Professor of Biochemistry Adrenal cortical hormones Dr. Saidunnisa Professor of Biochemistry Adrenal cortical hormones

Adrenal Cortex Hormones produced by the adrenal cortex are referred to as corticosteroids. These comprise mineralocorticoids, glucocorticoids and androgens. The cortex is divided into three regions: zona glomerulosa zona fasciculata zona reticularis

Adrenal cortical hormones Outermost zone – Zona Glomerulosa secretes mineralocorticoids involved in regulation of electrolytes in ECF. Naturally synthesized mineralocorticoid of most importance is aldosterone. Middle zone –Zona Fasciculata secretes glucocorticoids involved in increasing of blood glucose levels. The naturally synthesized glucocorticoids of most importance is cortisol.

Zona Reticularis Innermost zone – between the fasciculata and medulla Primary secretion is androgens. Androgenic hormones exhibit approximately the same effects as the male sex hormone – testosterone.

Synthesis of steroid hormones Cholesterol is acted upon by the enzyme system that catalyzes the Six carbon unit cleavage reaction by a P450-linked side chain cleaving enzyme (P450ssc) or 20,22-desmolase. Which is found in the mitochondria of steroid-producing cells. This is a common precursor for all steroid hormones. This is a rate limiting step. ACTH stimulates this step.

Aldosterone synthesis Pregnenolone is converted into Progesterone in two steps: β -hydroxyl group is converted to a keto group. Shift of a double bond from c5 to c4 Progesterone is further converted into mineralocorticoids, glucocorticoids, and sex steroids. All these are hydroxylation reaction specific Monoxygenases which are NADPH dependent. The major mineralocorticoid is aldosterone. Aldosterone has OH group at C11 and aldehyde group at C18

Aldosterone synthesis Progesterone is hydroxylated by 21 hydroxylase to form 11-deoxy-corticosterone (DOC). 11DOC is hydroxylated by 11β- hydroxylase to form corticosterone. Corticosterone is converted by 18 hydroxylase and 18hydroxy dehydrogenase to form aldosterone.

Transport of aldosterone in the blood 50% bound to plasma proteins 50% free circulating half-life 15 min All steroid hormones are metabolized and inactivated in the liver by reduction and conjugation.

Regulation of aldosterone secretion Renin-Angiotension-Aldosterone System Angiotensisn II can raise blood pressure by: vasoconstrictor effects. stimulating aldosterone secretion.

Effects of Aldosterone Renal effects : ECF volume regulation sodium and potassium ECF concentrations Promotes reabsorption of sodium from the ducts of sweat and salivary glands during excessive sweat/saliva loss. Enhances absorption of sodium from the intestine esp. colon. – absence leads to diarrhea.

Effects of Aldosterone Increase rate of tubular reabsorption of sodium. Increase rate of tubular reabsorption of chloride. Increase loss of k+ in urine resulting in hypokalemia Metabolic alkalosis. Plasma volume increases ECF increases

Synthesis of cortisol Progesterone is converted to 17 hydroxy progesterone this is further converted into 11deoxy cortisol and this is further converted into cortisol all by specific hydroxylases. Urinary steroids are referred to as 17-hydroxy steroids(derived from adrenal) and 17-ketosteroids (derived from adrenal and gonads).

Transport of cortisol in the blood 70% bound to CBP (corticosteroid binding protein = cortisol binding globulin = transcortin) 20% bound to albumin 20% free which is biologically active Half-life 120 minutes. Steroid hormones are metabolized in the liver and inactivated by the liver by conjugation and excreted in urine.

Mechanism of action All the steroid hormones exert their action by passing through the plasma membrane and binding to intracellular receptors.

Regulation of Cortisol Release Cortisol release is regulated by ACTH release follows a daily pattern – circadian secretion maximum at 8-10 h (morning) secretion minimum at 23 h (nights). Negative feedback by cortisol inhibits the secretion of ACTH and CRH Enhanced release can be caused by: physical trauma infection extreme heat and cold exercise to the point of exhaustion extreme mental anxiety

Effects of Cortisol Carbohydrates metabolism : Promotes gluconeogenesis. Decreased glycolysis and glucose utilization by the peripheral cells all lead to hyperglycemia. Lipid metabolism : Increase lipid mobilization and facilitate fat breakdown (lipolysis) Protein metabolism : Promotes Increased catabolism of proteins of skeletal muscle and nucleic acids.

Effects of Cortisol Fluid and electrolyte: increases water excretion by increasing GFR and inhibiting ADH secretion. Bone and calcium: decrease serum calcium by inhibiting osteoblastic activity leading to osteoporosis. Secretory action: stimulate secretion of gastric acid and induces acid peptic disease. Connective tissue: impaired collagen formation, poor wound healing. Immune system: immunosuppressant and anti-inflammatory and antiallergic.

Anti-inflammatory Effects of Cortisol Suppresses lymphoid tissue systemically therefore decrease in T cell and antibody production thereby decreasing immunity. Decrease immunity could be fatal in diseases such as tuberculosis Decrease immunity effect of cortisol is useful during transplant operations in reducing organ rejection. reduces fever suppresses allergic reactions wide spread therapeutic use

Assessment of Glucocorticoid secretion Basal level of cortisol: Plasma cortisol measured by RIA or ELISA or CLIA. (Normal range: 5-25micrograms/dl at 9AM : 2-5 micrograms/dl at 10PM) Estimation of urinary free cortisol: which is biologically active fraction, high levels are seen in hyper function and low levels in hypo function. Plasma ACTH: decreased levels are seen in hyperadrenalism and high levels in hypoadrenalism and Cushing's disease. CRH: This test is of importance in establishing the cause of adrenal hyperfunction (primary, secondary or tertiary).

Excess of hormones of adrenal cortex Glucocorticoids – Cushing’s syndrome defect in adrenal gland. Cushing's disease is due to excessive production of ACTH from pituitary (tumors) Hypertension “Adrenal diabetes” Hyper secretion of cortisol results in increase blood glucose levels, up to 2 x normal (200mg/dl) Prolonged over secretion of insulin “burns out” the beta cells of the pancreas resulting in life long diabetes mellitus decreased protein synthesis immune system - infections osteoporosis

Cushing’s Syndrome Hyper-Adrenalism Primarily the Glucocorticoids Buffalo torso Redistribution of fat from lower parts of the body to the thoracic and upper abdominal areas

Cushing’s Syndrome Collagen fibers in subcutaneous tissue tear forming striae “moon face” Moon Face Edematous appearance of face Acne & hirsutism( excess growth of facial hair) striae

Excess of hormones of adrenal cortex Mineralocorticoids – Conn’s syndrome due to aldosterone secreting tumor. Diagnosed by: Elevated Plasma aldosterone levels Plasma renin activity decreased Hypernatremia and Hypokalemia – muscle weakness Plasma pH is increased -(hypokalemic alkalosis) – increased neuromuscular excitability Osmolality increased- (hypertonic contraction) Hypervolemia – hypertension

Excess of hormones of adrenal cortex Androgenic hormones in childhood in boys pseudopubertas praecox: rapid development of male sexual organs in adulthood in men – non-visible in childhood in girls and in adulthood in women Masculinizing effect (virilizing): growth of clitoris, growth of beard, deeper voice, masculine distribution of hair

Lack of hormones of adrenal cortex Adrenal hypofunction Glucocorticoides and mineralocorticoides – Addison’s disease consequences of lack of aldosterone: decreased Na+ reabsorption, decreased ECF volume Hypercalcemia, mild acidosis rise of hematocrit – decrease of cardiac output consequences of lack of cortisol: depressed gluconeogenesis reduced fat and protein metabolism high level of ACTH - pigmentation Addisonian crisis - during stress (trauma, surgical operations) – extra need for glucocorticoids

Hypoadrenalism: Addison’s Disease Hyperpigmentation due to increased ACTH levels on MSH activity. Hyponatremia : plasma sodium decreases and may lead to circulatory collapse. Tiredness Dehydration

Melanin Pigmentation Characteristic of Addison’s disease is uneven distribution of melanin deposition in thin skin eg. Mucous membranes, lips, thin skin of the nipples. Feedback and effect on MSH

Treatment Total destruction, if untreated, could lead to death with a few days. Treatment – small quantities of mineralocorticoids and glucocorticoids daily.

Zona Reticularis Innermost zone – between the fasciculata and medulla Primary secretion is androgens. Androgenic hormones exhibit approximately the same effects as the male sex hormone – testosterone.

Synthesis of adrenal androgens

Inborn errors of metabolism These are autosomal recessive disorders. All the 5 enzymes involved in the synthesis can be deficient resulting in CAH.

Adrenogenital Syndrome Adrenal tumor Pituitary Involvement??? General Masculinization

Androgenital syndrome Congenital deficiency of steroid hydroxylases leading to deficient secretion of cortisol. The major feed back effect is not present ACTH secretion continues leading to CAH.

21-hydroxylase deficiency Depending on the enzyme defect the manifestations vary. 21-hydroxylase deficiency: common type production of cortisol is absent totally. Lack of feed back leads to increased androgen synthesis. This leads to virilization of female children who develop ambiguous genitilia. Precocious puberty in male children

11 alpha hydroxylase 11 alpha hydroxylase the symptoms are more serious. Manifests with hypertension. Prognosis is bad.

Sex Hormones Classic Sex Hormones: Gonad and Adrenal Estrogen Progesterone Dihydrotestosterone Testosterone