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,Endocrine

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system

Subject : to Physiolog)J of Endocrine system ! .. ! .

· Doctor : Salim # 1. I .. • ·

Done By: Slides .. ;., Date : 12/3/2013 ·

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TABLE 1-1 Organ Systems: Components and Functions

System Components

Nervous Brain, spinal cord, peripheral nerves, ganglia

Skeletal Bone, connective tissue Cardiovascular Heart, blood vessels, red blood cells

Respiratory Nose and throat, trachea, bronchi, bronchioles, lungs

Digestive Mouth, esophagus, stomach,· small and large intestines, salivary glands, liver gall bladder, pancreas

Urinary Kidneys, ureters, bladder, urethra

Endocrine Pituitary, adrenals, thyroid, parathyroids, gonads, pancreas; many other organs secrete hormones in addition to their other functions

Reproductive Male: testes, associated glands and ducts, penis Female: ovaries, fallopian tubes, uterus, vagina, clitoris, breasts

Lymphatic Lymph vessels, lymph nodes

Immune Lymphoid tissues, bone marrow, white blood cells, thymus

, . ..-'# ·,

Functions

Controls activities of other systems; receives information from the environment; stores memor initiates and controls behavior Support; mineral storage; production of blood ce Transports nutrients, gases, metabolic end produ< and hormones between organ systems Takes up oxygen and releases carbon dioxide to atmosphere; produces sounds; partly responsible regulating blood acidity Digestion, food storage, absorption of nutrients; protects against infection

Homeostasis of extracellular fluid volume and composition; excretion of waste products Regulation of reproduction, growth, metabolism: energy balance, extracellular fluid composition

Reproduction, sexual gratification

Fluid balance; transport of digested fat; cells of 1 immune system are also located within it

Resists infection, parasitization, and cancer

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.. E·X H. I B·l'T: ·18.1 ·:!COMPARISON OF NERVOUS 'I· .. ·, '• • "I 'I ' • '• 1>',, • • (I f . •

.. · : . . ... sYSTEM AND ENDOCRINE I 4.- ' I •. I 11 : • .;. II. I : • 1 • .

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HOMEOSTASIS

' •• · ;·.- j Nervous ;.:.·Characteristic · System

of Neurotransmitters • ("_ ': .r ' : . • ' I . ! j • ! I . ·J·-· -· released in rc-. • . •. _ _i '"

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Endocrine System

Hormones dcliv-crcd to tissues throughout the

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Muscle cells, Virtually all body · ·; gland cells, other cells. 'I neurons.

._.\··.Type of action Muscular contrac- Chan.gcs in meta-_._,that results· · : ·

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tion or glandular secretion .

: Typically within milliseconds.

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bolic acti vi tics.

Seconds to hours or days. Generally longer .. ·

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This section focuses on the classic endocrine glands and their hormones.

A hormone is chemical substance that is released into the blood in small amounts and that, after delivery by the circulation, elicits a ·typical physiologic response in other cells.

An endocrine gland is a group of cells that produce and secrete a hormone.

Endocrine · glands are also · called ductless glands to distinguish them from exocrine glands, which deliver their products through ducts to the outside of the body or the lumen of the gastrointestinal tract.

Fig. 1.3 Mode of of hormones to-their . larger cells: . .

·np·es

1. Autocrlne 2. Paracrlne deiiYety

4. Neuroendocrine delivery

S. Pheromonal delivery

delivery-chemical. message released dollvory-volalilo hormonos acts on the cells that synthesized it, e.g. the as pheromones) released into the environment ad Oi

cytokine prostaglandin E2 stimulates the olfactory cells in another individuallpheromones, myometrial cells that produced it allhough only found in other-species, may be

important in controlling human sexual behaviour).

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Endocrine

T A B L E 35-1. TYPES OF HOR1v10NE ACTION

Hormone synthesized in one location and released into plasma; binds to specific receptor in at a distant site to elicit characteristic response.

Example: The action of thjToid-stimulating hormone from the anterior pituitary gland on the th)TOid.

Neuroendocrine Hormone synthesized in nerve ending and released into extracellular space; interacts with receptors of cells at distant si'te. ;

£r.ample: The action of norepinephrine in splanchnic nerve ending on the heart N'euroc;ine Honnone synthesized in neurons and reieas.::d extracellular space; binds to receptor in

nearby cell and affects its function. · . £rample: The action on cardiac muscle cells of norepinephrine synthesized in ncr•e endings io .

the heart. Neurot.ransmission Honnone synthesized in neurons and relea.s...."<J from nerve endings; crosses S}1lapse and binds to

Paracrine

Autocrinc:

Exocrine

specific rtteptor in another neuron, affecting its action. £tamp!e: Rcle:!.SC of acetylcholine from preganglionic nerve fibers in S)m(Xlthctic ganglia and

binding to receptor in postganglionic neuron "'ith liberation of norepinephrine. Hormone synthesized in endocrine cells and released into interstitial space,; binds to specific

receptor of nearby cell and 31fects its funruon. £tample: Release of somatostatin from islet delta cells and its subsequent-action..on nearby

alpha and beta cells in the same pancreatic islet :· .. \

Hormone synthesized in endocrine cells :md sometimes released into interstitial space: binds to- .. receptor ori the ceU of origin. thereby autoregulating its function.

Etample: The action of somatostatin on its secretion. Honnone synthesized in endocrine: cells and rdeasro into lumen of gut: binds to cells lining the\·

gut at "ar:ing distances from the endocrine cells, thereby affecting their function. Example: The release of gastrin by mucosal ccl1s and its action on gastric acid secretion by the

stomach. • , .-'::i:·

(Modified from Vt'iilia.ms. R.H .• Ed.: Tat'OOok of Endocrinology. 6th cd. P'nibddpbU, W_B. Saunders Co_ 198 I. p. 99S.) •4

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' . rlGURE 15-1 Types of Intercellular Communication by

Messengers (a) Patacriue secretion. (b) Neurotransmitter ;ecretion. (c) Honnone secretion. (d) Neurohormone secretion.

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Secreting cell

Secreting cell (endocrine cell)

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(a) Par"'crine

(c) Hormopt Sftrc\ion.

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Endocrine cell

Neuron

-Endocrine signal

Neurotransmitter signal

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Target cell

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Figure 4-5. Extracellular messengers interact with receptors on the target cell. The distance between the cell secreting the messenger and the target cell containing the receptor is the

, basis for classifying the action as an autocrine, a paracrine, a neurotransmitter, or an endocrine event. ./

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Pheromones. Substances produced by an anifi?.al that act at a distance to produce hormonal; or other physiologic changes in .: ... same species have been called of insects are The ant pheromones vomeronasal ;Ygah play a prominent and dominance be-havior of • rodents._· including pheromones For- example, women who are good __ ':or'-i/f9R,[tmates tend to . synch_ro-nize armpit odor wom.en h b . h .. :-; ··.·. ·. '_'·'··,; lf; .. ;.;;·:."' .. H_1. '"''A!·· f d "fy" '· .. h ... as _ een s .. mo 1 tng:.·:t,. e

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___..--:--· · · The following points add to the co1nplcxity of tl1c cnclo-crine

A single endocrine may tJroduce multiple hormoilCS. The anterior pituitary, for exan1plc, secretes six·- different honnones; each is under different control mechanisms and has ···different Iurictions, · some being tropic and others

_l1eving nontropic effects.

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A single hormone may be secreted ._by more than one endocrine gland. For exatn}Jle, tl1c hy}Jothalamus and

both secrete the hormone somatostatin. ··-

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--- . . Freque11tly, a single hormone has tnorc than one type ol target cell and therefore can induce more than one type tJf . effect. As an example, vasopressin promotes H20_ rcab- , sorptio11 by the kidney tubules. as well as \rasoconstrictioi1 of arterioles throughout the body.' · · ···-· ..

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' 1\ sir1glc target cell 111a)' be in11uct1t:cd by 111orc tl1an 011e l1ort11nnc. Son1c cells contain an c;trray of receptors for responding in different ways to different hormones. To illustrate, insulin promotes conversion of glucose inlo gl)'Cllgcn \ViLI1in liver cells by stin1ulating one _lJarticlllar hepatic enzyme, ano.ther hormone, glucagon,

tl1e clcgratlati<.111 of gl)'Cl)gCI1 il1l0 \Vill1i11 li\'Cr cells l'Y acti\'ating )'Cl at1otl1cr 11c1Jalit C11ZYI11c. - .. . . .

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·-The same chemical messenger be or a neurotransmitter, depending on its mode of-delivery to the target cell.' as a 11or111onc by.-tllc as a n.curotransmiucr from sympathetic nerve fibers, is a prime example. · · · -- " -

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organs arc exclusively in, (t,hey specia.Hze in hormonal · tary and thyroid glands· · organs of the endocrine .. functions in adcJition to the testes produce sperm and also· secTete 111a1e S«!X hormone testosterone. Other examples of are the ovaries, digestive tract, pancreas,' l<ic.lncys·, ·even the brair1. l11 cacl1 case the brain, 111ixcd occurs . . : .

lJccausc .tl1c organ l1ouscs nonctido·crinc Lissuc plus isolaLed . . .

clusters of endocrine cells that tnigratcd to the organ .. during embryonic development. The cndocrin¢ of tl1e brain deri\'es the presence· of neurons. There are no endocrine cells as such in the brain. r \.. __ . .

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Ph'{slologlcal effects of hormone's on body functions:··:=·:·'·'',:'':;:·:··

Body function

metabolism

reproduction

digestion

blood circulation

transport or substrates to 11ssuos !blood composition)

defence against pathogens

growth

stress response

behaviour

Efforn of hormones

regulate metabolic processes, l.o. tho rotc of synthesis and degradation of carbohydrates, proteins, and lipids

control reproductive processes, including the development of the sex organs, secondary sexual characteristics. gametogenesis. and, the menstrual cycle

control digestive processes, Including gut n1ohlity and the secretion of dlgosllve enzymes, bile, gastric acid, and bicarbonate

regulate blood pressure by altering cardiac output, vascular constriction, and blood volume via tho control of water oxcrollon by ·tho kidneys

regulate blOod plasma concentrations of glucose. minerals (e.g. sodium, potassium, calcium), gosos (oxygen. carbon dloxldol, blood coils, wotor, and hydrogon Ions lpH regulation)

regulate Immune system responses. Including leucocyte activation, lnflammalion. antibody production, and lover

control cell division and dlfforcnilallon

regulate the bod'(s response to stress

control sexual and social behaviour d)

Fig. 1.2 Physiological effects of hormones on body

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jsiological effect I A

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8 c FIGURE 30.2 Negative, positive, and complex feedback mechanisms in the endocrine system. A, Negative feedback loop. 8, Positive feedback loop. C, A complex, multilevel feedback loop: the hypothalamic-pituitary-target gland axis. Black lines indicate stimulatory effects; blue lines indicate inhibitory, negative-feedback effects. EH, endocrine cell hormone; RH, releasing hormone; TH, trophic hormone.

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(±) llrJargef(il; PTH '<. kidney 1·

r=) + [Ca2•]pl ,.__ __ _.

Fig. 5.1.12 Direct negative feedback. A. General·principle. o. Exumple of direct negative feedback using PTH and its effect on plusmu calcium.

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Substratc-honnonc Mineral-hormone

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1 · i\'eural control . ( , Chronotrooic control . . .

evoke or su.ppress ho;mor.e Sefr"7ftoo} s.£>.r:rEted 10 dts.!inct pu1!9.!') I •

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cnkcphalincrgic Pain,·

Sh-e·SS'·- al(- "CCfr'l Tllodulate hormone throug·l1 J:et.cral nJfcllanisrns.

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Inhibit -::;.

Negative feedbacl{ loops regulating hormone< secretion in a typical hypothalamus-pituitary-peripheral

X, Peripheral gland honnona: XTH, pituitary tropic hprmone; XRH, hypotha.lo.mic reloneing hormone; XIH, hypothnlc. :nic inhibiting hormone. · ·

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J\ neural-honnonal positive feedback lcop. The sucking of an infant stitnulates receptors in the nipple of 1nam1nary gland. Neural signals travel to the hypotha\arnus, where they stilnulate, the release of

rrmn the ncurohypophys\s. tn\\10\s \\\ tho b\ood t\) ----· t1le tnanunary gland and stitnulales the release of tnilk.

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Triggers onset of parturition (leading proposal)

Responsible for progression of parturition

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. FIGURE 16-22 Positive Hormonal ·. \ . . Feedback during Parturition ....... --····

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Amines

OH

HO I )Qr CH- CH2 - NH2 (Norepinephrine)

HO

Polypeptides

(Oxytocin)

(Cortisol)

Steroids

CH20H I C=O

Thyroid Hormones

I I NH2

HoOoOcH2 -bH-cooH I

(3 ,5 ,3 ·-triiodothyronine, T 3)

Proteins

NH2

55 (Growth hormone)

OH (Vitamin D3)

FIGURE 30.3 Examples of different hormone chemical structures. A, Amine hormones. 8, Peptide hormones. C, Steroid hormones. (Modified from Griffin JE, Ojeda SR. Textbook of Endocrine Physiology. 4th Ed. Oxford: Oxford University Press, 2000: Fig. 1.1.) iiAQRW# ' .. .. ;; .• - -·· ,.. __ ···>··-t _., .. !L-ta--4§@$Q+R£ N·i ¥ f@N§

Eicosanoids

Animals fed a fat-free diet fail to grow, develop

skin & kidney lesions & become infertile. Adding

linolenic, linoleic & arachidonic acids to the diet

cures all the deficiency symptoms. These three acids

are polyunsaturated fatty acids & because of their

action are called essential fatty acids.

One of the reasons & possibly the only reason,

that essential fatty acids are necessary for health is

that they are the precursors of prostaglandins,

prostacyclin, thromboxanes, lipoxins, leukotrienes &

related compounds. These substances are called

eicosanoids.

The leukotrienes, thromboxanes, lipoxins &

prostaglandins have been called local hormones.

They undoubtedly act mainly in the tissues at sites in

which they are produced.

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Rr!gulnlibn and Tnlr!gralion of the Body 536 Unit :1

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Anterior lobe-=.: of prluilary . g!and

<DACTH released inlo blood

exert negative feedback on ACTH release

·--.::::--Q'l Glucocorticoids influence several

CD Capillary blood containing .. high concenlralion _. blood sugar of glucose ---- <? nevels inhibit

:Jus or t.J moru ulur.n::r. from lllood

insulin release

@Ca.ptllary blood in which glucose

cell:.

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(a) Hormonal targel organs (!') Humoral levels have dropped (c) Neural

Figure 17.3 tndocrine gland stim-uli. (a) Hormonal stimulus of endocrine gland activity. In the example illustrated, ACTH (adrenocort:i:otropic hormone) stimulates the release or glucocorticoid hormones by the adrenal cortex. As blood levels of rise. they inhibit

ACTH release. (b) Humoral stimulus of endocrine gland activity. High blood glu-

. cose levels trigger insulin release from the . ; pancreas. Insulin causes a rapid uptake

·or glucose by its target cells, ca•Jsing blood sugar levels to drop andthe stimu-lus lor insulin release to end. (c) Neural

stimulus of endocrine gland aclrvrlr 11··· stimulation of adrenal medullary cells h. sympathetic nervous system (SNSJ hl:ll'' triggers the release o: catechc:am:nes (epinephrine and norepinephn:1::J 1::

t.' blood. · , · ·

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TABLE 3

. -:fyrosine Dcrivati\'cs

Epinephrine: Non:pinc.-phrinc: Dopamine Triiodoth\Toninc: . Thyroxine

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Chemical Nature of the Classic Hormones

Steroids

T t-stostc:rone EstrJdiol Progc:stt:rone · Cort:isol Aldosterone Vitlmin D

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· (<20

0:\\1ocin . . Angiott.·ruin . . Md.1n0C)1e-stimubting homlOIH! Sonutosucin Th)TOtropin-rdcJSing honnonc! GonJdotr?pin-rdcJSing honnone

.,.. ·-··

,; .... ... . - . - 4 ;·· • ... ..:. ... :; . .---.' / .. -

..... - -- ...... -···: -- ... : . .-- ..... --::.·---·-·.'- •····- .....

. i . Jf' . .r·- ·- ..

Proteins (>20 amino acids)

I ruulin GlucJgon Adn:nocorticotropic . Thyroid-stimubting honnone Folliclc:-stimubting honnonc. Luteinizing hormone Growth honnone Probrtin Corticotropin-releasing _ho!Jn01_1e. .. Gro\\:th h,or:mone Pai-ath)7oid _· _·.

. · · · ._, ,; :; . · . Chorionic gonJdotropin Choriosonutonumn1·ottopirf- · ·· --·

....

/

I ?.

I .

Hormones present

Fat cells·

-

"

Thyroxine Jl ·.

"

Adrenaline

I , Thyroxine ·Adrenaline

.· . "j(.

· Result : . NO release · . Fatty acid release Increased fatty acid

. r.el eas.e . . .. . :

. ' I f . ·. .. . . . . . . )Fig. 11.1 Specific action_ of one depends_·· on the·., tpermissive' presence of another. \. ·

. . . . . ..

,.,

,. \,.,>

I

:

,J>

· One type of interaction is referred to as a·jJernzissive effect. In this interaction,

' -% the effect of one horn1one on a target cell requires a previous or simultanequs exposure to anothei· hor-lDOne(s.). Such previous exposure enhances the response of a target cell or increases the activity of another honnone. jJ-i exan1ple a pen11issive effect, as noted earlier, is the ·exposure of the uterus first to estrogens and then to pro-gesterone in order to prepare the organ for in1plantt1tion .

......... o...; _ _......_ •••

..

I I

i

,J'

- - - . -Another type of hor1nonal interaction is k.nown as a

syJtergistic effect. In this situation, the effects of two or. more hortn011es co1nple1nent each other in such a way that the target cell effectively to the sun1 of the horn1ones involved:For the production and se-cretion of n1ilk by the 1nan1n1a1y glands requires, arnong others, the synergistic effects of estrogens, progesterone; prolactin (PRL), and O.A)rtocin (OT). ·

. ., ·'· :,• .. ·: ··,::·: ... ·'· ; · .. .: . . :.:·> .. -..·.

TABLE.SS-7 0 ••

HORMONES AFFECTING THE rv1AMMARY GLAND DURINC, AND BREAST-FEEDING Mamm.ogen.i:c ho.rm.o.r;a.es (promote cell proliferation)

Lobu.loa.lveolar growth Estrog.en Growth hormone (IGF-1) Cortisol Prolactin Relaxin?

Ductal growth Estrogen Growth hormone Cortisol Relaxin

Lactogenic hormones (promote of milk pro-duction by alveolar cells) · Prolactin ·

.. - _, hCS· (or .hPL) Cortisol Insulin (IGF-1) Thyroid hormones . Growth hormone? Withdrawal of estrogens and progesterone

\

Ga1actokinetic hormones (promote contraction of myoepithelial cells, and thus milk ejection) Oxytocin

· Vasopressin (1 as powerful as OT)

Galactopoietic hormones (maintain milk production after it has been established) Protactin (primary) Cortisol and other metabolic hormones (permissive)

hCS, human chorionic somatomammotropin; hPL, human pla-cental lactogen; IGF-1, insulin-like growth factor type I; OT, oxy-tocin.

;.t

i'

"

< '

A final exan1ple of a born16nal interaction is an aJ·z-tagorListic effect. 1-Iere, the effect ofone horn1one on . a target cell is opposed by another examgk is calcitonin (CT), which lo\vers blood level, and parathyroid honnone (PTH), which blood cafciu1n

Ll:vel (see situation . 1

I /Yt.V J_ v f..-1 tM ) / w k.:.cA .( b w j b l IJ tJ d ./ ·. o ,.. 1£-- · r M.l .t v-v._l J

(/.)-;.)-- ..

. '··. <

•":

.. . :·,.

·:' ....... ·-:·

......

'·

. l l

'·· ···: ....... .. ,

. .'

(a)

·;··:. .·

•f"

·_ · ···•· .. I .•

Down-regulation

.t·

.. _., :·,,,,_

-:.··.· .; . ......... -::. . ···:··· .:-:: ' .

. ·· ...

··: ..

·:·(b) •.'

. .Figure 17.28 Modula . , :. sensitivity to a hormone. (

:-----.,

•

·, ......

··· ·· · • •' ··· . ensitivity. (a) \'lhich a cell produces "in ore receptors and increases its own 'in which a cell reducesthe:&nsitY'of its receptors and'leSsens"·'it:S sensitivity to ·a..hormo_ne .

.. .; - ·: .. ,. ·:. .. .· ... . ... ,· - . . . ·:· .. :0·. :. ... ..

.·, .;

l

---·- ... -·- .. ·-·-··------· ·;/

.. ... · changing tl1e 2ffinity of the receptors for the hormone.Tne greater . :he number of receptors for a hormone, the greater the_ maximal response. The higher the affinity of the : receptor for the hormone, the greater the likelipood of response. .

tffj}\ change in the number or in the affinity of receptors is called down-regulation or up-regulation. Down-regulation means that the number of recep-tors or the affinity of the receptors for the hormone has decreased. Up-regulation means that the num-ber or the· affinity of the receptors has increased.

?Hormones may down-regulate or up-regulate their own receptors in target tissues and even may regu-late receptors for related hormones.

"""

·,

(.,

·,., .. .. ;.:

."!·

Receptor

G protein (inactive)

...._

Hormone

G protein (active)

,<._ /.

GTP-activated target protein

(enzyme)

Figure 74-4 Mechanism of activation of a G protein-coupled receptor. When the hormone activates the receptor, the inactive andy G protein complex associates with the receptor and is activated, with an exchange of guanosine triphosphate (GTP) for guanosine diphos-phate (GpP). This causes the a subunit (to which the GTP is bound) to dissociate from and"{ subunits of the G protein and to interact with membrane-bound target proteins (enzymes) that initiate intracellular signals.

Hormone

l ATP

Active l Inactive cAMP- -<( cAMP-

dependent dependent protein protein kinase kinase " .

Protein - P04 + ADP + ATP

t Cell's response

Figure 74-7 Cyclic adenosine monophosphate (cAMP) mecha-nism by which many hormones exert their control of cell function. ADP, adenosine diphosphate; ATP, adenosine triphosphate.

..

. .;

Table 7 4-2 Hormones That Use the Adenylyl Cyclase-cAMP Second Messenger System

Adrenocorticotropic hormone (ACTH) Angiotensin II (epithelial cells) Calcitonin Catecholamines receptors) Corticotropin-releasing hormone (CRH)

hormone (FSH) Glucagon Human chorionic gonadotropin (HCG) Luteinizing hormone (LH) Parathyroid hormone (PTH) Secretin Somatostatin Thyroid.,.stimulating hormone (TSH) Vasopressin (V2 receptor, epithelial cells)

:-.

t,-/

(IIAPHR 9 [HDO(RIII[ PIIYSIDtOGl 345

ADENYL YL CYCLASE MECHANISM

lnaollvo ,._, 0. pudnln ,._,

"(

:.;'t < ·. ·. _il.• ... : : .. ,'_:·•. .. ,. ·:.

Hormone

....... - ----·-'----,---- .. .. --........................ ..

,._,

--·---------··· ...... - '"·-····--.o. ............ _ ........... :.. ......... .

Active ,._,

l Lll

® y

.. ·· .·· cAMP

S'AMP ••• •• (inactive)

0 •• •

r,'-0 • _l.,e •• •• ,•

<I'('.·· . ... ··:

l® Aclivotlon ol

prolein kinas a A

l® Phosphorylation

ol proto Ins

10 Physiologic nclions

!1-5. Steps lnv<jlvcd In lhc ndc:nylyl cyclnHc (cAMI'J mcchnntHm of nctlun. Clrclccl numhcn corrc•pond tu steps discussed In lhc text. AMP, odcnoslnc monophosphatc; ,-.;TI'. 11dcno•lnc triphosphiltc; GDI', uunnoslnc GTI', lrli>hosphMc.

lyzes the conversion of ATP to cAMP, which serves as the second messenger (Step 4). Although not shown, intrinsic GTPase activity converts GTP back to GDP, and the u, subunit returns to its inactive s"tate.

3. cAMP, via a series of steps involving activa-tion of protein kinase A, phosphorylates intrac.:ellu-lat· proteins (Step.-; 5 and fJ'). These phosphorylated proteins then execute the final physiologic actions (Step 7).

4. Intracellular cAMP is degraded to an inac-tive metabolite, 5' AMP, by the enzyme phosphodi-esterase, thereby turning orr the action o[ the sec.:-

- ond messenger.

Phospholipase C Mechanism Hormones that utilize the phospholipase C (IP;.!

Ca2 •) mechanism also arc listed in Table 9-3. The rncc.:hanlsm involves binding of hormone to a recep-tor, collpllng vin a G. or G1 protein, :mel or inhibition of phospholipase C. lnlraccllular levels of IP3 and Ca2 + are either increased or decreased. producing the final physiologic actions. The steps in the phospholipase C (lP:JCa<+) mechanism nrc shown in Figure 9-6. A hormone that utilizes a G. protein is shown.

The receptor-G.-phospholipase C complex is im-bedded in the cell membrane. With no hormone bound to the receptor, the C'C, subunit binds GOP. In this configuration, the G. protein is inactive. When

·Extracellular fluid

Cytoplasm

. . .

Active ' Inactive protein ..-: protein

kinase C kinase C

Protein- P04 .C: )lr Ca++

t t Cell's response

Figure 7 4-8 The cell membrane phospholipid second messenger system by which some hormones exert their control of cell func-tion. DAG, diacylglycerol; IP 3, inositol triphosphate; PIP 2, phosphati-dylinositol biphosphate.

,,

346 PlmiOLOGY

PHOSPHOLIPASE C MECHANISM ·. ': .. ·:··.·::: 'I

lnactlvo ,_.., G. prololn ,_,

'( ·, · . • ·.. ··; •• :• 1.· ••

. I

,·. : .. ···.!. :-- .· f1\' .· l . . \..V , ._ ... _:

.''Active

1 •.. ;I ,; ; ... ,. 1®. . ... ·.'.'' . .:''.'=··:.:·.:\'./ · .... ,!·.·::' /:PI':'2

. ·-·. , ., ..

' ··;::.'

. ,·· :·· ... . \: ....

; ,, :::,i.O::·

eyl

.. . · · · · Ca2• released •· · ·. :·.' ·t protoln kinase C . . ·· !rom ER or SR .

• , • •• •• •• 0 0 ·:.::. '0 '; ., 'l :.-: 1: • : • • · 0 :. : ,·. 0 ··.:·· · .. ,.·'·'· ,· 0 ., .. , .. :t·, .. .. ·•·

·· · : ,: . · :·r:· :'.i;i·l. ·· FIGURE !l-6. Steps Involved In the phospholipase C (IPJCa") mechanism of nctlon. Circled numbers correspond to steps In the text. ER, endoplasmic reticulum; GDP, guanosine diphosphate; GTI', guanosine triphosphate; II',, Inositol I ,4,5-triphosphate; PI I',, phosphatldyllnosilol 4,5-diphosphate; !iH, sarcoplasmic reticulum.

the hormone binds to the receptor, G, Is activated, whlc:h activates phospholipase C, In the following steps.

I. Hormone binds to its receptor in the cell membrane, producing a conformational change in the o:. subunit (Step 1). GOP is released from the a. subunit, is replaced by GTP, and the u. subunit detaches from the G. protein (Step 2).

2. The a.-GTP complex migrates within the cell membrane and binds to and activates phospho-lipase C (Step .'J). Activated phospholipase C cata-lyzes llu: lihernllon of and 11':, front phosplwlidylinosil ol ,,!i-dlphosphatc (I '11',). a lllt:JII-hranc phospholipid (Sic!fl 4). Tlw IP, causes the release of Ca2 + from intracellular stores in the endoplasmic or sarcoplasmic reticulum, re-sulting in an increase in intracellular Ca'' C:OJICI!IIlra-tion (Step 5).

3. Together, Ca•• and diacylglycerol activate protein ldnasc C (.S'tep 6), which phosphorylates proteins and produces the final physiologic actions (Step 7).

Steroid and Thyroid Hormone Mechanism . Steroid hormones and thyroid hormones have the same mechanism of action. In contrast to the aclenylyl cyclase and phospholipase C mechanisms, which Involve cell membrane receptors and the gen-eration of intmcellular second messengers, the ste-roid hormone mechanism involves nuclear re-ceptors, DNA transcription, and synthesis of new proteins. In further contrast to peptide hormones, which act quickly on their target cells (within min-utes), steroid hormones act slowly (laking hours).

The steps in the steroid hormone mechanism are shown in Figure !l-7 and ck);criiH.:d as follows.

I. The st<..:rold hormone dill uses across the cell membrane into the cytoplasm (not shown) and then across the nuclcnr membrane (Step 1). In the nu-cleus, the hormone binds to a nudear receptor at a site ncar the C terminus of a receptor p1:otcin. Once the hormone is bound, a conformational change oc-curs, activating the receptor. The conformational change includes moving blocking proteins out of the way and exposing the DNA-binding domain of the

if'',(.<"., :1.

il

j

. ..,.i

Table 7 4-3 Hormones That Use the Phospholipase C Second Messenger System

Angiotensin II (vascular smooth muscle) Catecholamines (a receptors) Gonadotropin-releasing hormone {GnRH) Growth hormone-releasing hormone {GHRH) Oxytocin Thyrotropin releasing hormone (TRH) Vasopressin {V1 receptor, vascular smooth muscle)

.,

'W Lipophilic hormone Extracellular fluid

_j Diffusion

J ·-----r'-: -.. .. : _,

- / ·· . .'· ... ;'- .... / •... _ "..'JI ;-·-- . .;_ __ ;'DNA_ - . /\ ' ' : '-·····, .. v ·._, · • ... :Nuclear: ---- -- ·." · .. <r···:J ·r • · · --;;- : ,: • -· · r _, _ (

_.. , ' .. 'recepto. . . ..: ..... -----._ (;,, .

·'-->: >::·- -- --.., ···v-. ' .. I .. ·;-- ..... ___ - \ , __ .. ' mANA v··,_. . j ... .\L., .. \ 11 _.

I , I ' ' \ I mRNA

Ribosome

receptor , .--- ! .. • :. •C·' \reS.P.Q!l.SO.- ·, complex .... ,/i!19_ment __

-- I I I . ·• - • ' --- A . . ! \. ! . I .:· - ! ___ ,,__ r Nuclear pore ..... ,./< ... __ /r --- Nuclear envelope

:/" ....... \. _.,.··\ . '. .. -:,.. .. \,

Figure 74-6 Mechanisms of inter-action of lipophilic hormones, such as steroids, with intracellular recep-tors in target cells. After the hor-mone binds to the receptor in the cytoplasm or in the nucleus, the hormone-receptor complex binds to the hormone response element (promoter) on the DNA. This either activates or inhibits gene transcrip-tion, formation of messenger RNA (mRNA), and protein synthesis.

(1\HJU 9 [NDOCllNl PHTIIOlOGY 347

ST!;ROID AND THYROID HORMONE MUCHANI!iM

1-iormono

;-------·--··:::..:·;_-_::.,::· .. :.:-;·---··-·----·-: ----------·--·-···-- N,u:lnt1r 111111111JIIHIU

N lorminuG C lormlnus Nucloua

l® Trnnscrlpllon ol DNA

1® of mHNA

10 Synlhor.i:; of now proloin:J Cyloplosrn

f"IGUJ(J; D-7. Stc(ls Involved In the alerul<.l hormone mec:hunlsm of ncllon. Circled numbers <:orrc-srond to steps discussed In the text. DNA, deoxyribonucleic ncld: mltNA, mcucnijcr rllwnuclcl<: acid. '

receptor. The exposed DNA-binding domain now binds DNA, beginning the transcription process to generate new mRNA (Slap 2).

2. The mechanism continues In the cytoplasm, where mRNA Is translated (Step 3) and new pro-teins arc synthesized (Siep 1). The nature or the new proteins Is specific to the hormone and accounts lor lht; speclliclty or the hormone's physiologic actions (Step 5). For example, 1,25-dlhydroxycholecalciCerol ·Induces the synthesis of a Ca2 +-bJndlng protein, which aids In tl\e absorption of Ca2+ from the gastro-Intestinal tract; aldosterone Induces the synthesis of Na + channels In renal principal cells, which aids in the reabsorption of Na + in the kidney; and thyroid hormones Induce the synthesis of Na +.K + ATPase, which incrcm;e:; Ol consumption and metabolic rate. Each hormone luclut:I!S lin: syrrllrc);ill or proteins and llils cliflerenl physiologic actions, depending (JCI the nature:: or that protein.

1® Physiologic octions

Is Important to vlsuillize the anatomic relationships between the hypothalamus and the pituitary, since these relationships underlie the functional connec-tion:; between the glands.

The pituitary gland, which also Is cnllecl the hypophysis, consists or a posterior lobe n.ncl an ante-rior lobe. The posterio1·lobe (or posterior pituitary) Is also called the neurohypophysis. The nnlc1·lor lobe (or anterior pituitary) Is also called the adeno-hypophysis. The hypothalamus Is connected to the pituitary gland by a thin stalk called the infundibu-lum. Functionally, the hypothalamus controls the pituitary gland by both neural and hormonal mecha-nisms (Figure 9-8).

·>·· ..... I'. i"

PIIY\IOlOtY

OF HORMONE ACTION AND ;ECOND MESSENGERS

llor11111111: ;u:llow; 1111 wiH'II tlw lllriiHlllc: lllud:; 111 11 llll'llllJrnuc: n:c:qJtor, lon11h1J{ 11 l'lruuuu:-rc:<:c:plor lu IIIHIIY lull"llllllllll sy:;-

llu: c'11111plc•x 1:; c'u11plc·cl lu :lfcclcJr prcJidlls by I ripllosphiilt: (<•i'l"l' )· Jinding proteins (G proteins). The clfcclor proteins JSUally arc enzymes, <:ithcr aclenylyl cyclase or >hospholipase C. When the cf!eclor prolc:ins •ctlvatt:d, a :.t:<:ond m<.::-;:H!Ill-(cr, r.ithc:r <:AMP or ll':o "iii<J!iilol I ,-t,!i-lriphu:-;phnte), is pruducc:d. which nm->llfics the original hormonal sigual and then orcht:s-ratcs the physiologit.: actions.

The three major mechanisms ol hormone «ction m target are the adcnylyl cyclase mcclianism, n which cAMP is the sc.cond messenger; the phos->holipasc C mechanism, in which IPJ/Ca2 ' is the ;econd messenger; and the steroid hormone mech-thism. In uddition, insulin und insulin-like growth ;Jctors (IGF) act on their turgct cells by a tyrosine dna.'!c mechanism. Finally, sr:vcrul hormones acti-/at<: J(uanylatc cyclase, in whil:h !'ydic l{llilliiiSiJw noll<lphuspllilte (cyclic GMP, c(jMI') is the St!COJIII ncsscnger. The three major mechanisms o! hor-nonc: action arc discussed in this section; the lyro-;inc kinase mechanism is discuss<:d in l111: st:clit111 m insulin. The rneclwnisms ol ;Jction ol the major 10rmones ;1rc summarized in Table !J-:1.

:; Proteins (j llr<•t<:ins an: discussr:d in :! i11 1111:.

:onlcxt tJI ;iutonomit: n:c<:l'>tt,rs. llril:lly, (i prolt:ius ire i1 family o( membrane-bound proteins that COil· )le hormone receptors to effector enzymes (e.g., 1dcnylyl cyclase). Thus, G proteins serve as "molcc-Jiar switches" that decide whether the hormone 1ction can proceed.

At the molecular level, G proteins are helero-:rimil'rl!: (i.e., having three subunits) serpenllnc pro-. cins ·th;1t span the cell membrane scvt:n linH:s, Ninding like u "sn.1ke. •; The three subunits arc clcsig-1ated as alpha (u), beta and gamma ('y). The u mhunit can bind either ·guanosine diphosphate

"(.

v

(! ;J)I') or (iT!', and il nllll;tins GTI'nst: iH:livily. Wlwn c;IJ(' Is hound lo tlw It Sllhllnil, llw c prol!'ln 1:<

wht•n <iTI' Is lu1111111, llw (j proldn Is illlll l'illl )ll'r!lll"lll liS I'OIIjlilll){ hllll'llt>ll,

Ci prolc•l11s !'1111 IH' l'lllll'r stl11111lai111"Y ur lnhlhl-tory and an· ill'r'IIJ'dhll{ly, (;. Ill" (;,, Sllluula-I<II"Y Ill" lnill),ltoi'Y lll'llvlty l"l'llldr•!l 111 tlu: u l!IIIHIIIII, which an: <:;Jilt•d u, or u,.

In summ<try, when GTI' Is bound to I he n, sub-unit or a G, protein, the G, protein stimulutes the

t:nzyme (e.g.,t·aclcnylyl cyclnse). When GTP i:; llou11d to tlu: u, s bunil o! n G, protein, the G, prolcin illlli/Jits the cl ·ctor c1uyme.

Adcnylyl Cyclase The ndenylyl cyclase/cAMP mechanism is uti-

lized by many hormonal systems (see Table 9-3). This mechnnism involves binding or n hormone to n rect:ptor, coupling by a G. or G, protein, and then iiCtiV.:tlion or inhibition or adeny(y\ cyclnse, lending lu increases or decreases in intracellular cAMP. cAMP, th<: second messr!llJ:.1er, then amplifies the hnr-Jnon;ll to produce I he lin;ll physiologic ac-i ions.

Th<: slt:p:; in tlH: cyclase/cAM!' mecha-nism arc shown in Figure !l-!i. In this example, the llor111onc utilizes a G, protein (rather lhan <1 G, prn-lc:in). The rcccplor-G.-adenylyl cydasc complex is iJniJcdcled in lht: cell membrane. Wln:n no hormone is b01111d to the receptor, the tt, subunit ol the G, proll!in hlncls (iDI'. In this con!igurillion, lhc G, prn-ll'in I:-; luacllvc. Wlll:n hoi"I>HllH! binds tolls receptor,

(i, proll!in is activated, and llw lollowing occur.

I. Hormone binds to its receptor in the cell membrane, producing a con!onnation•ll change in the a. subunit (Step I), which produces two changes: GDP is released !rom the n, subunit and is replaced by GTI', and the u, subunit detaches !rom the G, protein (Step :J) .

:.!. The u.-GTP complex migrates within the cell membrune and binds to and activates nclenylyl cyclase (Step 3). Activated adenylyl cyclase cata-

TAliLE !J-:1. Mcch;111isms or llormmn: Action

Atlcnylyl Mcchunlllm (cAMP)

1\C"rt I 1.11 FSII TSII 1\DH ry, receptor) liCG MSII

I CHI-I Calcitonin I'Tl·l Cihlt:ilgtJII l1r cuacl f\:o

. 'Phospholipase C Mcchunhnn (IP:JCn'•)

(juJU I ·. TIUI

CiHHII AII!Jinlcnsin II ADH (V, receptor) Oxytocin u Heccplurs

Slc1·oid Hormone

Cih•r·o•:r,rlit:••ilh;

ProHcSlc!tcm(:

Aldoslcrolll: I,Z!i-Dihydroxycholccaldlcrol Thyroid hormones

Ty1·o,;ine Kinase Mechnnism

lGI'-1

Gunnylnle Cycln5e (cGI\tP)

i\lrl:oi n:tl riun·ll<' hon11un" Enduthcli:tl-dt•rivcd rclnxinJ:

lilctor (EDI{I·) Nitric oxide (NO)

Leptin receptor ;-----j r----·-;

/ f . ly·'ily \ Activation •: \

of enzymes : HY :'f8)

l I .JViiiJI

q.'lf /' 0 Physiological '-- ./''q.'lf

effects · · ·._.-_ ( Stat3 \@

. . -- .· . . I.

I --- ,- \ !I

Figure 7 4-5 An enzyme-linked receptor-the leptin receptor. The receptor exists as a homodimer (two identical parts). and leptin binds to the extracellular part of the receptor, causing phosphory-lation and activation of the intracellular associated janus kinase 2 (JAK2). This causes phosphorylation of signal transducer and acti-vator of transcription (STAT) proteins, which then activates the transcription of target genes and the synthesis of proteins. JAK2 phosphorylation also activates several other enzyme systems that mediate some of the more rapid effects of leptin.

Enzyme-Linked Hormone Receptors. Some recep-tors, when activated, function directly as enzymes or are closely associated with enzymes that they activate. These enzyme-linked receptors are proteins that pass through the membrane only once, in contrast to the seven-trans-membrane G protein-coupled receptors. Enzyme-linked receptors have their hormone-binding site on the outside of the cell membrane and their catalytic or enzyme-bind-ing site on the inside. When the hormone binds to the extracellular part of the receptor, an enzyme immediately inside the cell membrane is activated (or occasionally inactivated). · - - · · 'f- example of an enzyme-linked receptor is the leptzn receptor (Figure 74-5). Leptin is a hormone

by fat cells and has many physiological effects, but It IS especially important in regulating appetite and energy balance. as discussed in Chapter 71. The lep-