Endocrine Sys. , Adrenal gland.pdf

Physiology Endocrine System Chapter 20 |Adrenal Gland Endocrine System | Adrenal Gland Contents : Introduction 3 Adrenal Medulla 9 Adrenal Cortex 19 Adrenocortical Hormones 25 Physiologic Effects Of Glucocorticoids 37 Pharmacologic & Pathologic Effects Of Glucocorticoids 47 Regulation Of Glucocortic...

Physiology Endocrine System Chapter 20 |Adrenal Gland Endocrine System | Adrenal Gland Contents : Introduction 3 Adrenal Medulla 9 Adrenal Cortex 19 Adrenocortical Hormones 25 Physiologic Effects Of Glucocorticoids 37 Pharmacologic & Pathologic Effects Of Glucocorticoids 47 Regulation Of Glucocorticoid Secretion 55 Regulation Of Aldosterone Secretion 64 Chapter summary 74 Endocrine System | Adrenal Gland The Adrenal Medulla & Adrenal Cortex : There are two endocrine organs in the adrenal gland, one surrounding the other. The main secretions of the inner adrenal medulla are the catecholamines, epinephrine, norepinephrine, and dopamine; the outer adrenal cortex secretes steroid hormones. Endocrine System | Adrenal Gland The adrenal cortex secretes glucocorticoids, steroids with widespread effects on the metabolism of carbohydrate and protein; and a mineralocorticoid essential to the maintenance of Na+ balance and extracellular fluid (ECF) volume. It is also a secondary site of androgen synthesis, secreting sex hormones such as testosterone, which can exert effects on reproductive function. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland The adrenal medulla, which constitutes 28% of the mass of the adrenal gland, two cell types can be distinguished morphologically: an epinephrinesecreting type and a norepinephrine-secreting type. In humans, 90% of the cells are the epinephrine secreting type and 10% are the norepinephrinesecreting type. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland In adult mammals, the adrenal cortex is divided into three zones ,the outer zona glomerulosa , then zona fasciculate and zona reticularis. All three cortical zones secrete corticosterone, but the active enzymatic mechanism for aldosterone biosynthesis is limited to the zona glomerulosa, whereas the enzymatic mechanisms for forming cortisol and sex hormones are found in the two inner zones. Adrenal Medulla Endocrine System | Adrenal Gland Adrenal Medulla : Structure & Function Of Medullary Hormones: Catecholamines Norepinephrine, epinephrine, and small amounts of dopamine are synthesized by the adrenal medulla. Norepinephrine is formed by hydroxylation and decarboxylation of tyrosine, and epinephrine by methylation of norepinephrine. Endocrine System | Adrenal Gland In plasma, about 95% of the dopamine and 70% of the norepinephrine and epinephrine are conjugated to sulfate. Sulfate conjugates are inactive and their function is unsettled. The catecholamines have a half-life of about 2 min in the circulation. Endocrine System | Adrenal Gland Effects Of Epinephrine & Norepinephrine : The norepinephrine and epinephrine exert metabolic effects that include glycogenolysis in liver and skeletal muscle, mobilization of free fatty acids (FFA), increased plasma lactate, and stimulation of the metabolic rate. The effects of norepinephrine and epinephrine are brought about by actions on two classes of receptors: α- and β-adrenergic receptors. Endocrine System | Adrenal Gland In addition, the catecholamines increase the secretion of insulin and glucagon via β-adrenergic mechanisms and inhibit the secretion of these hormones via α-adrenergic mechanisms. Norepinephrine and epinephrine both increase the force and rate of contraction of the isolated heart. These responses are mediated by β1-receptors. Norepinephrine produces vasoconstriction in most if not all organs via α1-receptors, but epinephrine dilates the blood vessels in skeletal muscle and the liver via β2-receptors. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Effects Of Dopamine : The physiologic function of the dopamine in the circulation is unknown. However, injected dopamine produces renal vasodilation, probably by acting on a specific dopaminergic receptor. It produces vasoconstriction, probably by releasing norepinephrine, and it has a positive inotropic effect on the heart by an action on β1-adrenergic receptors. Dopamine is made in the renal cortex. It causes natriuresis and may exert this effect by inhibiting renal Na, K, ATPase. Endocrine System | Adrenal Gland Regulation Of Adrenal Medullary Secretion : Certain drugs act directly on the adrenal medulla, but physiologic stimuli affect medullary secretion through the nervous system. Catecholamine secretion is low in basal states, but the secretion of epinephrine and, to a lesser extent, that of norepinephrine is reduced even further during sleep. Endocrine System | Adrenal Gland Increased adrenal medullary secretion is part of the diffuse sympathetic discharge provoked in emergency situations, which Cannon called the “emergency function of the sympathoadrenal system.” The ways in which this discharge prepares the individual for flight or fight and the increases in plasma catecholamines under various conditions. Adrenal Cortex Endocrine System | Adrenal Gland Adrenal Cortex: : Structure & Biosynthesis Of Adrenocortical Hormones Classification & Structure The hormones of the adrenal cortex are derivatives of cholesterol. Like cholesterol, bile acids, vitamin D, and ovarian and testicular steroids, they contain the cyclopentanoperhydrophenanthrene nucleus. Endocrine System | Adrenal Gland Secreted Steroids : Innumerable steroids have been isolated from adrenal tissue, but the only steroids normally secreted in physiologically significant amounts are the mineralocorticoid aldosterone, the glucocorticoids, cortisol and corticosterone, and the androgens dehydroepiandrosterone (DHEA) and androstenedione. Deoxycorticosterone is a mineralocorticoid that is normally secreted in about the same amount as aldosterone but has only 3% of the mineralocorticoid activity of aldosterone Endocrine System | Adrenal Gland Steroid Biosynthesis : The precursor of all steroids is cholesterol. Some of the cholesterol is synthesized from acetate, but most of it is taken up from LDL in the circulation. Cholesterol ester hydrolase catalyzes the formation of free cholesterol in the lipid droplets. The cholesterol is transported to mitochondria by a sterol carrier protein. In the mitochondria, it is converted to pregnenolone. Endocrine System | Adrenal Gland Pregnenolone moves to the smooth endoplasmic reticulum, where some of it is dehydrogenated to form progesterone. ACTH binds to high-affinity receptors on the plasma membrane of adrenocortical cells. This activates adenylyl cyclase via Gs. The resulting reactions lead to a prompt increase in the formation of pregnenolone and its derivatives. Over longer periods, ACTH also increases the synthesis of the P450s involved in the synthesis of glucocorticoids. Endocrine System | Adrenal Gland Adrenocortical Hormones Endocrine System | Adrenal Gland Transport, Metabolism, & Excretion Of Adrenocortical Hormones : Glucocorticoid Glucocorticoid Binding Cortisol is bound in the circulation to an α globulin called transcortin or corticosteroid-binding globulin (CBG). CBG is synthesized in the liver and its production is increased by estrogen. Endocrine System | Adrenal Gland CBG levels are elevated during pregnancy and depressed in cirrhosis, nephrosis, and multiple myeloma. When the CBG level rises, more cortisol is bound, and initially the free cortisol level drops. This stimulates ACTH secretion, and more cortisol is secreted. Changes in the opposite direction occur when the CBG level falls. A minor degree of binding to albumin also takes place. The half-life of cortisol in the circulation is therefore longer (about 60–90 min). Endocrine System | Adrenal Gland Bound steroids are physiologically inactive. In addition, relatively little free cortisol & corticosterone are found in the urine because of protein binding. The bound cortisol functions as a circulating reservoir of hormone that keeps a supply of free cortisol available to the tissue. Endocrine System | Adrenal Gland Metabolism & Excretion Of Glucocorticoids : Cortisol is metabolized in the liver, which is the principal site of glucocorticoid catabolism. Most of the cortisol is reduced to dihydrocortisol and then to tetrahydrocortisol, which is conjugated to glucuronic acid. Cortisone is an active glucocorticoid because it is converted to cortisol, and it is well known because of its extensive use in medicine. Endocrine System | Adrenal Gland It is not secreted in appreciable quantities by the adrenal glands. Little, if any, of the cortisone formed in the liver enters the circulation, because it is promptly reduced and conjugated to form tetrahydrocortisone glucuronides. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Aldosterone : Aldosterone is bound to protein to only a slight extent, and its half-life is short (about 20 min). The amount secreted is small when compared with a cortisol level (bound and free). Much of the aldosterone is converted in the liver to the tetrahydroglucuronide derivative, but some is changed in the liver and in the kidneys to an 18-glucuronide. Endocrine System | Adrenal Gland 17-ketosteroids The major adrenal androgen is the 17-ketosteroid dehydroepiandrosterone, although androstenedione is also secreted. The 11-hydroxy derivative of androstenedione and the 17-ketosteroids formed from cortisol and cortisone by side chain cleavage in the liver. Testosterone is also converted to a 17-ketosteroid. Because the daily 17-ketosteroid excretion in normal adults is 15 mg in men and 10 mg in women, about two-thirds of the urinary ketosteroids in men are secreted by the adrenal or formed from cortisol in the liver and about one-third are of testicular origin. Endocrine System | Adrenal Gland Effects Of Adrenal Androgens & Estrogens : Androgens Androgens are the hormones that exert masculinizing effects and they promote protein anabolism and growth. Testosterone from the testes is the most active androgen and the adrenal androgens have less than 20% of its activity. Secretion of the adrenal androgens is controlled acutely by ACTH and not by gonadotropins. Endocrine System | Adrenal Gland In normal males, so it is clear that these hormones exert very little masculinizing effect when secreted in normal amounts. However, they can produce appreciable masculinization when secreted in excessive amounts. In adult males, excess adrenal androgens merely accentuate existing. Endocrine System | Adrenal Gland Estrogens The adrenal androgen androstenedione is converted to testosterone and to estrogens (aromatized) in fat and other peripheral tissues. This is an important source of estrogens in men and postmenopausal women. Physiologic Effects Of Glucocorticoids Endocrine System | Adrenal Gland Physiologic Effects Of Glucocorticoids : Mechanism Of Action The multiple effects of glucocorticoids are triggered by binding to glucocorticoid receptors, and the steroid–receptor complexes act as transcription factors that promote the transcription of certain segments of DNA. Endocrine System | Adrenal Gland Effects On Intermediary Metabolism: They include increased protein catabolism and increased hepatic glycogenesis and gluconeogenesis. Glucose-6-phosphatase activity is increased, and the plasma glucose level rises. Glucocorticoids exert an anti-insulin action in peripheral tissues and make diabetes worse. Endocrine System | Adrenal Gland However, the brain and the heart are spared, so the increase in plasma glucose provides extra glucose to these vital organs. In diabetics, glucocorticoids raise plasma lipid levels and increase ketone body formation. Endocrine System | Adrenal Gland Effects On ACTH Secretion Glucocorticoids inhibit ACTH secretion, which represents a negative feedback response on the pituitary. Effects On The Nervous System Changes in the nervous system in adrenal insufficiency that are reversed only by glucocorticoids include the appearance of electroencephalographic waves slower than the normal β rhythm, and personality changes. The latter, which are mild, include irritability, apprehension, and inability to concentrate. Endocrine System | Adrenal Gland Effects On Water Metabolism Adrenal insufficiency is characterized by an inability to excrete a water load, causing the possibility of water intoxication. Only glucocorticoids repair this deficit. In patients with adrenal insufficiency who have not received glucocorticoids, glucose infusion may cause high fever (“glucose fever”) followed by collapse and death. Endocrine System | Adrenal Gland Effects On The Blood Cells & Lymphatic Organs: Glucocorticoids decrease the number of circulating eosinophils by increasing their sequestration in the spleen and lungs. Glucocorticoids also lower the number of basophils in the circulation and increase the number of neutrophils, platelets, and red blood cells. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Resistance To Stress The term stress as used in biology has been defined as any change in the environment that changes or threatens to change an existing optimal steady state. Most, if not all, of these stresses activate processes at the molecular, cellular, or systemic level that tend to restore the previous state, that is, they are homeostatic reactions. Some, but not all, of the stresses stimulate ACTH secretion. The increase in ACTH secretion is essential for survival when the stress is severe. Endocrine System | Adrenal Gland Most of the stressful stimuli that increase ACTH secretion also activate the sympathetic nervous system, and part of the function of circulating glucocorticoids may be maintenance of vascular reactivity to catecholamines. It should also be noted that the increase in ACTH, which is beneficial in the short term, becomes harmful and disruptive in the long term, causing among other things, the abnormalities of Cushing syndrome Pharmacologic & Pathologic Effects Of Glucocorticoids Endocrine System | Adrenal Gland Pharmacologic & Pathologic Effects Of Glucocorticoids: Cushing Syndrome The clinical picture produced by prolonged increases in plasma glucocorticoids was described by Harvey Cushing and is called Cushing syndrome. Patients with Cushing syndrome are protein-depleted as a result of excess protein catabolism. The skin and subcutaneous tissues are therefore thin and the muscles are poorly developed. Endocrine System | Adrenal Gland The hair is thin and scraggly. Many patients with the disease have some increase in facial hair and acne, but this is caused by the increased secretion of adrenal androgens and often accompanies the increase in glucocorticoid secretion. Body fat is redistributed in a characteristic way. The extremities are thin, but fat collects in the abdominal wall, face, and upper back, where it produces a “buffalo hump.” Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland The salt and water retention plus the facial obesity cause the characteristic plethoric, rounded “moon-faced” appearance, and there may be significant K+ depletion and weakness. About 85% of patients with Cushing syndrome are hypertensive. The hypertension may be due to increased deoxycorticosterone secretion, increased angiotensinogen secretion, or a direct glucocorticoid effect on blood vessels. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Anti-inflammatory & Anti-allergic Effects Of Glucocorticoids : Glucocorticoids inhibit the inflammatory response to tissue injury. The glucocorticoids also suppress manifestations of allergic disease that are due to the release of histamine from mast cells and basophils. Both of these effects require high levels of circulating glucocorticoids and cannot be produced by administering steroids without producing the other manifestations of glucocorticoid excess. Endocrine System | Adrenal Gland Regulation Of Glucocorticoid Secretion Endocrine System | Adrenal Gland Regulation Of Glucocorticoid Secretion: Role Of ACTH Both basal secretion of glucocorticoids and the increased secretion provoked by stress depend on ACTH from the anterior pituitary, its half-life in the circulation in humans is about 10 min. ACTH not only produces prompt increases in glucocorticoid secretion but also increases the sensitivity of the adrenal to subsequent doses of ACTH. ACTH are necessary to restore normal adrenal responses to ACTH. Endocrine System | Adrenal Gland Circadian Rhythm ACTH is secreted in irregular bursts throughout the day and plasma cortisol tends to rise and fall in response to these bursts. In humans, the bursts are most frequent in the early morning, and about 75% of the daily production of cortisol occurs between 4:00 AM and 10:00 AM. The bursts are least frequent in the evening. This diurnal (circadian) rhythm in ACTH secretion is present in patients with adrenal insufficiency receiving constant doses of glucocorticoids. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Glucocorticoid Feedback Free glucocorticoids inhibit ACTH secretion, and the degree of pituitary inhibition is proportional to the circulating glucocorticoid level. The inhibitory effect is exerted at both the pituitary and the hypothalamic levels. A drop in resting corticoid levels stimulates ACTH secretion, and in chronic adrenal insufficiency the rate of ACTH synthesis and secretion is markedly increased. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Effects Of Mineralocorticoids : Actions Aldosterone and other steroids with mineralocorticoid activity increase the reabsorption of Na+ from the urine, sweat, saliva, and the contents of the colon. Thus, mineralocorticoids cause retention of Na+ in the ECF. This expands ECF volume. Under the influence of aldosterone, increased amounts of Na+ are in effect exchanged for K+ and H+ in the renal tubules, producing a K+ diuresis and an increase in urine acidity. Endocrine System | Adrenal Gland Mechanism Of Action Like many other steroids, aldosterone binds to a cytoplasmic receptor, and the receptor–hormone complex moves to the nucleus where it alters the transcription of mRNAs. The aldosterone-stimulated proteins have two effects: 1) A rapid effect, to increase the activity of epithelial sodium channels (ENaCs) by increasing the insertion of these channels into the cell membrane from a cytoplasmic pool. 2) A slower effect to increase the synthesis of ENaCs. Endocrine System | Adrenal Gland Regulation Of Aldosterone Secretion Endocrine System | Adrenal Gland Regulation Of Aldosterone Secretion : Stimuli The principal conditions that increase aldosterone secretion are summarized in Table. Some of them also increase glucocorticoid secretion; others selectively affect the output of aldosterone. The primary regulatory factors involved are ACTH from the pituitary, renin from the kidney via angiotensin II, and a direct stimulatory effect on the adrenal cortex of a rise in plasma K+ concentration. Endocrine System | Adrenal Gland Table: Conditions that increase aldosterone secretion. Glucocorticoid secretion also increased Glucocorticoid secretion unaffected Surgery High potassium intake Anxiety Low sodium intake Physical trauma Constriction of inferior vena cava in thorax Hemorrhage Standing Secondary hyperaldosteronism (in some cases of heart failure, cirrhosis, and nephrosis) Endocrine System | Adrenal Gland Effect Of ACTH When first administered, ACTH stimulates the output of aldosterone as well as that of glucocorticoids and sex hormones. Although the amount of ACTH required to increase aldosterone output is somewhat greater than the amount that stimulates maximal glucocorticoid secretion. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Effects Of Angiotensin II & Renin The angiotensin II is formed in the body from angiotensin I, which is liberated by the action of renin on circulating angiotensinogen. Injections of angiotensin II stimulate adrenocortical secretion and, in small doses, affect primarily the secretion of aldosterone. Endocrine System | Adrenal Gland Hemorrhage stimulates ACTH and renin secretion. Like hemorrhage, standing and constriction of the thoracic inferior vena cava decrease intrarenal arterial pressure. Dietary sodium restriction also increases aldosterone secretion via the renin–angiotensin system. Such restriction reduces ECF volume, but aldosterone and renin secretion are increased before any consistent decrease in blood pressure takes place. Endocrine System | Adrenal Gland Endocrine System | Adrenal Gland Role Of Mineralocorticoids In The Regulation Of Salt Balance : Variations in aldosterone secretion is only one of many factors affecting Na+ excretion. Other major factors include the glomerular filtration rate, ANP, the presence or absence of osmotic diuresis, and changes in tubular reabsorption of Na+ independent of aldosterone. It takes some time for aldosterone to act. When one rises from the supine to the standing position, aldosterone secretion increases and Na+ is retained from the urine. Endocrine System | Adrenal Gland However, the decrease in Na+ excretion develops too rapidly to be explained solely by increased aldosterone secretion. The primary function of the aldosterone-secreting mechanism is the defense of intravascular volume, but it is only one of the homeostatic mechanisms involved in this regulation. Chapter Summary Endocrine System | Adrenal Gland Chapter Summary : The adrenal gland consists of the adrenal medulla that secretes dopamine and the catecholamines epinephrine and norepinephrine, and the adrenal cortex that secretes steroid hormones. Norepinephrine and epinephrine act on two classes of receptors, α- and β-adrenergic receptors, and exert metabolic effects that include glycogenolysis in liver and skeletal muscle, mobilization of FFA, increased plasma lactate, and stimulation of the metabolic rate. Endocrine System | Adrenal Gland The hormones of the adrenal cortex are derivatives of cholesterol and include the mineralocorticoid aldosterone, the glucocorticoids cortisol and corticosterone, and the androgens dehydroepiandrosterone (DHEA) and androstenedione. Androgens are the hormones that exert masculinizing effects, and they promote protein anabolism and growth. The adrenal androgen androstenedione is converted to testosterone and to estrogens (aromatized) in fat and other peripheral tissues. This is an important source of estrogens in men and postmenopausal women. Endocrine System | Adrenal Gland The mineralocorticoid aldosterone has effects on Na+ and K+ excretion and glucocorticoids affect glucose and protein metabolism. Glucocorticoid secretion is dependent on ACTH from the anterior pituitary and is increased by stress. Angiotensin II increases the secretion of aldosterone.