7/28/2016 Treatmentofadrenalinsufficiencyinadults

OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Treatmentofadrenalinsufficiencyinadults

Author SectionEditor DeputyEditor

LynnetteKNieman,MD AndrLacroix,MD KathrynAMartin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2016.|Thistopiclastupdated:Apr22,2016.
INTRODUCTIONPrimaryadrenalinsufficiency(Addison'sdisease)isduetoadrenocorticaldisease,whilesecondary
andtertiaryadrenalinsufficiencyareduetodisordersofthepituitarygland(adrenocorticotropichormone[ACTH]secretion)
orthehypothalamus(corticotropicreleasinghormonesecretion),respectively.Primaryadrenalinsufficiencyisassociated
withbothcortisolandmineralocorticoiddeficiency.Incontrast,secondaryandtertiaryadrenalinsufficiencyareassociated
withcortisol,butnotmineralocorticoiddeficiency,becausealdosteroneisregulatedprimarilybythereninangiotensin
system,whichisindependentofthehypothalamusandpituitary.Thisdistinctionaccountsforthedifferentclinical
presentationandmanagementofthesedisorders.

Themanagementofallformsofadrenalinsufficiencyisreviewedhere.Thecauses,clinicalmanifestations,anddiagnosis
ofadrenalinsufficiencyinadultsarereviewedseparately.(See"Causesofprimaryadrenalinsufficiency(Addison's
disease)"and"Clinicalmanifestationsofadrenalinsufficiencyinadults"and"Diagnosisofadrenalinsufficiencyinadults".)

ADRENALCRISISAdrenalcrisisreferstoacuteadrenalinsufficiencyitismostcommoninpatientswithprimary
adrenalinsufficiency,butmayalsooccurinthosewithsecondaryortertiaryadrenalinsufficiency.Itisalifethreatening
emergencythatrequiresimmediatetreatment(table1).

Inpatientswithprimaryadrenalinsufficiency,themajorclinicalfeaturesofadrenalcrisisarevolumedepletionand
hypotension,resultingmainlyfrommineralocorticoiddeficiency.

Whilesecondaryortertiaryadrenalinsufficiency(isolatedglucocorticoiddeficiency)doesnotleadtovolumedepletion,it
decreasesvasculartone,whichleadstohypotension.Thus,adrenalcrisisoccurslessfrequentlyinpatientswith
secondaryortertiaryadrenalinsufficiency.Whentheydohaveadrenalcrisis,ittendstobeduringacutestress,orwith
acutecortisoldeficiencyduetopituitaryinfarctionoraftersurgicalcureofCushing'ssyndrome.(See"Clinical
manifestationsofadrenalinsufficiencyinadults",sectionon'Pituitaryapoplexy'.)

Adrenalcrisismayalsooccurinpatientswhoareabruptlywithdrawnfromexogenousglucocorticoids.(See"Clinical
manifestationsofadrenalinsufficiencyinadults".)

Thebiochemicalfeaturesofadrenalcrisisinprimaryadrenalinsufficiencyincludehyperkalemiaandhyponatremia.
Hyponatremiaoccursbecauseofmineralocorticoiddeficiencyandalsoduetoinappropriatesecretionofantidiuretic
hormone(vasopressin)thatiscausedbycortisol(notaldosterone)deficiency.Inthesepatients,combined
mineralocorticoidandglucocorticoiddeficiencyleadtourinarysodiumloss,plasmavolumedepletionwithincreasedserum
urea.(See"Hyponatremiaandhyperkalemiainadrenalinsufficiency".)

Patientswithpurecortisoldeficiency(eg,secondaryortertiaryadrenalinsufficiency)haveslightlyincreasedbloodvolume,
dilutionalhyponatremia,lessurinarysodiumloss,andnohyperkalemia.

ManagementAdrenalcrisisrequiresurgentdiagnosisandintervention(table1).

Treatmentofpatientswhopresentinpossibleadrenalcrisisshouldnotbedelayedwhilediagnostictestsare
performed.Bloodforserumcortisol,adrenocorticotropichormone(ACTH),aldosterone,renin,andserumchemistry
shouldbedrawnandtherapyinitiatedimmediately.Theserumchemistryresultsguideinitialtreatmentthehormone
valuesreturnlaterandareusedtoconfirmthediagnosis(cortisolandaldosterone)orevaluatethedifferential
diagnosis(ACTHandrenin).

1to3litersof0.9percentsalinesolutionor5percentdextrosein0.9percentsaline(tocorrectpossible
hypoglycemia)shouldbeinfusedintravenously(IV)withinthefirst12to24hoursbasedonassessmentofvolume
statusandurineoutput.

Hypotonicsalineshouldnotbeusedbecauseitcanworsenthehyponatremia.

ChoiceofglucocorticoidInapatientwithoutapreviousdiagnosisofadrenalinsufficiency,dexamethasone(4mg
IVbolus)ispreferredbecause,incontrasttohydrocortisone,itisnotmeasuredinserumcortisolassays[1].

Forpatientswithaknowndiagnosisofadrenalinsufficiencywhopresentwithadrenalcrisis,hydrocortisone(100mgIV
bolus),dexamethasone(4mgIVbolus),oranyIVglucocorticoidpreparationmaybeused(table2).Thiscanrapidly
decreasetheinappropriatevasopressinproductionwithincreasedclearanceoffreewaterandcorrectionofhyponatremia.

Incontrasttoglucocorticoidreplacement,mineralocorticoidreplacementisnotnecessaryacutelybecauseittakes
severaldaysforitssodiumretainingeffectstoappear,andadequatesodiumreplacementcanbeachievedbyIV
salinealone.However,inpatientswithknownprimaryadrenalinsufficiencyorthosewithpotassium>6.0mEq/L,
hydrocortisoneispreferredbecauseofitsmineralocorticoidactivity.

Aftertheinitialbolus,hydrocortisone50mgIVbolusisadministeredeveryeighthoursuntilstabilizationofvitalsigns
andcapacitytoeatandtakemedicationorally.

Unlessthereisamajorcomplicatingillness,parenteralglucocorticoidtherapycanbetaperedoveronetothreedays
andchangedtoanoralstressormaintenancedose.
https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 1/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

DiagnostictestsAfterinitialtreatment,theprecipitatingcauseoftheadrenalcrisis(asanexample,bacterial
infection,viralgastroenteritis)shouldbesoughtandappropriatelytreated.

Oncethepatient'sconditionisstable,thediagnosiscanbeconfirmedinpatientsnotknowntohaveadrenalinsufficiency
withashortACTHstimulationtest.Thisshouldbefollowedbyteststodeterminethecauseoftheadrenalinsufficiency.
(See"Diagnosisofadrenalinsufficiencyinadults".)

CHRONICADRENALINSUFFICIENCYOneoftheimportantcomponentsoftherapyinchronicadrenalinsufficiency
ispatienteducation(table3).Thepatientshouldbetoldthattheycanleadanactiveandvigorouslifeaslongastheytake
replacementtherapyandfollowafewcommonsenseprecautions.Thepatientandresponsiblefamilymembersshouldbe
instructedabout:

Thenatureofthehormonaldeficitandtherationalefortreatment
Maintenancemedicationsandadjustmentduringminorillnesses
Whentoconsultaclinician
Whenandhowtoinjectaglucocorticoidforemergencies

GlucocorticoidregimensTheidealglucocorticoidreplacementtherapywould:

Mimictheendogenouscortisolrhythm,withanadiratbedtimeandpeakvaluesintheearlymorningbeforewaking

Havelittleinterindividualvariabilityinmetabolism,sothatthecorrectdosecouldbepredicted

Beamenabletoeasydosetitration

Beeasilymonitored

Minimizetheriskofovertreatment,resultinginiatrogenicCushingssyndrome(obesity,osteoporosis,facialplethora)
(see'Monitoringdose'belowand"EpidemiologyandclinicalmanifestationsofCushing'ssyndrome",sectionon
'IatrogenicCushing'ssyndrome')

Unfortunately,therearenoheadtoheadcomparisonsofvariousglucocorticoidreplacementregimens.Variousregimens
havebeenadvocated,usingshortacting(cortisoneacetateorhydrocortisone)orlongacting(prednisone/prednisolone,
dexamethasone)agents(table2).

ShortactingglucocorticoidsWesuggestreplacementwithashortactingglucocorticoid,hydrocortisone,intwoor
threedivideddosesastheglucocorticoidofchoiceforthemanagementofchronicprimaryadrenalinsufficiency.We
suggestusingthelowestglucocorticoiddosethatrelievessymptomsofglucocorticoiddeficiency.

Shortactingregimensroughlymimicthenormaldiurnalrhythm.Thebioavailabilityofhydrocortisoneisnearly100percent,
andserumcortisolconcentrationsriserapidlyinthe30minutesorsoafteringestion.However,afteralargedose,the
abilityofcorticosteroidbindingglobulin(CBG)tobindcortisolisexceeded(itcannotbindanymorecortisolataround25
mcg/dL)[2].Asaresult,theserumfreecortisolincreases,andisrapidlyfilteredintotheurine,resultinginarapiddecline
inserumtotalcortisolconcentrationsto25mcg/dL(690nmol/L),afterwhichthedeclineslows(averageplasmahalflife
about95minutes).Onestudyfoundelevatedurinaryfreecortisol(UFC)for24hoursafterasingle25mghydrocortisone
dose,butadecreasetothereferencerange,whenthe25mgdailydosewasgiveninfive5mgdoses[3].

Tobecomebiologicallyactive,cortisonemustundergohepaticconversiontocortisol.Itiseitherlargelyunabsorbedornot
metabolizedafterintramuscularadministration[4].Becauseoftheseshortcomings,hydrocortisoneisgenerallyconsidered
tobethebetterchoiceforashortactingglucocorticoidregimen.

Ingeneral,thereplacementdoseofglucocorticoidisaimedatreplacingthemissingcortisoloritsequivalent.Theaverage
dailysecretionrateofcortisolinnormalsubjectsis2.7to14mg/m2/day[5],andtherangeofreplacementdosesiswider
duetointerindividualvariationinmetabolismofthesteroidsandthefactthatasingledoseislesseffectivethanthesame
amountofsteroidadministeredinmultipledoses.Basedontheknownsecretionrate,werecommendatotaldaily
hydrocortisonedoseof10to12mg/m2.

Becauseofitsshorthalflife,thetotaldailydoseofhydrocortisoneisdividedintotwoorthreedoses.Thricedaily
administrationmimicsthedaycurveofcortisolseeninhealthyvolunteers[6].Atypicaltwicedailyregimenconsistsof
takingabouttwothirdsofthetotaldoseuponarisinginthemorningandonethirdintheafternoontosimulatethenormal
cortisolcircadianrhythm.Threetimesdailyregimensusedecreasingdosesinthemorning,earlyafternoon,andlate
afternoon/earlyevening(eg,10/5/2.5mg).Mostregimensavoideveningdoses,becausenormalsubjectssecretelittle
cortisolfromabout6PMto3AM.

Authorsrecommendavarietyofreplacementdoses,including5mg/m2giventhricedaily,10mgmorning,and5mginthe
afternoon[7],20mgtotaldose[8],and15to25mgdailygivenintwoorthreedivideddoses[9].Hydrocortisonehassome
mineralocorticoidactivity,sofludrocortisonereplacement(ifneeded)mustbedecreasedappropriately.Hydrocortisone
doserecommendationsaresimilarforpatientswithsecondaryadrenalinsufficiency[1012].(See"Treatmentof
hypopituitarism",sectionon'ACTHdeficiency'.)

TheinteractionofconcurrentmedicationsthatalterCYP3A4metabolismofglucocorticoidsshouldbeconsideredwhen
choosingthedose,asitmayrequireadjustment[13,14].

Whilesomepatientsdowellonsingledoseadministration,werecommendthatasplitdosebeusedwheninitiating
therapy,andthatasingledosebeusedonlyifpatientsarenotcompliantwiththeafternoondose.Inonesmallstudy,
qualityoflifeandpatientpreferenceweregreatestduringthreeweekswithasplitdoseregimen(20mgat0700hand10
mgat1900h)ratherthanasingletotaldoseinthemorningorevening[15].Therearenostudiescomparingqualityoflifeof
twoversusthreedoseregimens.
https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 2/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

Advantagesofhydrocortisoneincludethepotentialforfinedoseadjustmentsusingvarioustabletstrengths.Additionally,
onestudyfoundthatsmallerfractionateddosesofhydrocortisone(10mgtwicedaily)avoidedincreasedintraocular
pressurefoundwithahigherdose(20mgand10mgsplitdose)[16].

Adisadvantageofhydrocortisonetherapyisthefactthatanormaldiurnalrhythmcannotbetrulyreplicated:atthetimeof
themorningdose,endogenousserumcortisolconcentrationswouldnormallyalreadybeatorafterthecircadianpeak.This
transientearlymorningadrenalinsufficiencyprobablyaccountsforthesymptomsoffatigue,lassitude,mildnausea,or
headachethatareoftenpresentuponawakeningandthatarerelievedwithin30to60minutesaftertakingthemorning
doseofhydrocortisone.Somepatientsfindithelpfultotaketheirinitialdoseofhydrocortisoneintheearlymorningandgo
backtosleepforafewhours.However,slowreleasepreparationsindevelopmentmayaddressthisproblem[1719].

Aoncedailydualreleasehydrocortisonetabletbasedonanimmediatereleasecoatingcombinedwithanextendedrelease
coreisbeinginvestigatedasanalternativetostandardtwiceorthreetimesdailydosingforpatientswithadrenal
insufficiency.Inonereport,patientstakingtheoncedailytablethadamorephysiologicserumcortisolprofile,andlower
bodyweightandbloodpressurewhencomparedwiththosetakinganequivalentdoseofhydrocortisoneadministeredasa
threetimesdailyregimen[20].

LongactingglucocorticoidsLongeractingagentssuchasdexamethasoneorprednisoneprovideasmoother
physiologicaleffectandavoidthemarkedchangesinserumglucocorticoidlevelsthatoccurwithshortactingdrugs.Itis
notknownifthisisclinicallyimportant.Theusualoraldailyreplacementdosesare0.5mgand5mgfordexamethasone
andprednisone,respectively.Somepatientsrequire2.5or7.5mgforprednisoneor0.25or0.75mgfordexamethasone
(table2).

Longactingagentsmaybeusefulinpatientswhoarenoncompliantwithmultipledailydoseschedules,orinthosewith
severelateeveningorearlymorningsymptomsthatarenotamelioratedbythreetimesdailyhydrocortisone.
Disadvantagesoflongactingagentsincludethevariableinterindividualmetabolismofdexamethasoneand,asaresult,
aninabilitytopredictthecorrectdose.Asaresult,patientsmaybeovertreated.

Obesepatientsandthosewhometabolizeglucocorticoidsmorerapidlythanaveragemayneedhigherdoseschildrenor
smalladultsandpatientswhometabolizeglucocorticoidslessrapidlythanaveragemayneedlowerdoses.The
dexamethasonedosemayneedtobeincreasedinpatientstakingdrugsthatacceleratehepaticsteroidmetabolism,such
asphenytoin,barbiturates,rifampin,andmitotane[2124].

MonitoringdoseWesuggestusingthelowestglucocorticoiddosethatrelievessymptomsofglucocorticoid
deficiencyandavoidssignsandsymptomsofglucocorticoidexcess.(See"Epidemiologyandclinicalmanifestationsof
Cushing'ssyndrome",sectionon'IatrogenicCushing'ssyndrome'.)

Symptomassessment

Thedosemaybetoolowifsymptomsofapparentglucocorticoiddeficiencyarepresent.If,however,increasingthe
dosedoesnotpromptlyrelievethesymptoms,thentheyhaveothercausesandthelowersteroiddoseshouldbe
resumed.

Thedosemaybetoohighifexcessiveweightgain,facialplethoraorothersymptomsorsignsofCushing's
syndromearepresent.(See"EpidemiologyandclinicalmanifestationsofCushing'ssyndrome",sectionon'Clinical
manifestations'.)

Osteoporosisismorelikelywithexcessiveglucocorticoidtherapy[25,26].Increasedbonelossinwomen,butnotmen,
withtreatedprimaryadrenalinsufficiencywasreportedinonestudy[27]andinmenbutnotwomeninanother[28].
Comparisonofbonelossinpatientstreatedwithdailyhydrocortisone30mgorprednisone7.5mg(dosesthatarehigher
thantherecommendedmaintenancedoses)foundnodifferenceinonestudy,butlowerbonemineraldensitywith
prednisoneinanother[29,30](see"Pathogenesis,clinicalfeatures,andevaluationofglucocorticoidinducedosteoporosis",
sectionon'Effectoflowdoseglucocorticoidtherapy').Astudyofninepatientsreceivingthreedifferentregimensin
randomordersuggestedthatmorningdexamethasone0.1mg/15kgbodyweighthadadverseeffectsonserummarkersof
boneturnoverascomparedwithhydrocortisone10mg/5mgor10/5/5mgsplitdoses[31].Althoughthisissueremains
unresolved,itdoeshighlighttheimportanceofavoidingexcessivedosesofglucocorticoid,andmaysuggestthatlong
actingglucocorticoidsaremorelikelytoreducebonemineraldensity.(See"Pathogenesis,clinicalfeatures,andevaluation
ofglucocorticoidinducedosteoporosis",sectionon'Effectoflowdoseglucocorticoidtherapy'.)

PlasmaACTH

Alownormalorsuppressedmorningplasmaadrenocorticotropichormone(ACTH)concentrationindicatesexcessive
glucocorticoidreplacementinpatientswithprimaryadrenalinsufficiency.Theearlymorningadrenalinsufficiencywith
hydrocortisoneresultsinplasmaACTHconcentrationsthataretwotoeighttimeshigherthannormalforseveral
hoursintheearlymorningandforseveralhoursafterthecortisolistaken[3234].ACTHlevelsweresignificantly
lowercomparedwithconventionaloraltherapy,butremainedabouttwofoldelevatedintwopatientsreceiving
hydrocortisoneinfusion[34].MeasurementsofplasmaACTHarenothelpfulinpatientswithsecondaryinsufficiency,
inwhomlevelsareexpectedtobelow.

Whilesomeadvocateuseofnormativedaycurvecortisolvaluestoassesstheadequacyofhydrocortisonetherapy
[6],otherreportssuggestthatclinicalassessmentaloneworksequallywell[35].

MineralocorticoidreplacementMostpatientswithprimaryadrenalinsufficiencyeventuallyrequiremineralocorticoid
replacementtopreventsodiumloss,intravascularvolumedepletion,andhyperkalemia.Fludrocortisone(9alpha
fluorohydrocortisone),apotentsyntheticmineralocorticoid,isgivenorallyinausualdoseof0.1mg/day.Alowerdose
(suchas0.05mg/day)maybesufficientinpatientsreceivinghydrocortisone,whichhassomemineralocorticoidactivity.
https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 3/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

Rarepatientsaresufficientlyreplacedwithhydrocortisonealoneandbecomehypertensive,hypokalemicwitheven0.05
mgFlorineftwiceaweek.Manypatientsreceivingprednisoneordexamethasonerequireupto0.2mg/dayof
fludrocortisonetolowertheirplasmareninactivitytotheuppernormalrange[36,37].(See'Monitoring'below.)

Themineralocorticoiddosemayhavetobeincreasedinthesummer,whensaltlossinperspirationincreases,especiallyif
thepatientisroutinelyexposedtotemperaturesaboveabout29C(85F).Saltintakeshouldbeliberal,especiallywhen
exercising.

Primaryhypertension(formerlycalled"essential"hypertension)inpatientswithprimaryadrenalinsufficiencyshouldbe
treatedbydietarysodiumrestrictionandalowerdoseoffludrocortisone[38,39].Mineralocorticoidtherapyusuallycannot
bediscontinuedwithoutriskingsodiumdepletion.Ifanantihypertensivedrugisneeded,diureticdrugsandspironolactone
shouldnotbeused,sincetheysimplycounteracttheactionoffludrocortisone.

MineralocorticoidreplacementisrarelyrequiredinpatientswithsecondaryadrenalinsufficiencybecauseACTHisnotthe
mainphysiologicalregulatorofaldosteronerelease.

MonitoringTheadequacyofmineralocorticoidreplacementshouldbemonitoredbyaskingaboutsymptomsof
posturalhypotensionandmeasuringsupineanduprightbloodpressureandpulse,serumpotassium,andplasmarenin
activity(PRA).Hypertension,edema,andhypokalemiaaresignsofexcessivemineralocorticoidreplacement[38].

WesuggestadjustingthefludrocortisonedosetolowerthePRAtotheuppernormalrange[36,37].Normalmorning
plasmareninactivityforseatedsubjectsrangesfromabout1to4ng/mLperhour(0.8to3.0nmol/Lperhour).(See
"Assaysofthereninangiotensinaldosteronesysteminadrenaldisease",sectionon'Plasmareninactivity'.)

ItisusefultomeasurePRAannuallyinallpatientsandin:

Newlydiagnosedpatients,untiltheyareonastabledoseofmineralocorticoids.

Patientswithsymptomsconsistentwithmineralocorticoiddeficiencysuchassaltcravingandintermittentmild
nauseawhohaveotherwisenormalfindingsonphysicalexamination.

InasymptomaticpatientswithnormalserumelectrolyteconcentrationsbuthighPRA,thefludrocortisonedoseshouldnot
beraisedtonormalizePRA.Althoughonemightpredictthatthiswouldbeaphysiologicdose(normalPRAinan
asymptomatic,normokalemicpatient),patientsmaydevelophypokalemiaandedema[40].(See"Pathophysiologyand
clinicalfeaturesofprimaryaldosteronism".)

Androgenreplacement(DHEA)Manywomenwithadrenalinsufficiencydescribeadecreaseinqualityoflifeinspite
ofadequateglucocorticoidandmineralocorticoidreplacement.Thisobservationhasledtointerestinfindingadditional
therapies,inparticular,androgens,toimprovewellbeing.

Theadrenalcortexistheprimarysourceofandrogenintheformofdehydroepiandrosterone(DHEA)andDHEAsulfate
(DHEAS).Inwomenwithadrenalinsufficiency,serumconcentrationsofDHEAareextremelylow.Therefore,DHEAhas
beenstudiedasatherapytoimprovemoodandqualityoflife.

Mood/qualityoflifeClinicaltrialdatasuggestthatinwomenwithprimaryadrenalinsufficiency,replacementwith
50mgofDHEAdailymaybebeneficialforoutcomessuchasmoodandpsychologicalwellbeing.

Inwomenwithsecondaryadrenalinsufficiency,DHEAappearstohaveamodestbeneficialeffectonpsychologicalwell
being.However,theavailabledataarefromwomenwithpanhypopituitarism,whohavecombinedadrenalandovarian
androgendeficiency.NodataareavailableinwomenwithisolatedACTHdeficiency,averyraredisorder.

ThebestavailabledataontheeffectofDHEAonmoodandqualityoflifeinwomenwithadrenalinsufficiencycomesfrom
ametaanalysisof10randomized,placebocontrolledtrials[41].Whencomparedwithplacebo,DHEAresultedinasmall
improvementinhealthrelatedqualityoflife.Therewasalsoasmallbeneficialeffectondepression,butnosignificant
effectonanxietyorsexualwellbeing.

OthereffectsTwelveweekcrossoverstudiesofpatientswithprimaryandsecondaryadrenalinsufficiencydidnot
findsignificantimprovementsinvascularmarkersinmenandwomen(arterialstiffnessandendothelialfunction)or
metabolicmarkers(lipids,HOMAIR,highsensitivityCRP,adiponectin,plasminogenactivatorinhibitor1),physical
performance,bodycomposition,proteinmetabolism,ormusclemitochondrialbiogenesisinwomenreceivingDHEA50mg
daily[4244].

AdverseeffectsInthemetaanalysis,most,butnotall,studiesreportedcommonandrogenicsideeffectsincluding
oilyskin,hirsutism,acne,andincreasedsweatingandodor[41].Althoughseriousadverseeffectswerenotreported,the
longtermsafetyofDHEAtherapyhasnotbeenestablished.

Otheradverseeffects,includingdecreasesinserumhighdensitylipoprotein(HDL)concentrations,havebeenreported.
(See"Dehydroepiandrosteroneanditssulfate",sectionon'Adverseeffects'.)

SuggestedapproachThereisinsufficientevidencetorecommendtherapyinallpatientswithadrenalinsufficiency,
particularlymen.Inwomenwithadrenalinsufficiency(primaryorsecondary),wesuggestDHEAtherapyonlyforthose
whohavesignificantlyimpairedmoodorsenseofwellbeingdespiteoptimalglucocorticoidandmineralocorticoid
replacement.Wetypicallystartwith25to50mgdailyforthreetosixmonthsandadjustthedosebasedupontheclinical
response(improvementinlibido,senseofwellbeing,andandrogenicsideeffects).Adverseeffectsandbiochemical
monitoringarediscussedseparately.(See"Dehydroepiandrosteroneanditssulfate".)

Ifnoobviousbenefithasbeenseenaftersixmonthsorifadverseeffectsoccur,wediscontinueDHEA.IntheUnited
States,thisapproachisseverelylimitedbythelackofproductqualitycontrol,asDHEAisconsideredtobeadietary

https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 4/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

supplementratherthanahormonepreparation.Therefore,DHEAsupplementsavailablecommerciallymaynotactually
containtheadvertiseddose.Thistopicisdiscussedindetailseparately.(See"Dehydroepiandrosteroneanditssulfate".)

Considerationsinsecondaryadrenalinsufficiency

Patientswithsecondaryadrenalinsufficiencyshouldreceiveevaluationandadequatereplacementforotherpituitary
hormonedeficiencies.Replacementofthyroidhormonewithoutreplacementofglucocorticoidscanprecipitateacute
adrenalinsufficiency.

PatientswithhypopituitarismwhohavepartialortotalACTHdeficiencyandarereceivingsuboptimalcortisolor
cortisonereplacementmaybeatriskofdevelopingsymptomsofcortisoldeficiencywhengrowthhormonetherapyis
initiated.Thisisduetotheinhibitoryeffectofgrowthhormoneon11betahydroxysteroiddehydrogenasetype1,the
enzymethatconvertscortisonetocortisol[34].

IllnessorsurgeryCortisolsecretionnormallyincreaseswiththestressofillnessandsurgery.Thisfacthasprompted
theusualclinicalpracticeofgivinghigherdosesofglucocorticoidtopatientswithadrenalinsufficiencyinthesesituations.
Unfortunately,thereislittleinformationabouthowmuchadditionalglucocorticoidisneeded.

IllnessDuringminorillnesses,suchasupperrespiratoryinfections,thepatientcanincreasethedoseof
glucocorticoidtotwotothreetimestheusualdailydoseforthreedayswithoutconsultingaclinician(knownasthe3x3
rule).Theincreaseddosewilldecreasefeverandmalaiseandwillnotcompromisetheimmuneresponse.Iftheillness
becomesworseduringthethreedaysorifthepatientcannotresumetheusualmaintenancedoseonthefourthday,heor
sheshouldconsultacliniciantodetermineifothertreatment(eg,antibiotics)isindicated.

Asdescribedbelow,patientswithnauseaandvomitingwhoareunabletoretainoralmedicationsshouldhavealow
thresholdforinjectingglucocorticoid.Furthermedicalattentionshouldthenbesought.(See'Emergencyprecautions'
below.)

SurgeryTheappropriatedoseandtimingofglucocorticoidsforpatientsundergoingsurgeryiscontroversial.Early
reportsofdeathaftersurgeryledtoarecommendationtogiveglucocorticoidsindosesequivalentto1000mgof
hydrocortisonedaily[45].Thisisclearlyinexcessoftheincreasedproductionofupto200mgdaily.Prolonged
postoperativepharmacologicglucocorticoidtherapycanmasksymptomsandsignsofinfectionandcauseundesirable
sideeffects.Forexample,traditionaldosesof300to400mghydrocortisoneforafewdayscancausesignificant
hypokalemiaandedema.(See"Thesurgicalpatienttakingglucocorticoids".)

Currentrecommendationsforglucocorticoidsupplementationatsurgerytakeintoaccounttheseverityoftheoperationand
suggestlowerdailydoses[45,46].Forminorproceduressuchasherniorrhaphy,adoseequivalenttohydrocortisone25mg
issuggestedforthedayofoperationonly,withareturntotheusualreplacementdoseonthesecondday.Formoderate
surgicalstress(eg,cholecystectomy,jointreplacement),dividedintravenous(IV)dosesequivalenttohydrocortisone50to
75mgaresuggestedonthedayofsurgeryandthefirstpostoperativeday,withareturntotheusualdoseonthesecond
postoperativeday(usingoralorIVpreparationasappropriate).Theauthorssuggestatotaldailydoseequivalentto100to
150mghydrocortisoneformajorsurgicalprocedures(eg,cardiacbypass)givenindivideddosesfortwotothreedays,
thenreturningtotheusualdose.Alternatively,thedoseusedonthedayofsurgerycanbehalvedonpostoperativeday
one.(See"Thesurgicalpatienttakingglucocorticoids".)

EmergencyprecautionsThemajorrisktothepatientwithadrenalinsufficiencyisthelackofanormalserum
cortisolresponsetostressand,inpatientswithprimaryadrenalinsufficiency,ofanormalreninangiotensinaldosterone
responsetohypovolemia.Consequently,thepatientmustanticipatethesesituationsandbepreparedtomodifytherapyto
meettheseneeds.

Everypatientshouldwearamedicalalert(MedicAlert)braceletornecklaceandcarrytheEmergencyMedicalInformation
Cardthatissuppliedwithit.Bothshouldindicatethediagnosis,thedailymedicationsanddoses,andthecliniciantocall
intheeventofanemergency.

Eachpatientshouldhaveinjectableglucocorticoid,suchas100mgvialsofhydrocortisone(SoluCortef)or4mgvialsof
dexamethasone,alongwithvialsofsterile0.9percentnormalsalineandsyringes.Thepatientandoneormore
responsiblefamilyorhouseholdmembersshouldbeinstructedonhowtoreconstituteandinjectthemedication
subcutaneouslyorintramuscularlyanywhereonthepatient'sbodyifanyofthefollowingoccur:

Aninjurywithsubstantialbloodloss(morethanacup)orfracture

Nauseaandvomitingandinabilitytoretainoralmedications

Symptomsofacuteadrenalinsufficiency

Thepatientisfoundunresponsive

Theentiredoseofmedicationshouldbeinjected(100mgofhydrocortisoneor4mgdexamethasone).Patientandfamily
instructionshouldincludetheneedtogetmedicalhelpimmediatelyaftertheinjection.Thepatientshouldbeinstructedto
havealowthresholdforinjectingtheglucocorticoid:ifitmightbenecessary,itshouldbeinjectedandmedicalattention
shouldbesought.Itisunlikely,however,thatapatientwillneedtheinjectableglucocorticoidmorethantwoorthreetimes
ayear,andmostpatientsgoforyearswithoutusingit.

CriticalillnessAdrenalcortisolsecretionincreasesduringcriticalillness,buttheincreasemaynotbedetectedif
onlytotalserumcortisolconcentrationsaremeasured.Somecriticallyillpatientsmayhave"functionaladrenal
insufficiency,"butthereiscurrentlynoconsensusondiagnosticcriteriaorindicationsfortreatment.Thistopicis
discussedindetailseparately.(See"Corticosteroidtherapyinsepticshock",sectionon'Relativeadrenalinsufficiency'

https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 5/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

and"EvaluationoftheresponsetoACTHinadrenalinsufficiency".)

PREGNANCYPregnancycomplicatedbyprimaryadrenalinsufficiencyhasbeenreportedinabout100women[47].
Beforeglucocorticoidreplacementtherapybecameavailable,pregnancyinwomenwithprimaryadrenalinsufficiencywas
associatedwithamaternalmortalityrateashighas35to45percentandfetalgrowthretardationwascommon[4850].At
present,mostwomenadequatelytreatedforadrenalinsufficiencygothroughpregnancy,labor,anddeliverywithout
difficulty,andbabiesachieveanormalbirthweight.Theusualglucocorticoidandmineralocorticoidreplacementdosesare
continuedanoccasionalwomanrequiresslightlymoreglucocorticoidinthethirdtrimester[39,47,51].

Duringlabor,adequatesalinehydrationand25mghydrocortisoneshouldbeadministeredintravenously(IV)every
sixhours.

Atthetimeofdelivery,oriflaborisprolonged,hydrocortisoneshouldbeadministeredIVinadoseof100mgevery
sixhoursorasacontinuousinfusion.

Afterdelivery,thedosecanbetaperedrapidlytomaintenancewithinthreedays[52].

Anoccasionalwomanwithseverenauseaandvomitinginthefirsttrimestermayrequireintramusculardexamethasoneat
aslightlyincreaseddose(1mgdaily).

Theregulationofplasmavolumeduringpregnancyiscomplex.Secondaryhyperaldosteronismisnormal[53],associated
withincreasedplasmareninactivityandserumaldosteroneconcentrations[54,55].Serumconcentrationsofprogesterone,
whichcompeteswithaldosteroneforbindingtothetype1corticosteroid(mineralocorticoid)receptorinthekidneyandhas
anatriureticeffect,areincreasedthroughoutpregnancy[56,57].Plasmaatrialnatriureticpeptideconcentrationsreachtheir
nadirlateinthethirdtrimester[58],whenplasmareninactivityandserumaldosteroneconcentrationsreachtheirpeak
[54].

Therearenostudiesofmineralocorticoidrequirementduringpregnancyinwomenwithadrenalinsufficiency.Patients
shouldbefollowedcloselythroughoutpregnancyforelectrolyteabnormalitiesandsignsofvolumedepletion.Plasmarenin
activitymaybeusedasanindexofadequatefludrocortisonedose,butshouldnotbesuppressedtovalueslessthan
thoseinpregnantwomenwithoutadrenalinsufficiency(ie,20to25ng/mLperhoursupineorstanding)[54,55,58].

PROGNOSISTheprognosisforpatientswithadrenalinsufficiencywaspoorbeforetheavailabilityofglucocorticoids,
withmorethan80percentofpatientsdyingwithintwoyearsafterdiagnosis[59].Subsequentreportsafterglucocorticoids
becameavailablefortreatmentsuggestedthatpatientswithautoimmuneadrenalinsufficiencyshouldhaveanormallife
spanandcanleadafullyactivelife,includingvigorousexercise[51,59].Bycontrast,astudybasedontheSwedishdeath
registryfoundthatpatientswithadrenalinsufficiencyhaveatwofoldhighermortalityratethanthebackgroundpopulation
[60].Thereasonsforthisdiscrepancyarenotunderstoodandfurtherstudiesareneededtoevaluatewhetherthese
patientshaveprematuremortality.

Studiesreportsignificantlyreducedsubjectivequalityoflifeandincreasedratesofworkdisabilityinpatientswithadrenal
insufficiency.ANorwegianstudyof79patientswhoansweredapostalsurveyshowedimpairedgeneralhealthandvitality
perceptionandanincreaseinreportedfatigue.Selfperceptionofphysicalfunctioningwaslowinwomen.Working
disabilityatages18to67yearswas26percent,comparedwith10percentinthecorrespondinggeneralNorwegian
population[61].AGermanstudyreportedincreaseddepressionscoresandreducedqualityoflifescoresin210patients,
18.3percentofwhomdidnotworkbecauseofdisability[62].Itispossiblethatimprovedtherapythatbettermimicsthe
normaldiurnalcortisolrhythmoradditionaltherapywithdehydroepiandrosterone(DHEA)mightamelioratethisproblem,
butdataarenotavailabletoaddressthis.

Onestudynotedthepresenceofheartfailurein7of22patientswithlongstandingprimaryadrenalinsufficiencyreceiving
conventionaltreatmentafterameanof26years[39].However,thecausalrelationship,ifany,totheadrenalinsufficiency
oritstherapyisunclear.

Lineargrowthandpubertaldevelopmentproceednormallyincorrectly(ie,adequatelybutnotoverly)treatedchildrenwith
adrenalinsufficiency[63,64].Asnoted,overreplacementcanleadtobonelossandosteoporosis[28,29].

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:Addison'sdisease(TheBasics)"and"Patientinformation:Adrenalcrisis
(TheBasics)")

BeyondtheBasicstopics(see"Patientinformation:Adrenalinsufficiency(Addison'sdisease)(BeyondtheBasics)")

SUMMARYANDRECOMMENDATIONS

Adrenalcrisisisalifethreateningemergencythatrequiresimmediatetreatment(table1).(See'Adrenalcrisis'
above.)

Thegoaloftherapyistreatmentofhypotensionandreversalofelectrolyteabnormalitiesandofcortisoldeficiency.
https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 6/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

Largevolumes(1to3liters)of0.9percentsalinesolutionor5percentdextrosein0.9percentsalineshouldbe
infusedintravenously(IV)tocorrecthypovolemiaandhyponatremiaassociatedwithmineralocorticoiddeficiency
and/orsyndromeofinappropriateantidiuretichormonesecretion(SIADH).

Itisessentialthattreatmentofpatientswhopresentinpossibleadrenalcrisisnotbedelayedwhilediagnostictests
areperformed.

Inapatientwithoutapreviousdiagnosisofadrenalinsufficiency,dexamethasone,whichisnotmeasuredincortisol
assays,shouldbeusedratherthanhydrocortisonewhilebiochemicaltestingisperformed.(See'Adrenalcrisis'
above.)

Forpatientswithapreviouslyknowndiagnosisofadrenalinsufficiency,IVhydrocortisoneoranyotherglucocorticoid
preparationmaybeusedbecausediagnostictestingisnotnecessary.

Mineralocorticoidadministrationisnotnecessaryintheacutesetting.(See'Adrenalcrisis'above.)

Wesuggestreplacementwithhydrocortisoneintwoorthreedivideddoses(totaldoseof10to12mg/m2/day)asthe
glucocorticoidofchoiceforthemanagementofchronicprimaryadrenalinsufficiency(Grade2C).Adailydoseof
dexamethasoneorprednisonemayalsobeused.Wesuggestusingthelowestglucocorticoiddosethatrelieves
symptomsofglucocorticoiddeficiency.

Measurementofearlymorningplasmaadrenocorticotropichormone(ACTH)concentrationisnothelpfulinpatients
withsecondaryadrenalinsufficiencybecausevaluesareexpectedtobelow.Inpatientswithprimaryadrenal
insufficiency,measurementofearlymorningplasmaACTHconcentrationisnotnecessaryforroutinemonitoring,but
maydetectoverreplacement,inwhichcasethevaluewillbeinthelownormalrange.

Measurementofurinecortisolexcretionisnotcompletelyreliabletoassistindosetitrationofhydrocortisone.

Thevastmajorityofpatientswithprimaryadrenalinsufficiencyeventuallyrequiremineralocorticoidreplacementwith
fludrocortisone.Wesuggestadjustingthefludrocortisonedosetolowertheplasmareninactivitytotheuppernormal
range(Grade2B).(See'Mineralocorticoidreplacement'above.)

Wesuggestdehydroepiandrosterone(DHEA)therapyonlyinwomenwithimpairedmoodorsenseofwellbeing
despiteoptimalglucocorticoidand,ifneeded,mineralocorticoidreplacement.However,thisapproachislimitedby
thelackofreliablesourceofthiscompoundinsomecountries(Grade2B).(See'Androgenreplacement(DHEA)'
above.)

Forminorillnesses,wesuggesttwotothreetimestheusualmaintenanceglucocorticoiddoseforthreedays(known
asthe3x3rule)(Grade2C).(See'Illnessorsurgery'above.)

Forsurgicalproceduresorsevereillness,wesuggestcoveragewithgradeddosesofhydrocortisoneorits
equivalent,asnotedabove.

Allpatientsshouldwearamedicalalertbraceletandhavesuppliesforemergencyglucocorticoidinjections.

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

REFERENCES

1.TaylorRL,GrebeSK,SinghRJ.Quantitative,highlysensitiveliquidchromatographytandemmassspectrometry
methodfordetectionofsyntheticcorticosteroids.ClinChem200450:2345.
2.DerendorfH,MllmannH,BarthJ,etal.Pharmacokineticsandoralbioavailabilityofhydrocortisone.JClin
Pharmacol199131:473.
3.BliesenerN,SteckelbroeckS,RedelL,KlingmllerD.Dosedistributioninhydrocortisonereplacementtherapyhas
asignificantinfluenceonurinefreecortisolexcretion.ExpClinEndocrinolDiabetes2003111:443.
4.FarissBL,HaneS,ShinsakoJ,ForshamPH.Comparisonofabsorptionofcortisoneacetateandhydrocortisone
hemisuccinate.JClinEndocrinolMetab197847:1137.
5.PurnellJQ,BrandonDD,IsabelleLM,etal.Associationof24hourcortisolproductionrates,cortisolbindingglobulin,
andplasmafreecortisollevelswithbodycomposition,leptinlevels,andaginginadultmenandwomen.JClin
EndocrinolMetab200489:281.
6.MahPM,JenkinsRC,RostamiHodjeganA,etal.Weightrelateddosing,timingandmonitoringhydrocortisone
replacementtherapyinpatientswithadrenalinsufficiency.ClinEndocrinol(Oxf)200461:367.
7.CrownA,LightmanS.Whyisthemanagementofglucocorticoiddeficiencystillcontroversial:areviewofthe
literature.ClinEndocrinol(Oxf)200563:483.
8.WichersM,SpringerW,BidlingmaierF,KlingmllerD.Theinfluenceofhydrocortisonesubstitutiononthequalityof
lifeandparametersofbonemetabolisminpatientswithsecondaryhypocortisolism.ClinEndocrinol(Oxf)1999
50:759.
9.ArltW,AllolioB.Adrenalinsufficiency.Lancet2003361:1881.
10.EstebanNV,LoughlinT,YergeyAL,etal.Dailycortisolproductionrateinmandeterminedbystableisotope
dilution/massspectrometry.JClinEndocrinolMetab199172:39.
11.ArafahBM.Medicalmanagementofhypopituitarisminpatientswithpituitaryadenomas.Pituitary20025:109.
12.GrossmanAB.ClinicalReview#:Thediagnosisandmanagementofcentralhypoadrenalism.JClinEndocrinol
Metab201095:4855.
13.ArltW.Theapproachtotheadultwithnewlydiagnosedadrenalinsufficiency.JClinEndocrinolMetab2009
94:1059.
https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 7/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

14.Jacob,K,Trainer,PJ.Topiramatecaninducehypoadrenalisminpatientstakingoralcorticosteroidreplacement.BMJ
2009338:1788.
15.RiedelM,WieseA,SchrmeyerTH,BrabantG.QualityoflifeinpatientswithAddison'sdisease:effectsof
differentcortisolreplacementmodes.ExpClinEndocrinol1993101:106.
16.LiVoonChongJS,SenJ,JohnsonZ,etal.Hydrocortisonereplacementdosageinfluencesintraocularpressurein
patientswithprimaryandsecondaryhypocortisolism.ClinEndocrinol(Oxf)200154:267.
17.JohannssonG,FilipssonH,BergthorsdottirR,etal.Longactinghydrocortisoneforglucocorticoidreplacement
therapy.HormRes200768Suppl5:182.
18.DebonoM,RossRJ,NewellPriceJ.Inadequaciesofglucocorticoidreplacementandimprovementsby
physiologicalcircadiantherapy.EurJEndocrinol2009160:719.
19.WhitakerMJ,DebonoM,HuatanH,etal.Anoralmultiparticulate,modifiedrelease,hydrocortisonereplacement
therapythatprovidesphysiologicalcortisolexposure.ClinEndocrinol(Oxf)201480:554.
20.JohannssonG,NilssonAG,BergthorsdottirR,etal.Improvedcortisolexposuretimeprofileandoutcomeinpatients
withadrenalinsufficiency:aprospectiverandomizedtrialofanovelhydrocortisonedualreleaseformulation.JClin
EndocrinolMetab201297:473.
21.EliasAN,GwinupG.Effectsofsomeclinicallyencountereddrugsonsteroidsynthesisanddegradation.Metabolism
198029:582.
22.KyriazopoulouV,ParparousiO,VagenakisAG.Rifampicininducedadrenalcrisisinaddisonianpatientsreceiving
corticosteroidreplacementtherapy.JClinEndocrinolMetab198459:1204.
23.RobinsonBG,HalesIB,HennikerAJ,etal.Theeffectofo,p'DDDonadrenalsteroidreplacementtherapy
requirements.ClinEndocrinol(Oxf)198727:437.
24.SantenRJ,LiptonA,KendallJ.Successfulmedicaladrenalectomywithaminoglutethimide.Roleofaltereddrug
metabolism.JAMA1974230:1661.
25.PeaceySR,GuoCY,RobinsonAM,etal.Glucocorticoidreplacementtherapy:arepatientsovertreatedanddoesit
matter?ClinEndocrinol(Oxf)199746:255.
26.LvsK,GjesdalCG,ChristensenM,etal.GlucocorticoidreplacementtherapyandpharmacogeneticsinAddison's
disease:effectsonbone.EurJEndocrinol2009160:993.
27.FlorkowskiCM,HolmesSJ,ElliotJR,etal.Bonemineraldensityisreducedinfemalebutnotmalesubjectswith
Addison'sdisease.NZMedJ1994107:52.
28.ZelissenPM,CroughsRJ,vanRijkPP,RaymakersJA.Effectofglucocorticoidreplacementtherapyonbone
mineraldensityinpatientswithAddisondisease.AnnInternMed1994120:207.
29.ValeroMA,LeonM,RuizValdepeasMP,etal.BonedensityandturnoverinAddison'sdisease:effectof
glucocorticoidtreatment.BoneMiner199426:9.
30.JdarE,ValdepeasMP,MartinezG,etal.LongtermfollowupofbonemineraldensityinAddison'sdisease.Clin
Endocrinol(Oxf)200358:617.
31.SulimanAM,FreaneyR,SmithTP,etal.Theimpactofdifferentglucocorticoidreplacementschedulesonbone
turnoverandinsulinsensitivityinpatientswithadrenalinsufficiency.ClinEndocrinol(Oxf)200359:380.
32.ScottRS,DonaldRA,EspinerEA.PlasmaACTHandcortisolprofilesinAddisonianpatientsreceivingconventional
substitutiontherapy.ClinEndocrinol(Oxf)19789:571.
33.FeekCM,RatcliffeJG,SethJ,etal.PatternsofplasmacortisolandACTHconcentrationsinpatientswith
Addison'sdiseasetreatedwithconventionalcorticosteroidreplacement.ClinEndocrinol(Oxf)198114:451.
34.MerzaZ,RostamiHodjeganA,MemmottA,etal.Circadianhydrocortisoneinfusionsinpatientswithadrenal
insufficiencyandcongenitaladrenalhyperplasia.ClinEndocrinol(Oxf)200665:45.
35.ArltW,RosenthalC,HahnerS,AllolioB.Qualityofglucocorticoidreplacementinadrenalinsufficiency:clinical
assessmentvs.timedserumcortisolmeasurements.ClinEndocrinol(Oxf)200664:384.
36.SmithSJ,MacGregorGA,MarkanduND,etal.EvidencethatpatientswithAddison'sdiseaseareundertreatedwith
fludrocortisone.Lancet19841:11.
37.OelkersW,DiederichS,BhrV.DiagnosisandtherapysurveillanceinAddison'sdisease:rapidadrenocorticotropin
(ACTH)testandmeasurementofplasmaACTH,reninactivity,andaldosterone.JClinEndocrinolMetab1992
75:259.
38.JadoulM,FerrantA,DePlaenJF,CrabbJ.Mineralocorticoidsinthemanagementofprimaryadrenocortical
insufficiency.JEndocrinolInvest199114:87.
39.KnowltonAI,BaerL.CardiacfailureinAddison'sdisease.AmJMed198374:829.
40.FladTM,ConwayJD,CunninghamSK,McKennaTJ.Theroleofplasmareninactivityinevaluatingtheadequacy
ofmineralocorticoidreplacementinprimaryadrenalinsufficiency.ClinEndocrinol(Oxf)199645:529.
41.Alkataib,AA,Cosma,M,Elamin,MB,etal.JClinEndocrinolMetab200994:3676.
42.RiceSP,AgarwalN,BolusaniH,etal.Effectsofdehydroepiandrosteronereplacementonvascularfunctionin
primaryandsecondaryadrenalinsufficiency:arandomizedcrossovertrial.JClinEndocrinolMetab200994:1966.
43.SrinivasanM,IrvingBA,DhatariyaK,etal.Effectofdehydroepiandrosteronereplacementonlipoproteinprofilein
hypoadrenalwomen.JClinEndocrinolMetab200994:761.
44.DhatariyaKK,GreenlundLJ,BigelowML,etal.Dehydroepiandrosteronereplacementtherapyinhypoadrenal
women:proteinanabolismandskeletalmusclefunction.MayoClinProc200883:1218.
45.SalemM,TainshREJr,BrombergJ,etal.Perioperativeglucocorticoidcoverage.Areassessment42yearsafter
emergenceofaproblem.AnnSurg1994219:416.
46.CoursinDB,WoodKE.Corticosteroidsupplementationforadrenalinsufficiency.JAMA2002287:236.
47.LindsayJR,NiemanLK.Thehypothalamicpituitaryadrenalaxisinpregnancy:challengesindiseasedetectionand
treatment.EndocrRev200526:775.
48.O'ShaughnessyRW,HackettKJ.MaternalAddison'sdiseaseandfetalgrowthretardation.Acasereport.JReprod
Med198429:752.
49.WieackerP,AlexopoulosA,DeGregorioG,BreckwoldtM.[PregnancyinAddison'sdisease].DtschMed
https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 8/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

Wochenschr1989114:1117.
50.BRENTF.Addison'sdiseaseandpregnancy.AmJSurg195079:645.
51.IrvineWJ,BarnesEW.Adrenocorticalinsufficiency.ClinEndocrinolMetab19721:549.
52.BurrowGN,FerrisTF.MedicalComplicationsDuringPregnancy,WBSaunders,Philadelphia1988.
53.CorryDB,TuckML.Secondaryaldosteronism.EndocrinolMetabClinNorthAm199524:511.
54.WuSJ,TsaiYL,HsiehBS.Sequentialchangesinplasmareninactivityandaldosteronelevelduringpregnancy.J
FormosMedAssoc199190:932.
55.FagundesVG,LamasCC,FrancischettiEA.Reninangiotensinaldosteronesysteminnormalandhypertensive
pregnancy.Responsetoposturalstimuli.Hypertension199219:II74.
56.DrrHG,HellerA,VersmoldHT,etal.Longitudinalstudyofprogestins,mineralocorticoids,andglucocorticoids
throughouthumanpregnancy.JClinEndocrinolMetab198968:863.
57.FunderJW.Aldosteroneaction:fact,failureandthefuture.ClinExpPharmacolPhysiolSuppl199825:S47.
58.ThomsenJK,FoghAndersenN,JaszczakP,GieseJ.Atrialnatriureticpeptide(ANP)decreaseduringnormal
pregnancyasrelatedtohemodynamicchangesandvolumeregulation.ActaObstetGynecolScand199372:103.
59.DUNLOPD.EIGHTYSIXCASESOFADDISON'SDISEASE.BrMedJ19632:887.
60.BergthorsdottirR,LeonssonZachrissonM,OdnA,JohannssonG.PrematuremortalityinpatientswithAddison's
disease:apopulationbasedstudy.JClinEndocrinolMetab200691:4849.
61.LvsK,LogeJH,HusebyeES.SubjectivehealthstatusinNorwegianpatientswithAddison'sdisease.Clin
Endocrinol(Oxf)200256:581.
62.HahnerS,LoefflerM,FassnachtM,etal.Impairedsubjectivehealthstatusin256patientswithadrenal
insufficiencyonstandardtherapybasedoncrosssectionalanalysis.JClinEndocrinolMetab200792:3912.
63.GrantDB,BarnesND,MoncrieffMW,SavageMO.Clinicalpresentation,growth,andpubertaldevelopmentin
Addison'sdisease.ArchDisChild198560:925.
64.UrbanMD,LeePA,GutaiJP,MigeonCJ.AndrogensinpubertalmaleswithAddison'sdisease.JClinEndocrinol
Metab198051:925.

Topic155Version15.0

https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&searc 9/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

GRAPHICS

Treatmentofacuteadrenalinsufficiency(adrenalcrisis)inadults

Emergencymeasures
1.Establishintravenousaccesswithalargegaugeneedle.

2.Drawbloodforimmediateserumelectrolytesandglucoseandroutinemeasurementofplasmacortisol
andACTH.Donotwaitforlabresults.

3.Infuse2to3litersofisotonicsalineor5percentdextroseinisotonicsalineasquicklyaspossible.
Frequenthemodynamicmonitoringandmeasurementofserumelectrolytesshouldbeperformedtoavoid
iatrogenicfluidoverload.

4.Give4mgdexamethasoneasintravenousbolusoveronetofiveminutesandevery12hours
thereafter.Dexamethasoneisthedrugofchoicebecauseitdoesnotinterferewiththemeasurementof
plasmacortisol.Ifdexamethasoneisunavailable,intravenoushydrocortisone,100mgimmediatelyand
everysixhoursthereafter,maybeused.

5.Usesupportivemeasuresasneeded.*

Subacutemeasuresafterstabilizationofthepatient
1.Continueintravenousisotonicsalineataslowerratefornext24to48hours.

2.Searchforandtreatpossibleinfectiousprecipitatingcausesoftheadrenalcrisis.

3.PerformashortACTHstimulationtesttoconfirmthediagnosisofadrenalinsufficiency,ifpatientdoes
nothaveknownadrenalinsufficiency.

4.Determinethetypeofadrenalinsufficiencyanditscauseifnotalreadyknown.

5.Taperparenteralglucocorticoidoveronetothreedays,ifprecipitatingorcomplicatingillnesspermits,to
oralglucocorticoidmaintenancedose.

6.Beginmineralocorticoidreplacementwithfludrocortisone,0.1mgbymouthdaily,whensalineinfusion
isstopped.

*Electrolyteabnormalitiesmayincludehyponatremia,hyperkalemiaorrarelyhypercalcemia.Hyponatremiais
rapidlycorrectedbycortisolandvolumerepletion.

Graphic67329Version6.0

https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&sear 10/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

Comparisonofrepresentativeglucocorticoidpreparations

Equivalent Relative Relative Duration

doses* antiinflammatory mineralocorticoid ofaction
(mg) activity activity (hours)
Hydrocortisone 20 1 1 8to12
(cortisol)

Cortisoneacetate 25 0.8 0.8 8to12

Prednisone 5 4 0.8 12to36

Prednisolone 5 4 0.8 12to36

Methylprednisolone 4 5 0.5 12to36

Triamcinolone 4 5 0 12to36

Fludrocortisone Notusedforan 10 125 12to36

antiinflammatory
effect

Dexamethasone 0.75 30 0 36to72

Prednisoneandprednisolonearepotentglucocorticoidsandweakmineralocorticoids.Dexamethasone
hasnomineralocorticoideffect.

*Equivalentantiinflammatorydoseshownisfororalorintravenous(IV)administration.Relativepotencyfor
intraarticularorintramuscularadministrationmayvaryconsiderably.
Glucocorticoiddoseswhichprovideamineralocorticoideffectthatisapproximatelyequivalentto0.1mg
fludrocortisoneareprednisoneorprednisolone50mg,orhydrocortisone20mg.

Datafrom:
1.SchimmerBP,ParkerKL.Adrenocorticotropichormoneadrenocorticalsteroidsandtheirsynthetic
analogsinhibitorsofthesynthesisandactionsofadrenocorticalhormones.In:ThePharmacologicalBasis
ofTherapeutics,11thed,BruntonLL,LazoJS,ParkerKL(Eds),McGrawHill,NY.p.1587.Copyright
2006.
2.DonohouePA.Theadrenalglandanditsdisorders.KappyMS,AllenDB,GeffnerME(Eds),CharlesC
Thomas,Springfield,IL.p.403.Copyright2005CharlesCThomas,Publisher,Ltd.

Graphic64138Version16.0

https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&sear 11/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

Treatmentofchronicprimaryadrenalinsufficiency

Glucocorticoidreplacement
1.Dexamethasone0.5(0.25to0.75)mgorprednisone5(2.5to7.5)mgorallyatbedtime.Supplement
withhydrocortisone5to10mgorallyinmidafternoonifindicated.

2.Alternativetherapyiswithhydrocortisone15to20mguponawakeningand5to10mginearly
afternoon.

3.MonitorclinicalsymptomsandmorningplasmaACTH.

Mineralocorticoidreplacement
1.Fludrocortisone0.1(0.05to0.2)mgorally.

2.Liberalsaltintake.

3.Monitorlyingandstandingbloodpressureandpulse,edema,serumpotassiumandplasmarenin
activity.

Androgenreplacement
1.Dehydroepiandrosterone25to50mgorallyinwomen.

Patienteducation
1.Educatepatientaboutthedisease,howtomanageminorillnessesandmajorstresses,andhowto
injectdexamethasoneintramuscularly.

Emergencyprecautions
1.ObtainMedicAlertbracelet/necklace,EmergencyMedicalInformationCard,andprefilledsyringes
containingdexamethasone4mgin1mLsaline.

Treatmentofminorfebrileillnessorstress
1.Increaseglucocorticoiddosetwotothreefoldforthefewdaysofillness.Donotchange
mineralocorticoiddose.

2.Contactphysicianifillnessworsensorpersistsformorethanthreedays.

3.Noextrasupplementationisneededformostuncomplicated,outpatientdentalproceduresunderlocal
anesthesia.Generalanesthesiaorintravenoussedationshouldnotbeusedintheoffice.

Emergencytreatmentofseverestressortrauma
1.Injectcontentsofprefilleddexamethasone(4mg)syringeintramuscularly.

2.Gettophysicianasquicklyaspossible.

Graphic78904Version3.0

https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&sear 12/13
7/28/2016 Treatmentofadrenalinsufficiencyinadults

ContributorDisclosures
LynnetteKNieman,MDGrant/Research/ClinicalTrialSupport:HRAPharma[Cushing'ssyndrome(Metapirone)].Andr
Lacroix,MDGrant/Research/ClinicalTrialSupport:Novartis[Pituitarytumors,Cushingssyndrome(Pasireotide,
octreotide,osilodrostat)]Cortendo[Cushing'ssyndrome(Levoketoconazole)].Speaker'sBureau:Novartis[Cushings
syndrome(Pasireotide,octreotide,osilodrostat)]EMDSerono[Cushing'ssyndrome(Lanreotide)].Consultant/Advisory
Boards:Novartis[Pituitarytumors,Cushing'ssyndrome(Pasireotide,octreotide,osilodrostat)]EMDSerono[Pituitary
tumors(Lanreotide)].KathrynAMartin,MDNothingtodisclose.

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.
AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.

Conflictofinterestpolicy

https://www.uptodate.com/contents/treatmentofadrenalinsufficiencyinadults?topicKey=ENDO%2F155&elapsedTimeMs=19&source=search_result&sear 13/13