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Etiology,diagnosis,andtreatmentofprimaryamenorrhea

OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate

Etiology,diagnosis,andtreatmentofprimaryamenorrhea
Authors
CorrineKWelt,MD
RobertLBarbieri,MD

SectionEditors
PeterJSnyder,MD
WilliamFCrowley,Jr,MD
MitchellGeffner,MD

DeputyEditor
KathrynAMartin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Mar11,2014.
INTRODUCTIONAmenorrhea(absenceofmenses)canbeatransient,intermittent,orpermanentcondition
resultingfromdysfunctionofthehypothalamus,pituitary,ovaries,uterus,orvagina(table1andtable2).Itisoften
classifiedaseitherprimary(absenceofmenarchebyage15years)orsecondary(absenceofmensesformore
thanthreecycleintervalsorsixmonthsinwomenwhowerepreviouslymenstruating).Themenstrualcycleis
susceptibletooutsideinfluencesthus,missingasinglemenstrualperiodisrarelyimportant.Incontrast,
prolongedamenorrheamightbetheearliestsignofadeclineingeneralhealthorsignalanunderlyingcondition,
suchasapituitarytumor.
Thecausesanddiagnosisofprimaryamenorrhea,aswellasabriefsummaryoftreatmentoptions,arereviewed
here.Theetiology,diagnosis,andtreatmentofsecondaryamenorrheaarediscussedseparately.(See"Etiology,
diagnosis,andtreatmentofsecondaryamenorrhea".)
DEFINITIONPrimaryamenorrheaisdefinedastheabsenceofmensesatage15yearsinthepresenceof
normalgrowthandsecondarysexualcharacteristics.Duetothisseculartrendofanearlieronsetofmenarche,
someauthoritiesrecommendevaluatingagirlforprimaryamenorrheaifhermenseshavenotoccurredbyage15
years[1].Atage13years,ifnomenseshaveoccurredandthereisanabsenceofsecondarysexual
characteristics,suchasbreastdevelopment,evaluationforprimaryamenorrheashouldbebegun.Inaddition,at
age12or13years,ifcyclicpelvicpainispresent,obstructedmllerianoutflowtrack,acauseofbothprimary
amenorrheaandpelvicpain,shouldbeconsideredinthedifferentialdiagnosis.
ETIOLOGYPrimaryamenorrheaisusuallytheresultofageneticoranatomicabnormality.However,allcauses
ofsecondaryamenorrheacanalsopresentasprimaryamenorrhea.Inalargecaseseriesofprimaryamenorrhea,
themostcommonetiologieswere[2]:
Chromosomalabnormalitiescausinggonadaldysgenesis(ovarianinsufficiencyduetothepremature
depletionofalloocytesandfollicles)50percent
Hypothalamichypogonadismincludingfunctionalhypothalamicamenorrhea20percent
Absenceoftheuterus,cervixand/orvagina,mllerianagenesis15percent
Transversevaginalseptumorimperforatehymen5percent
Pituitarydisease5percent
Theetiologyintheremaining5percentofcasesincludesacombinationofdisorders,suchasandrogen
insensitivityduetomutationsintheandrogenreceptor,congenitaladrenalhyperplasia,andpolycysticovary
syndrome(seeappropriatetopicreviews).
Alogicalapproachtothewomanwitheitherprimaryorsecondaryamenorrheaistoconsiderdisordersbasedupon
thelevelofcontrolofthemenstrualcycle:hypothalamusandpituitary,ovary,anduterusandvagina.Inaddition,
steroidreceptorabnormalitiesanddeficienciesinenzymesofsteroidogenesiscauseprimaryamenorrheaatthe
leveloftheovaryandtheadrenalgland.
HypothalamicandpituitarydiseaseAcommoncauseofprimaryamenorrheaisfunctionalhypothalamic
amenorrhea.Lesscommonly,tumorsandinfiltrativelesionsofthehypothalamusorpituitarycanresultin
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amenorrhea,usuallyinassociationwithhyperprolactinemia(table1).
FunctionalhypothalamicamenorrheaFunctionalhypothalamicamenorrheaisadisorderthat,by
definition,excludespathologicdisease.Itischaracterizedbyabnormalhypothalamicgonadotropinreleasing
hormone(GnRH)secretion,leadingtodecreasedgonadotropinpulsations,lowornormalserumluteinizing
hormone(LH)concentrations,absentLHsurges,absenceofnormalfolliculardevelopment,anovulation,andlow
serumconcentrationsofestradiol[3].Serumfolliclestimulatinghormone(FSH)concentrationsareofteninthe
normalrange,withahighFSHtoLHratiosimilartothepatterninprepubertalgirls.
Multiplefactorsmaycontributetothepathogenesisoffunctionalhypothalamicamenorrhea,includingeating
disorders(suchasanorexianervosa),exercise,andstress.Thetermhypothalamicamenorrheaisoftenused
interchangeablywithfunctionalhypothalamicamenorrhea.Thetopicoffunctionalhypothalamicamenorrheais
discussedindetailelsewhere.(See"Etiology,diagnosis,andtreatmentofsecondaryamenorrhea",sectionon
'Functionalhypothalamicamenorrhea'and"Amenorrheaandinfertilityassociatedwithexercise"and"Eating
disorders:Overviewofepidemiology,diagnosis,andcourseofillness".)
CongenitalGnRHdeficiencyAlthoughrare,primaryamenorrheacanbeduetocompletecongenitalGnRH
deficiency.Thissyndromeiscalledidiopathichypogonadotropichypogonadismor,ifitisassociatedwithanosmia,
Kallmann'ssyndrome[4].Thesewomentypicallyhaveapulsatileandprepubertallowserumgonadotropin
concentrationsduetotheabsenceofhypothalamicGnRH.CongenitalGnRHdeficiencycanbeinheritedasan
autosomaldominant,autosomalrecessive,orXlinkedcondition.However,overtwothirdsofcasesaresporadic.
(See"Congenitalgonadotropinreleasinghormonedeficiency(idiopathichypogonadotropichypogonadism)".)
ConstitutionaldelayofpubertyAlthoughconstitutionaldelayofpubertyiscommoninboyswithafamily
historyofdelayedpuberty,itisanuncommoncauseofdelayedpubertyorprimaryamenorrheaingirls.
Constitutionaldelayischaracterizedbybothdelayedadrenarcheandgonadarche,andisoftendifficultto
distinguishclinicallyfromcongenitalGnRHdeficiency.Patientswithconstitutionaldelaygoontohavecompletely
normalpubertaldevelopment,albeitatalaterage.(See"Diagnosisandtreatmentofdelayedpuberty".)
HyperprolactinemiaHyperprolactinemiaisararecauseofprimaryamenorrheaandanovulation.The
presentationissimilartohypothalamicamenorrheaexceptfortheadditionalfindingofgalactorrheainmanywomen
withhyperprolactinemia.Prolactinsecretingpituitaryadenomasandcranialtumorscausepituitarystalk
compression.(See"Clinicalmanifestationsandevaluationofhyperprolactinemia".)
Inmostlaboratories,aserumprolactinconcentrationabove15to20ng/mL(15to20mcg/L)isconsidered
abnormalinwomenofreproductiveage.Stress,sleep,exercise,intercourse,andmealscanraiseserumprolactin
concentrationstransiently.Thus,werecommendthathighserumprolactinconcentrationsberecordedatleast
twicebeforeamagneticresonanceimaging(MRI)isordered.
OtherManyinfiltrativediseasesandtumorsofthehypothalamusandpituitarycanresultindiminishedGnRH
releaseorgonadotropedestructionandamenorrheatheseincludecraniopharyngioma,germinoma,and
Langerhanscellhistiocytosis.Themainindicationsformagneticresonanceimagingareprimaryhypogonadotropic
hypogonadism,visualfielddefects,headaches,otherevidenceofhypothalamicorpituitarydysfunction,or
suggestiveotherdiseases(suchassarcoidosis).Ironstudiestoruleouthemochromatosisshouldbeperformedif
thereisanappropriatefamilyhistoryorifthewomanhasothersuggestivemanifestationssuchasbronzedskin,
diabetesmellitus,orotherwiseunexplainedheartorliverdisease.(See"Approachtothepatientwithsuspected
ironoverload".)
OvarianetiologiesThemostcommoncauseofprimaryamenorrheaisgonadaldysgenesiscausedby
chromosomalabnormalitiesthatresultinprematuredepletionofallovarianoocytesandfollicles.Alesscommon
ovarianetiologyofprimaryamenorrheaisthepolycysticovarysyndrome.
GonadaldysgenesisInyoungwomenwithprimaryamenorrhea,thesinglemostcommoncauseisprimary
ovarianinsufficiencyduetogonadaldysgenesis.ThesewomenhavesignificantlyelevatedFSHlevelsduetothe
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absenceofovarianoocytesandfollicles,leadingtoareductioninnegativefeedbackonFSHfromestradioland
inhibinsAandB.ThelargestnumberofpatientswithprimaryamenorrheaandovarianinsufficiencyhaveTurner's
syndrome(45,X)followedby46,XXgonadaldysgenesisand,rarely,46,XYgonadaldysgenesis.
TurnersyndromeWomenwithTurnersyndromeareusuallymissingallofoneXchromosome(45,X
gonadaldysgenesis)[5].Amenorrheaoccursbecausetheoocytesandfolliclesundergoapoptosisandtheovaries
arereplacedwithfibroustissueandcannotproduceestrogenwithoutfollicles.Incontrast,theexternalfemale
genitalia,uterus,andfallopiantubesdevelopnormallyuntilpubertywhenestrogeninducedmaturationfailsto
occur.Spontaneouspubertyandmenstruationoccursmorecommonlyinwomenwithamosaickaryotype
(45,X/46,XX),butcanoccurinwomenwitha45,Xkaryotype,althoughspontaneouspregnancyisunlikelywitha
45,Xkaryotype[6,7].(See"ClinicalmanifestationsanddiagnosisofTurnersyndrome(gonadaldysgenesis)".)
Estrogenandcyclicprogesteronereplacementatpubertywillresultinnormalpubertaldevelopment:pubicand
axillaryhair,breastgrowth,cyclicvaginalbleeding,andgrowthandmaturationoftheuterusandexternalgenitalia.
Postmenopausalhormonetherapymaybeprecededbygrowthhormonetherapytogainmaximalheight.
Pregnancyispossiblewithoocytedonation.(See"ManagementofTurnersyndrome(gonadaldysgenesis)".)
PartialdeletionsandstructuralrearrangementsoftheXchromosomecanalsoresultinprimaryorsecondary
amenorrheaandtheTurnerphenotype[8].Inaddition,somecasesofgonadaldysgenesisresultfromautosomal
recessiveinheritance(46,XXgonadaldysgenesis)thefewcasesthathavebeendescribedlackthesomatic
featuresofTurnersyndrome[9].(See"Congenitalcytogeneticabnormalities".)
PolycysticovarysyndromeThemenstrualdisturbancesinwomenwiththepolycysticovarysyndrome
(PCOS)classicallyhaveaperipubertalonset.Whilesomewomenmaypresentwithprimaryamenorrhea,typically
thosewhohavehigherandrogenlevelsandaremoreoverweight[10],mosthaveanormalorslightlydelayed
menarchefollowedbyirregularcyclesorsecondaryamenorrhea.Thediagnosiscanbemadeinagirlwithclinical
andbiochemicalevidenceofhyperandrogenisminthepresenceofadvancedpubertaldevelopment(ie,Tanner
stage4breastdevelopment)andintheabsenceofotherdisorderscausingamenorrheaandhyperandrogenism
[11].ThediagnosisofPCOSisreviewedindetailseparately.(See"Definition,clinicalfeaturesanddifferential
diagnosisofpolycysticovarysyndromeinadolescents"and"Diagnosisofpolycysticovarysyndromeinadults".)
OtherOthercausesofovarianinsufficiencysuchasautoimmuneoophoritis,chemotherapyorradiation
inducedovarianinsufficiencyandFMR1premutationcarriersgenerallypresentassecondaryamenorrhea.(See
"Clinicalfeaturesanddiagnosisofautoimmuneprimaryovarianinsufficiency(prematureovarianfailure)"and
"Ovarianfailureduetoanticancerdrugsandradiation".)
CongenitalanatomiclesionsoftheuterusandvaginaCongenitalabnormalitiesofthefemalereproductive
organsaccountforapproximately20percentofcasesofprimaryamenorrhea.Mensescannotoccurwithoutan
intactuterus,endometrium,cervix,cervicalos,andvaginalconduit.Pelvicorlowerabdominalpainisacommon
presentingsymptomingirlswithprimaryamenorrheaandanobstructedreproductivetract.Congenitalanomalies
oftheuterusandvaginawillbereviewedbrieflyinthissectionandingreaterdetailelsewhere.(See"Clinical
manifestationsanddiagnosisofcongenitalanomaliesoftheuterus"and"Diagnosisandmanagementofcongenital
anomaliesofthevagina".)
ImperforatehymenAnimperforatehymenisthesimplestdefectthatresultsinprimaryamenorrhea.Itmay
beassociatedwithcyclicpelvicpainandaperirectalmassfromsequestrationofbloodinthevagina
(hematocolpos).Similarfindingscanbeseenwithdefectsinperinealdevelopment,whichcanresultinabsenceof
thedistalthirdofthevaginaandthereforeabsenceofanoutflowtract.Bothoftheseconditionsarediagnosedby
physicalexamination.Animperforatehymeniseasilycorrectedwithsurgery.(See"Diagnosisandmanagementof
congenitalanomaliesofthevagina".)
TransversevaginalseptumOneormoretransversevaginalseptaecanoccuratanylevelbetweenthe
hymenalringandthecervix.Aftermenarche,themajorsymptomsaresimilartothoseassociatedwithan
imperforatehymen.(See"Diagnosisandmanagementofcongenitalanomaliesofthevagina".)
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VaginalagenesisVaginalagenesis,alsoknownasmllerianagenesisorMayerRokitanskyKsterHauser
(MRKH)syndrome,referstocongenitalabsenceofthevaginawithvariableuterinedevelopment.Thedefect
resultsfromagenesisorhypoplasiaofthemllerianductsystem.HeterozygousmutationsinWNT4accountfora
smallsubsetofthesecases[12].Vaginalagenesisisusuallyaccompaniedbycervicalanduterineagenesis
however,7to10percentofwomenhaveanormalbutobstructedorrudimentaryuteruswithfunctional
endometrium(figure1andfigure2).Themostcommonlycitedincidenceforvaginalagenesisis1in5000(range:1
per4000to10,000females).
Differentialdiagnosisofvaginalagenesisincludesandrogeninsensitivity,lowlyingtransversevaginalseptum,
agenesisoftheuterusandvagina,imperforatehymen,andmaturityonsetdiabetesoftheyoung(MODY)caused
byHNF1mutations[13].Vaginalagenesiscanbedifferentiatedfromandrogeninsensitivitybaseduponanormal
femalerangeserumtotaltestosteroneinvaginalagenesisandamalerangeserumtestosteroneinandrogen
insensitivity.Imagingstudies(ultrasoundand/orMRI)helptoclarifythenatureofthevaginalagenesisandto
differentiateitfromlowlyingtransversevaginalseptum,agenesisoftheuterusandvagina,andimperforate
hymen.
Theclinicalmanifestations,evaluation,andmanagementofvaginalagenesisarereviewedindetailelsewhere.
(See"Diagnosisandmanagementofcongenitalanomaliesofthevagina".)
RECEPTORABNORMALITIESANDENZYMEDEFICIENCIES
CompleteandrogeninsensitivitysyndromeThecompleteandrogeninsensitivitysyndromeisanXlinked
recessivedisorderinwhich46,XYsubjectsappearasnormalwomen.Thesepatientsareresistanttotestosterone
duetoadefectintheandrogenreceptorand,therefore,failtodevelopallofthemalesexualcharacteristicsthat
aredependentupontestosterone[14](see"Diagnosisandtreatmentofdisordersoftheandrogenreceptor").The
externalgenitaliaaretypicallyfemaleinappearance,buttestesmaybepalpableinthelabiaoringuinalarea.The
testesmakemllerianinhibitingsubstance,whichisfunctionalandcausesregressionofallmllerianstructures:
thefallopiantubes,uterus,andupperthirdofthevagina.Atpuberty,breastdevelopmentoccurs,buttheareolae
arepaleandpubicandaxillaryhairissparse.Carrierfemales(46,XX)developnormalinternalandexternal
genitalia.
Thediagnosisofthisdisorderisbasedupontheabsenceoftheuppervagina,uterus,andfallopiantubeson
physicalexaminationandpelvicultrasonography,highserumtestosteroneconcentrations(intherangefornormal
men),andamale(46,XY)karyotype.Thetestesshouldbesurgicallyexcisedafterpubertybecauseofthe
increasedrisk(2to5percent)ofdevelopingtesticularcancerafterage25years[15].(See"Diagnosisand
treatmentofdisordersoftheandrogenreceptor".)
5alphareductasedeficiency5alphareductasedeficiencyisanothercongenitaldefectthatcanresultin
primaryamenorrheaina46,XYsubject.Atbirth,theseneonatesmayappearfemaleorhaveambiguousgenitalia.
Atpuberty,thedisorderismorerecognizablebecauseoftheonsetofvirilizationduetothenormalperipubertal
increaseintestosteronesecretioninmales.However,thesesubjectscannotconverttestosterone(via5alpha
reductase)toitsevenmorepotentmetabolitedihydrotestosterone(DHT).Asaresult,theyfailtoundergoDHT
dependentmasculinization,leadingtolackofenlargementofthemaleexternalgenitaliaandprostate.By
comparison,testosteronedependentprocessesareintact,includingmalepatternhairgrowth,musclemass,and
voicedeepening.(See"Steroid5alphareductase2deficiency"and"Evaluationoftheinfantwithambiguous
genitalia".)
VanishingtestessyndromeThevanishingtestessyndromeoccursin46,XYsubjectswhoappeartobe
normalfemales.Thegonadsapparentlyfailtodevelopinthisdisorder,resultinginavariablephenotypedepending
uponwhenthefailureoccurred.Earlyfailurepriortotesticulardevelopment(beforeabouteightweeksofgestation)
isassociatedwithstreaklikeinactivegonadsthatneverproducetestosterone,estrogen,ormllerianinhibiting
substance.Theneteffectisfeminizationofboththeinternalandexternalgenitaliaandgonadalfailure.
Alateronsetoftesticularfailureresultsinvariableabnormalities.Asanexample,althoughnormalmalegenitalia
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maybeapparentatbirth,pubertalchangesdonotoccurduetogonadalfailure.
Thediagnosisofthevanishingtestessyndromeismadefromthefindingsofgonadalfailure,lackofprogression
throughpuberty,andhighserumfolliclestimulatinghormone(FSH)andluteinizinghormone(LH)concentrationsin
thepresenceofamalekaryotype.Thereisahighrisk(30percent)ofdevelopingagonadaltumor
(gonadoblastomaordysgerminoma)sothatearlyextirpationoftesticularremnantsisrecommended[15].(See
"Evaluationoftheinfantwithambiguousgenitalia".)
AbsenttestisdeterminingfactorAsimilarphenotypicappearancetoearlyonsetvanishingtestessyndrome
canoccurinsubjectswithdeletionormutationinthetestisdeterminingfactorgenelocatedontheYchromosome
thisdisorderiscalledtheUllrichTurnersyndrome[16].These46,XYsubjectsdonotdeveloptestesandtherefore
donotproducetestosteroneormllerianinhibitingsubstance,resultinginfeminizationoftheexternalandinternal
genitaliainassociationwithprimarygonadalfailure.Thediagnosisismadebydemonstratingtheabnormalityof
theshortarmoftheYchromosomebyYDNAhybridizationstudies.
17alphahydroxylase(CYP17)deficiencyThisraredisorder,whichcanoccurin46,XXor46,XYsubjects,is
characterizedbydeficiencyoftheproductoftheCYP17gene,whichisanenzymethathasboth17hydroxylase
and17,20lyase(desmolase,orsidechaincleavage)activities(figure3).Asaresult,thereisdecreasedcortisol
synthesisbutoverproductionofcorticotropinhormone(ACTH),corticosterone,anddeoxycorticosterone.Adrenal
andgonadalsexsteroidsarenotproducedsothataffectedsubjectstypicallypresentasphenotypicfemaleswith
hypertension(duetomineralocorticoidexcess),lackofpubertaldevelopment,andeitherfemale(if46,XX)or
incompletelydeveloped(if46,XY)externalgenitalia.Thistopicisdiscussedindetailelsewhere.(See"Uncommon
causesofcongenitaladrenalhyperplasia"and"Evaluationoftheinfantwithambiguousgenitalia".)
P450oxidoreductasemutationsTheP450oxidoreductase(POR)donateselectronstocytochromeP450
enzymes,including17alphahydroxylase/17,20lyase.RecessivemutationsresultinAntleyBixlersyndrome,a
disorderofabnormalsteroidogenesis,genitalanomaliesincludingambiguousgenitaliainmalesandfemales,
cranialsynostosis,radioulnarandradiohumeralsynostosis,andotherskeletalanomalies[17].However,the
spectrumofPORmutationshasexpandedandincludeswomenwithprimaryamenorrheaandinfertility.Women
mightpresentwithapatternofatypicalcongenitaladrenalhyperplasiauponACTHstimulation,includinglow
cortisolandandrostenedionelevelsandelevated17OHprogesteroneandprogesteronelevels,inthesettingofan
elevatedACTH.Womenmayalsopresentwithamenorrheainthesettingofmultiplelargeovariancystsbutlow
estradiollevels.
EstrogenresistanceAmutationinthegeneencodingestrogenreceptoralpha(ESR1),whichhadpreviously
beendescribedonlyinamale,hasnowbeenidentifiedinan18yearoldgirlwithprimaryamenorrheaandprofound
estrogenresistance.Shepresentedwithveryhighserumestradiolconcentrations(3500pg/mL[12,849pmol/L]),
inappropriatelyelevatedserumgonadotropins(LH9.6mIU/mL,FSH6.7mIU/mL),enlargedmulticysticovaries,
andnoevidenceofendometrialthickening[18].Inspiteofthehyperestrogenemia,shehadnormalserum
concentrationsofsexhormonebindingconcentration(SHBG),cortisolbindingglobulin(CBG),thyroxinebinding
globulin(TBG),andtriglycerides.Shealsohaddelayedboneage(13.5years),lowbonemineraldensity(Zscore
2.4),andhergrowthvelocitychartsuggestedalackofanestrogeninducedadolescentgrowthspurt.DNA
sequencingidentifiedahomozygousmutationinESR1thatseverelyimpairedestrogensignalingexceptwith
administrationofpharmacologicdosesofestrogen,whenminimalsignalingwasobserved.Theprevalenceof
ESR1mutationsinhumansisunknown,buttheyarelikelytobeveryrare.Althoughtheyhavenotbeenidentified
clinically,milderESR1mutationscouldresultinincompleteestrogenresistanceanalogoustothepartialandrogen
insensitivitysyndromecausedbymildmutationsintheandrogenreceptorgene.(See"Pathogenesisandclinical
manifestationsofdisordersofandrogenaction",sectionon'Partialandrogeninsensitivity(PAIS)'.)
DIAGNOSTICEVALUATION
OverviewPrimaryamenorrheaisevaluatedmostefficientlybyfocusingonthepresenceorabsenceofbreast
development(amarkerofestrogenactionandthereforefunctionoftheovary),thepresenceorabsenceofthe
uterus(asdeterminedbyultrasound,orinmorecomplexcasesbymagneticresonanceimaging)andthefollicle
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stimulatinghormone(FSH)level.
IfthereisnobreastdevelopmentandtheFSHleveliselevated,theprobablediagnosisisgonadal
dysgenesis,andakaryotypeshouldbeobtained.Inthisscenario,a46,XYkaryotypeisassociatedwitha
highriskforthedevelopmentofgonadoblastomaanddysgerminomaandsurgicalremovalofthegonadsis
necessary.
IftheultrasoundindicatesthattheuterusisabsentandFSHisnormal,theprobablediagnosisismllerian
agenesisorandrogeninsensitivitysyndrome.Inthecaseofmllerianagenesis,thecirculatingtestosterone
isinthenormalrangeforwomenandinthecaseofandrogeninsensitivity,thecirculatingtestosteroneisin
themalerange.
IftheFSHisnormal,andbothbreastdevelopmentandtheuterusarepresent,thentheworkupshouldfocus
onthecommoncausesofsecondaryamenorrhea,wheretheinitialworkupincludesmeasurementofheight
andweight,serumFSH,prolactinandthyroidstimulatinghormone(TSH).(See"Etiology,diagnosis,and
treatmentofsecondaryamenorrhea".)
Aseriesofsequentialdiagnosticstepshelpwiththepreciseidentificationofacauseofprimaryamenorrhea:
Step1:HistoryAlthoughthereareseveraluniquecausesofprimaryamenorrhea,allcausesofsecondary
amenorrheacanalsocauseprimarydisease(see"Etiology,diagnosis,andtreatmentofsecondaryamenorrhea").
Thus,thefollowingquestionsshouldbeaskedofawomanwithprimaryamenorrhea:
Hasshecompletedotherstagesofpuberty,includingagrowthspurt,developmentofaxillaryandpubichair,
apocrinesweatglands,andbreastdevelopment?Lackofpubertaldevelopmentsuggestsovarianorpituitary
failureorachromosomalabnormality.
Isthereafamilyhistoryofdelayedorabsentpuberty(suggestingapossiblefamilialdisorder)?
Whatisthewoman'sheightrelativetofamilymembers?ShortstaturemayindicateTurnersyndromeor
hypothalamicpituitarydisease.
Wasneonatalandchildhoodhealthnormal?Neonatalcrisissuggestscongenitaladrenalhyperplasia.
Alternatively,poorhealthmaybeamanifestationofhypothalamicpituitarydisease.
Arethereanysymptomsofvirilization?Thepresenceofvirilizationsuggestspolycysticovarysyndrome,an
androgensecretingovarianoradrenaltumor,orthepresenceofYchromosomematerial.
Lately,hastherebeenstress,changeinweight,diet,orexercisehabits,orillnessthatmightresultin
hypothalamicamenorrhea?
Isshetakinganydrugsthatmightcauseorbeassociatedwithamenorrhea?Themedicationmaybetaken
forasystemicillnessthatitselfcancausehypothalamicamenorrhea(eg,sarcoidosis).Alternatively,drugs
suchasheroinandmethadonecanalterhypothalamicgonadotropinsecretion.
Istheregalactorrhea(suggestiveofexcessprolactin)?Somedrugscauseamenorrheabyincreasingserum
prolactinconcentrations,includingmetoclopramideandantipsychoticdrugs.(See"Causesof
hyperprolactinemia".)
Aretheresymptomsofotherhypothalamicpituitarydisease,includingheadaches,visualfielddefects,
fatigue,orpolyuriaandpolydipsia?
Step2:PhysicalexaminationThephysicalexaminationinawomanwithprimaryamenorrheashouldbegin
with:
Anevaluationofpubertaldevelopment,includingcurrentheight,weight,andarmspan(normalarmspanfor
adultsiswithin5cmofheight)andanevaluationofthewoman'sgrowthchart.
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Anassessmentofbreastdevelopment(eg,byTannerstaging)(table3andfigure4).(See"Normalpuberty".)
Acarefulgenitalexaminationshouldbeperformedforclitoralsize,pubertalhairdevelopment,intactnessof
thehymen,depthofthevagina,andpresenceofacervix,uterus,andovaries.Ifthevaginacannotbe
penetratedwithafinger,rectalexaminationmayallowevaluationoftheinternalorgans.Pelvicultrasoundis
alsousefultodeterminethepresenceorabsenceofmllerianstructures.
Examinationoftheskinforhirsutism,acne,striae,increasedpigmentation,andvitiligo.
EvaluationfortheclassicphysicalfeaturesofTurnersyndromesuchaslowhairline,webneck,shield
chest,andwidelyspacednipplesshouldbenoted.Thebloodpressureshouldbemeasuredinbotharmsif
Turnersyndromeissuspected,becauseitisassociatedwithanincreasedincidenceofcoarctationofthe
aorta.
Step3:BasiclaboratorytestingThelaboratoryevaluationofawomanwithprimaryamenorrheadependsupon
thefindingsonphysicalexamination,inparticular,whethermllerianstructuresarepresentorabsent.Thus,the
singlemostimportantstepintheevaluationistodeterminebyphysicalexaminationorultrasonographywhether
thereareanyanatomicabnormalitiesofthevagina,cervix,oruterus.
Ifanormalvaginaoruterusisnotobviouslypresentonphysicalexamination,pelvicultrasonographyshouldbe
performedtoconfirmthepresenceorabsenceofovaries,uterus,andcervix.Inaddition,ultrasonographycanbe
usefultolookforvaginalorcervicaloutletobstructioninpatientswithcyclicpain.
UterusabsentForthosewithabsenceoftheuterus,furtherevaluationshouldincludeakaryotypeand
measurementofserumtestosterone.Thesetestsshouldthenallowthecliniciantodistinguishbetweenabnormal
mlleriandevelopment(46,XXkaryotypewithnormalfemaleserumtestosteroneconcentrations)andandrogen
insensitivitysyndrome(46,XYkaryotypeandnormalmaleserumtestosteroneconcentrations).Patientswith5
alphareductasedeficiencyalsohavea46,XYkaryotypeandnormalmaleserumtestosteroneconcentrationsbut,
incontrasttotheandrogeninsensitivitysyndrome,whichisassociatedwithafemalephenotype,thesepatients
undergostrikingvirilizationatthetimeofpuberty(normaldevelopmentofsecondarysexualhair,musclemass,
anddeepeningofthevoice).
UteruspresentForpatientswithnormalmllerianstructuresandnoevidenceofanimperforatehymen,
vaginalseptum,orcongenitalabsenceofthevagina,anendocrineevaluationshouldbeperformed.Thisincludes
measurementofserumbetahumanchorionicgonadotropintoexcludepregnancyandofserumFSH,andperhaps
otherhormones.
AhighserumFSHconcentrationisindicativeofprimaryovarianinsufficiency.Akaryotypeisthenrequired
andmaydemonstratecompleteorpartialdeletionoftheXchromosome(Turnersyndrome)orthepresenceof
Ychromatin.ThepresenceofaYchromosome(eg,vanishingtestessyndrome,absenttestisdetermining
factor)isassociatedwithahigherriskofgonadaltumorsandmakesgonadectomymandatory[1921].
Inaddition,evaluationforotherdiseasesassociatedwiththespecifictypeofovarianinsufficiencyshouldbe
performed.Asexamples,congenitalheartdisease,hypertension,andhearinglossarecommoninwomen
withTurnersyndrome,whileevaluationforautoimmunethyroidandadrenaldiseaseshouldbedoneinall
womenwithautoimmuneoophoritis.(See"ClinicalmanifestationsanddiagnosisofTurnersyndrome
(gonadaldysgenesis)"and"Clinicalfeaturesanddiagnosisofautoimmuneprimaryovarianinsufficiency
(prematureovarianfailure)".)
AlowornormalserumFSHconcentrationsuggestsfunctionalhypothalamicamenorrhea,congenital
gonadotropinreleasinghormone(GnRH)deficiency,orotherdisordersofthehypothalamicpituitaryaxis.
Cranialmagneticresonance(MR)imagingisindicatedinmostcasesofhypogonadotropichypogonadismto
evaluateforhypothalamicorpituitarydisease.Werecommendcranialimaginginallwomenwithprimary
hypogonadotropichypogonadism,visualfielddefects,headaches,oranyothersignsofhypothalamic
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pituitarydysfunction.
SerumprolactinandthyrotropinshouldbemeasuredifFSHislowornormal,especiallyifgalactorrheais
present.
Iftherearesignsorsymptomsofhyperandrogenism,serumtestosteroneanddehydroepiandrosteronesulfate
(DHEAS)shouldbemeasuredtoassessforanandrogensecretingtumor.
Amongwomenwhoarealsohypertensive,bloodtestsshouldbedrawnforevaluationfor17alpha
hydroxylase(CYP17)deficiency.Thecharacteristicfindingsareelevationsinserumprogesterone(>3ng/mL
[9.5nmol/L])anddeoxycorticosteroneandlowvaluesforserum17alphahydroxyprogesterone(<0.2ng/mL
[0.6nmol/L]).(See"Uncommoncausesofcongenitaladrenalhyperplasia".)
TREATMENTTreatmentofprimaryamenorrheaisdirectedatcorrectingtheunderlyingpathology(ifpossible),
helpingthewomantoachievefertility(ifdesired),andpreventionofcomplicationsofthediseaseprocess(eg,
estrogenreplacementtopreventosteoporosis).Abriefsummaryoftreatmentoptionsispresentedhere,whilethe
treatmentofspecificdisordersisdiscussedindetailintheappropriatetopicreviews.
Allwomenwithprimaryamenorrheashouldbecounseledregardingitscause,treatment,andtheir
reproductivepotential.Psychologicalcounselingisparticularlyimportantinpatientswithabsentmllerian
structuresoraYchromosome.
SurgerymayberequiredinpatientswitheithercongenitalanatomiclesionsorYchromosomematerial.The
etiologyoftheprimaryamenorrheawilldeterminethetypeofsurgicalprocedurerequired.Asanexample,
surgicalcorrectionofavaginaloutletobstructionisnecessaryassoonasthediagnosisismadeafter
menarchetoallowpassageofmenstrualblood.Creationofaneovaginaforpatientswithmllerianfailureis
usuallydelayeduntilthewomenareemotionallymatureandreadytoparticipateinthepostoperativecare
requiredtomaintainvaginalpatency.
InthosepatientsinwhomYchromosomematerialisfound,gonadectomyshouldbeperformedtopreventthe
developmentofgonadalneoplasia[1921].However,gonadectomyshouldbedelayeduntilafterpubertyin
patientswithcompleteandrogeninsensitivitysyndrome.Thesepatientshaveanormalpubertalgrowthspurt
andfeminizeatthetimeofexpectedpubertytumorsdonotusuallydevelopuntilafterthistime.(See
"Diagnosisandtreatmentofdisordersoftheandrogenreceptor".)
Womenwithprimaryovarianinsufficiency(prematureovarianfailure)shouldbecounseledregardingthe
benefitsandrisksofpostmenopausalhormonetherapy.Foryoungwomen,thebenefitsandrisksof
postmenopausalhormonetherapyaremarkedlydifferentthanfora60yearoldwoman.Ingeneral,inwomen
ofreproductiveagewithhypoestrogenism,thebenefitsofhormonereplacementoutweightherisksof
myocardialinfarction,stroke,andbreastcancer.(See"Menopausalhormonetherapy:Benefitsandrisks"and
"Managementofspontaneousprimaryovarianinsufficiency(prematureovarianfailure)".)
Inwomenwithpolycysticovarysyndrome(PCOS),treatmentofhyperandrogenismisdirectedtoward
achievingthewoman'sgoal(eg,reliefofhirsutism,resumptionofmenses,fertility)andpreventingthelong
termconsequencesofPCOS(eg,endometrialhyperplasia,obesity,andmetabolicdefects).(See"Treatment
ofpolycysticovarysyndromeinadults".)
Inmostcases,functionalhypothalamicamenorrheacanbereversedbyweightgain,reductioninthe
intensityofexercise,orresolutionofillnessoremotionalstress.Forwomenwhowanttocontinueto
exercise,estrogenprogestinreplacementtherapyshouldbegiventothosenotseekingfertilitytoprevent
osteoporosisandheartdisease.Womenwhowanttobecomepregnantcanbetreatedwithexogenous
gonadotropinsorpulsatilegonadotropinreleasinghormone(GnRH),butincreasedcaloricintakeissimpler
andclearlypreferable.Furthermore,ifawomandoesnoteatenoughtohaveregularcyclesandnormal
fertility,hernutrientintakeduringahormonallyinducedpregnancyislikelytobeinadequatefornormalfetal
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growthanddevelopment.(See"Amenorrheaandinfertilityassociatedwithexercise".)
Thesameconsiderationsapplytowomenwithhypothalamicorpituitarydysfunctionthatisnotreversible
(eg,congenitalGnRHdeficiency).Forwomenwhowanttobecomepregnant,eitherexogenous
gonadotropinsorpulsatileGnRHcanbegiven.Inaretrospectivecomparativestudy,pulsatileGnRH
producedahigherrateofconception(96versus72percent)andalowerrateofhigherordermultiple
gestations[22].(See"Congenitalgonadotropinreleasinghormonedeficiency(idiopathichypogonadotropic
hypogonadism)".)
Advancesinassistedreproductivetechnologiesnowmakeitpossibleformanywomenwithprimary
amenorrheatoparticipateinreproduction.Forwomenwithgonadaldysgenesis,theuseofdonoroocytesand
theirpartners'spermwithinvitrofertilization(IVF)allowthewomentocarryapregnancyintheirownuterus
(see"Oocytedonationforassistedreproduction").Forwomenwithanabsentuterus,useoftheirown
oocytesinIVFandtransferoftheirembryostoagestationalcarriercanallowthesewomentohave
geneticallyrelatedchildren.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Absentorirregularperiods(TheBasics)"and"Patientinformation:
Latepuberty(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Absentorirregularperiods(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Primaryamenorrheaisdefinedastheabsenceofmensesbyage15years.
Themostcommoncauseofprimaryamenorrheaischromosomalanomaliesresultingingonadaldysgenesis
(50percent).(See'Etiology'above.)
Centralcausesofprimaryamenorrheaincludetumorsandinfiltrativedisordersofthehypothalamusand
pituitary,alongwithcongenitalgonadotropinreleasinghormone(GnRH)deficiencyandhyperprolactinemia.
However,functionalhypothalamicamenorrhea,inwhichhypothalamicGnRHpulsationisdisruptedbecause
oflowenergybalance,isbyfarthemostcommon.Togethertheseaccountforapproximately25percentof
cases.(See'Hypothalamicandpituitarydisease'above.)
Polycysticovarysyndromeusuallypresentsassecondaryamenorrhea,butcansometimespresentas
primaryamenorrhea.(See'Polycysticovarysyndrome'above.)
Anatomicabnormalities,includingabsenceorabnormalitiesoftheuterus,cervix,andvaginamakeup20
percentofprimaryamenorrhea.(See'Congenitalanatomiclesionsoftheuterusandvagina'above.)
Raredisordersofsteroidsynthesisandreceptorfunctionalsocauseprimaryamenorrhea.(See'Receptor
abnormalitiesandenzymedeficiencies'above.)
Theevaluationofprimaryamenorrheaincludesacarefulhistoryandexamforsignsofpubertaldevelopment
andthepresenceofnormalinternalstructures,folliclestimulatinghormone(FSH)leveltodeterminewhether
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thecauseiscentralorovarian,andfurtherdirecteddiagnostictestingbasedonhistoryandphysicalexam.
(See'Diagnosticevaluation'above.)
Treatmentofprimaryamenorrheaisdirectedatcorrectingtheunderlyingpathology(ifpossible),helpingthe
womantoachievefertility(ifdesired),andpreventionofcomplicationsofthediseaseprocess(eg,estrogen
replacementtopreventosteoporosis).Abriefsummaryoftreatmentoptionsispresentedinthistopic,while
thetreatmentofspecificdisordersisdiscussedindetailintheappropriatetopicreviews.(See'Treatment'
above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1. PracticeCommitteeoftheAmericanSocietyforReproductiveMedicine.Currentevaluationofamenorrhea.
FertilSteril200686:S148.
2. ReindollarRH,ByrdJR,McDonoughPG.Delayedsexualdevelopment:astudyof252patients.AmJ
ObstetGynecol1981140:371.
3. SantoroN,FilicoriM,CrowleyWFJr.Hypogonadotropicdisordersinmenandwomen:diagnosisand
therapywithpulsatilegonadotropinreleasinghormone.EndocrRev19867:11.
4. CrowleyWFJr,JamesonJL.Clinicalcounterpoint:gonadotropinreleasinghormonedeficiency:perspectives
fromclinicalinvestigation.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.Primaryamenorrheaasamanifestationofpolycysticovarian
syndromeinadolescents:auniquesubgroup?ArchPediatrAdolescMed2008162:521.
11. LegroRS,ArslanianSA,EhrmannDA,etal.Diagnosisandtreatmentofpolycysticovarysyndrome:an
EndocrineSocietyclinicalpracticeguideline.JClinEndocrinolMetab201398:4565.
12. BiasonLauberA,KonradD,NavratilF,SchoenleEJ.AWNT4mutationassociatedwithMllerianduct
regressionandvirilizationina46,XXwoman.NEnglJMed2004351:792.
13. LindnerTH,NjolstadPR,HorikawaY,etal.Anovelsyndromeofdiabetesmellitus,renaldysfunctionand
genitalmalformationassociatedwithapartialdeletionofthepseudoPOUdomainofhepatocytenuclear
factor1beta.HumMolGenet19998:2001.
14. GustafsonML,DonahoePK.Malesexdetermination:currentconceptsofmalesexualdifferentiation.Annu
RevMed199445:505.
15. VerpMS,SimpsonJL.Abnormalsexualdifferentiationandneoplasia.CancerGenetCytogenet1987
25:191.
16. BlagowidowN,PageDC,HuffD,MennutiMT.UllrichTurnersyndromeinanXYfemalefetuswithdeletion
ofthesexdeterminingportionoftheYchromosome.AmJMedGenet198934:159.
17. SahakitrungruangT,HuangN,TeeMK,etal.Clinical,genetic,andenzymaticcharacterizationofP450
oxidoreductasedeficiencyinfourpatients.JClinEndocrinolMetab200994:4992.
18. QuaynorSD,StradtmanEWJr,KimHG,etal.Delayedpubertyandestrogenresistanceinawomanwith
estrogenreceptorvariant.NEnglJMed2013369:164.
19. KrasnaIH,LeeML,SmilowP,etal.Riskofmalignancyinbilateralstreakgonads:theroleoftheY
chromosome.JPediatrSurg199227:1376.
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20. DeArceMA,CostiganC,GosdenJR,etal.FurtherevidenceconsistentwithYqhasanindicatorofriskof
gonadalblastomainYbearingmosaicTurnersyndrome.ClinGenet199241:28.
21. LukusaT,FrynsJP,KleczkowskaA,VandenBergheH.Roleofgonadaldysgenesisingonadoblastoma
inductionin46,XYindividuals.TheLeuvenexperiencein46,XYpuregonadaldysgenesisandtesticular
feminizationsyndromes.GenetCouns19912:9.
22. MartinKA,HallJE,AdamsJM,CrowleyWFJr.Comparisonofexogenousgonadotropinsandpulsatile
gonadotropinreleasinghormoneforinductionofovulationinhypogonadotropicamenorrhea.JClinEndocrinol
Metab199377:125.
Topic7403Version12.0

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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

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Majorcausesofamenorrheaduetoabnormalitiesinthe
hypothalamicpituitaryovarianaxis
Abnormality
Hypothalamic
dysfunction

Causes
Congenitalgonadotropinreleasinghormone(GnRH)deficiency
Functionalhypothalamicamenorrhea
Weightloss,eatingdisorders
Exercise
Stress
Severeorprolongedillness
HeterozygousmutationsFGFR1,PROKR2,KAL1

Inflammatoryorinfiltrativediseases
Braintumorseg,craniopharyngioma
Cranialirradiation
Traumaticbraininjury
OthersyndromesPraderWilli,LaurenceMoonBiedl
Pituitarydysfunction

Hyperprolactinemiaincludinglactotrophadenomas
Otherpituitarytumorsacromegaly,corticotrophadenomas(Cushing's
disease)
Othertumorsmeninigioma,germinoma,glioma
Geneticcausesofhypopituitarism
Emptysellasyndrome
Pituitaryinfarctorapoplexy

Ovariandysfunction

Polycysticovarysyndrome
Prematureovarianfailure(primaryovarianinsufficiency)
Surgical
Autoimmune,genetic,ovariantoxins,idiopathic

Other

Hyperthyroidism
Hypothyroidism
Diabetesmellitus
Exogenousandrogenuse

Graphic73995Version4.0

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Vaginalagenesiswithrudimentaryuterinehorns

Ofnote,incasesofvaginalagenesistheuterusmaybenormalor
exhibitavarietyofmalformations.
Reproducedwithpermissionfrom:LauferMR.Structuralabnormalitiesofthe
femalereproductivetract.In:Pediatricandadolescentgynecology,6thed,
EmansSJ,LauferMR,GoldsteinDP(Eds),LippincottWilliams&Wilkins,
Philadelphia2012.Copyright2012LippincottWilliams&Wilkins.
www.lww.com.
Graphic69536Version11.0

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Vaginalagenesiswithagenesisofthecervix

Reproducedwithpermissionfrom:LauferMR.Structuralabnormalitiesofthe
femalereproductivetract.In:Pediatricandadolescentgynecology,6thed,
EmansSJ,LauferMR,GoldsteinDP(Eds),LippincottWilliams&Wilkins,
Philadelphia2012.Copyright2012LippincottWilliams&Wilkins.
www.lww.com.
Graphic80263Version11.0

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Syntheticpathwaysforadrenalsteroidsynthesis

ThefirststepinadrenalsteroidsynthesisisthecombinationofacetylCoAand
squalenetoformcholesterol,whichisthenconvertedintopregnenolone.The
enclosedareacontainsthecoresteroidogenicpathwayutilizedbytheadrenalglands
andgonads.
17:17alphahydroxylase(CYP17,P450c17)17,20:17,20lyase(alsomediatedbyCYP17)
3:3betahydroxysteroiddehydrogenase21:21hydroxylase(CYP21A2,P450c21)11:11
betahydroxylase(CYP11B1,P450c11)18referstothetwostepprocessofaldosterone
synthase(CYP11B2,P450c11as),resultingintheadditionofanhydroxylgroupthatisthen
oxidizedtoanaldehydegroupatthe18carbonposition17R:17betareductase5R:5
alphareductaseDHEA:dehydroepiandrosteroneDHEAS:DHEAsulfateA:aromatase
(CYP19)SK:sulfokinaseSL:sulfotransferase.
Graphic70372Version3.0

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Sexualmaturityrating(Tannerstages)ofsecondarysexual
characteristics
BoysDevelopmentofexternalgenitalia
Stage1:Prepubertal
Stage2:Enlargementofscrotumandtestesscrotalskinreddensandchangesintexture
Stage3:Enlargementofpenis(lengthatfirst)furthergrowthoftestes
Stage4:Increasedsizeofpeniswithgrowthinbreadthanddevelopmentofglanstestesand
scrotumlarger,scrotalskindarker
Stage5:Adultgenitalia

GirlsBreastdevelopment
Stage1:Prepubertal
Stage2:Breastbudstagewithelevationofbreastandpapillaenlargementofareola
Stage3:Furtherenlargementofbreastandareolanoseparationoftheircontour
Stage4:Areolaandpapillaformasecondarymoundabovelevelofbreast
Stage5:Maturestage:projectionofpapillaonly,relatedtorecessionofareola

BoysandgirlsPubichair
Stage1:Prepubertal(thepubicareamayhavevellushair,similartothatofforearms)
Stage2:Sparsegrowthoflong,slightlypigmentedhair,straightorcurled,atbaseofpenisor
alonglabia
Stage3:Darker,coarserandmorecurledhair,spreadingsparselyoverjunctionofpubes
Stage4:Hairadultintype,butcoveringsmallerareathaninadultnospreadtomedialsurface
ofthighs
Stage5:Adultfemaleintypeandquantity,withhorizontalupperborder
Graphic55329Version7.0

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Tannerstagingofbreastdevelopmentingirls

Stage1:Prepubertal.
Stage2:Breastbudstagewithelevationofbreastandpapillaenlargementof
areola.
Stage3:Furtherenlargementofbreastandareolanoseparationoftheircontour.
Stage4:Areolaandpapillaformasecondarymoundabovelevelofbreast.
Stage5:Maturestagewithprojectionofpapillaonly,relatedtorecessionof
areola.
Graphic67072Version4.0

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Disclosures
Disclosures:CorrineKWelt,MDConsultant/AdvisoryBoards:Takeda[Ovarianfailureduetoanticancerdrugs(Leuprolideacetate
{Offlabeluseforovariansuppression,noconsultingrolerelatedtothisproduct})].RobertLBarbieri,MDNothingtodisclose.PeterJ
Snyder,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(Diagnostic
laboratorytesting)].MitchellGeffner,MDGrant/Research/ClinicalTrialSupport:EliLillyInc[growth(rhGH)]Genentech[growth
(rhGH)]NovoNordisk[growth(rhGH)]Pfizer[growth(rhGH)]Verartis[growth(longactingrhGH)]Ipsen[growth(rhIGFI)]Endo
Pharmaceuticals[puberty(GnRHagonist)].Consultant/AdvisoryBoards:DaiichiSankyo[T2DM(colesevelam)]EndoPharmaceuticals
[puberty(GnRHagonist)]Ipsen[growth(rhIGFI)]Pfizer[growth(rhGH)].OtherFinancialInterest:McGrawHill[pediatricendocrinology
(textbookroyalties)].KathrynAMartin,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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