ESE Audit on Management of Adult Growth Hormone Deficiency In

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European Journal of Endocrinology -20-1180 Group, and London, CharterhouseSquare,UK, Harvey ResearchInstitute,BartsandTheLondonSchoolofMedicineDentistry,QueenMaryUniversity Research &ScienceWorkpackageandmemberofEndo-ERNPituitaryThematicGroup, Clinical Medicine–TheDepartmentofEndocrinologyandDiabetes,Arhus,Denmark, Pituitary andNeuroendocrinology,EuropeanSocietyofEndocrinology,StarlingHouse,Bristol,UK, Investigación BiomédicaenReddeEnfermedadesRaras(CIBER-ER,Unit747),ISCIII,Barcelona,Catalunya,Spain, 1 Susan M Webb Luciana Martel-Duguech hormone deficiencyinclinicalpractice ESE auditonmanagementofadultgrowth care ofadultswithGHD. European countries.Knowledgeamongprofessionalsand healthadministratorsneedsimprovementtooptimisethe Conclusion: being improved. non-endocrine professionalsandhealthcareadministrators. PostgraduateAGHDcurriculumtrainingdeserves was notavailableinfourcountriesandonlychildhood-onsetGHDanother.AGHDawarenesslowamong serum IGF-I,toleranceandside-effects.Inonecountry,AGHDtreatmentwasnotapproved.Fullpublicreimbursement patients, butonlywomen remaining, in 52%(GHRH+arginine:45%;insulin-tolerance:42%,glucagon:6%;GHRHaloneandclonidinetests:7%);the (13%) andgenetic/congenitalmidlinemalformations(13%).DiagnosisofGHDwasconfirmedbyastimulationtest childhood-onset GHD.Aetiologywasmostfrequentlynon-functioningpituitaryadenoma(26%),craniopharyngioma Results: diagnosed ortreatedin2017–2018. Patients Design: To evaluateeducationalstatusofhealthcareprofessionalsaboutAGHD. Aims: deficiency (AGHD);however,clinicalpracticeisnotuniform. Guidelines recommendadultswithpituitarydiseaseinwhomGHtherapyiscontemplated,tobetestedfor Abstract * (DetailsoftheESEAGHDStudygroupareprentedinAcknowledgementssection) IIB-Sant PauandDepartmentofEndocrinology/Medicine,HospitalSantPau,Universitat AutónomadeBarcelona,andCentro https://doi.org/ https://eje.bioscientifica.com Clinical Study (1)TorecordcurrentpracticeofAGHDmanagementthroughoutEuropeandbenchmarkitagainstguidelines;(2) OnlinesurveyinendocrinecentresthroughoutEurope. Twenty-eightcentresfrom17Europeancountriesparticipated,including2139AGHDpatients,28%of

and 7 Institute ofMedicine,SahlgrenskaAcademy,UniversityGothenburg, Göteborg,Sweden Despiteguidelinerecommendations,GHreplacementin AGHDisstillnotavailableorreimbursedinall 10.1530/EJE ≥

m 3 pituitarydeficienciesandlowserumIGF-Iwerediagnostic.InitialGHdosewaslowerinolder ethods: 1 onbehalfoftheESEAGHDStudyGroup*foraPan-Europeanaudit -20-1180 EndocrinologistsvoluntarilycompletedanelectronicquestionnaireregardingAGHDpatients < 2 26 yearswereprescribedahigherdosethanmen;titrationwasbasedonnormal 1 , Jens Otto LJorgensen others L Martel-Duguechand 6 Member ofEndo-ERNGrowthand GeneticObesitySyndromeThematic Published by Bioscientifica Ltd. Printed inGreat Britain © 2021Theauthors 2 , 3 , MártaKorbonits practice ESE auditonAGHDinclinical 4 Adult ChairoftheEndo-ERN 5 Endocrinology, William 4 , 5 3 , GudmundurJohannsson Department of Attribution 4.0International License. This workislicensed under a Downloaded fromBioscientifica.com at05/05/202101:12:14AM 2 Clinical Lead, (2021) Endocrinology European Journalof [email protected] [email protected] Email to S M Webb should be addressed Correspondence 184 184 :2 , 323–334 Creative Commons 6 , 7

and

323 or via Macquarie University

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European Journal of Endocrinology https://eje.bioscientifica.com follow up,safetyandtreatment goals.Patientsdiagnosed diagnostic criteria,patient selection,GHdosingand end of this article)and included sections on demographics, Table, seesection on from 17Europeancountrieswereincluded. to participaterepeatedly, viae-mail.Finally, 28centres restrictions. We identified70centreswhichwere invited or whocouldnottreatAGHDduetolocalconditionsand who currentlytreatedatleast10AGHDpatientsperyear Societies (ECAS).SuitablecentreswerethosefromEurope, Network (Endo-ERN)andtheESECouncilofAffiliated through theRareEndocrineDiseaseEuropeanReference recommendations. aghd ( bycountry country collect informationondiagnosisandtreatmentpractices to An ESESteeringGrouppreparedanonlinesurvey Patients andmethods individuals, witheithertreatedoruntreatedAGHD. from regional centres representing several thousand 19 to benchmark it against existent guidelines ( investigate thecurrentpracticeofAGHDmanagement Society ofEndocrinology(ESE)thereforeaimedto therapy isnotavailableinsomecountries.TheEuropean a distinctentityandreimbursementforGHreplacement ( diseaseshouldbetestedandtreatedforAGHD pituitary ( not perceive anybenefitandprefernottobeGHreplaced 13 willing tocontinuetreatment( most patients benefit froma dailyinjection of GHand are that accumulated evidenceisnowadaysoverwhelming AGHD wasestablishedmorethan30yearsago,andthe adverse cardiovascularriskprofile( quality oflifeaswellanincreasebodyfatand body mass,exercise capacity, and overall health-related characterised by a reduction in bone mineral density, lean 100 000patients across Europe( 200 and300patients/millionpopulation,approximately Adult growth hormone deficiency (AGHD) affects between Introduction 17 15 Clinical Study , , , , 20 14 The survey consisted of 44 questions (Supplementary consisted of 44 questions (Supplementary The survey Invitations toparticipateweredistributedatECE2018, Current guidelinesrecommendthatpatientswith 16 18 ) and to compare everyday practicewithguideline ) andtocompareeveryday ). Thegoalwastocollectaggregatedpatientdata ). Nevertheless,asmallpercentage ofpatientsdo ). , 19 , 20 ). Still,itisnotuniversallyrecognisedas supplementary materials supplementary https://www.ese-hormones.org/ 4 , others L Martel-Duguechand 5 , 1 2 6 ). The condition is , , 3 7 ). Theconceptof , 8 , 9 givenatthe , 10 , 17 11 , , 12 18 , , practise per centre, ethics approval was not required in all ofpatientdataandclinical questions butasummary perspectives. the questionsonlocalpracticesandcurrentsite-specific Table),(Form CandSupplementary whichalsocaptured information submittedtotheESEinanonlinee-survey form wasgenerated (Form B), which was the basis of the Access database(FormA).Anaggregateddatasummary on thebasisofpublishedguidelines( to AGHD in each local setting. Questions were developed and trainingresources andthelevelofsatisfactionrelated policies anddistributionofthedrug,availableeducation treatmentreimbursement statistics onAGHD,country endocrinologist incharge,namelysectionsonnational and perspectivesofeachcentreasreportedbythesenior included. Additionally, tenquestionsreflectedthepractice and/or treatedbetween01/01/2017and31/12/2018were per year(Barcelona, Genoa,Ljubljana,Lyon Marseille, patients declared to follow more than 500 pituitary independently of theirGHD status ( and radiotherapy treatments per year were collected, patients,aswell as surgical total numberofpituitary patients,the centre inthemanagementofpituitary participation. and Slovenia(20%)werethecountrieswithhighest areshownin patients percountry different countries( centres andpatientsaresummarisedin (four centres).Thegeneralcharacteristicsofparticipating contributing countrieswereItaly(fivecentres)andSpain collected from28centresin17countries.Thelargest were 2020,28FormC-s(onlinesurvey) In January Results Chicago, IL). Analyses wereperformedusingSPSS21.0(SPSSInc., appropriate. Alevelof or ANOVA tests were used to analyse the data, where Descriptive statisticsandStudent’s t-test,Chi-squared Statistical analysis local approvalbytheirethicscommittee. countries, however, whennecessary, participantsobtained practice ESE auditonAGHDinclinical Since the survey didnotincludepersonalmedical Since thesurvey Individual patient data were captured in a dedicated In ordertoevaluatetheglobalexperienceofeach Based onthepublishedprevalenceofAGHDin 1 ), theestimatedandcapturedAGHD P

Downloaded fromBioscientifica.com at05/05/202101:12:14AM < 0.05 wasconsideredsignificant. Table 1 184 Fig. 2 17 ). Fig. 1 :2 ; Denmark(32%) ). Ninecentres . via Macquarie University 324 European Journal of Endocrinology UK Switzerland Sweden Spain Slovenia Slovakia Serbia Romania Portugal Lithuania Italy Hungary Greece France Denmark Croatia Bulgaria Countries reference ( Table 1 growth hormonedeficiency. survey initiation(January1,2017).CO-AGHD,childhood-onsetadultgrowthhormonedeficiency;AO-AGHD,adult-onset United Kingdom.*GHtreatmentongoingatsurveyinitiation(January1,2017).**PriorGHtherapyreceived,butinterrupted at Denmark, France,Greece,Hungary,Italy,Lithuania,Portugal,Romania,Serbia,Slovakia,Slovenia,Spain,Sweden,Switzerland, Number andgeneralcharacteristicsofcountries,centrespatientsinvolvedinthestudy. Figure 1 Clinical Study Estimated andcapturedprevalenceofpatientswithadultgrowthhormonedeficiency(AGHD)percountryfrom 1 ). Population inhabitants) 10 66 66 10 46 19 10 60 10 9 2 5 7 3 5 4 7 (million others L Martel-Duguechand Estimated AGHD 11 550 10 500 11 550 patients 1575 1750 8050 1225 3325 1750 1750 1750 1225 350 875 525 875 700 practice ESE auditonAGHDinclinical AGHD patients captured 254 192 622 206 281 91 18 70 67 30 83 65 10 45 28 25 87 based onestimatednumberofpatients Percentage ofcapturedAGHDpatients a Countries: Bulgaria,Croatia, Downloaded fromBioscientifica.com at05/05/202101:12:14AM https://eje.bioscientifica.com 184 14 20 32 1 1 3 8 2 2 4 2 6 3 2 1 4 7 :2 via Macquarie University 325 (%) European Journal of Endocrinology https://eje.bioscientifica.com performed onaverageperyear ineachcentre.(A)Centresthatfollow Number ofpituitarypatientsand identifiedAGHDpatientsfollowedandpituitarysurgeries andpituitaryradiotherapies Figure 2 pituitary patients;(C)centresthat follow Clinical Study others L Martel-Duguechand ≤ 100 patients.AGHD,adult growth hormonedeficiency. practice ESE auditonAGHDinclinical ≥ 500 pituitarypatients;(B)centres thatfollow Downloaded fromBioscientifica.com at05/05/202101:12:14AM 184 :2 < 500 to via Macquarie University 326 > 100 European Journal of Endocrinology luteinising hormone;PRL,prolactin; TSH, thyroidstimulationhormone. follicle-stimulating hormone;GHD,growth hormonedeficiency;LH, ACTH, adrenocorticotrophinhormone; ADH,antidiuretichormone;FSH, *Centres wereallowedtochoosemore thanonedeficiencyperpatient. PRL deficiency ADH deficiency ACTH deficiency LH/FSH deficiency TSH deficiency No otherpituitary Other pituitarydeficiencies* Not known Other Treated acromegaly Traumatic braininjury Idiopathic isolatedGHD Vascular causes Cushing’s syndrome Cranial irradiationdue Prolactinoma Other pituitarymass Genetic/congenital Craniopharyngioma Non-functioning Aetiology ofAGHD and thedegreeofhypopituitarisminpatientcohort. Table 2 and 45yearsin29%;46–6528%;olderthan of diagnosiswasfrom18to25yearsin10%;between26 among thosewithadult-onsetAGHD(AO-AGHD),age patients withchildhood-onsetAGHD(CO-AGHD); hormone deficiencies. insipidus andmostpatientshadadditionalpituitary each). Only 4% had isolated GHD; 22% had diabetes and geneticorcongenitalmidlinemalformations(13% (26% ofallcasesreported),followedbycraniopharyngioma adenoma cause ofAGHDwasanon-functioningpituitary hypopituitarism are shown in less peryear(between20and100). Thessaloniki, Zagreb)andtheremaining,100patientsor Basel, Bratislava,Bucharest,Milan,Sophia,Tenerife, 10, between100and500patients(Aarhus,Athens, Messina, Sheffield,Stockholmand Turin), another Clinical Study deficiency apoplexy, etc.) (Sheehan’s syndrome, disease to anothermalignant inflammatory) lesions (includingcysts, midline malformations pituitary adenoma Twenty-eight percent( The aetiologyofAGHDandthedegree Aetiology of adult growth hormone deficiency (AGHD) Aetiology ofadultgrowthhormonedeficiency(AGHD) No ofpatients n Table 2 = 594) corresponded to = 594)correspondedto others L Martel-Duguechand 1491 1622 1754 117 134 172 282 285 555 150 467 162 143 . The most common 82 50 57 81 82 94 ( n = 2139) 22 70 76 82 13 13 26 % 7 8 4 7 2 3 4 4 4 6 6 8

clinically contraindicatedorwasoflimiteddiagnostic in specificclinicalsituationswhenatestwaseither unavailable. ( to beenoughdiagnoseAGHD).Intheremaining34% plus alowserumIGF-I(reportedin54%ofthecentres deficiencies on thebasisof3ormoreotherpituitary not undergoanyGHstimulationtestbutwerediagnosed clonidine. Fourteenpercent( other testsinanother7%includingGHRHaloneand (ITT) (42%);in6%aglucagontestwasperformedand GHRH+arginine test(45%)oraninsulintolerance astimulationtest,mainly patients (52%)underwent treatment initiationafterthediagnosisofGHD. old: 4%),indicatingthat,ingeneral,therewasnodelay 13%; 26–45yearsold:31%;46–6530%; initiation was similar ( 65 years,lessthan5%.DistributionofageatGHtreatment was beguninsomebutnotall centres( AGHD andnocoexistent contraindications, treatment Lithuania (70%)andBulgaria (60%).Afterdiagnosisof (100% ofuntreatedpatients), PortugalandGreece(90%), GH therapy was not initiated in countries like Romania drug in hospital pharmacies) were the main reason why lack ofreimbursementandrestrictionstoprovidethe 11% ofparticipatingcentres.Administrativeissues(i.e. and centralobesity, however, wereonlyconsideredby for initiatingtreatment( and severefatigability)wereimportantdeterminants compliance andsymptoms(i.e.impairedqualityoflife remaining 10centres. initiate GHtherapy, forthe whilethiswasnotnecessary thirds of the centres (18/28) required IGF-I to be low to µg/L inItalypatientswithaBMI The diagnosticcut-offfortheGHRH+argininetestwas used thecut-off GH deficiencywas indication forsubstitutiontherapyinmanycountries. diseaseexists,sinceitisnotan underlying pituitary of centresdonotperformastimulationtestevenifan accuracy. when BMIis peak of (Romania, Sweden,SwitzerlandandUnitedKingdom)a Denmark, irrespectiveofBMI,whileinothercountries μ practice ESE auditonAGHDinclinical n g/L inpatientswithaBMI = 731)ofpatients,informationonstimulationtestswas As farasthetestsusedtodiagnoseAGHD,1103 When consideringGHsubstitutiontherapy, patient The diagnosticcut-offfortheITTtestusedtodiagnose When allotherendocrineaxesarenormal,34% < 11, Figure 3 < < 8 or 25, 25–30,or < 5 µg/L (Bratislava, Madrid and Sheffield). < < 4 wasconsidereddiagnosticofAGHD 3 µg/L,exceptforthreecentreswhich depictsthediagnostictestpreference < 18 years-old: 22%; 18–25 years-old: 18 years-old: 22%; 18–25 years-old: Downloaded fromBioscientifica.com at05/05/202101:12:14AM Table 3 > 30 kg/m ≥ 30 kg/m https://eje.bioscientifica.com n = 305)ofpatientsdid ); ageunder65years 184 2 < Fig. 4 , respectively. Two- 30 kg/m 2 :2 and ). Asfarasthe < 6 µg/Lin > 2 via Macquarie University and 65 years 65 years 327 < < 9 4 European Journal of Endocrinology https://eje.bioscientifica.com one factorperpatient. mineral density(Madrid);***Centres wereallowedtochoosemorethan current orpriorhistoryofmalignancy (Athens)anddecreasedbone *Centres wereallowedtochoosemore thanonerequirement;**No None Other Concomitant diabetesmellitus Age Persistent andstablepituitary Compliance considerations Administrative issues Factors thatstoppedinitiation Others** Central obesity Age Severe fatigability Impaired qualityoflife Patient compliance Requirements forGH hormone (GH)substitutiontherapy.Dataispresentedas Table 3 and 0.5mg/dayifagedbetween1825)thaninmen doses wereprescribedinwomen(0.75mg/dayif However, inpatientsaged25yearsoryounger, higher in thoseaged46toabove65years,irrespectiveofgender. as first choice in those aged 26–45 years, and 0.2 mg/day starting doseofGH,0.3mg/daywasmostoftenprescribed than onetestpereachsituation.ITT,Insulintolerancetest;GHRH,growthhormone-releasinghormone. Number ofcentresthatchosetoperformdifferentstimulationtestsinspecificsituations.Centreswereallowedchoose more Figure 3 Clinical Study tumour rests of GHtherapy*** treatment initiation > < 65 years 65 years Features consideredwheninitiatinggrowth

others L Martel-Duguechand Centres 12 (43) 21 (75) 3 (11) 3 (11) 9 (32) ( n 2 (7) = 28)

1270 (59) 220 (10) ( Patients < n 141 (7) 119 (6) 20 (1) 52 (2) 96 (4) 18 years = 2139) n (%).

for treatmentinterruption, dischargebythepaediatric to stop GH treatmentwasthemostfrequentreason While lackofreimbursement andpatientsowndecision during transition to adult care are shown in ( transitioning toadultcareformorethan24months patients, GH substitution wasinterrupted during this informationwasunavailable.In224/594CO-AGHD seen afterdirectpatientinquiry. Intheremaining(15%), practitioner toadultcare(68%),although17%were patients werereferredbythepaediatricianoranother missing intheremainingcentre).MostofCO-AGHD and 18yearsinanother8centres(thisinformationwas care, theagewas while ontherapy, anddeath(4%)werealsoreported. administrative reasonsandlackofperceived improvement responsible in57%ofthecases,whilelackcompliance, interruption areshownin at thetimeofsurvey. ThecausesofGHtreatment replacement dose(26%). (57%) and considering anincrease in hydrocortisone of freeT4whentakingthyroxinreplacementtherapy monitoring forpatients transdermal ortransvaginaloestrogens(10%),increased the evening(60%) and consideredaswitchfromoralto according tothepatient’s bodyweight. (0.2 mg/day).InPortugal,theinitialdosewasprescribed practice ESE auditonAGHDinclinical n = 157).ThereasonsforGH treatment interruption As far as the transitioning from childhood to adult In 284patients,GHsubstitutionhadbeeninterrupted Most recommendedadministeringGHinjectionsin > 18 yearsin19centresandbetween14 Downloaded fromBioscientifica.com at05/05/202101:12:14AM > 65 yearsold(4%),checking Table 4 . Adverseeventswere 184 :2 via Macquarie University Table 5 328 . European Journal of Endocrinology 61% of patients, while the number of sick day leave wellbeing andenergylevel wasregularlyaskedforin 34% (728/2139),andbody fat: 13%(270/2139).Overall mineral density:41%(876/2139), waistcircumference: low-density lipoprotein(LDL): 47%(1006/2139),bone high-density lipoprotein(HDL):52%(1223/2139), 58% (1240/2139),totalcholesterol:56%(1203/2139), 60% (1284/2139),bloodpressure:58%(1245/2139),BMI: titration, werebodyweight: 62% (1319/2139), HbA1c: at alow-normalrange.Othervariables used forGHdose range, 14%aimedatahigh-normal and 3%aimed within thenormalrange,26%mid-normal to bereachedduringtreatment,40%aimedatavalue reached. ConsideringthetargetedIGF-Iconcentration 12monthsonce a stabledosewas treatment andevery the centres measured IGF-I 2–3 months after initiating referral toanadultclinicwerealsoreported. consultant orpoorpatientcomplianceanddifficultyin hormone ineachcentre.CO-AGHD,childhood-onsetAGHD;AO-AGHD,adult-onsetAGHD. Number ofpatientsdiagnosedwithadultgrowthhormonedeficiency(AGHD),whowereeithertreatedornot Figure 4 Clinical Study As farasfollow-upafterstartingGHtherapy, half others L Martel-Duguechand is notreimbursed.InLithuania andPortugal,fullpublic without residualtumour. with residualtumour, andafter12months inpatients months afterinitiatingGH treatment(85%)inpatients Additionally, mostcentresperformednewMRIs 6–12 was performedintheselatterpatientsnotcollected. and in6%theanswerwasnegative;whetheraCTscan was positive;in10%thisinformationunavailable at initialevaluation,in84%ofthepatientsanswer (SF-36). (QLS-H) ( Questions on Life Satisfaction Hypopituitarism Module Deficiency Adultsquestionnaire(QoL-AGHDA)andthe most commonlyusedwereTheQoLAssessmentofGH treatment monitoringin45%ofAGHDpatients.The quality oflife(QoL)questionnairewasadministeredfor and partnersatisfactioninlessthan11%.Aspecific practice ESE auditonAGHDinclinical In Romania,theindicationof GHtreatmentforAGHD MRIwas performed When askedwhetherapituitary 21 , 22 ). In2%,agenericquestionnairewasused Downloaded fromBioscientifica.com at05/05/202101:12:14AM https://eje.bioscientifica.com 184 :2 via Macquarie University 329 European Journal of Endocrinology https://eje.bioscientifica.com interruption perpatient. *Centres wereabletochoosemore than onecausefortreatment Not known/notanswered Difficulty inreferraltoan Poor patientcompliance Discharge bythepaediatric Patient electingtostopthe Lack ofreimbursement transition toadultcare.* in childhood-onsetadultgrowthhormonedeficiencyduring Table 5 satisfaction wasintheextentandqualityofnursetraining, local settingisshownin and trainingresources and AGHDmanagementineach service. GH athome,viaaregisteredonlinedelivery and Sweden)patientshadtheoptionofreceivingtheir in the local pharmacy. Intwocountries (United Kingdom pharmacies (18/28),whileintheothersitwasdispensed frequently dispensedinregionalorreferencehospital able toprescribeGHsubstitution. endocrinologists whoworkataccreditedGHcentresare is onlyapprovedinCO-AGHD.InHungary, onlythose supply GH,whileinBulgariafullpublicreimbursement despite approval,hospitalpharmaciesarereluctantto whereas, inSlovakia,reimbursementispartial.InGreece, reimbursement was approved only recently (2018–2019), interruption perpatient. *Centres wereabletochoosemorethanonecausefortreatment Not specified Death Lack ofpositiveeffect Administrative reasons Lack ofcompliance Other Headache Hyperglycaemia Arthromyalgia Fluid retention/oedema Tumour recurrence New cancer Adverse events in adultgrowthhormonedeficiencypatients.* Table 4 Clinical Study adult clinic consultant treatment perceived bythepatient The levelofsatisfactionregardingavailableeducation As farasthedispensationofdrug,itwasmost Causes ofgrowthhormonetreatmentinterruption Causes ofgrowthhormonetreatmentinterruption Fig. 5 Number ofpatients Number ofpatients . Whilethegreatestlevelof others L Martel-Duguechand 146 15 29 68 75 5 106 162 12 51 54 61 63 13 16 25 36 0 9 ( ( n n = 284) = 224) 64 13 30 33 37 18 19 22 22 12 57 % % 2 7 4 0 5 8 6 9 We oncurrentpracticeofAGHD reportdatafromasurvey Discussion reimbursement ofGHtherapy( treatment ineachsettingcorrelatedwithfullpublic of satisfaction with the overall quality of AGHD patient treatments were prescribed ( public treatmentreimbursementwasavailable,moreGH in the formers ( level ofsatisfactioninoverallqualityAGHDtreatment percentage, withahigher acorrelationwasobserved under GHtreatmentwerecomparedtothosewithalower postgraduate trainingrelatedtoAGHD. there wasroomforimprovementinthecurriculumof by non-endocrinehealthcareprofessionals;additionally, dissatisfaction washighinrelationtoAGHDawareness are allowedtoprescribereimbursed GHsubstitutionfor only endocrinologistswhowork ataccreditedGHcentres they arediagnosedasCO-AGHD. Finally, inHungary, full publicreimbursementis onlyapprovedforadultsif reasons despiteapprovalof theindication.InBulgaria, pharmacies are reluctant to supply treatment for budget reimbursement isonlypartial,andinGreecehospital for AGHDwasonlyrecentlyapproved.InSlovakia Romania; inLithuaniaandPortugal,reimbursement approved indicationforGHtherapyreimbursement in interruption duringtransition,sinceAGHDisnotan normal IGF-IdoesnotruleoutGHDatanyage. of thecentres,despitethatguidelinesstate a IGF-I levelwasrequiredtostartGHtherapyintwo-thirds considered fortheGHRH+argininetest( guidelines, BMI-dependentcut-offvalueswerenotalways Society consensusof Bratislava, MadridandSheffieldacceptedtheEndocrine the Europeanconsensusof ITT diagnosticthresholdforAGHD,mostcentresfollowed clonidine, wereusedincertaincentres( considered valid in adults, such as GHRH alone or were reported, an entity not recognised as occurring (4%) patientswithidiopathicisolatedadult-onsetGHD disease wascongruentwiththeguidelines.Only81/2139 life datawithpertinentguidelines( management acrossEuropeandbenchmarkedthesereal- novo practice ESE auditonAGHDinclinical When thecentreswithahigherpercentage ofpatients Administrative reasonscontributedtotreatment As farasdiagnostictests,stimulationtestsnot Underlying diagnosesofhypothalamic–pituitary inadults( 17 P ). = 0.005). Not surprisingly, where full < 5 µg/L( Downloaded fromBioscientifica.com at05/05/202101:12:14AM P < P 20 = 0.020). Also, the level 3 µg/L( = 0.018). ). In contrast with the ). Incontrastwiththe 17 184 , 18 17 17 :2 , ). A low baseline ). Alowbaseline ). Regarding the ). Regardingthe 19 17 , ), although ), although 20 ). via Macquarie University 330 de European Journal of Endocrinology years, starting doses declined with age, but no gender years, startingdosesdeclined withage,butnogender doses thanmen,asstated intheguidelines.After26 and improvementpersistsduring chronictreatment( development, accrualofmaximal boneandmusclemass, GHD after attaining final height, since itenables full somatic especially ifsymptomaticandinyoungadultswithpersistent now convincingofthebenefitsGHreplacementtherapy, benefits byknowledgeablehealthcareproviders,evidence is AGHD requiresadetailedevaluationofpotentialrisksand indicated inthesecases.Eventhoughthedecisiontotreat regulation inmanycountries,whereGHtreatmentisnot rest oftheendocrineaxesarenormal;thisisinlinewith third ofcentresdonotperformstimulationtestswhenthe underdiagnosed and therefore not reported, since up to a some patientswithorganicisolatedAGHDcouldbe initiated werenotreportedinmanycentres.Additionally, Thus, eligiblepatientsinwhomGHtherapywasnot AGHD shouldbeconfirmediftreatmentisapossibility. therapy after diagnosis. In fact, the guidelines state that patients, especiallyincountrieswheremostareoffered and poorpatientcompliance. at transitionincludedpatientpreference,losttofollow-up adults. OtherreportedreasonsforstoppingGHtreatment Level ofsatisfactionacrosscentres( Figure 5 Clinical Study Not all centres reported data on non-treated AGHD Not all centres reported dataon non-treated AGHD Only inpatients < 25 years did women receive higher 25 yearsdidwomenreceive higher n others L Martel-Duguechand = 28).AGHD,adultgrowthhormonedeficiency. 17 ). prolonged insomecentres. is, afterradiotherapy, betweenimagingwas theinterval on theunderlyingdiagnosis andtreatmentreceived,that betweensubsequentimagingdepended follow-up, interval as suggestedintheguidelines; however, inlong-term MRIswereperformed forsafety and follow-up,pituitary any wasrelatedtoGHtherapy. (0.56% ofthe2139patients),butitisnotknownwhether reasons wereasexpected.Twelve deathswerereported compliance or perceived benefit, as well as administrative effect oforaloestrogensonhepaticsynthesisIGF-I( transdermal ortransvaginalroute,giventheinhibitory that only 10%considered switching oraloestrogensto a replacementtherapies.However,pituitary itwassurprising most centresconsideredadjustingthedoseofother response, andonanannualbasisthereafter;additionally, after 2–3monthsbasedonIGF-Iconcentrationandclinical the case in over 40% of patients. Dose was initially adjusted mimicking the greater nocturnal secretion, but this was not recommended GHtobeadministeredintheevening, not recommendedintheguidelines( was prescribed basedonbodyweight,althoughthisis differences indosingwerereported.InPortugal,GHdose practice ESE auditonAGHDinclinical As far as safety during GH treatment, both at baseline Treatment interruptiondue toadverseevents,lackof Downloaded fromBioscientifica.com at05/05/202101:12:14AM https://eje.bioscientifica.com 184 17 :2 ). Most centres ). Mostcentres via Macquarie University 331 17 ). European Journal of Endocrinology https://eje.bioscientifica.com an opportunity for a joint effort, of the ESE and the National an opportunityforajointeffort, oftheESEandNational GH is minimal. Basedon the results of this survey, this gap is contribution tothisexpense ofsubstitutiontherapywith .cat/ca/salut-a-z/m/malalties_ minoritaries/tractament Accessed August24,2020, via: Department ofHealth.GeneralitatCatalonia;2020. drugs intheyear2019’.Barcelona. CatalanHealthSystem. Treatment ofraredisease withindividuallyauthorised Sweden andinCatalonia(’Reportonevaluationofresults: expenditure in countriessuch as The Netherlands,France, rare diseases is around 5% of the global pharmaceutical those withlessexperience. was higherincentresthattreatedmorepatientsthan in nurse training.Notsurprisingly, thedegree ofsatisfaction management, andespeciallywiththeextentqualityof satisfied withtheoverallqualityofAGHDpatients’ to evaluateitsscopeandcost. of GHtreatedpatientsinplace,allowinghealthauthorities costs. Onlyinsomecountries,werecentraldatacollection to preventillicituseofthedrug( hospital pharmacies,whichinsomecentreswasenforced used, whichisinaccordancewiththeguidelines. In othercountries,however, QoLquestionnairesarenot GH substitution( the AGHDAquestionnaireisaprerequisitetoinitiate diabetes mellituspreventedtreatmentin whereas tumourremnants,patientage (mostly lackofreimbursement)preventedGHtherapy, initiating GHtherapy( impaired QoL and severe fatigue were considered before and partnersatisfactionwererecordedinlessthan11%. questioned in only 61%, while the number of sick days ( was oftennotcontemplated,althoughconsideredessential vitality, to monitor treatmentresponse during follow up, life, energylevel,partnersatisfaction,sickdayleaveand including bloodpressureandlipids. A1c, and surrogate biomarkers of cardiovascular risk patients, wereBMIandwaistcircumference, haemoglobin Other efficacyvariablesreportedinapproximatelyhalfthe in 83%ofthepatientswhominformationwasavailable. range, alsoifIGF-Iwasnormal( maintained withintheage-andgender-relatednormal 17 Clinical Study ). Overall wellbeing and energy level were routinely ). Overallwellbeingandenergylevelwereroutinely The global cost of orphan drugs for the 7 to 8 thousand The globalcostoforphandrugsforthe7to8thousand Eighteen outofthe28participatingcentreswere Growth hormone was predominantly provided by In theUnitedKingdom,impairedbaselineQoLusing Good patientcompliance,andtoalesserextent, Finally, attentivequestioningtoassessqualityof For efficacy, theguidelinesstatethatIGF-Ishouldbe 21 ), andQoLissupposedtoimprove. 23 ). In10%,administrativeissues 17 , 20 others L Martel-Duguechand 20 https://canalsalut.gencat ) and this was evidenced ) andthiswasevidenced ) orinordertoreduce < 5% ofpatients. > 65 yearsor ). The ). The prevalent than currently thought in practice and probably AGHD patientsacrossEurope,thisdiseaseismore Considering thegapbetweenestimatedandcaptured large countries,suchasGermany, didnotparticipate. based estimationofAGHDpatientsin12countries.Some and 14%inSweden,butlessthan5%ofthepopulation- estimated patients in Denmark, one-fifth in Slovenia, participation indifferentcountries, reaching athirdof helpful( with otherpatientscanbevery offer treatmenttoeligiblepatients( patients,arestrongargumentsto therapy inhypopituitary outcome andqualityoflifewithoptimalsubstitution of perceived healthwithGHtherapy, aswelllong-term and Diabetesisalsodesirable( pan-European curriculumforEndocrinology, Metabolism officials andfundingbodies.IncludingthistopicintheESE medical communitybutprimarilyalsotohealthpolicy Societies toraiseawarenessaroundAGHD,notjustinthe of AGHD patients;education and a greater alert of guaranteed forAGHD.To improvethefinaloutcome Network forRareEndocrine Diseases)isnotglobally Directives and EndoERN (the European Reference for rarediseases,anaimof boththeEuropeanHealth AGHD consensus ( years havepassedsincetheinitial1996PostStephens global healthcostsisnegligible.Despitethatnearly25 the factthatcostofGHtreatmentincomparison to to be a priority among health administrators, despite identified. GHsubstitutioninadultsdoesnotappear are followed to a large extent, several exceptionswere management ofAGHDpatients.Althoughtheguidelines differencesinthe diagnosisandcountry-specific update oftheguidelineswouldseempertinent. an become available, confirming the benefits oftreatment, data onefficacyandsafetyGHtherapyinAGHDhave were publishedin2007and2016thatsincethenfurther management ofAGHD.Giventhatthecurrentguidelines data fromclinicalcentresresponsibleforthediagnosisand benefit scheme.Astrength,however, iscollectingreal-life Australia, buthasnowbecomepartofthepharmaceutical initiationin2017,GHwasnotreimbursed that atsurvey centre providedninecases;however, itisworthmentioning other countrieswasnotfeasiblesinceonlyoneAustralian from centreswithatleasttentreatedpatients. considered ofgreatereducationalvaluetocollectdata and treatmentofAGHDwerenotincluded,sinceitwas not sorare.Centreswithlessexperienceinthediagnosis practice ESE auditonAGHDinclinical Among the limitations of this survey isthevariable Among thelimitationsofthissurvey In summary, thisESE-led audithasidentified The initialideaofcomparingresultsfromEuropeanwith 29 ), equality of healthcareinEurope Downloaded fromBioscientifica.com at05/05/202101:12:14AM 2 , 3 , 24 27 , 25 184 ). Sharing experience ). Sharingexperience 28 , 26 :2 ). ). Improvement ). Improvement via Macquarie University 332 European Journal of Endocrinology Medicine, Health Center, Hungarian Defense Forces, Budapest, Hungary; Budapest, Forces, Defense Hungarian Center, Health Medicine, Goth, I M Italy; Turin, D Olah and L Kovacs, Division of Endocrinology, 2nd Department of Turin, of University Metabolism, Gregorio and Diabetes Hospital Endocrinology, of Marañón, Madrid, Spain; E Ghigo and V Gasco, Division of Endocrinology, Department García, R Croatia; UK; TDusek, Department ofEndocrinology,University HospitalCenterZagreb, Sheffield, Hospitals, Teaching Sheffield Endocrinology of Department Debono, M Switzerland; Basel, Basel, of Hospital of University Center ENETS Endocrinology, Excellence, DivisionofEndocrinology,DiabetologyandMetabolism, Interdisciplinary Christ, Porto, Saúde, E em Inovação Portugal; e Investigação de Instituto Universidade – i3S Medicine, Porto, of do João/Faculty S. de Universitário Hospitalar D Salazar, Department of Endocrinology, Diabetes and Metabolism Centro of Human Pathology, University of Messina, Messina, Italy; D Carvalho and of Unit Cannavo, Endocrinology, University Hospital S ‘G. Martino’ and France; O R Cotta, (MMG), Department Genetics (AP-HM), Medical Marseille U1251, Marseille de Publique-Hôpitaux Brue Hôpital delaConception,13005,Marseille,andAix-MarseilleUniversité, Assistance T Italy; Albarel, Genoa, F Genoa, and of University DIMI, Unit, Endocrinology Biomedical Research (CEBR), University of Genoa, and S Ricci Bitti, Medicine and Medical Specialties (DIMI) and Centre of Excellence for San Martino,Genoa,ItalyandEndocrinologyUnit,DepartmentofInternal Policlinico Ospedale IRCCS Unit, Endocrinology M Ferone, D Romania; and Boschetti Bucharest, Pharmacy, and Medicine of University ‘C. Davila’, Endocrinology of Institute National Badiu, C Maggiore Italy; Ospedale Milan, Policlinico, Granda Cà IRCCS Fondazione Milan, of University Giavoli, Department ofClinicalSciencesandCommunityHealth,EndocrineUnit, C and Arosio M Greece; Thessaloniki, Thessaloniki, of Hospital Mintziori, Department ofEndocrinology&Metabolism,HippokrationGeneral G and Adamidou F by formed is Group study AGHD ESE The and discussions helpful suggestions ofDirkdeRijdtareverymuchappreciated. The possible. been have not would survey this of Nik Screen in applying to the Independent Learning & Change call, insight of Holger Franz is gratefully acknowledged. Without the contribution and discussions specific the and (Berlin), Birkner & Lohmann by provided was collection data for forms the design to support Technical Italy. Genoa, of InternalMedicine andMedical Specialties (DIMI), University ofGenoa, Department Unit, Endocrinology from Franco Marta and France (MMG), Marseille, andAix-Marseille Université,U1251, Marseille MedicalGenetics Publique-Hôpitaux de Marseille(AP-HM), Hôpital delaConception, thank Haifa Rahabi-Layachi andAude Bourgeois-André from Assistance The authorswish to acknowledge the contribution in data collection and Acknowledgements & for Learning Grant Independent Pfizer a Change: (IGLC):ID9939445. by funded was work This Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest E This islinkedtotheonline version ofthepaperat Supplementary materials non-endocrine healthcareproviders. deficient patientswouldseemdesirable,includingby the advantagesofGHsubstitutiontherapyinthese JE-20 Clinical Study -1180 . others L Martel-Duguechand https ://do i.org /10.1 530/ Neural Sciences,University of Modena and Reggio Emilia,Modena,Italy L M and Rochira Monzani, Unit V of Endocrinology, France; Department of Lyon, Biomedical, Metabolic Pradel, and Louis Hôpital Est, Hospitalier Centre deRéférenceMaladiesRaresHypophysaires(HYPO),Groupement d’Endocrinologie, Fédération Borson-Chazot, F and Raverot G Australia; Sydney, University, Macquarie Sciences, Health and Medicine of Faculty Medicine, Clinical of Department Preda, V Spain; Alicante, ISCIII, 13), GCV de InvestigaciónBiomédicaenRedEnfermedadesRaras(CIBERER, Centro Hernandez, Miguel University Alicante, de Universitario General Health andBiomedicalResearchInstituteofAlicante(ISABIAL),Hospital Department, Nutrition & Endocrinology Pico, A Spain; Tenerife, de Cruz Santa Laguna, La of University Sciences, Health of Faculty Canarias, de J Serbia; Perez Luis, Division Belgrade, of Endocrinology and Nutrition, Belgrade, Hospital Universitario of for University Faculty, Clinic Medical & Serbia Milijic, of D and Pekic S Endocrinology, Diabetes andDiseases of Metabolism,ClinicalCenter Croatia; Split, Split, Center Hospital Mili T and Novak A Serbia; Endocrinology, Sad, Novi for Vojvodina, of Center Clinic Clinical Disease, Metabolic Medicine, and Diabetes of Faculty Sad, Novi and of University Medicine of Stojanoska, Medic Faculty M Slovakia; Bratislava, Bratislava, University Hospital University Comenius Medicine, Internal of Department 5th Payer, Juraj and Kužma M Slovenia; Ljubljana, Ljubljana, Centre Ljubljana, Ljubljana, Slovenia and Faculty of Medicine, University of Department Kozamernik, of Endocrinology,DiabetesandMetabolicDiseases,UniversityMedical Mlekuš K and Kocjan T Sweden; Stockholm, C Höybye,DepartmentofEndocrinology,KarolinskaUniversityHospital, References Health Sciences,Kaunas,Lithuania. 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