【医学课件】内分泌生理 ENRINE PHYSIOLOGY（全英文课件）

Chapter11

ENDOCRINEPHYSIOLOGY

内分泌生理

WangGuoqingDepartmentofPhysiology,MedicalSchool,SoochowUniversity,Suzhou215123,ChinaE-I. EndocrineandhormoneII. Endocrineofhypothalamus-pituitaryglandandpinealgland*III. Endocrineofthyroidgland**IV. Endocrineofparathyroidgland,thyroidCcellandVitaminD3V. Endocrineofpancreaticislet**Endocrineofadrenalgland**Endocrineoftissuehormoneandfunctionalorgan

Whatwillwediscussinthischapter?(Outline)I. Endocrineandhormone1.Basicprinciplesandorganization

DefinitionoftheEndocrineSystemEndocrineandnervoussystemscoordinatecomplexbodyfunctions.Classicdistinctionbetweenthesetwoisthattheendocrinesystemcommunicatestodistanttissuesthroughblood-carriedchemicalswhilethenervoussystemcommunicatestoadjacenttissuebylocalchemicalrelease(neurotransmitter,神经递质).Organsoftheendocrinesystemincludeadrenal,gonads,hypothalamus,pancreas,parathyroid,pituitary,thyroid,aswellasothers,suchastheheart,kidney,andgastrointestinaltract.Distinctionbetweenthesetwocommunicationsystems

—NervoussystemandEndocrinesystemNervesintheposteriorpituitaryreleaseoxytocin〔催产素〕andantidiuretichormone〔抗利尿激素〕,whichactonthebreastandkidneys,respectively;Nervesreleaseepinephrinefromtheadrenalmedulla,whichactsontheheart,skeletalmuscle,andtheliver;Nervesofthehypothalamussecretechemicals(releasinghormones)thatactontheanteriorpituitarytocausehormonerelease.Therefore,thedefinitionoftheendocrinesystemshouldalsoincludesuchneuroendocrinesystems.GeneraldefinitionforhormoneClassicdefinition(ByStarlingandBayliss)Thehormonesarechemicalsubstancesproducedbyspecializedtissuesandsecretedintoblood,inwhichtheyarecarriedtotargetorgansandtriggersspecificbiologicalfunctions.Limitsofclassicdefinition:SpecializedtissuesforhormonesynthesisBloodforhormonedistributionAseparatetargetorganBroaderdefinitionAhormoneisachemicalnon-nutrient,intercellularmessengerthatiseffectiveatmicromolarconcentrationsorless(highefficiency).LivingthingsthatcansecretehomonesMulticelluar:Animal,Plant,InsectandSomefungi.ConcentrationPeptidalhormoneinanimalblood10-12~10-10M,Steroidhormoneinanimalblood10-10~10-8M.EndocrinecellandTargetCell,tissueandorgan.PowerfulBiologicalEffectsMetabolicandPhysiologicaleffect.Afurtherunderstandingonhormones

TABLEENDOCRINEGLANDS,HORMONESSECRETED,ANDTISSUEEFFECTENDOCRINEGLANDHORMONESSECRETEDTISSUEEFFECTHypothalamusCorticotropin-releasinghormone(CRH)StimulatesACTHsecretionDopamineInhibitsprolactinsecretionGonadotropin-releasinghormone(GnRH)StimulatesLHandFSHsecretionGrowth-hormonereleasinghormone(GHRH)StimulatesGHsecretionSomatostatinInhibitsGHsecretionThyrotropin-releasinghormone(TRH)StimulatesTSHandprolactinsecretionAnteriorAdrenocorticotropichormone(ACTH)Stimulatessynthesis/secretionpituitaryofcortisol,androgensandaldosteroneFollicle-stimulatinghormone(FSH)Stimulatesspermmaturation;developmentofovarianfolliclesGrowthhormone(GH)StimulatesproteinsynthesisandgrowthLuteinizinghormone(LH)Stimulatestestosterone,estrogen,progesteronesynthesis;stimulatesovulationMelanocyte-stimulatinghormone(MSH)StimulatesmelaninsynthesisProlactinStimulatesmilkproductionThyroid-stimulatinghormone(TSH)Stimulatesthyroidhormonesynthesis/secretionPosteriorOxytocinStimulatesmilkejectionandPituitaryuterinecontractionAntidiuretichormone(ADH)StimulatesrenalwaterreabsorptionThyroidTriiodothyronine(T3)andStimulatesgrowth,oxygenthyroxine(T4)consumption,heatproduction,metabolism,nervoussystemdevelopmentContinuednext

TABLEENDOCRINEGLANDS,HORMONESSECRETED,ANDTISSUEEFFECT(continued)ENDOCRINEGLANDHORMONESSECRETEDTISSUEEFFECTThyroidCalcitoninDecreasesbloodCaconcentrationParathyroidParathyroidhormone(PTH)IncreasesbloodCaconcentrationAdrenalcortexCortisolIncreasesglucosesynthesis;mediates“stress〞responseAldosteroneIncreasesrenalreabsorptionofNa+,secretionofK+,andH+AndrogensSimilartotestosteronebutweakerAdrenalmedullaEpinephrineStimulatesfatandcarbohydratemetabolismPancreasInsulinDecreasesbloodglucoselevels;anaboliceffectsonlipidandproteinmetabolismGlucagonIncreasesbloodglucoselevelsTestesTestosteroneStimulatesspermatogenesisandsecondarysexcharacteristicsOvariesEstradiolStimulatesgrowth/developmentoffemalereproductivesystemandbreasts,follicularphaseofmenstrualcycle,prolactinsecretion,andmaintainspregnancyProgesteroneLutealphaseofmenstrualcycleandmaintainspregnancyCorpusluteumEstradiolandprogesteroneSeeabovePlacentaHumanchorionicgonadotropin(hCG)Stimulatesestrogen/progesteronesynthesisbycorpusluteumHumanplacentallactogen(hPL)ActslikeGHandprolactinduringpregnancyEstriolActslikeestradiolProgesteroneSeeaboveThistableliststhemajorendocrineorgans,thehormoneseachorgansecretes,andthemajortissueeffectofthehormone.EndocrineSystem2.ChemicalNatureofHormonesClassicdefinitionofahormoneisachemicalproducedbyanorganinasmallamountthatisreleasedintothebloodstreamtoactoncellsinadistanttissue.Thisdefinitionneedstobeexpandedtoincludechemicalsthathaveparacrineandautocrinefunctions.Hormonesaredividedintofourgroupsbasedonchemicalstructure:

(1)amines，胺类(comefromtheaminoacidtyrosine),(2)peptides，肽类(lessthan20aminoacids),(3)smallproteins，小蛋白(morethan20aminoacids),(4)steroids，类固醇(comefromcholesterol).TABLEMAJORHORMONESGROUPEDBYCHEMICALSTRUCTURE

AMINESPEPTIDESPROTEINSSTEROIDSDopamineAntidiureticAdrenocorticotropicAldosteronehormone(ADH)Hormone(ACTH)EpinephrineGonadotropin-releasingCalcitoninCortisolhormone(GnRH)ThyroxineMelanocyte-StimulatingHumanchorionicEstradiol(T4)hormone(MSH)gonadotropin(hCG)Triiodothy-OxytocinHumanplacentalEstriolronine(T3)lactogen(hPL)Thyrotropin-releasingCorticotropin-releasingProgesteroneHormone(TRH)hormone(CRH)SomatostainGlucagonTestosteroneGrowthhormone(GH)1,25-vitaminDGrowthhormone-releasinghormone(GHRH)Follicle-stimulatinghormone(FSH)InsulinInsulin-likegrowthfactor(IGF-1)Luteinizinghormone(LH)Parathyroidhormone(PTH)ProlactinThyroid-stimulatinghormone(TSH)Thistablegroupsthemajorhormonesaccordingtotheirchemicalcomposition

Hormonehavefourgroupsbasedonitschemicalstructure3.CommunicationofthehormonesTelecrinesignalsNeurocrinesignalsCommunicationofthehormonesEndocrineCellEndocrinehormoneBloodFlowTargetCellTargetCellParacrineHormoneAutocrineHormoneParacrineCellAutocrineCellTargetCellParacrineHormoneReceptor4.MechanismofhormoneactionHormonesactthroughspecificreceptorsthatdefinetissueselectivityandresponse.Receptorsforamine,protein,andpeptidehormonesarelocatedonthecellmembrane,whilethoseforsteroidandthyroidhormonesarewithinthecell.Membranereceptorsareoffourtypesbasedontheirsignalingmechanisms:Gprotein,tyrosinekinase,guanylylcyclase,cytokinefamily.Steroidandthyroidhormonesactthroughnuclearreceptorsthatstimulategeneexpression.Membrane-receptormediatedhormoneselicitrapid(minutes)cellularresponses;nuclear-receptormediatedhormoneselicitslow(hours),longlastingcellularresponses(becauseofslowproteindegradation).

FourTypesoftheMembraneReceptorsBasedonTheirIntracellularSignalingMechanisms

TABLEHORMONESSIGNALINGTHROUGHMEMBRANERECEPTORSG-ProteinReceptorsLinkedto:AdenylylPhospho-TyrosineKinaseGuanylylCyclaseCytokineReceptorCyclaselipaseCReceptorsReceptorsFamilyACTH,ADH,Insulin,ANPGH,Calcitonin,GHRH,Insulin-likeprolactinCRH,GnRH,growthDopamineOxytocin,factor-1Epinephrine,TRH(IGF-1)FSH,Glucagons,hCG,LH,MSH,PTH,Somatostatin,TSHThistablegroupsthemajorhormonesaccordingtotheirsignalingmechanisms.AcombinationofhormoneandreceptorHormoneHormoneReceptorReceptorChangesinconformationofhormonecombiningwithreceptorA:ChangesinconfigurationofreceptorinducedbyhormoneB:ChangesinconfigurationofhormoneinducedbyreceptorLabeledUnlabeledorreceptorComplexofHormoneandReceptorLabeledUnlabeledComplexAcombinationofhormoneandreceptorReceptorquantitylimitcombinationofhormoneandreceptorReceptorquantitylimitcombinationofhormoneandreceptorCombinationofAbandAgComponentsofmembranereceptorsMembranereceptorsconsistofthreecomponents:(1)anextracellulardomainthatbindsthehormone;(2)atransmembranedomainthatanchorsitinthemembrane;(3)anintracellulardomainthatcouplesthereceptortoanintracellularsignalingsystem.

ItwasevidencedthatFortheG-proteincoupledreceptors,thetransmembranedomainloopsbackandforththroughthemembrane7times,whileforothersitpassesthroughonlyonce.Whenthehormonestimulatesthereceptor,anintracellularsignalingsystemisactivatedthatinitiatesacascadeofcellulareventsculminatinginthehormoneresponse.ThestructureofG-proteinG-proteinReceptorReceptorEnzymeThestructureofG-proteincoupledreceptorsOutsidecellInsidecellCellmembraneCarbohydrategroupofglycoproteinReceptoroftransmembrane7timesCombiningpositionofphosphorylationInteractionbetweenthehormones,receptorsandG-proteinsBasicstatusReceptoractivationSubunitsdisassociationReactoractivationGTPaseR:receptor;E:enzyme;H:hormone;S:substance;P:productSignalconductivemechanismof

G-proteinlinkedmembranereceptorsG-proteinlinkedreceptorshavethecharacteristicofbeinglinkedtoanintracellularclassofproteinscalledGproteins.Gproteinsareaclusterofthreeproteins(subunits)that,whenactivatedbyhormonebindingtotheextracellulardomainofthereceptor,causestimulationofoneoftwoenzymes,adenylylcyclase(腺苷环化酶AC)orphospholipaseC.ActivationofACleadstotheformationofcyclicadenosinemonophosphate(cyclicAMP,cAMP),andactivationofphospholipaseCleadstotheformationofinositoltrisphosphate(IP3)ordiacylglyercerol(DAGorDG),oractivationofproteinkinaseC(蛋白激酶C,PKC).Thesenamedsecondmessengermoleculesinitiateacascadeofeventsculminatinginthehormoneresponse.Signaltransductionmechanismof

G-proteincoupledreceptorsR:RegulativesubunitC:catalysissubunitPhysiologicalandBiochemicalfunctionACTH,Calcitonin,CRH,Dopamine,FSH,Glucagon,hCG,LH,MSH,PTH,Somatostatin,TSHCascadeofeventsculminatinginthehormoneresponseEffectsofAdenylylCyclase(AC)ReceptorsCellmembraneProteinProteinBiologicalfunctionMechanismofhormoneactingonmembranereceptorH:hormone;R:receptor;GP:G-protein;AC:adenylylcyclase;PDE:phosphodiesterase;PKr:proteinkinaseregulativesubunit;PKc:proteinkinasecatalysissubunitphosphorylationSignaltransductionofG-proteincoupledreceptorsACTH,Calcitonin,CRH,Dopamine,Epinephrine,FSH,Glucagon,hCG,LH,MSH,PTH,Somatostatin,TSHTheoryofthesecondmessengers

forG-proteincoupledreceptorCellmembraneAdenylylcyclaseHormoneHormoneHormoneInactiveproteinkinaseActiveproteinkinaseProteinphosphorylationGlycogendecompositionFatdecompositionSteroidHormonessynthesisHistone-nucleicacidsynthesis

Nuclein-proteinsynthesisMembraneprotein-membranepermeabilityCanaliculussecretedmovementAC:Adenylylcyclase;R:regulativepartinthereceptor;C:partforreactionPrincipleofhormoneactingonmembranereceptorACPhysiologicalandBiochemicalFunctionsSecondMessengerWorkingmechanismofphospholipaseCreceptorCellmembraneHormone(ADH,GHRH,GnRH,OXT,TRH)ReceptorG-proteinPhospholipaseCEndoplasmicreticulumPhysiologicalandBiochemicalreactionSignaltransductionprocessesofphospholipidacylinositolPIP2:phospholipidacylinositoldisphosphate;DG:diacylglyercerol;IP3:inositoltrisphosphate;PKC:proteinkinaseC;CaM:calcium-mediatedproteinSecondMessengerEffectsofGuanylylCyclase(GC)ReceptorsTheguanylylkinasereceptors(onthemembrane,combinedwithANP)havetheenzymeguanylylcyclase〔尿苷酸激酶〕asaportionoftheirintracellulardomain.Bindingofhormonetotheextracellulardomainleadstoactivationofguanylylcyclaseandtheformationofcyclicguanosinemonophosphate(cyclicGMPorcGMP).Thissecondmessengerinitiatesthehormoneresponse.FormationandmechanismofseveralsecondmessengersCyclicadenosinemonophosphate(cAMP)Cyclicguanosinemonophosphate(cGMP)InositoltrisphosphateRegulativesubunitcatalysissubunitProteinkinaseA(PKA)DiacylglyercerolReleaseProteinkinaseG(PKG)ProteinkinaseC(PKC)PK(IP3)R:receptor;Rs:stimulativereceptor;Ri:inhibitoryreceptor;G:G-protein;Gs:stimulativeG-protein;Gi:inhibitoryG-protein;AC:adenylylcyclase;GC:guanylylcyclase;PC:phospholipaseC;CaM:calcium-modulatedprotein;Tn:troponinC.(DGisactuallyinthecellmembrane)EffectsofTyrosineKinase(TK)ReceptorsThetyrosinekinase〔酪氨酸激酶〕receptorsaredistinguishedbyhavinganintracellulardomainthatphosphorylatesproteinsonspecifictyrosinemolecules.Thesetyrosine-phosphorylatedproteinsactassecondmessengerstoinitiateacascadeofeventsleadingtohormoneresponse.Mechanismoftyrosinekinase(TK)receptorsCellmembraneOutsidecellInsidecellInactivetyrosinekinase(TK)Activetyrosinekinase(TK)HormoneReceptorsReceptorsSecondMessengerInsulin,IGF-1SummarizationPLEASETAKEDOWNMechanismsofhormoneactingonmembranereceptors(summing-up)EffectsofCytokineReceptorsFamilyCytokinereceptorfamilyisdistinguishedbythefactthatreceptor(onthemembrane,combinedwithGH,Prolactin)activationindirectlyleadstointracellularproteintyrosinephosphorylation.HormonebindingtotheextracellularreceptordomainenablestheintracellulardomaintobindsolubletyrosinekinasescalledJanuskinases(orJAKkinases).BindingactivatestheJAKkinases,whichphosphorylateintracellularproteinsandproducethehormoneresponse.EffectsofSteroidandThyroidHormonesSteroidandthyroidhormones(primarilyT3)signalthroughintracellularreceptors,whichactsolelytoinitiategeneexpression.Bothhormonetypesdiffusethroughthecellmembranetoactontheirintracellularreceptors.ThereceptorsareproteinmoleculesthatbindtospecificDNAsequencesknownashormoneresponseelements(激素反响元件HRE).Thehormone-receptorcomplexactivatestheHRE,initiatingDNAtranscriptionleadingtoproteinsynthesis.MechanismofSteroidHormonesEffectHormoneCellmembraneCytoplasmicreceptorNuclearmembraneNuclearreceptorSpecificmRNARibosomeNewproducedproteinStructuraldomaincombinedwithhormone;Structuraldomainofsignalorientationinthenucleus;StructuraldomaincombinedwithDNA;Structuraldomainoftranscriptionalactivation—TheoryoftheGenesExpressionsMechanismofSteroid

HormonesEffectCellmembraneNucleusHormoneReceptorChangesinreceptorconfigurationTranscriptionTranslationSpecificproteinMetabolicreactionMechanismofSteroidHormonesEffectMechanismsofT3andT4EffectsCellmembraneMitochondriaNucleusNucleusreceptorTranscriptionTranslationSpecificproteinEnzyme5.GeneralcharacteristicsofhormoneactionSpecificaction:onehormone,onetarget,likeonekey,onelock;Messengereffect:serveasfirstmessenger;HighefficiencyInteraction：coordination,confrontationandpermissiveaction,etc.6.SynthesisofhormonesPeptideandproteinhormonesaresynthesizedfromaminoacidsasprohormonesorpreprohormones,whicharesubsequentlymodifiedandstoredinintracellularvesiclesuntilsecretedbyexocytosis.Amineandsteroidhormonesaresynthesizedfromprecursormolecules(tyrosine,cholesterol)presentintheblood.Thyroidandsteroidhormonesarenotstoredinsecretoryvesicles,buttheaminehormoneepinephrineis.Synthesisandreleaseofpeptideandproteinhormones(RoughER)ProcessesfrompreprohormonetohormoneProcessesfromprohormonetohormone7.ControlofHormoneReleaseMosthormonesarereleasedinapulsatilemanner〔脉冲式〕withafrequencythatvariesfromminutestomonthsandischaracteristicofthehormone.Hormonereleaseisinfluencedinpartbypositiveandnegativefeedbackmechanisms,especiallythelatter.Controlofhormonesecretion

(CommonMechanism)Solidlinemeanspositivefeedback;BrokenlinerepresentsnegativefeedbackSupershortfeedbackShortfeedbackLongfeedbackOthermechanisms:biologicalrhythmicsecretion;nervoueregulation,etc.Humoralregulation8.HormoneTransportintheBloodAmine,peptide,andsmallproteinhormonescirculateinafreeforminbloodbecausetheyarewatersoluble.Steroidandthyroidhormonesarecarriedinthebloodboundtoproteins(ascarrier,e.g.albumin)becausetheyarewaterinsoluble.Proteinbindingreduceshormoneslossthroughthekidneysincetheprotein-hormonecomplexcannotbefiltered.

Onlythefreeformofthehormonecanstimulatetissuereceptorsbecauseofthecapillaryendotheliumpermeability.Mosthormonesareremovedfromthebloodbytheliverandkidneyshortlyafterbeingsecretedeventhoughtheirtissueeffectcontinues(half-lifeofhormone，激素的半衰期).Half-lifeofhormoneinthebloodTherateatwhichtheamountofhormoneinblooddecreasesiscalleditshalf-life.Thisisthetimeittakestheconcentrationofthehormonetofalltoonehalfofitspreviouslevel.Half-livesvaryfromminutesfortheaminehormonestohoursforsteroidandthyroidhormones.Hormoneconcentration(µg/Lplasma)Half-lifeII.Endocrineofhypothalamus-pituitaryglandandpinealgland

GeneralOrganizationPituitaryglandandhypothalamusfunctioninacoordinatedmannertointegratemanyendocrineglands.Pituitaryglandislocatedjustbelowthehypothalamusatthebaseofthebraintowhichitisconnectedbyashortstalk(namedtheinfundibulum，动脉圆锥).Pituitaryisdividedintoanteriorandposteriorportions.Secretionofanteriorpituitaryhormonesisunderthecontrolofhypothalamicreleasinghormones.Posteriorpituitaryhormonesaresynthesizedinhypothalamicnerveswhoseaxonsendintheposteriorpituitarywherehormoneisreleasedintotheblood.1.RelationshipofhypothalamusandpituitaryglandRelationshipofHypothalamusandAnteriorPituitaryGland(Releasinghormones)RelationshipofHypothalamusandPosteriorPituitaryGland2.HypothalamicHormonesInfluenceAnteriorPituitaryHormoneSecretion

Manyhormonesarereleasedfromthehypothalamusthatcontrolthereleaseofanteriorpituitaryhormones:TRH,dopamine,GnRH,CRH,GHRH,somatostatin,etc.(1)thyrotropin-releasinghormone(TRH，促甲状腺激素释放激素)actsonthethyrotrophsandlactotrophsstimulatingTSHandprolactinsecretion,respectively.(2)Dopamineinhibitslactotrophsecretionofprolactin.(3)Gonadotropinhormone-releasinghormone(GnRH，促性腺激素释放激素)stimulatesFSHandLHsecretionfromthegonadotrophs.(4)Corticotropin-releasinghormone(CRH，促肾上腺皮质激素释放激素)stimulatescorticotrophsecretionofACTH.(5)Growthhormone-releasinghormone(GHRH，生长激素释放激素)and(6)somatostatin〔生长抑素〕bothactonanteriorpituitarysomatotrophswit