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Treatment of hypopituitarism - UpToDate

OfficialreprintfromUpToDate
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Treatmentofhypopituitarism
Author: PeterJSnyder,MD
SectionEditor: DavidSCooper,MD
DeputyEditor: KathrynAMartin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2016.|Thistopiclastupdated:Nov03,2015.
INTRODUCTIONTreatmentofpatientswithhypopituitarismisthesumofthetreatmentsofeachoftheindividualpituitaryhormonaldeficiencies
detectedwhenapatientwithapituitaryorhypothalamicdiseaseistested.Thetreatmentsofadrenocorticotropichormone(ACTH),thyroidstimulating
hormone(TSH),andluteinizinghormone(LH)andfolliclestimulatinghormone(FSH)deficienciesareinmanywaysthesameasthetreatmentsof
primarydeficienciesoftherespectivetargetglands,butinotherwaystheydiffer.Boththesimilaritiesanddifferenceswillbehighlightedbelow.
Treatmentofgrowthhormone(GH)deficiencyisuniquetohypopituitarism.
Thespecificsoftherapyforhypopituitarismwillbereviewedhere.Thecauses,clinicalmanifestations,anddiagnosisofhypopituitarism,aswellasGH
deficiencyinadultsandthemanagementofindividualhormonedeficiencies,arereviewedinmoredetailelsewhere.(See"Causesofhypopituitarism"
and"Clinicalmanifestationsofhypopituitarism"and"Diagnostictestingforhypopituitarism"and"Growthhormonedeficiencyinadults".)
IMPORTANCEOFTREATMENTOnereasontooptimizetreatmentisthatinaretrospectivestudyof344patientswhohadhypopituitarismafter
pituitarysurgery,thelongtermmortalitywasaboutdoublethatofthegeneralpopulation[1].Mostoftheexcessmortalitywasduetocerebrovascular
disease.Therelationshipbetweenthehypopituitarismandtheexcessmortalityremainsunknown,andwedonotknowifevenoptimaltreatmentwill
improvemortality.
ACTHDEFICIENCYTheprimaryconsequenceoflackofadrenocorticotropichormone(ACTH)iscortisoldeficiency.Asaresult,treatmentconsists
oftheadministrationofhydrocortisoneorotherglucocorticoidinanamountandtimingtomimicthenormalpatternofcortisolsecretion.Becausethere
isnotesttoassesstheadequacyofthereplacement,theoptimalreplacementglucocorticoidandtheoptimaldosesarenotknown.Mostauthorities
recommendreplacementwithhydrocortisonebecausethatisthehormonetheadrenalglandsmakenormally,butotherspreferprednisoneor
dexamethasonefortheirlongerdurationsofaction.
PreparationanddoseMostauthoritiesrecommendhydrocortisonedosesof15to25mg/day[2,3]becausethosedosesaresimilartodaily
productionrates[4].Patientswhoaremoreseverelydeficientorweighmoretendtoneeddosesattheupperendofthisrangeandviceversa.Some
patients,however,needevenlargerdosestoavoidseverelysymptomaticadrenalinsufficiency,andotherscangetbyonsmalleramounts.
Althoughdividingthetotaldailydoseintotwooreventhreedoses(withthelargestdoseonarisinginthemorning)makessensephysiologically,many
patientscannotremembertotakedosesinthemiddleoftheday.Forthem,takingtheentiredoseinthemorningispreferabletomissingdoses.Most
patientsfeelwellwhiletakingtheentiredoseonarising.
Whateverthepreparationanddose,thepatientshouldbeinstructedintheneedforlargerdosesintimesofillness,surgery,procedures,andother
stresses.(See"Treatmentofadrenalinsufficiencyinadults",sectionon'Illnessorsurgery'.)
Aninadequatedosemayresultinpersistence(orrecurrence)ofthesymptomsofcortisoldeficiency,whileanexcessivedosecanleadtosymptomsof
cortisolexcessandtoboneloss.Smalldeviationsfromtheoptimaldoseareusuallynotdetectedclinically.(See"Epidemiologyandclinical
manifestationsofCushing'ssyndrome".)
AssessmentofdoseadequacyUnlikereplacementofotherpituitarydependenthormones,notestsexisttoassessobjectivelytheadequacyof
thereplacementofcortisol,asillustratedbythefollowing:
PlasmaACTHmeasurementscannotbeusedbecausethevaluesarelowornormalbeforetreatment.
Serumcortisolvaluesvaryfrompatienttopatientandinrelationtothetimingofthehydrocortisonedose.Thiswasillustratedinastudyof46
patientswithadrenalinsufficiency,23ofwhomhadasecondarycause,stablytreatedwithcortisoneacetate.Clinicalstatuswasassessedbya
questionnaireandserumcortisolconcentrationsweremeasuredforuptoeighthoursafterasingle25mgdose[5].Inthe33patientsconsidered
clinicallywellreplaced,theserumcortisolconcentrationsnotonlyfluctuatedfromameanmaximumofapproximately21mcg/dLattwohours
afterthedoseto7mcg/dLsixhoursafterthedose,butvariedamongindividualsfrom<14to>28mcg/dLattwohoursandfromvirtually
undetectableto>14mcg/dLatsixhours.
Salivarycortisolvaluesalsofluctuatewidelyanddonotcorrelatewithplasmavaluesafteroraladministration.Inastudyof27patientswith
adrenalinsufficiency,18ofwhomhadasecondarycauseandwhowerestablytreatedwithhydrocortisone,plasmaandsalivarycortisolwere
measuredforeighthoursafterasingle20mgdose[6].Theplasmaconcentrationfluctuatedwidelyamongpatients,asshownbyafivefold
variationinareaunderthecurve.Thecorrelationbetweenplasmaandsalivarycortisolwaspoor.
Urinarycortisolvaluesarealsounreliablefortheassessmentofadequacyofhydrocortisonedose.
Consequently,theadequacyofthereplacementdosemustbejudgedbythemuchcruderclinicalcriteria,suchasCushingoidfeatureswhenthe
doseisquiteexcessiveandsymptomsofadrenalinsufficiencywhenthedoseisquiteinsufficient.
SubjectivehealthstatusAsapossibleconsequenceofthelackofobjectivemeasurementsoftheadequacyofthereplacementdoseof
glucocorticoid,patientswithadrenalinsufficiencyhaveimpairedselfreportedhealthstatusbystandardquestionnaires.Thiswasillustratedinastudy
of210patientswithadrenalinsufficiency,78ofwhomhadasecondarycause.Scoresonvalidatedselfassessmentquestionnaires(SF36,Geissen
ComplaintList,andHospitalAnxietyandDepressionScale)weresignificantlyimpairedcomparedwithageandgendermatchedcontrols[7].Patients
withsecondaryinsufficiencywereslightlymoreimpairedthanthosewithprimaryadrenalinsufficiency.
UnmaskingdiabetesinsipidusAnunusualsideeffectofglucocorticoidreplacementistheunmaskingofunderlyingcentraldiabetesinsipidus,
leadingtomarkedpolyuria[8].Correctionofcortisoldeficiencycanincreasethebloodpressureandrenalbloodflowand,inpatientswithpartial
diabetesinsipidus,reducethesecretionofvasopressin.Alloftheseeffectsincreaseurineoutput.(See"Urineoutputindiabetesinsipidus".)
NeedformineralocorticoidcoverageUnlikethesituationinprimaryadrenalinsufficiency,mineralocorticoidreplacementisrarelynecessaryin
hypopituitarism.AngiotensinIIandpotassium,notACTH,arethemajorregulatorsofaldosteronesecretion[9,10].
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AdrenalandrogenreplacementInwomenwithsecondaryadrenalinsufficiency,exogenousdehydroepiandrosterone(DHEA)replacementappears
tohaveamodestbeneficialeffectonpsychologicalwellbeing.However,theavailabledataarefromwomenwithpanhypopituitarism,whohave
combinedadrenalandovarianandrogendeficiency.NodataareavailableinwomenwithisolatedACTHdeficiency,averyraredisorder.(See
"Dehydroepiandrosteroneanditssulfate",sectionon'Useinadrenalinsufficiency'and"Treatmentofadrenalinsufficiencyinadults",sectionon
'Androgenreplacement(DHEA)'.)
TSHDEFICIENCYThyroidstimulatinghormone(TSH)deficiencyresultsinthyroxine(T4)deficiencyandistreatedwithT4(levothyroxine).The
factorsthatinfluencedosingaresimilartothoseofprimaryhypothyroidism.However,treatmentofsecondaryhypothyroidismdiffersintwoways:
T4shouldnotbeadministereduntiladrenalfunction,includingadrenocorticotropichormone(ACTH)reserve,hasbeenevaluatedandeitherfound
tobenormalortreated.Inapatientwithcoexistinghypothyroidismandhypoadrenalism,treatmentofthehypothyroidismalonemayincreasethe
clearanceofthelittlecortisolthatisproduced,therebyincreasingtheseverityofthecortisoldeficiency.
MeasurementofserumTSHcannotbeusedasaguidetotheadequacyofT4replacementtherapy.WesuggeststartingwithaweightbasedT4
doseof1.6mcg/kg.WhiletheAmericanThyroidAssociation(ATA)recommendsadjustingthedosetomaintaintheserumfreeT4concentrationin
theupperhalfofthereferencerange,theauthorofthistopicsuggestsalowergoal:maintainingtheserumT4orfreeT4valuesinthemiddleof
thenormalrange.(See"Centralhypothyroidism",sectionon'Treatment'.)
LHANDFSHDEFICIENCYTreatmentofluteinizinghormone(LH)andfolliclestimulatinghormone(FSH)deficiencydependsupongenderand
whetherornotfertilityisdesired.
MenTestosteronereplacementisindicatedinmenwhohavesecondaryhypogonadismandwhoarenotinterestedinfertility.Thechoiceof
treatmentdoesnotdifferfromthatinmenwithprimaryhypogonadism,butserumLHmeasurementscannotbeusedtomonitortheadequacyof
therapy.Thiscanbeachievedbymeasurementsofserumtestosterone.(See"Testosteronetreatmentofmalehypogonadism",sectionon'Monitoring'.)
Menwithsecondaryhypogonadismwhowishtobecomefertilecanbetreatedwithgonadotropinsiftheyhavepituitarydiseaseorwitheither
gonadotropinsorgonadotropinreleasinghormone(GnRH)iftheyhavehypothalamicdisease.(See"Inductionoffertilityinmenwithsecondary
hypogonadism".)
WomenWomenwithhypogonadismduetopituitarydisease,whoarenotinterestedinfertility,shouldbetreatedwithestrogenprogestin
replacementtherapy.Thegoaloftreatmentisnotthesameasinpostmenopausalwomen,inwhomthegoalistogiveestrogenandprogestinonlyif
necessarytorelievehotflushes.Instead,thegoaloftreatmentofwomenofpremenopausalageissimilartothatofreplacementofthyroxine(T4)and
cortisol,ie,toreplacethemissinghormonesasphysiologicallyaspossible.
Towardthisend,wesuggesttreatmentwithestradiol(theestrogenthehumanovariessecrete)transdermally,soestradiolisabsorbedintothe
systemiccirculation(aswhenitissecretedbytheovaries).Womenwithanintactuterusmustalsotakeaprogestintoavoidtheriskofendometrial
hyperplasiaorcarcinoma.Wealsorecommendthatestradiolbeadministeredcyclicallywithprogesteroneoraprogestin.Someclinicianssuggesta
traditionalregimenofestradiolondays1through25ofeachmonthandprogesteroneondays16through25ofeachmonth.Thegoalsaretoachieve
bothanormallatefollicularserumestradiolconcentrationandmensesthepatientconsidersnormal.Anotherregimenistogivetransdermalestradiol
continuouslythroughoutthemonth,withprogestinaddeddays1to10ofthecalendarmonth.Thisregimenissimilartothatusedfortreatmentof
prematureovarianfailure(see"Managementofspontaneousprimaryovarianinsufficiency(prematureovarianfailure)").Forwomenwhodevelopcyclic
moodchanges(premenstrualsyndrome)oneitheroftheseregimens,acontinuousdailyregimenofbothestrogenandalowerdoseofprogestinis
usuallybettertolerated.(See"Epidemiologyandpathogenesisofpremenstrualsyndromeandpremenstrualdysphoricdisorder".)
Womenwithsecondaryhypogonadismwhowishtobecomefertileshouldbeofferedovulationinduction.WomenwithGnRHdeficiencyarecandidates
foreithergonadotropintherapyorpulsatileGnRH,whilethosewithgonadotropindeficiencyduetopituitarydiseasearecandidatesonlyfor
gonadotropintherapy.(See"Isolatedgonadotropinreleasinghormonedeficiency(idiopathichypogonadotropichypogonadism)",sectionon'Treatment'
and"Overviewofovulationinduction",sectionon'Gonadotropintherapy'.)
AndrogenreplacementSerumandrogenconcentrationsinwomenwithhypopituitarism,particularlythosewithbothgonadotropinand
adrenocorticotropichormone(ACTH)deficiency,aresignificantlylowerthanthoseinnormalcontrolwomen[11].Adrenalandrogenreplacementis
discussedabove.Theroleofexogenoustestosteronetherapyinthesewomenisunclear,butisnotrecommended.
Theeffectofexogenoustestosteronetherapyinwomenwithandrogendeficiencyduetohypopituitarismwasaddressedinastudyof51suchpatients
takingexogenousestrogenorally.Testosteronereplacementwasadministeredtransdermallyatdosesof150to300mcg/dayforoneyear,resultingin
serumfreetestosteroneconcentrationsinthenormalrangeandincreasedmeanbonemineraldensityofthehipandradius,butnotthespine[12].
Othereffectsincludedanincreaseinfatfreemassandthighmusclearea,andimprovementsinsomeaspectsofmood,sexualfunction,andqualityof
life,asassessedbyquestionnaires.Onethirdofthewomenreceivingtestosteronedevelopedacnebutnopatientsdevelopedhirsutismorother
hyperandrogenicsideeffects.Androgentherapyinwomenisdiscussedinmoredetailseparately.(See"Overviewofandrogendeficiencyandtherapy
inwomen"and"Sexualdysfunctioninwomen:Management",sectionon'Androgens'.)
GROWTHHORMONEDEFICIENCYWedonotrecommendrecombinanthumangrowthhormone(GH)asroutinetreatmentforallpatientswith
adultonsetGHdeficiency.TheavailabilityofseveralrecombinanthumanGHpreparations(Humatrope,Nutropin,Serostim,andGenotropin)for
treatingadultswithGHdeficiencyallowsclinicianstoprescribethistreatment.PatientswithGHdeficiencyacquiredasanadultmust,tobereimbursed
byinsurancecompaniesintheUnitedStates,meetatleasttwocriteriafortherapy:alowinsulinlikegrowthfactor1(IGF1)concentrationorapoor
GHresponsetoatleasttwostandardstimuli,andhypopituitarismduetopituitaryorhypothalamicdamage.Thecriteriaaredifferentinchildrenin
whomGHisrequiredfornormalgrowth.(See"Treatmentofgrowthhormonedeficiencyinchildren".)
ManypatientswhodevelopGHdeficiencyinadulthoodhaveunfavorableserumlipidprofiles,increasedbodyfat,decreasedmusclemass,decreased
bonemineraldensity,andadiminishedsenseofwellbeing.ThereissubstantialevidencethatGHtreatmentinthesepatientsincreasesmusclemass
andreducesbodyfat.Theevidenceforimprovementinbonemineraldensityisgoodformenbutnotforwomen.Theevidenceconcerning
improvementsinthesenseofwellbeing,musclestrength,andserumlipidsisconflicting.(See"Growthhormonedeficiencyinadults".)
PROLACTINDEFICIENCYTheonlyknownpresentationofprolactindeficiencyistheinabilitytolactateafterdelivery,forwhichthereiscurrentlyno
availabletreatment.Recombinanthumanprolactin(rhPRL),althoughnotcommerciallyavailable,hasbeenusedexperimentallyinanopenlabelpilot
studyoffivewomenwithprolactindeficiencyduetoSheehansyndromeorothercauses[13].Prolactindeficiencywasdefinedasbaselineorpeak
serumprolactinlevelsbelowthenormalrangefortheirpostpartumdateandproductionoflessthan8mLofmilkperday.Subcutaneousadministration
ofrhPRLevery12hoursfor28daysincreasedmeanmilkproductionfrom3.41.6mLto66.18.3mLperday.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyondtheBasics.TheBasics
patienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatient
mighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.
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BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgrade
readinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalso
locatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patienteducation:Panhypopituitarism(TheBasics)")
SUMMARYTreatmentofpatientswithhypopituitarismisthesumofthetreatmentsofeachoftheindividualpituitaryhormonaldeficienciesdetected
whenapatientwithapituitaryorhypothalamicdiseaseistested.Thetreatmentsofadrenocorticotropichormone(ACTH),thyroidstimulatinghormone
(TSH),andluteinizinghormone(LH)andfolliclestimulatinghormone(FSH)deficienciesareinmanywaysthesameasthetreatmentsofprimary
deficienciesoftherespectivetargetglands,butinotherwaystheydiffer.
LackofACTHprimarilycausescortisoldeficiency.Treatmentconsistsoftheadministrationofhydrocortisoneorotherglucocorticoidinanamount
andtimingtomimicthenormalpatternofcortisolsecretion.(See'ACTHdeficiency'above.)
TSHdeficiency,whichresultsinthyroxine(T4)deficiency,istreatedwithT4(levothyroxine).T4shouldnotbeadministereduntiladrenalfunction,
includingACTHreserve,hasbeenevaluatedandeitherfoundtobenormalortreated.MeasurementofserumTSHcannotbeusedasaguideto
theadequacyofT4replacementtherapy.WesuggeststartingwithaweightbasedT4doseof1.6mcg/kg.Thedoseshouldbeadjustedaccording
totheserumT4orfreeT4values,aimingtomaintaintheminthemiddlepartofthenormalrange.(See'TSHdeficiency'aboveand"Central
hypothyroidism",sectionon'Treatment'.)
Inmenwithgonadotropindeficiency,testosteronereplacementisindicatedwhenfertilityisnotdesired.Menwithsecondaryhypogonadismwho
wishtobecomefertilemaybetreatedwithgonadotropinsiftheyhavepituitarydiseaseorwitheithergonadotropinsorgonadotropinreleasing
hormone(GnRH)iftheyhavehypothalamicGnRHdeficiency.(See'Men'above.)
Inwomenwithgonadotropindeficiency,treatmentdependsuponthepatient'sgoals.Estradiolandprogestinreplacementsareindicatedinwomen
whoarenotpursuingfertility,whilegonadotropinorpulsatileGnRHtherapymaybeusedwhenovulationinductionandfertilityarethegoal.(See
'Women'above.)
Theroleofandrogentherapyinwomenwithhypopituitarismisunclear.(See'Adrenalandrogenreplacement'aboveand'Androgenreplacement'
above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1.BlowB,HagmarL,MikoczyZ,etal.Increasedcerebrovascularmortalityinpatientswithhypopituitarism.ClinEndocrinol(Oxf)199746:75.
2.ArafahBM.Medicalmanagementofhypopituitarisminpatientswithpituitaryadenomas.Pituitary20025:109.
3.GrossmanAB.ClinicalReview#:Thediagnosisandmanagementofcentralhypoadrenalism.JClinEndocrinolMetab201095:4855.
4.EstebanNV,LoughlinT,YergeyAL,etal.Dailycortisolproductionrateinmandeterminedbystableisotopedilution/massspectrometry.JClin
EndocrinolMetab199172:39.
5.ArltW,RosenthalC,HahnerS,AllolioB.Qualityofglucocorticoidreplacementinadrenalinsufficiency:clinicalassessmentvs.timedserum
cortisolmeasurements.ClinEndocrinol(Oxf)200664:384.
6.ThomsonAH,DeversMC,WallaceAM,etal.Variabilityinhydrocortisoneplasmaandsalivapharmacokineticsfollowingintravenousandoral
administrationtopatientswithadrenalinsufficiency.ClinEndocrinol(Oxf)200766:789.
7.HahnerS,LoefflerM,FassnachtM,etal.Impairedsubjectivehealthstatusin256patientswithadrenalinsufficiencyonstandardtherapybased
oncrosssectionalanalysis.JClinEndocrinolMetab200792:3912.
8.MartinMM.Coexistinganteriorpituitaryandneurohypophysealinsufficiency.Asyndromewithdiagnosticimplication.ArchInternMed1969
123:409.
9.ShibataH,OgishimaT,MitaniF,etal.RegulationofaldosteronesynthasecytochromeP450inratadrenalsbyangiotensinIIandpotassium.
Endocrinology1991128:2534.
10.WhitePC.Disordersofaldosteronebiosynthesisandaction.NEnglJMed1994331:250.
11.MillerKK,SesmiloG,SchillerA,etal.Androgendeficiencyinwomenwithhypopituitarism.JClinEndocrinolMetab200186:561.
12.MillerKK,BillerBM,BeauregardC,etal.Effectsoftestosteronereplacementinandrogendeficientwomenwithhypopituitarism:arandomized,
doubleblind,placebocontrolledstudy.JClinEndocrinolMetab200691:1683.
13.PoweCE,AllenM,PuopoloKM,etal.Recombinanthumanprolactinforthetreatmentoflactationinsufficiency.ClinEndocrinol(Oxf)2010
73:645.
Topic6640Version14.0

Contributor Disclosures
Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism (Testosterone gel)]; Novo Nordisk [Growth hormone
(Somatropin)]; Novartis [Cushing's (Pasireotide)]; Cortendo [Cushing's]. Consultant/Advisory Boards: Novartis [Cushing's (Pasireotide)]; Pzer
[Acromegaly (Pegvisomant)]. Watson [Testosterone (Testosterone gel)]. David S Cooper, MD Nothing to disclose Kathryn A Martin, MD Nothing to
disclose
Contributor disclosures are reviewed for conicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conict of interest policy

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