Steroid hormones are synthesized and secreted in response to hormonal signals. The corticosteroids and androgens are made in different regions of the adrenal cortex and are secreted into blood in response to different signals. [Note: The adrenal medulla makes catecholamines (see p. 285).] 1. Cortisol: Its production in the middle layer (zona fasciculata) of the adrenal cortex is controlled by the hypothalamus, to which the pituitary gland is attached (Fig. 18.26). In response to severe stress (for example, infection), corticotropin-releasing hormone (CRH), produced by the hypothalamus, travels through capillaries to the anterior lobe of the pituitary, where it induces the production and secretion of adrenocorticotropic hormone (ACTH), a peptide. ACTH stimulates the adrenal cortex to synthesize and secrete the glucocorticoid cortisol, the stress hormone. [Note: ACTH binds to a membrane G protein–coupled receptor, resulting in cyclic AMP (cAMP) production and activation of protein kinase A ([PKA] see p. 94). PKA phosphorylates and activates both the esterase that converts cholesteryl ester to free cholesterol and StAR protein.] Cortisol allows the body to respond to stress through its effects on intermediary metabolism (for example, increased gluconeogenesis) and the inflammatory and immune responses (which are decreased). As cortisol levels rise, the release of CRH and ACTH is inhibited. [Note: The reduction of cortisol in CAH results in a rise in ACTH that causes adrenal hyperplasia.] 2. Aldosterone: Its production in the outer layer (zona glomerulosa) of the adrenal cortex is induced by a decrease in the plasma Na+/potassium (K+) ratio and by the hormone angiotensin II (Ang-II). Ang-II (an octapeptide) is produced from angiotensin I ([Ang-I] a decapeptide) by angiotensinconverting enzyme (ACE), an enzyme found predominantly in the lungs but also distributed widely in the body. [Note: Ang-I is produced in the blood by cleavage of an inactive precursor, angiotensinogen, secreted by the liver. Cleavage is catalyzed by renin, made and secreted by the kidneys.] Ang-II binds to cell surface receptors. However, in contrast to ACTH, its effects are mediated through the phosphatidylinositol 4,5bisphosphate pathway (see p. 205) and not by cAMP. Aldosterone’s primary effect is on the kidney tubules, where it stimulates Na+ and water uptake and K+ excretion (Fig. 18.27). [Note: An effect of aldosterone is an increase in blood pressure. Competitive inhibitors of ACE are used to treat renin-dependent hypertension.] 3. Androgens: Both the inner (zona reticularis) and middle layers of the adrenal cortex produce androgens, primarily dehydroepiandrosterone and androstenedione. Although adrenal androgens themselves are weak, they are converted by aromatase (CYP19) to testosterone, a stronger androgen, in the testes and to estrogens in the ovaries (primarily) of premenopausal women. [Note: Postmenopausal women produce estrogen at extragonadal sites such as the breast. Aromatase inhibitors are used in the treatment of estrogen-responsive breast cancer in these women.]
C. Gonadal steroid hormones