Frontalskullbossing (resultinginanunusuallyprominentforeheadandheavybrow ridge),mandibularprognathism(protrudinglowerjaw),jawmalocclusionandoverbite,skinthickening,andincreasedshoeand ringsize(Figure1).ChronicexposuretoGHandIGF1hypersecretionleadstosofttissueswellingoftongue,heart,kidney,colon, andvocalcordsandperiarticularandcartilaginousthickening, resultingultimatelyinpainfullarge-jointosteoarthritis.Upto60 ofpatientsexhibitspinalkyphoscoliosis(outwardcurvatureofthe spine)anddiffuseskeletalhyperostosis(overgrowthofbone).Diseaseduration,IGF1levels,andconcurrenthypogonadismdeterminetheprevalenceofvertebralfractures(S2).Elevatedlevelsof thehormoneprolactin(PRL),observedinapproximately30 of individuals,canbeascribedtomixedtumorGHandPRLcosecretionortopituitarystalkimpingementbythetumormass.Rarely, plurihormonaltumorscosecretethethyroid-stimulatinghormone thyrotropin(TSH),leadingtohyperthyroxinemia(elevatedcirculatingthyroxinelevels),oradrenocorticotropin(ACTH),leadingto hypercortisolemia(elevatedcirculatingcortisollevels).Conflictofinterest:Theauthorreceivespreclinicalresearchgrantsupportfrom NovartisandisaresearchconsultantforIpsen. Citationforthisarticle:J. Clin. Invest.119:3189202(2009).doi:ten.1172/JCI39375.Thisarticlereviewsrecentscientificdiscoveriesthathavehadan impactonourunderstandingofacromegalypathogenesisandclinicalfeatures.Novelapprovedandexperimentaltherapieshaveevolved fromthesefundamentalinsightsandarediscussedinthecontextof providingaddedbenefittopatientcareanddiseasecontrol. Diagnosis ThediagnosisofacromegalyrequiresdemonstrationofdysregulatedandenhancedGHsecretionaswellaselevatedIGF1levels, reflectiveofperipheraltissueexposuretotonicallyelevatedGH concentrations(6).Inacromegaly,basalGHsecretionistonically elevatedwithrelativelybluntedbursts(Figure2).Accordingly,a randomGHvalueoflessthan0.04g/leffectivelyexcludesthe diagnosis of acromegaly. Importantly, an elevated randomly obtainedGHmeasurementmaynotnecessarilyimplyexcessive integratedGHsecretion.NetGHsecretionisattenuatedafterage 60(when24-hourGHsecretionislessthan50 ofthatinyounger subjects)andbyelevatedBMI. OlderGHradioimmunoassayswererelativelyinsensitiveand poorlyreproducible.Newerimmunoradiometricassaysandimmunoluminometricassaysarebasedontheuseoftwo-sitemonoclonalantibodies,andalthoughtheydetectGHconcentrationsofless than0.05g/l,theseassaysarebesetbychallengesofreproducibility.Efonidipine hydrochloride monoethanolate Lackofuniversalstandards,nonuniformantibodyrecognition ofGHisoforms,andthepresenceofcirculatingGH-bindingproteinscontributetomethod-dependentandpatient-specificvariabilityofGHmeasurements.α-Vitamin E InamulticenterstudyofGHnadir afteranoralglucosetolerancetest(OGTT),referencerangesvaried byapproximately50 ,and30 ofobtainedresultswereinconsistentwiththecorrectdiagnosis(7).PMID:25804060 Thereisacompellingneedfor reliableGHassaysbasedonrobustreferencestandards. AfunctionalhallmarkofaGH-secretingpituitaryadenomais theinabilitytorespondappropriatelytoaglucose-inducedneuroendocrinesuppressivesignal.TheinabilitytosuppressGHsecretiontolessthan1g/lduring2hoursafteranoralglucoseload (75grams)isthecurrentconsensusfordiagnosingacromegaly (eight).On the other hand,thiscutoffmayinfactbeinsensitive,andpatients havebeenidentifiedwithclinicalfeaturesofacromegaly,elevated IGF1levels,andnadirpostglucoseGHlevelsoflessthan1g/l (9).UsingultrasensitiveGHassays,anadirGHcutoffoflessthanTheJournalofClinicalInvestigation http://www.jci.org Volume119 Number11 Novemberscience in medicineSidebar 1 Effect of long-term GH and IGF1 exposureOrgan/tissue Bone.
