Cholesterol and the steroid production pathway

Cholesterol is the building block of steroid hormones. All steroid-producing organs with the exception of the placenta can synthesize cholesterol from acetate. Under most circumstances, however, local synthesis cannot meet demand and circulating cholesterol must be used. The major carriers of cholesterol in the bloodstream are the low-density lipoproteins (LDLs). LDL is removed from the blood by steroidogenic cells using cell surface receptors that recognize specific surface proteins on LDL called apoproteins. Once in the cell, cholesterol is carried through a sequence of enzymatic changes to produce a final product that belongs to one of the major classes of steroid hormones: progestins, androgens and estrogens (sex), glucocorticoids (sugar) and mineralocorticoids (salt). All steroid-producing tissues use a common sequence of precursor molecules and enzymes (Fig. 2.1). Tissue specificity is conferred by the presence or absence of specific enzymes in the sequence. For instance, the gonads differ from the adrenal glands in that ovaries and testes do not express the 21-hydroxylase or 11β-hydroxylase enzymes that are necessary to produce corticosteroids. Therefore, the gonads only produce three classes of steroids: progestins, androgens and estrogens.

During conversion of cholesterol to steroid metabolites, the number of total carbon atoms decreases sequentially. Progestins have 21 carbons (C-21); androgens have 19 carbons (C-19); and estrogens have 18 carbons (C-18). Thus, progestins are obligatory precursors of both androgens and estrogens. Likewise, androgens are obligatory precursors of estrogens.

Most of the steroidogenic enzymes are members of the cytochrome P450 class of oxidases. A single mitochondrial protein P450scc, the cholesterol side chain cleavage enzyme, mediates all steps in the conversion of cholesterol to pregnenolone. The activity of this protein represents the rate-limiting step for the entire steroid pathway. Not surprisingly, it is also the major site of tropic hormone stimulation. Genetic mutations of P450scc are very rare and usually lethal. No steroid hormones can be produced by an individual with an inactive P450scc enzyme.

Once pregnenolone is formed, steroid production can proceed down one of two paths, through either progesterone or 17α-hydroxypregnenolone. All but two of the enzymes responsible for producing the steroid hormones are packaged within the endoplasmic reticulum, together with other members of the P450 system. The biosynthetic units are very tightly linked together, thereby ensuring that very few of the steroid intermediates leave the cell. This packaging is also highly efficient in that it can convert an entire class of steroids to another. Thus, 17,20-desmolase will convert all progestins to androgens, and aromatase will convert all androgens but dihydrotestosterone (DHT) to estrogens.