Synthesis involves shortening the hydrocarbon chain of cholesterol and hydroxylating the steroid nucleus. The initial and rate-limiting reaction converts cholesterol to the 21-carbon pregnenolone. It is catalyzed by the cholesterol side-chain cleavage enzyme, a cytochrome P450 (CYP) mixed function oxidase of the inner mitochondrial membrane (see p. 149) that is also known as P450scc and desmolase. NADPH and O2 are required for the reaction. The cholesterol substrate can be newly synthesized, taken up from lipoproteins, or released by an esterase from cholesteryl esters stored in the cytosol of steroidogenic tissues. The cholesterol moves to the outer mitochondrial membrane. An important control point is the subsequent movement from the outer to the inner mitochondrial membrane. This process is mediated by StAR (steroidogenic acute regulatory) protein. Pregnenolone is the parent compound for all steroid hormones (see Fig. 18.25). It is oxidized and then isomerized to progesterone, which is further modified to the other steroid hormones by CYP protein–catalyzed hydroxylation reactions in the SER and mitochondria. A defect in the activity or amount of an enzyme in this pathway can lead to a deficiency in the synthesis of hormones beyond the affected step and to an excess in the hormones or metabolites before that step. Because all members of the pathway have potent biologic activity, serious metabolic imbalances occur with enzyme deficiencies (see Fig. 18.25). Collectively, these disorders are known as the congenital adrenal hyperplasias (CAH), because they result in enlarged adrenals. [Note: Addison disease, due to autoimmune destruction of the adrenal cortex, is characterized by adrenocortical insufficiency.]
B. Adrenal cortical steroid hormones