REVIEW Open Access GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo - PDF document

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 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