Adrenal Gland : Q & A

Adrenal Gland : Q & A Prof. Dr. Tarik H. Al-Khayat
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1. Outline the steps in the biosynthesis of adrenal steroid hormones.
1) Conversion of cholesterol to pregnenolone catalyzed by mitochondrial cytochrome P450-dependent side chain cleavage (P450scc). This involves hydroxylation of cholesterol at C22 and C20, followed by removal of a 6-carbon fragment, isocaproaldehyde. This is the rate-limiting step in steroidj hormone biosynthesis.
2) Conversion of pregnenolone to progesterone by the action of 3B-hydroxysteroid dehydrogenase (3?-OHSD) and ?5.4-isomerase present in the smooth endoplasmic reticulum.
3) Progressive hydroxylation of progesterone at positions C21, C11, and C18, to form aldosterone via the intermediates 11-deoxycorticosterone and corticosterone.
4) Formation of Cortisol from pregnenolone, which involves oxidation, double bond isomerization.and hydroxylations at positions C17, C21. and C11.
5) Removal of the side chain in pregnenolone by a 17,20 lyase to form androgens. DHEA, the major androgen produced by the adrenal cortex, is converted to its
sulphate as well as testosterone via androstenedione.
Adrenal Gland : Q & A Prof. Dr. Tarik H. Al-Khayat
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2. How is glucocorticoid synthesis regulated?
The synthesis of glucocorticoids is regulated by the anterior pituitary and the hypothalamus.
? Corticotrophin-releasing hormone (CRH) from the hypothalamus releases ACTH from the anterior pituitary which, in turn, stimulates the synthesis and secretion of glucocorticoids.
? The secretion of CRH and ACTH is increased by stress and feedback inhibited by high Cortisol levels.
? Both CRH and ACTH as well as Cortisol exhibit circadian variations with high levels in the morning and gradually reaching a minimum during the first few hours of sleeps.
3. How are the adrenal steroid hormones transported in circulation?
? The adrenal steroid hormones circulate bound to plasma proteins.
? About 95% of Cortisol is bound to plasma proteins, chiefly corticosteroid-binding globulin (CBG) or transcortin. The remaining 5% is found free in circulation and is the biologically active form.
? Androgens are bound to sex hormone-binding globulin (SHBG) and albumin in circulation.
4. How are the cortical steroids metabolized?
? The catabolism of adrenal cortical steroids occurs primarily in the liver and to some extent in the skin, the kidney, and the adrenal gland.
? The cortical steroids undergo reduction, oxidation, hydroxylation, side chain cleavage, and conjugation.
? The conjugated metabolites are excreted mainly in the urine. The androgens are excreted as 17-keto compounds.
5. Enumerate the biological effects of glucocorticoids.
Cortisol and cortisone exhibit the following biological effects:
? Increase blood glucose by inhibiting insulin secretion, and stimulating hepatic gluconeogenesis.
? Protein anabolic effect at physiological concentrations and protein catabolic effect with negative nitrogen balance at higher concentrations.
? Increase fat mobilization from adipose tissue by activation of lipase with increase in plasma free fatty acids.
? Maintain ECF volume and normal blood pressure by inhibiting ADH secretion.
Adrenal Gland : Q & A Prof. Dr. Tarik H. Al-Khayat
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? Weak mineralocorticoid effects (renal tubular reabsorption of sodium and excretion of potassium)?
? Anti-inflammatory effects: Glucocorticoids inhibit capillary permeability, and the production and action of inflammatory mediators such as lymphokines and prostaglandins and interferon.
6. Briefly explain the principle of adrenal cortical function tests?
Adrenal cortical function can be assessed by the following tests:
1) Measurement Of Plasma Hormone Levels
? Plasma Cortisol levels show diurnal variations with highest levels in the morning and lowest at night. Loss of diurnal variation is an early feature of adrenal hyperfunction.
? Plasma aldosterone levels are influenced by posture, and by dietary Na+ and K+.
? Low plasma ACTH indicates primary adrenal cortical tumor, while high levels occur due to an abnormality in the hypothalamic-pituitary axis or ectopic production.
2) Urinary Steroid Levels
? Urinary free Cortisol is useful in the diagnosis of adrenocortical hyperactivity.
? Urinary aldosterone is useful in the diagnosis of hyperaidosteronism.
? Urinary 17-ketosteroids are increased in bilateral hyperplasia of the adrenal cortex and in adrenal and testicular tumors, and are decreased in Addison s disease.
3) Stimulation Tests
? Synacthen test: In the rapid test, Synacthen (250 ug), a synthetic ACJH that.stimulates Cortisol 0r production, is administered by intramuscular injection.In normal persons, both the baseline and peak levels of Cortisol are high; whereas in adrenal failure, the response is blunted. In the long test, depot Synacthen (1 mg i.m.), which has longer duration of action, is given daily for 3 days and plasma cortisol determined every day and 24 h after the last dose. Plasma Cortisol levels are low in primary adrenal failure and high in secondary adrenal failure.
? Stimulation tests for mineralocorticoids are based on volume depletion by sodium restriction, diuretics, or upright posture. Aldosterone secretion is increased 3-5 days after severe sodium restriction.
Adrenal Gland : Q & A Prof. Dr. Tarik H. Al-Khayat
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4) Suppression tests
? Suppression tests for glucocorticoids use dexamethasone, a synthetic glucocorticoid that suppresses ACTH release. These tests are based on the fact that an increase in plasma Cortisol feedback inhibits ACTH release.
? Suppression tests for mineralocorticoids require increasing ECF volume by saline, oral salt load, or deoxycorticosterone which inhibit renin release with decrease in plasma and urinary aldosterone.
5) Monitoring the pituitary-adrenal axis
? Metyrapone test. It is based on the fact that administration of metyrapone [2-methyl-l,2 bis- (3 -pyridyl)-propan-l-one], an inhibitor of 11?-hydroxylase that catalyzes the formation of Cortisol from 11-deoxyCortisol, decreases Cortisol levels with increased ACTH release by feedback stimulation.
? Insulin hypoglycemia test is useful in investigating pituitary function because plasma Cortisol increases in response to insulin-induced hypoglycemia.
7. Enumerate the causes of Cushing s syndrome.
Cushing s syndrome is characterized by hypersecretion of Cortisol resulting from:
? Primary adrenal disease due to adrenal hyperplasia or cortisol-secreting tumors of the adrenal - cortex with autonomous secretion of Cortisol, which inhibits ACTH.
? Hypothalamic disease with inappropriate CRH release.
? Cushing s disease in which there is bilateral adrenal hyperplasia secondary to adenoma of the anterior pituitary gland. ACTH secretion is increased because the pituitary is insensitive to feedback inhibition by Cortisol.
? Ectopic ACTH production by small cell carcinoma of the lung and carcinoid tumors that cause bilateral adrenal hyperplasia, with excessive production of Cortisol that inhibits ACTH secretion by the pituitary.
8. Elucidate the clinical and metabolic features of Cushing s syndrome?
? Clinical Features
? Characteristic truncal obesity with moon face , and buffalo hump .
? Protuberant abdomen with purplish striae on the abdominal wall.
? Osteoporosis.
? Muscle wasting.
Adrenal Gland : Q & A Prof. Dr. Tarik H. Al-Khayat
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? Reduced immunity.
? Hypertension due to Na+ and water retention.
? Increased androgen secretion in women, leading to acne, hirsutism, and menstrual disturbances.
? Psychiatric disturbances.
? Metabolic Abnormalities
? Impaired glucose tolerance test with hyperglycemia and glycosuria.
? Increased protein catabolism associated with reduced protein synthesis.
? Proteinuria.
? Negative nitrogen balance.
? Hypokalemic alkalosis due to increased urinary loss of potassium.
9. Explain the tests useful in the differential diagnosis of Cushing s syndrome.
The following tests are useful in the differential diagnosis of Cushing s syndrome:
1) Plasma and urinary Cortisol: Loss of diurnal variation in plasma Cortisol levels with high levels in the late evening and increased urinary excretion of free Cortisol are characteristic of Cushing’s syndrome.
2) Dexamethasone suppression test: Failure of suppression in the overnight test, and low plasma cortisol levels with suppression in the high dose test are characteristic of Cushing s disease. In ectopic ACTH production and adrenal tumors where the pituitary ACTH is already suppressed, even high doses of dexamethasone will have no effect.
3) Plasma ACTH: It is low in adrenal tumors, moderately high in Cushing s disease, and very high in ectopic ACTH production.
4) Insulin tolerance test: Plasma Cortisol levels fail to increase in response to insulin-induced hypoglycemia.
5) CRH test: While administration of CRH (100 ug i.v.) increases plasma ACTH and Cortisol levels in Cushing s disease, no response is seen in ectopic ACTH secretion.
10. What is hyperaldosteronism?
Hyperaldosteronism refers to increased mineralocorticoid activity. This is of two types:
? Primary aldosteronism (Conn s syndrome) in which hypersecretion of aldosterone is due to adrenal adenoma, bilateral adrenal hypertrophy, or adrenal carcinoma. The clinical and metabolic features include:
? High plasma aldosterone and low renin.
? Failure of aldosterone suppression following salt load.
? Sodium retention, potassium excretion, and hypokalemia without edema.
Adrenal Gland : Q & A Prof. Dr. Tarik H. Al-Khayat
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? Hypertension, muscle weakness, and fatigue.
? Polyuria and compensatory polydipsia.
? Metabolic alkalosis with increase in plasma bicarbonate and H+ excretion.
? Secondary aldosteronism is due to extra-adrenal causes such as hepatic cirrhosis, nephrotic syndrome, and congestive cardiac failure. This condition is characterized by an increase in plasma renin.
11. What are the consequences of hypersecretion of androgens?
Hypersecretion of adrenal androgenic steroids occurs due to overproduction of dehydroepiandro-sterone and androstenedione. Adrenal androgen excess results in:
? Adrenal virilism in adult women with masculinization, deepening of voice, cessation menstruation, atrophy of the breasts, acne, and hirsutism.
? Excessive masculinization in men.
? Congenital adrenal hyperplasia commonly due to deficiency of C-21 hydroxylase involved in steroid - hormone biosynthesis, with accumulation, of 17?-hydroxyprogesterone. This causes virilization of female infants and cortisol deficiency or without salt-losing tendency.
12. What are the causes of adrenal cortical hypofunction?
Hypofunction of the adrenal cortex may be :
? Primary (Addison s disease), due to destruction of adrenal tissues by surgery, tuberculosis, autoimmune diseases, AIDS, or drugs such as rifampin.
? Secondary, due to ACTH deficiency resulting from excess glucocorticoids or panhypopituitarism.
13. What are the clinical and metabolic features of adrenal cortical insufficiency?
Adrenal cortical insufficiency is characterized by the following clinical and metabolic features:
? Weakness, fatigue, weight loss.
? Gastrointestinal symptoms: Anorexia, nausea, and vomiting.
? Deficiency of aldosterone, which causes
? Impaired Na+ reabsorption.
? Failure of K+ and H+ secretion in exchange for Na+.
? Hyperkalemia.
Adrenal Gland : Q & A Prof. Dr. Tarik H. Al-Khayat
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? Loss of Na+, Cl-, and water in urine.
? Mild acidosis.
? Decrease in ECF volume, leading to hemoconcentration, decreased cardiac output, renal circulatory insufficiency, decrease in the glomerular Filtration rate, and eventually uremia.
? Cortisol deficiency, that causes:
? Hypoglycemia.
? Hypotension due to reduced sensitivity of arteriolar smooth muscle to catecholamines.
? Hyponatremia.
? Susceptibility to stress.
? Increased pigmentation of skin and mucosa in primary adrenal cortical insufficiency due to high plasma ACTH, which has melanocyte stimulating activity and absence of pigmentation in secondary adrenal insufficiency in which plasma ACTH is low.
?
14. How is catecholamine metabolism regulated?
Catecholamine biosynthesis is increased by:
? Stress.
? Feeding.
? ?-adrenergic stimulation.
? Pituitary hyperactivity.
? Administration of ACTH or corticosteroids.
Catecholamine biosynthesis is decreased by disulfiram, an inhibitor of dopamine ?-hydroxylase.
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Prof. Dr. Tarik H. Al-Khayat
Printed By: Ali Al-Taie [AT]
Mohammed Al-Haddad
ممثل المرحلة : حسين شاكر محمد
“A man who dares to waste one hour of time has not discovered the value of life.” Charles Darwin
Adrenal Gland : Q & A Prof. Dr. Tarik H. Al-Khayat
8 | D e p a r t m e n t O f B i o c h e m i s t r y A T