Adrenal Medulla and Cortex PDF

ADRENAL MEDULLA AND CORTEX Ani sergeenko Adrenal glands The adrenal medulla, -secretes the hormones epinephrine and norepinephrine The adrenal cortex secretes hormones, called corticosteroids CORTICOSTEROIDS: mineralocorticoids;affect the electrolytes (the “minerals”) of the extra...

ADRENAL MEDULLA AND CORTEX Ani sergeenko Adrenal glands The adrenal medulla, -secretes the hormones epinephrine and norepinephrine The adrenal cortex secretes hormones, called corticosteroids CORTICOSTEROIDS: mineralocorticoids;affect the electrolytes (the “minerals”) of the extracellular fluids, especially Na and K glucocorticoids exhibit important effects that increase blood glucose concentration.have additional effects on protein and fat metabolism. androgen androgenic hormones, which exhibit about the same effects in the body as the male sex hormone testosterone. SYNTHESIS AND SECRETION OF ADRENOCORTICAL HORMONES THE ADRENAL CORTEX HAS THREE DISTINCT LAYERS. The zona glomerulosa-contain the enzyme aldosterone synthase, which is necessary for synthesis of aldosterone. controlled mainly by the extracellular fluid concentrations of angiotensin II and potassium, both stimulate aldosterone secretion The zona fasciculata,-secretes the glucocorticoids cortisol and corticosterone, as well as small amounts of adrenal androgens and estrogens.controlled by adrenocorticotropic hormone (ACTH). The zona reticularis,secretes the adrenal androgens dehydroepiandrosterone and androstenedione, and small amounts of estrogens and some glucocorticoids. ACTH regulates secretion of these cells, other factors such as cortical androgen-stimulating hormone, released from the pituitary, may also be involved.. Structures of Adrenocortical Steroids All of the steroids of the adrenal cortex are chemical modifications of a basic steroid nucleus, which is illustrated in the structure of cholesterol In summary, cholesterol, progesterone, the glucocorticoids, and the mineralocorticoids are 21- carbon steroids; androgens are 19-carbon steroids; and estrogens (produced primarily in the ovaries) are 18-carbon Steroids  Biosynthetic Pathways in the Adrenal Cortex Figure 9.23 is a schematic diagram of the biosynthetic pathways of the adrenocortical steroids The precursor for all adrenocortical steroids is cholesterol. Most of the cholesterol is provided to the adrenal cortex via the circulation, and small amounts are synthesized de novo within the adrenal cortical cells. Cholesterol circulates bound to low-density lipoproteins. ; the lipoprotein cholesterol complex binds receptors and is transferred into the adrenocortical cell by endocytosis. Inside the cells, cholesterol is esterified and stored in cytoplasmic vesicles until it is needed for synthesis of steroid hormones. The enzymes catalyzing the conversion of cholesterol to active steroid hormones require cytochrome P-450, molecular oxygen, and NADPH flavoprotein. enzyme called adrenodoxin reductase and an iron-containing protein called adrenodoxin are intermediates in the transfer of hydrogen from NADPH to the cytochrome P-450 enzymes. The first step in each pathway is catalyzed by cholesterol Desmolase stimulated by ACTH  ♦ Glucocorticoids (cortisol). The major glucocorticoid produced in humans is cortisol (hydrocortisone), which is synthesized in the zonae fasciculata/ reticularis Cortisol is not the only steroid in the pathway with glucocorticoid activity; corticosterone is also a glucocorticoid. For example, if the 17α-hydroxylase step is blocked, the zona fasciculata still can produce corticosterone without deleterious effect. Thus cortisol is not absolutely necessary to sustain life as long as corticosterone is being synthesized. Blocks at the cholesterol desmolase, 3β-hydroxysteroid dehydrogenase, 21β- hydroxylase, or 11β-hydroxylase steps are devastating because they prevent the production of cortisol and corticosterone; in these cases, death will ensue without appropriate hormone replacement therapy. Metyrapone inhibits 11β-hydroxylase, the last step in cortisol synthesis. Ketoconazole inhibits several steps in the pathway including cholesterol desmolase, the first step.  ♦ Adrenal androgens (DHEA and androstenedione). DHEA and androstenedione are androgenic steroids produced by the zonae fasciculata/reticularis. These compounds have weak androgenic activity, but in the testes they are converted to testosterone, a more potent androgen. In males, adrenal androgens are of little significance; the testes produce their own testosterone from cholesterol and do not require the adrenal precursors Adrenal androgens have a ketone group at C17 group Thus the major adrenal androgens are called 17-ketosteroids, which can be measured in the urine. The zonae fasciculata/reticularis also produce small amounts of testosterone and 17β-estradiol  ♦ Mineralocorticoids (aldosterone). The major mineralocorticoid in the body is aldosterone, which is synthesized only in the zona glomerulosa. aldosterone synthase in the zona glomerulosa converts corticosterone to aldosterone. Aldosterone is not the only steroid with mineralocorticoid activity; 11- deoxycorticosterone (DOC) and corticosterone also have mineralocorticoid activity. Thus if the mineralocorticoid pathway is blocked below the level of DOC (e.g., absence of 11β-hydroxylase or aldosterone synthase), mineralocorticoidsm will continue to be produced. if the pathway is blocked above the level of DOC (e.g., absence of 21β-hydroxylase), then no mineralocorticoids will be produced. Regulation of Secretion of Adrenocortical Steroids vFig. 9.25 Regulation of cortisol secretion. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone the synthesis and secretion of steroid hormones by the adrenal cortex depend on the stimulation of cholesterol desmolase (the first step) by ACTH ♦ The zonae fasciculata/reticularis, which secrete glucocorticoids and androgens, are under the exclusive control of the hypothalamic-pituitary axis. The hypothalamic hormone is corticotropin-releasing hormone (CRH), and the anterior pituitary hormone is ACTH. ♦ The zona glomerulosa, which secretes mineralocorticoids, depends on ACTH for the first step in steroid biosynthesis, but otherwise it is controlled separately via the renin- angiotensin-aldosterone system Regulation of Glucocorticoid and Adrenal Androgen Secretion An impressive feature of the regulation of cortisol secretion is its pulsatile nature and its diurnal (daily) pattern 10 secretory bursts during a 24-hour period. The lowest secretory rates occur during the evening hours and just after falling asleep (e.g., midnight), and the highest secretory rates occur just before awakening in the morning Other adrenal steroids (e.g., adrenal androgens) are secreted in similar bursting diurnal patterns. ACTH secretion also exhibits the same diurnal pattern; The secretion of glucocorticoids The secretion of glucocorticoids by the zona fasciculata/reticularis is regulated exclusively by the hypothalamic- pituitary axis (Fig. 9.25). ACTH Secretion Is Controlled by Corticotropin-Releasing Factor CRF From the Hypothalamus ACTH Activates Adrenocortical Cells to Produce Steroids by Increasing cAMP Effects of ACTH Effects of ACTH are to stimulate transfer of stored cholesterol to the mitochondria, to stimulate binding of cholesterol to cytochrome P-450, and to activate cholesterol desmolase. Long-term effects of ACTH include stimulation of transcription of the genes for cytochrome P-450 and adrenodoxin and up- regulation of ACTH receptors. Chronic effects of elevated ACTH levels include hypertrophy and hyperplasia of the adrenal cortical cells, mediated by local growth factors (e.g., IGF-2). As noted, ACTH has a pulsatile and diurnal secretory pattern that drives a parallel pattern of cortisol secretion  ♦ Negative feedback ♦ Negative feedback is exerted by cortisol at three points in the hypothalamic- pituitary axis. (1) Cortisol directly inhibits secretion of CRH from the hypothalamus. (2) Cortisol indirectly inhibits CRH secretion by effects on hippocampal neurons, which synapse on the hypothalamus. (3) Cortisol inhibits the action of CRH on the anterior pituitary, resulting in inhibition of ACTH secretion. Thus chronic deficiency of cortisol leads to stimulation of the CRH ACTH axis and to increased ACTH levels; Chronic excess of cortisol leads to inhibition (suppression) of the CRH-ACTH axis and decreased ACTH levels.. ♦ The dexamethasone suppression test Dexamethasone is a synthetic glucocorticoid that has all of the actions of cortisol in healthy person, it inhibits (or “suppresses”) ACTH, low ACTH then causes decreased cortisol secretion, which is measured in the test. The major use of the dexamethasone suppression test is in persons with hypercortisolism (high levels of cortisol) In Cushing syndrome (primary adrenal defect with a normal CRH- ACTH axis), because the adrenal tumor functions autonomously, cortisol secretion is not suppressed by either low- or high-dose dexamethasone. In Cushing disease, ACTH and cortisol secretion are suppressed by high- dose dexamethasone but not by low dose dexamethasone.  Regulation of Aldosterone Secretion primary regulation of aldosterone secretion occurs not by ACTH but through changes in ECF volume via the renin–angiotensin II–aldosterone system and through changes in serum potassium (K+) levels ♦ Renin–angiotensin II–aldosterone. The major control of aldosterone secretion angiotensin II, which increases the synthesis and secretion of aldosterone by stimulating cholesterol desmolase and aldosterone synthase, the first and last steps in the pathway angiotensin II binds to AT1 receptors that are coupled to phospholipase C via a Gq protein system decreases in ECF volume stimulate aldosterone secretion, and aldosterone stimulates Na+ reabsorption by the kidney to help restore ECF Na+ content and ECF volume. ♦ Serum K+ concentration. The other factor that controls aldosterone secretion increase in serum K+ concentration acts on adrenal cells by depolarizing them and opening voltage-sensitive Ca2+ channels and stimulates aldosterone secretion  Actions of Adrenocortical Steroids TABLE 9.11 Actions of Adrenocortical Steroids ♦ Stimulation of gluconeogenesis Cortisol increases protein catabolism in muscle and decreases new protein synthesis, thereby providing additional amino acids to the liver for gluconeogenesis. Cortisol increases lipolysis, which provides additional glycerol ♦ Anti-inflammatory effects. Cortisol has three actions (1) Cortisol induces the synthesis of lipocortin, an inhibitor of the enzyme phospholipase A2. Phospholipase A2 liberates arachidonic acid from membrane phospholipids and provides the precursor for the prostaglandins and leukotrienes that mediate the inflammatory response. (2) Cortisol inhibits the production of interleukin-2 (IL-2) and the proliferation of T lymphocytes. (3) Cortisol inhibits the release of histamine and serotonin from mast cells and platelets. ♦ Suppression of immune response. As previously noted, cortisol inhibits the production of IL-2 and the proliferation of T lymphocytes  Continue.. TABLE 9.11 Actions of Adrenocortical Steroids ♦ Maintenance of vascular responsiveness to Catecholamines role in the arterioles by up-regulating α1-adrenergic receptors. In this way, cortisol is required for the vasoconstrictive response of the arterioles to catecholamines. In hypocortisolism, there is hypotension; in hypercortisolism, there is hypertension. ♦ Inhibition of bone formation. Cortisol inhibits bone formation by decreasing the synthesis of type I collagen, the major component of bone matrix; by decreasing formation of new bone by osteoblasts; and by decreasing intestinal Ca2+ absorption. ♦ Increases in glomerular filtration rate (GFR). Cortisol increases GFR by causing vasodilation of afferent arterioles, thereby increasing RBF and GFR. ♦ Effects on CNS Glucocorticoid receptors are found in the brain, particularly in the limbic system. Cortisol decreases REM sleep, increases slow-wave sleep, and increases awake time Actions of Mineralocorticoids The actions of mineralocorticoids (e.g., aldosterone increases Na+ reabsorption, increases K+ secretion, increases H+ secretion Thus when aldosterone levels are increased (e.g., due to an aldosterone-secreting tumor), Na+ reabsorption, K+ secretion, and H+ secretion all are increased. These changes in renal transport result in ECF volume expansion and hypertension, hypokalemia, and metabolic alkalosis. Conversely, when aldosterone levels are decreased (e.g., due to adrenal insufficiency),opposite.. An interesting “problem” the affinity of mineralocorticoid receptors for cortisol is, surprisingly, just as high as their affinity for Aldosterone the renal cells themselves. They contain the enzyme 11β-hydroxysteroid dehydrogenase, which converts cortisol to cortisone; in contrast to cortisol, cortisone has a low affinity for mineralocorticoid receptors Actions of Adrenal Androgens The adrenal cortex produces the androgenic compounds, DHEA and androstenedione In males, adrenal androgens play only a minor role In females, adrenal androgens are the major androgens, and they are responsible for the development of pubic and axillary hair and for libido. In conditions such as adrenogenital syndrome, in which there is increased synthesis of adrenal androgens, the high levels of DHEA and androstenedione lead to masculinization in females, early development of axillary and pubic hair, and suppression of gonadal function in both males and females. Also, in the adrenogenital syndromes, due to the overproduction of adrenal androgens, there will be increased urinary levels of 17-ketosteroids  Pathophysiology of the Adrenal Cortex TABLE 9.12 Pathophysiology of the Adrenal Cortex Disorders of the adrenal cortex can be caused by a primary defect in the adrenal cortex or by a primary defect in the hypothalamic-pituitary axis. Or, in the case of aldosterone, the defect may be in the renin–angiotensin II axis. For example, symptoms consistent with overproduction of an adrenocortical hormone (e.g., hypercortisolism) may be caused by a primary defect in the adrenal cortex. Or, the symptoms may be caused by a primary defect in the anterior pituitary or the hypothalamus, which then produces a secondary effect on the adrenal cortex. The etiology of the disorder may not be deduced until circulating levels of CRH and ACTH are measured and the feedback regulation of the CRH-ACTH axis is evaluated. For disorders caused by enzyme deficiencies in the steroid hormone biosynthetic pathway, the pathways can be visualized to predict the effects of a given enzyme block (see Fig. 9.23  Pathophysiology of the adrenal cortex a. Adrenocortical insufficiency (1) Addison’s disease Primary adrenocortical insufficiency— is most commonly caused by autoimmune destruction of the adrenal cortex and causes acute adrenal crisis. is characterized by the following: (a) ↓ adrenal glucocorticoid, androgen, and mineralocorticoid (b) ↑ ACTH (Low cortisol levels stimulate ACTH secretion by negative feedback.) (c) Hypoglycemia (caused by cortisol deficiency) (d) Weight loss, weakness, nausea, and vomiting (e) Hyperpigmentation (Low cortisol levels stimulate ACTH secretion; ACTH contains the MSH fragment.) (f) ↓ pubic and axillary hair in women (caused by the deficiency of adrenal androgens) (g) ECF volume contraction, hypotension, hyperkalemia, and metabolic acidosis (caused by aldosterone deficiency) Treatment of Addison disease includes glucocorticoid and mineralocorticoid replacement (2) Secondary adrenocortical insufficiency is caused by primary deficiency of ACTH. does not exhibit hyperpigmentation (because there is a deficiency of ACTH). does not exhibit volume contraction, hyperkalemia, or metabolic acidosis (because aldosterone levels are normal). Symptoms are otherwise similar to those of Addison’s disease( hypoglycemia)  Adrenocortical excess—Cushing’s syndrome is most commonly caused by the administration of pharmacologic doses of glucocorticoids. is also caused by primary hyperplasia of the adrenal glands. is called Cushing’s disease when it is caused by overproduction of ACTH in anterior pituitary. is characterized by the following: (1) ↑ cortisol and androgen levels (2) ↓ ACTH (if caused by primary adrenal hyperplasia or pharmacologic doses of glucocorticosteroids); ↑ ACTH (if caused by overproduction of ACTH, as in Cushing’s disease) (3) Hyperglycemia (caused by elevated cortisol levels) (4) ↑ protein catabolism and muscle wasting (5) Central obesity (round face, supraclavicular fat, buffalo hump) (6) Poor wound healing (7) Virilization of women (caused by elevated levels of adrenal androgens) (8) Hypertension (caused by elevated levels of cortisol and aldosterone) (9) Osteoporosis (elevated cortisol levels cause increased bone resorption) (10) Striae t Ketoconazole, an inhibitor of steroid hormone synthesis, can be used to treat Cushing’s disease bilateral adrenalectomy coupled with steroid hormone replacement may be required. Because of its different etiology, treatment of Cushing disease involves surgical removal of the ACTH secreting tumor.. Cushing syndrome and Cushing disease exhibit similar clinical features, but they differ in the circulating levels of ACTH. In Cushing syndrome, the primary defect is in the adrenal cortex, which is overproducing cortisol. Accordingly, ACTH levels are low because the high cortisol levels feed back on the anterior pituitary and inhibit ACTH secretion. In Cushing disease, the primary defect is in the anterior pituitary, which is overproducing ACTH; ACTH levels are elevated. As already described, the dexamethasone suppression test, In Cushing syndrome (primary adrenal defect with a normal CRH-ACTH axis), because the adrenal tumor functions autonomously, cortisol secretion is not suppressed Hyperaldosteronism—Conn’s syndrome is caused by an aldosterone-secreting tumor. is characterized by the following: (1) Hypertension (because aldosterone increases Na+ reabsorption, which leads to increases in ECF volume and blood volume) (2) Hypokalemia (because aldosterone increases K+ secretion) (3) Metabolic alkalosis (because aldosterone increases H+ secretion) (4) ↓ renin secretion (because increased ECF volume and blood pressure inhibit renin secretion by negative feedback) muscle paralysis develops becauses decreased effects of K ions diagnostic criteria is a decreased plasma renin concentration. resulting from feedback suppression of renin secretion caused by the excess aldosterone Treatment surgical removal of the tumor or of most of the adrenal tissue when hyperplasia is the cause. pharmacological antagonism of the mineralocorticoid receptor with spironolactone or eplerenone Adrenogenital Syndrome Occasionally an adrenocortical tumor secretes excessive quantities of androgens that cause intense masculinizing effects throughout the body. If this phenomenon occurs in a female, virile characteristics develop In the prepubertal male, a virilizing adrenal tumor causes the same characteristics as in the female plus rapid development of the male sexual organs In the adult male, the virilizing characteristics of adrenogenital syndrome are usually obscured by the normal virilizing characteristics  21β-hydroxylase deficiency belongs to a group of disorders of adrenogenital syndrome Without 21β-hydroxylase, decrease å cortisol and aldosterone levels (because the enzyme block prevents the production of 11- deoxycorticosterone and 11-deoxycortisol, the precursors for cortisol and aldosterone) Steroid intermediates will accumulate above the enzyme block and be shunted toward production of the adrenal androgens causes virilization in females. There will be increased urinary levels of 17-ketosteroids. If the defect is present in utero in a female fetus, the excess androgens cause masculinization of the external genitalia, ACTH levels will be elevated because of negative feedback from low cortisol adrenocortical hyperplasia will develop Treatment of 21β-hydroxylase deficiency consists of replacement of both glucocorticoids and mineralocorticoids  17α-Hydroxylase Deficiency neither glucocorticoids nor adrenal androgens will be produced by the adrenal cortex. steroid intermediates are shunted toward the production of mineralocorticoids Interestingly, the levels of aldosterone are decreased because the feedback regulation of the renin– angiotensin II–aldosterone system also here will be overproduction of deoxycortisol and corticosterone, both of which have mineralocorticoid activity.cause symptoms of mineralocorticoid excess: hypertension, metabolic alkalosis, and hypokalemia. Hypertension inhibits renin secretion, thus leading to decreased levels of angiotensin II and aldosterone; hypokalemia also inhibits aldosterone secretion directly.