7/28/2016 Treatmentofhypopituitarism

OfficialreprintfromUpToDate
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Treatmentofhypopituitarism

Author SectionEditor DeputyEditor

PeterJSnyder,MD DavidSCooper,MD KathrynAMartin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2016.|Thistopiclastupdated:Nov03,2015.
INTRODUCTIONTreatmentofpatientswithhypopituitarismisthesumofthetreatmentsofeachoftheindividual
pituitaryhormonaldeficienciesdetectedwhenapatientwithapituitaryorhypothalamicdiseaseistested.Thetreatments
ofadrenocorticotropichormone(ACTH),thyroidstimulatinghormone(TSH),andluteinizinghormone(LH)andfollicle
stimulatinghormone(FSH)deficienciesareinmanywaysthesameasthetreatmentsofprimarydeficienciesofthe
respectivetargetglands,butinotherwaystheydiffer.Boththesimilaritiesanddifferenceswillbehighlightedbelow.
Treatmentofgrowthhormone(GH)deficiencyisuniquetohypopituitarism.

Thespecificsoftherapyforhypopituitarismwillbereviewedhere.Thecauses,clinicalmanifestations,anddiagnosisof
hypopituitarism,aswellasGHdeficiencyinadultsandthemanagementofindividualhormonedeficiencies,arereviewed
inmoredetailelsewhere.(See"Causesofhypopituitarism"and"Clinicalmanifestationsofhypopituitarism"and
"Diagnostictestingforhypopituitarism"and"Growthhormonedeficiencyinadults".)

IMPORTANCEOFTREATMENTOnereasontooptimizetreatmentisthatinaretrospectivestudyof344patientswho
hadhypopituitarismafterpituitarysurgery,thelongtermmortalitywasaboutdoublethatofthegeneralpopulation[1].Most
oftheexcessmortalitywasduetocerebrovasculardisease.Therelationshipbetweenthehypopituitarismandtheexcess
mortalityremainsunknown,andwedonotknowifevenoptimaltreatmentwillimprovemortality.

ACTHDEFICIENCYTheprimaryconsequenceoflackofadrenocorticotropichormone(ACTH)iscortisoldeficiency.
Asaresult,treatmentconsistsoftheadministrationofhydrocortisoneorotherglucocorticoidinanamountandtimingto
mimicthenormalpatternofcortisolsecretion.Becausethereisnotesttoassesstheadequacyofthereplacement,the
optimalreplacementglucocorticoidandtheoptimaldosesarenotknown.Mostauthoritiesrecommendreplacementwith
hydrocortisonebecausethatisthehormonetheadrenalglandsmakenormally,butotherspreferprednisoneor
dexamethasonefortheirlongerdurationsofaction.

PreparationanddoseMostauthoritiesrecommendhydrocortisonedosesof15to25mg/day[2,3]becausethose
dosesaresimilartodailyproductionrates[4].Patientswhoaremoreseverelydeficientorweighmoretendtoneeddoses
attheupperendofthisrangeandviceversa.Somepatients,however,needevenlargerdosestoavoidseverely
symptomaticadrenalinsufficiency,andotherscangetbyonsmalleramounts.

Althoughdividingthetotaldailydoseintotwooreventhreedoses(withthelargestdoseonarisinginthemorning)makes
sensephysiologically,manypatientscannotremembertotakedosesinthemiddleoftheday.Forthem,takingtheentire
doseinthemorningispreferabletomissingdoses.Mostpatientsfeelwellwhiletakingtheentiredoseonarising.

Whateverthepreparationanddose,thepatientshouldbeinstructedintheneedforlargerdosesintimesofillness,
surgery,procedures,andotherstresses.(See"Treatmentofadrenalinsufficiencyinadults",sectionon'Illnessor
surgery'.)

Aninadequatedosemayresultinpersistence(orrecurrence)ofthesymptomsofcortisoldeficiency,whileanexcessive
dosecanleadtosymptomsofcortisolexcessandtoboneloss.Smalldeviationsfromtheoptimaldoseareusuallynot
detectedclinically.(See"EpidemiologyandclinicalmanifestationsofCushing'ssyndrome".)

AssessmentofdoseadequacyUnlikereplacementofotherpituitarydependenthormones,notestsexistto
assessobjectivelytheadequacyofthereplacementofcortisol,asillustratedbythefollowing:

PlasmaACTHmeasurementscannotbeusedbecausethevaluesarelowornormalbeforetreatment.

Serumcortisolvaluesvaryfrompatienttopatientandinrelationtothetimingofthehydrocortisonedose.Thiswas
illustratedinastudyof46patientswithadrenalinsufficiency,23ofwhomhadasecondarycause,stablytreatedwith
cortisoneacetate.Clinicalstatuswasassessedbyaquestionnaireandserumcortisolconcentrationswere
measuredforuptoeighthoursafterasingle25mgdose[5].Inthe33patientsconsideredclinicallywellreplaced,
theserumcortisolconcentrationsnotonlyfluctuatedfromameanmaximumofapproximately21mcg/dLattwo
hoursafterthedoseto7mcg/dLsixhoursafterthedose,butvariedamongindividualsfrom<14to>28mcg/dLat
twohoursandfromvirtuallyundetectableto>14mcg/dLatsixhours.

Salivarycortisolvaluesalsofluctuatewidelyanddonotcorrelatewithplasmavaluesafteroraladministration.Ina
studyof27patientswithadrenalinsufficiency,18ofwhomhadasecondarycauseandwhowerestablytreatedwith
hydrocortisone,plasmaandsalivarycortisolweremeasuredforeighthoursafterasingle20mgdose[6].The
plasmaconcentrationfluctuatedwidelyamongpatients,asshownbyafivefoldvariationinareaunderthecurve.The
correlationbetweenplasmaandsalivarycortisolwaspoor.

Urinarycortisolvaluesarealsounreliablefortheassessmentofadequacyofhydrocortisonedose.

Consequently,theadequacyofthereplacementdosemustbejudgedbythemuchcruderclinicalcriteria,suchas
Cushingoidfeatureswhenthedoseisquiteexcessiveandsymptomsofadrenalinsufficiencywhenthedoseisquite
insufficient.

SubjectivehealthstatusAsapossibleconsequenceofthelackofobjectivemeasurementsoftheadequacyofthe
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replacementdoseofglucocorticoid,patientswithadrenalinsufficiencyhaveimpairedselfreportedhealthstatusby
standardquestionnaires.Thiswasillustratedinastudyof210patientswithadrenalinsufficiency,78ofwhomhada
secondarycause.Scoresonvalidatedselfassessmentquestionnaires(SF36,GeissenComplaintList,andHospital
AnxietyandDepressionScale)weresignificantlyimpairedcomparedwithageandgendermatchedcontrols[7].Patients
withsecondaryinsufficiencywereslightlymoreimpairedthanthosewithprimaryadrenalinsufficiency.

UnmaskingdiabetesinsipidusAnunusualsideeffectofglucocorticoidreplacementistheunmaskingofunderlying
centraldiabetesinsipidus,leadingtomarkedpolyuria[8].Correctionofcortisoldeficiencycanincreasethebloodpressure
andrenalbloodflowand,inpatientswithpartialdiabetesinsipidus,reducethesecretionofvasopressin.Allofthese
effectsincreaseurineoutput.(See"Urineoutputindiabetesinsipidus".)

NeedformineralocorticoidcoverageUnlikethesituationinprimaryadrenalinsufficiency,mineralocorticoid
replacementisrarelynecessaryinhypopituitarism.AngiotensinIIandpotassium,notACTH,arethemajorregulatorsof
aldosteronesecretion[9,10].

AdrenalandrogenreplacementInwomenwithsecondaryadrenalinsufficiency,exogenousdehydroepiandrosterone
(DHEA)replacementappearstohaveamodestbeneficialeffectonpsychologicalwellbeing.However,theavailabledata
arefromwomenwithpanhypopituitarism,whohavecombinedadrenalandovarianandrogendeficiency.Nodataare
availableinwomenwithisolatedACTHdeficiency,averyraredisorder.(See"Dehydroepiandrosteroneanditssulfate",
sectionon'Useinadrenalinsufficiency'and"Treatmentofadrenalinsufficiencyinadults",sectionon'Androgen
replacement(DHEA)'.)

TSHDEFICIENCYThyroidstimulatinghormone(TSH)deficiencyresultsinthyroxine(T4)deficiencyandistreated
withT4(levothyroxine).Thefactorsthatinfluencedosingaresimilartothoseofprimaryhypothyroidism.However,
treatmentofsecondaryhypothyroidismdiffersintwoways:

T4shouldnotbeadministereduntiladrenalfunction,includingadrenocorticotropichormone(ACTH)reserve,has
beenevaluatedandeitherfoundtobenormalortreated.Inapatientwithcoexistinghypothyroidismand
hypoadrenalism,treatmentofthehypothyroidismalonemayincreasetheclearanceofthelittlecortisolthatis
produced,therebyincreasingtheseverityofthecortisoldeficiency.

MeasurementofserumTSHcannotbeusedasaguidetotheadequacyofT4replacementtherapy.Wesuggest
startingwithaweightbasedT4doseof1.6mcg/kg.WhiletheAmericanThyroidAssociation(ATA)recommends
adjustingthedosetomaintaintheserumfreeT4concentrationintheupperhalfofthereferencerange,theauthorof
thistopicsuggestsalowergoal:maintainingtheserumT4orfreeT4valuesinthemiddleofthenormalrange.(See
"Centralhypothyroidism",sectionon'Treatment'.)

LHANDFSHDEFICIENCYTreatmentofluteinizinghormone(LH)andfolliclestimulatinghormone(FSH)deficiency
dependsupongenderandwhetherornotfertilityisdesired.

MenTestosteronereplacementisindicatedinmenwhohavesecondaryhypogonadismandwhoarenotinterestedin
fertility.Thechoiceoftreatmentdoesnotdifferfromthatinmenwithprimaryhypogonadism,butserumLHmeasurements
cannotbeusedtomonitortheadequacyoftherapy.Thiscanbeachievedbymeasurementsofserumtestosterone.(See
"Testosteronetreatmentofmalehypogonadism",sectionon'Monitoring'.)

Menwithsecondaryhypogonadismwhowishtobecomefertilecanbetreatedwithgonadotropinsiftheyhavepituitary
diseaseorwitheithergonadotropinsorgonadotropinreleasinghormone(GnRH)iftheyhavehypothalamicdisease.(See
"Inductionoffertilityinmenwithsecondaryhypogonadism".)

WomenWomenwithhypogonadismduetopituitarydisease,whoarenotinterestedinfertility,shouldbetreatedwith
estrogenprogestinreplacementtherapy.Thegoaloftreatmentisnotthesameasinpostmenopausalwomen,inwhomthe
goalistogiveestrogenandprogestinonlyifnecessarytorelievehotflushes.Instead,thegoaloftreatmentofwomenof
premenopausalageissimilartothatofreplacementofthyroxine(T4)andcortisol,ie,toreplacethemissinghormonesas
physiologicallyaspossible.

Towardthisend,wesuggesttreatmentwithestradiol(theestrogenthehumanovariessecrete)transdermally,soestradiol
isabsorbedintothesystemiccirculation(aswhenitissecretedbytheovaries).Womenwithanintactuterusmustalso
takeaprogestintoavoidtheriskofendometrialhyperplasiaorcarcinoma.Wealsorecommendthatestradiolbe
administeredcyclicallywithprogesteroneoraprogestin.Someclinicianssuggestatraditionalregimenofestradiolondays
1through25ofeachmonthandprogesteroneondays16through25ofeachmonth.Thegoalsaretoachievebotha
normallatefollicularserumestradiolconcentrationandmensesthepatientconsidersnormal.Anotherregimenistogive
transdermalestradiolcontinuouslythroughoutthemonth,withprogestinaddeddays1to10ofthecalendarmonth.This
regimenissimilartothatusedfortreatmentofprematureovarianfailure(see"Managementofspontaneousprimary
ovarianinsufficiency(prematureovarianfailure)").Forwomenwhodevelopcyclicmoodchanges(premenstrualsyndrome)
oneitheroftheseregimens,acontinuousdailyregimenofbothestrogenandalowerdoseofprogestinisusuallybetter
tolerated.(See"Epidemiologyandpathogenesisofpremenstrualsyndromeandpremenstrualdysphoricdisorder".)

Womenwithsecondaryhypogonadismwhowishtobecomefertileshouldbeofferedovulationinduction.Womenwith
GnRHdeficiencyarecandidatesforeithergonadotropintherapyorpulsatileGnRH,whilethosewithgonadotropin
deficiencyduetopituitarydiseasearecandidatesonlyforgonadotropintherapy.(See"Congenitalgonadotropinreleasing
hormonedeficiency(idiopathichypogonadotropichypogonadism)",sectionon'Treatment'and"Overviewofovulation
induction",sectionon'Gonadotropintherapy'.)

AndrogenreplacementSerumandrogenconcentrationsinwomenwithhypopituitarism,particularlythosewithboth
gonadotropinandadrenocorticotropichormone(ACTH)deficiency,aresignificantlylowerthanthoseinnormalcontrol
women[11].Adrenalandrogenreplacementisdiscussedabove.Theroleofexogenoustestosteronetherapyinthese
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womenisunclear,butisnotrecommended.

Theeffectofexogenoustestosteronetherapyinwomenwithandrogendeficiencyduetohypopituitarismwasaddressedin
astudyof51suchpatientstakingexogenousestrogenorally.Testosteronereplacementwasadministeredtransdermally
atdosesof150to300mcg/dayforoneyear,resultinginserumfreetestosteroneconcentrationsinthenormalrangeand
increasedmeanbonemineraldensityofthehipandradius,butnotthespine[12].Othereffectsincludedanincreasein
fatfreemassandthighmusclearea,andimprovementsinsomeaspectsofmood,sexualfunction,andqualityoflife,as
assessedbyquestionnaires.Onethirdofthewomenreceivingtestosteronedevelopedacnebutnopatientsdeveloped
hirsutismorotherhyperandrogenicsideeffects.Androgentherapyinwomenisdiscussedinmoredetailseparately.(See
"Overviewofandrogendeficiencyandtherapyinwomen"and"Sexualdysfunctioninwomen:Management",sectionon
'Androgens'.)

GROWTHHORMONEDEFICIENCYWedonotrecommendrecombinanthumangrowthhormone(GH)asroutine
treatmentforallpatientswithadultonsetGHdeficiency.TheavailabilityofseveralrecombinanthumanGHpreparations
(Humatrope,Nutropin,Serostim,andGenotropin)fortreatingadultswithGHdeficiencyallowsclinicianstoprescribethis
treatment.PatientswithGHdeficiencyacquiredasanadultmust,tobereimbursedbyinsurancecompaniesintheUnited
States,meetatleasttwocriteriafortherapy:alowinsulinlikegrowthfactor1(IGF1)concentrationorapoorGH
responsetoatleasttwostandardstimuli,andhypopituitarismduetopituitaryorhypothalamicdamage.Thecriteriaare
differentinchildreninwhomGHisrequiredfornormalgrowth.(See"Treatmentofgrowthhormonedeficiencyinchildren".)

ManypatientswhodevelopGHdeficiencyinadulthoodhaveunfavorableserumlipidprofiles,increasedbodyfat,
decreasedmusclemass,decreasedbonemineraldensity,andadiminishedsenseofwellbeing.Thereissubstantial
evidencethatGHtreatmentinthesepatientsincreasesmusclemassandreducesbodyfat.Theevidencefor
improvementinbonemineraldensityisgoodformenbutnotforwomen.Theevidenceconcerningimprovementsinthe
senseofwellbeing,musclestrength,andserumlipidsisconflicting.(See"Growthhormonedeficiencyinadults".)

PROLACTINDEFICIENCYTheonlyknownpresentationofprolactindeficiencyistheinabilitytolactateafterdelivery,
forwhichthereiscurrentlynoavailabletreatment.Recombinanthumanprolactin(rhPRL),althoughnotcommercially
available,hasbeenusedexperimentallyinanopenlabelpilotstudyoffivewomenwithprolactindeficiencydueto
Sheehansyndromeorothercauses[13].Prolactindeficiencywasdefinedasbaselineorpeakserumprolactinlevels
belowthenormalrangefortheirpostpartumdateandproductionoflessthan8mLofmilkperday.Subcutaneous
administrationofrhPRLevery12hoursfor28daysincreasedmeanmilkproductionfrom3.41.6mLto66.18.3mLper
day.

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:Panhypopituitarism(TheBasics)")

SUMMARYTreatmentofpatientswithhypopituitarismisthesumofthetreatmentsofeachoftheindividualpituitary
hormonaldeficienciesdetectedwhenapatientwithapituitaryorhypothalamicdiseaseistested.Thetreatmentsof
adrenocorticotropichormone(ACTH),thyroidstimulatinghormone(TSH),andluteinizinghormone(LH)andfollicle
stimulatinghormone(FSH)deficienciesareinmanywaysthesameasthetreatmentsofprimarydeficienciesofthe
respectivetargetglands,butinotherwaystheydiffer.

LackofACTHprimarilycausescortisoldeficiency.Treatmentconsistsoftheadministrationofhydrocortisoneor
otherglucocorticoidinanamountandtimingtomimicthenormalpatternofcortisolsecretion.(See'ACTH
deficiency'above.)

TSHdeficiency,whichresultsinthyroxine(T4)deficiency,istreatedwithT4(levothyroxine).T4shouldnotbe
administereduntiladrenalfunction,includingACTHreserve,hasbeenevaluatedandeitherfoundtobenormalor
treated.MeasurementofserumTSHcannotbeusedasaguidetotheadequacyofT4replacementtherapy.We
suggeststartingwithaweightbasedT4doseof1.6mcg/kg.ThedoseshouldbeadjustedaccordingtotheserumT4
orfreeT4values,aimingtomaintaintheminthemiddlepartofthenormalrange.(See'TSHdeficiency'aboveand
"Centralhypothyroidism",sectionon'Treatment'.)

Inmenwithgonadotropindeficiency,testosteronereplacementisindicatedwhenfertilityisnotdesired.Menwith
secondaryhypogonadismwhowishtobecomefertilemaybetreatedwithgonadotropinsiftheyhavepituitary
diseaseorwitheithergonadotropinsorgonadotropinreleasinghormone(GnRH)iftheyhavehypothalamicGnRH
deficiency.(See'Men'above.)

Inwomenwithgonadotropindeficiency,treatmentdependsuponthepatient'sgoals.Estradiolandprogestin
replacementsareindicatedinwomenwhoarenotpursuingfertility,whilegonadotropinorpulsatileGnRHtherapy
maybeusedwhenovulationinductionandfertilityarethegoal.(See'Women'above.)

Theroleofandrogentherapyinwomenwithhypopituitarismisunclear.(See'Adrenalandrogenreplacement'above
and'Androgenreplacement'above.)

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REFERENCES

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insufficiencyonstandardtherapybasedoncrosssectionalanalysis.JClinEndocrinolMetab200792:3912.
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implication.ArchInternMed1969123:409.
9.ShibataH,OgishimaT,MitaniF,etal.RegulationofaldosteronesynthasecytochromeP450inratadrenalsby
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10.WhitePC.Disordersofaldosteronebiosynthesisandaction.NEnglJMed1994331:250.
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200186:561.
12.MillerKK,BillerBM,BeauregardC,etal.Effectsoftestosteronereplacementinandrogendeficientwomenwith
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Endocrinol(Oxf)201073:645.

Topic6640Version13.0

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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