42 The Diversity of the Endocrine System

434TheDiversityoftheEndocrineSystem42DarylK.Granner,MDBIOMEDICALIMPORTANCEThesurvivalofmulticellularorganismsdependsontheirabilitytoadapttoaconstantlychangingenvironment.Intercellularcommunicationmechanismsarenecessaryrequirementsforthisadaptation.Thenervoussystemandtheendocrinesystemprovidethisintercellular,or-ganism-widecommunication.Thenervoussystemwasoriginallyviewedasprovidingafixedcommunicationsystem,whereastheendocrinesystemsuppliedhor-mones,whicharemobilemessages.Infact,thereisare-markableconvergenceoftheseregulatorysystems.Forexample,neuralregulationoftheendocrinesystemisimportantintheproductionandsecretionofsomehor-mones;manyneurotransmittersresemblehormonesintheirsynthesis,transport,andmechanismofaction;andmanyhormonesaresynthesizedinthenervoussystem.Theword“hormone”isderivedfromaGreektermthatmeanstoarousetoactivity.Asclassicallydefined,ahor-moneisasubstancethatissynthesizedinoneorganandtransportedbythecirculatorysystemtoactonanothertissue.However,thisoriginaldescriptionistoorestric-tivebecausehormonescanactonadjacentcells(paracrineaction)andonthecellinwhichtheyweresynthesized(autocrineaction)withoutenteringthesys-temiccirculation.Adiversearrayofhormones—eachwithdistinctivemechanismsofactionandpropertiesofbiosynthesis,storage,secretion,transport,andmetabo-lism—hasevolvedtoprovidehomeostaticresponses.Thisbiochemicaldiversityisthetopicofthischapter.THETARGETCELLCONCEPTThereareabout200typesofdifferentiatedcellsinhu-mans.Onlyafewproducehormones,butvirtuallyallofthe75trillioncellsinahumanaretargetsofoneormoreoftheover50knownhormones.Theconceptofthetargetcellisausefulwayoflookingathormoneac-tion.Itwasthoughtthathormonesaffectedasinglecelltype—oronlyafewkindsofcells—andthatahormoneelicitedauniquebiochemicalorphysiologicaction.Wenowknowthatagivenhormonecanaffectseveraldif-ferentcelltypes;thatmorethanonehormonecanaffectagivencelltype;andthathormonescanexertmanydif-ACTHAdrenocorticotropichormoneANFAtrialnatriureticfactorcAMPCyclicadenosinemonophosphateCBGCorticosteroid-bindingglobulinCGChorionicgonadotropincGMPCyclicguanosinemonophosphateCLIPCorticotropin-likeintermediatelobepeptideDBHDopamineβ-hydroxylaseDHEADehydroepiandrosteroneDHTDihydrotestosteroneDITDiiodotyrosineDOCDeoxycorticosteroneEGFEpidermalgrowthfactorFSHFollicle-stimulatinghormoneGHGrowthhormoneIGF-IInsulin-likegrowthfactor-ILHLuteotropichormoneLPHLipotropinMITMonoiodotyrosineMSHMelanocyte-stimulatinghormoneOHSDHydroxysteroiddehydrogenasePNMTPhenylethanolamine-N-methyltransferasePOMCPro-opiomelanocortinSHBGSexhormone-bindingglobulinStARSteroidogenicacuteregulatory(protein)TBGThyroxine-bindingglobulinTEBGTestosterone-estrogen-bindingglobulinTRHThyrotropin-releasinghormoneTSHThyrotropin-stimulatinghormonech42.qxd2/14/20038:44AMPage434THEDIVERSITYOFTHEENDOCRINESYSTEM/435Table42–1.Determinantsoftheconcentrationofahormoneatthetargetcell.Therateofsynthesisandsecretionofthehormones.Theproximityofthetargetcelltothehormonesource(dilu-tioneffect).Thedissociationconstantsofthehormonewithspecificplasmatransportproteins(ifany).Theconversionofinactiveorsuboptimallyactiveformsofthehormoneintothefullyactiveform.Therateofclearancefromplasmabyothertissuesorbydigestion,metabolism,orexcretion.Table42–2.Determinantsofthetargetcellresponse.Thenumber,relativeactivity,andstateofoccupancyofthespecificreceptorsontheplasmamembraneorinthecytoplasmornucleus.Themetabolism(activationorinactivation)ofthehormoneinthetargetcell.Thepresenceofotherfactorswithinthecellthatareneces-saryforthehormoneresponse.Up-ordown-regulationofthereceptorconsequenttotheinteractionwiththeligand.Postreceptordesensitzationofthecell,includingdown-regulationofthereceptor.ferenteffectsinonecellorindifferentcells.Withthediscoveryofspecificcell-surfaceandintracellularhor-monereceptors,thedefinitionofatargethasbeenex-pandedtoincludeanycellinwhichthehormone(lig-and)bindstoitsreceptor,whetherornotabiochemicalorphysiologicresponsehasyetbeendetermined.Severalfactorsdeterminetheresponseofatargetcelltoahormone.Thesecanbethoughtofintwogeneralways:(1)asfactorsthataffecttheconcentrationofthehormoneatthetargetcell(seeTable42–1)and(2)asfactorsthataffecttheactualresponseofthetargetcelltothehormone(seeTable42–2).HORMONERECEPTORSAREOFCENTRALIMPORTANCEReceptorsDiscriminatePreciselyOneofthemajorchallengesfacedinmakingthehor-mone-basedcommunicationsystemworkisillustratedinFigure42–1.Hormonesarepresentatverylowcon-centrationsintheextracellularfluid,generallyintherangeof10–15to10–9mol/L.Thisconcentrationismuchlowerthanthatofthemanystructurallysimilarmolecules(sterols,aminoacids,peptides,proteins)andothermoleculesthatcirculateatconcentrationsinthe10–5to10–3mol/Lrange.Targetcells,therefore,mustdistinguishnotonlybetweendifferenthormonespre-sentinsmallamountsbutalsobetweenagivenhor-moneandthe106-to109-foldexcessofothersimilarmolecules.Thishighdegreeofdiscriminationispro-videdbycell-associatedrecognitionmoleculescalledre-ceptors.Hormonesinitiatetheirbiologiceffectsbybindingtospecificreceptors,andsinceanyeffectivecontrolsystema