etiology, diagnosis, and treatment of primary amenorrhea

4/23/2015 Etiology,diagnosis,andtreatmentofprimaryamenorrhea

http://0www.uptodate.com.millennium.midwestern.edu/contents/etiologydiagnosisandtreatmentofprimaryamenorrhea?topicKey=ENDO%2F7403&elaps 1/19

OfficialreprintfromUpToDate www.uptodate.com2015UpToDate

AuthorsCorrineKWelt,MDRobertLBarbieri,MD

SectionEditorsPeterJSnyder,MDWilliamFCrowley,Jr,MDMitchellGeffner,MD

DeputyEditorKathrynAMartin,MD

Etiology,diagnosis,andtreatmentofprimaryamenorrhea

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Mar11,2014.

INTRODUCTIONAmenorrhea(absenceofmenses)canbeatransient,intermittent,orpermanentconditionresultingfromdysfunctionofthehypothalamus,pituitary,ovaries,uterus,orvagina(table1andtable2).Itisoftenclassifiedaseitherprimary(absenceofmenarchebyage15years)orsecondary(absenceofmensesformorethanthreecycleintervalsorsixmonthsinwomenwhowerepreviouslymenstruating).Themenstrualcycleissusceptibletooutsideinfluencesthus,missingasinglemenstrualperiodisrarelyimportant.Incontrast,prolongedamenorrheamightbetheearliestsignofadeclineingeneralhealthorsignalanunderlyingcondition,suchasapituitarytumor.

Thecausesanddiagnosisofprimaryamenorrhea,aswellasabriefsummaryoftreatmentoptions,arereviewedhere.Theetiology,diagnosis,andtreatmentofsecondaryamenorrheaarediscussedseparately.(See"Etiology,diagnosis,andtreatmentofsecondaryamenorrhea".)

DEFINITIONPrimaryamenorrheaisdefinedastheabsenceofmensesatage15yearsinthepresenceofnormalgrowthandsecondarysexualcharacteristics.Duetothisseculartrendofanearlieronsetofmenarche,someauthoritiesrecommendevaluatingagirlforprimaryamenorrheaifhermenseshavenotoccurredbyage15years[1].Atage13years,ifnomenseshaveoccurredandthereisanabsenceofsecondarysexualcharacteristics,suchasbreastdevelopment,evaluationforprimaryamenorrheashouldbebegun.Inaddition,atage12or13years,ifcyclicpelvicpainispresent,obstructedmllerianoutflowtrack,acauseofbothprimaryamenorrheaandpelvicpain,shouldbeconsideredinthedifferentialdiagnosis.

ETIOLOGYPrimaryamenorrheaisusuallytheresultofageneticoranatomicabnormality.However,allcausesofsecondaryamenorrheacanalsopresentasprimaryamenorrhea.Inalargecaseseriesofprimaryamenorrhea,themostcommonetiologieswere[2]:

Theetiologyintheremaining5percentofcasesincludesacombinationofdisorders,suchasandrogeninsensitivityduetomutationsintheandrogenreceptor,congenitaladrenalhyperplasia,andpolycysticovarysyndrome(seeappropriatetopicreviews).

Alogicalapproachtothewomanwitheitherprimaryorsecondaryamenorrheaistoconsiderdisordersbaseduponthelevelofcontrolofthemenstrualcycle:hypothalamusandpituitary,ovary,anduterusandvagina.Inaddition,steroidreceptorabnormalitiesanddeficienciesinenzymesofsteroidogenesiscauseprimaryamenorrheaattheleveloftheovaryandtheadrenalgland.

HypothalamicandpituitarydiseaseAcommoncauseofprimaryamenorrheaisfunctionalhypothalamicamenorrhea.Lesscommonly,tumorsandinfiltrativelesionsofthehypothalamusorpituitarycanresultin

Chromosomalabnormalitiescausinggonadaldysgenesis(ovarianinsufficiencyduetotheprematuredepletionofalloocytesandfollicles)50percent

Hypothalamichypogonadismincludingfunctionalhypothalamicamenorrhea20percentAbsenceoftheuterus,cervixand/orvagina,mllerianagenesis15percentTransversevaginalseptumorimperforatehymen5percentPituitarydisease5percent



amenorrhea,usuallyinassociationwithhyperprolactinemia(table1).

FunctionalhypothalamicamenorrheaFunctionalhypothalamicamenorrheaisadisorderthat,bydefinition,excludespathologicdisease.Itischaracterizedbyabnormalhypothalamicgonadotropinreleasinghormone(GnRH)secretion,leadingtodecreasedgonadotropinpulsations,lowornormalserumluteinizinghormone(LH)concentrations,absentLHsurges,absenceofnormalfolliculardevelopment,anovulation,andlowserumconcentrationsofestradiol[3].Serumfolliclestimulatinghormone(FSH)concentrationsareofteninthenormalrange,withahighFSHtoLHratiosimilartothepatterninprepubertalgirls.

Multiplefactorsmaycontributetothepathogenesisoffunctionalhypothalamicamenorrhea,includingeatingdisorders(suchasanorexianervosa),exercise,andstress.Thetermhypothalamicamenorrheaisoftenusedinterchangeablywithfunctionalhypothalamicamenorrhea.Thetopicoffunctionalhypothalamicamenorrheaisdiscussedindetailelsewhere.(See"Etiology,diagnosis,andtreatmentofsecondaryamenorrhea",sectionon'Functionalhypothalamicamenorrhea'and"Amenorrheaandinfertilityassociatedwithexercise"and"Eatingdisorders:Overviewofepidemiology,diagnosis,andcourseofillness".)

CongenitalGnRHdeficiencyAlthoughrare,primaryamenorrheacanbeduetocompletecongenitalGnRHdeficiency.Thissyndromeiscalledidiopathichypogonadotropichypogonadismor,ifitisassociatedwithanosmia,Kallmann'ssyndrome[4].ThesewomentypicallyhaveapulsatileandprepubertallowserumgonadotropinconcentrationsduetotheabsenceofhypothalamicGnRH.CongenitalGnRHdeficiencycanbeinheritedasanautosomaldominant,autosomalrecessive,orXlinkedcondition.However,overtwothirdsofcasesaresporadic.(See"Congenitalgonadotropinreleasinghormonedeficiency(idiopathichypogonadotropichypogonadism)".)

ConstitutionaldelayofpubertyAlthoughconstitutionaldelayofpubertyiscommoninboyswithafamilyhistoryofdelayedpuberty,itisanuncommoncauseofdelayedpubertyorprimaryamenorrheaingirls.Constitutionaldelayischaracterizedbybothdelayedadrenarcheandgonadarche,andisoftendifficulttodistinguishclinicallyfromcongenitalGnRHdeficiency.Patientswithconstitutionaldelaygoontohavecompletelynormalpubertaldevelopment,albeitatalaterage.(See"Diagnosisandtreatmentofdelayedpuberty".)

HyperprolactinemiaHyperprolactinemiaisararecauseofprimaryamenorrheaandanovulation.Thepresentationissimilartohypothalamicamenorrheaexceptfortheadditionalfindingofgalactorrheainmanywomenwithhyperprolactinemia.Prolactinsecretingpituitaryadenomasandcranialtumorscausepituitarystalkcompression.(See"Clinicalmanifestationsandevaluationofhyperprolactinemia".)

Inmostlaboratories,aserumprolactinconcentrationabove15to20ng/mL(15to20mcg/L)isconsideredabnormalinwomenofreproductiveage.Stress,sleep,exercise,intercourse,andmealscanraiseserumprolactinconcentrationstransiently.Thus,werecommendthathighserumprolactinconcentrationsberecordedatleasttwicebeforeamagneticresonanceimaging(MRI)isordered.

OtherManyinfiltrativediseasesandtumorsofthehypothalamusandpituitarycanresultindiminishedGnRHreleaseorgonadotropedestructionandamenorrheatheseincludecraniopharyngioma,germinoma,andLangerhanscellhistiocytosis.Themainindicationsformagneticresonanceimagingareprimaryhypogonadotropichypogonadism,visualfielddefects,headaches,otherevidenceofhypothalamicorpituitarydysfunction,orsuggestiveotherdiseases(suchassarcoidosis).Ironstudiestoruleouthemochromatosisshouldbeperformedifthereisanappropriatefamilyhistoryorifthewomanhasothersuggestivemanifestationssuchasbronzedskin,diabetesmellitus,orotherwiseunexplainedheartorliverdisease.(See"Approachtothepatientwithsuspectedironoverload".)

OvarianetiologiesThemostcommoncauseofprimaryamenorrheaisgonadaldysgenesiscausedbychromosomalabnormalitiesthatresultinprematuredepletionofallovarianoocytesandfollicles.Alesscommonovarianetiologyofprimaryamenorrheaisthepolycysticovarysyndrome.

GonadaldysgenesisInyoungwomenwithprimaryamenorrhea,thesinglemostcommoncauseisprimaryovarianinsufficiencyduetogonadaldysgenesis.ThesewomenhavesignificantlyelevatedFSHlevelsduetothe



absenceofovarianoocytesandfollicles,leadingtoareductioninnegativefeedbackonFSHfromestradiolandinhibinsAandB.ThelargestnumberofpatientswithprimaryamenorrheaandovarianinsufficiencyhaveTurner'ssyndrome(45,X)followedby46,XXgonadaldysgenesisand,rarely,46,XYgonadaldysgenesis.

TurnersyndromeWomenwithTurnersyndromeareusuallymissingallofoneXchromosome(45,Xgonadaldysgenesis)[5].Amenorrheaoccursbecausetheoocytesandfolliclesundergoapoptosisandtheovariesarereplacedwithfibroustissueandcannotproduceestrogenwithoutfollicles.Incontrast,theexternalfemalegenitalia,uterus,andfallopiantubesdevelopnormallyuntilpubertywhenestrogeninducedmaturationfailstooccur.Spontaneouspubertyandmenstruationoccursmorecommonlyinwomenwithamosaickaryotype(45,X/46,XX),butcanoccurinwomenwitha45,Xkaryotype,althoughspontaneouspregnancyisunlikelywitha45,Xkaryotype[6,7].(See"ClinicalmanifestationsanddiagnosisofTurnersyndrome(gonadaldysgenesis)".)

Estrogenandcyclicprogesteronereplacementatpubertywillresultinnormalpubertaldevelopment:pubicandaxillaryhair,breastgrowth,cyclicvaginalbleeding,andgrowthandmaturationoftheuterusandexternalgenitalia.Postmenopausalhormonetherapymaybeprecededbygrowthhormonetherapytogainmaximalheight.Pregnancyispossiblewithoocytedonation.(See"ManagementofTurnersyndrome(gonadaldysgenesis)".)

PartialdeletionsandstructuralrearrangementsoftheXchromosomecanalsoresultinprimaryorsecondaryamenorrheaandtheTurnerphenotype[8].Inaddition,somecasesofgonadaldysgenesisresultfromautosomalrecessiveinheritance(46,XXgonadaldysgenesis)thefewcasesthathavebeendescribedlackthesomaticfeaturesofTurnersyndrome[9].(See"Congenitalcytogeneticabnormalities".)

PolycysticovarysyndromeThemenstrualdisturbancesinwomenwiththepolycysticovarysyndrome(PCOS)classicallyhaveaperipubertalonset.Whilesomewomenmaypresentwithprimaryamenorrhea,typicallythosewhohavehigherandrogenlevelsandaremoreoverweight[10],mosthaveanormalorslightlydelayedmenarchefollowedbyirregularcyclesorsecondaryamenorrhea.Thediagnosiscanbemadeinagirlwithclinicalandbiochemicalevidenceofhyperandrogenisminthepresenceofadvancedpubertaldevelopment(ie,Tannerstage4breastdevelopment)andintheabsenceofotherdisorderscausingamenorrheaandhyperandrogenism[11].ThediagnosisofPCOSisreviewedindetailseparately.(See"Definition,clinicalfeaturesanddifferentialdiagnosisofpolycysticovarysyndromeinadolescents"and"Diagnosisofpolycysticovarysyndromeinadults".)

OtherOthercausesofovarianinsufficiencysuchasautoimmuneoophoritis,chemotherapyorradiationinducedovarianinsufficiencyandFMR1premutationcarriersgenerallypresentassecondaryamenorrhea.(See"Clinicalfeaturesanddiagnosisofautoimmuneprimaryovarianinsufficiency(prematureovarianfailure)"and"Ovarianfailureduetoanticancerdrugsandradiation".)

CongenitalanatomiclesionsoftheuterusandvaginaCongenitalabnormalitiesofthefemalereproductiveorgansaccountforapproximately20percentofcasesofprimaryamenorrhea.Mensescannotoccurwithoutanintactuterus,endometrium,cervix,cervicalos,andvaginalconduit.Pelvicorlowerabdominalpainisacommonpresentingsymptomingirlswithprimaryamenorrheaandanobstructedreproductivetract.Congenitalanomaliesoftheuterusandvaginawillbereviewedbrieflyinthissectionandingreaterdetailelsewhere.(See"Clinicalmanifestationsanddiagnosisofcongenitalanomaliesoftheuterus"and"Diagnosisandmanagementofcongenitalanomaliesofthevagina".)

ImperforatehymenAnimperforatehymenisthesimplestdefectthatresultsinprimaryamenorrhea.Itmaybeassociatedwithcyclicpelvicpainandaperirectalmassfromsequestrationofbloodinthevagina(hematocolpos).Similarfindingscanbeseenwithdefectsinperinealdevelopment,whichcanresultinabsenceofthedistalthirdofthevaginaandthereforeabsenceofanoutflowtract.Bothoftheseconditionsarediagnosedbyphysicalexamination.Animperforatehymeniseasilycorrectedwithsurgery.(See"Diagnosisandmanagementofcongenitalanomaliesofthevagina".)

TransversevaginalseptumOneormoretransversevaginalseptaecanoccuratanylevelbetweenthehymenalringandthecervix.Aftermenarche,themajorsymptomsaresimilartothoseassociatedwithanimperforatehymen.(See"Diagnosisandmanagementofcongenitalanomaliesofthevagina".)



VaginalagenesisVaginalagenesis,alsoknownasmllerianagenesisorMayerRokitanskyKsterHauser(MRKH)syndrome,referstocongenitalabsenceofthevaginawithvariableuterinedevelopment.Thedefectresultsfromagenesisorhypoplasiaofthemllerianductsystem.HeterozygousmutationsinWNT4accountforasmallsubsetofthesecases[12].Vaginalagenesisisusuallyaccompaniedbycervicalanduterineagenesishowever,7to10percentofwomenhaveanormalbutobstructedorrudimentaryuteruswithfunctionalendometrium(figure1andfigure2).Themostcommonlycitedincidenceforvaginalagenesisis1in5000(range:1per4000to10,000females).

Differentialdiagnosisofvaginalagenesisincludesandrogeninsensitivity,lowlyingtransversevaginalseptum,agenesisoftheuterusandvagina,imperforatehymen,andmaturityonsetdiabetesoftheyoung(MODY)causedbyHNF1mutations[13].Vaginalagenesiscanbedifferentiatedfromandrogeninsensitivitybaseduponanormalfemalerangeserumtotaltestosteroneinvaginalagenesisandamalerangeserumtestosteroneinandrogeninsensitivity.Imagingstudies(ultrasoundand/orMRI)helptoclarifythenatureofthevaginalagenesisandtodifferentiateitfromlowlyingtransversevaginalseptum,agenesisoftheuterusandvagina,andimperforatehymen.

Theclinicalmanifestations,evaluation,andmanagementofvaginalagenesisarereviewedindetailelsewhere.(See"Diagnosisandmanagementofcongenitalanomaliesofthevagina".)

RECEPTORABNORMALITIESANDENZYMEDEFICIENCIES

CompleteandrogeninsensitivitysyndromeThecompleteandrogeninsensitivitysyndromeisanXlinkedrecessivedisorderinwhich46,XYsubjectsappearasnormalwomen.Thesepatientsareresistanttotestosteroneduetoadefectintheandrogenreceptorand,therefore,failtodevelopallofthemalesexualcharacteristicsthataredependentupontestosterone[14](see"Diagnosisandtreatmentofdisordersoftheandrogenreceptor").Theexternalgenitaliaaretypicallyfemaleinappearance,buttestesmaybepalpableinthelabiaoringuinalarea.Thetestesmakemllerianinhibitingsubstance,whichisfunctionalandcausesregressionofallmllerianstructures:thefallopiantubes,uterus,andupperthirdofthevagina.Atpuberty,breastdevelopmentoccurs,buttheareolaearepaleandpubicandaxillaryhairissparse.Carrierfemales(46,XX)developnormalinternalandexternalgenitalia.

Thediagnosisofthisdisorderisbasedupontheabsenceoftheuppervagina,uterus,andfallopiantubesonphysicalexaminationandpelvicultrasonography,highserumtestosteroneconcentrations(intherangefornormalmen),andamale(46,XY)karyotype.Thetestesshouldbesurgicallyexcisedafterpubertybecauseoftheincreasedrisk(2to5percent)ofdevelopingtesticularcancerafterage25years[15].(See"Diagnosisandtreatmentofdisordersoftheandrogenreceptor".)

5alphareductasedeficiency5alphareductasedeficiencyisanothercongenitaldefectthatcanresultinprimaryamenorrheaina46,XYsubject.Atbirth,theseneonatesmayappearfemaleorhaveambiguousgenitalia.Atpuberty,thedisorderismorerecognizablebecauseoftheonsetofvirilizationduetothenormalperipubertalincreaseintestosteronesecretioninmales.However,thesesubjectscannotconverttestosterone(via5alphareductase)toitsevenmorepotentmetabolitedihydrotestosterone(DHT).Asaresult,theyfailtoundergoDHTdependentmasculinization,leadingtolackofenlargementofthemaleexternalgenitaliaandprostate.Bycomparison,testosteronedependentprocessesareintact,includingmalepatternhairgrowth,musclemass,andvoicedeepening.(See"Steroid5alphareductase2deficiency"and"Evaluationoftheinfantwithambiguousgenitalia".)

VanishingtestessyndromeThevanishingtestessyndromeoccursin46,XYsubjectswhoappeartobenormalfemales.Thegonadsapparentlyfailtodevelopinthisdisorder,resultinginavariablephenotypedependinguponwhenthefailureoccurred.Earlyfailurepriortotesticulardevelopment(beforeabouteightweeksofgestation)isassociatedwithstreaklikeinactivegonadsthatneverproducetestosterone,estrogen,ormllerianinhibitingsubstance.Theneteffectisfeminizationofboththeinternalandexternalgenitaliaandgonadalfailure.

Alateronsetoftesticularfailureresultsinvariableabnormalities.Asanexample,althoughnormalmalegenitalia



maybeapparentatbirth,pubertalchangesdonotoccurduetogonadalfailure.

Thediagnosisofthevanishingtestessyndromeismadefromthefindingsofgonadalfailure,lackofprogressionthroughpuberty,andhighserumfolliclestimulatinghormone(FSH)andluteinizinghormone(LH)concentrationsinthepresenceofamalekaryotype.Thereisahighrisk(30percent)ofdevelopingagonadaltumor(gonadoblastomaordysgerminoma)sothatearlyextirpationoftesticularremnantsisrecommended[15].(See"Evaluationoftheinfantwithambiguousgenitalia".)

AbsenttestisdeterminingfactorAsimilarphenotypicappearancetoearlyonsetvanishingtestessyndromecanoccurinsubjectswithdeletionormutationinthetestisdeterminingfactorgenelocatedontheYchromosomethisdisorderiscalledtheUllrichTurnersyndrome[16].These46,XYsubjectsdonotdeveloptestesandthereforedonotproducetestosteroneormllerianinhibitingsubstance,resultinginfeminizationoftheexternalandinternalgenitaliainassociationwithprimarygonadalfailure.ThediagnosisismadebydemonstratingtheabnormalityoftheshortarmoftheYchromosomebyYDNAhybridizationstudies.

17alphahydroxylase(CYP17)deficiencyThisraredisorder,whichcanoccurin46,XXor46,XYsubjects,ischaracterizedbydeficiencyoftheproductoftheCYP17gene,whichisanenzymethathasboth17hydroxylaseand17,20lyase(desmolase,orsidechaincleavage)activities(figure3).Asaresult,thereisdecreasedcortisolsynthesisbutoverproductionofcorticotropinhormone(ACTH),corticosterone,anddeoxycorticosterone.Adrenalandgonadalsexsteroidsarenotproducedsothataffectedsubjectstypicallypresentasphenotypicfemaleswithhypertension(duetomineralocorticoidexcess),lackofpubertaldevelopment,andeitherfemale(if46,XX)orincompletelydeveloped(if46,XY)externalgenitalia.Thistopicisdiscussedindetailelsewhere.(See"Uncommoncausesofcongenitaladrenalhyperplasia"and"Evaluationoftheinfantwithambiguousgenitalia".)

P450oxidoreductasemutationsTheP450oxidoreductase(POR)donateselectronstocytochromeP450enzymes,including17alphahydroxylase/17,20lyase.RecessivemutationsresultinAntleyBixlersyndrome,adisorderofabnormalsteroidogenesis,genitalanomaliesincludingambiguousgenitaliainmalesandfemales,cranialsynostosis,radioulnarandradiohumeralsynostosis,andotherskeletalanomalies[17].However,thespectrumofPORmutationshasexpandedandincludeswomenwithprimaryamenorrheaandinfertility.WomenmightpresentwithapatternofatypicalcongenitaladrenalhyperplasiauponACTHstimulation,includinglowcortisolandandrostenedionelevelsandelevated17OHprogesteroneandprogesteronelevels,inthesettingofanelevatedACTH.Womenmayalsopresentwithamenorrheainthesettingofmultiplelargeovariancystsbutlowestradiollevels.

EstrogenresistanceAmutationinthegeneencodingestrogenreceptoralpha(ESR1),whichhadpreviouslybeendescribedonlyinamale,hasnowbeenidentifiedinan18yearoldgirlwithprimaryamenorrheaandprofoundestrogenresistance.Shepresentedwithveryhighserumestradiolconcentrations(3500pg/mL[12,849pmol/L]),inappropriatelyelevatedserumgonadotropins(LH9.6mIU/mL,FSH6.7mIU/mL),enlargedmulticysticovaries,andnoevidenceofendometrialthickening[18].Inspiteofthehyperestrogenemia,shehadnormalserumconcentrationsofsexhormonebindingconcentration(SHBG),cortisolbindingglobulin(CBG),thyroxinebindingglobulin(TBG),andtriglycerides.Shealsohaddelayedboneage(13.5years),lowbonemineraldensity(Zscore2.4),andhergrowthvelocitychartsuggestedalackofanestrogeninducedadolescentgrowthspurt.DNAsequencingidentifiedahomozygousmutationinESR1thatseverelyimpairedestrogensignalingexceptwithadministrationofpharmacologicdosesofestrogen,whenminimalsignalingwasobserved.TheprevalenceofESR1mutationsinhumansisunknown,buttheyarelikelytobeveryrare.Althoughtheyhavenotbeenidentifiedclinically,milderESR1mutationscouldresultinincompleteestrogenresistanceanalogoustothepartialandrogeninsensitivitysyndromecausedbymildmutationsintheandrogenreceptorgene.(See"Pathogenesisandclinicalmanifestationsofdisordersofandrogenaction",sectionon'Partialandrogeninsensitivity(PAIS)'.)

DIAGNOSTICEVALUATION

OverviewPrimaryamenorrheaisevaluatedmostefficientlybyfocusingonthepresenceorabsenceofbreastdevelopment(amarkerofestrogenactionandthereforefunctionoftheovary),thepresenceorabsenceoftheuterus(asdeterminedbyultrasound,orinmorecomplexcasesbymagneticresonanceimaging)andthefollicle



stimulatinghormone(FSH)level.

Aseriesofsequentialdiagnosticstepshelpwiththepreciseidentificationofacauseofprimaryamenorrhea:

Step1:HistoryAlthoughthereareseveraluniquecausesofprimaryamenorrhea,allcausesofsecondaryamenorrheacanalsocauseprimarydisease(see"Etiology,diagnosis,andtreatmentofsecondaryamenorrhea").Thus,thefollowingquestionsshouldbeaskedofawomanwithprimaryamenorrhea:

Step2:PhysicalexaminationThephysicalexaminationinawomanwithprimaryamenorrheashouldbeginwith:

IfthereisnobreastdevelopmentandtheFSHleveliselevated,theprobablediagnosisisgonadaldysgenesis,andakaryotypeshouldbeobtained.Inthisscenario,a46,XYkaryotypeisassociatedwithahighriskforthedevelopmentofgonadoblastomaanddysgerminomaandsurgicalremovalofthegonadsisnecessary.

IftheultrasoundindicatesthattheuterusisabsentandFSHisnormal,theprobablediagnosisismllerianagenesisorandrogeninsensitivitysyndrome.Inthecaseofmllerianagenesis,thecirculatingtestosteroneisinthenormalrangeforwomenandinthecaseofandrogeninsensitivity,thecirculatingtestosteroneisinthemalerange.

IftheFSHisnormal,andbothbreastdevelopmentandtheuterusarepresent,thentheworkupshouldfocusonthecommoncausesofsecondaryamenorrhea,wheretheinitialworkupincludesmeasurementofheightandweight,serumFSH,prolactinandthyroidstimulatinghormone(TSH).(See"Etiology,diagnosis,andtreatmentofsecondaryamenorrhea".)

Hasshecompletedotherstagesofpuberty,includingagrowthspurt,developmentofaxillaryandpubichair,apocrinesweatglands,andbreastdevelopment?Lackofpubertaldevelopmentsuggestsovarianorpituitaryfailureorachromosomalabnormality.

Isthereafamilyhistoryofdelayedorabsentpuberty(suggestingapossiblefamilialdisorder)?

Whatisthewoman'sheightrelativetofamilymembers?ShortstaturemayindicateTurnersyndromeorhypothalamicpituitarydisease.

Wasneonatalandchildhoodhealthnormal?Neonatalcrisissuggestscongenitaladrenalhyperplasia.Alternatively,poorhealthmaybeamanifestationofhypothalamicpituitarydisease.

Arethereanysymptomsofvirilization?Thepresenceofvirilizationsuggestspolycysticovarysyndrome,anandrogensecretingovarianoradrenaltumor,orthepresenceofYchromosomematerial.

Lately,hastherebeenstress,changeinweight,diet,orexercisehabits,orillnessthatmightresultinhypothalamicamenorrhea?

Isshetakinganydrugsthatmightcauseorbeassociatedwithamenorrhea?Themedicationmaybetakenforasystemicillnessthatitselfcancausehypothalamicamenorrhea(eg,sarcoidosis).Alternatively,drugssuchasheroinandmethadonecanalterhypothalamicgonadotropinsecretion.

Istheregalactorrhea(suggestiveofexcessprolactin)?Somedrugscauseamenorrheabyincreasingserumprolactinconcentrations,includingmetoclopramideandantipsychoticdrugs.(See"Causesofhyperprolactinemia".)

Aretheresymptomsofotherhypothalamicpituitarydisease,includingheadaches,visualfielddefects,fatigue,orpolyuriaandpolydipsia?

Anevaluationofpubertaldevelopment,includingcurrentheight,weight,andarmspan(normalarmspanforadultsiswithin5cmofheight)andanevaluationofthewoman'sgrowthchart.



Step3:BasiclaboratorytestingThelaboratoryevaluationofawomanwithprimaryamenorrheadependsuponthefindingsonphysicalexamination,inparticular,whethermllerianstructuresarepresentorabsent.Thus,thesinglemostimportantstepintheevaluationistodeterminebyphysicalexaminationorultrasonographywhetherthereareanyanatomicabnormalitiesofthevagina,cervix,oruterus.

Ifanormalvaginaoruterusisnotobviouslypresentonphysicalexamination,pelvicultrasonographyshouldbeperformedtoconfirmthepresenceorabsenceofovaries,uterus,andcervix.Inaddition,ultrasonographycanbeusefultolookforvaginalorcervicaloutletobstructioninpatientswithcyclicpain.

UterusabsentForthosewithabsenceoftheuterus,furtherevaluationshouldincludeakaryotypeandmeasurementofserumtestosterone.Thesetestsshouldthenallowthecliniciantodistinguishbetweenabnormalmlleriandevelopment(46,XXkaryotypewithnormalfemaleserumtestosteroneconcentrations)andandrogeninsensitivitysyndrome(46,XYkaryotypeandnormalmaleserumtestosteroneconcentrations).Patientswith5alphareductasedeficiencyalsohavea46,XYkaryotypeandnormalmaleserumtestosteroneconcentrationsbut,incontrasttotheandrogeninsensitivitysyndrome,whichisassociatedwithafemalephenotype,thesepatientsundergostrikingvirilizationatthetimeofpuberty(normaldevelopmentofsecondarysexualhair,musclemass,anddeepeningofthevoice).

UteruspresentForpatientswithnormalmllerianstructuresandnoevidenceofanimperforatehymen,vaginalseptum,orcongenitalabsenceofthevagina,anendocrineevaluationshouldbeperformed.ThisincludesmeasurementofserumbetahumanchorionicgonadotropintoexcludepregnancyandofserumFSH,andperhapsotherhormones.

Anassessmentofbreastdevelopment(eg,byTannerstaging)(table3andfigure4).(See"Normalpuberty".)

Acarefulgenitalexaminationshouldbeperformedforclitoralsize,pubertalhairdevelopment,intactnessofthehymen,depthofthevagina,andpresenceofacervix,uterus,andovaries.Ifthevaginacannotbepenetratedwithafinger,rectalexaminationmayallowevaluationoftheinternalorgans.Pelvicultrasoundisalsousefultodeterminethepresenceorabsenceofmllerianstructures.

Examinationoftheskinforhirsutism,acne,striae,increasedpigmentation,andvitiligo.

EvaluationfortheclassicphysicalfeaturesofTurnersyndromesuchaslowhairline,webneck,shieldchest,andwidelyspacednipplesshouldbenoted.ThebloodpressureshouldbemeasuredinbotharmsifTurnersyndromeissuspected,becauseitisassociatedwithanincreasedincidenceofcoarctationoftheaorta.

AhighserumFSHconcentrationisindicativeofprimaryovarianinsufficiency.AkaryotypeisthenrequiredandmaydemonstratecompleteorpartialdeletionoftheXchromosome(Turnersyndrome)orthepresenceofYchromatin.ThepresenceofaYchromosome(eg,vanishingtestessyndrome,absenttestisdeterminingfactor)isassociatedwithahigherriskofgonadaltumorsandmakesgonadectomymandatory[1921].

Inaddition,evaluationforotherdiseasesassociatedwiththespecifictypeofovarianinsufficiencyshouldbeperformed.Asexamples,congenitalheartdisease,hypertension,andhearinglossarecommoninwomenwithTurnersyndrome,whileevaluationforautoimmunethyroidandadrenaldiseaseshouldbedoneinallwomenwithautoimmuneoophoritis.(See"ClinicalmanifestationsanddiagnosisofTurnersyndrome(gonadaldysgenesis)"and"Clinicalfeaturesanddiagnosisofautoimmuneprimaryovarianinsufficiency(prematureovarianfailure)".)

AlowornormalserumFSHconcentrationsuggestsfunctionalhypothalamicamenorrhea,congenitalgonadotropinreleasinghormone(GnRH)deficiency,orotherdisordersofthehypothalamicpituitaryaxis.Cranialmagneticresonance(MR)imagingisindicatedinmostcasesofhypogonadotropichypogonadismtoevaluateforhypothalamicorpituitarydisease.Werecommendcranialimaginginallwomenwithprimaryhypogonadotropichypogonadism,visualfielddefects,headaches,oranyothersignsofhypothalamic

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TREATMENTTreatmentofprimaryamenorrheaisdirectedatcorrectingtheunderlyingpathology(ifpossible),helpingthewomantoachievefertility(ifdesired),andpreventionofcomplicationsofthediseaseprocess(eg,estrogenreplacementtopreventosteoporosis).Abriefsummaryoftreatmentoptionsispresentedhere,whilethetreatmentofspecificdisordersisdiscussedindetailintheappropriatetopicreviews.

pituitarydysfunction.

SerumprolactinandthyrotropinshouldbemeasuredifFSHislowornormal,especiallyifgalactorrheaispresent.

Iftherearesignsorsymptomsofhyperandrogenism,serumtestosteroneanddehydroepiandrosteronesulfate(DHEAS)shouldbemeasuredtoassessforanandrogensecretingtumor.

Amongwomenwhoarealsohypertensive,bloodtestsshouldbedrawnforevaluationfor17alphahydroxylase(CYP17)deficiency.Thecharacteristicfindingsareelevationsinserumprogesterone(>3ng/mL[9.5nmol/L])anddeoxycorticosteroneandlowvaluesforserum17alphahydroxyprogesterone(



INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5 to6 gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10 to12 gradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthekeyword(s)ofinterest.)

SUMMARYANDRECOMMENDATIONS

growthanddevelopment.(See"Amenorrheaandinfertilityassociatedwithexercise".)

Thesameconsiderationsapplytowomenwithhypothalamicorpituitarydysfunctionthatisnotreversible(eg,congenitalGnRHdeficiency).Forwomenwhowanttobecomepregnant,eitherexogenousgonadotropinsorpulsatileGnRHcanbegiven.Inaretrospectivecomparativestudy,pulsatileGnRHproducedahigherrateofconception(96versus72percent)andalowerrateofhigherordermultiplegestations[22].(See"Congenitalgonadotropinreleasinghormonedeficiency(idiopathichypogonadotropichypogonadism)".)

Advancesinassistedreproductivetechnologiesnowmakeitpossibleformanywomenwithprimaryamenorrheatoparticipateinreproduction.Forwomenwithgonadaldysgenesis,theuseofdonoroocytesandtheirpartners'spermwithinvitrofertilization(IVF)allowthewomentocarryapregnancyintheirownuterus(see"Oocytedonationforassistedreproduction").Forwomenwithanabsentuterus,useoftheirownoocytesinIVFandtransferoftheirembryostoagestationalcarriercanallowthesewomentohavegeneticallyrelatedchildren.

th th

th th

Basicstopics(see"Patientinformation:Absentorirregularperiods(TheBasics)"and"Patientinformation:Latepuberty(TheBasics)")

BeyondtheBasicstopics(see"Patientinformation:Absentorirregularperiods(BeyondtheBasics)")

Primaryamenorrheaisdefinedastheabsenceofmensesbyage15years.

Themostcommoncauseofprimaryamenorrheaischromosomalanomaliesresultingingonadaldysgenesis(50percent).(See'Etiology'above.)

Centralcausesofprimaryamenorrheaincludetumorsandinfiltrativedisordersofthehypothalamusandpituitary,alongwithcongenitalgonadotropinreleasinghormone(GnRH)deficiencyandhyperprolactinemia.However,functionalhypothalamicamenorrhea,inwhichhypothalamicGnRHpulsationisdisruptedbecauseoflowenergybalance,isbyfarthemostcommon.Togethertheseaccountforapproximately25percentofcases.(See'Hypothalamicandpituitarydisease'above.)

Polycysticovarysyndromeusuallypresentsassecondaryamenorrhea,butcansometimespresentasprimaryamenorrhea.(See'Polycysticovarysyndrome'above.)

Anatomicabnormalities,includingabsenceorabnormalitiesoftheuterus,cervix,andvaginamakeup20percentofprimaryamenorrhea.(See'Congenitalanatomiclesionsoftheuterusandvagina'above.)

Raredisordersofsteroidsynthesisandreceptorfunctionalsocauseprimaryamenorrhea.(See'Receptorabnormalitiesandenzymedeficiencies'above.)

Theevaluationofprimaryamenorrheaincludesacarefulhistoryandexamforsignsofpubertaldevelopmentandthepresenceofnormalinternalstructures,folliclestimulatinghormone(FSH)leveltodeterminewhether


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REFERENCES

1. PracticeCommitteeoftheAmericanSocietyforReproductiveMedicine.Currentevaluationofamenorrhea.FertilSteril200686:S148.

2. ReindollarRH,ByrdJR,McDonoughPG.Delayedsexualdevelopment:astudyof252patients.AmJObstetGynecol1981140:371.

3. SantoroN,FilicoriM,CrowleyWFJr.Hypogonadotropicdisordersinmenandwomen:diagnosisandtherapywithpulsatilegonadotropinreleasinghormone.EndocrRev19867:11.

4. CrowleyWFJr,JamesonJL.Clinicalcounterpoint:gonadotropinreleasinghormonedeficiency:perspectivesfromclinicalinvestigation.EndocrRev199213:635.

5. SaengerP.Turner'ssyndrome.NEnglJMed1996335:1749.6. MassaranoAA,AdamsJA,PreeceMA,BrookCG.OvarianultrasoundappearancesinTurnersyndrome.J

Pediatr1989114:568.7. ZhongQ,LaymanLC.GeneticconsiderationsinthepatientwithTurnersyndrome45,Xwithorwithout

mosaicism.FertilSteril201298:775.8. WyssD,DeLozierCD,DaniellJ,EngelE.StructuralanomaliesoftheXchromosome:personalobservation

andreviewofnonmosaiccases.ClinGenet198221:145.9. PortuondoJA,NeyroJL,BenitoJA,etal.Familial46,XXgonadaldysgenesis.IntJFertil198732:56.

10. RachmielM,KivesS,AtenafuE,HamiltonJ.Primaryamenorrheaasamanifestationofpolycysticovariansyndromeinadolescents:auniquesubgroup?ArchPediatrAdolescMed2008162:521.

11. LegroRS,ArslanianSA,EhrmannDA,etal.Diagnosisandtreatmentofpolycysticovarysyndrome:anEndocrineSocietyclinicalpracticeguideline.JClinEndocrinolMetab201398:4565.

12. BiasonLauberA,KonradD,NavratilF,SchoenleEJ.AWNT4mutationassociatedwithMllerianductregressionandvirilizationina46,XXwoman.NEnglJMed2004351:792.

13. LindnerTH,NjolstadPR,HorikawaY,etal.Anovelsyndromeofdiabetesmellitus,renaldysfunctionandgenitalmalformationassociatedwithapartialdeletionofthepseudoPOUdomainofhepatocytenuclearfactor1beta.HumMolGenet19998:2001.

14. GustafsonML,DonahoePK.Malesexdetermination:currentconceptsofmalesexualdifferentiation.AnnuRevMed199445:505.

15. VerpMS,SimpsonJL.Abnormalsexualdifferentiationandneoplasia.CancerGenetCytogenet198725:191.

16. BlagowidowN,PageDC,HuffD,MennutiMT.UllrichTurnersyndromeinanXYfemalefetuswithdeletionofthesexdeterminingportionoftheYchromosome.AmJMedGenet198934:159.

17. SahakitrungruangT,HuangN,TeeMK,etal.Clinical,genetic,andenzymaticcharacterizationofP450oxidoreductasedeficiencyinfourpatients.JClinEndocrinolMetab200994:4992.

18. QuaynorSD,StradtmanEWJr,KimHG,etal.Delayedpubertyandestrogenresistanceinawomanwithestrogenreceptorvariant.NEnglJMed2013369:164.

19. KrasnaIH,LeeML,SmilowP,etal.Riskofmalignancyinbilateralstreakgonads:theroleoftheYchromosome.JPediatrSurg199227:1376.

thecauseiscentralorovarian,andfurtherdirecteddiagnostictestingbasedonhistoryandphysicalexam.(See'Diagnosticevaluation'above.)

Treatmentofprimaryamenorrheaisdirectedatcorrectingtheunderlyingpathology(ifpossible),helpingthewomantoachievefertility(ifdesired),andpreventionofcomplicationsofthediseaseprocess(eg,estrogenreplacementtopreventosteoporosis).Abriefsummaryoftreatmentoptionsispresentedinthistopic,whilethetreatmentofspecificdisordersisdiscussedindetailintheappropriatetopicreviews.(See'Treatment'above.)



20. DeArceMA,CostiganC,GosdenJR,etal.FurtherevidenceconsistentwithYqhasanindicatorofriskofgonadalblastomainYbearingmosaicTurnersyndrome.ClinGenet199241:28.

21. LukusaT,FrynsJP,KleczkowskaA,VandenBergheH.Roleofgonadaldysgenesisingonadoblastomainductionin46,XYindividuals.TheLeuvenexperiencein46,XYpuregonadaldysgenesisandtesticularfeminizationsyndromes.GenetCouns19912:9.

22. MartinKA,HallJE,AdamsJM,CrowleyWFJr.Comparisonofexogenousgonadotropinsandpulsatilegonadotropinreleasinghormoneforinductionofovulationinhypogonadotropicamenorrhea.JClinEndocrinolMetab199377:125.

Topic7403Version12.0



GRAPHICS

Majorcausesofprimaryandsecondaryamenorrhea

Abnormality Causes

Pregnancy

Anatomicabnormalities

CongenitalabnormalityinMulleriandevelopment* Isolateddefect

Androgeninsensitivitysyndrome

5Alphareductasedeficiency

Vanishingtestessyndrome

DefectinSRYgene

Congenitaldefectofurogenitalsinusdevelopment* Agenesisoflowervagina

Imperforatehymen

Acquiredablationorscarringofendometrium Ashermansyndrome

Tuberculosis

Disordersofthehypothalamicpituitaryovarianaxis

Hypothalamicdysfunction

Pituitarydysfunction

Ovariandysfunction

Other

*Presentasprimaryamenorrheaonly.Themultiplecausesofhormonaldysfunctionarelistedonthenexttable.

Graphic59801Version3.0



Majorcausesofamenorrheaduetoabnormalitiesinthehypothalamicpituitaryovarianaxis

Abnormality Causes

Hypothalamicdysfunction

Congenitalgonadotropinreleasinghormone(GnRH)deficiency

Functionalhypothalamicamenorrhea

Weightloss,eatingdisorders

Exercise

Stress

Severeorprolongedillness

HeterozygousmutationsFGFR1,PROKR2,KAL1

Inflammatoryorinfiltrativediseases

Braintumorseg,craniopharyngioma

Cranialirradiation

Traumaticbraininjury

OthersyndromesPraderWilli,LaurenceMoonBiedl

Pituitarydysfunction Hyperprolactinemiaincludinglactotrophadenomas

Otherpituitarytumorsacromegaly,corticotrophadenomas(Cushing'sdisease)

Othertumorsmeninigioma,germinoma,glioma

Geneticcausesofhypopituitarism

Emptysellasyndrome

Pituitaryinfarctorapoplexy

Ovariandysfunction Polycysticovarysyndrome

Prematureovarianfailure(primaryovarianinsufficiency)

Surgical

Autoimmune,genetic,ovariantoxins,idiopathic

Other Hyperthyroidism

Hypothyroidism

Diabetesmellitus

Exogenousandrogenuse




Vaginalagenesiswithrudimentaryuterinehorns

Ofnote,incasesofvaginalagenesistheuterusmaybenormalorexhibitavarietyofmalformations.

Reproducedwithpermissionfrom:LauferMR.Structuralabnormalitiesofthefemalereproductivetract.In:Pediatricandadolescentgynecology,6thed,EmansSJ,LauferMR,GoldsteinDP(Eds),LippincottWilliams&Wilkins,Philadelphia2012.Copyright2012LippincottWilliams&Wilkins.www.lww.com.




Vaginalagenesiswithagenesisofthecervix

Reproducedwithpermissionfrom:LauferMR.Structuralabnormalitiesofthefemalereproductivetract.In:Pediatricandadolescentgynecology,6thed,EmansSJ,LauferMR,GoldsteinDP(Eds),LippincottWilliams&Wilkins,Philadelphia2012.Copyright2012LippincottWilliams&Wilkins.www.lww.com.




Syntheticpathwaysforadrenalsteroidsynthesis

ThefirststepinadrenalsteroidsynthesisisthecombinationofacetylCoAandsqualenetoformcholesterol,whichisthenconvertedintopregnenolone.Theenclosedareacontainsthecoresteroidogenicpathwayutilizedbytheadrenalglandsandgonads.

17:17alphahydroxylase(CYP17,P450c17)17,20:17,20lyase(alsomediatedbyCYP17)3:3betahydroxysteroiddehydrogenase21:21hydroxylase(CYP21A2,P450c21)11:11betahydroxylase(CYP11B1,P450c11)18referstothetwostepprocessofaldosteronesynthase(CYP11B2,P450c11as),resultingintheadditionofanhydroxylgroupthatisthenoxidizedtoanaldehydegroupatthe18carbonposition17R:17betareductase5R:5alphareductaseDHEA:dehydroepiandrosteroneDHEAS:DHEAsulfateA:aromatase(CYP19)SK:sulfokinaseSL:sulfotransferase.




Sexualmaturityrating(Tannerstages)ofsecondarysexualcharacteristics

BoysDevelopmentofexternalgenitaliaStage1:Prepubertal

Stage2:Enlargementofscrotumandtestesscrotalskinreddensandchangesintexture

Stage3:Enlargementofpenis(lengthatfirst)furthergrowthoftestes

Stage4:Increasedsizeofpeniswithgrowthinbreadthanddevelopmentofglanstestesandscrotumlarger,scrotalskindarker

Stage5:Adultgenitalia

GirlsBreastdevelopmentStage1:Prepubertal

Stage2:Breastbudstagewithelevationofbreastandpapillaenlargementofareola

Stage3:Furtherenlargementofbreastandareolanoseparationoftheircontour

Stage4:Areolaandpapillaformasecondarymoundabovelevelofbreast

Stage5:Maturestage:projectionofpapillaonly,relatedtorecessionofareola

BoysandgirlsPubichairStage1:Prepubertal(thepubicareamayhavevellushair,similartothatofforearms)

Stage2:Sparsegrowthoflong,slightlypigmentedhair,straightorcurled,atbaseofpenisoralonglabia

Stage3:Darker,coarserandmorecurledhair,spreadingsparselyoverjunctionofpubes

Stage4:Hairadultintype,butcoveringsmallerareathaninadultnospreadtomedialsurfaceofthighs

Stage5:Adultfemaleintypeandquantity,withhorizontalupperborder




Tannerstagingofbreastdevelopmentingirls

Stage1:Prepubertal.Stage2:Breastbudstagewithelevationofbreastandpapillaenlargementofareola.Stage3:Furtherenlargementofbreastandareolanoseparationoftheircontour.Stage4:Areolaandpapillaformasecondarymoundabovelevelofbreast.Stage5:Maturestagewithprojectionofpapillaonly,relatedtorecessionofareola.




Disclosures:CorrineKWelt,MDConsultant/AdvisoryBoards:Takeda[Ovarianfailureduetoanticancerdrugs(Leuprolideacetate{Offlabeluseforovariansuppression,noconsultingrolerelatedtothisproduct})].RobertLBarbieri,MDNothingtodisclose.PeterJSnyder,MDGrant/Research/ClinicalTrialSupport:AbbVie[Hypogonadism(Testosteronegel)]NovoNordisk[GHdeficiency(Norditropin)]Ipsen[Acromegaly(Lanreotide)].Consultant/AdvisoryBoards:Novartis[Cushing'ssyndrome(Pasireotide)]Pfizer[Acromegaly(Pegvisomant)].WilliamFCrowley,Jr,MDConsultant/AdvisoryBoards:QuestDiagnostics[Endocrinology(Diagnosticlaboratorytesting)].MitchellGeffner,MDGrant/Research/ClinicalTrialSupport:EliLillyInc[growth(rhGH)]Genentech[growth(rhGH)]NovoNordisk[growth(rhGH)]Pfizer[growth(rhGH)]Verartis[growth(longactingrhGH)]Ipsen[growth(rhIGFI)]EndoPharmaceuticals[puberty(GnRHagonist)].Consultant/AdvisoryBoards:DaiichiSankyo[T2DM(colesevelam)]EndoPharmaceuticals[puberty(GnRHagonist)]Ipsen[growth(rhIGFI)]Pfizer[growth(rhGH)].OtherFinancialInterest:McGrawHill[pediatricendocrinology(textbookroyalties)].KathrynAMartin,MDNothingtodisclose.Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.Conflictofinterestpolicy

Disclosures

etiology, diagnosis, and treatment of primary amenorrhea

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