreatedforIVFwithgonadotrophinsandGnRH analogues,istheprobabilityoflivebirthdependentonthetypeof analogueused?Asystematicreviewandmeta-analysis. HumReprod Update 2006, 12 (6):651 – 671. 40.GriesingerG,KolibianakisEM,VenetisC,DiedrichK,TarlatzisB: Oral contraceptivepretreatmentsignificantlyreducesongoingpregnancy likelihoodingonadotropin-releasinghormoneantagonistcycles:an updatedmeta-analysis. FertilSteril 2010, 94 (6):2382 – 2384. 41.KosmasIP,ZikopoulosK,GorgiouI,ParaskevaidisE,BlockeelC,TournayeH, VanDerElstJ,DevroeyP: Low-doseHCGmayimprovepregnancyrates andlowerOHSSinantagonistcycles:ameta-analysis. ReprodBiomed Online 2009, 19 (5):619 – 630. 42.EuropeanandMiddleEastOrgalutranStudyGroup: Comparableclinical outcomeusingtheGnRHantagonistganirelixoralongprotocolofthe GnRHagonisttriptorelinforthepreventionofprematureLHsurgesin womenundergoingovarianstimulation. HumReprod 2001, 16 (4):644 – 651. 43.HuirneJA,LambalkCB: Gonadotropin-releasing-hormone-receptor antagonists. Lancet 2001, 358 (9295):1793 – 1803. 44.EngelJB,GriesingerG,Schultze-MosgauA,FelberbaumR,DiedrichK: GnRH agonistsandantagonistsinassistedreproduction:pregnancyrate. ReprodBiomedOnline 2006, 13 (1):84 – 87. 45.DepaloR,LorussoF,PalmisanoM,BassiE,TotaroI,VaccaM, etal : Follicular growthandoocytematurationinGnRHagonistandantagonist protocolsforinvitrofertilisationandembryotransfer. GynecolEndocrinol 2009, 25 (5):328 – 334. 46.Johnston-MacAnannyEB,DiLuigiAJ,EngmannLL,MaierDB,BenadivaCA, NulsenJC: Selectionoffirstinvitrofertilizationcyclestimulationprotocol forgoodprognosispatients:gonadotropinreleasinghormone antagonistversusagonistprotocols. JReprodMed 2011, 56 (1 – 2):12 – 26. doi:10.1186/1477-7827-10-26 Citethisarticleas: Depalo etal. : GnRHagonistversusGnRHantagonist in invitro fertilizationandembryotransfer(IVF/ET). ReproductiveBiology andEndocrinology 2012 10 :26. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Depalo etal.ReproductiveBiologyandEndocrinology 2012, 10 :26Page8of8 http://www.rbej.com/content/10/1/26

Shom More....
giovanna-bartolotta
By: giovanna-bartolotta
Views: 165
Type: Public

Download Section

Please download the presentation from below link :


Download Pdf - The PPT/PDF document "REVIEW Open Access GnRH agonist versus G..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.

Try DocSlides online tool for compressing your PDF Files Try Now