endocrine system

Endocrine Endocrine SystemSystem

Huiping Wang (Huiping Wang (王会平王会平 ), PhD), PhD

Department of PhysiologyDepartment of Physiology

Rm C516, Block C, Research Building, School of MedicineRm C516, Block C, Research Building, School of Medicine

Tel: 88208252Tel: 88208252

Email: [email protected]: [email protected]

RECOMMENDED TEXTBOOK:RECOMMENDED TEXTBOOK: Widmaier EP, Raff H, Strang KT (2006) Widmaier EP, Raff H, Strang KT (2006) Vander’s Human PhysiologyVander’s Human Physiology: The Mechanisms of Body Function, Tenth : The Mechanisms of Body Function, Tenth Edition. McGraw-Hill.Edition. McGraw-Hill.

SUPPLEMENTARY READING:SUPPLEMENTARY READING: Stephan Sanders (2003) Stephan Sanders (2003) Endocrine and Reproductive systemsEndocrine and Reproductive systems, Second Edition. Mosby., Second Edition. Mosby.

COURSE WEBSITERS:COURSE WEBSITERS: http://www.endocrineweb.com/http://www.endocrineweb.com/

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/index.htmlhttp://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/index.html http://medical.physiology.uab.edu/cardio.htmhttp://medical.physiology.uab.edu/cardio.htm http://www.mhhe.com/biosci/ap/foxhumphys/student/olc/index.htmhttp://www.mhhe.com/biosci/ap/foxhumphys/student/olc/index.htm

Endocrine Endocrine SystemSystem

General Principles of Endocrine PhysiologyGeneral Principles of Endocrine Physiology

Hypothalamus and pituitary glandHypothalamus and pituitary gland

Thyroid glandThyroid gland

Endocrine Regulation of Calcium and Phosphate Endocrine Regulation of Calcium and Phosphate

MetabolismMetabolism

Adrenal glandAdrenal gland

Pancreatic hormonesPancreatic hormones

General Principles General Principles

of Endocrine Physiologyof Endocrine Physiology

OutlineOutline

Endocrine system and Endocrine system and HormoneHormone Hormone types Hormone types Hormone synthesis, storage, release, Hormone synthesis, storage, release,

transport, clearance and action modestransport, clearance and action modes Characteristics of hormonesCharacteristics of hormones Regulation of Hormone SecretionRegulation of Hormone Secretion Mechanisms of hormone actionMechanisms of hormone action

Endocrine System

One of the two major communication systems in the body Have much longer delays Last for much greater lengths of time

Integrate stimuli and responses to changes in external and internal environment

crucial to coordinated functions of highly differentiated cells, tissues and organs

Endocrine gland (ductless) is a group of cells that produce and secret a hormone

Endocrine GlandsHypothalamus

Pituitary (Anterior and Posterior)

Thyroid / Parathyroid

Endocrine Pancreas (islets)

Adrenal Cortex and Medulla

Gonad (Ovary and Testis)

Endocrine System

The endocrine system broadcasts its

hormonal messages to target cells by

secretion into blood and extracellular

fluid. Like a radio broadcast, it requires a

receiver to get the message - in the case

of endocrine messages, cells must bear

a receptor for the hormone being

broadcast in order to respond.

What is a hormone?What is a hormone?

Chemical Chemical messengermessenger synthesized by specific ensynthesized by specific endocrine cells in response to certain stimuli and sdocrine cells in response to certain stimuli and secreted into the bloodecreted into the blood

Travel via the circulation to affect one or moreTravel via the circulation to affect one or more grgroups of different cellsoups of different cells ( (target cellstarget cells)) to elicit a ph to elicit a physiologicalysiological responseresponse

Hormones are primarily informationHormones are primarily information transferring moleculestransferring molecules

Types of Hormones

Types Amines Steroids Protein and

peptides

Example T4, T3,T4, T3,

catecholaminecatecholamine

Hormones from Hormones from adrenal cortexadrenal cortex

and gonadsand gonads

Most of hormonesMost of hormones

insulin, oxytocin, insulin, oxytocin, GHGH

Synthesis Tyrosine Cholesterol DNA – mRNA –DNA – mRNA –

Preprohormone -Preprohormone -

ProhormoneProhormone

Feature lipid insolublelipid insoluble lipid solublelipid soluble lipid insolublelipid insoluble

NUCLEUS

The DNA code is “transcribed” into mRNA.

RIBOSOMES

The mRNA is “translated” to give instructions for proteins synthesis.

Synthesis of peptide hormonesSynthesis of peptide hormones

Typical synthesis of peptide hormonesTypical synthesis of peptide hormones

PreprohormonesPreprohormones- larger hormones - larger hormones

produced on the ribosomes of the produced on the ribosomes of the

endocrine cellsendocrine cells

ProhormonesProhormones- cleavage of - cleavage of

preprohormones by proteolytic preprohormones by proteolytic

enzymes in rERenzymes in rER

ProhormonesProhormones- packaged into - packaged into

secretory vesicles by the Golgi secretory vesicles by the Golgi

apparatusapparatus

ProhormonesProhormones- cleaved to give - cleaved to give

active hormone and pro-fragmentsactive hormone and pro-fragments

pre-pro-insulin pro-insulin insulin

Synthesis of steroid hormonesSynthesis of steroid hormones

Hormone Storage and Release

Thyroid and steroid hormonesThyroid and steroid hormones Not stored as secretory granulesNot stored as secretory granules Transferring through plasma membraneTransferring through plasma membrane

Protein and catecholamine hormonesProtein and catecholamine hormones Stored as secretory granulesStored as secretory granules Released by exocytosisReleased by exocytosis

Hormones are not secreted at auniform rate

In a pulsatile patternIn a pulsatile pattern

Diurnal (circadian) rhythm:Diurnal (circadian) rhythm: linked to sleep-wake cycles linked to sleep-wake cycles

(cortisol, growth hormone)(cortisol, growth hormone)

Be aware of the pulsatile Be aware of the pulsatile nature and rhythmic nature and rhythmic pattern of hormone pattern of hormone secretion when relating the secretion when relating the serum hormone serum hormone measurements to normal measurements to normal valuesvalues

Hormones are not secreted at auniform rate

Rhythmic secretionRhythmic secretion

CyclicCyclic

oestrogen, oestrogen,

progesterone, LHprogesterone, LH

Modes of ActionModes of Action

EndocrineEndocrine – transmission of a – transmission of a signal signal from a classicfrom a classic endocrine cell throughendocrine cell through bloodstream to a distant targetbloodstream to a distant target cellcell e.g. testosterone e.g. testosterone

NeurocrineNeurocrine – hormone is – hormone is released frreleased from a neuron downom a neuron down its axon and then its axon and then travels viatravels via the bloodstream to target the bloodstream to target cellcell

ParacrineParacrine - hormone acts on - hormone acts on adjacenadjacent cellst cells e.g. histamine released at site e.g. histamine released at site of injury to constrict blood vessel of injury to constrict blood vessel walls and stop bleedingwalls and stop bleeding

AutocrineAutocrine – hormone is – hormone is released and released and acts on the cellacts on the cell that secreted it.that secreted it. e.g. e.g. norepinephrine itself inhibits further norepinephrine itself inhibits further release by that cellrelease by that cell in the adrenal mein the adrenal medulla dulla

A secretion may have several sites of action simultaneously

Example:Example:

NorepinephrineNorepinephrine

- - Autocrine Autocrine action action causes negative causes negative feedback on feedback on secretion. secretion.

- Simultaneously, - Simultaneously, endocrine endocrine action action causes respiration causes respiration rate to increase, rate to increase, peripheral blood peripheral blood vessels to constrict, vessels to constrict, etc.etc.

Hormone Transport

Peptides and catecholaminePeptides and catecholamine water solublewater soluble dissolve in blooddissolve in blood circulate in blood mainly in free formcirculate in blood mainly in free form

Steroid and thyroid hormonesSteroid and thyroid hormones circulate in blood mainly bound to plasma proteinscirculate in blood mainly bound to plasma proteins the free form is biologically activethe free form is biologically active the greater binding, the longer half-lifethe greater binding, the longer half-life

Hormone Clearance The half-life of a hormone in bloodThe half-life of a hormone in blood

is the period of time needed for its concentration to be reduced by is the period of time needed for its concentration to be reduced by half.half.

Free: minFree: min Binding: mins, hrs, daysBinding: mins, hrs, days

e.g. T4 (6 days); Insulin (0.006 days)e.g. T4 (6 days); Insulin (0.006 days)

Hormone concentration in blood is determined byHormone concentration in blood is determined by secretion ratesecretion rate clearance rateclearance rate

Ways of ClearanceWays of Clearance target cell uptaketarget cell uptake metabolic degradationmetabolic degradation urinary or biliary excretionurinary or biliary excretion

The “metabolic fate” of a given hormone molecule in the blood

CharacteristicsCharacteristics of H of Hormoneormoness

Regulates Regulates rate of reactionrate of reaction

Do notDo not initiate initiate

Very specificVery specific

Amplification effectAmplification effect

Present in very small quantityPresent in very small quantity

pg/mL ~ pg/mL ~ g/mLg/mL

CharacteristicsCharacteristics of H of Hormoneormoness

Interaction between hormonesInteraction between hormones Synergistic actionSynergistic action

Antagonistic actionAntagonistic action

Permissive actionPermissive action Hormone A must be present for the Hormone A must be present for the

full strength of hormone B’s effect.full strength of hormone B’s effect.

Up-regulation of one hormone’s Up-regulation of one hormone’s

receptors by another hormonereceptors by another hormone

the facilitation of the action of one the facilitation of the action of one

hormone by anotherhormone by another

e.g. the ability of TH to “permit” epinephrine-induced e.g. the ability of TH to “permit” epinephrine-induced release of fatty acids from adipose tissue cells (TH release of fatty acids from adipose tissue cells (TH causes an causes an no. of epinephrine receptors on the cell) no. of epinephrine receptors on the cell)

Three types of inputs to endocrine cells that stimulate or inhibit hormone secretion.

Regulation of Hormone Secretion

Regulation of Hormone Secretion

Negative feedbackNegative feedback Most commonMost common Occurs when a hormone Occurs when a hormone

produces a biologic effect produces a biologic effect that, on attaining sufficient that, on attaining sufficient magnitude, inhibits further magnitude, inhibits further secretionsecretion

Positive feedbackPositive feedback Less commonLess common Amplify the initial biological Amplify the initial biological

effect of the hormoneeffect of the hormone

Negative FeedbackNegative Feedback

Characteristic of control systems in which system’s Characteristic of control systems in which system’s

response opposes the original change in the system.response opposes the original change in the system.

Hormone Hormone itselfitself feeds back to inhibit its own synthesis.feeds back to inhibit its own synthesis.

Regulated product Regulated product ((metabolite)metabolite) feeds back to inhibit feeds back to inhibit

hormone synthesis.hormone synthesis.

Important for homeostatic control.Important for homeostatic control.

Example: Control of blood glucose by insulinExample: Control of blood glucose by insulin

Positive FeedbackPositive Feedback

Characteristic of control systems in which an iCharacteristic of control systems in which an i

nitial disturbance sets off train of events that nitial disturbance sets off train of events that ii

ncreases the disturbance even furtherncreases the disturbance even further..

AmplifiesAmplifies the deviation from the normal levels the deviation from the normal levels Example: Oxytocin (suckling)Example: Oxytocin (suckling)

Important for amplification of level for actionImportant for amplification of level for action

Hormone action mediated by the specific receptors Most hormones circulate in blood, coming into contact with

essentially all cells. However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone.

Mechanisms of hormone actionsMechanisms of hormone actions

Hormone Receptors

Structure Recognition domain binds hormone Coupling domain generates signal

Location cell membrane (e.g. for insulin) cytoplasm (for steroids) nucleus (e.g. for thyroid hormone)

Receptor capacity exposure to excess hormone down-regulates capacity low hormone concentration up-regulates capacity

The receptor provides link between a specific extracellular hormoneand the activation of a specific signal-transduction system

Two general mechanisms ofhormone action

Second messengers – enzyme activity

↑↓(rapid, cytosolic effects)

Gene expression - enzymes synthesis

↑↓(slow, nuclear effects)

Mechanisms of Peptide Hormone ActionMechanisms of Peptide Hormone Action

G proteins are GTP-binding proteins couple hormone receptors to adjacent effector molecule have intrinsic GTPase activity have three subunits: α, β, γ α subunit bound to GDP → inactive G protein α subunit bound to GTP → active G protein the effect can be either stimulatory (Gs) or inhibitory (Gi)

Second messengers cAMP second message system IP3 mechanism Ca2+-calmodulin mechanism

Signal transduction pathway involving adenylate cyclase

Cyclic AMP signaling-sequence of eventsCyclic AMP signaling-sequence of events

The The hormonehormone ( (11stst messenger messenger) binds to the membrane receptor; the ) binds to the membrane receptor; the membrane receptor changes shape and bind to G protein (GTP-membrane receptor changes shape and bind to G protein (GTP-binding protein)binding protein)

G protein is activated; binds to GTP (Guanosine 5’- triphosphate) and G protein is activated; binds to GTP (Guanosine 5’- triphosphate) and release GDPrelease GDP

Activated G protein moves to membrane and binds and activates Activated G protein moves to membrane and binds and activates adenylate cyclase (GTP is hydrolysed by GTPase activity of G protein)adenylate cyclase (GTP is hydrolysed by GTPase activity of G protein)

Activated adenylate cyclase converts Activated adenylate cyclase converts ATP to cAMP (ATP to cAMP (second second messengermessenger) ) (if inhibited, no catalysed reaction by AC)(if inhibited, no catalysed reaction by AC)

cAMP is free to circulate inside the cell; triggers activation of one to cAMP is free to circulate inside the cell; triggers activation of one to several protein kinase molecules; protein kinase phosphorylates many several protein kinase molecules; protein kinase phosphorylates many proteinsproteins

The phosphorylated proteins may either be activated or inhibited by The phosphorylated proteins may either be activated or inhibited by phosphorylationphosphorylation

Adenylyl cyclase forms cAMP,a “second messenger” that activates enzymes used in cellular responses.

The phosphodiesterase enzymes “terminate” thesecond messenger cAMP.

The cAMP system rapidly amplifies the responsecapacity of cells: here, one “first messenger” ledto the formation of one million product molecules.

Amplification effect

Each protein kinase can catalyse hundreds of reactions

This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels.

PIP-calcium signaling mechanism

A hormone A hormone (first messenger)(first messenger) binding to its receptor causes the receptor to binding to its receptor causes the receptor to bind inactive G proteinbind inactive G protein

G protein G protein is activated; binds GTP & releases GDPis activated; binds GTP & releases GDP Activated G protein binds & activates a membrane-bound phospholipase Activated G protein binds & activates a membrane-bound phospholipase

enzyme;enzyme; G protein becomes inactiveG protein becomes inactive

Phospholipase splits Phospholipase splits phosphatidyl inositol biphosphate phosphatidyl inositol biphosphate (PIP(PIP22) to) to

diacylglycerol diacylglycerol (DAG)(DAG) & & inositol triphosphate inositol triphosphate (IP3);(IP3); DAG DAG activates protein kinases on the plasma membrane; activates protein kinases on the plasma membrane; IP3 IP3 triggers triggers calcium calcium

ionion release from the ER release from the ER Released Released calcium ionscalcium ions (second messengers)(second messengers) alter activity specific enzymes’ alter activity specific enzymes’

activity and ion channels or bind to the regulatory protein calmodulin;activity and ion channels or bind to the regulatory protein calmodulin; Calmodulin Calmodulin also activates specific enzymes to amplify the cellular responsealso activates specific enzymes to amplify the cellular response

PIP-calcium signaling mechanism

Ca-calmodulin system Ca-calmodulin system

Mechanisms of steroid Hormone ActionMechanisms of steroid Hormone Action

Modulation of gene

expression Steroid hormones bind to

intracellular receptors

The steroid-receptor complex

binds to DNA, turning specific

genes on or off

Steroid hormone receptorSteroid hormone receptor

Sequence of events for steroid hormone binding

Steroids are lipid-based and can diffuse into cells easilySteroids are lipid-based and can diffuse into cells easily No need for intracellular second messengerNo need for intracellular second messenger Mobile receptorsMobile receptors Some steroids bind to a cytoplasmic receptor, which then Some steroids bind to a cytoplasmic receptor, which then

translocates to the nucleustranslocates to the nucleus Other receptors for steroids are located in the nucleus or are Other receptors for steroids are located in the nucleus or are

nuclear receptor proteins nuclear receptor proteins In both cases, the steroid-receptor complex formed can then bind In both cases, the steroid-receptor complex formed can then bind

to specific regions of DNA and activate specific genes to specific regions of DNA and activate specific genes Activated genes transcribe into messenger RNA and instruct the Activated genes transcribe into messenger RNA and instruct the

cell to synthesize specific enzyme proteins that change the cell to synthesize specific enzyme proteins that change the metabolism of the target cell metabolism of the target cell

Radioimmunoassay (RIA)

(from the Nobel lecture by Dr. Rosalyn Yalow, 1977)(from the Nobel lecture by Dr. Rosalyn Yalow, 1977)

The main difference between the modes of action of The main difference between the modes of action of peptide hormones and steroid hormones is thatpeptide hormones and steroid hormones is that

a. peptide hormones bind to intracellular receptors whereas steroid a. peptide hormones bind to intracellular receptors whereas steroid hormones bind to receptors on the cell surface.hormones bind to receptors on the cell surface.

b. peptide hormones bind to receptors in the nucleus whereas steroid b. peptide hormones bind to receptors in the nucleus whereas steroid hormones bind to receptors in the cytosol.hormones bind to receptors in the cytosol.

c. peptide hormones bind to receptors on the cell surface whereas c. peptide hormones bind to receptors on the cell surface whereas steroid hormones act as second messengers.steroid hormones act as second messengers.

d. peptide hormones bind to receptors on the cell surface whereas d. peptide hormones bind to receptors on the cell surface whereas steroid hormones bind to intracellular receptors.steroid hormones bind to intracellular receptors.

e. there are no differences; both act by binding to receptors on the cell e. there are no differences; both act by binding to receptors on the cell surface.surface.

QUIZ

In the absence of thyroid hormone, epinephrine stimulates release of a small In the absence of thyroid hormone, epinephrine stimulates release of a small amount of fatty acids from adipose cells. In the presence of thyroid hormone amount of fatty acids from adipose cells. In the presence of thyroid hormone (which has no effect by itself), epinephrine causes a much more substantial (which has no effect by itself), epinephrine causes a much more substantial release of fatty acids from the cells. The effect of thyroid hormone on release of fatty acids from the cells. The effect of thyroid hormone on epinephrine's actions is calledepinephrine's actions is called

a. antagonistic.a. antagonistic.

b. agonistic.b. agonistic.

c. permissive.c. permissive.

d. direct.d. direct.

e. paracrine.e. paracrine.

QUIZ

SummarySummary HormoneHormone

Primarily information transferring moleculesPrimarily information transferring molecules Transfer information from one set of cells to anotherTransfer information from one set of cells to another Travel via the circulation to affect one or more groups of different cells to Travel via the circulation to affect one or more groups of different cells to

elicit a physiological responseelicit a physiological response

Hormone typesHormone types Protein and peptides Protein and peptides AminesAmines SteroidsSteroids

Action modes of hormonesAction modes of hormones Endocrine Paracrine Autocrine Neurocrine

SummarySummary

Regulation of Hormone SecretionRegulation of Hormone Secretion Negative feedbackNegative feedback Positive feedbackPositive feedback

Mechanisms of hormone actionMechanisms of hormone action Mechanisms of Peptide Hormone ActionMechanisms of Peptide Hormone Action

Second messenger signaling pathwaySecond messenger signaling pathway cAMP second message systemcAMP second message system

IPIP33 mechanism mechanism

CaCa2+2+-calmodulin mechanism-calmodulin mechanism

Mechanisms of Steroid Hormone ActionMechanisms of Steroid Hormone Action Modification of gene expressionModification of gene expression

endocrine system

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