17 α-HYDROXYPROGESTERONE AND 21-DESOXYHYDROCORTISONE; THEIR METABOLISM AND POSSIBLE ROLE IN CONGENITAL ADRENAL VIRILISM 1

Abstract

Although virilism due to bilateral adrenal hyper-plasia is a relatively rare condition, this syndrome has stimulated much interest and research. Previ-ous work has demonstrated that the adrenals of patients with this disease respond differently from the normal when they are further stimulated with exogenous ACTH. Lewis and Wilkins (1), Bartter and his associates (2), and Jailer, Lou-chart, and Cahill (3) have shown that although the administration of ACTH to patients with con-genital adrenal hyperplasia results in a further increase in the already elevated urinary 17-keto-steroids, other responses are different from those seen in normal subjects. For example, following the administration of ACTH to patients with adrenal virilism there is no appreciable rise in uri-nary corticoids, measured as reducing or formalde-hydogenic steroids, no decrease in the circulating eosinophils, and no sodium retention. Further-more, Kelley, Ely, and Raile (4), and then sub-sequently Bayliss, Broadbent, and Steinbeck (5), Bongiovanni, Eberlein, and Cara (6) and Christy, Wallace, and Jailer (7) have shown that there is no increase in plasma corticoids in the great ma-jority of these patients under these circumstances. That the administration of cortisone or hydro-cortisone to patients with congenital virilism re-sults in a fall in the urinary 17-ketosteroids and a regression in the characteristic virilizing symptoms of this disease was first demonstrated by Wilkins, Lewis, Klein, and Rosemberg (8) and confirmed by others (2, 9, 10). It is generally accepted that this effect of cortisone is mediated through the inhibition of ACTH secretion by the pituitary. The underlying steroidal pathology in the adrenals of these patients has been the subject of some speculation. Bartter, Albright, Forbes, Leaf, "Aided by Grants from the National Institutes of Health, The U.S.P.H.S., and the Upjohn Company. Dempsey, and Carroll (2) have postulated that this condition is characterized by an increased se-cretion of adrenal androgen(s) and a decreased production of hydrocortisone. Consequently, an increased amount of ACTH would be required to stimulate the adrenal to secrete the normal amount of hydrocortisone needed for homeostasis. Ex-cessive amounts of circulating ACTH have been found in the blood of such patients (Sydnor, Kelley, Raile, Ely, and Sayers [ 11]). Apparently, the excessive amounts of adrenal androgen (s) are incapable of inhibiting ACTH secretion. Jailer (12) suggested that the defect in this syn-drome may reside in the enzymatic hydroxyla-tion mechanisms which had previously been shown by Hechter, Zaffaroni, Jacobsen, Levy, Jeanloz, Schenker, Pincus, Hayano, and Dorfman (13-15) to be essential for the biosynthesis of Com-pounds B and F from simpler steroidal intermedi-ates. This group had previously demonstrated that surviving adrenal tissue possesses hydroxyl-ases which are capable of introducing hydroxyl groups into certain C-21 steroids at carbons 11, 17 and 21, to yield the adrenal hormones: corti-costerone and hydrocortisone (15). The simplest C-21 precursor which can be hydroxylated in this fashion may be pregnenolone, a substance which has been proven to be an intermediate in the for-mation of these hormones from cholesterol (16, 17). The possibility that one of the important meta-bolic defects in congenital adrenal hyperplasia may be the inability of the adrenal gland to accomplish the complete enzymatic hydroxylation of the ster-oidal precursors has been suggested (12). Such a failure might result in the formation of partially hydroxylated secretory products, some of which could be androgenic in nature or others which