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figure Role of ACTH in Regulation and Action of Adrenocorticoids

Adrenocorticotropic hormone maintains normal secretory activity of the inner zones of the cortex. After removal of the pituitary, the z. fasciculata and z. reticularis atrophy. However, the zona glomerulosa remains largely unaffected. In cells of all three zones, ACTH interacts with a specific membrane receptor and triggers production of cAMP by activating adenylate cyclase (see top figure). cAMP activates protein kinase A, which catalyzes the phosphorylation of a variety of proteins and, thereby, modifies their activity. The critical consequence of increased cAMP production in the adrenocortical cell is that the rate limiting step of pregnenolone formation from cholesterol is stimulated.

ACTH is not an important regulator of aldosterone production, although it its required for optimal secretion. Angiotensin II, whose production is regulated by the kidney stimulates production of aldosterone (see bottom figure). Angiotensin II reacts with specific membrane receptors on cells of the zona glomerulosa, but does not use cAMP as a second messenger. Instead, it acts through protein kinase C and calcium to promote conversion of cholesterol to pregnenolone via the same side chain cleavage enzyme.

ACTH also exerts other trophic effects on the adrenal cortex. It increases blood flow to the adrenal glands increasing oxygen and metabolic substrates to the cells, as well as, increasing capacity of the gland to deliver newly secreted hormone to the general circulation. ACTH maintains the functional integrity of the adrenal cortex: chronic stimulation increases its mass by cellular hypertrophy. Angiotensin II produces hypertrophy of zona glomerulosa cells which atrophy in its absence.

Stimulation with ACTH increases steroid hormone secretion within 1 to 2 min, and peak rates are seen in about 15 min. Steroid hormones are not stored. Hence their rate of synthesis is reflected in their rate of secretion. Because steroid hormones are lipid-soluble they readily diffuse through plasma membranes and, probably, enter the circulation through simple diffusion down their concentration gradient. Thus, the increase in blood flow resulting from ACTH stimulation further enhances the secretory capacity of the adrenal by keeping the gradient steep.
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