7/28/2016 Clinicalmanifestationsanddiagnosisofgonadotrophandotherclinicallynonfunctioningpituitaryadenomas

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Clinicalmanifestationsanddiagnosisofgonadotrophandotherclinicallynonfunctioningpituitaryadenomas

Author SectionEditor DeputyEditor

PeterJSnyder,MD DavidSCooper,MD KathrynAMartin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2016.|Thistopiclastupdated:Jul20,2016.
INTRODUCTIONMostpatientswithpituitaryadenomaspresentwithsignsandsymptomsofhormonehypersecretion
(eg,hyperprolactinemia,growthhormone[GH]excess,orhypercortisolism).However,25to30percentofpituitary
adenomasareclinicallynonfunctioningor"silent"80to90percentofthesearegonadotrophadenomas,makingthemthe
mostcommontypeofpituitarymacroadenoma.Patientswithclinicallynonfunctioningadenomasmostoftenpresentwith
neurologicsymptomsduetomasseffects,whileothersmaybecompletelyasymptomaticandbefirstdetectedonan
imagingstudydoneforreasonsotherthanpituitarysymptomsordisease.Bythetimepatientspresent,ahighpercentage
hasbiochemicalevidenceofhypopituitarismduetocompressionofnormalpituitarycellsbythemacroadenoma.

Theclinicalfeatures,evaluation,anddiagnosisofclinicallynonfunctioningpituitaryadenomasarereviewedhere.The
treatmentofthesetumorsandanoverviewofincidentallydiscoveredsellarmasses(pituitaryincidentalomas)are
discussedseparately.(See"Treatmentofgonadotrophandotherclinicallynonfunctioningadenomas"and"Incidentally
discoveredsellarmasses(pituitaryincidentalomas)".)

OVERVIEWPituitaryadenomasareclassifiedbytheircelloforigin(lactotroph,gonadotroph,somatotroph,corticotroph,
andthyrotroph)andtheirsize(microadenomas<1cm,macroadenomas1cm).Mostadenomas(65to70percent)secrete
anexcessamountofhormoneincludingprolactin,growthhormone(GH),corticotropin(ACTH),orthyroidstimulating
hormone(TSH).(See"Causesofhyperprolactinemia"and"Causesandclinicalmanifestationsofacromegaly"and
"CausesandpathophysiologyofCushing'ssyndrome"and"TSHsecretingpituitaryadenomas".)

Theremainderofpituitaryadenomas(30to35percent)areclinicallynonfunctioningor"silent."Ofthese,80to90percent
aregonadotrophadenomas[1].Therearealsoclinicallynonfunctioningsomatotroph[2,3],lactotroph,andcorticotroph
adenomas[4],althoughthesearelesscommon.

Themajorityofgonadotrophadenomasareclinically"silent"anddifficulttoidentifybecausetheyarepoorlydifferentiated
andproduceandsecretehormonesinefficiently.Thegonadotropins,luteinizinghormone(LH)andfolliclestimulating
hormone(FSH),consistofacommonalphasubunit,andauniquebetasubunit.TSHandhCGalsoconsistofthe
commonalphasubunitandauniquebetasubunit.Thehormonessecretedbygonadotrophadenomasinorderof
decreasingfrequencyinclude:FSH,FSHbeta,alphasubunit,LH,andLHbeta[5].

Alphasubunitisnotbiologicallyactiveandalsodoesnotresultinaclinicalsymptomduetoitssecretion.However,itis
measuredtoevaluatepatientswithsellarmassestodetermineifthemassispituitaryinoriginandwhetherthereis
accompanyinghormonalhypersecretion.(See'Hormonehypersecretion'below.)

EPIDEMIOLOGYEstimatesoftheprevalenceofpituitaryadenomasarevariable,andareoftenbaseduponautopsyor
magneticresonanceimaging(MRI)series.Inareportfromasinglecommunityofover80,000inhabitantsinEngland,the
prevalenceofnonfunctioningpituitaryadenomas(thathadcometotheattentionofaclinician)was22per100,000[6].
Thisislikelyanunderestimateofthetrueprevalence,asmanynonfunctioningpituitaryadenomasgoundiagnoseduntil
theyareverylargeorareidentifiedonanimagingstudydoneforunrelatedreasons.

Gonadotrophadenomasarethoughttobemostcommoninmenoverage50years[1],andlesscommoninsimilaraged
women,butthiscouldbeduetodifficultyinrecognizinggonadotrophadenomasinthispopulation.Highserum
gonadotropinswouldbeunlikelytoraisesuspicionforagonadotrophadenomainawomanover50years,sincesheis
likelytohaveelevatedbasalserumgonadotropinconcentrationsfromthenormalmenopause[7].(See"Clinical
manifestationsanddiagnosisofmenopause".)

PATHOGENESISGonadotrophadenomas,likeotherpituitaryadenomas,appeartobetrueclonalneoplasms[8,9],but
themutationsthatcausethemarenotknown.Genesthathavebeenfoundtobeoverexpressedincludethepituitarytumor
transforminggene,Ki67,andFGFR[1012].Thematernallyexpressedgene3(MEG3)isunderexpressed[13].

CLINICALPRESENTATIONSNonfunctioningpituitaryadenomas(includingthemajorityofgonadotrophadenomas)
aredifficulttorecognizeclinicallyuntiltheyarelargeenoughtocausesymptomsduetoamasseffect.Thethreemost
commonpresentationsincludethefollowing(table1)[14]:

Neurologicsymptoms,mostcommonlyvisualsymptomslesscommonlyheadache.

Apituitarymassthatisdiscoveredasanincidentalfindingwhenanimagingprocedureisdoneforreasonsotherthan
pituitarysymptomsordisease.

Pituitaryhypofunctionduetocompressionofnormalpituitarytissuebytheadenoma.

Lesscommonly,patientswithgonadotrophadenomasmaypresentwithclinicalsyndromesduetohypersecretionof
folliclestimulatinghormone(FSH)or,lesscommonly,luteinizinghormone(LH)(ovarianhyperstimulationorprecocious
puberty).(See'Gonadotrophadenomas:Hormoneexcess'below.)

Neurologicsymptoms

VisualimpairmentImpairedvision,causedbysuprasellarextensionoftheadenomathatcompressestheoptic

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chiasm,isthemostcommonsymptomthatleadsapatientwithagonadotrophorotherclinicallynonfunctioningadenoma
toseekmedicalattention(image1)[1416].

Themostcommontypeofvisionimpairmentisvisualfieldloss,typicallydiminishedvisioninthetemporalfields
(superiortemporalquadrantanopsiaortemporalhemianopsia).Oneorbotheyesmaybeaffected.Inareviewofeight
seriesof1719patientswithclinicallynonfunctioningpituitaryadenomas,visualfielddisturbanceswerepresentin
798(46percent)[14],whileinasinglecenterseriesof295patients,thefrequencywasevenhigher(192of295,65
percent)[15].

Diminishedvisualacuity,whichoccurswhentheopticchiasmismoreseverelycompressed[16],wasreportedin
approximately30percentofpatientsinoneseries[15].Thus,anintrasellarlesionshouldbesuspectedwhenthereis
anyunexplainedpatternofvisualloss.

Theonsetofvisualdeficitsisusuallysogradualthatmanypatientsdonotseekophthalmologicconsultationfor
monthsorevenyears.

Diplopia,inducedbyoculomotornervecompressionresultingfromlateralextensionoftheadenomamayoccur,but
islesscommon,occurringinupto10to15percentofpatientsinseverallargeseries[14].

HeadacheHeadaches,thesecondmostcommonneurologicsymptom,occurin30to40percentofpatients
[14,15],andarethoughttobeduetosellarexpansion.Thereisnodistinguishingcharacteristicoftheheadaches,although
theyareusuallydiffuse.

OtherOtherlesscommonneurologicsymptomsinclude[16]:

Cerebrospinalfluidrhinorrhea,causedbyinferiorextensionoftheadenoma,rarelyoccursspontaneously[17].

Pituitaryapoplexy(suddenhemorrhageintoapituitarymacroadenoma),isalsorare.Itcausesexcruciatingheadache
andvisualimpairment[18].Thismayoccurspontaneously,buthasalsobeenreportedduringpregnancy,surgery,
andwithanticoagulantuse[19].Ithasbeendescribedlesscommonlyafterthyrotropinreleasinghormone(TRH)and
gonadotropinreleasinghormone(GnRH)stimulationtests[20,21]andwithgonadotropinreleasinghormone(GnRH)
agonisttherapyforprostatecancer[22,23].

IncidentalfindingonimagingThecommonuseofmagneticresonanceimaging(MRI)toevaluatesymptomsinthe
headorneckhasresultedintheincidentaldiscoveryofmanyintrasellarlesions.IntwoMRIseriesof100[24]and52[25]
normalvolunteers,10(10percent)and25(38percent),respectively,hadpreviouslyunsuspectedsellarlesions,butalmost
allwere<10mm.However,inonereviewofeightseriesofpituitary"incidentalomas"discoveredonMRI,68percentwere
macroadenomas[14].Thispercentageismuchhigherthanotherimagingseries,suggestingthatpatientslikelyhad
symptomssuggestiveofasellarmassthatledtotheimagingstudy.

Theevaluationandmanagementoftheseadenomasarereviewedseparately.(See"Incidentallydiscoveredsellarmasses
(pituitaryincidentalomas)".)

SymptomsduetohormonalabnormalitiesClinicallynonfunctioningadenomasoftenpresentwithevidenceof
hypopituitarism(usuallybiochemical).Onrareoccasions,gonadotrophadenomaspresentwithhormonalhypersecretion
causingaclinicalsyndromesuchasovarianhyperstimulationorprecociouspuberty.

Gonadotrophadenomas,likeallothertypesofpituitaryadenomas,canoccuraspartofthemultipleendocrineneoplasia
type1(MEN1)syndrome,arareheritabledisorderclassicallycharacterizedbyapredispositiontotumorsofthe
parathyroidglands,anteriorpituitary,andpancreaticisletcells.(See"Multipleendocrineneoplasiatype1:Definitionand
genetics",sectionon'MEN1gene'.)

HormonedeficienciesPatientswhopresentwithneurologicsymptoms,whencarefullyquestioned,may
acknowledgesymptomsofpituitaryhormonedeficienciesthatareduetocompressionofnonadenomatouscellsbythe
macroadenoma.However,thesesymptomstendtobenonspecific(fatigueandlethargy),andarenotusuallythereason
thatthepatientseeksmedicalattention.

Themostcommonclinicalhormonedeficiencyisimpairedsecretionofgonadotropinsresultinginhypogonadism.Ina
seriesof295patientswithnonfunctioningpituitaryadenomas,61of161men(38percent)hadlowserumgonadotropins,
resultinginlowserumtestosterone,decreasedlibido,anderectiledysfunction[15].Inthesamereport,33percentofthe
womenofreproductiveagehadmenstrualcycledisorders.

Higherpercentagesofhypopituitarismmaybedetectedbiochemicallyinpatientswithclinicallynonfunctioningadenomas.
Inareviewofeightseriesof1719patients,993(58percent)hadlaboratoryevidenceofpituitaryhormonedeficiency[14].
Themostcommonpituitaryhormonedeficiencieswere:

Growthhormone(GH)(87percent,220of252tested).TestingforGHdeficiencywaslesscommoninolderseries,
becauseGHdeficiencywasnotthoughttohaveimportantclinicalconsequences.(See"Growthhormonedeficiency
inadults".)

LH/FSH(hypogonadotropichypogonadism:1216of1699patientstested,72percent).

Corticotropin(ACTH)(secondaryadrenalinsufficiency:514of1699,30percent).

Thyroidstimulatinghormone(TSH)(centralhypothyroidism:402of1699,24percent).

Gonadotrophadenomas:HormoneexcessAlthoughgonadotrophadenomasareconsideredtobe
"nonfunctioning",mostdoproduceintactgonadotropinsortheirsubunits.However,theseadenomasaretypicallypoorly
differentiatedandinefficientproducers/secretorsanddonotraiseserumgonadotropinconcentrations.Thus,theyare
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usuallyclinically"silent"andcannotbedistinguishedfromotherclinicallynonfunctioningadenomasuntil
immunohistochemistryisperformedafterpituitarysurgery.

However,about35percentofgonadotrophadenomassecreteenoughLHorFSHtoraiseserumgonadotropinlevels[26],
butclinicalsyndromesduetohypersecretionofintactgonadotropinsarerare.However,severalsyndromeshavebeen
recognized(table2):

Ovarianhyperstimulationhasbeenreportedinpremenopausalwomen[2733]andrarelyinprepubertalgirls[34,35].
Theslight,butpersistently,elevatedserumFSHconcentrationsleadtorecruitmentofmultipledominantfollicles,
highserumestradiol(E2)concentrations(>500pg/mL),andthickenedendometriumonpelvicultrasound(potentially
suggestiveofendometrialhyperplasia).TheclinicalpictureissimilartoovarianstimulationwithexogenousFSH
whenadministeredforfertilitytreatment(image2).

Becausethemultiplefolliclesarenottriggeredtoovulate,womenpresentwithamenorrheaoroligomenorrhea[27
33],andprepubertalgirlspresentwithbreastdevelopment,vaginalbleeding,andabdominaldistension[34,35].If
pituitarysurgeryissuccessfulinremovingtheadenomabutnotremovingthenormalpituitary,gonadotropinsecretion
andovarianfunctionreturnstonormal[32,3639].

AnLHsecretingpituitaryadenomaresultinginprecociouspubertyhasbeenreportedintwoboys[40,41].

Althoughgonadotrophadenomasarethoughttooccurmostcommonlyinmiddleagedmen,clinicalfindingsdueto
hypersecretionofintactLHorFSHarerareinthisgroup.However,elevatedserumtestosteroneconcentrationdueto
hypersecretionofintactLH[5,42]andtesticularenlargementduetoFSHhypersecretionhavebeendescribed[43].

Themajorityofgonadotrophadenomasthatsecreteintactgonadotropinsoccurinmiddleagedadultsanddonotresultina
clinicalsyndrome.Inpostmenopausalwomen,forexample,agonadotrophadenomathatsecretesintactgonadotropins
wouldnotresultinaclinicalsyndrome,becausegonadotropinlevelsarealreadyhigh,andapostmenopausalovarycannot
bestimulatedtoproducefolliclesorestrogen.

Otherpituitaryadenomas:Hormoneexcess

In100consecutivepatientswithpituitaryadenomasthatweresurgicallyexcised,24hadsomatotrophadenomasby
immunochemicalstaining[3].Ofthese,eight(onethird)hadanelevatedIGF1concentrationbutnotevensubtle
manifestationsofacromegalyandcouldthereforebeconsideredtobeclinicallysilent.

ClinicallysilentcorticotrophadenomasmightberecognizablebyhigherplasmaACTHconcentrationsthanother
macroadenomas[4].

ElevatedprolactinMacroadenomasoftencompressthepituitarystalkandobstructthenormalinhibitory
hypothalamicinfluenceontheprolactinproducingcells,resultinginmodestlyelevatedserumprolactinconcentrations
(usually<100ng/mLbutsometimesashighas200ng/mL).Illustratedinonestudyof226patientswithnonfunctioning
macroadenomasaserumprolactinconcentration>94ng/mLreliablydistinguishedbetweenlactotrophadenomasand
nonfunctioningadenomas[44].Rarelygonadotrophadenomascosecreteprolactinandgonadotropins.

CharacteristicimagingfeaturesAsnoted,gonadotrophadenomasaregenerallyhormonallyinefficientasaresult,by
thetimeagonadotrophadenomaproducessupranormalserumconcentrationsofintactgonadotropinsortheirsubunits,it
isamacroadenoma(>1cm)byimaging(image1).MRIinapatientwithneurologicsymptomsusuallyshowsalarge
intrasellarmassthatisfrequentlyextendingoutsideofthesella.Elevationoftheopticchiasmorextensionintothe
cavernoussinusesorsphenoidsinuscanalsobedetected.MRIwithgadoliniumispreferredtocomputedtomography
(CT)becauseitprovidessuperiorresolutionofthemassanditsrelationtosurroundingstructures.(See'Pituitaryimaging'
belowand"Causes,presentation,andevaluationofsellarmasses",sectionon'MRI'.)

EVALUATION

GeneralapproachOurapproachtothepatientwhosepresentingsigns,symptomsorpriorimagingsuggestsasellar
massincludesthefollowing:

Takeadetailedhistoryandperformaphysicalexamination,recognizingthatanyvisualabnormalitiesorother
neurologicsymptomscouldrepresentasellarmass.Thehistoryshouldalsofocusonpossiblesymptomsof
hypopituitarism,includingsymptomsofhypogonadisminmen(fatigue,decreasedlibido,erectiledysfunction)and
women(amenorrhea/oligomenorrhea).(See'Neurologicsymptoms'aboveand'Hormonedeficiencies'above.)

Confirmthepresenceofasellarmassbyamagneticresonanceimaging(MRI)dedicatedtothisregionifnotalready
done.Ifasellarmassisconfirmed,assessitssize,relationshiptochiasmandcavernoussinuses.

Performvisualfieldandvisualacuitytesting.(See'Visualfieldtesting'below.)

Performbiochemicaltestingtodetectotherkindsofpituitaryadenomasbytheirexcessivehormonalsecretion(eg,
lactotroph,somatotrophand,lesscommonly,corticotrophadenomas).(See'Hormonehypersecretion'below.)

Testforexcessivesecretionofgonadotropinsandtheirsubunits,astheyarecharacteristicofgonadotroph
adenomas.Thisincludesmeasurementofserumluteinizinghormone(LH),folliclestimulatinghormone(FSH),and
alphasubunitconcentrations.(See'Hormonehypersecretion'below.)

Testalsoforpituitaryhypofunctionduetocompressionofnormalpituitarycellsbytheadenoma.(See
'Hypopituitarism'below.)

WeagreewithTheEndocrineSocietyClinicalPracticeGuidelinesonPituitaryIncidentalomaandsuggestMRI,visual

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fieldtesting,andbiochemicalevaluationforhormonehypersecretionandhypopituitarismforpatientswithpituitary
incidentalomasthatare>1cminsize[45].

PituitaryimagingWesuggestMRIfortheinitialimagingstudyforsuspectedadenomas,becauseofitssuperior
resolutionanditsabilitytodemonstratetheopticchiasm.MRIwithgadoliniumispreferredtocomputedtomography(CT)
becauseitprovidessuperiorresolutionofthemassanditsrelationtosurroundingstructures.MRIisalsoabletodetect
blood,therebypermittingrecognitionofhemorrhageintothepituitaryanddistinctionofananeurysmfromotherintrasellar
lesions(image1).

However,MRIwillnotdistinguishadenomatoustissuefromnormalpituitarytissue.MRIwillalsonotdistinguisha
gonadotrophadenomafromotherpituitarymacroadenomasandoftennotevenfromnonpituitarylesions.Thistopicis
reviewedinmoredetailseparately.(See"Causes,presentation,andevaluationofsellarmasses",sectionon'MRI'.)

VisualfieldtestingAllpatientswithsellarmasseselevatingtheopticchiasm,includingthosewhodenyvisual
symptoms,shouldundergobaselineHumphreyvisualfieldtestingandevaluationofvisualacuity.Aclinicianexperienced
inevaluatingvisualfieldabnormalities,suchasaneuroophthalmologist,shouldinterprettheresults.

HormonalevaluationHypothalamicpituitaryhormonalfunction(bothhyperandhypofunction)shouldbeevaluated
wheneveralargesellarmassisseenonMRItodetermineifitisapituitaryadenomathatcanberecognizedbyhormonal
hypersecretion.

HormonehypersecretionThepossibilityofhormoneexcessshouldbeevaluatedtodetectthepresenceof
functioningpituitaryadenomas.Wethereforesuggestmeasurementsof:

SerumLH,FSH,andalphasubunit(gonadotrophadenoma).Incountrieswherethyrotropinreleasinghormone(TRH)
isavailable,theFSHandalphasubunitresponsetoTRHwillalsoidentifyagonadotrophadenoma(table2).

Serumprolactin(lactotrophadenomas).

Insulinlikegrowthfactor1(IGF1)(somatotrophadenomas).

24hoururinefreecortisol(corticotrophadenomas).

GonadotrophadenomasInpostmenopausalwomen,asellarmasscanberecognizedasagonadotroph
adenomabiochemicallybythecombinationofanelevatedFSHand/oralphasubunitandasuppressedLH(table2)[16].

Alphasubunitvaluesshouldbeinterpretedinthecontextofnormalvaluesforthespecificpatientgroupandspecific
assay.Theserumconcentrationofuncombinedalphasubunitiselevatedinwomeninthreephysiologicconditions[4648]:

Menopause,inwhichthegonadotrophcellsofthepituitaryhypersecreteintactFSHandLHanduncombinedalpha
subunit
Pregnancy,inwhichtheplacentasecretesintacthCGanduncombinedalphasubunit
Ovarianstimulationwithexogenousgonadotropins(hCG,hMG,FSH)forthetreatmentofinfertility

Inmen,asellarmasscanberecognizedasagonadotrophadenomabyasupranormalbasalserumFSHconcentration
(figure1)[49].Anelevatedconcentrationofalphasubunitindicatesagonadotrophadenoma,thyrotrophadenoma,orless
differentiatedglycoproteinadenoma.AsupranormalresponseofintactFSHoralphasubunittoTRHalsoindicatesa
gonadotrophadenoma.

SomatotrophadenomasAlthoughsomatotrophadenomastypicallycausethecharacteristicclinicalsyndrome
ofacromegaly,somearesilent.Theycanresultinexcessivehormonalsecretionwithouteventhesubtlestclinicalchange
("clinicallysilent")ornoclinicalorbiochemicalevidenceofexcessivehormonalsecretion("totallysilent").In100
consecutivepatientswithpituitaryadenomasthatweresurgicallyexcised,24hadsomatotrophadenomasby
immunochemicalstaining[3].Ofthese,eight(onethird)hadanelevatedIGF1concentrationbutnotevensubtle
manifestationsofacromegalyandcouldthereforebeconsideredtobeclinicallysilent.

CorticotrophadenomasCorticotrophmacroadenomas,unlikemicroadenomas,donottypicallycause
Cushing'ssyndrome.However,theymaybeclinicallysilentandrecognizablebyelevatedplasmaadrenocorticotropic
hormone(ACTH)concentrations[4].

LactotrophadenomasMostlactotrophmacroadenomasproduceveryhighserumprolactinconcentrations,but
someareinefficientanddonot.Thesemaybedifficulttodistinguishfromothersellarlesionsthatcompressthepituitary
stalkandobstructthenormalinhibitoryhypothalamicinfluenceontheprolactinproducingcells,resultinginmodestly
elevatedserumprolactinconcentrations(usually<100ng/mLbutsometimesashighas200ng/mL).Illustratedinone
studyof226patientswithnonfunctioningmacroadenomas,aserumprolactinconcentration>94ng/mLreliably
distinguishedbetweenlactotrophadenomasandnonfunctioningadenomas[44].Rarely,gonadotrophadenomascosecrete
prolactinandgonadotropins.

Findingevidenceforagonadotrophadenomawillnotinfluencethechoiceoftherapy(whichispituitarysurgery),but
recognizingthatasellarmassisagonadotrophadenomaandnotanonpituitarylesioncouldinfluencetherouteofsurgery
andcanbeusedasatumormarkerbywhichtoevaluatetheresultofsurgeryandforsubsequentmonitoring.Finding
evidenceforoneoftheothertypesofclinicallynonfunctioningadenomascouldalsoopenthepossibilityofpharmacologic
treatment.

HypopituitarismDeficientsecretionofotherpituitaryhormonesoftenoccursduetothemasseffectofthetypically
largegonadotrophadenomasandshouldalwaysbeinvestigated.Additionaltestingforhormonedeficienciesdueto
compressionofthenormalpituitarytissueincludesmeasurementoftheserumconcentrationsof:

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8AMcortisol

Thyroxine(T4)(ifelevated,measurethyroidstimulatinghormone[TSH]toevaluatethepossibilityofathyrotroph
adenoma)

Testosteroneinmen

Estradiol(E2)inwomenofpremenopausalagewithamenorrhea

Theinterpretationofpituitarytestsandthediagnosisofhypopituitarismarediscussedseparately.(See"Diagnostictesting
forhypopituitarism".)

DIAGNOSISAdefinitivediagnosisofagonadotrophadenomaismadebypathologicevaluationoftheexcisedtissue.
Pituitaryadenomastypicallyshoweffacementofthenormallobularpituitaryarchitectureandinsteadshowamonomorphic
populationofcellsandlossofthenormalreticulinpattern.Immunochemicalstainingispositiveforfolliclestimulating
hormone(FSH)beta,luteinizinghormone(LH)beta,and/oralphasubunit.

However,thediagnosisofagonadotrophadenomacanbemadewithareasonabledegreeofcertaintypreoperativelyina
patientwithalargesellarmassinthefollowingcircumstances:

Serumprolactinconcentrationlessthan100ng/mL.(See'Elevatedprolactin'above.)

Nosymptomsorsignsofacromegalyandserumconcentrationofinsulinlikegrowthfactor1(IGF1)notelevated.
(See"Causesandclinicalmanifestationsofacromegaly"and"Diagnosisofacromegaly".)

NosignsorsymptomsofCushing'ssyndromeand24hoururinecortisolexcretionnotelevated.(See"Epidemiology
andclinicalmanifestationsofCushing'ssyndrome"and"EstablishingthediagnosisofCushing'ssyndrome".)

Inmen,elevatedbasalserumconcentrationsofintactFSHand/orofalphasubunit(table2).Incountrieswhere
thyrotropinreleasinghormone(TRH)isavailable,anFSHresponsetoTRH.Rarely,elevatedLHandtestosterone.
ElevatedFSHandLHandsubnormaltestosteroneindicateprimaryhypogonadism.(See'Primaryhypogonadism'
below.)

Inpremenopausalwomen,irregularmenses,elevatedFSHandestradiol(E2),lowLH,andonpelvicultrasound,
massivepolycysticovariesandthickenedendometrium.

Inpostmenopausalwomen,elevatedFSHand/oralphasubunitandlowLH(table2).ElevationofbothFSHandLH
likelyindicateonlynormalpostmenopausalgonadotropinsecretion.

DIFFERENTIALDIAGNOSISPituitaryadenomasarethemostcommoncauseofalargesellarmass,butother
causesincludecraniopharyngioma,meningioma,malignanttumors,Rathke'scleftcysts,andhypophysitis.Anysellar
masses>1cmmaypresentwithneurologicsymptomssimilartoclinicallynonfunctioningpituitaryadenomas.Evaluation
ofalargesellarmassincludesimagingwithmagneticresonanceimaging(MRI),andhormonalevaluationforpituitary
hyperandhypofunction.(See"Causes,presentation,andevaluationofsellarmasses",sectionon'Evaluationofasellar
mass'and"Incidentallydiscoveredsellarmasses(pituitaryincidentalomas)",sectionon'Lesions10mmorlarger'.)

LactotrophmacroadenomaAsnotedabove,alargesellarmassassociatedwithaprolactinconcentration<100ng/mL
probablydoesnotrepresentalactotrophadenoma.Largesellarmassescompressthepituitarystalkandtherebyprevent
dopaminefromthehypothalamusfromreachingthepituitary,thusdecreasingnormalinhibitionofprolactinsecretion.The
resultisamildelevationofserumprolactin(>20ng/mL[eg,higherthannormal]butusually<100ng/mL)[44,50].(See
'Elevatedprolactin'aboveand"Clinicalmanifestationsandevaluationofhyperprolactinemia".)

PrimaryhypogonadismLongstandingprimaryhypogonadismcancausegonadotrophcellhypertrophyandtherefore
overallpituitaryenlargement[51,52]and,inthisway,aswellasinelevatedgonadotropinconcentrations,issimilarto
gonadotrophadenomas.Primaryhypogonadismdiffersfromgonadotrophadenomasinseveralways:

Thedegreeofpituitaryenlargementismuchless
Bothluteinizinghormone(LH)andfolliclestimulatinghormone(FSH)areelevated
NeitherintactgonadotropinsnortheirsubunitsrespondtoTRH[49,53]

PolycysticovarysyndromeWomenwithpolycysticovarysyndrome(PCOS)havemultiplefolliclesonpelvic
ultrasound.However,theyaresmallandarrangedinaperipheralpattern,unlikethefolliclesdescribedinthecasesof
ovarianhyperstimulationsyndromeinwomenwithgonadotrophadenomas(image2)[2733].Inaddition,serumFSH
concentrationsarelowinPCOS,notnormalorhighastheywouldbewithagonadotrophadenoma.Lastly,aserum
estradiol(E2)concentration>500pg/mLshouldstronglyraisethesuspicionthatthemultipleovariancystsareduetoa
gonadotrophadenoma(image2)ratherthanPCOS.

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Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicsto
yourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthe
keyword(s)ofinterest.)

Basicstopics(see"Patientinformation:Pituitaryadenoma(TheBasics)")
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SUMMARY

Approximately25to30percentofallpituitaryadenomasareclinicallynonfunctioningor"silent"80to90percentof
thesearegonadotrophadenomas.(See'Overview'above.)

Clinicallynonfunctioningadenomas(includinggonadotrophadenomas)usuallycometoclinicalattentionwhenthey
becomelargeenoughtocauseneurologicsymptomssuchasimpairedvision(diminishedvisioninthetemporalfields
[bitemporalhemianopsia],anddiminishedvisualacuity),nonspecificheadaches,diplopia,cerebrospinalfluid
rhinorrhea,andpituitaryapoplexy.(See'Neurologicsymptoms'above.)

Somearedetectedasanincidentalfindingwhenanmagneticresonanceimaging(MRI)isdoneforotherreasons.
(See'Incidentalfindingonimaging'above.)

Approximately60percentofpatientsatthetimeofdiagnosishavehypopituitarismduetocompressionbythe
macroadenoma,butthehormonaldeficienciesareusuallynotthepresentingsymptomsandnotdetecteduntilthe
patientundergoesbiochemicaltesting.(See'Hormonedeficiencies'above.)

Gonadotrophadenomasaredifficulttorecognizebecausetheysecretevariablyandinefficiently,andtheresulting
productsoftendonotcauseaclinicalsyndrome.Only35percentsecreteenoughintactfolliclestimulatinghormone
(FSH)oralphasubunittoraisetheirserumlevels.Uncommonly,however,gonadotrophadenomashypersecreteFSH
inpremenopausalwomenandcauseovarianhyperstimulationand,rarely,somehypersecreteluteinizinghormone
(LH)inaboyormanandcauseanincreasedserumtestosteroneconcentration.(See'Gonadotrophadenomas:
Hormoneexcess'above.)

Evaluationofthepatientwhopresentswithneurologicsymptomssuggestiveofaclinicallynonfunctioningsellar
massshouldinclude(see'Evaluation'above):

PituitaryMRI

Visualfieldtesting

Biochemicaltestingforhormonehypersecretion(serumprolactin,insulinlikegrowthfactor1[IGF1],and24
hoururinefreecortisol)(see'Gonadotrophadenomas:Hormoneexcess'above)

Testingforhypopituitarism8AMcortisol,thyroxine(T4)(plusTSHiftheT4ishigh),testosteroneinmenand
estradiol(E2)inwomenofpremenopausalage,FSH,LHandalphasubunit(see'Hypopituitarism'above)

Thediagnosisofagonadotrophadenomaislikelyifthereisalargesellarmass,noclinicalorbiochemicalevidence
ofacromegalyorCushing'ssyndrome,theserumprolactinis<100ng/mL,andtheconcentrationsofgonadotropins
arecharacteristic(table2).(See'Diagnosis'above.)

Inmen,characteristicpatternsareanelevatedserumFSHand/oralphasubunitor,rarely,elevatedLHand
testosterone.

Inwomenofpremenopausalage,characteristicpatternsareanelevatedFSH,withorwithoutalphasubunit,
andE2.

Inpostmenopausalwomen,thepatternsareanelevatedFSHand/oralphasubunitbutlowLH.Thediagnosisis
confirmedifhistologicexaminationoftheexcisedtissueshowsapituitaryadenomaandimmunocytochemical
stainingshowsstainingforFSH,LH,and/oralphasubunit.

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GRAPHICS

Clinicalpresentationsofgonadotrophadenomas

Neurologicsymptoms(mostcommon)
Visualimpairment

Headache

Other(includingdiplopia,seizures,andCSFrhinorrhea)

Incidentalfinding
Whenanimagingprocedureisperformedbecauseofanunrelatedsymptom

Hypopituitarism
Biochemicalevidence(mostcommon)

Clinicalsymptoms(lesscommon,butincludeoligomenorrheaoramenorrheainwomen,decreasedlibido
and/orerectiledysfunctioninmen)

Clinicalsyndromesduetohormonalhypersecretion(rare)
OvarianhyperstimulationwhenFSHissecretedexcessivelyinapremenopausalwoman

PrematurepubertywhenintactLHissecretedinaprepubertalboy

CSF:cerebrospinalfluidFSH:folliclestimulatinghormoneLH:luteinizinghormone.

Graphic58084Version3.0

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MRIimagesofalargesellarmassafteradministrationof
gadolinium

(A)MRIimage,takenaftertheadministrationofgadolinium,depictinga
coronalviewofalargesellarmassthatwasagonadotrophadenoma.Thearrow
pointstothemass.Thearrowheadpointstotheopticchiasmelevatedbythe
mass.
(B)MRIimage,takenaftertheadministrationofgadolinium,depictinga
sagittalviewofthesamelargesellarmassthatwasagonadotrophadenoma.
Thearrowpointstothemass.

MRI:magneticresonanceimaging.

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Hormonalcriteriaforthediagnosisofgonadotrophadenomas*(anyone
orcombinationofthefollowing)

Men Women
Supranormalbasalserum FSH FSHbutnotLH
concentrations
alpha,LHbeta,orFSHbeta AnysubunitrelativetointactFSH
subunits andLH
LHandtestosterone

SupranormalresponsetoTRH FSH FSH

LH LH
LHbeta(mostcommon) LHbeta(mostcommon)

FSH:folliclestimulatinghormoneLH:luteinizinghormoneTRH:thyrotropinreleasinghormone.
*Assumingthepatienthasasellarmass.
Assumingthepatientdoesnothaveahistoryofprimaryhypogonadism.

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Transvaginalultrasoundexaminationoftheovary(A)
anduterus(B)ofa39yearoldwomanwitha
gonadotrophadenomaandFSHhypersecretion

(A)Multiplecysts(arrows)withinthesubstanceoftheovary.
(B)Inacoronalviewoftheuterus(outlinedbynarrowarrows),amarkedly
thickened,echogenicendometrialstripe(widearrows)isshown.
Scale:distancebetweenopenarrows=10mm.

FSH:folliclestimulatinghormone.

Reproducedwithpermissionfrom:DjerassiA,CoutifarisC,WestVA.Gonadotroph
adenomainapremenopausalwomansecretingfolliclestimulatinghormoneand
causingovarianhyperstimulation.JClinEndocrinolMetab199580:591.
http://jcem.endojournals.org/.Copyright1995TheEndocrineSociety.

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Hormonelevelsinmenwithagonadotroph
adenoma

BasalserumconcentrationsofFSH,LH,freealphasubunit,andLH
subunitin38menwithclinicallynonfunctioninggonadotroph
macroadenomas.Eachdotrepresentsthevalueinasinglepatient
thehorizontallinesencompasstherangesofanagematchedcontrol
group.Seventeenmenhadsupranormallevelsofatleastoneintact
hormoneorsubunit,andfourhadmultiplebasalelevations.

FSH:folliclestimulatinghormoneLH:luteinizinghormone.

Datafrom:DaneshdoostL,GennarelliTA,BasheyHM,etal.Identificationof
gonadotrophadenomasinmenwithclinicallynonfunctioningadenomasbythe
luteinizinghormonebetasubunitresponsetothyrotropinreleasing
hormone.JClinEndocrinolMetab199377:1352.

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ContributorDisclosures
PeterJSnyder,MDGrant/Research/ClinicalTrialSupport:AbbVie[Hypogonadism(Testosteronegel)]NovoNordisk
[Growthhormone(Somatropin)]Novartis[Cushing's(Pasireotide)]Cortendo[Cushing's].Consultant/AdvisoryBoards:
Novartis[Cushing'ssyndrome(Pasireotide)]Pfizer[Acromegaly(Pegvisomant)].Watson[Testosterone(Testosterone
gel)].DavidSCooper,MDNothingtodisclose.KathrynAMartin,MDNothingtodisclose.

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.
AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.

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