EXTRAADRENAL MINERALOCORTICOSTEROID FORMATION-METABOLISM

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The extraglandular formation of bioactive steroid hormones from plasma-borne precursors is recognized as an important endocrinologic phenomenon in physiologic and pathophysiologic processes in humans. The most recently discovered example of the formation of a potent steroid hormone in extraglandular tissues is the biosynthesis of deoxycorticosterone (DOC) from plasma progesterone. It also is recognized that biologically active steroid hormones may be formed in situ in tissue sites of action. This also is true in the case of the extraglandular formation of DOC because extraadrenal steroid 21-hydroxylase activity is demonstrable in tissues believed to be responsive to the action of mineralocorticosteroids, e.g., kidney, skin intestine, and lymphoid tissues. Uniquely, the transfer constant of conversion of plasma progesterone to DOC among persons varies strikingly (20-fold or more), but it is constant in a given person from time-to-time irrespective of the plasma concentration of progesterone. These several findings are supportive of the possibility that extraadrenal DOC may serve a role in pathophysiological processes through mechanisms that would be difficult to detect by conventional means of ascertaining the existence of mineralocorticosteroid excess. The long-range goals of the research proposed are (i) to define further the origin and metabolism of DOC, DOC-SO4, and 21-hydroxypregnenolone (and sulfate esters thereof) in women, men, and the human fetus and to identify and characterize the cytochrome P-450(s) of extraadrenal tissues that catalyzes the 21-hydroxylation of progesterone and other C21-steroid substrates and (ii) to evaluate the role of DOC that is formed in extraadrenal tissues on physiologic or pathophysiologic processes. To address the first goal, we seek to ascertain whether delta5-3beta- hydroxy-C21-steroids also serve as plasma precursors for extraadrenal 21-hydroxylase activity and whether there is more than one extraadrenal 21-hydroxylase enzyme, for example, one that preferentially catalyzes the 21-hydroxylation of delta4-3- keto-C21-steroids and another (or other) that catalyzes the 21- hydroxylation of delta-3beta-hydroxy-c21-steroids. In particular, we seek to identify the source of DOC-SO4, which is present in high concentration in human pregnancy (but is not derived from plasma DOC), and to ascertain whether delta5-3delta-hydroxy- C21-steroids can serve as plasma-borne precursors of extraadrenal DOC in men and postmenopausal women. To address the second goal, we suggest that ovulatory women are ideal models for study because of cyclic, predictable, and striking changes in progesterone production that occur during the ovarian cycle. Variations in extraadrenal DOC formation among ovulatory women may be fundamental to differences in selected responses that women experience during the premenstrual phase of the ovarian cycle. In particular, we ask whether there is a role for extraadrenal DOC in the pathogenesis of the premenstrual syndrome.