1. Synthesis, action and regulation of Adreno-cortical hormones Mahmoud Alfaqih BDS PhD

2. Overview The two adrenal glands lie at the superior poles of the two kidneys. Each gland is composed of two distinct parts, the adrenal medulla and the adrenal cortex. The adrenal medulla, the central 20% of the gland, secretes the hormones epinephrine and norepinephrine in response to sympathetic stimulation.

3. Overview The adrenal cortex secretes a different group of hormones, called corticosteroids. Cortocosteroids are all synthesized from the steroid cholesterol.

4. Hormones of the adrenal cortex Two major types of hormones, the mineralocorticoids and the glucocorticoids, are secreted by the adrenal cortex. Small amounts of sex hormones are also secreted, especially androgenic hormones. Androgenic hormones exhibit the same effects as testosterone. Androgens are normally of only slight importance. In certain abnormalities of the adrenal cortices, extreme quantities of androgens can be secreted and result in masculinizing effects.

6. Histology of the adrenal gland The Adrenal Cortex Has Three Distinct Layers: 1.The zona glomerulosa (G- zone)  Constitutes about 15 per cent of the adrenal cortex.  These cells secrete significant amounts of aldosterone because they contain the enzyme corticosterone methyl oxidase 2.  The secretion of aldosterone is controlled mainly by ECF concentrations of angiotensin II and potassium, both of which stimulate aldosterone secretion.

7. 2. The zona fasciculata (F- zone)  Constitutes about 75 per cent of the adrenal cortex and secretes the glucocorticoids cortisol and corticosterone.  The secretion of glucocorticoids is controlled by the hypothalamic-pituitary axis via adrenocorticotropic hormone (ACTH).

8. 3. The zona reticularis (R zone) Secretes the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione as well as small amounts of estrogens and some glucocorticoids. ACTH regulates secretion of these hormones as well. Mechanism of regulation is not that well understood.

9. Important note Aldosterone and cortisol secretion are regulated by independent mechanisms. Angiotensin II specifically increases the output of aldosterone and causes hypertrophy of the zona glomerulosa. Angiotensin II has no effect on the other two zones.

10. ACTH increase secretion of cortisol and adrenal androgens and cause hypertrophy of the zona fasciculata and zona reticularis. ACTH have little or no effect on the zona glomerulosa.

11. Synthesis of corticosteroids The hormones secreted by the adrenal cortex are synthesized from cholesterol. You need to know this pathway to understand congenital adrenal hyperplasia, a group of conditions each caused by a lack of one of these enzymes.

13. Action and regulation of glucocorticoids Glucocorticoid activity of adrenal secretions 95% of the glucocorticoid activity of the adrenocortical secretions results from the secretion of cortisol. A small but significant amount of glucocorticoid activity is provided by corticosterone.

14. Action and regulation of glucocorticoids Effect on carbohydrate metabolism 1.Stimulation of Gluconeogenesis. 2.Decreased Glucose Utilization by Cells. 3.Elevated Blood Glucose Concentration and “Adrenal Diabetes.” 4.Reduce the sensitivity of skeletal muscle and adipose tissue, to the effects of insulin on glucose uptake.

15. Effects on protein metabolism 1.Reduction of the protein stores in all body cells except the liver. 2.Increases Liver and Plasma Proteins. 3.Increased Blood Amino Acids. 4.Diminished Transport of Amino Acids into Extrahepatic Cells, and Enhanced Transport into Hepatic Cells.

16. Effect on fat metabolism 1. Promotes mobilization of fatty acids from adipose tissue. 2.Obesity Caused by Excess Cortisol. 3.Cortisol is Important in Resisting Stress and Inflammation.

17. Note Cortisol has very slight mineralocorticoid activity. This activity becomes significant in cases where large amounts of cortisol are secreted (cushing syndrome).

19. Moon face appearance as a result of excessive secretion of cortisol Before treatmentAfter treatment

20. Regulation of Cortisol Secretion by Adrenocorticotropic Hormone (ACTH) from the Pituitary Gland No stimuli have direct control effects on the adrenal cells that secrete cortisol. Secretion of cortisol is controlled almost entirely by ACTH secreted by the anterior pituitary gland.

21. ACTH Secretion Is Controlled by Corticotropin-Releasing Factor (CRF) from the Hypothalamus The anterior pituitary gland can secrete only minute quantities of ACTH in the absence of CRF. Conditions that cause high ACTH secretory rates initiate this secretion by CRF.

23. Action of ACTH on Cortisol Production ACTH Gs  AC ATP cyclic AMP PKA cholesterol ester free cholesterol P450scc pregnenolone cortisol IGF-II growth

24. Circadian Rhythm of Glucocorticoid Secretion The secretory rates of CRF, ACTH, and cortisol are high in the early morning but low in the late evening. The plasma cortisol level ranges between a high of about 20 mg/dl an hour before arising in the morning and a low of about 5 mg/dl around midnight. When a person changes daily sleeping habits, the cycle changes correspondingly. Measurements of blood cortisol levels are meaningful only when expressed in terms of the time in the cycle at which the measurements are made.

25. Blood for cortisol measurement should usually be drawn between 08:00 A.M and 09:00 P.M. Samples can be taken at 11:00 P.M h to detect loss of the diurnal variation (circadian rhythm). Loss of diurnal variation is an early feature of adrenal hyperfunction (Cushing's syndrome). Random measurements are rarely of any value in the diagnosis of adrenal disease.

28. Synthesis and Secretion of ACTH in Association with Melanocyte-Stimulating Hormone, Lipotropin, and Endorphin When ACTH is secreted by the anterior pituitary gland other hormones are secreted together with ACTH. ACTH is initially synthesized as a considerably large protein, a preprohormone called proopiomelanocortin (POMC) POMC is the precursor of ACTH as well as melanocyte stimulating hormone, beta lipotropin and beta endorphin. Under normal conditions, none of these hormones is secreted in enough quantity by the pituitary to have a significant effect.

29. Differential cleavage of POMC POMC is synthesized in several tissues, including the anterior pituitary, hypothalamus, cells of the dermis, and lymphoid tissue. POMC is cleaved to form a series of smaller peptides. The precise type of POMC cleavage products from a particular tissue depends on the type of enzymes present in the tissue. Pituitary corticotroph cells express prohormone convertase 1 (PC1), but not PC2, resulting in the production of N-terminal peptide, joining peptide, ACTH, beta endorphin, and beta lipotropin

30. Differential cleavage of POMC In the hypothalamus, the expression of PC2 leads to the production of alpha, beta, and gamma MSH, but not ACTH.

32. Note ACTH, because it contains an MSH sequence, has about 1/30 as much melanocyte-stimulating effect as MSH. The quantities of pure MSH secreted in the human being are extremely small, whereas those of ACTH are large. ACTH normally is more important than MSH in determining the amount of melanin in the skin.

33. Actions and secretion of mineralocorticoids Main actions of aldosterone 1.Aldosterone Increases Renal Tubular Reabsorption of Sodium and Secretion of Potassium. 2.Excess Aldosterone Increases Extracellular Fluid Volume and Arterial Pressure. 3.Excess aldosterone Has Only a Small Effect on Plasma Sodium Concentration.

35. 4. Excess Aldosterone Increases Tubular Hydrogen Ion Secretion, and Causes Mild Alkalosis. 5. Mineralocorticoid Deficiency Causes Severe Renal Sodium Chloride loss and Hyperkalemia.

36. Regulation of aldosterone secretion The regulation of aldosterone secretion by the zona glomerulosa cells is independent of the regulation of cortisol and androgens by the zona fasciculata and zona reticularis. Factors that are important in regulation of Aldosterone secretion are: 1.Increased potassium ion concentration in the extracellular fluid greatly increases aldosterone secretion. 2.Increased activity of the renin-angiotensin system (increased levels of angiotensin II) also greatly increases aldosterone secretion.

37. 3. Increased sodium ion concentration in the extracellular fluid very slightly decreases aldosterone secretion. 4. ACTH from the anterior pituitary gland is necessary for aldosterone secretion but has little effect in controlling the rate of secretion. Potassium ion concentration and the renin-angiotensin system are by far the most potent in regulating aldosterone secretion