Genetic diseases of steroid metabolism.

All major classes of biologically active steroid hormones (progestins, mineralocorticoids, glucocorticoids, and sex steroids) are synthesized from cholesterol through 11 different bioconversions. With the exception of 5 alpha-reductase, all the enzymes mediating these reactions fall into two classes, cytochromes P450 and short-chain dehydrogenases. Cytochromes P450 are heme-containing membrane-bound proteins with molecular weights of approximately 50,000 that utilize molecular oxygen and electrons from NADPH-dependent accessory proteins to hydroxylate substrates. Short-chain dehydrogenases have molecular weights of 30,000-40,000, have tyrosine and lysine residues at the active site, and remove a hydride from the substrate, transferring the electrons of the hydride to NAD+ or NADP+. In most cases, this reaction is reversible so that the dehydrogenase can also function as a reductase under appropriate conditions. Inherited disorders in enzymes required for steroid biosynthesis have varying effects. Defects that prevent cortisol from being synthesized are referred to collectively as congenital adrenal hyperplasia. Because the enzymes required for cortisol biosynthesis in the adrenal cortex are in many cases required for the synthesis of mineralocorticoids and/or sex steroids, these classes of steroids may also not be synthesized normally. Thus, cholesterol desmolase and 3 beta-hydroxysteroid dehydrogenase deficiencies affect synthesis of all classes of steroids in both the adrenals and gonads. Steroid 21-hydroxylase deficiency, the most common cause (> 90% of cases) of congenital adrenal hyperplasia, can affect both mineralocorticoid and glucocorticoid synthesis, but androgen secretion is usually abnormally high due to shunting of accumulated precursors into this pathway. Excessive secretion of androgens and mineralocorticoids occurs in 11 beta-hydroxylase deficiency (the second most frequent form of congenital adrenal hyperplasia). Mineralocorticoid excess is also seen in 17 alpha-hydroxylase deficiency, but in this disorder sex steroid synthesis is defective. All defects that affect estrogen synthesis (deficiencies of cholesterol desmolase, 3 beta-hydroxysteroid dehydrogenase, 17 alpha-hydroxylase, aromatase, and 17 beta-hydroxysteroid dehydrogenase) are very rare, suggesting that the inability to synthesize placental estrogens may adversely affect fetal survival. A number of enzymes are expressed at sites of steroid action and regulate the amount of active steroid available to steroid receptors. Steroid 5 alpha-reductase converts testosterone to the more active dihydrotestosterone. Deficiency of this activity leads to incomplete development of male genitalia; 17 beta-hydroxysteroid dehydrogenase deficiency has similar phenotypic effects.(ABSTRACT TRUNCATED AT 400 WORDS)