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Evaluationandmanagementofsecondaryamenorrhea
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Evaluationandmanagementofsecondaryamenorrhea
Authors
CorrineKWelt,MD
RobertLBarbieri,MD

SectionEditors
WilliamFCrowley,Jr,MD
MitchellGeffner,MD

DeputyEditor
KathrynAMartin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jul2016.|Thistopiclastupdated:Jan12,2016.
INTRODUCTIONAmenorrhea(absenceofmenses)canbeatransient,intermittent,orpermanentconditionresulting
fromdysfunctionofthehypothalamus,pituitary,ovaries,uterus,orvagina(table1andtable2).Itisoftenclassifiedas
eitherprimary(absenceofmenarchebyage15years)orsecondary(absenceofmensesformorethanthreemonthsin
girlsorwomenwhopreviouslyhadregularmenstrualcyclesorsixmonthsingirlsorwomenwhohadirregularmenses
[1]).Missingasinglemenstrualperiodmaynotbeimportanttoassess,butamenorrhealastingthreemonthsormoreand
oligomenorrhea(fewerthanninemenstrualcyclesperyearorcyclelengthgreaterthan35days)requireinvestigation.The
etiologicanddiagnosticconsiderationsforoligomenorrheaarethesameasforsecondaryamenorrhea.
Theevaluationofsecondaryamenorrheaandabriefsummaryoftreatmentoptionsarereviewedhere.Theepidemiology
andcausesofsecondaryamenorrhea,andoverviewsofprimaryamenorrheaandabnormaluterinebleedingin
adolescents,arediscussedseparately.(See"Epidemiologyandcausesofsecondaryamenorrhea"and"Evaluationand
managementofprimaryamenorrhea"and"Abnormaluterinebleedinginadolescents:Evaluationandapproachto
diagnosis".)
APPROACHTOEVALUATIONOncepregnancyhasbeenruledout,alogicalapproachtowomenwitheitherprimary
orsecondaryamenorrheaistoconsiderdisordersbaseduponthelevelsofcontrolofthemenstrualcycle:hypothalamus,
pituitary,ovary,anduterus.Determiningthesiteofthedefectisimportantbecauseitdeterminestheappropriate
therapeuticregimen.Whilethemostcommoncausesofsecondaryamenorrheaarelikelytobefunctionalhypothalamic
amenorrheaorpolycysticovarysyndrome(PCOS),disorderswithananatomicorpathologiccausemustberuledout
[2,3].
RuleoutpregnancyApregnancytestisrecommendedasafirststepinevaluatinganywomanwithsecondary
amenorrhea.Measurementofserumbetasubunitofhumanchorionicgonadotropin(hCG)isthemostsensitivetest.
CommerciallyavailablehomekitsformeasurementofhCGinurineareimproving,buttheclinicianwhosuspects
pregnancyshouldorderaserumhCGmeasurement,evenifthewomanhadanegativehometest.
HistoryThewomanshouldbeaskedaboutanypastmedicalhistory,riskfactors,orsymptomsthatmightsuggestany
ofthemajorcausesofsecondaryamenorrheaoroligomenorrhea(table1).Thehistoryshouldincludethefollowing
questions:
Hastherebeenstress,changeinweight,diet,orexercisehabitsoristhereaneatingdisorderorillness(thatmight
resultinfunctionalhypothalamicamenorrhea)?(See"Epidemiologyandcausesofsecondaryamenorrhea",section
on'Functionalhypothalamicamenorrhea'.)
Isthewomantakinganydrugsthatmightcauseorbeassociatedwithamenorrhea?Thedrugmaybetakenfora
systemicillnessthatitselfcancausehypothalamicamenorrhea.Newlyinitiatedordiscontinuedoralcontraceptives
canbeassociatedwithseveralmonthsofamenorrhea,ascanandrogenicdrugslikedanazolorahighdose
progestin.OtherdrugscauseamenorrheabyincreasingserumPRLconcentrations,includingmetoclopramideand
antipsychoticdrugs.(See"Causesofhyperprolactinemia".)
Istherehirsutism,acne,andahistoryofirregularmenses(suggestiveofhyperandrogenism)?(See"Clinical
manifestationsofpolycysticovarysyndromeinadults".)
Aretheresymptomsofhypothalamicpituitarydisease,includingheadaches,visualfielddefects,fatigue,orpolyuria
andpolydipsia?(See"Causes,presentation,andevaluationofsellarmasses".)
Arethereanysymptomsofestrogendeficiency,includinghotflashes,vaginaldryness,poorsleep,ordecreased
libido?Thesesymptomsmaybeprominentwithprimaryovarianinsufficiency(POI).Incontrast,womenwith
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hypothalamicamenorrheadonotusuallyhavethesesymptoms,despitethepresenceofsimilarlylowserum
estradiolconcentrations.(See"Clinicalfeaturesanddiagnosisofautoimmuneprimaryovarianinsufficiency
(prematureovarianfailure)"and"Pathogenesisandcausesofspontaneousprimaryovarianinsufficiency(premature
ovarianfailure)".)
Hasthepatienthadgalactorrhea,whichsuggestshyperprolactinemia?
Isthereahistoryofobstetricalcatastrophe,severebleeding,dilatationandcurettage,orendometritisorother
infectionthatmighthavecausedscarringoftheendometriallining(Ashermansyndrome)?(See"Intrauterine
adhesions".)
PhysicalexamInadditiontothemedicalhistory,thephysicalexaminationmayprovidecluesaboutthepossiblecause
ofamenorrhea(table1).Theexaminationinwomenwithsecondaryamenorrheashouldincludemeasurementsofheight
andweight.Abodymassindex(BMI)greaterthan30kg/m2isobservedin50percentormoreofwomenwithPCOS,
dependingonthepopulationstudied.WomenwithaBMIlessthan18.5kg/m2mayhavefunctionalhypothalamic
amenorrheaduetoaneatingdisorder,strenuousexercise,orasystemicillnessassociatedwithweightloss.
Thepatientshouldalsobeexaminedforhirsutism,acne,striae,acanthosisnigricans,vitiligo,andeasybruisability.
Breastsshouldbeexaminedforevidenceofgalactorrhea,andavulvovaginalexamshouldlookforsignsofestrogen
deficiency.Parotidglandswellingand/orerosionofdentalenamelwouldsuggestaneatingdisorder(bulimianervosa).(See
"Clinicalmanifestationsofpolycysticovarysyndromeinadults"and"Bulimianervosaandbingeeatingdisorderinadults:
Medicalcomplicationsandtheirmanagement",sectionon'Physicalexamination'.)
InitiallaboratorytestingTheinitiallaboratoryevaluation(afterrulingoutpregnancy)forwomenwithsecondary
amenorrheashouldincludefolliclestimulatinghormone(FSH),serumprolactin[PRL],andthyroidstimulatinghormone
(TSH)totestforPOI,hyperprolactinemia,andthyroiddisease,respectively.Iftherehasbeenarecentmenstrualcycle,a
testondays2to4wouldbeappropriate,butinprolongedamenorrhea,thetestingcanbeperformedonarandomday.
Theclinicalutilityofthisapproach(measuringFSH,PRL,TSH)wasexaminedinastudyof127womenwithadultonset
amenorrhea[4].HighserumFSHconcentrations,highPRL,andabnormalTSHwereseenin10,7.5,and2.5percentof
patients,respectively,suggestingthatthisisareasonableapproachtoinitialtestinginwomenwithsecondary
amenorrhea.
Someclinicians,includingoneoftheeditors,suggestaddingserumestradiol(E2)asoneoftheinitialteststousewiththe
serumFSHtoevaluatethepituitaryovarianaxis.LowornormalE2thatisassociatedwithanelevatedFSHindicates
POI,whilelowornormalE2associatedwithFSHthatisnormalorlowsuggeststhepossibilityofsecondary(pituitaryor
hypothalamic)hypogonadism,eitherstructuralorfunctional.InterpretationoftheserumE2shouldalsotakeintoaccount
thatitmaybevariableinwomenwitheitherearlyPOIorfunctionalhypothalamicamenorrhea(duringrecovery).In
addition,asinglesamplemaynotreflectexposuretoE2overweeks.Forthisreason,E2statusshouldalsobeassessed
withaprogestinwithdrawaltestormeasurementofendometrialthicknessonpelvicultrasound.(See'Assessmentof
estrogenstatus'below.)
Ifthereisclinicalevidenceofhyperandrogenism(hirsutism,acne,scalphairloss[alopecia]),serumtotaltestosterone
shouldbemeasuredinadditiontotheinitiallaboratorytestslistedforwomenwithouthyperandrogenism.Manyclinicians
alsomeasureserumdehydroepiandrosteronesulfate(DHEAS)concentration.Inaddition,manymeasure17
hydroxyprogesteroneattheinitialvisittoruleoutnonclassic21hydroxylasedeficiency.(See'Highserumandrogen
concentrations'belowand"Evaluationofpremenopausalwomenwithhirsutism",sectionon'Biochemicaltesting'.)
FollowuptestingbaseduponinitialresultsFurtherevaluationdependsupontheresultsoftheinitialevaluation.
AssessmentofestrogenstatusAnassessmentofestrogenstatusshouldbedoneinsomecasestohelpwith
interpretingtheFSHvaluesandinotherstohelpguidetherapy(eg,hypoestrogenicpatientsneedestrogentherapyfor
preventionofboneloss,whilethosemakingestrogenneedendometrialprotectionwithprogesterone).Estrogenstatus
overtimecanbeassessedwithaprogestinwithdrawaltest(medroxyprogesterone10mgfor10days).Withdrawal
bleedingconfirmsthattherehasbeenendogenousestrogenexposure.Absenceofbleedingcanbeduetoeither
hypoestrogenismoranoutflowtractdisorder.(See'Normallaboratoryresultsandhistoryofuterineinstrumentation'
below.)

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Somecliniciansuseendometrialthicknessonpelvicultrasound(<4mmisconsistentwithhypoestrogenism),butthisis
notperformedroutinely[5,6].Wetypicallyperformtheprogestinwithdrawaltestinstead.
SerumE2measurementscanalsobeusedtoassessestrogenstatus,asdescribedabove.(See'Initiallaboratorytesting'
above.)
NormalorlowserumFSHconcentrationsWomenwithnormalserumPRLandTSH,alowornormalserumFSH
concentration,andnohistoryofuterineinstrumentationarelikelytohaveahypothalamicpituitarydisorderorPCOS.A
serumFSHconcentrationthatislowornormalisinappropriatelylowinthepresenceofalowserumestradiol
concentrationandindicatessecondary(hypogonadotropic)hypogonadism.Thisconstellationisoneofthemostcommon
outcomesoflaboratorytestinginwomenwithamenorrhea.
Althoughwedonotrecommendmeasuringserumluteinizinghormone(LH)levelasoneofourinitiallaboratorytests,itcan
behelpfulintheoccasionalpatientwhohasfeaturesofbothfunctionalhypothalamicamenorrheaandPCOS(eg,
amenorrheawithmildhirsutismand/oracne,butnormal/lowBMIandahistoryofexercise)[7,8].SerumFSH
concentrationsarelowornormalinbothfunctionalhypothalamicamenorrheaandPCOS.SerumFSHistypicallyhigher
thanLHinwomenwithfunctionalhypothalamicamenorrheainwomenwithPCOS,serumFSHistypicallylowerthanLH.
Inaddition,womenwithfunctionalhypothalamicamenorrheaarehypoestrogenic,whilewomenwithPCOSaretypically
wellestrogenized.(See'Assessmentofestrogenstatus'above.)
Hypothalamicamenorrheacanalsobeseenwithsystemicillnesssuchasceliacdiseaseandtype1diabetesmellitus.
Wethereforesuggestmeasurementoffastingbloodglucoseorglycatedhemoglobin(A1C)toruleoutdiabetesmellitusif
thepatienthaspolyuriaandpolydipsiaandserologicscreeningforceliacdiseasewithimmunoglobulinAantibodies
againsttissuetransglutaminase(tTGIgA)(see"Diagnosisofceliacdiseaseinchildren").Otherspecifictestsmaybe
done,dependingupontheclinicalhistory.Asanexample,ironstudiestotestforhemochromatosisshouldbeperformedif
thereisanappropriatefamilyhistoryorifthepatienthasmanifestationsofironoverload(bronzedskin,diabetesmellitus,
orunexplainedheartorliverdisease).(See"Approachtothepatientwithsuspectedironoverload".)
Magneticresonanceimaging(MRI)ofthesellaregionisindicatedinallwomenwithoutaclearexplanationfor
hypogonadotropichypogonadismsuchasweightloss,exercise,orstress,andinallwomenwhohavenormallaboratory
findingsandsymptomssuchasvisualfielddefects,headaches,orothersignsofhypothalamicpituitarydysfunction(see
"Epidemiologyandcausesofsecondaryamenorrhea").Incontrast,nofurthertestingisrequirediftheonsetofamenorrhea
occurredrecentlyoriseasilyexplainedandtherearenosymptomssuggestiveofotherdisease.
HighserumprolactinconcentrationPRLsecretioncanbetransientlyincreasedbystress.Asaresult,ifserum
PRLishigh,werecommendthatitberepeatedbeforepituitaryMRIisordered,particularlyinwomenwithmildelevations
(<50ng/mL[<50mcg/L]).Allofthesewomenshouldbescreenedforthyroiddiseasebecausehypothyroidismcan
sometimescausehyperprolactinemia.(See'AbnormalTSH'below.)
IfamildlyelevatedserumPRLisconfirmedtobehighonasecondsample,oriftheinitialsampleis>50ng/mL(>50
mcg/L),apituitaryMRIshouldbeperformedunlessaveryclearexplanationisfoundfortheelevation(eg,untreated
hypothyroidismorantipsychoticdruguse).Thegoalofimagingistoevaluatethepossibilityofahypothalamicorpituitary
lesion.Inthecaseofalactotrophadenoma,theimagewillallowdeterminationofwhetheritisamicroadenomaora
macroadenoma(1or>1cm,respectively).(See"Clinicalmanifestationsandevaluationofhyperprolactinemia",section
on'Laboratory/imagingtests'.)
HighserumFSHconcentrationAhighserumFSHconcentrationindicatesPOI,formerlyreferredtoaspremature
ovarianfailure.Itshouldbekeptinmind,however,thatintermittentfolliculardevelopmentdoesoccurinwomenwithPOI,
resultingintransientnormalizationofserumFSHconcentrations.Duringtimesofovarianinactivityandamenorrhea,FSH
ishighandserumestradiolislow,similartowhatisseeninnormalmenopause.Thepresenceofhotflashesand/or
vaginaldrynessissuggestiveofPOI,asthesesymptomsareuncommoninwomenwithmenstrualdisturbancesdueto
othercauses.(See"Clinicalmanifestationsandevaluationofspontaneousprimaryovarianinsufficiency(premature
ovarianfailure)".)
ForpatientswithoutanobviousprecipitatingfactorforPOI(gonadotoxicchemotherapyorradiotherapy),additionaltesting
toruleoutthemostcommonetiologiesofPOIshouldbeperformed,includingakaryotypetolookforTurnersyndrome
(includingmosaicism).Inwomenwith46,XXspontaneousPOI,wealsosuggesttestingforantiadrenalantibodiesandthe
fragileXpremutation.(See"ClinicalmanifestationsanddiagnosisofTurnersyndrome",sectionon'Diagnosis'and
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"Pathogenesisandcausesofspontaneousprimaryovarianinsufficiency(prematureovarianfailure)"and"Clinical
manifestationsandevaluationofspontaneousprimaryovarianinsufficiency(prematureovarianfailure)".)
NormallaboratoryresultsandhistoryofuterineinstrumentationWomenwithnormallaboratoryresultsanda
historyofuterineinstrumentationshouldbeevaluatedforintrauterineadhesions(Ashermansyndrome).Manyclinicians
startwithaprogestinchallenge(medroxyprogesteroneacetate10mgfor10days).Ifwithdrawalbleedingoccurs,an
outflowtractdisorderhasbeenruledout.
Ifbleedingdoesnotoccur,estrogenandprogestinmaybeadministered.Theendometriummaybeprimedwithoral
conjugatedestrogens0.625mg/dayortheirequivalent(oralestradiol1mg/day,transdermalestradiol0.05mg)for35days.
Aprogestinisthenaddedfromdays26to35(typicallymedroxyprogesterone10mg/day).Failuretobleeduponcessation
ofthistherapystronglysuggestsendometrialscarring.Inthissituation,ahysterosalpingogramordirectvisualizationofthe
endometrialcavitywithahysteroscopecanconfirmthediagnosisofintrauterineadhesions.(See"Intrauterineadhesions".)
HighserumandrogenconcentrationsDependingupontheclinicalpicture,ahighserumandrogenvaluemaybe
consistentwiththediagnosisofPCOS,orifitisextremelyhigh,itmayraisethequestionofanandrogensecretingtumor
oftheovaryoradrenalgland.Ofnote,manywomenwithPCOSpresentwithhyperandrogenism(acne,hirsutism)without
hyperandrogenemia.(See"Clinicalmanifestationsofpolycysticovarysyndromeinadults"and"Diagnosisofpolycystic
ovarysyndromeinadults",sectionon'Diagnosis'.)
Androgensecretingtumorsaretypicallyassociatedwiththerapidonsetofvirilizingsymptomsand,insomeadrenal
cases,withglucocorticoidexcess.Mostcliniciansinitiateevaluationforatumoriftheserumconcentrationoftestosterone
isgreaterthan150to200ng/dL(5.2to6.9nmol/L)orthatofDHEASisgreaterthan700mcg/dL(18.9mol/L).Thistopic
isdiscussedindetailseparately.(See"Evaluationofpremenopausalwomenwithhirsutism",sectionon'Biochemical
testing'and"Evaluationofpremenopausalwomenwithhirsutism",sectionon'Additionalevaluationforsevere
hyperandrogenemia'.)
AbnormalTSHBothhypoandhyperthyroidismcanbeassociatedwitholigooramenorrhea.Athirdgeneration
TSHassayisusuallyallthatisneededtodiagnosehypoorhyperthyroidism.Theonlyexceptionwouldbeincentral
hypothyroidism,wherefreeT4andTSHwillbothbelow.Insevereeatingdisorders,asuppressedTSHandfreeT4may
alsobeseen.
Insomecasesofprofoundhypothyroidism,theremaybeaslightincreaseinserumPRL(duetoapresumedincreasein
hypothalamicthyrotropinreleasinghormone[TRH],whichstimulatesbothTSHandPRLsecretion)[9](see'Highserum
prolactinconcentration'above).TreatmentofthehypothyroidismrestoresserumPRLtonormal.Therefore,apituitaryMRI
shouldnotbeperformedunlesshyperprolactinemiapersistsafterthepatientiseuthyroid.
MANAGEMENT
GoalsTheoverallgoalsofmanagementinwomenwithsecondaryamenorrheainclude:
Correctingtheunderlyingpathology,ifpossible
Helpingthewomantoachievefertility,ifdesired
Preventingcomplicationsofthediseaseprocess(eg,estrogenreplacementtopreventosteoporosis)
Abriefsummaryoftreatmentoptionsispresentedhere.Moredetaileddiscussionsarefoundseparately.
Hypothalamicamenorrhea
LifestylechangesFormanyathleticwomen,explainingtheneedforadequatecaloricintaketomatchenergy
expendituresometimesresultsinincreasedcaloricintakeorreducedexercise,followedbyresumptionofmenses.
However,manywomenarereluctanttomodifytheirbehaviors.(See"Amenorrheaandinfertilityassociatedwith
exercise",sectionon'Relativecaloricdeficiency'.)
Nonathleticwomenwhoareunderweightorwhoappeartohavenutritionaldeficienciesshouldhavenutritional
counseling,andtheycanbereferredtoamultidisciplinaryteamspecializingintheassessmentandtreatmentof
individualswitheatingdisorders.(See"Eatingdisorders:Overviewoftreatment".)
CognitivebehavioraltherapyCognitivebehavioraltherapy(CBT)maybeeffectiveforrestoringovulatorycycles
insomewomen.Inone20weekstudy,16womenwithfunctionalhypothalamicamenorrheawererandomlyassigned
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toreceiveCBT(16individualsessionswithaclinicianoverthe20weeks,focusingonhealthyeatingpatternsand
modifyingmaladaptiveattitudestowardseatingandweight)orobservation[10].SixofeightwomenintheCBTarm
resumedovulatorycycles,comparedwithtwoofeightintheobservationgroup.Althoughthisstudywassmall,it
suggeststhatCBTmaybeareasonableinterventionforwomenwithfunctionalhypothalamicamenorrhea.
Experimental(leptinadministration)Womenwithfunctionalhypothalamicamenorrheahaverelativeleptin
deficiency(see"Physiologyofleptin").Twostudiesofrecombinantleptintherapyhavereportedrestorationof
ovulatorycyclesinsomewomenwithfunctionalhypothalamicamenorrhea[11,12].Leptintherapyisexperimental
additionaldataarerequiredtobetterdetermineitseffectsonweight,thereproductiveaxis,bone,andotherendocrine
systems,aswellastoestablishitssafety.Metreleptin,ananalogofhumanleptin,isapprovedinsomecountries,
includingtheUnitedStates,fortreatmentofleptindeficiencyinpatientswithcongenitalgeneralizedoracquired
generalizedlipodystrophy.(See"Lipodystrophicsyndromes",sectionon'Leptinreplacement'.)
ManagementoflowbonedensityTheeffectofestrogentherapyonboneandtheapproachtowomenwith
exerciseassociatedamenorrheaarediscussedseparately.Anoverviewoflowbonedensityisalsoreviewed
separately.(See"Amenorrheaandinfertilityassociatedwithexercise",sectionon'Bonedensity'and"Evaluationand
treatmentofpremenopausalosteoporosis".)
HyperprolactinemiaThemanagementofwomenwithamenorrheaduetohyperprolactinemiadependsuponthecause
ofthehyperprolactinemiaandthepatientsgoals(eg,pursuingfertilityornot).Thistopicisreviewedindetailseparately.
(See"Managementofhyperprolactinemia".)
Primaryovarianinsufficiency(prematureovarianfailure)Womenwithprimaryovarianinsufficiency(POI)should
receiveestrogentherapyforpreventionofboneloss.Thiscanbeeitheranoralcontraceptive(ifthepatientishaving
intermittentovarianfunctionanddoesnotwishtobecomepregnant),orreplacementdosesofestrogenandprogestin.
Regimensforthelatterarereviewedseparately.(See"Managementofspontaneousprimaryovarianinsufficiency
(prematureovarianfailure)".)
IntrauterineadhesionsTherapyofAshermansyndrome(intrauterineadhesions)consistsofhysteroscopiclysisof
adhesionsfollowedbylongtermestrogenadministrationtostimulateregrowthofendometrialtissue[13].(See"Intrauterine
adhesions".)
PolycysticovarysyndromeTreatmentofhyperandrogenismisdirectedtowardachievingthewoman'sgoal(eg,relief
ofhirsutism,resumptionofmenses,fertility)andpreventingthelongtermconsequencesofpolycysticovarysyndrome
(PCOS),suchasendometrialhyperplasia,obesity,andmetabolicdisorders.ForwomenwithPCOS,thetypeoftherapy
dependsuponwhetherfertilityisdesired.(See"Treatmentofpolycysticovarysyndromeinadults".)
ThyroiddiseaseThemanagementofthyroiddisordersisreviewedseparately.(See"Treatmentofhypothyroidism"and
"Graves'hyperthyroidisminnonpregnantadults:Overviewoftreatment".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyond
theBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,and
theyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestfor
patientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducation
piecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevel
andarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicsto
yourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthe
keyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Absentorirregularperiods(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Absentorirregularperiods(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONSSecondaryamenorrheaisdefinedastheabsenceofmensesformorethan
threemonthsingirlsorwomenwhopreviouslyhadregularmenstrualcyclesorsixmonthsingirlsorwomenwho
previouslyhadirregularmenses.Astepwiseapproachtothehistory,physicalexamination,andlaboratorytestingusually
resultsinaspecificdiagnosis.(See'Approachtoevaluation'above.)
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Pregnancyisacommoncauseofsecondaryamenorrheaandshouldbeexcludedbasedonasensitivepregnancy
test(humanchorionicgonadotropin[hCG]).(See'Ruleoutpregnancy'above.)
Thehistoryandphysicalexammayprovidecluesaboutthepossiblecauseofamenorrhea(table1).(See'History'
above.)
Theinitiallaboratoryevaluation(afterrulingoutpregnancy)forwomenwithsecondaryamenorrheaisslightlydifferent
forthosewithandwithouthyperandrogenism.(See'Initiallaboratorytesting'above.)
Initiallaboratorytestingforwomenwithamenorrheawithouthyperandrogenismshouldincludeserumprolactin
(PRL),folliclestimulatinghormone(FSH),andthyroidstimulatinghormone(TSH)totestforhyperprolactinemia,
ovarianfailure,andthyroiddisease,respectively.(See'Initiallaboratorytesting'above.)
AssessmentofestrogenstatusisdoneinsomecasestohelpwithinterpretingtheFSHvalues,andinothers
tohelpguidetherapy(eg,hypoestrogenicpatientsneedestrogentherapyforpreventionofboneloss,while
thosemakingestrogenneedendometrialprotectionwithprogesterone).(See'Assessmentofestrogenstatus'
above.)
Ifthereisclinicalevidenceofhyperandrogenism(hirsutism,acne,scalphairloss[alopecia]),serumtotal
testosteroneshouldbemeasuredinadditiontotheinitiallaboratorytests.(See'Highserumandrogen
concentrations'above.)
Furtherevaluationdependsupontheresultsoftheinitialevaluation.Importantcategoriesincludenormalorlow
serumFSH,highFSH,highserumPRL,normallabresultswithahistoryofuterineinstrumentation,highserum
androgenconcentrations,andabnormalTSH.(See'Followuptestingbaseduponinitialresults'above.)
Detaileddiscussionsoftreatmentoptionsforeachdisorderarefoundelsewhere.Treatmentdependsuponthecause
ofthesecondaryamenorrheaandthepatientsgoals.Theoverallgoalsofmanagementinclude(see'Management'
above):
Correctingtheunderlyingpathology,ifpossible
Helpingthewomantoachievefertility,whendesired
Preventingcomplicationsofthediseaseprocess(eg,estrogenreplacementtopreventosteoporosis)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1.DeligeoroglouE,AthanasopoulosN,TsimarisP,etal.Evaluationandmanagementofadolescentamenorrhea.Ann
NYAcadSci20101205:23.
2.ReindollarRH,NovakM,ThoSP,McDonoughPG.Adultonsetamenorrhea:astudyof262patients.AmJObstet
Gynecol1986155:531.
3.PracticeCommitteeoftheAmericanSocietyforReproductiveMedicine.Currentevaluationofamenorrhea.Fertil
Steril200686:S148.
4.LauferMR,FloorAE,ParsonsKE,etal.Hormonetestinginwomenwithadultonsetamenorrhea.GynecolObstet
Invest199540:200.
5.NakamuraS,DouchiT,OkiT,etal.Relationshipbetweensonographicendometrialthicknessandprogestininduced
withdrawalbleeding.ObstetGynecol199687:722.
6.RebarRW,ConnollyHV.Clinicalfeaturesofyoungwomenwithhypergonadotropicamenorrhea.FertilSteril1990
53:804.
7.SumM,WarrenMP.Hypothalamicamenorrheainyoungwomenwithunderlyingpolycysticovarysyndrome.Fertil
Steril200992:2106.
8.WangJG,LoboRA.Thecomplexrelationshipbetweenhypothalamicamenorrheaandpolycysticovarysyndrome.J
ClinEndocrinolMetab200893:1394.
9.GoelP,NarangS,GuptaBK,etal.Evaluationofserumprolactinlevelinpatientsofsubclinicalandovert
hypothyroidism.JClinDiagnRes20159:BC15.
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10.BergaSL,MarcusMD,LoucksTL,etal.Recoveryofovarianactivityinwomenwithfunctionalhypothalamic
amenorrheawhoweretreatedwithcognitivebehaviortherapy.FertilSteril200380:976.
11.WeltCK,ChanJL,BullenJ,etal.Recombinanthumanleptininwomenwithhypothalamicamenorrhea.NEnglJ
Med2004351:987.
12.ChouSH,ChamberlandJP,LiuX,etal.Leptinisaneffectivetreatmentforhypothalamicamenorrhea.ProcNatl
AcadSciUSA2011108:6585.
13.BroomeJD,VancaillieTG.FluoroscopicallyguidedhysteroscopicdivisionofadhesionsinsevereAsherman
syndrome.ObstetGynecol199993:1041.
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GRAPHICS
Majorcausesofprimaryandsecondaryamenorrhea
Abnormality

Causes

Pregnancy
Anatomicabnormalities
Congenitalabnormalityinmllerian
development*

Isolateddefect
Androgeninsensitivitysyndrome
5alphareductasedeficiency

Congenitaldefectofurogenitalsinus
development*

Agenesisoflowervagina

Intrauterineadhesions

Ashermansyndrome

Imperforatehymen

Tuberculousendometritis
Disordersofthehypothalamicpituitaryovarianaxis
Hypothalamicdysfunction

Pituitarydysfunction

Ovariandysfunction

Gonadaldysgenesis(Turnersyndrome,46,XY*)
Othercausesofprimaryovarianinsufficiency

Other

*Presentasprimaryamenorrheaonly.
RefertoUpToDategraphicsonthemultiplecausesofhormonaldysfunction.
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Majorcausesofamenorrheaduetoabnormalitiesinthehypothalamic
pituitaryovarianaxis
Abnormality
Hypothalamic
dysfunction

Causes
IsolatedGnRHdeficiency
Functionalhypothalamicamenorrhea
Weightloss,eatingdisorders
Exercise(includingbutnotexclusively:running,balletdancing,figureskating,
gymnastics)
Stress
Severeorprolongedillness

Inflammatoryorinfiltrativediseases
Braintumorseg,craniopharyngioma
Cranialirradiation
Traumaticbraininjury
OthersyndromesPraderWilli,LaurenceMoonBiedl,leptinmutations
Pituitary
dysfunction

Hyperprolactinemia,includinglactotrophadenomas
Otherpituitarytumorsacromegaly,corticotrophadenomas(Cushing'sdisease)
Othertumorsmeninigioma,germinoma,glioma
Geneticcausesofhypopituitarism
Emptysellasyndrome
Pituitaryinfarctorapoplexy

Ovarian
dysfunction

Primaryovarianinsufficiency(prematureovarianfailure)

Other

Polycysticovarysyndrome

Turnersyndrome,fragileXpermutation,chemotherapyandradiotherapy,somatic
chromosomaldefects,autoimmune,idiopathic

Hyperthyroidism
Hypothyroidism
Diabetesmellitustypes1and2
Exogenousandrogenuse
GnRH:gonadotropinreleasinghormone.
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ContributorDisclosures
CorrineKWelt,MDNothingtodisclose.RobertLBarbieri,MDNothingtodisclose.WilliamFCrowley,Jr,MD
Consultant/AdvisoryBoards:JuniperPharmaceuticals[Endocrinology(Vaginalprogesterone)].OtherFinancialInterest:
Stockownership:JuniperPharmaceuticals[Endocrinology(Vaginalprogesterone)].MitchellGeffner,MD
Grant/Research/ClinicalTrialSupport:Genentech[growth(somatropin)]NovoNordisk[growth(somatropin)]Versartis
[growth(somatropin)].Consultant/AdvisoryBoards:Abbvie[puberty(leuprolide)]DaiichiSankyo[type2diabetes
(colesevelam)]Diurnal[congenitaladrenalhyperplasia(hydrocortisone)]Ipsen[growth(mecasermin)]Pfizer[growth
(somatropin)]Sandoz[growth(somatropin)]Tolmar[DSMBpuberty(leuprolide)].FinancialInterest:McGrawHill
[pediatricendocrinology(textbookroyalties)].KathrynAMartin,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.
AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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