Efectele hormonilor

Table 17.4 pt 1

Table 17.4 pt 2

Table 17.5

Growth HormoneTargets liver to produce somatomedins mitosis + cellular differentiation for tissue growthprotein synthesis mRNA translated, DNA transciption for mRNA productionenhances amino acid transport into cells, catabolismlipid metabolism stimulates FFA and glycerol release, protein sparingCHO metabolismglucose sparing effect- glucose stored as glycogenElectrolyte balancepromotes Na+, K+, Cl- retention, Ca+2 absorption

Growth Hormone 2Childhoodbone, cartilage and muscle growthAdulthoodosteoblastic activity, appositional growth affecting bone thickening and remodelingLevels of GH higher during first 2 hours of deep sleep, after high protein meals, after vigorous exerciselower after high CHO mealsdecline with age

EFFECTS OF VASOPRESSIN AND OXYTOCINVasopressin 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 extracellular 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 V2 receptors, which are coupled to activation of adenylate cyclase and elevation of cAMP.

The second effect of vasopressin is the constriction of visceral blood vessels. This effect is mediated by receptors of type V1, located in the smooth muscle of these blood vessels. V1 receptors activate PI-PLC, and thus cause an increase in cytosolic calcium ions.Oxytocin also has two important effects. The first one is stimulation of uterine contraction. Oxytocin activates its receptors in the uterine smooth muscle (myometrium), which are coupled to the activation of PI-PLC.The other effect of oxytocin is stimulation of milk ejection from the mammary glands under the stimulus of suckling. This effect is also mediated by activation of PI-PLC.

Table 17.7

EFFECTS OF THYROID HORMONESThyroid hormones affect virtually all cell types.The mode of action of thyroid hormones is described in the presentation on Nuclear Receptors.The half-life of T4 and T3 is 7 days and one day, respectively. These half-lives are extremely long compared to other hormones.The first group of actions of thyroid hormones includes effects of development and growth. Only some of them are adequately undestood.Very prominent in importance is the requirement 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 normalizes (or almost normalizes) child development.Replacement means T4 taken orally (as is the case in hypothyroidism which develops in adulthood).Thyroid hormones also play an important role in children growth.Growth hormone (GH), 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 required for the expression of growth hormone. Thus hypothyroidism in children impairs growth.

Most of the effects of the thyroid hormones are related to increasing the rate of body metabolism.One 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 oxidative processes cells.

Among the effects of thyroid hormones, a major group is due to increased expression of type adrenergic receptors (ARs). This results in enhancement of the effects of epinephrine and norepinephrine via receptors (see the presentation on the adrenal medulla).Increased expression of AR1 in the heart results in increased heart rate and increased force of heart muscle contraction. This increases energy utilization by the heart.An increase in the same receptors in adipose tissue results in increased lipolysis.Increased expression of AR2 in liver and skeletal muscle stimulates glycogenolysis and inhibits glycogen synthesis.

All the processes described above, plus a few others accelerated by thyroid hormones, result in increased rates of ATP utilization, ATP (and heat) production, and the supply of substrates for oxidation.All these contribute to a parameter called basal metabolic rate (BMR), which is determined by oxygen consumption when the animal is at rest. Thyroid hormones were found to increase BMR many years ago, before many of the mechanisms involved were recognized.Thyroid hormones increase alertness, rapidity of responses, and nervousness. This is also a result of their augmentation of adrenergic receptor expression.

CALCITONINOutside 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 (PTH) and vitamin D.Parathyroid hormone is produced by four tiny glands, the parathyroid glands, which are attached on the outside of the thyroid. However, they are functionally independent of the thyroid and are independently regulated

EFFECTS OF ACTH ON THE CORTISOL-PRODUCING CELLSACTH activates adenylate cyclase, and its action are mediated by cAMP.ACTH can stimulate cortisol production within minutes. This effect is due to the phosphorylation (via PKA) of StAR (steroidogenic acute regulatory protein). Activated StAR stimulates the transport of cholesterol across the mitochondrial inner membrane, to the matrix. The Matrix is the location of the first enzyme in steroidogenesis, the cholesterol side-chain cleavage enzyme (P450scc). This reaction is rate-limiting in steroidogenesis, but substrate availability, rather than the intrinsic enzyme activity, is the limiting factor.

ACTH also have slower stimulatory effects on the adrenal cortisol-producing cells. These are due to increased transcription of genes required for cortisol synthesis. They include StAR, as well as all the steroidogenic enzymes which participate in cortisol production. As a result of these actions these adrenal cells increase in size (a hypertrophic effect).ACTH also stimulates proliferation of the cortisol-producing cells (a hyperplastic effect).Thus, prolonged exposure to large amounts of ACTH (as in chronic illness) results in abnormally large adrenals.

EFFECTS OF CORTISOLCortisol has many target cells and many effects. Most 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. Many effects of cortisol result in restraining (inhibiting) the immune system, since too extensive immune responses can be life-threatening. Another stress situation which can benefit from cortisol actions is prolonged extensive physical effort.

METABOLIC EFFECTS OF CORTISOLIn the liver, cortisol stimulates gluconeogenesis (production of glucose from non-sugar compounds: amino acids, glycerol, lactate) . See the presentation on the adrenal medulla for details on the biochemistry of gluconeogenesis.At 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 (the glucocorticoid receptor) 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. Red blood cells (erythrocytes) also require glucose exclusively).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 expressed 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. Steroid sex hormones, which go up at adolescence, cause epiphysis closure (disappearance). Cortisol just 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 oxaloacetate, which are substrates for gluconeogenesis.A major effect of cortisol is stimulation of the expression of two gluconeogenic enzymes: glucose-6-phosphatase and phosphoenol-pyruvate carboxykinase (PEPCK).Cortisol, paradoxically, stimulates the activity of glycogen synthase. However, glycogen synthase requires glucose-6-phosphate as an allosteric activator. Thus, glycogen is synthesized only if excessive glucose is transiently found in the liver.

EFFECTS OF CORTISOL ON THE IMMUNE SYSTEMAll 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 expression of dozens of genes encoding cytokines and various hydrolytic enzymes, acting either directly on their genes or indirectly. Cortisol inhibits the synthesis of eicosanoids (prostaglandins, thromboxane, leukotrienes). These compounds are all derivatives of the polyunsaturated fatty acid arachidonic acid. They act as local regulators via membranal receptors coupled to heterotrimeric G-proteins.

Eicosanoids play an important role in processes of inflammation and allergy, including pain. Drugs like aspirin, ibuprofen (nurofen, advil), and acamol inhibit the production of some eicosanoids.Most of the immunosuppressive effects of cortisol are exerted by binding to, and neutralizing the activity of, some transcription factors, which play a key role in the immune response (e.g., NF-B, AP-1 or Jun.Fos).However, some of the immunosuppressive effects are mediated by stimulating the expression of genes, where a glucocorticoid receptor (GR) homodimer binds directly to the DNA.

Most, if not all, of the metabolic effects of cortisol (see above) are mediated by direct binding of GR homodimer to the DNA in the relevant promoters.Numerous structural anlogs of cortisol are used in clinical medicine for the suppression of the immune response. Unfortunately, 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 extent, cortisol can activate the mineralocorticoid receptor, thus mimicking the action of aldosterone. However, the synthetic glucocorticoids are almost free of such activity.

Renin Converts angiotensinogen to angiotensin IAngiotensin I is converted to angiotensin II Angiotensin II Stimulates adrenal production of aldosteroneStimulates pituitary release of ADH Promotes thirstElevates blood pressure

HeartProduces natriuretic peptides (ANP and BNP):when blood volume becomes excessiveNatriuretic PeptideAction opposes angiotensin IIResulting in reduction in blood volume and blood pressure

Thymus Produces thymosin hormones: that helps develop and maintain normal immune defensesTestesProduce androgens in interstitial cells: testosteroneSecrete inhibin in sustentacular cells: support differentiation & physical maturation of spermOvariesProduce estrogensAfter ovulation, follicle cells:reorganize into corpus luteumrelease estrogens & progestins, especially progesterone

Adipose Tissue SecretionsLeptin: feedback control for appetitecontrols normal levels of GnRH, gonadotropin synthesisResistin: reduces insulin sensitivity

Endocrine Functions of Other OrgansHeart - atrial natriuretic factor blood volume + BP, from Na+ and H2O loss by kidneysKidneyscalcitriol - Ca+2 and phosphate: absorption, loss for bone depositionerythropoietin - stimulates bone marrow to produce RBCsStomach and small intestines - enteric hormonescoordinate digestive motility and secretion

Endocrine Functions of Other Organs 2Liverangiotensinogen (a prohormone)precursor of angiotensin II, a vasoconstrictorerythropoietin (15%)somatomedins - mediate action of GHPlacentasecretes estrogen, progesterone and othersregulate pregnancy, stimulate development of fetus and mammary glands