Principles of Endocrinology and Hormone Action PDF
Preview Principles of Endocrinology and Hormone Action
The Endocrine System Angela M. Leung and Alan P. Farwell Contents Introduction....................................................................................... 2 InterrelationshipswithOtherSystems........................................................... 4 ClassesofHormones............................................................................. 5 Hormone-ReceptorBinding...................................................................... 7 HormonesBindingtoCellSurfaceReceptors............................................... 7 HormonesBindingtoNuclearReceptors.................................................... 8 RolesofHormones............................................................................... 10 EnergyProduction............................................................................ 10 IntermediaryMetabolism,Growth,andDevelopment....................................... 10 Reproduction.................................................................................. 11 MineralandWaterMetabolism............................................................... 11 CardiovascularFunctions..................................................................... 11 TropicActions................................................................................. 12 HormoneSynthesis,Storage,andSecretion..................................................... 12 PeptideandAmineHormones................................................................ 12 SteroidHormones............................................................................. 13 RatesofHormoneSecretion.................................................................. 13 TransportofHormones........................................................................... 14 HormoneMetabolism............................................................................. 15 RegulationofHormoneSecretion................................................................ 16 DisordersoftheEndocrineSystem.............................................................. 17 A.M.Leung(*) DivisionofEndocrinology,DepartmentofMedicine,UCLADavidGeffenSchoolofMedicine,Los Angeles,CA,USA DivisionofEndocrinology,DepartmentofMedicine,VAGreaterLosAngelesHealthcareSystem, LosAngeles,CA,USA e-mail:[email protected] A.P.Farwell SectionofEndocrinology,Diabetes,andNutrition,BostonMedicalCenter;Departmentof Medicine,BostonUniversitySchoolofMedicine,Boston,MA,USA e-mail:[email protected];[email protected] #SpringerInternationalPublishingAG2016 1 A.Belfiore,D.LeRoith(eds.),PrinciplesofEndocrinologyandHormoneAction, Endocrinology2,DOI10.1007/978-3-319-27318-1_1-1 2 A.M.LeungandA.P.Farwell HormoneDeficiencySyndromes............................................................. 18 HormoneExcessSyndromes................................................................. 19 EvaluationoftheEndocrineSystem............................................................. 21 ClinicalEvaluation............................................................................ 21 LaboratoryEvaluation........................................................................ 21 ProvocativeTesting........................................................................... 22 Summary.......................................................................................... 23 Abstract The endocrine system allows for the communication between the multiple cells andorgansandiscomprised ofcomplexnetwork ofhormones,hormonerecep- tors, carrier molecules, and signaling pathways. Characteristic of this system is that hormones generally act on cells that are physically separated from the secretorycell/gland,oftentravelingthroughthecirculatorysystemtoreachtarget tissues. Hormonal regulation is achieved by the ability of hormones to have specific biologic activity at their target tissues, important for energy production andmetabolism,somaticgrowthanddevelopment,reproduction,andabilityfor thebodytorespondtointernalandexternalstimuli.Thesecomplexinteractions utilize controlled mechanisms of hormone synthesis and secretion and commu- nicationwithothersignalingmolecules.Hormonedeficiencyorexcesscaneach result from glandular or extraglandular processes and can be assessed clinically bylaboratorytestingthatmayincludeprovocativetestingifindicated. Keywords Endocrine(cid:129)Hormone(cid:129)Hormonereceptor(cid:129)Signaling Introduction Theendocrinesystemrefers tothecomplex,interrelated mechanismsofcommuni- cationbetweencellsofanorganism.Thesystemiscomprisedofadiverseseriesof signalingmechanismsrequiredfortheregulation,processes,andfunctionsrequired of multiple organs. Communication in the endocrine system is made possible by hormones, biologically active chemical substances that are secreted from ductless glands in the body and circulate through the bloodstream to act on target cells or organs. The actions of hormones in the endocrine system allow for the exquisite regulationofenergyproductionandmetabolism,somaticgrowthanddevelopment, reproduction,andresponsestointernalandexternalstimuli. Hormoneactioncanbeclassifiedintoendocrine,paracrine,andautocrineactions (Fig. 1). The endocrine action of hormones refers to the transport of hormones in circulation to exert their metabolic actions at target tissues. Hormones can bind to carrierproteinsinthecirculatorysystemandthusexistinboththeirunbound(also termed free) and bound forms. However, in most cases, only the unbound/free hormone has biological activity. The differential affinity of binding proteins to hormones enables the precise availability of hormones in circulation and at target TheEndocrineSystem 3 nerve cell hormone PARACRINE neurotransmitter ACTION hormone AUTOCRINE ACTION endocrine gland cell extraglandular target cell ENDOCRINE ACTION bloodstream hormone Fig.1 Classesofhormoneaction site(s).Onceattheirtargetsites,hormonesinteractwithhormonereceptors,proteins whichrecognizeauniquebindingsiteofthehormone.Hormonereceptorsfacilitate the transmission of information carried by the hormone to generate a cellular response.Hormonereceptorsmaybelocatedonthetargetcell’ssurfaceorintracel- lularly,thelatterwhichrequiresamechanismofentryofthehormoneintothecellto exertitsaction. However, some hormones also or exclusively have paracrine actions, in which hormonesarelocallysecretedtoactuponsurroundingcells.Examplesofparacrine actionsincludethe release of testosterone bythetestes tocontrol spermatogenesis, insulin-like growth factor in most tissues to control cell proliferation, somatostatin bythedeltacellsofthepancreaticisletstoinhibitsecretionofinsulinfromthebeta cellsandglucagonfromthealphacells,andgrowthfactorsinbone.Paracrinefactors areusuallyproducedandsecretedinmuchsmallerquantitiesthanhormoneswhich haveendocrineaction,giventhespecificityoftheparacrinefactoratlocaltissuesand absenceoftheneedtocirculatethroughoutthebody.Finally,ahormonecanalsoact onitsowncelloforigin(autocrineaction),suchastheinhibitoryactionofinsulinon itsownsecretionbythepancreaticbetacells. The ability to achieve high hormone concentrations within a tissue is also facilitatedbylocaldiffusionofthehormonefromitssiteofsecretion.Oneexample is the delivery of testosterone from the Leydig cells of the testes to the adjacent spermatogenetictubules.Additionally,thelocalproductionofactivehormonefrom 4 A.M.LeungandA.P.Farwell a circulating hormone precursor can increase the intracellular concentration of a hormone. This is demonstrated by the conversion of testosterone to dihydrotestos- terone(DHT)intheprostateandtheproductionof3,5,30-triiodothyronine(T3)from thedeiodinationofthyroxineinthepituitary,withinthebrain,andinothertissues. The above definitions are adequate to define the concepts of hormones and receptors in most cases. However, increased understanding of the actions of other moleculeshasledtosomebroadeneddefinitions.Regulatorymoleculesthatmainly actasneurotransmitters,suchascatecholaminesandacetylcholine,mayalsoactas classic hormones. Conversely, small peptides, such as thyrotropin-releasing hor- mone(TRH)thatisproducedinthehypothalamusandactsontheanteriorpituitary toreleasethyrotropinandprolactin,arealsofoundinneuronsthroughoutthebody andcanfunctionasneurotransmitters. The classic endocrine glands, whose primary function is hormone production, include the thyroid, pituitary, adrenal, and parathyroid glands and the pancreatic islets.However,notallhormonesareproducedbypureendocrineglands.Theovary andtestes,whichproduce thesex hormones, also produce oocytesandsperm. The brainisamajorsourceformanypeptidehormones,includingproopiomelanocortin (POMC), the precursor molecule for corticotropin (ACTH), endorphins, and melanocyte-stimulating hormone (MSH). Lipotropin is synthesized not only in the anterior pituitary but also in the placenta and the gastrointestinal tract. Other body systemsthatproducehormones,yetwhileservingotherprimaryfunctions,include the heart (which secretes atrial natriuretic factor), the liver (which secretes insulin- like growth factor-I and angiotensinogen and enables the conversion of thyroxine (T4)intothemetabolicallyactiveT3),thekidney(whichsecreteserythropoietinand theactiveformofvitaminD),andthegastrointestinaltract(whichsecretesgastrin, cholecystokinin,somatostatin,andotherhormones). Interrelationships with Other Systems The functions and actions of the endocrine system overlap considerably with the nervoussystemandtheimmune system,whichalsohavekeyrolesinextracellular communication. Like the endocrine system, the nervous system has evolved to release regulatory substances from nerve cells that act across synaptic junctions to transmitasignaltoadjacentcells.Asnotedabove,theseneurotransmittersmayalso function as true circulating hormones, while some hormones also function as neurogenicmediatorsinthecentralnervoussystem.Thus,ifaregulatorymolecule isreleasedintothecirculationtoact,itisconsideredahormone;ifitisreleasedfrom anerveterminaltoactlocally,itisaneurotransmitter.Thesameregulatorymolecule maythereforebebothahormoneandaneurotransmitter. Thehypothalamus serves asadirectconnectionbetween thenervous andendo- crinesystems,asthesourceofbothhormonesthatarestoredintheposteriorpituitary and releasing peptides that regulate hormone secretion from the anterior pituitary. The autonomic nervous system often exerts control over the function of endocrine tissues. The pituitary, pancreatic islets, renal juxtaglomerular cells, and the adrenal TheEndocrineSystem 5 glandallrespondtoneuralstimulation.Thus,thesamecellcanfunctionasbothan endocrineandaneuralcell. Theimmunesystem,initiallythoughttofunctionautonomously,isnowknownto be subject to both neural and endocrine regulation. The cytokine regulators of the immune system are not usually considered hormones, but they clearly fit the definitionasregulatorymoleculesthataresecretedbyonecellandinfluenceanother cell.Theactionsofcytokinesarenotlimitedtoimmunomodulation,asinterleukins, interferons, and tumor necrosis factor produced by the immune system during systemicillness exert amajor influence onhormonemetabolism,especially thatof thyroidhormone.Similarly,corticosteroidsaremajorimmunomodulators,asarethe metabolicderangementsproducedbyendocrinedysfunction,suchashyperglycemia inuncontrolleddiabetesmellitus.Thus,whilethecentralfocusofendocrinologyis onhormones,itisclearthatnotallhormonesbelongtotheendocrinesystemandthat thereisconsiderableoverlapbetweentheendocrine,nervous,andimmunesystems. Classes of Hormones Hormones can be categorized into three classes according to their major compo- nents:peptidehormones,aminoacidanalogues,andsteroidhormones(Table1). Peptide hormones are the most prevalent and diverse. They include hormones thataredefinedbyawiderangeofsizes,composition,numberofchains,modifica- tionofgroups,andmechanismsofproduction.Someexamplesarelargesingle-chain peptides, such as the 192-amino acid growth hormone (GH), the cyclic peptide of TRHthatiscomprisedofjustthreeaminoacids,andprolactin.Theanteriorpituitary hormones, thyrotropin (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are glycosylated and consist of two chains each, one of which is common to all three hormones (α chain), while the other is distinct and confers specificity to the hormone (β chain). Insulin is comprised of two chains that are derived from posttranslational cleavage of a single gene product (preproinsulin), while adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), and β-endorphin are single-chain proteolytic products of a large precursor molecule,proopiomelanocortin(POMC). The amino acid analogue hormones are water-soluble and derived from amino acids. Specifically, the amines are derived from tyrosine and secreted from the thyroid (these are termed iodothyronines) and adrenal medulla. The precursor of the iodothyronines is thyroglobulin, a 660,000-Da glycoprotein that is synthesized bythethyroidfollicularcellcontaining>100tyrosineresidues.Theiodothyronines are formed by iodination and coupling of two tyrosines and are the only iodinated compoundswithsignificantbiologicactivity.Intheadrenalcatecholamine-secreting cells,tyrosineisconvertedsequentiallytodopamine,norepinephrine,andepineph- rine.Serotonin(5-hydroxytryptamine)isderivedfromtryptophan. Steroidhormonesarederivativesofcholesterolcontainingasimilarcoreknown as the cyclopentanoperhydrophenanthrene ring. Synthesis of the steroid hormones occursasaresultofenzymaticallyinducedchangestothecholesterolcore.Synthesis 6 A.M.LeungandA.P.Farwell Table1 Classesofhormones Peptidehormones Smallpeptides Vasopressin(ADH) Oxytocin Melanocyte-stimulatinghormone(MSH) Thyrotropin-releasinghormone(TRH) Gonadotropin-releasinghormone(GnRH) Intermediatepeptides Insulin Glucagon Growthhormone(GH) Prolactin(PRL) Parathyroidhormone(PTH) Calcitonin Corticotropin(ACTH) Corticotropin-releasinghormone(CRH) β-Endorphin Gastrointestinalpeptides Cytokines Growthfactors Glycoproteins Proopiomelanocortin(POMC) Follicle-stimulatinghormone(FSH) Luteinizinghormone(LH) Thyrotropin(TSH) Chorionicgonadotropin(CG) Aminoacidanalogues Iodothyronines Thyroxine(T4) 3,5,30-Triiodothyronine(T3) 30,50,3-Triiodothyronine(rT3) Amines Dopamine Epinephrine Norepinephrine Melatonin Serotonin Steroidhormones Estrogens Progesterone(P) Testosterone(T) Dihydrotestosterone(DHT) Cortisol Aldosterone VitaminD Retinoicacid Prostaglandins TheEndocrineSystem 7 of the adrenal and sex steroids occurs in the adrenal cortex and testes or ovaries, respectively. Hormone-Receptor Binding Hormoneactionrequiresbindingofthehormonetoareceptoratthetargetcell.This allows the hormone to be distinguished from all other substances and to activate a cellularresponseuponhormonebinding.Furtherregulationisachievedbyavariable numberofhormonereceptorspertypeoftargetcell.Hormonescanbegroupedinto twocategoriesaccordingtothelocationofitsreceptoratthetargetcell:onthecell surface(cellsurfacereceptors)orintracellularlyatthelevelofthenucleus(nuclear receptors). Most peptide hormones bind to cell surface receptors, while the amino acid derivatives and steroid hormones are usually ligands for nuclear receptors. In someinstances,mutationalchangesinthestructureofahormonereceptorresultin theconstitutiveinactivationoractivationofthehormonebinding,leadingtoclinical scenariosofhormonedeficiencyandexcess,respectively. Hormones Binding to Cell Surface Receptors Cell surface receptors are glycoproteins that are highly mobile within the plasma membrane.Hydrophilicportionsofthereceptorareexposedatthecellsurface,while the hydrophobic portions of the molecule are buried within the lipid bilayer. Cell surface receptors bind water-soluble hormones, such as peptide hormones, mono- amines, and prostaglandins. Since these water-soluble hormones are not able to transverse the lipid bilayer to enter the cell, the cell surface receptor serves to transmit the hormonal “message” to the interior of the cell. The binding of the hormone to the cell surface receptor is reversible, allowing the receptor to be activatedrepeatedly,althoughthehormone-receptorcomplexmayalsobeinternal- ized, thus producing a single response from a single ligand-receptor interaction. Although there may be a variable number of cell surface receptors, the principal target tissues for a particular hormone generally contain the largest complement of receptormoleculesandareexposedtothehighestconcentrationofhormone. The binding of a hormone to a cell surface receptor stimulates a cascade of complex events through the generation of second messengers. The activation of protein kinases results in phosphorylations and altered conformation of a diverse numberofmolecules,whichthenproducesaseriesofmetaboliceffects.Posttrans- lational modifications of the receptor can affect downstream signaling pathways. Pathologic factors, such as genetics, autoimmune processes, and exogenous toxin exposures,mayfurthercontributetowardregulationofhormonesensitivity. Cell surface receptors which trigger intracellular signaling pathways can be subcategorizedbytheirdifferentmolecularmechanisms:ligand-gatedionchannels, receptor tyrosine kinases, receptor serine/threonine kinases, receptor guanylate cyclase, G-protein-coupled receptors, and cytokine receptors (Fig. 2). The action 8 A.M.LeungandA.P.Farwell Receptor G Protein-coupled Ligand Gated Kinase Receptors Ion Channels Protein Second Ions Kinase Messenger Protein Kinases Phosphorylation- Non Phosphorylation- mediated Actions mediated Actions Fig.2 Cellsurfacereceptorresponsepathways ofG-protein-coupledreceptorsandcytokinereceptorsdependsontherecruitmentof othermolecules,whiletheremainingtypesofcellsurfacereceptorscanalsofunction asionchannelsorenzymestoachieveeffectorfunction.Thus,hormonesmayutilize avarietyofintracellularmediators,andagivenhormonemayutilizeoneormoreof theseintracellularpathways.Themetaboliceventsregulatedbytheactivationofcell surface receptors may either be rapid alterations in ion or substrate flux across the plasma membrane or slower alterations in protein levels by modulation of gene transcription. Hormones Binding to Nuclear Receptors Lipid-solublehormonesaresmallligands(molecularmass<1,000Da)andthusable to penetrate the plasma membrane to interact with intracellular nuclear receptors, whicharemuchlargerproteins(molecularmass50,000–100,000Da)(Fig.3).The classic nuclear receptors are those for the thyroid and steroid hormones, the latter which include aldosterone, cortisol, estradiol, progesterone, and testosterone. Vita- mins A and D metabolites are other lipophilic signaling molecules that also utilize nuclearreceptors. While most lipid-soluble hormones enter cells by passive diffusion, the thyroid hormones utilize active transport proteins, such as monocarboxylate transporter 8 (MCT8), MCT10, and organic anion transporting polypeptide 1 (OATP1C1), to interact with the thyroid nuclear receptors. Vitamin A is stored in the liver and metabolized to retinoic acid, which acts as a ligand for the retinoic acid receptor TheEndocrineSystem 9 hormone transcription -> mRNA -> protein HRE nucleus Fig.3 Nuclearreceptorsignalingpathways (RARs)inthenucleus,orifconvertedtoitsisomer,anothernuclearreceptortermed theretinoidXreceptor(RXR).VitaminD3isproducedintheskinasaresultofthe actionofultravioletradiationon7-dehydrocholesterol.VitaminD3istransportedto the liver, where it is converted to 25-hydroxy vitamin D, and then to the kidney tubuletobeconvertedtoitsactiveform,1,25-dihydroxyvitaminD.Thisactiveform ofvitaminDbindstothevitaminDreceptor(VDR)thatislocatedincellsofalmost allorgans. Nuclearhormonereceptorscanalsobeencodedbymorethanonegene,suchas thyroidandestrogen;bothofthesereceptorshaveanαandaβgene.Somereceptors can also mediate the signals of more than one hormone, such as the androgen receptorthatcaninteractwithbothDHTandtestosterone. Nuclear receptors bind to lipophilic ligands with high affinity. This binding is mediated by the C-terminal ligand-binding domain and domains D and E of the nuclearreceptor.Meanwhile,specificityofligand-receptorbindingisaccomplished by binding of the C domain of nuclear receptors to the hormone response element (HRE)genesequencesoftheligand.MostnuclearreceptorsbindtoHREsasdimers. As the metabolic effects of these proteins are then produced by the translation products of the thyroid or steroid hormone-regulated mRNAs, the actions of these hormonesarerelativelyslow,comparedtocellsurfacereceptors. 10 A.M.LeungandA.P.Farwell Roles of Hormones Hormones have many roles that work together to achieve the exquisite regulation requiredofmany bodyprocesses. Thisregulationbytheendocrinesystem isoften the result of different mechanisms at many targets, thereby allowing the body to respond to a diverse variety of concurrent physiologic changes and pathologic insults.Themajorbodyprocessesregulatedbyhormonesincludeenergyproduction, utilizationand storage(intermediary metabolism), growth, development, reproduc- tion, and maintenance of the internal environment (mineral and water metabolism andcardiovasculareffects). Energy Production Hormonesaretheprimarymediatorsofsubstratefluxandtheconversionoffoodinto energy production. The utilization of glucose and other fuels is regulated by a numberofdifferenthormones.Catecholamines,ghrelin,growthhormone,testoster- one,andcortisolinducethebreakdownoflipidsandthehydrolysisoftriglycerides into glycerol and free fatty acids (lipolysis). Glucocorticoids, catecholamines, growth hormone, cortisol, and glucagon promote hyperglycemia. Consistent with the occasional need for rapid mobilization of fuels, many of these catabolic hor- monesexerttheiractionsbytheactivationofadenylcyclase.Incontrast,insulinand theinsulingrowthfactors(IGFs)areanabolichormonesandstorefuelforlateruse. Finally, the thyroid hormones directly affect energy production at the level of the mitochondria,whichhavetheirownspecificthyroidhormonereceptors. Intermediary Metabolism, Growth, and Development Hormones are crucial for normal somatic growth and development. The major hormones involved in development and growth are thyroid hormone, growth hor- mone, the sex steroids, insulin, and other growth factors. Thyroid hormone affects both growth and development and has a particularly critical role in early neurodevelopment. Growth hormone primarily regulates growth, and the sex ste- roidsmainlyregulatesexualdevelopment. Androgens, estrogens, growthhormone, thyroid hormone, and prolactin can act asgrowthfactors.Theactionofsomeoftheseisreliantontheavailabilityofother hormonestoactasgrowthfactors.Oneexampleisgrowthhormone,whichrequires thyroidhormoneforitsnormalsynthesisandsecretion,inpartthroughthestimula- tionandactionofIGF-1bythyroidhormone.Incontrast,glucocorticoidsinexcess andsomatostatininhibitthesecretionofgrowthhormoneandTSH.
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