REVIEW Open Access Optimal usage of the GnRH antagonis - PDF document

REVIEWOpenAccess OptimalusageoftheGnRHantagonists:areview oftheliterature AlanBCopperman 1,2* andClaudioBenadiva 3 Gonadotropin-releasinghormone(GnRH)antagonists,whichbecamecommerciallyavailablefrom1999,havebeen usedforthepreventionofprematureluteinizinghormone(LH)surgesincontrolledovarianstimulationforinvitro fertilizationorintracytoplasmicsperminjection.ThisreviewfocusesontherecentliteratureontheuseofGnRH antagonistsandprovidesguidelinesforoptimaluseinlightofincreasingevidenceshowingthatGnRHantagonists aresafeandeffective,allowingflexibilityoftreatmentinawiderangeofpatientpopulations.Thisincludespatients undergoingfirst-linecontrolledovarianstimulation,poorresponders,andwomendiagnosedwithpolycysticovary syndrome.TheGnRHantagonistoffersaviablealternativetothelongagonists,providingashorterdurationof treatmentwithfewerinjectionsandwithnoadverseeffectsonassistedreproductivetechnologyoutcome.This resultsinasignificantlyloweramountofgonadotropinsrequired,whichislikelytoleadtoimprovedpatient compliance. Keywords: GnRHantagonists,GnRHagonists,IVF,Ovarianstimulation,OHSS Background Gonadotropinswerefirstintroducedintheearly1960s andhavebeenusedinovarianstimulationcyclestoinduce multiplefolliculardevelopment,particularlyduringthe past3decades,inwomenundergoinginvitrofertilization (IVF)treatment.Gonadotropin-releasinghormone(GnRH) analogsareadministeredalongwithgonadotropinstopre- venttheoccurrenceofasurgeinluteinizinghormone (LH),whichmayoccurprematurelybeforetheleading folliclereachestheoptimumdiameter(
17mm)fortrig- geringovulationbyhumanchorionicgonadotropin(hCG) wouldoccurinapproximately20%ofstimulatedIVFpa- tients[1,2].PreventingLHsurgesusingGnRHanalogsim- provesoocyteyieldwithmoreembryos,allowingbetter selectionand,therefore,leadingtoanincreaseinpreg- nancyrates[3]. Sincetheearly1980s,theuseofGnRHagonistsin ovarianstimulationhasgreatlyimprovedthesuccess rateofIVF[4].GnRHagonistsreducetheincidenceof prematureLHsurges[5,6]bysuppressinggonadotropin releaseviapituitarydesensitizationfollowinganinitial shortperiodofgonadotropinhypersecretion.Morere- cently,GnRHantagonistswithhighpotencyandfewer sideeffectshavebeenintroducedintoIVFandhave emergedasanalternativeinpreventingprematureLH surges.UnlikeGnRHagonists,thesepotentGnRHan- tagonistscauseimmediate,rapidgonadotropinsuppres- sionbycompetitivelyblockingGnRHreceptorsinthe anteriorpituitarygland,therebypreventingendogenous GnRHfrominducingLHandfollicle-stimulatinghor- mone(FSH)releasefromthepituitarycells.Further- more,GnRHantagonistsuppressionofgonadotropin secretioncanbequicklyreversed[7-9].Thisdifferent pharmacologicmechanismofactionmakesGnRHan- tagonistsamorelogicalchoicetouseinIVFforthepre- ventionofprematureLHsurges[5]. Ganirelix(Orgalutran,N.V.Organon,Oss,The Netherlands)andcetroreli x(Cetrotide,SeronoInter- nationalS.A.,Geneva,Switzerland)aresubcutaneously inIVFtherapy[10,11].Since1999,GnRHantagonistshave beenusedforthepreventionofprematureLHsurgesin womenundergoingcontrolledovarianstimulationfor IVF.Clinically,stimulationwithurinaryFSHorrecombin- anthumanFSH(rFSH),eitheraloneorincombination *Correspondence: acopperman@rmaofny.com 1 MountSinaiMedicalCenter,NewYork,NY,USA 2 ReproductiveMedicineAssociatesofNewYork,NewYork,NY,USA Fulllistofauthorinformationisavailableattheendofthearticle ©2013CoppermanandBenadiva;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsof theCreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse, distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. CoppermanandBenadiva ReproductiveBiologyandEndocrinology 2013, 11 :20 http://www.rbej.com/content/11/1/20 withurinary-derivedhumanmenopausalgonadotropin (hMG),isstartedonday2or3ofthemenstrualcycleand theGnRHantagonistisadministeredinthelatefollicular phase,fromday5or6ofstimulationonward.Thedoseof gonadotropinsmaybeadjusted accordingtoindividualre- sponse.Bothgonadotropins arecontinueddailyuntiltwo tothreefolliclesreach
17mmindiameter(onultrasound assessment)atwhichtimehCGisadministeredtoinduce finaloocytematuration(Figure1).Thisreviewfocuseson literatureconcerningtheuseofGnRHantagonistsinovar- ianstimulationforIVFandprovidesguidelinesforoptimal use. PotentialadvantagesofGnRHantagonistprotocols ThereareanumberoftheoreticaladvantagesofGnRH antagonistsversusGnRHagonists[12,13],includinga shorterdurationofinjectabledrugtreatment,absenceof vasomotorsymptoms,lessriskofinadvertentadministra- tionduringearlypregnancy,avoidanceofovariancystfor- mation,andasignificantlysmallerdoseofgonadotropin percycle,whichtranslatetoimprovedpatientconvenience [9,14].Theliteratureregardingthecosteffectivenessof GnRHantagonistprotocolsiscurrentlycontradictory.Ina randomizedtrialbyBadrawietal.[15],thecostofmedica- tionpercycleandperpregnancywasshowntobehigher inaGnRHantagonistprotocolthanaGnRHagonist protocol,whileanobservationalstudybyKamathetal. [16]foundcostsofthetwoprotocolstobesimilar. CurrentevidencesuggeststhatGnRHantagonistsand agonistsaresimilarlyeffectiveinthecontextofoocyte donation[17].However,duetotheirincreasedconveni- ence,GnRHantagonistprotocolsareoftentheregimen ofchoiceforoocytedonors.Morerecently,ithasbeen recommendedthattreatmentguidelinesforthepreven- tionofovarianhyperstimulationsyndrome(OHSS)[18] shouldbeupdatedtoincorporatefindingsfromthelit- eratureoverthepast5years.Theliteratureshowsthat GnRHantagonistprotocolsandGnRHagonisttriggering offinaloocytematuration,especiallywhenusedin combination,mayreduceOHSSandhaveconsiderable promiseinpreventingOHSS[19]. PotentialdisadvantagesofGnRHantagonistprotocols PotentialdisadvantagesofGnRHantagonistprotocols overGnRHagonistprotocolsincludelessflexibleoptions intermsofcycleprogrammingandearlystudiessug- gestingaminorreductioninpregnancyratespercycle [20,21].IncreasingflexibilityofGnRHantagonistproto- colscanbeachievedwithoralcontraceptives[20].Pre- treatmentwithoralcontraceptivesallowsprogrammingof cycles,wherebystimulationcanbestartedduringa5-day intervalfollowingwithdrawaloftheoralcontraceptive [22].UseoforalcontraceptiveswithaGnRHantagonist protocolandthepregnancyoutcomesofGnRHantagonist protocolsarediscussedbelow. PregnancyoutcomesofGnRHantagonistprotocols Despiteaninitialtrendtowardalowerpregnancyrate withGnRHantagonistscomparedwithagonistsina numberofearlyrandomizedcontrolledstudies,ameta- analysisbyKolibianakisetal.[23]andareviewbyTur- KaspaandEzcurra[24]foundnosignificantdifference intheprobabilityoflivebirthrateswiththeuseofeither aGnRHagonistorantagonistprotocol[23](Table1). Innormalresponders,theuseofGnRHantagonistver- suslongGnRHagonistprotocolswasassociatedwitha statisticallysignificantreductionofOHSS,withnoevi- denceofadifferenceinlivebirthrates[45].GnRHantag- onistprotocolshavebeenshowntoresultinbetter outcomesthanGnRHagonistsinpatientswithpoorprog- nosis[52,53].Inameta-analysisofsixclinicaltrialscom- paringGnRHantagonistversusGnRHagonistprotocols inpoorovarianrespondersinIVF/intracytoplasmicsperm injection(ICSI)cyclesFrancoetal.[54]indicatednodif- ferencebetweenGnRHantagonistsandagonistswith respecttocyclecancellationrate,numberofmatureoo- cytes,andclinicalpregnancyratepercycleinitiated,per oocyteretrieval,andperembryotransfer.Al-Inanyetal. Figure1 Schematicpresentationoftheganirelixtreatmentregimen. CoppermanandBenadiva ReproductiveBiologyandEndocrinology 2013, 11 :20Page2of13 http://www.rbej.com/content/11/1/20 Table1Resultsofmeta-analysesofGnRHanalogsamongpatientstreatedforIVFoddsratiooflivebirthrateGnRHantagonistsGnRHagonistsWeightOddsratio(95%CI)EventsTotalEventsTotalRCTsincludedinKolibianakisetal.[Albano2001[]3419819950.83(0.44-1.55)European2000[]97486612440.75(0.52Olivennes2000[]221269430.80(0.34NAmerican2001[]60208361050.78(0.47MiddleEast2001[]72236371190.97(0.60Akman2001[]4245240.76(0.18Hohmann2003[]1811110580.93(0.40Martinez2003[]4213231.57(0.31Franco2003[]314260.55(0.07Hwang2004[]8278291.11(0.35Sauer2004[]9249251.07(0.33Loutradis2004[]95812580.70(0.27Check2004[]8305301.82(0.52Xavier2005[]7668650.85(0.29Malmusi2005[]5305301.00(0.28Marci2005[]43003010.38(0.53Cheung2005[]3332331.55(0.24Barmat2005[]134017400.65(0.26Bahceci2005[]297333750.84(0.44Badrawi2005[]115013500.80(0.32Schmidt2005[]3243241.00(0.18Lee2005[]13418200.70(0.23Total(n=22)436195030512260.86(0RCTsincludedinAl-Inanyetal.[AllwomenAlbano2000[]34198199513.5%0.83(0.44Barmat2005[]134017407.3%0.65(0.26Heijnen2007[]702057819933.0%0.80(0.54Hurine2006[]179117918.8%1.00(0.47Kim2009[]13548285.1%0.79(0.28Kurzawa2008[]143718377.1%0.64(0.25Lin2006[]226021608.4%1.08(0.51Marci2005[]4300300.3%10.36(0.53Ye2009[]351093911116.6%0.87(0.50Subtotal(95%CI)824691100.0%0.86(0Totalevents222217Heijnen2007[]702057819979.7%0.80(0.54Lin2006[]226021608.4%1.08(0.51Subtotal(95%CI)265259100.0%0.89(0Totalevents97102Heterogeneity:=0.32,=1(P=0.57)Testforoveralleffect:=0.66(P=0.51)CoppermanandBenadivaReproductiveBiologyandEndocrinology:20Page3of13http://www.rbej.com/content/11/1/20 [45]foundnosignificantdifferencefollowingtheuseofGnRHantagonistandagonistprotocolsinarecentCochranereview.Inoocytedonation[55]andembryotransfer[56]cycles,thereplacementofGnRHagonistwithaGnRHantagonisthadnoimpactonthepregnancyandimplantationrates.Higherpregnancyrateswerealsoshowninagonado-tropinintrauterineinseminationcyclethaninacyclewherenointerventiontookplace[57].Inaprospectiverandomizedtrial,Prapasetal.[58]reportedthatGnRHantagonistadministrationduringtheproliferativephasedidnotadverselyaffectendometrialreceptivityinoocyterecipients.OptimaluseofGnRHantagonistsindiversetreatmentFirst-linetreatmentGnRHantagonistshavebeenshowntobeaneffectivetreatmentinwomenundergoingcontrolledovariansti-mulationforIVFinmultiplemeta-analysesandclinicalstudies.Inthesystematicreviewandmeta-analysesbyKolibianakisetal.[23],itwasshownthattheprobabilityoflivebirthwasnotdependentonthetypeofGnRHana-logusedforthesuppressionofprematureLHrises(oddsratio0.86;95%confidenceinterval0.72-1.02).Inamorerecentsystematicreview,Al-Inanyetal.[45]alsoreportedthattherewasnosignificantdifferenceinlivebirthratesfollowingaGnRHantagonistorGnRHagonistprotocol(oddsratio0.86,95%confidenceinterval0.69-1.08).InaretrospectivereviewofpatientswithgoodprognosisundergoingtheirfirstIVFcycle,Johnston-MacAnannyetal.[59]showedthatclinicalandongoingpregnancyratesandimplantationratesweresimilarin755goodre-sponderpatientsundergoingaGnRHagonistprotocoland378goodresponderpatientsundergoingaGnRHan-tagonistprotocolduringtheirfirstcycleofIVF.BormandMannaerts[8]evaluatedtheefficacyandsafetyofganirelixin730womenundergoingovarianstimulationwithrFSH.Thepatientswererandomizedina2:1ratiotoeither0.25mgganirelixorbuserelin(thetrialwasdesignedasanoninferioritystudyusingalongprotocolofintranasalbuserelinandrFSHasareferencetreatment).Ganirelixincomparisonwithbuserelinresultedinashorterdurationoftreatment(5vs26days).Comparisonofthenumberandsizeoffolliclesindicatedthatintheganirelixgroup,thefinalnumberoffolliclesonthedayofhCGadminis-tration,wassmaller(10.7vs11.8)andproducedlesspeakestradiolconcentration(1190vs1700pg/ml)thanthebuserelingroup.Theganirelixregimenresultedinthere-coveryofgood-qualityoocytes,asreflectedbythehighfertilizationrate(62.1%),andasimilarnumberofgood-qualityembryos(3.3),asthereferencegroup(3.5).Theclinicaloutcome(definedastheongoingpregnancyrateperattempt)wasgood(20.3%),althoughpregnancyrateswerefoundtobeslightlyhigherinthereferencegroup(25.7%).Interestingly,theongoingpregnancyrateperat-temptforpatientstreatedatstudysites(n=10)thathadpreviousexperiencewiththeganirelixregimenwas Table1Resultsofmeta-analysesofGnRHanalogsamongpatientstreatedforIVFoddsratiooflivebirthrateCetrorelixonlyAlbano2000[]34198199526.3%0.83(0.44Hurine2006[]1791179117.1%1.00(0.47Kim2009[]13548289.9%0.79(0.28Kurzawa2008[]1437183713.8%0.64(0.25Marci2005[]4300300.5%10.36(0.53Ye2009[]351093911132.4%0.87(0.50Subtotal(95%CI)519392100.0%089(0.65Totalevents97102Heterogeneity:=3.31,=5(P=0.65)Testforoveralleffect:=0.70(P=0.49)GanirelixonlyBarmat2005[]13401740100.0%0.65(0.26Subtotal(95%CI)4040100.0%0.65(0.26Totalevents97102Heterogeneity:notapplicableTestforoveralleffect:=0.70(P=0.36)AdaptedfromKolibianakis2006[]andAl-Inany2011[GnRH=gonadotropin-releasinghormone;IVF=invitrofertilization.CoppermanandBenadivaReproductiveBiologyandEndocrinology:20Page4of13http://www.rbej.com/content/11/1/20 similar,thatis,24.2%intheganirelixgroupvs23.6%inthebuserelingroup.Thissuggeststhattheslightlylowerpregnancyratesobservedinearlytrialsmayhavebeenre-latedtolackofexperiencewiththeuseofantagonistpro-tocols.Withregardtosafety,ganirelixwasfoundtobesafeandwelltoleratedwithatwo-foldlower(2.4%)inci-denceofOHSSthanwasfoundinthebuserelin(5.9%)group.Overall,thestudydemonstratedthatganirelixpro-videsasafe,short,andconvenienttreatmentoptionforpatientsundergoingcontrolledovarianhyperstimulationforIVF/ICSIandresultsingoodclinicaloutcome.Second-linetreatment(treatmentofpoorresponders)GnRHantagonistshavebeenusedeffectivelyinpatientswhohaveapoorprognosisorwhohaveshownadimin-ishedovarianresponsetocontrolledovarianstimulation.Inthesystematicreviewandmeta-analysesbyKolibianakisetal.[23],itwasshownthattheprobabilityoflivebirthinpoorresponderswasnotdependentonthetypeofGnRHanalogusedforthesuppressionofprematureLHrises(oddsratio1.34;95%confidenceinterval0.70-2.59).Inamorerecentsystematicreview,Al-Inanyetal.[45]alsoreportednosignificantdifferencesinclinicalpregnancyratesinpoorrespondersfollowingaGnRHantagonistandGnRHagonistprotocol(oddsratio0.71,95%confidenceinterval0.49-1.02).Schmidtetal.[43]showedthattheuseofGnRHan-tagonistswasaseffectiveastheconventionalmicrodoseprotocolandthatembryoquality,implantationrates,andongoingpregnancyrateswerecomparableinaran-domizedprospectivestudycomparingganirelixwithamicrodoseGnRHagonistinpatientswithpoorovarianresponse.Themicrodoseflareprotocolhasbeenproventoincreasebothclinicalandongoingpregnancyratesinpoorresponders.Theauthorsconcludedthattheganirelixprotocolmaybepreferablebecauseitrequiressignificantlyfewerinjectionsandashortertreatmentcourse,resultingincostsavingsandimprovedconveni-enceforthepatient.AnearlierreviewbyCopperman[60]alsonotedthattheuseofaGnRHantagonistforthesuppressionofprematureLHsurgesinpoorre-spondersisatleastasgoodasthemicrodoseflareandprovidesbettercycleoutcomesthanthelonglutealleuprolideacetatedownregulationprotocols.TheuseofGnRHantagonistsamongpatientswithpoorprognosiswasalsoevaluatedbyShapiroetal.[12]inanonrandomized,noncontrolled,retrospectivereviewof204patients(165cyclesinpatientswithanormalIVFprogno-sisand60cyclesinthosewithapoorprognosis).Overall,thepregnancyratesperinitiatedcycleandperembryotransferwere33.3%and42.1%,respectively,withacyclecancellationrateof21%.Thepatientswithpoorprognosishadapregnancyrateof8.3%perattemptand15%pertransfercomparedwith40%and45%,respectively,inpatientswithnormalprognosis.WhilethisretrospectiveanalysissupportstheuseofGnRHantagonistprotocolsasanalternativetoagonistprotocolsinnormalresponders,theuseofGnRHantagonistsinpatientswithpoorIVFprognosisresultedinpredictablypooroutcomes.Inarecentmeta-analysiscomparingtheefficacyofGnRHantagonistsversusagonistsinpoorresponders,Puetal.[61]showedthatGnRHantagonistsresultedinashorterdurationofstimulation,buttherewasnodiffer-enceinthenumberofoocytesretrieved,thecyclecan-cellationrate,ortheclinicalpregnancyrate.Theabilitytoofferpatientswhohavesufferednumerousfailedcycleattemptsachoiceofeffectivealternativesmayimproveoutcomesforthesewomen.Currently,inmanycenters,thelutealphaseestradiolpatch/GnRHantagonist(LPG)protocolisthetreatmentofchoiceforwomenwithapoorresponsetoovarianstimulation.Thisprotocolin-volvesadministrationoftransdermalestradiolpatchesandaGnRHantagonistinthelutealphaseoftheprecedingmenstrualcycle,followedbyhigh-dosefollicularphasego-nadotropinstimulationwithadjunctiveGnRHantagonist.Dragisicetal.[62]firstdescribedthisnovelprotocolin2005anddemonstratedthatitimprovedovarianrespon-sivenessamongpoorresponders,withmoreuniformfolliculardevelopment,moreoocytesretrieved,highernumberoftransferredembryos,andimprovedpregnancyrates.Weitzmanetal.[63]retrospectivelycomparedtheoutcomesofpatientswithahistoryoffailedcycleswhohadundergoneovarianstimulationwitheitheranLPGprotocol(n=45)oramicrodoseagonistprotocol(n=76)overa1-yearperiod[63].Allclinicaloutcomes,includingongoingpregnancyrates,werecomparablebetweenthetwogroups,suggestingthattheuseofanLPGprotocolisatleastaseffectiveasamicrodoseagonistprotocol.Simi-larfindingswereobtainedbythesamegroupofinvestiga-torsinasubsequentprospectiverandomizedcontrolledtrial(RCT)[64].DosingschedulesSingledoseCetrorelixacetate,aUSFoodandDrugAdministration-approvedGnRHantagonist,hasbeenshowntobeef-fectiveandsafeasasingle-dose(3mg)ormultiple-doseregimen(0.25mgdaily)[65,66].Inaprospectiveran-domizedtrial,Vlaisvljevicetal.[67]showedthat3mgcetrorelixhadcomparableefficacytotheGnRHagonistgoserelin.However,multiple-doseprotocolsarenowthestandardandsingle-doseprotocolsarerarelyused.MultipledoseGanirelixisonlyavailableasamultiple-doseregimen.Themultiple-doseprotocolforganirelixinvolvesthead-ministrationof0.25mgdailyfromday6or7ofstimula-tion,orwhentheleadingfollicleis1415mm,untilCoppermanandBenadivaReproductiveBiologyandEndocrinology:20Page5of13http://www.rbej.com/content/11/1/20 hCGadministration[68].TheGanirelixDose-FindingStudy[69]wasthefirstmulticenter,double-blind,ran-domizeddose-findingstudytoestablishtheminimalef-fectivedoseofganirelixtopreventprematureLHsurgesin333womenundergoingovarianstimulationwithrFSH.Sixdifferentganirelixdoses(0.0652,0.125,0.25,0.5,1.0,and2.0mg/0.5ml)wereadministereddailybysubcutane-ousinjection.Inthisstudy,patientsweretreatedwithafixeddoseof150IUrFSHfor5daysbeforestartingganirelix.Thestudyrevealedthat0.25mg/dwasthemin-imaleffectivedosewithregardtopreventingLHsurgesandresultedinagoodclinicaloutcomewithanongoingpregnancyrateof34%perattemptand37%pertransfer.Administrationof0.25mgdailyganirelixhasbeenshowntobesafeandeffectiveinthepreventionofprematureLHsurgeinfurtherstudies[8,27,28].TheNorthAmericanGanirelixStudyGroupadminis-teredthisGnRHantagonistto313patientsforwhomcontrolledovarianhyperstimulationandIVF/ICSIwereindicated[27].PatientsreceivedonecontrolledovarianhyperstimulationcyclewithganirelixoralongprotocolofleuprolideacetateinconjunctionwithrFSH[27].Fromday6ofrFSHtreatment,ganirelix(0.25mg)wasadministereddailyuptoandincludingthedayofhCGadministration.Themeannumberofoocytesretrievedperattemptwas11.6intheganirelixgroupand14.1intheleuprolidegroup.Fertilizationrateswere62.4%and61.9%andimplantationrateswere21.1%and26.1%intheganirelixandleuprolidegroups,respectively.Clinicalandongoingpregnancyratesperattempt,respectively,were35.4%and30.8%intheganirelixgroupand38.4%and36.4%intheleuprolideacetategroup.Fewermoder-ateandsevereinjection-sitereactionswerereportedwithganirelix(11.9%and0.6%)thanwithleuprolide(24.4%and1.1%).TheEuropeanandMiddleEastOrgalutranStudyGroup,comparedtheuseofganirelix(0.25mgadminis-teredfromday6ofrFSHtreatmentuptoandincludingthedayofhCGadministration)withtheGnRHagonisttriptorelin(0.1mg),asareferencetreatmentinalongprotocol[28].Overall,theresultsshowedthatganirelixachievedsimilarclinicalefficacywithashorterdurationoftreatmentcomparedwiththeGnRHagonist.Theganirelixregimenwas17daysshorter(9vs26days)thanthetriptorelinregimenwithamedianreductioninthetotaldoseofrFSHutilizedof450IU(1350vs1800IU).Thefertilizationratesandthenumberofgood-qualityembryosweresimilarinbothtreatmentgroups.Theimplantationratesofthetwotreatmentarmswereidentical(22.9%)withsimilarongoingpregnancyrates(31.0%forganirelixvs33.9%fortriptorelin).Further-more,localtoleranceofganirelixappearedtobebetterthanthatoftriptorelin,asthepercentageofsubjectswithatleastonelocalskinreactionwastwo-foldlowerwhenusingtheganirelixregimen(11.9%forganirelixvs24.1%fortriptorelin).Inaprospectiverandomizedtrialin185patientsunder-goingassistedreproductivetechnologiesWilcoxetal.[70]comparedasingleinjectionofcetrorelix(3mg)withadailydoseof0.25mgofganirelixinaflexibleprotocol.Cetrorelixandganirelixwerefoundtobeequallyeffective;nopatientineithertreatmentgrouphadaprematureLHsurgeandtherewerenostatisticallysignificantdifferencesbetweentreatmentsforanyIVF/ICSIoutcomes,includingpregnancyrates.Cetrorelixisalsoavailableasamultiple-doseregimen(0.25mgdaily).Hsiehetal.[71]reportedthattheminimumeffectivedoseofcetrorelixforpituitarysuppressionis0.25mg,resultingincomparablepregnancyrates.Olivennesetal.[65]showedthatthemultiple-doseregimenofcetrorelix(0.25mgdaily)offersequalefficacyandsafetytothesingle-doseregimen(3mg).Similareffi-cacyandsafetyresultswereshowninacetrorelix(0.25mgdaily)orbuserelinprotocol[21].FlexibleversusfixeddosingFlexibledosingwasintroducedtoreducethenumberofan-tagonistinjectionsandthedurationofstimulation.Itisrecommendedthatfixeddosingisstartedfromday5or6ofstimulation[72,73]whileflexibledosingstartswhenthefolliclesreachasizeof�14mm[74-76].Ithasbeensug-gestedthatdevelopmentofflexibledosingregimens,thatis,individualizingortailoringGnRHantagonistadminis-tration,mightleadtobetterclinicaloutcomesinGnRHantagonist-treatedpatients[77].Resultsfromseveralclin-icalstudiessupporttheefficacyandsafetyofflexible-dosingregimenswithganirelix,thoughsomeshownosignificantadvantageoverthestandardfixed-doseregimen[78-80].Nevertheless,thereisevidencethatflexibledosingregi-mensleadtoimprovementintheoutcomesofovarianstimulationcycles.Inaprospective,randomized,single-centerstudycomparingfixedmultiple-doseantagonistwithaflexibleganirelixregimen,Ludwigetal.[75]showedanimprovedoutcomewhenatailoredratherthanastan-dardizedfixedprotocolwasusedtoschedulethestartoftheGnRHantagonist;ahigheryieldofoocyteswasachieveddespitelessrFSHused.Therewere,however,nodifferencesinpregnancyratesamongthethreegroups.ThebenefitsofflexibleGnRHantagonistadministrationaccordingtofollicularsizeversusstartingdosingonafixeddaywerealsohighlightedbyAl-Inanyetal.[81]inameta-analysisoffourrandomizedtrials.Althoughnostatisticallysignificantdifferenceinpregnancyratewasobservedbe-tweenflexibleandfixedprotocols,therewasasignificantreductionintheamountofrFSHwiththeflexibleprotocol.UsewithGnRHagonisttriggerOvulationcaneitherbeinducedwithabolusinjectionofhCGoraGnRHagonist.AnadvantageofusingaCoppermanandBenadivaReproductiveBiologyandEndocrinology:20Page6of13http://www.rbej.com/content/11/1/20 GnRHagonisttotriggerfinaloocytematurationisthepotentialreductionintheriskofOHSS[22].Asanef-fectivealternativetohCG-inducedovulation,GnRHag-onistsinduceasustainedreleaseofLH(andFSH)fromthepituitarythateffectivelyinducesoocytematurationandovulation.ApossibleadvantageofaGnRHagonistfortriggerincomparisonwithhCGisthesimultaneousinductionofaFSHsurgecomparabletothesurgeofanaturalcycle[82].GnRHagonisttriggering,however,re-sultsinashorterendogenousLHsurgethatleadstoade-fectivecorpusluteumformationandaninadequatelutealphase[83,84].TheprofoundluteolysisobservedafterGnRHagonisttriggeringincontrasttotheprolongedluteotropiceffectoftenseenaftertriggeringwithhCGhasbeenshowntoalmostcompletelyeliminatetheriskofOHSSinhighresponders,avoidingtheneedforcyclecancellation[82,85].BecauseoftheinadequatelutealphaseafterGnRHagonisttrigger,theuseofstandardlutealphasesupportisinadequateandresultsinlowerconceptionandhighermiscarriagerates[86].Therefore,lutealsupportstrategiesincludingonebolusoflow-dosehCG,repeatedbolusesofhCG,recombinantLHadd-back,andmoreintensiveestradiolandprogesteronesupplemen-tationwereproposedtoachieveoptimalconceptionratesratesEngmannetal.[87]showedthatthisapproachwasef-fectiveinaclinicalstudyinwhich66patientsathighriskfordevelopingOHSSwererandomizedtoanovarianstimulationprotocolconsistingofeitheraGnRHagonisttriggerafterco-treatmentwithganirelixoracontrolgroupthatreceivedhCGtriggerafterdualpituitarysuppressionwithbirthcontrolpillsandaGnRHagonist.NoneofthepatientsreceivingganirelixdevelopedOHSScomparedwith31%ofthepatientsinthecontrolgroup.Thestudyalsofoundnosignificantdifferencesintheratesofim-plantation(36.0%withganirelixvs31.0%withcontrol),clinicalpregnancy(56.7%vs51.7%),andongoingpreg-nancy(53.3%vs48.3%).Inconcluding,theauthorssug-gestedthataprotocolconsistingofaGnRHagonisttriggerafterGnRHantagonistco-treatmentcombinedwithlutealphaseandearlypregnancyestradiolandprogesteronesup-plementationshouldbegivenstrongconsiderationforpatientsathighriskofdevelopingOHSS.InamorerecentpublicationreviewingthepredictivefactorsofsuccessfuloutcomeafterGnRHagonisttriggerandintensivelutealsupport,Kummeretal.[90]identi-fiedserumLHonthedayoftriggerandpeakestradiollevels4000pg/mlasthemostimportantpredictorsofsuccess.Womenwithpeakestradiol4000pg/mlhadasignificantlyhigherclinicalpregnancyratethanwomenwithpeakestradiolpg/mlafterGnRHagonisttrigger(53.6%vs38.1%)[90].Thesamegroupofinvesti-gatorssubsequentlyreportedthatadualtriggeroffinaloocytematurationwithaGnRHagonistandlow-dosehCG(1000IU)resultedinimprovedimplantation,clin-icalpregnancy,andlivebirthratescomparedwithaGnRHagonistalone,withoutincreasingtheriskofclin-icallysignificantOHSSinpatientswithpeakestradiollevels0pg/ml[91].Griesingeretal.[92]investigatedtheeffectofcryo-preservationofalltwopronuclei-stagezygotesfollowingGnRHagonisttriggerontheincidenceofsevereOHSSandongoingpregnancyrateinaprospective,observa-tional,proof-of-conceptstudy.Theongoingpregnancyratewas36.8%(95%confidenceinterval19.159.0).NopatientsdevelopedmoderateorsevereOHSS[92].LHadd-backDespitetheadvantagesofGnRHantagoniststhatis,muchshortertreatmentregimens,fewerinjections,andtheneedforlessgonadotropinthemoregeneralaccept-anceofantagonistregimenshasbeenhamperedbytheirperceivedassociationwithslightlylowerpregnancyandimplantationratescomparedwithGnRHagonistprotocols.Resultsfromearlystudiessuggestedthatlowimplant-ationrateswereduetohighdailydosesofGnRHantag-onists(0.5,1,or2mgoncedaily)inducingasharpdecreaseinserumLHconcentrationsduringthefollicu-larphaseofovarianstimulation[93,94].Supplementa-tionwithexogenousrecombinanthumanLH(rLH)wassuggestedasanalternativetocountertheconsequencesofLHdepletion.InanRCTthatincluded60patients,Garcia-Velascoetal.[95]employedaninnovativeproto-colinwhichthepituitaryresponsewassuppressedwithhigh-doseGnRHantagonistandrLHwasaddedbacktocorrectthediminishedimplantationrate.GnRHan-tagonisttreatment(2mg/d)wasinitiatedonday6ofstimulationtogetherwith375IUrLH,andmaintaineduntilthedayofhCGadministration,whilecontrolsub-jectsreceivedthestandarddoseof0.25mg/d.Fluctuat-ingLHconcentrationswerepresentondays3and6inbothgroups.Thisfluctuationcontinuedonday8andonthedayofhCGadministrationinthecontrol(low-dose)group,where30%ofpatientshadLHconcentrationsIU/LonthehCGday.Thestudy(high-dose)groupshowedstableLHconcentrationsonday8andonthehCGday,withnoLHsurges.Noclinicaldifferencesinoutcomeswerefoundbetweenthetreatmentgroups.TheLHadd-backstrategy(375IU/d)appearedtores-theadverseeffectsthathighdosesofGnRHantag-onisthavebeenseentoimposeonimplantation.Morerecently,Boschetal.[96]assessedtheimpactofLHadd-backoncycleoutcomeduringovarianstimula-tionwithGnRHantagonistsinanRCTperformedintwoagesubgroups35years(n=380)and3639years(n=340).rLHadministrationsignificantlyincreasedtheimplantationrateintheolderpopulation,andaclinicallyrelevant(althoughnotstatisticallysignificant)betterCoppermanandBenadivaReproductiveBiologyandEndocrinology:20Page7of13http://www.rbej.com/content/11/1/20 ongoingpregnancyratepercyclewasobserved.Interest-ingly,nobenefitfromrLHadministrationwasdemon-stratedinpatientsyoungerthan36years.UsewithandwithoutoralcontraceptivesOralcontraceptivepillpretreatmentinGnRHantagonistcycleshasbeenadvocatedforschedulingovarianstimula-tionandoocyteretrievalinIVFprograms.AnRCT,byRombautsetal.[97],assessedtheimpactoforalcontra-ceptiveschedulingwithaganirelixregimenontheovarianresponseofwomenundergoingrFSHstimulationforIVF,comparedwithanonscheduledganirelixregimenandalongGnRHagonist(nafarelin)protocol.Thestudyfoundthatinthethreegroupsthenumberofoocytesretrievedandthenumberofgood-qualityembryosweresimilar.EvidencefromseveralotherRCTsintheliteraturesup-portstheuseoforalcontraceptiveschedulingandshowsthatsuccessratesarethesame[98,99],althoughithasbeenfoundthatafteroralcontraceptivepretreatmentitmaytakeanextradaytostimulate[100].InthemostrecentCochranereview,asubgroupanalysisof10RCTsthatusedoralcontraceptivespretreatmentshowedthattherewerenosignificantdifferencesinongoingpregnancyratesinGnRHantagonistprotocolscomparedwithGnRHagonistprotocols[45].Conversely,Griesingeretal.[101]showedastatisticallysignificantreductioninthelikelihoodofongoingpregnancywithoralcontraceptivepretreatmentwhenapill-freeinter-valof25daysisusedbeforestartinggonadotropinstimu-lationinameta-analysisofsixRCTsonoralcontraceptivepretreatmentinGnRHantagonistIVFcyclesinvolving1343patients.ThenegativeeffectoftheoralcontraceptivepretreatmentontheIVFoutcomemaybeexplainedbythefactthatsomeofthestudiesincludedinthemeta-analysis[101]startedovarianstimulation23daysafterthelastoralcontraceptivepillratherthan5dayslater.Moreresearchisneededtodeterminethemostreli-ableandefficaciouswaytoscheduleGnRHantagoniststimulationcycleswithoralcontraceptivepretreatment.UsewithandwithoutestrogenpretreatmentEstrogenpretreatmentinGnRHantagonistcycleshasalsobeensuggestedasanalternativemethodtoachievegonado-tropinsuppressionduringtheearlyfollicularphasesothatschedulingovarianstimulationandoocyteretrievalinIVFprogramscanbeplanned.Guivarch-Levêqueetal.[102]foundthatestrogenpretreatmentwassafeinalargepro-spectivestudyofpatientsundergoingIVF/ICSI.AgreaterrequirementofFSHandalongerdurationofstimulationwereassociatedwithestrogenpretreatment[103,104].HoweverestrogenpretreatmentdidnotaffecttheIVF/ICSIoutcomes[103].DecreasingOHSSwithGnRHantagonistsOHSSisapreventableconditionandimplementingevidence-basedpreventionstrategiesshouldenableclini-cianstoreduceitsoccurrence.Aswehavediscussed,GnRHantagonistprotocolsandtheuseofaGnRHagon-isttotriggerfinaloocytematurationinaGnRHantagonistprotocolaretwotreatmentstrategiesthatcouldreduceorpreventOHSS,especiallywhenusedinconjunction.Significantlyelevatedorrapidlyrisingserumestradiolconcentrationsareknowntopredisposepatientstode-velopmentofOHSS.Therefore,sinceGnRHantagonisttreatmentisassociatedwithreducedestradiolconcentra-tions,itmightbeexpectedtodecreasetheriskofOHSS[105].Gustofsonetal.[105]showedthatganirelixtreat-mentrapidlyreducedcirculatingestradiolconcentrationswithoutadverselyaffectingoocytematuration,fertilizationrates,orembryoqualityandresultedinahighpregnancyrateinthesubgroupofwomenwithovarianhyper-responsewhowerepretreatedwithaGnRHagonist.Des-pitethetreatmentcohortbeingathighriskofdevelopingOHSS,onlytwocasesofsevereOHSSoccurred.TheRCTbyLainasetal.[106]providedfurtherevidencetosupporttheuseofGnRHantagonistsamongpatientsatriskofOHSS.ThisstudycomparedaflexibleGnRHantagonistprotocolwiththelongGnRHagonistdown-regulationprotocolin220patientswithpolycysticovarysyndrome(PCOS).Whilepregnancyratesweresimilarinthetwoprotocols,theGnRHantagonistprotocolwasassociatedwithasignificantlylowerincidenceofOHSS.ThereductionintheincidenceofOHSSwithGnRHan-tagonistprotocolswasshownintheCochranereviewof27RCTsin2006[107]and29RCTsin2011[45].Thesesys-tematicreviewscomparedGnRHantagonists(ganirelixorcetrorelix)withthelongprotocolofGnRHagonist.Asta-tisticallysignificantreductionintheincidenceofsevereOHSSwiththeantagonistprotocol(27RCTs:relativeriskratio,0.61;95%confidenceinterval,0.42=0.01[107];29RCTs:oddsratio0.43,95%confidenceinterval0.57[45])wasobserved.Inaddition,interventionstopreventOHSS,suchascoastingandcyclecancellation,wereadministeredmorefrequentlyintheagonistgroup(27RCTs:oddsratio,0.44;95%confidenceinterval,0.21=0.03[107];29RCTs:oddsratio,0.50,95%confi-denceinterval,0.33=0.001[45]).Inameta-analysisof7RCTs,Xiaoetal.[108]showedthattherateofOHSSwassignificantlylowerintheGnRHantagonistgroupthantheGnRHagonistgroupinwomenwithPCOS(oddsratio0.36,95%confidenceinterval0.25Alternatively,theriskofOHSScanbereducedbytrig-geringfinaloocytematurationwithaGnRHagonist.ThereductionoftheriskofOHSSusingaGnRHagon-isttriggerhasbeendiscussedabove.Anothernewmethodoftertiarypreventionofearly-onsetOHSSusingGnRHantagonistshasbeenreportedCoppermanandBenadivaReproductiveBiologyandEndocrinology:20Page8of13http://www.rbej.com/content/11/1/20 byLainasandcolleagues[109].Antagonistadministrationwasre-initiatedatadailydoseof0.25mgafterpatientsdevelopedearlyOHSS,andcontinueddailyforaweek,whileallembryoswerecryopreserved.NoprogressionofsevereearlyOHSSwasobservedinanyofthepatientsandnoneofthepatientsrequiredhospitalization.NeonataloutcomesLong-termoutcomesafterGnRHantagonisttreatmentdonotdifferfromthoseobservedwithGnRHagonistregi-mens.Obstetricalandneonataldataon839pregnancies,resultingin969live-borninfantsafterganirelixtreatmentwerecomparedwithahistoricalcohortof753pregnanciesafterlongGnRHagonist(buserelin)treatment,resultingin963live-borninfants[110].Therewerenodifferencesinmaternalcharacteristics,fertilizationmethod,andpreg-nancyanddeliverycomplicationsbetweentheganirelixandhistoricalGnRHagonistgroups.WomenexperiencedmoremultiplepregnanciesinthehistoricalGnRHagonistgroup(31.9%)thantheganirelixgroup(18.7%;0.0001),andbothgroupswerecomparablewithrespecttopreg-nancylossafter16weeksgestation.Theincidenceofmajorcongenitalmalformationsinfetuseswithgestational26weekswas5.0%intheganirelixcohortversus5.4%inthehistoricalGnRHagonistgroup(oddsratio,0.94;95%confidenceinterval,0.62Boerrigteretal.[111]conductedapooledanalysisofallfollow-updataofthephase2and3trialsforthede-velopmentofganirelix.Dataon340ongoingpregnanciesandneonataloutcomesfor432childrenshowedthattherewerenodifferencesbetweentheGnRHantagonistandGnRHagonistregimenswithrespecttopregnancylossafter16weeksgestation,andtheincidenceandna-tureofcomplicationsduringpregnancyanddeliverydidnotdifferbetweenthetwogroups[111].Nomajordif-ferenceswereobservedinneonatalcharacteristicsofin-fantsintheganirelixandagonistgroups,whohadanoverallmeanbirthweightonaverageof3200gforsin-gletons,2300gfortwins,and18001900gfortriplets.Congenitalmalformationswereobservedin32of424(7.5%)fetusesintheganirelixgroupandin10of181(5.5%)intheagonistgroup.ConclusionsWereviewedthescientificliteratureontheuseofGnRHantagonists,concentratingonthemostrecentlyavailableevidence.Antagonisttreatmentprotocolsareaviableal-ternativetoagonisttreatment.Themultiple-doseprotocoliseffectiveinthepreventionofprematureLHsurge.Comparedwiththelongagonistprotocol,GnRHantagon-isttreatmentisshorter,rapidlyabsorbed,rapidlyrevers-ible,requiresfewerinjections,andappearstorequirealoweramountofgonadotropins,whichislikelytoleadtoimprovedpatientcomplianceandlowercosts.ThelowerpregnancyratereportedinsomeearlyRCTshasbeenoff-setbythefindingsofsubsequentmeta-analyses,andthisisprobablytheresultofoptimizationoftheantagonisttreatmentprotocol.TheonlycontraindicationstotheuseofGnRHantagonistsfortheinhibitionofprematureLHsurgesinwomenundergoingcontrolledovarianstimula-tionarehypersensitivitytoGnRHantagonistsorpreg-nancy[112].GnRHantagonistshavebeenusedsafelyandeffectivelyinawiderangeofpatients(Table2),suchasthoseundergoingfirst-linecontrolledovarianstimulation[8],thosewithapoorprognosis[12],andpatientstakingoralcontraceptivestoregulatemenstrualcycles[97].Theantagonistflexible-dosingregimenhasalsoshownprom-iseamongwomendiagnosedwithPCOS[114].Certainotherpatientpopulationsmightparticularlybenefitfromganirelixprotocols,suchaspatientswhohavenotrespondedtoothercontrolledovarianhyperstimulationregimens(includingthosewithGnRHagonist)[113]or,totheotherextreme,patientswithahighriskofdevelopingOHSS[93,105].TherearenoadverseeffectsassociatedwithaGnRHantagonistprotocolonassistedreproductivetechnologyoutcomes.Duetotheabilitytotriggerfinaloo-cytematurationwithaGnRHagonisttopreventOHSS,antagonistprotocolsarebecomingthetreatmentofchoiceforovarianstimulationofoocytedonors[17].Overall,GnRHantagonisttreatmentprotocolsareef-fective,easytouse,allowflexibilityoftreatmentand,therefore,appeartoofferapromisingalternativetothelong-establishedGnRHagonistregimensforpreventionofaprematureLHsurgeduringovarianstimulationforassistedreproductivetechniques.CompetinginterestsABChasreceivedpaymentsforspeakersbureausfromSchering-Plough,EMDSerono,andFerring.CBhasreceivedpaymentsforlecturesfromMerck.ABCandCBparticipatedinthedraftingofthemanuscriptandcontributedtothecriticaldiscussion.Bothauthorsgavefinalapprovaloftheversiontobepublished. Table2SuitablecandidatesforGnRHantagonistPatientpopulationsbenefitingfromGnRHantagonistprotocolsPatientsundergoingfirst-linecontrolledovarianstimulation[Patientswhohavenotrespondedtoothercontrolledovarianstimulationregimens,includingthosewithgonadotropin-releasinghormoneagonist[Patientswithapoorprognosis[Oocytedonors[Patientsatriskforovarianhyperstimulationsyndrome[Patientswithpolycysticovariansyndrome[Patientstakingoralcontraceptivetoregulatemenstrualcycles[CoppermanandBenadivaReproductiveBiologyandEndocrinology:20Page9of13http://www.rbej.com/content/11/1/20 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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 CoppermanandBenadiva ReproductiveBiologyandEndocrinology 2013, 11 :20Page13of13 http://www.rbej.com/content/11/1/20