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K Laugesen and others Glucocorticoid-induced adrenal 184:3 R111–R122 Review insufficiency

MANAGEMENT OF ENDOCRINE DISEASE Glucocorticoid-induced : replace while we wait for evidence?

Kristina Laugesen 1, Leonie H A Broersen2, Simon Bøggild Hansen3,4, Olaf M Dekkers 1,2, Henrik Toft Sørensen1 and Jens Otto L Jorgensen4

1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark, 2Division of , Correspondence Department of Medicine, Leiden University Medical Centre, ZA Leiden, the Netherlands, 3Department of Clinical should be addressed , and 4Department of Endocrinology and Internal Medicine, Aarhus University Hospital, to K Laugesen Aarhus, Denmark Email [email protected]

Abstract

Glucocorticoids are, besides non-steroidal anti-inflammatory , the most widely used anti-inflammatory . Prevalence studies indicate substantial use of both systemic and locally acting agents. A recognised adverse effect of glucocorticoid treatment is adrenal insufficiency, which is highly prevalent based on biochemical testing, but its clinical implications are poorly understood. Current evidence, including randomised trials and observational studies, indicates substantial variation among patients in both risk and course of glucocorticoid- induced adrenal insufficiency, but both are currently unpredictable. Oral and intra-articular formulations, as well as long-term and high-dose treatments, carry the highest risk of glucocorticoid-induced adrenal insufficiency defined by biochemical tests. However, no , treatment duration, or dose can be considered without risk. More research is needed to estimate the risk and temporal pattern of glucocorticoid-induced adrenal insufficiency, to investigate its clinical implications, and to identify predictors of risk and prognosis. Randomized trials are required to evaluate whether replacement therapy mitigates risk and symptoms of glucocorticoid-induced

European Journal of Endocrinology adrenal insufficiency in patients discontinuing glucocorticoid treatment. This review aims to provide an overview of the available evidence, pointing to knowledge gaps and unmet needs.

European Journal of Endocrinology (2021) 184, R111–R122

Invited Author’s profile Jens Otto Lunde Jørgensen is Professor and Chair of the Department of Clinical Medicine and the Department of Endocrinology and , Aarhus University Hospital, Denmark. Prof Jørgensen’s main research interests include pituitary endocrinology including GH deficiency, acromegaly, Cushing syndrome. He is currently principal investigator of a novel Novo Nordisk Foundation grant entitled DOUBLE EDGE, which will focus on the consequences of long term glucocorticoid treatment involving clinical epidemiology and randomised clinical trials in close collaboration with Danish and international co-investigators.

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-20-1199 European Journal of Endocrinology https://eje.bioscientifica.com (HPA)hypothalamic–pituitary–adrenal axis. cortex ( produced in the of the adrenal Cortisol isanactive endogenous glucocorticoid The hypothalamic–pituitary–adrenalaxis 10%) andsystemicglucocorticoids(≈3%)( population indicatessubstantialuseofbothtopical(≈0.1– The annualprevalenceofglucocorticoiduseintheDanish of long-termuse( settings, timeperiodandmethodology, and the prevalence glucocorticoid userangesfrom0.5to20%,dependingon Prevalence studiesfoundthattheprevalenceoforal Extent ofglucocorticoiduse recommend directionsforfutureresearch. available evidence,(ii)identifyknowledgegaps,and(iii) insufficiency, ofthe weaimto(i)provideanoverview studies. observational insufficiency; andabsenceofrelevantrandomisedtrials in riskandcourseofglucocorticoid-inducedadrenal modes ofadministration;widevariationamongpatients numerous indicationsforglucocorticoidtherapy;multiple adrenal insufficiencylikelyreflectsavarietyoffactors: guidelines on the management of glucocorticoid-induced be documented( to glucocorticoid-inducedadrenalinsufficiencyremains are well-known,thedegreetowhichthesefeaturesapply adrenalinsufficiency clinical pictureandseverityofprimary insufficiency remainpoorlycharacterised( clinical implicationsofglucocorticoid-inducedadrenal is highlyprevalentbasedonbiochemicaltesting.Still,the In addition,glucocorticoid-inducedadrenalinsufficiency long-term suchlikeosteoporosisandcardiovasculardisease. hyperglycaemia andneuropsychiatricsymptomsonthe has manyadverseeffects,bothontheshort-termsuchas drugs. Itisrecognisedthatglucocorticoidtreatmentalso drugs, besidesfromnon-steroidalanti-inflammatory are amongthemostfrequentlyprescribedanti-inflammatory in PhysiologyorMedicine1950( led Kendall,Reichstein,andHenchtoreceivetheNobelPrize well asforsymptomreliefincertaincancers.Thisdiscovery andautoimmuneconditions,as numerous inflammatory properties of glucocorticoids are effective in managing andimmunosuppressive The potentanti-inflammatory Introduction Review In thisreviewofglucocorticoid-inducedadrenal 12 ). Plasmacortisollevelsare regulatedbythe 4 , ≥ 5 3 months)is≈1%( ). The lack of evidence-based clinical ). Thelackofevidence-basedclinical K Laugesenandothers 1 ). Today glucocorticoids 6 , 2 7 Fig. 1 , , 3 8 ). While the ). Whilethe , 9 ). , 10 , 11 ). ). year. Reference:medstat.dk,accessed04/08/2020. year dividedbythenumberofpeopleinpopulationeach redeemed atleastoneprescriptionforaglucocorticoideach administration. *Definedasthenumberofpeoplewho population from1999to2019,stratifiedbyrouteof Annual prevalence*(%)ofglucocorticoiduseintheDanish Figure 1 interconversion between cortisol and cortisoneiscatalysed inactive cortisoneregulates intracellularbioactivity. The but abalancebetweenbiologically activecortisoland cortisol diffusesfreelythrough thecellmembrane, . Duetotheir lipophilicstructure,unbound regulates byeithertransactivation or receptors.Bindingtothesereceptors through bindingtotheintracellularglucocorticoidand Cortisol exertsphysiological(andadverse)effects trauma, surgery, hypoglycaemia, andmentalstress. greatly duringsuchstressorsasinfections,acuteillness, production isintherangeof10–20mg/dayandincreases and activityofenzymeshormonalsystems.Cortisol rather allowsthemtooccurbyincreasingtheexpression cortisol itselfdoesnotinitiatephysiological processes, but systems( nervous vasopressin), aswellthereproductiveandcentral and electrolytehomeostasis(throughregulationof andimmunesystem,water function, theinflammatory foetal development,substratemetabolism,cardiovascular resting as well as -related and impacts few percentunboundandbiologicallyactive. globulin (75–80%)andalbumin(10–15%),leavingonlya , cortisolisboundtocortisol-binding early morningandanadiratmidnight( circadian rhythmicitycharacterised bypeaklevelsinthe secretion isstimulatedbystresssignalsandsubjectto insufficiency Glucocorticoid-induced adrenal Prevalence (%) 10 11 0 1 2 3 4 5 6 7 8 9 Many oftheactionsarepermissive,meaningthat regulatorof Cortisol isanessentialandpervasive 1999 2001 Inhaled 2003 Fig. 3 2005 Inhaled (combinationtherap ) ( 2007 Downloaded fromBioscientifica.com at10/02/202107:04:04PM 12 ). Ye 2009 ar y) 2011 IntestineS 184 2013 Fig. 2 :3 kin 2015 Systemic ) ( 12 2017 ). Inthe R112 2019 via freeaccess European Journal of Endocrinology exist. Althoughthereisno goldstandard,theshort of hypocortisolism.Several diagnosticstimulationtests Adrenal insufficiencyisabiochemically defineddiagnosis Glucocorticoid-induced adrenal insufficiency cell membraneandinthecytosol. through interactionswithbothlipidsandproteinsonthe accumulating evidencesuggestsfasteractionsmediated 11 by 11 genomic andnon-genomicpathways. negative feedbackonCRHandACTHreleasethroughboth trophic effectsontheadrenalcortex.Inturn,cortisolexerts release ofcortisolfromtheadrenalglands.ACTHalsoexerts from theanteriorpituitary.ACTHpromotessynthesisand stimulates thereleaseofadrenocorticotropichormone(ACTH) secretes corticotropin-releasinghormone(CRH),which When stimulated,thehypothalamicparaventricularnucleus Overview ofthehypothalamic–pituitary–adrenal(HPA)axis. Figure 2 Review β -HSD2 ( β -hydroxysteroid dehydrogenase 1 (11 13 ). Asidefromeffectsongenetranscription, K Laugesenandothers β -HSD1) and within thefirstweek(50/74 studies).In22studies,the range of0–30days,buttesting wasmostlyperformed between lastglucocorticoid dose andfirsttestwasinthe insufficiency via feedback suppression of CRH and ‘glucocorticoid-induced adrenalinsufficiency’. insufficiency. In this review, term weuse theexpository condition asiatrogenic,secondary, adrenal ortertiary induced adrenal insufficiency, with some referring to the The terminology has not been finalised for glucocorticoid- insufficiency when it iscaused by hypothalamic disease. disorders ( or hypothalamic (ACTH) deficiency arising from pituitary insufficiency involvesadrenocorticotropic hormone adrenal by deficientlevelsofaldosterone.Secondary denotes adrenaldiseaseandisusuallyaccompanied adrenalinsufficiency underlying mechanism.Primary modern assays,thecut-offis abnormal cortisol responseis assay-dependent. In many practice. Thecortisolcut-offvalueusedtodefinean Synacthen test(SST)isusedmostcommonlyinclinical and ≈4%forintranasaladministration ( for inhaledglucocorticoids,≈5% fortopicaladministration, for oraluse,≈52%intra-articularadministration,≈8% insufficiency duringtreatmentoratcessationwere≈50% ( or aroundcessation,stratifiedbyrouteofadministration with glucocorticoid-inducedadrenalinsufficiencyduring years ofage)andestimatedpooledpercentages ofpatients analysis encompassed74studiesand3753patients( 16 summarised insystematicreviewsandmeta-analyses( insufficiency hasbeenexaminedinnumerousstudiesand Biochemically definedglucocorticoid-inducedadrenal Occurrence less clearclinicalimplications( adrenal insufficiency is much more prevalent, but with saving ( and hormonereplacementtherapyisconsideredlife- recognised seriousconditionsrequiringpromptdiagnosis rare (prevalence adrenal insufficiencyduetostructuraldisordersare adrenalinsufficiencyandsecondary treatment. Primary insufficiency maypersistaftercessationofglucocorticoid produce an adequate cortisol response to stress. Adrenal and , and rendering the HPA axis unable to ACTH, eventuallyinducingadrenocorticalhypoplasia insufficiency Glucocorticoid-induced adrenal Fig. 4 ). Broersen Glucocorticoid treatmentmaycauseadrenal Adrenal insufficiencyiscategorisedaccordingtothe ). Thepooledpercentages ofpatientswithadrenal 4 , 4 5 , , et al. 5 15 , = ). In contrast, glucocorticoid-induced

100–200 permillionpersons),butare 15 ’s ( ’s ). Some refer to tertiary adrenal ). Somerefertotertiary 2 ) 2015systematicreviewandmeta- Downloaded fromBioscientifica.com at10/02/202107:04:04PM < 420nmol/L( 2 https://eje.bioscientifica.com , 3 , 16 184 ). :3 Fig. 4 14 ) ( ). 2 ). Time R113 2 ≥ , 12 via freeaccess 3 , European Journal of Endocrinology https://eje.bioscientifica.com (50/74 studies).In22studiesthey didnotreportthistimegap. days, butthetestwasmostlyperformed withinthefirstweek glucocorticoid doseandfirsttest wasintherangeof0–30 Meta-Analysis. Insufficiency inCorticosteroidsUse:SystematicReviewand adapted withpermissionfromBroersenLHA, cessation, stratifiedbyroutesofadministration.Figure induced adrenalinsufficiencyduringtreatmentoraround Pooled percentagesofbiochemicallyverifiedglucocorticoid- Figure 4 of treatment(interquartilerange:13–63%)( systemic glucocorticoidusersduringoraroundcessation for glucocorticoid-inducedadrenalinsufficiencyamong ( review, which encompassed 73 studies and 3166 patients line withthesestudies,Joseph ( been publishedforpaediatricpatientstreatedwithsystemic authors didnotreportthetimegap.Similarfindingshave ≥ 16 Multiple form Nasal Topical Inhalation Intra-articular Oral Review 16 yearsofage),reportedamedianpercentage of37% ), inhaled( 2015 s Studi The JournalofClinicalEndocrinology and 17 11 15 60 38 100 8 4 es/ , 18 pa 1418 1419 2171–280.Timebetweenlast , tients 354 173 320 19 69 ), ortopicalglucocorticoids( 0 25 et al. 50 K Laugesenandothers ’s ( ’s Pooled percentages 75 3 ) 2016systematic 100 et al. 3 42.7 (28.6-58.0) 4.2 (0.5-28.9) 4.7 (1.1-18.5) 7.8 (4.2-13.9) 52.2 (40.5-63.6) 48.7 (36.9-60.6) ). Adrenal (95% 20

CI ). In ) and choiceofbiochemicalmethods(testtype,assay, and form, doseandduration),aswelloutcomeassessment treatment regimens(glucocorticoidtype,administration heterogeneous regardingpatientselection,glucocorticoid (including cohort studies with secondary reporting of(including cohort studies with secondary this article)providesareview ofthirteencasereports section on been studiedextensively. Table Supplementary 1(see glucocorticoid-induced adrenal insufficiencyhavenot As notedearlier, theclinicalimplicationsof Clinical implications after glucocorticoiduse. the potentiallong-termnatureofadrenalinsufficiency 5% threeyearsfollowingcessation( 25 up to 40% six months following cessation ( oral treatmentcessationdeclinesovertime,butremains percentage ofpatients with adrenalinsufficiency following discontinuation ofglucocorticoidtreatment.The oftheHPAA keyissueistimetorecovery axisfollowing Recovery oftheHPAaxis difficult tointerprettheresultsinclinicalcontext. absolute risksorincidencerates,whichmakesitmore circumvented directreporting ofeffectmeasuresas many cohortstudiesorrandomisedtrialsonthesubject and shouldbeinterpretedwithcaution.Furthermore, analysis byBroersen among studies.Hence,thepooledpercentages inthemeta- cut-off values).Itisthereforedifficulttomakecomparisons insufficiency Glucocorticoid-induced adrenal ), 20% two years following cessation ( It is important to note that current studies are highly It isimportanttonotethatcurrentstudiesarehighly supplementary materials supplementary Physiological effectsofcortisol. Figure 3 et al. Downloaded fromBioscientifica.com at10/02/202107:04:04PM ’s ( ’s 2 ) may be difficult to evaluate ) maybedifficulttoevaluate 26 givenattheendof 184 ). Thisunderscores :3 26 21 , 27 , 22 , 28 , 23 R114 ), and , 24 via freeaccess , European Journal of Endocrinology insufficiency inthisgroup may below. treatment ( to one-thirdofpatientson low-doseoralglucocorticoid glucocorticoid-induced adrenal insufficiencyoccursinup replacement duringstress.This isagenuineconcern,as treatment therefore may require extra glucocorticoid distress ( illnesses, trauma, surgery, or psychological starvation, factors foranadrenalcrisisincludeinfections,otheracute from thisclinical picture described earlier. Precipitating of glucocorticoid-inducedadrenalinsufficiencydiffers to clarifywhetherthecourse(severityandoutcome) seizures, andeventuallycoma.Littleevidenceisavailable symptoms, cardiovascularcollapse,hypoglycaemia, an acuteadrenalcrisiswithseveregastrointestinal Insufficient cortisolresponsivenesstostressmayinduce weight loss,, andneuropsychiatricsymptoms. symptoms suchasfatigue,anorexia,nausea,hyponatremia, crisis duringtreatmentdiscontinuation( speculated ifthiscontrastwasattributabletoadrenal those without(mortalityrateratioof2.09).Theauthors with apriorrecordofadrenalinsufficiencycomparedto of non-usemortalityratewashigheramongpeople rates (mortalityrateratioof1.02),butduringperiods without adrenalinsufficiencyhadsimilarmortality periods of glucocorticoid treatment, people with and 1000 person years during entire follow-up. During adrenal insufficiency, themortalityratewas51per as aresult.Amongpeoplewithglucocorticoid-induced condition amongclinicians with likelyunderreporting lower thanthetrueratesduetoalackofawarenessthis mg in the past year ( person-years forperiodswithcumulativedose during periodsof Incidence rateswereupto0.86per1000person-years orhospitalcare( insufficiency diagnosedinprimary dose-dependent ratesofglucocorticoid-inducedadrenal UK ( glucocorticoid treatmentitself.Acohortstudyfrom treatment suchaschemotherapy, andindeedthe (such ascancer)oradverseeffectsofconcomitant of adrenalinsufficiencyfromthetreatmentindication inherently difficulttodistinguishsymptomsandsigns in therandomisedtrialsorcohortstudies.Further, itis screening forclinicaloutcomesorincompletefollowup on thistopic.Mostwerehamperedbynon-standardised studies ( 35 symptoms andsigns)( Review , 36 Prolonged hypocortisolemiamaycausenon-specific n , 37 = 70638oralglucocorticoidusers)quantified 27 15 , 38 , 45 ). Patientsreceivinglow-doseglucocorticoid 41 ), two randomised trials ( ), and awareness of the potential for adrenal ) andtwocross-sectionalstudies( ≥ 7.5 mg/dayandupto30per1000 44 24 ). The observed rates were likely). The observed , 25 , 28 K Laugesenandothers , 29 , 39 30 , , 44 40 31 ). ), two cohort , 32 , 42 33 ≥ 3055 , , 44 43 34 ). ). ) , – – test (SST). the insulin tolerance test (ITT) and the short Synachten glucocorticoid-induced adrenalinsufficiency, including Several stimulationtestsexisttoconfirmthediagnosisof and theshortSynacthentest Diagnostic accuracyoftheinsulintolerancetest insufficiency) ( SST was developed for Addison’s adrenal disease (primary test shouldbevalidatedbefore useinclinical practice. The and theSSTisstillconsidered superior. pragmatic alternative,butsufficientevidenceislacking Measuring morningcortisol/ACTHmayprovide a insufficiency Glucocorticoid-induced adrenal – – axis at the level. It was originally devised axis attheadrenalglandlevel.Itwasoriginallydevised The SST, the most widely used test, evaluates the HPA hypoglycaemia candiffer. well, the ITT may not be reliable, as levels of induced ofcardiovasculardiseaseorseizures.As a history for thepatients and contraindicated in patients with clinical practice,asitislabour-intensive,unpleasant insufficiency. However, itisrarelyusedinroutine adrenal the goldstandardfordiagnosingsecondary level)andisconsidered (hypothalamic andpituitary The ITT evaluates the HPA axis atthe central level condition aswellitsmanyunknownaspects. adrenal insufficiency, partlyduetothecomplexity ofthe lack goldstandardtodefineglucocorticoid-induced context. Acentralconsiderationisthatwecurrently therefore, beinterpretedincombinationwiththeclinical specificity). Values close to the normal range should, cut-off valuesprovideahighersensitivitybutlower value isamatterofsensitivityandspecificity(higher MS. Cliniciansshouldmindthatthischoiceofcut-off plasma cortisol in healthy adults measured by LC-MS/ of 420nmol/Lisdecidedbasedonthe2.5percentile of measured withimmunoassays.Thecortisolcut-offvalue ( LC-MS/MS avoidscross-reactivitywithothersteroids most specificformeasureofplasmacortisollevels,as (LC-MS/MS)isconsidered tandem massspectrometry many modernassays( is assay-dependent;avalueof420nmol/Lusedin an adequateadrenalresponse.Thecortisolcut-offvalue value 30minpost-Synacthenadministrationindicates (Synachten). Aplasmacortisolvalueabovethecut-off intravenous administrationof250 performed bymeasuringcortisolbeforeand30minafter adrenal insufficiency.for diagnosingprimary Thetestis 14 Ideally, thediagnostic accuracyofanybiochemical ). Inclinicalsettings,plasmacortisolis,however, often 46 ) andthediagnosticaccuracy ofthetest Downloaded fromBioscientifica.com at10/02/202107:04:04PM 14 ). Theliquidchromatography- https://eje.bioscientifica.com μ 184 g of synthetic ACTH g of synthetic ACTH :3 R115 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com associated withadverseeffects duetoovertreatment. questions, ashydrocortisone replacementmayalsobe the contextofaprospective trial?Thisisanimportant ask ifnotthetimehascome totestthisassumptionin and often dynamic nature of this condition, one could However, given its high prevalence, specific pathogenesis, patients withglucocorticoid-inducedadrenalinsufficiency. It istemptingtoextrapolatethisclinicalexperience to replacement iftheyrespondinsufficientlytotheSST( that affectedpatientsshouldbeofferedhydrocortisone intact aldosteroneproduction.Itisuniformlyaccepted some residualadrenalfunctionmayremain,including adrenalinsufficiencyisoften lesssevere,since of secondary replacement areself-evident( test of time and the life-saving effects of hydrocortisone adrenalinsufficiencyhasstoodthe of severeprimary disease( patients withpituitary adrenalfailure,typicallyin used todiagnosesecondary adrenalinsufficiency( primary As mentioned,theSSTwasoriginallydevelopedtodiagnose – unanswered. We discusstwoquestions: outcomes isunknownandseveralquestionsremain The associationbetweentheSynacthentestandclinical clinical outcomes The associationbetweentheSynacthentestand the concomitanttreatmentandunderlyingdiseases. the diagnosis, giventhe overlap inclinical symptoms with in many patients the clinical picture is of limited value for pragmatic choiceofsensitivityandspecificitylevels.Fourth, a value toruleoutorinadrenalinsufficiencyremains adrenalinsufficiency.primary Third,thecortisolcut-off yield afalsenormalresponseintheearlystageofanynon- test evaluatestheHPA axisattheadrenalglandlevel,itmay diagnostic accuracyofthetestisunknown.Second,as glucocorticoid-induced adrenalinsufficiency. First,the validate theSST( partly duetoalackofgoldstandardagainstwhich The studyexcludedpatientsonglucocorticoidtreatment relative highspecificity(0.93)andlowsensitivity(0.64). disorders) documented insufficiency (due topituitary adrenal the diagnosticaccuracyofSSTinsecondary remains unknown.Ameta-analysisthatinvestigated in relationtoglucocorticoid-inducedadrenalinsufficiency – Review adrenal insufficiency? test correlate withsymptomsandclinicaloutcomesof response toastimulation First, doesaninsufficientcortisol Several concerns are salient in use of the SST to diagnose Several concernsaresalientinuseoftheSSTtodiagnose 47 ). 49 46 , 48 K Laugesenandothers 50 ) and subsequently was ) andsubsequentlywas ). The clinical picture ). Theclinicalpicture ). The clinical picture ). Theclinicalpicture 51 ). ). glucocorticoid withdrawalsyndromeisunknown. induced adrenalinsufficiency, theclinicalimpactof disrupted after discontinuation ( treatment, thebodyadjuststoanewequilibrium,whichis and dependence.Duringtheperiodofglucocorticoid considered tobeaconsequenceoftolerancedevelopment symptoms resembleadrenalinsufficiency. Thesyndromeis desquamation,andposturalhypotension( headache andlethargy, fever, myalgiaandarthralgia, such asanorexiaandweightloss,nauseavomiting, doses. Ittypicallymanifestswithunspecific symptoms withdrawal syndrome is likelyrelated to high glucocorticoid treatment, someexhibitwithdrawalsymptoms( insufficiency followingcessationofglucocorticoid Even amongpatientswithoutbiochemicaladrenal – As displayedin pharmacokinetic andpharmacodynamic properties. The generictypesofglucocorticoids havedifferent Generic typesofglucocorticoids safe fromthisrisk( routes ofadministration can be consideredcompletely glucocorticoid-induced adrenalinsufficiency, butno articular glucocorticoidscarriesthehighestrisk of As statedpreviously, treatmentwithoral andintra- Route ofadministration induced adrenalinsufficiencyandHPA time. axisrecovery heterogeneous andmayaffecttheriskofglucocorticoid- type, dose,duration,androuteofadministration)arehighly Glucocorticoid treatmentregimens(genericglucocorticoid Treatment regimens insufficiency areunpredictable,asdiscussedsubsequently. the riskandcourseofglucocorticoid-inducedadrenal to stratifypatientsintorelevantriskcategories.Currently, adverse outcomes.Thepurposeofsuchpredictorswouldbe identify validpredictorsofdiagnosis,recovery, andclinical glucocorticoid-induced adrenalinsufficiency, itiscriticalto substantial individualvariationinsusceptibilityto Given thewidespreaduseofglucocorticoidsand insufficiency andrecovery Predictors ofglucocorticoid-inducedadrenal insufficiency Glucocorticoid-induced adrenal – out related clinicalsymptomsandoutcomes? response testrule stimulatedcortisol Second, doesanormal Table 1 2 ). Downloaded fromBioscientifica.com at10/02/202107:04:04PM , 5 mg of oral is , 5mgoforalprednisolone is 52 ). As with glucocorticoid- 184 :3 52 52 ). These ). These R116 ). The ). The via freeaccess European Journal of Endocrinology AE, approximateequivalent;GC,glucocorticoid; MC,mineralocorticoid. suppression. *Equivalent anti-inflammatorydose isfororalorintravenousadministration.**Thebiologiceffectivehalf-life isbasedonthedurationofACTH Long-acting Prednisolone Intermediate-acting Hydrocortisone Short-acting Systemic glucocorticoid Table 1 and routeofadministrationareintercorrelated. Asan to recognisethatfactorssuchasdose,treatmentduration, adrenal insufficiencybytreatmentregimen,itisimportant systemic glucocorticoids( by averagedailydose,duration,orcumulativedoseof by Joseph completely without risk ( insufficiency. However, notreatmentdoseordurationis produced a higher risk of glucocorticoid-induced adrenal that high-doseandlong-termglucocorticoidtreatment The meta-analysisconductedbyBroersen induced adrenalinsufficiencyremainscontroversial. The effectofdoseanddurationonriskglucocorticoid- Dose andduration children treated with prednisolone vs dexamethasone ( ( incidence of glucocorticoid-induced adrenal insufficiency lymphoblastic leukaemiafoundnodifferenceinthe vs dexamethasonetreatmentinchildrenwithacute controlled trialsthatcomparedhigh-doseprednisolone dose anddurationoftreatment).Two randomised short-acting glucocorticoids(givensameequivalent induced adrenal insufficiency compared to for example, formulations mayincreasetheriskofglucocorticoid- direct reflectionoftimeACTH-suppression,long-acting their biologicalhalf-life( long-acting (dexamethasone,betamethasone)basedon (prednisolone, prednisone,methylprednisolone), and into short-acting(hydrocortisone),intermediate-acting ( potency dexamethasone inconcerntoanti-inflammatory mg ofmethylprednisoloneand0.75beta-or considered equivalentto20mgofhydrocortisone,4 40 53 Review , ). Furthermore,systemicglucocorticoidsarecategorised When evaluating the risk of glucocorticoid-induced When evaluatingtheriskofglucocorticoid-induced 54 ). A cohort study observed earlier recovery in in earlierrecovery ). Acohortstudyobserved Pharmacokinetic andpharmacodynamicpropertiesofselected oralglucocorticoids. et al. foundnoobviouspatternafterstratifying Fig. 5 3 53 ). ). As biological half-life is a ). Asbiologicalhalf-lifeisa ) ( 2 K Laugesenandothers ). The systematic review AE dose* 0.75 0.75 et al. 20 4 5 5 (mg) showed 25 ). Relative GCactivity a subgroup of 110 patients with glucocorticoid-induced a subgroupof110patientswithglucocorticoid-induced ( the SSTtopredictadrenalrecovery time.Onestudyisavailablethatassesseduseof axis recovery Test resultscouldbeavaluableclinicaltooltopredictHPA Test results treatment periodsandnotjustpriortocessation. average daily glucocorticoid dose during the entire the majorityofstudiesincludedinthosereviewsreported reviews byBroersen induced adrenalinsufficiency. Inaddition,thesystematic relatively low percentage of associated glucocorticoid- with lowbioavailability, whichislikelytounderliethe topically applied glucocorticoidsare low-dose formulations glucocorticoid-induced adrenalinsufficiency. Incontrast, This likelyexplainsthehighpercentage ofassociated formulations withunavoidablesystemicabsorption. example, intra-articulartreatmentsarehigh-dosedepot 24-hour metabolome, soluble CD16, insufficiency, butpotentialcandidatesincludethe or clinicalcourseofglucocorticoid-inducedadrenal Currently, nobiomarkersexisttopredictdiagnosis Biomarkers andgenotypes second SSTatthetimeofstudyinclusion( the studywaspronetoselectionbias,asitstipulatedafuture days forpatientswithΔcortisol in patientswithΔcortisol timewas262days (AUC) was0.77andthemedianrecovery ofthereceiveroperatingcurve The areaunderthecurve nmol/L and cortisol afterSynacthen–basalcortisol)dividedinto adrenal insufficiency. In this subgroup, Δ cortisol (30 min insufficiency Glucocorticoid-induced adrenal 30 30 5 4 4 1 ≤ 100 nmol/Lwaspredictiveofadrenalrecovery. Minimal Minimal Minimal 0.8 0.8 1 Relative MCactivity et al Downloaded fromBioscientifica.com at10/02/202107:04:04PM . ( > 2 100 nmol/L, compared to 974 100 nmol/L,comparedto974 ),

≤ Joseph 100 nmol/L( https://eje.bioscientifica.com 55 184 ). The study included ). Thestudyincluded et al :3 55 Half-life** . ( ). 55 3 36–54 36–54 12–36 12–36 12–36 8–12 ), as well as ), aswell ). However, R117 (h) > 100 100 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com responsible for CD16 shredding. Last, glucocorticoid in solubleCD16.ADAM17is themainmetalloproteinase glucocorticoid deficiency, henceleadingtoanincrease , butshredding mayoccurinstatesof of natural killer cells, , , and controls ( with adrenalinsufficiencycomparedhealthy soluble CD16andADAM17areincreasedinpatients prognostic prediction( metabolism andmaybeusedfordiagnostic associated withdisordersofsteroidbiosynthesisand profiling, therefore,providesuniquefingerprints the 24-hoururinesteroidmetabolome.Metabolome Steroid biosynthesisandmetabolismaremirroredby containing 17)orCDF15,amongothers( ADAM17 (disintegrinandmetalloproteinasedomain- provide ahomogeneouspatientpopulation. opposed totheentirepopulationofglucocorticoidusers, 2. Analysiswasperformedforasthmapatientsonly,as exact schemeofdoseranges,pleaseseeSupplementaryTable categorisation, averagedoseanddurationwereused.For low-dose, anddosesabovetheupperboundashigh-dose.For coded asmedium-dose,dosesbelowthelowerbound between thelowerandupperboundsofrecommendation categorised accordingtorecommendeddoses,withthedoses month -1year;long-term: categorised asfollows:short-term: Metabolism Meta-Analysis. Insufficiency inCorticosteroidsUse:SystematicReviewand adapted withpermissionfromBroersenLHA cessation, stratifiedbytreatmentdoseandduration.Figure induced adrenalinsufficiencyduringtreatmentoraround Pooled percentagesofbiochemicallyverifiedglucocorticoid- Figure 5 High dos Medium dose Low dose Long term Medium term Short term Review e 57 2015 ). CD16isnormallyexpressedatthesurface Studi The JournalofClinicalEndocrinologyand 23 33 17 28 20 9 100 es / pati 2171–280.Treatmentdurationwas 464 900 248 483 738 420 ents 0 > 56 1 year.Treatmentdosewas ). Further, concentrations of 25 < 50 K Laugesenandothers 1 month;medium-term: Pooled percentages 75 et al. 100 21.5 (12.0-35.5 8.5 (4.2-16.8) 2.4 (0.6-9.3) 27.4 (17.7-39.8 11.9 (5.8-23.1 1.4 (0.3-7.4) 56 Adrenal , ( 95% 57 , CI 58 ) ) ) ) ). ). of steroid-producingcellsandsteroidogenesis( signalling pathwayisimportantforthedevelopment is highlyexpressedintheadrenalglandsandPDGFD inhaled glucocorticoidsforasthmaorCOPD( adrenal suppressioninchildrenandadultstreatedwith growth factorD(PDGFD)genelocuswasassociatedwith study foundthatgeneticvariationintheplatelet-derived signalling pathways. A recent genome-wide association to allcomponentsoftheHPA axisandglucocorticoid limited. Biologicallyplausiblegenecandidatescouldrelate focusing ongenotypeaspredictiveoretiologicalfactorsis glucocorticoid-induced adrenalinsufficiency, research aversive responsetowardsfoodintake( stress-induced hormone acting in the brain to induce an deficiency isassociatedwithelevatedlevelsofGDF15, a response toglucocorticoidsvariesconsiderablyamong or the 11 Other plausiblegenelociincludethosecodingforthe biochemically verifiedadrenal insufficiency( receiving low-doseoralglucocorticoid treatmenthave treatment. Nevertheless,up toone-thirdofpatients possible effectiveglucocorticoid doseandthentapering available clinicalguidelines recommend usingthelowest as glucocorticoid-inducedadrenalinsufficiency, most effective, uniform,andeconomicalmonitoring. based clinicalguidelinesneedtobedeveloped,provide patient-safety andcost-effectivenessperspective,evidence- individual clinicians’knowledgeandawareness.From a of treatmentisunsystematic,sporadic,andrelianton adrenal insufficiency during and following cessation or prevention. based clinicalguidelinestosupportmanagement cause ofadrenalinsufficiency, buttherearenoevidence- Glucocorticoid treatmentisbyfarthemostcommon Clinical practice–acallforevidence disentangle etiologicalpathways. Gene-environment studies on this subject are needed to for thelargevariationinglucocorticoidresponse( well as11 the gene loci encoding the glucocorticoid receptor as suppression test ( as demonstratedbythelow-dosedexamethasone to glucocorticoid-induced adrenal insufficiency, individuals andthismayalsoaffectsusceptibility insufficiency Glucocorticoid-induced adrenal Despite the individual variation in susceptibility to To reducetheadverseeffectsofglucocorticoids, such Currently, monitoring β -HSD areleadingcandidategenestoaccount 62 ). Atpresent, polymorphisms in Downloaded fromBioscientifica.com at10/02/202107:04:04PM of glucocorticoid-induced 184 58 :3 ). β 59 -HSD. The 45 ). PDGFD ). These ). These 60 R118 , 61 63 via freeaccess ). ). European Journal of Endocrinology to supportevidence-based clinicaldecision-making. More research is needed to refine the diagnosis and is likelytopresentandneeds tobeinvestigatedfurther. threatening. Nonetheless,substantial individualvariation based on biochemical testing and potentially life- Glucocorticoid-induced adrenalinsufficiencyisprevalent Conclusion andfutureperspectives relevant morbidity. diagnosed adrenalinsufficiencytranslatesintoclinically remains to beclarified which extent biochemically and ifconcomitantadministrationformsareused.Italso byadministration forms prevention mayfurthervary biochemical measures. Strategies formanagementand tapering forexampleinrelationtotheinterpretationof Further, switchingtohydrocortisoneeasesmonitoringof the same equivalent dose), but no evidence on this exist. oftheHPAmay alsoshortentimetorecovery axis(given therefore, carrieslowestriskofadrenalinsufficiencyand systemic glucocorticoids.Theoretically, hydrocortisone, life) isshortestforhydrocortisonecomparedtotheother tapering is thattime of ACTH-suppression (biological half- other genericglucocorticoidstohydrocortisoneduring subject. Thephysiologicalrationaleforconvertingfrom based, pointingtotheneedforrandomisedtrialsonthis or withdrawal.Neitherofthesestrategiesareevidence- others adviseswitchingtohydrocortisoneduringtapering a lowthresholdtotestpatientsfollowingwithdrawal,and induced adrenal insufficiency. Some suggestthe need for the riskandclinicalconsequencesofglucocorticoid- needed forconflictingevidenceonstrategiestomitigate at 3yearspost-cessation( HPA axissuppressionat6monthspost-cessationand5% 40% offormeroralglucocorticoidusershavepersistent and safetyoftaperingregimens,asdespiteupto during stress.Evidenceisalsoneededabouttheefficacy day to day replacement and which only need replacement remains tobeinvestigatedwhich patients maybenefitfrom adrenal insufficiencyasassessedbytheSST. Further, it with moderateorborderlineglucocorticoid-induced benefit ofhydrocortisonereplacementtherapyinpatients placebo-controlled trialsthusareneededtoinvestigatethe need additionalstressdosesarenotwellknown.Randomised glucocorticoids, glucocorticoiddosebelowwhichpatients periods. Inpatientstreatedwithsupraphysiologicdosesof not cover the extra need for glucocorticoid during stressful during stressastheirglucocorticoidtreatmentdosedoes patients maybeparticularlyvulnerabletoadrenalcrisis Review 23 , 26 ). In addition, resolution is ). Inaddition,resolutionis K Laugesenandothers • • Current knowledgeandunsolvedquestions Highlights assessing prognosis,andtheeffectofreplacementtherapy. research thatidentifiesbiomarkersusefulfordiagnosis, discontinuation ofglucocorticoidtreatment,and(iv) mitigates theclinicalconsequencesduringandfollowing evaluate whetherhydrocortisonereplacementtherapy tapering strategies,(iii)randomisedcontrolledtrialsto morbidity, (ii) studies comparing the effect of different and howthebiochemical diagnosis translates into stepsare(i)studiesonriskandprognosis Necessary in thepublic,commercial,ornot-for-profit sectors. agency funding any from grant specific a by supported not was work This Funding to disclose. nothing have authors other The EJE. of Editor Deputy is Dekkers Olaf Declaration ofinterest EJE-20-1199. at paper the of version online the to linked is This Supplementary materials • • • to: Cohort studiesandrandomisedtrialsshouldbedesigned Future research directions • insufficiency Glucocorticoid-induced adrenal • • • • • • Predictors ofglucocorticoid-inducedadrenal may bepresentin≈50%ofpatientsafteroraltreatment. glucocorticoid-induced adrenalinsufficiency, which need forevidence-basedclinicalguidelinesonmanaging (annual prevalence≈3%fororaluse)underscoresthe The continuedwidespreaduseofglucocorticoids insufficiency. with respecttoglucocorticoid-inducedadrenal Studytheefficacyandsafetyofwithdrawalregimens novel biomarkers,andpatientoutcomes. Investigatethecorrelationbetweenbiochemicaltests, with thegoalofimprovingpatientmanagement. implications, andidentifymarkersofriskprognosis, induced adrenalinsufficiency, investigateitsclinical Estimatetheriskandtemporalpatternofglucocorticoid- of clinicalimplicationshasnotyetbeenelucidated. potentially life-threatening.However, thefullspectrum Glucocorticoid-induced adrenalinsufficiencyis it mayalsooccuraftertopicalorshort-termtreatment. as welloralandintra-articularadministration,but insufficiency includeprolongedhigh-dosetreatment, Downloaded fromBioscientifica.com at10/02/202107:04:04PM https://eje.bioscientifica.com 184 https://doi.org/10.1530/ :3 R119 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com References 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Review Bornstein SR. Predisposingfactorsforadrenalinsufficiency. 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