Adrenal Gland PDF

Adrenal Gland Supra-Renal Gland  Mineralocorticoids. Cortex 15 % Aldosterone....

Adrenal Gland Supra-Renal Gland  Mineralocorticoids. Cortex 15 % Aldosterone. Glucocorticoids. 75 % Cortisol -Cortisone. Sex Hormones. 10 % Androgens. Medulla o Modified sympathetic ganglia. o Secretes catecholamines; epinephrine, norepinephrine & dopamine in response to sympathetic stimulation. o Has the same effects as direct stimulation of sympathetic nerves. Functional Anatomy Situated on the upper pole of each kidney (i.e. suprarenal gland). Each weighs about 4 grams. Made of two parts: 1) Adrenal cortex: the portion constituting 80% of the gland. 2) Adrenal medulla: the central portion of gland constituting 20%. Adrenal medulla composed of three relatively distinct layers: A. Zona Glomerulosa: 15% of the adrenal cortex. Secrets aldosterone. In addition, it is important for formation of new cortical cells. B. Zona Fasciculata: 75% of the adrenal cortex Secretes glucocorticoids; cortisol &corticosterone. C. Zona Reticularis Secretes androgens Secreted steroid hormones A. Mineralocorticoids 1. Aldosterone. 2. Deoxycorticosterone: although secreted in about the same amount as aldosterone, but has only 3% of the mineralocorticoid activity of aldosterone. B. Glucocorticoids 1. Cortisol. secreted predominantly 2. Cortisone. The ratio of secreted cortisol to corticosterone of 7:1 C. Androgens 1. Dehydroepiandrosterone (DHEA) 2. Androstenedione. ❖(DHEA) is secreted conjugated with sulfate, the other steroids are secreted in the free, unconjugated form Synthesis of adrenocortical hormones Adrenocortical hormones are steroids derived from cholesterol. 80 % of the cholesterol is provided by plasm low-density lipoproteins (LDLs). Small amounts of cholesterol is synthesized from acetate by cells of adrenal cortex. The LDLs attach to specific receptors contained in structures called coated pits , then internalized by endocytosis, forming vesicles that eventually fuse with cell lysosomes and release cholesterol by the enzyme cholesterol ester hydrolase. Free cholesterol transferred into the inner mitochondrial matrix, by a protein called steroidogenic acute regulatory protein (StAR protein). Cholesterol is converted to pregnenolone in mitochondria by the enzyme cholesterol desmolase (sometimes called CYP11A1). Nearly all steps occur in two organelles; mitochondria and the endoplasmic reticulum, catalyzed by a specific enzyme system.  Cholesterol desmolase 17 α-hydroxylase Pregnenolone 17 – Hydroxy DHEA Pregnenolone 3β-hydroxysteroid dehydrogenase Progesterone 17 – Hydroxy Androstenedione Progesterone 21β-hydroxylase Testosterone 11-deoxycortisone 11-deoxycortisol Estradiol 11β-hydroxylase Corticosterone Cortisol Aldosterone synthase Aldosterone Transport, Metabolism, & Excretion of Adrenocortical Hormones  Glucocorticoid Binding Cortisol is bound in the circulation to an α globulin called corticosteroid-binding globulin (CBG) or transcortin. Corticosterone is similarly bound but to a lesser degree. Only smaller amount of aldosterone is bound The half life of circulating cortisol about 60–90 min compared to 50 min for corticosterone and 20 min for aldosterone. CBG is synthesized in the liver and its production is increased by estrogen. CBG levels are elevated during pregnancy and depressed in liver diseases like cirrhosis. When the CBG level rises: More cortisol is bound → ↓↓free cortisol level →↑ACTH and cortisol secretion until a new equilibrium is reached → ↑bound cortisol but the free cortisol is normal. Pregnant women have high total plasma cortisol levels without symptoms of glucocorticoid excess. Conversely, patients with cirrhosis have low total plasma cortisol without symptoms of glucocorticoid deficiency.  Metabolism of Adrenocortical Hormones Conjugated in the liver; conjugated to glucuronic acid and, to a lesser extent, to sulfates → inactive. About 25 percent of these conjugates are excreted in the bile, then in the feces. The remaining conjugates enter the circulation highly soluble, therefore filtered by the kidneys and excreted in the urine. Diseases of the liver markedly depress the rate of inactivation. Kidney diseases reduce the excretion of the inactive conjugates.  Regulation of secretion Aldosterone is secreted only by zona glomerulosa cells; contain the enzyme. It contains the enzyme aldosterone synthase. It lacks the enzyme 17-hydroxylase; cannot synthesize cortisol or sex hormones. The secretion is stimulated mainly by plasma potassium level and angiotensin II. Chronic increases in plasma angiotensin II, (e.g., sodium depletion) → hypertrophy and hyperplasia of zona glomerulosa cells only. Glucocorticoids and androgens; regulated by the hormone (ACTH) via hypothalamic-pituitary axis. Chronic excess of ACTH causes hypertrophy and hyperplasia of the inner two zones of the adrenal cortex. After hypophysectomy, → atrophy of the zona fasciculata and zona reticularis, whereas the zona glomerulosa is unchanged because of the action of angiotensin II. Functions of Adrenocortical Hormones  Mineralocorticoids (1) Aldosterone Accounts for 90 % of the adrenal mineralocorticoid. The remainder of the mineralocorticoid activity can be attributed to: (1) Deoxycorticosterone Has approximately 3 % of the mineralocorticoid activity of aldosterone (2) Cortisol Has a weak mineralocorticoid activity. Converted to cortisone by the enzyme 11β-hydroxysteroid dehydrogenase, which does not avidly bind mineralocorticoid receptors. Does not normally exert significant mineralocorticoid effects in vivo. Under conditions in which 11β-hydroxysteroid dehydrogenase is either congenitally absent or inhibited (e.g., during excessive licorice ingestion), cortisol may have substantial mineralocorticoid effects. Mineralocorticoids They act on the minerals (electrolytes) particularly Na & K. The most important mineralocorticoid is aldosterone. Cortisone & cortisol (glucocorticoids) have a slight mineralocorticoid activity. Functions of aldosterone: 1) Reabsorption of sodium followed by water ➔ ↑ECF volume and BP. 2) ↑ Excretion of K and H+ through the renal tubules. Acts primarily on the principal (P) and intercalated cells of the collecting tubules. Secretion of aldosterone is stimulated by: 1) ↑K (hyperkalemia). 2) Angiotensin II and Renin. K & RAS ➔ the most potent. 3) ↓Na, ↓ECF volume and ↓BP. 4) Adrenocorticotropic hormone (ACTH); Mainly stimulates the secretion of glucocorticoids. Has a mild stimulating effect on aldosterone secretion. Renin Angiotensin Aldosterone System  Aldosterone Escape Excess aldosterone increases extracellular fluid volume and arterial pressure but has only a small effect on plasma sodium concentration: a) Sodium reabsorption associated with simultaneous osmotic absorption of equivalent amounts of water. b) ↑ sodium stimulate thirst and water intake, and ↑ secretion of ADH. c) ↑ ECF volume → ↑ arterial pressure → excretion of both sodium and water (pressure natriuresis and diuresis). ❑This return to normal of sodium and water excretion by the kidneys as a result of pressure natriuresis and diuresis is called aldosterone escape. Functions of Glucocorticoids They act mainly on glucose metabolism. Cortisol is the primary secreted and the most potent glucocorticoids and is often characterized as a “stress hormone.” 1) Metabolic effects Carbohydrate; ↑blood glucose level →↑ insulin secretion Protein: catabolic, apparently on bone and muscles. Fat; Physiological response to stress; lipolytic, ketogenic. Chronically elevated; lipogenesis and truncal (abdominal/ visceral) adiposity. 2) Mild mineralocorticoid effect: Retention of Na and water and excretion of K Functions of Glucocorticoids 3) On Blood Cells ↑ RBCs, neutrophils and platelets. ↓ Eosinophils, basophils and lymphocytes ➔Anti-inflammatory, Anti-allergic& Immunosuppressive Effects 4) On Resistance to Stress Essential for life, because, it helps to withstand the stress and trauma in life. i.e. production of more energy, enhancement of vascular reactivity to catecholamines. 5) Anti-inflammatory and Immunosuppressive Actions Represses production of proinflammatory cytokines and stimulates production of anti- inflammatory cytokines. It inhibits phospholipase A2, a key enzyme in prostaglandin, leukotriene, & thromboxane synthesis. Stabilizes lysosomal membranes →↓ release of the proteolytic enzymes. ↓circulating T lymphocytes (particularly helper T lymphocytes). Functions of Glucocorticoids 3) Effects of Cortisol on Bone and muscles. ↑ bone resorption: Directly inhibit osteoblast bone-forming functions ↓ intestinal Ca++ absorption & renal Ca++ reabsorption → ↓[Ca++ ] → ↑ PTH On muscles; weakness and pain, due to proteolysis and hypokalemia. 4) Actions of Cortisol on Connective Tissue It inhibits fibroblast proliferation and collagen formation. ↑ ↑cortisol → thin skin and capillaries → bruising. 5) Actions of Cortisol on the Kidney Inhibits the secretion & action of antidiuretic hormone (ADH) (i.e. ADH antagonist). 6) On GIT Cortisol exerts a trophic effect on the GI mucosa. ↑ GI motility, ↑ gastric acid and enzyme production, ↑ appetite. Permissive Action Small amounts of glucocorticoids must be present for a number of metabolic reactions to occur. This effect is called permissive action. Permissive effects include the requirement for glucocorticoids to be present for: 1) Calorigenic effects of glucagon and catecholamines. 2) Pressor responses and bronchodilation of catecholamines. Regulation of secretion 1) ACTH (Anterior pituitary) mainly concerned with cortisol secretion. 2) ACTH secretion is regulated by hypothalamus through corticotropin releasing factor (CRF). 3) Cortisol regulates its own secretion through negative feedback control by inhibiting the release of CRF from hypothalamus and ACTH from anterior pituitary  ACTH A polypeptide, results from hydrolysis of pro-opiomelanocortin (POMC) in the anterior pituitary. ACTH is secreted in irregular bursts and plasma cortisol tends to rise and fall in response to these bursts. The bursts are most frequent in the early morning, between 4:00 AM and 10:00 AM and least frequent in the evening. The biologic clock responsible for the diurnal ACTH rhythm is located in the suprachiasmatic nuclei of the hypothalamus. When a person changes daily sleeping habits, the cycle changes correspondingly. Mechanism of action: activate adenylyl cyclase → formation of the 2nd messenger cAMP → activates the intracellular enzyme protein kinase A, → conversion of cholesterol to pregnenolone. Effects of ACTH: 1. Mainly stimulate glucocorticoids secretion. 2. Has a trophic effect on adrenal gland → increase its size (hypertrophy). 3. Melanocyte-stimulating hormone (MSH) activity → Pigmentation on the hands & mucous membranes. Adrenal Sex Hormones  Adrenal Sex Hormones Most of the hormones are male sex hormones (androgens; the hormones that exert masculinizing effects and they promote protein anabolism and growth). During fetal life, they stimulate formation of male sex organs and descent of the testes. Small quantities of estrogen & progesterone are also secreted by adrenal cortex. NB (1): during adult hood, adrenal androgens have insignificant physiological effects, because of the low amount of secretion both in males and females. During fetal life, the adrenal is large and under pituitary control, it synthesizes the sulfate conjugates of androgens (DHEAS) that are converted in the placenta to estrogens. In female adrenal androgens are important for libido, growth of axillary and pubic hair, and as anabolic hormone. Applied Physiology  Applied Physiology Hyperactivity of adrenal cortex 1. Excess glucocorticoid secretion causes Cushing’s syndrome 2. Excess mineralocorticoid secretion causes hyperaldosteronism (Conn’s syndrome). 3. Excess androgen secretion causes adrenogenital syndrome. Hypoactivity of adrenal cortex (hypoadrenalism) 1. Addison’s disease Cushing’s syndrome Excess glucocorticoid secretion Characterized by: 1. Diabetes; ↑production of glucose +↑insulin resistance. 2. Hypertension & K depletion; mineralocorticoid effect. 3. Redistribution of fat; moon face, buffalo hump, thin limbs 4. Protein depletion; osteoporosis, muscle weakness & wasting, thin skin 5. Poor wound healing. 6. ↑ in facial hair and acne, due to ↑ adrenal androgens often accompanies ↑ in glucocorticoid secretion. Cushing’s syndrome – Causes ACTH-independent 1. Glucocorticoid-secreting adrenal tumors, adrenal hyperplasia. 2. Prolonged administration of exogenous glucocorticoids. ACTH level is low as a result of negative feedback ACTH-dependent. 1. ACTH secreting tumors of the anterior pituitary → called Cushing disease. 2. Tumor secreting corticotropin releasing hormone (CRH). 3. Ectopic ACTH syndrome; e.g. lung cancer. ACTH level is high. Hyperaldosteronism Primary hyperaldosteronism (Conn syndrome) Due to primary adrenal disease such as an adenoma of the zona glomerulosa. In patients with primary hyperaldosteronism, renin secretion is depressed. Features: 1. ↑ECF volume, modest ↑ in plasma Na+ → hypertension 2. Hypokalemia, 3. Mild metabolic alkalosis Secondary hyperaldosteronism With high plasma renin activity, due to excess stimulation of RAAS, caused by: 1. Cirrhosis, heart failure, and nephrosis. 2. Renal artery constriction Adrenal Insufficiency A. Primary adrenal insufficiency (Addison disease) Due to disease processes that destroy the adrenal cortex such as tuberculosis and autoimmune inflammation. Features: 1. Hypotension → shock (Addison crises). 2. Hyperkalemia 3. Metabolic acidosis may develop. 4. Pigmentation of skin creases on the hands and the gums. B. Secondary adrenal insufficiency: Caused by pituitary diseases that decrease ACTH secretion C. Tertiary adrenal insufficiency: Caused by hypothalamic disorders disrupting CRH secretion. Both (B& C) are milder (electrolyte metabolism is less affected) and no pigmentation as plasma ACTH is low. Enzymes Deficiencies  Enzymes deficiencies Cholesterol desmolase deficiency Fatal in utero → placenta is unable to make the progesterone necessary for pregnancy to continue.  3β-Hydroxysteroid Dehydrogenase Deficiency ↑↑DHEA (weak androgen), cause: a) Some masculinization in females. b) Not adequate to produce full masculinization of the genitalia in genetic males → hypospadias; opening of the urethra is on the underside of the penis rather than its tip. Enzymes deficiencies 17α-hydroxylase deficiency: No sex hormones are produced, so female external genitalia are present. Intact corticosterone & aldosterone pathway →↑↑11-deoxycorticosterone & mineralocorticoids → hypertension and hypokalemia. Cortisol is deficient, but this is partially compensated by the glucocorticoid activity of corticosterone.  21β-hydroxylase Deficiency Common; ≥90% of the enzyme defciency cases. ↓↓cortisol & aldosterone → ↑ACTH→ adrenal hyperplasia ↑androgens → virilization. The characteristic pattern that develops in females in the absence of treatment is the adrenogenital syndrome. In 75% of the cases, aldosterone deficiency → loss of Na+ (salt-losing form of adrenal hyperplasia). The resulting hypovolemia can be severe Enzymes deficiencies 11β-hydroxylase deficiency: Virilization. ↑11-deoxycortisol (active mineralocorticoid) and 11- deoxycorticosterone → salt and water retention and, in two-thirds of the cases, hypertension (hypertensive form of congenital adrenal hyperplasia).