1. MINERALOCORTICOID SYNTHESIS "ALDOSTERONE"

2. Synthesis of aldosterone follows the mineralocorticoid pathway and occurs in the zona glomerulosa. Pregnenolone is converted to progesterone by the action of two smooth endoplasmic reticulum enzymes, *3-b–HYDROXYSTEROID DEHYDROGENASE (3b-OHSD) and * D5,4isomers. Progesterone is then hydroxylated at the C 21position to form 11-dehydroxycorticosterone (DOC), which is an active (Na+- retaining) mineralocorticoid. The next hydroxylation occurs at C11 produces corticosterone, which has glucocorticoid activity and is a weak mineralocorticoid (it has less than 5% of the potency of aldosterone).

3. C21hdroxylation is necessary for both mineralocorticoid and glucocorticoid activity, but most steroids with a C17 hydroxyl group have more glucocorticoid and less mineralocorticoid action. In the zona glomerulosa which does not have the smooth endoplasmic reticulum enzyme, 17 a-hydroxylase, a mitochonderial 18-hydroxylase is present, this enzyme acts on corticosterone to form 18- hydroxy corticosterone, which is changed to aldosterone by the conversion of 18- alcohol to an aldehyde.

5. ALDOSTERONE

7. GLUCOCORTICOID SYNTHESIS: Cortisol synthesis requires three hydroxylases that act sequentially on the C17, C21, and C11 positions. The first two reactions are rapid, while the C11 hydroxylation is relatively slow. If the C21position is hydroxylated first, the action of 17a-hydroxylase is impeded and the mineralocorticoid pathway is followed forming corticosterone or aldosterone, depending on cell type. *17-ahydroxylase is a smooth endoplasmic reticulum enzyme that acts upon either progesterone or more common Pregnenolone. 17-ahydroxyprogesterone is hydroxylated at C21 to form 11- deoxycortisol, which is then hydroxylated at C11 to form cortisol, which is the most potent natural glucocorticoid hormone in humans.

8. PLASAMA TRANSPORT OF STEROID HORMONES: A\ Glucocorticoids: 1- Cortisol circulates in plasma in protein - bound and free forms. 2- the main binding protein is a a -globulin called “ transcortin” or cortico-steroid- binding globulin (CBG). Estrogens like that of (TBG) increase 3- CBG is produced in the liver and its synthesis. CBG binds most of the hormone when plasma cortisol levels are within the normal range, much smaller amounts of cortisol are bound to albumin. Cortisol binds tightly to CBG and has a t1\2 of hrs. While corticosterone which binds less tightly, has a t1\2 of less than 1 hr. Deoxycorticosterone and progesterone interact with sufficient affinity to compete for cortisol binding. T he UN bound free fraction constitutes about (8%) of the total plasma cortisol and represents the biologically active fraction of cortisol.

9. B\MINERALOCORTICOIDS (ALDOSTERON): The most potent natural mineralocorticoid does not have specific plasma transport protein but it forms a very weak association with albumin. Corticosterone and 11-DOC and other steroids with mineralocorticoid effects bind to CBG.

10. METABOLISM AND EXCRETION RATES (depends on the presence or absence of carrier proteins). A\ Glucocorticoids: About half of the cortisol ( as well as cortisone , and 11-DOC) circulates in the form of the reduced dihydro and tetrahydrometabolites that are produced form -Reduction of the (A) ring double bond by NADPH –requiring dehydrogenases and from reduction of the 3-ketone group by reversible dehydrogenase reaction. - Substantial amounts of all these compounds are also modified by conjugation at the C3 position with glucuronide or to a lesser extent with sulfate. To form tetrahydrocortisol 3 glucoronide or tetrahydrocortiso-3-sulfate, but usually and major conjugation occur with glucoronide, or to form tetrahydro-aldosterone 3- glucoronide or 3-sulfate. - These modifications occur primarily in the liver and make the lipopholic steroid molecules water soluble and excretable. In human most of the conjugated steroids that enter the enterohepatic circulation reabsorbs the intestine by biliary excretion. About 70% of conjugated steroids are excreted in the urine, 20% leave in feces and the rest exit through the skin.

11. B\ MINERALOCORTICOIDS: Aldosterone is very rapidly cleared from the plasma by the liver, no doubt because it lacks a plasma carrier protein, the liver forms tetrahydro- Aldosterone 3 glocuronide which is excreted in the urine.

12. Regulation of the secretion of Adrenal cortical hrs
Regulation of the secretion of Adrenal cortical hrs. : -Glucocorticoids hrs.: the secretion of cortisol is dependent on ACTH ,which in turn is regulated by corticotrophin- releasing hormone(CRH) by a classic –ve feed back loop. -Mineralocorticoid hrs.: the production of the Aldosterone by glomerulosa cells is regulated in a completely different manner .The primary regulators are the renin-angiotensin system and potassium.Sodium and ACTH and neural mechanism are also involved.

13. Regulation of Na & K Balance: Aldosterone

14. THE RENIN ANGIOTENSIN SYSTEM This system is involved in the regulation of blood pressure and electrolyte metabolism, the primary hormone in these processes is angiotensin II an octapeptide made from angiotensinogen, an a2 globulin made in the liver is the substrate for renin an enzyme produced in the juxtaglomerular cells of the renal afferent arteriole. The position of these cells makes them particularly sensitive to *Bd. P. changes and many of the physiologic regulators of renin release act through renal baroreceptors.

15. These cells are also sensitive to changes in the Na+and CL – concentration in the renal tubular fluid so any combination factors that decrease fluid volume as (dehydration , decrease Bd.P , fluid or Bd. Loss) or decrease Na. Concentration stimulates renin release . Renin acts upon the substrate angiotensinogin to produce the decapeptide angiotensin I, the synthesis of angiotensinogen in liver is enhanced by glucocorticoids and estrogens. So hypertension associated with these hrs. may be due to increase plasma level of angiotensinogen.

17. Angiotensin-converting enzyme: This is a glycoprotein found in lungs, endothelial cells and plasma, removes 2 carboxyl terminal amino acids from decapeptide Angiotensin I to form angiotensinII ,this Angiotensin II the Bd.P by causing vasoconstriction of the arteriole and is a very potent vasoactive substance,also it inhibits renin release from the juxtraglomerular and is a potent stimulator of aldosterone production . Although Angiotensin II stimulates the adrenal directly, it has no effect on cortisol production.

18. The potassium: Aldosterone secretion is sensitive to changes in plasma levels, an as small as (0.1meq\L) simulate production, whereas a similar decrease reduce aldosterone production and secretion. Other effectors: in special circumstances ACTH and sodium may be involved in aldosterone production in humans.

19. METABOLIC FUNCTIONS OF ADRENALCORTEX HORMONES: Loss of adrenal cortical function can cause death unless replacement therapy is achieved particularly of the glucocorticoid and so adrenal cortical function is consider to be essential for life. Functions of glucocorticoids: I-Intermediary metabolism: -Increased glucose production by* increase the delivery of A.AS. from the peripheral tissue. ** Increase the rate of gluconeogenesis by increase the amount (and activity) of several key enzymes. *** By permitting other metabolic reactions to operate at maximal rate. -Increase the hepatic glycogen deposition by promoting the activation of glycogen synthetase. - Promote lipolysis in extremities, but can cause lipogenesis in other sites (face, trunk) aseptically at higher than physiologic levels. -Promote protein and RNA metabolism, this is an anabolic effect at physiologic levels but can be catabolic in certain conditions and at higher levels than physiologic.

20. II- Effects on host mechanisms: -Suppress the immune response, these hrs. Cause lysis of lymphocytes. -Suppress the inflammatory response by* decrease the No. Of circulating leukocytes and the migration of tissueleufocytes. *Inhibiting fibroblast proliferation. *And inducing lipocortins which inhibiting phospholipase A2, blunt the production of the potent anti-inflammatory molecules, the prostaglandin, leukotrienes. III- Other effects of glucocorticoids on functions of body: )Necessary for maintenance of Bd.P and cardiac out put. )Required for maintenance of normal water and electrolytes balance. )Necessary with adrenal medulla hrs. in allowing the organism to respond to stress.

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