Efectele hormonilor

Table 17.4 pt 1

Table 17.4 pt 2

Table 17.5

,rowth 'ormone
Targets liver to produce somatomedins mitosis + cellular differentiation for tissue growth
protein synthesis
m !" translated# $!" transciption for m !" production enhances amino acid transport into cells# catabolism

lipid metabolism
stimulates %%" and glycerol release# protein sparing

&'( metabolism
glucose sparing effect) glucose stored as glycogen

*lectrolyte balance
promotes !a+# ++# &l) retention# &a+2 absorption

,rowth 'ormone 2
&hildhood
bone# cartilage and muscle growth

"dulthood
osteoblastic activity# appositional growth affecting bone thic-ening and remodeling

.evels of ,'
higher during first 2 hours of deep sleep# after high protein meals# after vigorous e/ercise lower after high &'( meals decline with age

EFFECTS OF VASOPRESSIN AND OXYTOCIN

Vasopressin has two important actions, and each of its two names indicates one of them. The first target tissue is the kidney. In a certain part of the nephron water reabsorption depends on vasopressin, so that in its absence this section is impermeable to water. The drive for this water reabsorption is an osmotic gradient: the concentration of NaCl in the e tracellular fluid in that part of the kidney is much higher than in the lumen of the nephron. This is the antidiuretic effect of vasopressin. The action of vasopressin in the kidney is mediated by the V! receptors, which are coupled to activation of adenylate cyclase and elevation of c"#$.

The second effect of vasopressin is the constriction of visceral blood vessels. This effect is mediated by receptors of type V%, located in the smooth muscle of these blood vessels. V% receptors activate $I&$'C , and thus cause an increase in cytosolic calcium ions. ( ytocin also has two important effects. The first one is stimulation of uterine contraction. ( ytocin activates its receptors in the uterine smooth muscle )myometrium*, which are coupled to the activation of $I&$'C . The other effect of o ytocin is stimulation of milk e+ection from the mammary glands under the stimulus of suckling. This effect is also mediated by activation of $I&$'C .

Table 17.7

EFFECTS OF THYROID HORMONES Thyroid hormones affect virtually all cell types. The mode of action of thyroid hormones is described in the presentation on Nuclear ,eceptors. The half&life of T- and T. is / days and one day, respectively. These half&lives are e tremely long compared to other hormones. The first group of actions of thyroid hormones includes effects of development and growth. (nly some of them are ade0uately undestood. Very prominent in importance is the re0uirement of thyroid hormones for the development of the neural system. This refers to the fetus as well as to the child.

In the developed countries, including Israel, thyroid hormones are measured in every newborn. In cases of deficiency )thyroid malformation, or the rare cases of mutations in essential thyroid genes*, replacement started immediately after birth normali1es )or almost normali1es* child development. ,eplacement means T- taken orally )as is the case in hypothyroidism which develops in adulthood*. Thyroid hormones also play an important role in children2 growth. 3rowth hormone )34*, a protein hormone produced in the anterior pituitary )cell type: somatotroph*, acts to stimulate growth in children.

The activated receptor of thyroid hormones is one of the transcription factors re0uired for the e pression of growth hormone. Thus hypothyroidism in children impairs growth. #ost of the effects of the thyroid hormones are related to increasing the rate of body metabolism. (ne of the most important functions of thyroid hormones is the maintenance of body temperature. In severe hypothyroidism body temperature goes down drastically, which is a life&threatening condition. The main mechanism for increasing body temperature is accelerating the rate of o idative

"mong the effects of thyroid hormones, a ma+or group is due to increased e pression of type adrenergic receptors )",s*. This results in enhancement of the effects of epinephrine and norepinephrine via receptors )see the presentation on the adrenal medulla*. Increased e pression of ",% in the heart results in increased heart rate and increased force of heart muscle contraction. This increases energy utili1ation by the heart. "n increase in the same receptors in adipose tissue results in increased lipolysis. Increased e pression of ",! in liver and skeletal muscle stimulates glycogenolysis and inhibits glycogen synthesis.

"ll the processes described above, plus a few others accelerated by thyroid hormones, result in increased rates of "T$ utili1ation, "T$ )and heat* production, and the supply of substrates for o idation. "ll these contribute to a parameter called 5basal metabolic rate6 )7#,*, which is determined by o ygen consumption when the animal is at rest. Thyroid hormones were found to increase 7#, many years ago, before many of the mechanisms involved were recogni1ed. Thyroid hormones increase alertness, rapidity of responses, and nervousness. This is also a result of their augmentation of 8 adrenergic receptor e pression.

CALCITONIN (utside the follicular structure, cells of a different type can be observed: these are the C&cells which produce the hormone calcitonin. Calcitonin acts to decrease the concentration of calcium ions in the blood, and is relatively less important than other hormones which affect calcium metabolism in the body: parathyroid hormone )$T4* and vitamin 9. $arathyroid hormone is produced by four tiny glands, the parathyroid glands, which are attached on the outside of the thyroid. 4owever, they are functionally independent of the thyroid and are independently regulated

EFFECTS OF ACTH ON THE CORTISOL-PRODUCING CELLS

"CT4 activates adenylate cyclase, and its action are mediated by c"#$. "CT4 can stimulate cortisol production within minutes. This effect is due to the phosphorylation )via $:"* of ;t", )steroidogenic acute regulatory protein*. "ctivated ;t", stimulates the transport of cholesterol across the mitochondrial inner membrane, to the matri . The #atri is the location of the first en1yme in steroidogenesis, the cholesterol side&chain cleavage en1yme )$-<=scc*. This reaction is rate&limiting in steroidogenesis, but substrate availability, rather than the intrinsic en1yme activity, is the limiting factor.

"CT4 also have slower stimulatory effects on the adrenal cortisol&producing cells. These are due to increased transcription of genes re0uired for cortisol synthesis. They include ;t",, as well as all the steroidogenic en1ymes which participate in cortisol production. "s a result of these actions these adrenal cells increase in si1e )a hypertrophic effect*. "CT4 also stimulates proliferation of the cortisol& producing cells )a hyperplastic effect*. Thus, prolonged e posure to large amounts of "CT4 )as in chronic illness* results in abnormally large adrenals.

EFFECTS OF CORTISOL
Cortisol has many target cells and many effects. #ost of the effects are related to the need to cope with long&term stress. This includes actions aimed at keeping normal glucose levels in the face of food deprivation. This is often associated with the animal being wounded or ill, situations in which the immune system is stimulated. #any effects of cortisol result in restraining )inhibiting* the immune system, since too e tensive immune responses can be life&threatening. "nother stress situation which can benefit from cortisol actions is prolonged e tensive physical effort.

METABOLIC EFFECTS OF CORTISOL In the liver, cortisol stimulates gluconeogenesis )production of glucose from non&sugar compounds: amino acids, glycerol, lactate* . ;ee the presentation on the adrenal medulla for details on the biochemistry of gluconeogenesis. "t the same time, cortisol acts on many other tissues to shift their metabolic balance to catabolism rather than anabolism, thus making them suppliers of precursors for gluconeogenesis. Cortisol has nuclear receptors )5the glucocorticoid receptor6* and its effects are mediated by activation of this receptor )see the presentation on nuclear receptor*.

Cortisol has catabolic effects in skeletal muscle, connective tissue, bone, skin, adipose tissue, and other tissues. These catabolic effects are of course damaging, but the top priority of the body is supplying glucose to the brain, which is rapidly and irreversibly damaged by glucose shortage. ,ed blood cells )erythrocytes* also re0uire glucose e clusively*. In the peripheral tissues mentioned above, cortisol inhibits glucose uptake, and in skeletal muscle it also inhibits amino acid uptake. In each of these tissues cortisol inhibits the transcription of specific genes e pressed in that tissue. The inhibited genes usually code for proteins which are produced in large amounts.

In some tissues cortisol may also stimulate protein degradation. In adipose tissue cortisol increases lipolysis by supporting the lipolytic action of epinephrine. This supplies fatty acids for tissues which can use them as well as glycerol for gluconeogenesis. In children, cortisol inhibits growth by inhibiting the epiphyses. The epiphyses are strips of proliferating cells, found near the edges of long bones. These cells eventually differentiate to bone cells. ;teroid se hormones, which go up at adolescence, cause epiphysis closure )disappearance*. Cortisol +ust inhibits epiphyseal cell proliferation reversibly.

In the liver, cortisol stimulates gluconeogenesis in several ways. It increases amino acid transport into the liver, which is the main site of amino acid metabolism. This results in most cases in the formation of pyruvate or o aloacetate, which are substrates for gluconeogenesis. " ma+or effect of cortisol is stimulation of the e pression of two gluconeogenic en1ymes: glucose&>&phosphatase and phosphoenol& pyruvate carbo ykinase )$?$C:*. Cortisol, parado ically, stimulates the activity of glycogen synthase. 4owever, glycogen synthase re0uires glucose&>&phosphate as an allosteric activator. Thus, glycogen is synthesi1ed only if e cessive glucose is transiently found in the liver.

EFFECTS OF CORTISOL ON THE IMMUNE SYSTEM "ll cell types of the immune system have glucocorticoid receptors, and in each cell type cortisol inhibits the specific functions of this particular cell. Cortisol inhibits the e pression of do1ens of genes encoding cytokines and various hydrolytic en1ymes, acting either directly on their genes or indirectly. Cortisol inhibits the synthesis of eicosanoids )prostaglandins, thrombo ane, leukotrienes*. These compounds are all derivatives of the polyunsaturated fatty acid arachidonic acid. They act as local regulators via membranal receptors coupled to heterotrimeric 3& proteins.

?icosanoids play an important role in processes of inflammation and allergy, including pain. 9rugs like aspirin, ibuprofen )nurofen, advil*, and acamol inhibit the production of some eicosanoids. #ost of the immunosuppressive effects of cortisol are e erted by binding to, and neutrali1ing the activity of, some transcription factors, which play a key role in the immune response )e.g., N@& 7, "$&% or Aun.@os*. 4owever, some of the immunosuppressive effects are mediated by stimulating the e pression of genes, where a glucocorticoid receptor )3,* homodimer binds directly to the 9N".

#ost, if not all, of the metabolic effects of cortisol )see above* are mediated by direct binding of 3, homodimer to the 9N" in the relevant promoters. Numerous structural anlogs of cortisol are used in clinical medicine for the suppression of the immune response. Bnfortunately, these synthetic glucocorticoids have all the effects mediated by the glucocorticoid receptor, including the catabolic ones. These drugs have a half&life longer than that of cortisol. To some e tent, cortisol can activate the mineralocorticoid receptor, thus mimicking the action of aldosterone. 4owever, the synthetic glucocorticoids are almost free of such activity.

&onverts angiotensinogen to angiotensin 0 "ngiotensin 0 is converted to angiotensin 00

1. 1timulates adrenal

enin

"ngiotensin 00

2. 2. 4.

production of aldosterone 1timulates pituitary release of "$' 3romotes thirst *levates blood pressure

3roduces natriuretic peptides 4ANP and BNP56

when blood volume becomes e/cessive

'eart

"ction opposes angiotensin 00 esulting in reduction in blood volume and blood pressure

!atriuretic 3eptide

3roduces thymosin hormones6

that helps develop and maintain normal immune defenses

Thymus Testes

3roduce androgens in interstitial cells6

testosterone

1ecrete inhibin in sustentacular cells6

support differentiation 7 physical maturation of sperm

3roduce estrogens "fter ovulation# follicle cells6

(varies

reorgani8e into corpus luteum release estrogens 7 progestins# especially progesterone

1. .eptin6 feedbac- control for appetite controls normal levels of ,n '# gonadotropin synthesis 1.

"dipose Tissue 1ecretions

esistin6 reduces insulin sensitivity

*ndocrine %unctions of (ther (rgans

'eart ) atrial natriuretic factor
blood volume + 93# from !a+ and '2( loss by -idneys

+idneys
calcitriol ) &a+2 and phosphate6 absorption# loss for bone deposition erythropoietin ) stimulates bone marrow to produce 9&:s

1tomach and small intestines ) enteric hormones

*ndocrine %unctions of (ther (rgans 2

.iver
angiotensinogen 4a prohormone5
precursor of angiotensin 00# a vasoconstrictor

erythropoietin 415;5 somatomedins ) mediate action of ,'

3lacenta
secretes estrogen# progesterone and others
regulate pregnancy# stimulate development of fetus and mammary glands