European Journal of Endocrinology 10.1530/EJE-16-0968 stimulating hormone(FSH) andluteinizinghormone andcontrolthesecretionoffollicle- anterior pituitary portalsystemtoreachthe released intothepituitary projections tothehypothalamus whereGNRHis of neuronsabletosecrete GNRH. Theseneuronssend age group( disorder the most common endocrine abnormality in this at least1in15womenofreproductiveage,makingthis anovulation. Itaffectsupto10%ofwomen( disorder characterizedbyhyperandrogenismandchronic syndrome(PCOS)is a heterogeneous Polycystic ovary Introduction result suggeststhatgeneticalterationsinthehypothalamo–pituitaryaxismayplayrolepathogenesisof PCOS. not excludeapossibleinteractionoftheidentifiedvariantwithgeneticbackgroundand/orenvironment, our Conclusions heterozygous inbothparents. available individualsofthefamilyconfirmedthatvariantwashomozygousinthreeaffected sistersand coding exonofthe Results Methods with threesistersdiagnosedPCOS. Objective hallmarks. about 10%ofwomen.Itsetiologyispoorlyknown,butadysregulationgonadotropinsecretiononeits Context Abstract Haifa, Israel,and France, Cedex, France, 1 Stavit Shalev Sandrine Caburet ovary syndrome familial casediagnosedwithpolycystic A homozygousmutationof Institut JacquesMonod,UniversitéParisDiderot,Paris,France, DOI: 10.1530/EJE-16-0968 www.eje-www.eje-online.org Case Report Mammalian reproductiondependsontheactivity 5 Université ParisDescartes-ParisV, Paris,France, : Whole-exomesequencingallowedthedetectionofmissensevariantrs104893836locatedinfirst online.org : PCOSisaheterogeneousconditioncharacterizedbyhyperandrogenismandchronicanovulationaffects : Whole-exomesequencingandSangerconfirmation. : AstheetiologyofPCOSisunclear, wehaveperformedagenome-wideanalysisofconsanguineousfamily 3 3 : Thisisthefirstdescriptionofa OBGYN Department,HaEmekMedicalCenter, Afula,Israel, ). 7 Genetic Institute,HaemekMedicalCenter, Afula,Israel 6
, 7
and 1 GNRHR , 2 ReinerA Veitia , Ronit BeckFruchter geneandleadingtothep.Gln106Arg(p.Q106R)substitution.Sangersequencingofall © 2017EuropeanSociety ofEndocrinology © 2017EuropeanSociety ofEndocrinology S Caburetandothers 1 , 2 Printed inGreatBritain 3 6 The RappaportFacultyofMedicine,Technion, , Bérangère Legois GNRHR 1 , 2 Université ParisDiderot-ParisVII, 2 genemutationinpatientsdiagnosedwithPCOS.Althoughwedo ) and 4 Institut Cochin,Paris, beta pathway, insulin signaling or associated with type 2 leading toenhancedLHsecretion ( GNRH pulsegeneratortoinhibition byovariansteroids, range. This mayberelated to a decreased sensitivity of the often increasedandFSHisinthelowerfollicular of itshallmarks.InpatientswithPCOS,plasmaLH is known, a dysregulation of gonadotropin secretion is one PCOS ( hypogonadism (HH),hypothalamicamenorrheaand reproductive disorders such as hypogonadotropic (LH). Alterationsofthissystemareassociatedwith with PCOS Mutation in Published byBioscientifica Ltd. 1 , 2 Various susceptibilitygenesinvolvedinthe TGF- , Marc Fellous 4 ). Indeed,althoughtheetiologyofPCOSispoorly GNRHR GNRHR inafamily 4 , 5 , Downloaded fromBioscientifica.com at10/01/202105:11:29AM ina (2017) Endocrinology European Journal of [email protected] [email protected] Email S Shalev to Sandrine Caburet or should beaddressed Correspondence 176 5 ). 176 : 5 176 :5 , K9–K14
K 9–K14
or via freeaccess European Journal of Endocrinology GNRHR ahomozygous patients diagnosedwithPCOScarrying understanding thegeneticcontributiontothisdisorder. with variousdegreesofcertainty, wearestillfarfromfully PCOS susceptibility candidate genes have been detected suggested toplayarole( ( ( 7-like 2( insulin receptorsubstrate1( (normal range 0.5–5 mL (normalrange2–20 prolactin: rangefortheexamined patients8.55–20.32 patients 0.66–1.9 tests (17-hydroxyprogesterone: rangefortheexamined and hypothyroidismwereruledoutbytherelevant congenital adrenalhyperplasia,hyperprolactinemia to theRotterdamcriteriawasproposed.Nonclassic two criteriawerefulfilled,thediagnosisofPCOSaccording Ferriman–Gallwey scoringavailable).However, asatleast was obviousandhirsutismdiagnosedsubjectively(no morphology, suggestingaPCOS.Thepresence ofacne clinical hyperandrogenism and polycystic ovary Rotterdam criteria. All three sisters had oligomenorrhea, diagnosed withPCOS(V-16, V-17 andV-18) and2sons. other consanguineousmarriages.Theyhad3daughters Fig. 1A Arab origin.Theparents(individualsIV-11 andIV-12, approved bythelocalethicscommittee. performed accordingtotheDeclarationofHelsinkiand all individualsincludedinthestudy, andthestudieswere procedures. Written informedconsentwasobtainedfrom Genomic DNAisolationwasperformedbystandard samples werecollectedforhormonalandgeneticstudies. of theHaEmekMedicalCenterinAfula(Israel).Blood This family was recruited through the Genetic Institute in whichthreemembershadbeendiagnosedwithPCOS. We haveperformedamolecularanalysisoftheMO7family Participants anddatacollection Patients andmethods associated gene( fibrillin-3 ( with PCOS.Someofthemostoutstandingonesare diabetes and/orobesityhavebeentestedforassociation www.eje-online.org AMH SHBG Case Report The diagnosisofPCOSwasdoneaccordingtothe MO7 isaconsanguineousMiddleEastfamilyof Here, wereportonaconsanguineousfamilywiththree ) anditstypeIIreceptor( ) ( ) arefirstcousinsandconnectedbyatleastfour mutation. TCF7L2 5 ). Variants intheanti-Mullerianhormone FBN3 ), insulin( FTO ), calpain10( ng/mL (normalrange0.2–5 ) andsexhormone-bindingglobulin IU/L)). Normal gonadotropin levels ng/mL); TSH:1.79–4.2 INS 6 ). However, althoughsuch IRS1 ), insulinreceptor( CAPN10 AMHR2 S Caburetandothers ), transcriptionfactor ), fatandobesity- ) havealsobeen ng/mL); INSR IU/L ng/ ), Bioconductor DNACopypackage(DNAcopy1.32.0)by copy number variants (CNV) were assessed using the and environmentalcontributing factors. The presenceof multifactorial disorderwith variousgenetic,endocrine understood yet;however, PCOSisconsidered tobea The etiologyofthesyndrome isnotcompletely Results anddiscussion and Condel. damaging anddeleteriousaccordingtoPolyphen,SIFT of variantsbykeepingonlythosepredictedasprobably platform, VEPandVarSifter 1.7.We furtherrefinedthelist indels). The variants were filtered using IntegraGen’s ERIS control exomesforSNPsand130 and inanIntegraGeninternaldatabase(containing201 (ESP6500SI-V2-SSA137),HapMap3,ExAc Server/EVS Genomes Project(release_v320101123),ExomeVariant present in the public variant databases dbSNP132, 1000 (MAF) wassettobeunder1%whenthevariant heterozygosity inthemother. Theminorallelefrequency changes), homozygosityinbothaffectedsistersand impact ontranscriptorprotein(i.e.non-synonymous 5 reads,locationinthecodingsequenceswithpotential according tothefollowingcriteria:minimumdepthof filtered thesinglenucleotidevariants(SNV)andindels a diseaseallelefromoneoftheircommonancestors.We strongly suggestedanautosomalrecessiveinheritanceof sequence at 10× or greater. Consanguinity in this family read pairspersampleandcovered96%ofthetargeted exome sequencinggenerated55to103millionmapped comparing theexomedatatoreferencesamples.Whole- (Evry, France) using standard procedures ( and dataprocessingwereperformedbyIntegraGenSA IV-12. preparation,exomecapture,sequencing Library patients V-17 andV-18 andoftheirunaffectedmother performed a whole-exome sequencing of two PCOS To investigateapotentialunderlyinggeneticcause,we Whole-exome sequencingandvariantanalysis fertility treatment. infertility butconceivedeitherspontaneouslyorafter to adiagnosisofPCOS.Allthreesistersconsultedfor 3–20 patients: 3.07–6.6 follicular phase2–15 for theexaminedpatients:4.2–10.3 ruled outovarianfailure and classical HH (LH,range with PCOS Mutation in IU/L)). Alltheseelementstakentogetherpointed GNRHR inafamily IU/L (normalrange,follicularphase IU/L); FSH,rangefortheexamined Downloaded fromBioscientifica.com at10/01/202105:11:29AM IU/L (normalrange, 176 :5 7 ). Genomic K10 via freeaccess European Journal of Endocrinology representation ofthehumanGNRHR geneandprotein.Thepositionsofthesubstitutions(at DNAandproteinlevels)areshown. Forward (5 confirmed tobehomozygous for theQ106RvariantbySangersequencing(typicalchromatogram), usingtheprimersGNRHR-Ex1 heterozygous forthevariant.(C) Validation ofthe missense variantbySangersequencing.Thethreeaffected sisterswere above 200)andthevariantcounts showthatthetwoaffected sistersandtheunaffected motherarerespectivelyhomozygousand (B) Visualizationofwhole-exomesequencingdatainIGVaround the position in unions. Thebluearrowsindicatethethreeindividualsanalyzed bywhole-exomesequencing.Thegenotypeforthevariant respectively. Blackcirclesrepresentfemalesaffected withPCOS.Doublelinesconnectindividualsinvolvedinconsanguineous Analysis oftheconsanguineousMO7family. (A)PedigreeoftheMO7 family. Squares andcirclesindicatemalesfemales Figure 1 Case Report ′ GNRHR AGATCCGAGTGACGGTTACTTT-3 isindicatedbeloweachindividual(asshownbySangersequencing). T, wild-typeallele;C,mutatedallele. S Caburetandothers ′ ) andGNRHR-Ex1Reverse(5 with PCOS Mutation in GNRHR ′ -CTGTCCGACTTTGCTGTTGCTT-3 variant. The high coverage (i.e., total read count variant.Thehighcoverage(i.e.,totalreadcount GNRHR inafamily Downloaded fromBioscientifica.com at10/01/202105:11:29AM ′ ). (D) Schematic ). (D)Schematic 176 www.eje-online.org :5
K11 via freeaccess European Journal of Endocrinology www.eje-online.org IRS1 and FSH.p.Q106R is arather commonly occurringvariant second messengersystem.This causesthereleaseofLH G-proteins thatactivatethephosphatidylinositol–calcium After bindingofGNRH, the receptorinteractswith gonadotrope cells. displayed at thesurface of pituitary hormone receptor, which is a G protein-coupled receptor ( and heterozygousinbothparents(healthycarriers) GNRHR confirmed thatthers104893836(p.Q106R)variant in sequencing ofallavailableindividualsthefamily incriminated inotherreproductivephenotypes.Sanger on the a potentialimpactofthisvariantonPCOS,wefocused or reproductivedisorders.Althoughwecannotexclude progression ( plays aroleincellinvasion,migrationandhepatoma mutation Thr196IleinSpondin2( variant was4:1164836G leads tothep.Q106Rsubstitution( is locatedinthefirstcodingexonof This missensevariantchr4:68619737T a pathogenicalleleinthecontextofhumanreproduction. methods’ section, one was already known as giving rise to sequencing analysisdescribedinthe‘Patientsand we discussamuchmorecompellingcandidatevariant. PCOS canonlybeassessedbyanassociationstudy. Below, (http://dgv.tcag.ca/dgv/app/home) andtheirinfluenceon two genesarefrequent,accordingtotheDGVdatabase Although potentiallyinteresting,gainsorlossesofthese be implicatedintheexcretionofsteroidhormones( and and identifiedaduplicationinvolvingthe data for co-segregation of CNVs with the phenotype the involvementofsuchvariants.We alsocheckedexome and ourstudyisnotdesignedtoformallydemonstrate association of data ( patients andnotpresentintheunaffectedmother a MAF PCOS. In which have previously been tested for association with we could not identify any candidate variants in led ustoexploreapotentialgeneticetiology. three affectedsistersintheconsanguineousMO7family upeetr al 1 Table Supplementary Fig. 1B Case Report First ofall,despiteahighcoverageintheexomedata, The Amid the2SNVsthatpassedallfiltersofexome givenattheendofthisarticle).Nevertheless, , UGT2B15 TCF7L2 washomozygousinthethreeaffectedsisters and < GNRHR GNRHR 1% wasfoundheterozygousinthetwoPCOS FBN3
C 10 , genes,whosegeneproductsareknownto ). FBN3 ) buthasnoknownlinkwithreproduction CAPN10 geneencodesthegonadotropin-releasing genevariant,whichhasclearlybeen , onemissensevariant(p.D911V)with variants and PCOS is still unclear ( , , seesectionon FTO >
A leadingtothemissense , SHBG S Caburetandothers SPON2 i. 1B Fig. , > AMH GNRHR (rs104893836) C supplementary supplementary ). Thisprotein or ). Theother INS geneand UGT2B17 AMHR2 , INSR 9 8 ). ), , ,
patients, twomalesandonefemale,havebeenreportedto in compoundheterozygosity. However, threeunrelated effects function observed to GNRH( intracellular inositol-phosphateproductioninresponse also resultsinadecreasephospholipaseCactivityand have revealedasignificantlyreducedGNRHbinding.It HH ( fied, incompoundheterozygosity, inapatientwithpartial to haveappearedindependently. appear toliewithinthisfounderhaplotypeandislikely the variantrs104893836inMO7familydoesnot haplotype consistentwithafounderevent( Q106R variantwasshowntobeincludedinacommon populations and0.25%ingeneral.Interestingly, this It reachesanallelicfrequencyof0.4%inEuropean of GNRHR that affects its first extracellular loop ( the other was reported as eunuchoid ( One maledisplayedafertileeunuchsyndrome( two ofthem,aspontaneousreversalHHwasreported. mild phenotype,withapartialsexualdevelopmentandfor be homozygousforQ106R( in GNRHpulsatilitymight alsobeduetoadecreased women withPCOS,ithasbeen proposedthatdifferences atfirstsight.Indeed,in not appearstraightforward a greaterextentthanthatofLH ( reduce thesensitivityofFSHgenepromotertoGNRH to ( toalterationsinsteroidhormones secretion secondary or axisinPCOS isprimary of thehypothalamo–pituitary dysfunction ( excessive ovarianandrogenproductionandovulatory of LHandinsufficientFSHsecretion,whichcontribute to ovulation ( resistance duetotheQ106Rmutation,thusallowing pulsatile GNRHsecretion,overcoming thepartial withdrawal inducedatransientsituationofendogenous Itseemsthatcontraceptive the presenceoftwoembryos. hCG serumlevelandtransvaginalultrasoundrevealed withdrawal, thepatientwasamenorrheic,hadhighbeta- Interestingly, threemonths after contraceptive pill normal range,asisthecaseforpatientswedescribe. female patient, basal levels of FSH and LH were within the afteroralcontraceptivepillwithdrawal.Inthis 3 months idiopathic HHandachievedaspontaneouspregnancy old femalepatientwasreportedasaffectedwithpartial with PCOS Mutation in 2 ). Interestingly, thep.Q106Rvarianthasbeen shownto The p.Q106Rwasthefirst The linkbetween PCOS isassociatedwithalteredGNRHpulses,anexcess 12 in vivo ). Functionalanalysesofthep.Q106Rvariant 17 12 GNRHR 1 ). ( , ). It is not clear yet whether the alteration ). Itisnotclearyetwhetherthealteration 4 13 ). Thisvariantappearsmostofthetime ). However, despitethispartiallossof inafamily in vitro GNRHR Downloaded fromBioscientifica.com at10/01/202105:11:29AM , p.Q106Rseemstohavemild 14 ). Allthreepatientsdisplaya GNRHR variantsandPCOSmight 4 ). 176 varianttobeidenti 16 :5 ). The 27-year- 11 ). However, Fig. 1D 15 K12 ) and via freeaccess ). European Journal of Endocrinology exome data.BLperformedSanger sequencing.SC,RBF, MF, SS,BL S C,RBF, MF, Sand R AVdesignedthestudy. SCandRAVanalyzed Author contributionstatement program PJ1502024). Maladies Rares(‘Highthroughputsequencingandrarediseases’research pour la Recherche Médicale (grant DEQ20150331757) and the Fondation This studywassupportedbyUniversitéParisDiderot,theFondation Funding perceived asprejudicingtheimpartialityofthiscasereport. The authorsdeclarethatthereisnoconflictofinterestcould be Declaration ofinterest EJE-16-0968. This islinkedtotheonlineversionofpaperat Supplementary data axis may play a role in the pathogenesis of PCOS. pituitary suggests thatgeneticalterationsinthehypothalamo– the geneticbackgroundorenvironment,ourresult possible interactionbetweentheidentifiedvariantand diagnosed withPCOS.Althoughwecannotexcludea description of a and such astheSNVin to assessthepotentialimpactofco-occurringvariants, tofindanotherhomozygousindividualandalso necessary largePCOScohort( screening ofavery is frequentinsuchwomen,thisfigureimpliesthatthe females inreproductiveage) 1.6 ×10 of homozygousfemalesinreproductiveagewouldbe is expected at afrequency of 1.6 0.4% (0.004),ahomozygousindividual(maleorfemale) allelicfrequency of thevariantis that the(conservative) would beaminorcauseofPCOS.Indeed,ifweconsider patients withPCOS.Thatsaid,weexpectthatthisvariant additional mutationscreeningofthe PCO-like syndrome. led to(atmost)asubclinicalHHassociatedwith family describedhere,twodosesofthevariantp.Q106R that ofpatientswithPCOS( ovarian responsetoovulationinductionwassimilar patients withultrasoundevidenceforPCOS,inwhichthe However, apreviousworkhasdescribedgroupofHH unclear howa normal GNRHreceptivity( sensitivity toprogesteronefeedbackinthepresenceof Case Report To the best of our knowledge, this is the first Obviously, our findings need to be replicated through UGT2B15 −5
× 0.5 (proportionoffemales) , previously mentioned. GNRHR GNRHR FBN3 defectwouldfitinthispicture. gene mutation in three patients ortheCNVinvolving 19 18 = 4.10 ). Itispossiblethatinthe ). Forthemoment,itis S Caburetandothers −6 × . EventhoughPCOS 10 http://dx.doi.org/10.1530/ × > −5 0.5 (proportionof > GNRHR . Thefrequency 1000 women)is UGT2B15 genein
References They thankthreeanonymousrefereesfortheirmosthelpfulcomments. The authorsthankIntegraGenforbeingsoefficient andkindlyhelpful. Acknowledgements version ofthemanuscript. Vwrotethemanuscript.Allauthorsreadandapprovedfinal and R A
13 12 11 10 with PCOS Mutation in 4 3 2 1 8 7 6 5 9 Leaños-Miranda A,JanovickJA&Conn PM.Receptor-misrouting: Roux Nde,Young J,MisrahiM,GenetR,ChansonP, Schaison G, Choi JH,BalasubramanianR,LeePH,ShawND,HallJE,Plummer L, Liao CH,Yeh SC,HuangYH,ChenRN,Tsai MM,ChenWJ,Chi (GnRH) receptorhavedifferentialeffectsongonadotropingene occurring mutationsinthehumangonadotropin-releasinghormone GRF.0b013e31802f351b) Clinical ObstetricsandGynecology (doi:10.1186/s12958-016-0173-x) an update. & PetragliaF. Genetic,hormonalandmetabolicaspectsofPCOS: (doi:10.1056/NEJMcp1514916) syndrome. Hickey TE,GibsonMA,RaineyWE,CarrBR,MasonHD 89 ovarianinsufficiency.familial caseofprimary Fellous M,CaburetS&Veitia RA.Anon-senseMCM9mutationina Endocrinology its receptorSNPinthepathogenesisofPCOS. mce.2012.10.009) Molecular andCellularEndocrinology jc.2002-020806) Clinical EndocrinologyandMetabolism expression andonGnRH-mediatedsignaltransduction. releasing hormonereceptor-mediated hypogonadotropic an unexpectedlyprevalentandrescuable etiologyingonadotropin- NEJM199711273372205) ofMedicine New England Journal and mutationsinthegonadotropin-releasing hormonereceptor. & MilgromE.Afamilywithhypogonadotropichypogonadism Metabolism releasing hormonedeficiency. spectrum offoundermutationscausingisolatedgonadotropin- Buck CL,KottlerML,JarzabekK,Wołczynski S Endocrine-Related Cancer by thyroidhormoneisassociatedwithcellmigrationandinvasion. HC, Tai PJ,LiaoCJ,Wu SM jsbmb.2014.05.009) andMolecularBiology Biochemistry androgen metabolismandprostatecancerevolution. UDP-glucuronosyltransferase (UGT)2B15andUGT2B17enzymesin (doi:10.1093/molehr/gap072) human ovaries. candidate genefibrillin-3andotherfibrillinfamilymembersin syndrome and geneexpressionanalysesofthepolycysticovary Bedecarrats GY, LinherKD&KaiserUB.Two commonnaturally Trivax syndrome. B&AzzizR.Diagnosisofpolycysticovary De LeoV, MusacchioMC,CappelliV, MassaroMG,MorganteG McCartney CR&MarshallJC.Clinicalpractice.Polycysticovary Prodoehl MJ, Hatzirodos N, Irving-Rodgers HF,Prodoehl MJ,HatzirodosN,Irving-Rodgers ZhaoZZ,Painter JN, Fauchereau F, E,Beck-FruchterR,Legois B, ShalevS,Chervinsky Wang F, NiuWB,KongHJ,GuoYH&SunYP. TheroleofAMHand syndrome. Kosova G&UrbanekM.Geneticsofthepolycysticovary Gauthier-Landry L,BélangerA&BarbierO.Multiplerolesfor Gauthier-Landry 603–607. 2015 New England Journal ofMedicine New EnglandJournal Reproductive BiologyandEndocrinology GNRHR 2017 (doi:10.1111/cge.12736) Molecular HumanReproduction 100 439 inafamily E1378–E1385. 363–368. 2010 et al Downloaded fromBioscientifica.com at10/01/202105:11:29AM 17 Journal ofClinicalEndocrinologyand Journal 1997 . Positiveregulationofspondin2 2007 99–111. 2015 (doi:10.1016/j.mce.2016.09.023) 2013 (doi:10.1210/jc.2015-2262) 2003 337 50 145 373 168–177. 1597–1602. (doi:10.1677/ERC-09-0050) 2016 88 187–192. 176 29–38. 834–843. 2009 Molecular andCellular Clinical Genetics et al www.eje-online.org 2016 :5 375 . Expandingthe (doi:10.1097/ 15 54–64. (doi:10.1016/j. Journal ofSteroid Journal (doi:10.1016/j. (doi:10.1056/ 14 829–841. (doi:10.1210/ et al Journal of Journal 38. . Genetic 2016 K13 via freeaccess European Journal of Endocrinology www.eje-online.org 16 15 14 Case Report Beranova M,OliveiraLM,BédécarratsGY, SchipaniE,Vallejo M, Pitteloud N,BoepplePA, DeCruzS,Valkenburgh SB,CrowleyWF& Kim HG,Pedersen-WhiteJ,BhagavathB&LaymanLC.Genotype gonadotropin-releasing hormonereceptormutationsinidiopathic Prevalence, phenotypicspectrum,andmodesofinheritance Ammini AC,QuintosJB,HallJE,MartinKA,HayesFJ (doi:10.1210/jcem.86.6.7542) of ClinicalEndocrinologyandMetabolism mutation inthegonadotropin-releasinghormonereceptor. hypogonadism: spontaneousreversalassociatedwithahomozygous Hayes FJ.Thefertileeunuchvariantofidiopathichypogonadotropic (doi:10.1159/000312696) receptor mutations. and phenotypeofpatientswithgonadotropin-releasinghormone 87 hypogonadism. 4825–4828. (doi:10.1210/jc.2002-020961) Journal ofClinicalEndocrinologyand Metabolism Journal Frontiers of Hormone ResearchFrontiers ofHormone S Caburetandothers 2001 86 2470–2475. 2010 et al 39 94–110. . Journal Journal 2002 Accepted 30January2017 Revised versionreceived23January2017 Received 24November2016 19 18 17 with PCOS Mutation in Shoham Z,ConwayGS,PatelA&JacobsHS.Polycysticovariesin Burt SolorzanoCM,BellerJP, AbshireMY, CollinsJS,McCartney Dewailly D,BoucherA,DecanterC,LagardeJP, CounisR&Kottler S0015-0282(16)55134-6) ovarian syndrome. response togonadotropinstimulationinpatientswithpolycystic patients withhypogonadotropichypogonadism:similarityofovarian steroids.2011.12.007) syndrome. ovary CR &MarshallJC.Neuroendocrinedysfunctioninpolycystic 0282(02)03102-3) gene. the Q106Rmutationingonadotropin-releasinghormonereceptor ML. Spontaneouspregnancyinapatientwhowashomozygousfor and Metabolism hypogonadotropic hypogonadism. Fertility andSterility Fertility GNRHR 2001 Steroids Fertility andSterility Fertility inafamily 86 1580–1588. 2012 2002 Downloaded fromBioscientifica.com at10/01/202105:11:29AM 77 77 332–337. 1288–1291. Journal ofClinicalEndocrinology Journal (doi:10.1210/jcem.86.4.7395) 1992 (doi:10.1016/j. 176 58 (doi:10.1016/S0015- 37–45. :5 (doi:10.1016/ K14 via freeaccess