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Cholesterol (Precursor of Steroid Hormones)

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Cholesterol (Precursor of Steroid Hormones) Unit IV – Problem 5 – Biochemistry: Biosynthesis of Steroid Hormones & Steroid Hormone Receptor - Cholesterol (precursor of steroid hormones): It is composed of 27 carbons with four rings and a hydroxyl group (-OH) attached at carbon 3 and is found in cell membrane (why?) → to regulate membrane fluidity and permeability. Cholesterol from diet will be packaged in chylomicrons (in the gut) to be transported into lymph and then into plasma. Cholesterol is synthesized de novo (from scratch) in the cytosol of the liver. - Steroid Hormones: The rate-limiting irreversible step in steroid hormone synthesis is represented by the conversion of cholesterol into pregnenolone (which contains 21 carbons) via the enzyme desmolase. How to name steroids? 21 carbons: pregnanes (pregnenolone). 19 carbons: androstanes (testosterone). 18 carbons: estranges (estrogen). - Classes of steroid hormones: Mineralocorticoids: from zona glomerulosa of adrenal cortex. Glucocorticoids: from zona fasciculate of adrenal cortex. Androgens: from testes and zona reticularis of adrenal cortex. Estrogens and progestogens: from ovaries and placenta. - Synthesis of steroid hormones: Enzyme Sex Mineralocorticoids Cortisol Labs Presentation deficiency hormones XY: Hypertension, 17α- pseudohermaphroditism ↑ ↓ ↓ hypokalemia and hydroxylase XX: lack secondary ↓DHT sexual development Hypotension, Infancy: salt wasting; hyperkalemia, ↑ 21- childhood precocious ↓ ↓ ↑ renin activity and ↑ hydroxylase puberty; XX: 17- virilization hydroxyprogesterone ↓ aldosterone, ↑ 11- 11β- Hypertension (low deoxycorticosterone ↓ ↑ XX: virilization hydroxylase renin) (results in ↑ BP) - Glucocorticoids (natural): Synthesized in zona fasciculate of adrenal cortex. Regulated by: Corticotrophin-releasing hormone (CRH) which is secreted from the hypothalamus and then stimulating the anterior pituitary gland to produce adrenocorticotropic hormone (ACTH) which in turn will enhance the synthesis of cortisol from zona fasciculata. Functions of cortisol (BIG FIB): ↑ Blood pressure. ↑ Insulin resistance. ↑ Gluconeogenesis, lipolysis and proteolysis. ↑ Fibroblast activity (causing striae). ↓ Inflammatory and Immune responses. ↓ Bone formation. Cushing’s syndrome (prolonged exposure to high levels of cortisol): There are three main causes: Exogenous corticosteroids (primary cause). Primary adrenal adenoma, hyperplasia or carcinoma. ACTH-secreting pituitary adenoma (Cushing’s disease). Clinical manifestations: Upper body obesity. Moon face. Increased fat around the neck (buffalo hump). Relatively slender (thin) arms and legs. Fragile skin. Weak bones. Decreased fertility (in males). Menstrual irregularities (in females). - Mineralocorticoids (aldosterone): Synthesized in zona glomerulosa of adrenal cortex. Effect: increasing blood volume and blood pressure (see the image); absorption of sodium and water; secretion of potassium and hydrogen. - Androgens: Produced by testes and zona reticularis of adrenal cortex. Dehydroepiandrosterone will be converted to androstenedione and then to testosterone in peripheral tissues (which is stimulating anabolism, male secondary sexual characteristics and spermatogenesis). - Estrogens: Produced by the ovary. Functions: controlling menstrual cycle, female secondary sexual characteristics and growth of mammary glands (development of the breast). - Progestogens: Produced by ovary and placenta. It is the hormone of pregnancy which prepares the uterus for implantation, mammary glands for lactation and regulation of lactation. - Mechanism of action of steroids (see the image): They are hydrophobic molecules which act by: 1. Diffusion through cell membrane. 2. Binding to their cytosolic receptors. 3. Diffusing to nucleus to stimulate or suppress gene expression. .
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