1. MineraloCorticoid Synthesis "ALDOSTERONE"

2. Pregnenolone: produced directly from cholesterol, the precusor molecule for all C 18, C 19 and C 21 steroids Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstrual cycle, differentiation factor for mammary glands Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na + uptake.

3. Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na + uptake Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics Cortisol: dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na + uptake, numerous effects on the immune system

4. THE ADRENAL GLAND

5. In human an adrenal gland lies at the upper pole of each kidney. Each adult gland is roughly pyramidal in shape, approximately 2-3 cm wide, 4- 6 cm long and 1 cm thick, each weighs about 4 gm, regardless of age, weight, and gender. Each consist of a yellow outer cortex and a gray inner medulla, the cells of the adrenal cortex synthesize steroid hrs. Which are discussed in this lecture, while the cells of medulla synthesize catecholamines such as (dopamine, epinephrine, and nor- epinephrine.)

6. I t consist of 3 layers, the outer thin layer (zona glomerulosa) secretes only ALDOSTERONE, the inner 2 layers (zona fasciculata and zona reticularis) form a functional unit secrete most of the adrenocortical hrs. In the fetus there is a wider fourth layer which disappears soon after birth. During fetal life one of its most important function is together with the adrenal cortex synthesize oestriol in association with the placenta. THE ADRENAL CORTEX:

7. The adrenal medulla considers as part of the sympathetic nervous system. The adrenal cortex secrete or synthesize 3 classes of hrs.: 1.Mineralocortrticoids. 2.Glococorticoids. 3.Adrogenes.

8. General Steroid Chemistry: Steroids are compounds that contain the cyclopentanoperhydrophenanthrene nucleus as the back bone structure. The six –sided rings (A, B,C) constitute the phenanthrene nucleus to which is attached D or cyclopentane ring. The prefix “ perhydro” refers to the saturation of the compound with hydrogen atoms. This class of compounds includes such natural products as sterol (E.g. cholesterol), bile acids (e.g. cholanic acid), and sex hrs. (E.g. estrogens, androgens), vit. D and corticosteroids. The steroid hrs. Contain up to 21 C atoms named (21 steroids) numbered as shown in fig.

10. The c-atoms composing the rings and the hydrogen atom attached to them are not usually written in to the structure unless its necessary to draw special attention. Additional carbons can be added at position (10 ) and (13) or as side chain attached to (c17). NOTE: this carbon atom will take the No. 18, 19,20. That mean which attached to No. 10 will take No. 19 and with No. 13 will take No. 18 and so on.

11. * Steroid hrs. are three dimensional molecules with their constitutes atoms lying in different planes –such spatial arrangements give rise to isomers. The direction of the hydrogen atoms of the substituents and of side chain plays a much more important role in the distinction of various isomers. If the H atom points in same direction as that of the angular methyl group at C-10 the compound is said to be in the cis (B) or normal form and are represented in drawing by solid lines (__), if however, they are on the opposite sides the compound is said to be in the (trans) form,and are represented by a The dashed lines (--)

12. STEROID HRS. CHARACTERIZED BY THE PRESENCE OF DOUBLE BONDS WHICH ARE REFERRED TO BY THE NO. OF THE PRECEDING CARBON ATOM THAT IS INVOLVED WITH THE LABEL OF DELTA. NOTE THE NO. REFERRED TO THE INITIATION OR BEGINNING OF THE DOUBLE BOND EXAMPLE: MEAN DOUBLE BOND START FROM C 3 TO C4, AND SO ON. 3 4

13. These hrs. Shared in being acting by combining certain intracellular receptors, the hormone receptor complex will act on certain areas of DNA synthesis leading to altered gene synthesis which intermittently lead to altered rate of synthesis of certain protein that mediate the action on the target tissue, these hrs. Initiate their actions by combining with specific intracellular receptors and this complex binds to specific regions of DNA to regulate gene expression. This result in altered rates of synthesis of a small No. of proteins which interne affect a variety of metabolic processes e.g. gluconeogenesis and NA and K ions balance.

14. BIOSYNTHESIS OF STEROID HORMONES The adrenal steroid hormones are synthesized from cholesterol which is mostly derived from the plasma, but a small protein is synthesized insitu from acetyl- coa ( adrenal cortex ) via mevalonate and squalene cycle.Much of the cholesterol in the adrenal cortex is esterified and stored in cytoplasmic lipid droplets and kept there. Upon stimulation of the adrenal cortex by ACTH (or camp) an asterase enzyme is activated and free cholesterol formed which is transported in to mitochondria where a cytochrome p450 scc (side chain cleavage enzyme converts cholesterol to pregnenolone and alpha – isocapro aldehyde). The first step is hydroxylation of sateroidogenesis is the hydroxylation of C20 and C22 of the side chain. “Occur in mitochondria.”

16. The cleavage of C20 to C22 bond is catalyzed by aheme- containing enzyme called cholesterol demolase, which found in mitochondria. Yield the delta 5 pregnenolone and isocaproic aldehyde. Pregnenolone leave the mitochondria and enters the cytoplasm for further metabolism, there are 2 additional relatively fast acting hydroxylase located in the endoplasmic reticulum these are 17 alpha hydroxylase and 21 alpha hydroxylase. The transformation of cholesterol in to corticosteroids has been seen to follow 2 pathways, one terminating in ALDOSTERONE and the other in CORTISOL.

18. Cleavage of the side chain involves sequential hydroxylation at: 1- theC22 carbon atom. 2-the C20 carbon atom. These followed by side chain cleavage (removal of the six carbon fragments “ isocaproaldehyde to give 21 carbon atom steroids.” Zona glomerioloza lies beneath the adrenal capsule and its function to produce aldosterone where Zona fasiculata is an inner layer of the cortex and serve s to produced cortisol.

19. It has been estimated that in normal adult man: 10-20 mg of cortisol. 3mg of corticostrerone. Are synthesized daily. 0.3 mg of aldosterone.

20. 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-  –hydroxysteroid dehydrogenase (3  -ohsd), and   isomers. Progesterone is then hydroxylated at the C 21 position to form 11- dehydroxycorticosterone (DOC), which is an active (na + - retaining) mineralocorticoid. The next hydroxylation occurs at C 11 produces corticosterone, which has glucocorticoid activity and is a weak mineralocorticoid (it has less than 5% of the potency of aldosterone ).

22. C 21 hdroxylation is necessary for both mineralocorticoid and glucocorticoid activity, but most steroids with a C 17 hydroxyl group have more glucocorticoid and less mineralocorticoid action. In the zona glomerulosa which does not have the smooth endoplasmic reticulum enzyme, 17  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.

24. ALDOSTERONE

26. GLUCOCORTICOID SYNTHESIS: Cortisol synthesis requires three hydroxylases that act sequentially on the C 17, C 21, and C11 positions. The first two reactions are rapid, while the C 11 hydroxylation is relatively slow. If the c 21 position is hydroxylated first, the action of 17  hydroxylase is impeded and the mineralocorticoid pathway is followed forming corticosterone or aldosterone, depending on cell type. *17-  hydroxylase is a smooth endoplasmic reticulum enzyme that acts upon either progesterone or more common pregnenolone. 17-  hydroxyprogesterone is hydroxylated at C 21 to form 11- deoxycortisol, which is then hydroxylated at C 11 to form cortisol, which is the most potent natural glucocorticoid hormone in humans.

27. PLASAMA TRANSPORT OF STEROID HORMONES: 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  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 t 1\2 of 1.2-2 hrs. While corticosterone which binds less tightly, has a t 1\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.

28. 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.

29. 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.

30. 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.

31. Regulation of the secretion of adrenal cortical hormones: - 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.

32. Regulation of Na & K balance: ALDOSTERONE

33. 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  an octapeptide made from angiotensinogen, an  2 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 blood pressure. Changes and many of the physiologic regulators of renin release act through renal baroreceptors.

34. 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 blood pressure, fluid or blood 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. 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 tissue leucocytes inhibiting fibroblast proliferation. And inducing lipocortins which inhibiting phospholipase A 2, 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 hormones In allowing the organism to respond to stress.