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European Journal of Endocrinology -18-0306 It becameevidentthatspecies-specificdifferencesexisted and testedinhumansubjectsbyseveralgroups( Long, andgrowthhormone(GH)wasisolatedin1944 yearsagobyEvansand was discoveredalmosta100 extracts A growth-promotingactivityofanteriorpituitary Introduction though thisreducedmortalitycouldbeduetoselectionbias,GHreplacementinGHDAhasprovenbeneficial and safe. Observational datashowthatmortalityinGH-replacedpatientsisreducedcomparedtountreatedpatients.Even is reconfirmed.GHtreatmentoffrailelderlysubjectswithoutdocumentedpituitarydiseaseremainsunwarranted. Continuation ofGHreplacementintoadulthoodinpatientswithchildhood-onsetdiseaseisindicated,ifthediagnosis are reversibleanddosedependent.Therequirementdeclinesmarkedlywithageishigherinwomen. life, assessedbyquestionnaires,improves.Theknownsideeffects arefluidretentionandinsulinresistance,which Several ofthesefeaturesreverseandnormalizewithGHreplacement.Itremainscontroversialwhetherquality of abdominal obesity, reducedlean bodymass,osteopeniaandelevatedlevelsofcirculatingcardiovascularbiomarkers. mortality fromcardiovasculardiseaseandthephenotypeincludesfatigue,reducedaerobicexercisecapacity, in 1989withtheavailabilityofbiosynthetichumanGH.UntreatedGHDAisassociatedexcessmorbidityand patients morethan50 yearsago,andplacebo-controlledlong-termGHtrialsinGH-deficientadults(GHDA)surfaced The acutemetabolicactionsofpurifiedhumangrowthhormone(GH)werefirstdocumentedinadulthypopituitary Abstract 2 1 Jens O L Jørgensen experience adults: 30 yearsofpersonalclinical Growth hormonereplacement therapyin THERAPY OFENDOCRINEDISEASE Department ofGrowthandReproduction,Rigshospitalet,UniversityCopenhagen,Denmark Department ofEndocrinologyandInternalMedicine,AarhusUniversityHospital,Aarhus,Denmark https://doi.org/ www.ej Review Review insulin resistancestates,obesity, Cushingandghrelin. include growthhormone(GH), GHdeficiency, metabolicactionsofGHandacromegaly, withfurtherworkin of EndocrinologyandDiabetes, AarhusUniversityHospital,Denmark.Prof.Jørgensen’s mainresearch interests Jens OttoLundeJørgensen Invited Author’s profile e-online.org 10.1530/EJE -18-0306 1 and Anders Juul 1 isProf.andChairoftheDepartment ofClinicalMedicineandtheDepartment © 2018EuropeanSociety ofEndocrinology J OLJørgensenandAJuul 2 Printed inGreatBritain 1 ).
1962, whicharerecommendablereadingsowingtotheir Raben and summarized in two seminal publications in effects ofGHwerecomprehensivelytestedbyMaurice are activeinman.Theproteinanabolicandlipidcatabolic and thatonlyhuman–tosomeextentsimianGH in adults Growth hormonedeficiency Published byBioscientifica Ltd. Downloaded fromBioscientifica.com at09/29/202109:28:11AM (2018) Endocrinology European Journal of [email protected] Email to JOLJørgensen should beaddressed Correspondence 179
179 :1 , R47–R56
R47 –R56 via freeaccess European Journal of Endocrinology www.eje-online.org measured isotopically. Asignificant increase inmuscle filtration rate(GFR)andrenal plasmaflow(RPF)were assessed onabicycleergometer. Inaddition,glomerular isometric muscle strength andaerobic exercise capacity and fat volume of the thigh region assessed by CT scan, outcomes includedbodycompositionintermsofmuscle dose was4 studied attheendofeachstudyperiod.ThedailyGH a 4-monthwashoutperiodandwiththepatientsbeing design with 4-month treatment periods separated by study had a double-blind, placebo-controlled crossover The test, andthemeanageatstudystartwas≈24 years. reconfirmed priortothestudybyaclonidinestimulation Thediagnosiswas duration ofdiscontinuation≈6 years). (mean beforestudyentry discontinued atleast6 months years,whichwas replacement forameanperiodof≈7 least twoGHstimulationtestsandhadreceived ( endocrinologists andpublishedin1989( Denmark asacollaborationbetweenadultandpediatric The first placebo-controlled trial was performed in The pivotaltrials pivotal trialsandtheauthors’owncontributions. of GH replacement in adults with a focus on the history narrative reviewprovidesapersonalaccountonthe (GHD) in two investigator-initiated trials ( was GHreplacementinadultpatientswithdeficiency be toomuchGHchasingfewpatients.’ patients chasingtoolittleGHtoanerainwhichtherewill now movingfromanerainwhichthereweretoomany pediatric growthdisordersandauxology, stated‘We are In responsetothis,JamesTanner, aleadingexpert in unlimited supplyofpureanduncontaminatedGH. radically changedthescenebyprovidingapotentially first provedefficaciousinGH-deficientchildren( accelerated theapprovalofbiosynthetichumanGH,that transmission ofCreutzfeld–Jakobdisease( in severalcountries1985sinceitwasassociatedwith humanGHwashalted indications. Theuseofpituitary the limitedsupplyprecludedexplorationofother with hypopituitarismandseveregrowthretardation,but therapeutically topromotelongitudinalgrowthinchildren GH extractedfromhumancadavericpituitarieswasused hypopituitarism could be beneficial ( hypothesize thatGHreplacementtherapyinadultswith clarity andpropheticstrengths( n
Review = 22) allhadchildhood-onsetGHDverifiedbyat One ofthefirstpotentialindicationstobepursued IU/m 2 bodysurface(≈1.1 2 J OLJørgensenandAJuul , 3 ). Hewasthefirstto mg/day). Themajor 3 ). Subsequently, 6 ). Thepatients 6 4 , ), which 7 5 ). This ). This design ( demonstrated forthefirsttimeinaplacebo-controlled promotes theextrathyroidalconversionofT4toT3was bone remodeling( excretion ofdeoxypyridinoline,indicativeincreased fold) inthelevelsofserumosteocalcinandurinary with markedandconcertedelevations(two-tofive- trial revealedthatGHreplacementwasassociated (placebo) vs224 like growthfactor1(IGF1)levels(µg/L)occurred(96 expected, a treatment-induced increase in serum insulin- represented a normalization from subnormal levels. As ( ( accompanied byasignificantincreaseinexercise capacity in subscapularskinfoldthickness( volume ( volume ( clinical pictureofGHdeficiency inadults(GHDA)and introduced ‘syndrome’ as a term to describe the emerging In areviewofthe literature in 1992, Cuneo The syndrome ofGHdeficiencyinadults were alsoreportedfromtheoriginalstudy( GH replacementonexercise capacityandhyperlipidemia of glucoseandinsulin,wasreported.Beneficialeffects of insulin resistance,asjudgedbyincreasedfastinglevels correction forLBM.Inaddition,evidenceofGH-induced an increaseinrestingenergyexpenditure(REE)alsoafter significant reduction infatmass.Thiswasassociated with increased significantlyandwasaccompaniedby a using indirect calorimetry. Lean bodymass(LBM) and totalbodypotassium,restingenergyexpenditure assessed byconventionalanthropometricmeasurements years.Themainoutcomeswerebodycomposition ≈39 dose was≈1.9 each patientwasexaminedbeforeandafter. ThedailyGH treatmentperiodwhere parallel designwitha6 months tumoranditstreatment.Second,ithada to apituitary it mainlycomprisedpatientswithadult-onsetGHDdue lateranddifferedinseveralrespects( 7 months forearm bonemineralcontent( body composition, exercise capacity, muscle strength and therapy, whichdocumentedcontinuedimprovementin was extendedwithanopenphaseofuninterruptedGH which wasreversedbyGH( adults Growth hormonedeficiencyin P P
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< 14 .1, which 0.01), , 15 7 , ). First, 16 R48 t al et ). ± via freeaccess 9 . European Journal of Endocrinology composition ( after GHreplacementdespite favorablechangesinbody levels ofglucoseandinsulin arerecordedinGHDA ( invariably inducesacertain degreeofinsulinresistance GH pattern( the eveningareunabletofullyimitateendogenous ( operates inthefastingstate,whereinsulinactivityislow rapidly reversible ( inactivity. Thedirectinsulinantagonisticeffect ofGHis term consequencesofobesity, reducedLBM andphysical insulin resistance( naïve adult-onsetGHDmay, however, alsoexhibit opposite istrueforactiveacromegaly( and adolescentswithGHD( reactive hypoglycemiaarecharacteristicofchildren of GH( muscle, which is causally linked to the lipolytic effects on glucosemetabolisminboththeliverandskeletal rather the opposite. GH antagonizes the effects of insulin metabolic syndrome,isnot part oftheGHDAsyndrome, sweating capacity( was alsodocumentedandpartlyattributedtoreduced temperature ( thermoregulation inresponsetotheambientoutside GH-induced changes inbody composition ( increase inhydrationaccountsforalimitedpartofthe a directrenaleffectofGHorIGF1( ( activation ofthereninangiotensinaldosteronesystem sodium retention,butitisuncertainifmediatedby of GHtreatmentinadults.Themechanisminvolves was notedasafrequentanddose-dependentsideeffect by GHreplacement( water andextracellularfluidvolume( untreated GHDAwasaccompaniedbyreducedtotalbody contractility ( of GH on diastolic volume, stroke volume and myocardial effect Echocardiographic studiesdocumentedastimulatory adults( reported inGH-untreatedhypopituitary of prematurecardiovascular morbidity andmortality was hyperlipidemia andatherosclerosis.Moreover, evidence with themetabolicsyndromeasregardsvisceralobesity, replacement ( ( focusing onthephenotypicalfeaturesofuntreatedGHDA This conceptwassubstantiatedbystudiesfromSweden the effectsandsideofGHreplacement.( 32 18 49 48 Review , , , ). Consequently, moderate elevations in the fasting Insulin resistance,which is a hallmark ofthe 33 49 19 ), suppressionofatrial natriuretic peptide ( ). However, dailysubcutaneousGHinjectionsin , 40 20 ), and new data regarding the impact of GH ). Indeed,increasedinsulinsensitivityand 37 27 51 50 21 ) andduringstrenuousexercise ( , ). ); therefore,GHreplacementtherapy , 28 22 11 46 45 , , ). , ), whichlikelyrepresentsthelong- 29 47 23 31 , ), and in normal physiology, it , , 30 24 32 ). It was also observed that ). Itwasalsoobserved ). Thesyndromeoverlaps ). Indeed,fluidretention 41 J OLJørgensenandAJuul , 42 35 , 18 , 43 36 ), whichreverses 44 ), whereasthe ). Ofnote,this ). Treatment- 36 ). Impaired 25 38 34 , , 26 ) or 17 39 ). ) ) Pfizer until 2012 with the inclusion of more than 16 000 Pfizer until2012 with theinclusion of morethan 16 000 was initiatedbyPharmaciaandUpjohncontinued database withlongitudinaldataaboutGHtherapyinadults, the same year, KIMS, an international outcomes research Union in1994alongsidewithseveralothercountries.In replacement inGHDAwasapprovedbytheEuropean had beenestablishedin1993( issued bytheGrowthHormoneResearch Society, which guidelines forthediagnosisandmanagementofGHDA to females( male patientsaremoreresponsivetoGHascompared of serumIGF1generationandsideeffects( that adultpatientsarehighlysensitivetoGHinterms groups wereperformed( contributions ( fromthepivotaltrials,addedseveraloriginal observations to GHDA increasedalmostexponentiallyfromtwoin1989 hedonic adaptation ( to provideincreasedsatisfaction, aphenomenoncoined is possiblethatimprovements inrememberedQoLcease day-to-day experiencesinreal time;alongthesameline,it on therespondents’remembrance andmayfailtodetect specific questionnaires,whichmainlyrecordanddepend means. MostQoLstudieshaveutilizedgenericordisease- in open trials are prone to bias and regression toward the GH effectsinplacebo-controlledtrials,andimprovements but it has proven difficult to document significant positive doubt thatQoLisreducedinthetreatment-naïvepatients, provide unambiguousanswers( patient, sinceneitheroriginalstudiesnormeta-analyses quality oflife(QoL)orcognitivefunctionintheadult therapy improvespatient-reportedoutcomessuch as insulin resistance( well asthesideeffectsattributabletofluidretentionand mineral density, cardiacfunctionandexercise capacity, as effects ofGHreplacementonbodycomposition,bone analyses confirmed and substantiated both the beneficial ( ( risk factors( have beenpublishedonoutcomessuchascardiovascular meta-analyses ofpublisheddataonadultGHreplacement providers ofbiosyntheticGH.Inadditiontothis,several programs have been initiated by other surveillance peer-reviewed publications,alsorecently( pfizer.com/kims patients from31countries( adults Growth hormonedeficiencyin 65 61 > ) andcardiacfunction( , It remainsanopenquestionwhetherGHreplacement The annualnumberofpublicationsinthefield 200 in1999,which,additiontocorroborating the 62 ), bone mineral density ( 57 51 , 52 ), musclestrengthandexercise capacity 58 ). Thisresource hasgenerated numerous ). Dose-finding studies in different age ). Theseandotherdatatranslatedinto 51 , 70 65 ). In this regard, it isinteresting Downloaded fromBioscientifica.com at09/29/202109:28:11AM 53 ) ( 66 , Fig. 1 54 ) ( , 59 65 63 Fig. 1 https://medicaloutcomes. 55 ). ). TheindicationforGH , , 67 ), anditwasconfirmed 64 , ). Inshort,themeta- 179 ), body composition 68 www.eje-online.org , :1 69 60 ). Thereislittle 56 ), andsimilar ), andthat R49 via freeaccess European Journal of Endocrinology www.eje-online.org transition periodonmuscle andbonemassaccrual.The suggesting additionalphysiological actionsofGHinthis years after peak height velocity, remain elevated 2–5 levels in healthy subjects ( resulting ingrosslyelevated –evenacromegalicIGF1 depend inpartonamplifiedGHsecretionandaction the adultphenotype.Theseimportantphysicalchanges bone massincreasemarkedlyduringthisperiodleading to to attainmentofadultreproductivecapacity. Muscle and sexualcharacteristics leading development ofsecondary changes includingapubertalgrowthspurtandthe adulthood andrepresentsaperiodwithmarkedphysical Normal pubertymarksthetransitionfromchildhood to The transitionphase QoL improvementafter9-monthtreatment( demands discontinuationoftreatmentincasealack in ordertoinitiateadultGHreplacement,anditalso guidance/ta64 Excellence intheUnitedKingdom( ironically, theNationalInstituteforHealthandCare patient wasaskedtoscorethe( controlled crossover study, in which the spouse of the adult GHreplacementonQoLwasrecordedinaplacebo- that themostcompelling–andbeneficialeffectsof pressure; TG,triglycerides. Press). Chol.,cholesterol;D.B.P., diastolicbloodpressure;LeanBmass,bodymass;ns,nonsignificant;S.B.P., systolicblood Results ofmeta-analysisGHeffects oncardiovascularriskfactorsfromMaison Figure 1 Review ) requiresimpairedpretreatmentQoL 73 ) ( Fig. 2 J OLJørgensenandAJuul ). Serum IGF1 levels http://nice.org.uk/ 71 ). Somewhat 72 ). duration ofthetransitionphase. ModifiedfromJuul healthy subjectsofbothsexes. Thegrayareaindicatesthe Serum IGF1levelsasafunction ofchronologicalagein3851 Figure 2 replacement trialsdidnotcapturethisimportantperiod, during theentiretransitionphase.TheearlyadultGH introduction ofbiosyntheticGHenabledcontinuation achieved duetothescarce GH,butthe supply ofpituitary terminated as soon as acertain target height was age ≈20–23 years). in earlyadulthoodwhenpeakbonemassisreached(mean height isattained(meanage≈15–17 years) andterminates transition phasestartsinlatepubertywhenfinaladult adults Growth hormonedeficiencyin Before 1985,GHreplacementinchildhoodpatients et al . ( 51 ). (Copyright2004,OxfordUniversity Downloaded fromBioscientifica.com at09/29/202109:28:11AM 179 :1 et al R50 . ( 13 via freeaccess ) European Journal of Endocrinology high prevalenceofGH-related sideeffects( disease recordonlylimitedpositiveeffectsanda pituitary GH treatmentstudiesinelderly subjectswithoutovert beyond thescopeofourreview, butameta-analysisof coined ‘somatopause’( and thephysicalfrailtiesofaging,whichhasbeen about acausallinkbetweenreducedGHproduction secretion ( strongest andnegativedeterminantofendogenousGH Interestingly, in midlife adults, abdominal adiposity is the in bodycompositionandphysicalperformance( decline with age ( Endogenous GHproductionandserumIGF1levels The senescence between pediatricandadultendocrinologists( includes patientinvolvementandaclosecollaboration Third, thepropermanagementoftransitionpatients decelerating duetosexsteroid-inducedepiphysealclosure. continued inthetransitionperiodevenwhengrowthis high pubertalIGF1levels.TheseGHdosesareusually the appropriate pubertal growth response and the normal or bodysurface)translatesintohighdailydosestoachieve pediatric mode of GH dosing according to body size (weight panhypopituitarism or a genetic cause of GHD. Second, the retesting unlessthereisstrongevidenceofeitherorganic must beevaluatedonanindividualbasis,whichrequires indication forcontinuedGHreplacementinadulthood completion ofGHtreatment.Therefore,statusandthe exhibit normalstimulatedGHsecretionwhenretestedafter mention here( during thetransitionareavailableandafewissuesmerit discontinuation ofGHreplacement( 2004 fromanopenstudyof12-monthcontinuationvs resumption ofGH.Comparableresultswerereportedin fat ratioandglucoseoxidationratesincreasefollowing Likewise, increasedmusclevolumeofthethigh,muscle/ group. AfterresumptionofGH,LBMandIGF1increased. as increasedbodyfatandinsulinsensitivityintheplacebo that GH discontinuation resulted in decreased IGF1 as well cessation of linear growth ( the effectsofcontinuationvsdiscontinuationGHafter double-blind, placebo-controlledparallelstudyevaluated and body composition ( of transitioninducedunfavorablechangesinlipidprofile GH replacement in childhood-onset patients at the time but aprospectivestudyreportedthatdiscontinuationof Review Guidelines as regards management of GHD patients Guidelines asregardsmanagementofGHDpatients 80 ). Suchcorrelationshaveledtospeculations 78 ). First, a large proportion of GHD children ). First,alargeproportionofGHDchildren 79 ) in parallel with senescent changes 81 ). Thiscontroversialconcept is 74 75 ). Subsequently, aDanish , 76 J OLJørgensenandAJuul ). This study revealed 77 ). 82 ). 78 ). Fig. 2 ). gender. 53 authors ownexperienceanddata fromtheliterature( function ofchronologicalage. Thefiguresarebasedonthe a serumIGF1levelwithintheupper normalrangeforageasa Daily GHdose(mg)inGH-deficientadultsemployedtoensure Figure 3 underlying mechanismsmaybeequally–ormore to unsubstitutedGHD( been difficulttoresistthetemptationattributethis cardiovascular diseaseiswellestablished,andithas patientsdueto Increased mortalityinhypopituitary GH replacement andmortality declines withchronologicalage( the uppernormalrangeforageandtoavoidsideeffects, requirement in order not toexceed IGF1 levels above as youngerpatients( seem torespondGHreplacementinthesamemanner controls ( reduced GHandIGF1levelsascomparedtoage-matched pathology exhibit distinctly due towell-defined pituitary elderly patients aged 60–80 years with panhypopituitarism cancer incidenceareincreasedinacromegaly( deficiencies. Itisalsonoteworthy, thatmortalityand and suboptimalsubstitutionofadditionalpituitary including theunderlyingdisease,treatmentcomplications likely, forexampleadditionalfeaturesofhypopituitarism therapy withmortalityasanendpointdonotexistand Most importantly, controlledstudiesofGHreplacement and all-causemortalityinthegeneralpopulation( an U-shapedassociationbetweenserumIGF1levels 91 the IGF/insulinaxisandlongevityinmanyspecies( that astronginverserelationexistsbetweenactivationof adults Growth hormonedeficiencyin , ). Moreover, epidemiological human studies suggest 83 Despite theage-associateddeclineGHsecretion, , 85 ). Inadditiontoage,theGHdose alsodependson 83 ). Moreover, GHDA patients in this age group 84 , Downloaded fromBioscientifica.com at09/29/202109:28:11AM 85 26 , , 86 87 ). However, theGHdose Fig. 3 ). However, numerous 179 ). www.eje-online.org :1 88 , 89 42 R51 ), and , 52 92 90 via freeaccess , ). , European Journal of Endocrinology www.eje-online.org hypopituitarism remainsaclinical challenge.Cancerrisk 99 retire earlierandarelesslikely tolivewithapartner( a higherproportionofthe patientsareunemployed, patients ascomparedtothe backgroundpopulation,but The level of education is similar among GH-treated adult studies are likelybiased. from openandobservational placebo-controlled trials are ambiguous, and the results QoL improvesremainsuncertain,sincetheresultsfrom studies suggest a reduced fracture risk ( of osteoporoticfracturesisuncertain,butobservational least in male patients ( BMD, followedbyamoderatebutsustainedincrease at increases boneremodeling,whichtransientlyreduces and itisbelievedbymostthatGHreplacementinitially several opentrialsofprolongedGHreplacementtherapy, femoral neck( mineral density(BMD)ofboththelumbarspineand study of 18 months a significant increase inbone observed unchanged orevenreducedbonemass( trials forupto1 yearrecordincreasedboneturnover, but bone massandstrength,datafromplacebo-controlled aerobic exercise capacity andcardiacfunction. As regards robust effect.Moststudiesalsorecordimprovementsin with reducedfatmassandincreasedLBMisthemost studies.Thechangeinbodycomposition observational endocrinology intermsofplacebo-controlledtrialsand the best-documentedtherapeuticindicationinpituitary been reported.Indeed,GHtherapyinGHDAisprobably biosynthetic GH,andanumberofpositiveeffectshave years later with the introduction of became feasible 25 GHDA couldbebeneficial( ago, anditwasspeculatedthatGHreplacementin human GH more than half a century pituitary-derived used to investigate the short-term metabolic effects of patients,were Adult subjects,includinghypopituitary Discussion difference wasreportedrecentlybyStochholm 1.05–1.24) in GH-treated patients ( (95% CI:1.46–3.34)inGH-untreatedvs1.15 reported thatthestandardizedmortalityratewas2.40 to GH-untreated patients ( mortality is reduced in GH-replaced patients as compared However, studiesinGHDAsuggestthat observational mortality inGHDpatientsisthereforenotavailable. answer to the question whether GH replacement reduces unlikelytoappearinthefuture.Anundisputable are very Review ). Thesesocioeconomicoutcomes demonstratethat 97 ). AnincreaseinBMDisalsoreported 63 ). Whether this reduces the risk 87 2 , , 93 3 ). Thistherapeuticoption , J OLJørgensenandAJuul 94 87 , ), and an evenlarger 95 ). A meta-analysis 96 ), whereasone 98 ). Whether et al . ( 93 93 ). , if anything,isreduced( biomarkers ofGHtreatmentisaccentuatedbytherecent treatment isfarfromperfect( GH dependent, its performance as a biomarker of GH should berecalledthatalthoughserumIGF1isstrictly whether lifelongtreatmentisjustified?Inthisregard,it doses used in the early adult trials. This raises the question whichismorethanten-foldlowerthe observation), low as0.1 supernormal IGF1levelsandsideeffectsmaybecomeas elderly patient.The daily GH dose requirement to avoid mandated toavoidovertreatmentnotleastofthe concern. Nevertheless,cautionandvigilanceare dependent, rapidly reversible and probablyoflimited insulin sensitivityarerecognized,buttheydose by selectionbias(healthyuserbias). reassuring eventhoughit–toalargeextentisexplained is notincreasedwithGHtreatment,andmortality( References Erik SkakkebækandJens Sandahl Christiansen in the field of GHdeficiency. The authors wish toacknowledge the longtimecollaboration with Niels Acknowledgements the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagency in Funding unrestricted researchgrantsfromPfizer. J OLhasreceivedlecturefeesfromNovoNordisk,and Declaration ofinterest effects andjustifythistreatmentmodality. from numerous trials confirm the beneficial observations than coincidental’( cases toindicatewhetherthefavorableeffectwasmore willbeneededinmore concluded that‘observations GH replacementinapatientwithadulthypopituitarism result influctuatingserumIGF1levels( compounds incontrasttodailysubcutaneousGHtherapy introduction oflong-actingGHpreparations,sincethese adults Growth hormonedeficiencyin 3 2 1 Raben MS. Growthhormone. Raben MS. Growthhormone. Dyrenfurth I &Venning EH.Beck JC, Mcgarry EE, Metaboliceffects 266 266 884–885. of humanandmonkeygrowthhormone inman. Side effectsintermsoffluidretentionandimpaired In conclusion,thefirstanecdotalreportin1962of 82–86. 31–35. mg inmalepatientsaged (https://doi.org/10.1126/science.125.3253.884) (https://doi.org/10.1056/NEJM196201112660207) (https://doi.org/10.1056/NEJM196201042660109) 3 ). 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