Adrenal Corticoids Are Synthesized from Cholesterol; the Critical Difference in the Activity of These Corticoids Is Related to the Hydroxyl Group on C-17 of Glucocorticoids
The synthesis of adrenal steroids involves the classic pathways for steroid biosynthesis. As indicated previously, cholesterol is the major starting material for the synthesis of steroid hormones.
Cholesterol is readily available to the steroid- Synthesizing cells because it is stored in large quantities in ester form within lipid droplets in these cells. One of the initial steps in steroid formation is the hydrolysis of the ester. The first step in steroid synthesis involves an enzyme that cleaves the carbon side chain from the steroid molecule, leaving a C-21 steroid known as pregnenolone. This step occurs within the mitochondrion (Figure 34-8). The synthesis of all steroid hormones, regardless of their form, utilizes pregnenolone in the synthetic pathway (see Figure 33-5).The critical aspect of adrenal corticoid synthesis, which differentiates adrenal corticoids from the progesterone family of steroids, is a hydroxylation step at C-21 (directed by a C-21 hydroxylase). The difference between the mineralocorticoids (aldosterone) and the glucocorticoids (cortisol) is a hydroxyl group on C-17, which is part of the glucocorticoid molecule. As expected, cells of the zona fasciculata and zona reticularis have the hydroxylating enzyme for C-17 (17α-hydroxylase), whereas cells of the zona glomerulosa do not have this enzyme. Both aldosterone and cortisol have hydroxyl groups on C-11. Because of the marked difference in biological activity of the mineralocorticoids and glucocorticoids, it is useful to view the zona glomerulosa as an endocrine organ that is distinct from the zona fasciculata and zona reticularis.
Two intermediate compounds in the synthesis of aldosterone have significant adrenocortical activity. I I-Deoxycorticosterone has significant mineralocorticoid activity, although it is secreted in relatively small amounts. Corticosterone, the immediate precursor to aldosterone, is a relatively important glucocorticoid in animals, although its potency is less than that of cortisol.
In adrenal cortical cells, biosynthetic pathways allow some synthesis of androgens and estrogens. Although the amount of sex steroids produced by the adrenal cortex under normal conditions is low, significant amounts can be synthesized under pathological conditions.