Corticosteroid biogenesis will be examined at several points along the pathway to the final hormonal products, cortisol and aldosterone. the early portion of the pathway will be examined at the point of cleavage of the side-chain of cholesterol by establishing an animal model of the defect at this locus and the determination of the mechanism of deficiency of side-chain cleavage activity. Evidence will also be sought to confirm the hypothesis that a reversible block in cholesterol side-chain desmolase occurs naturally in the human fetus. The consequences of 21-hydroxylase deficiency on the synthesis of naturally occurring mineralocorticoid antagonist will be investigated as well as the nature of the defect in aldosterone biosynthesis in this inborn error. In the case of the distal aldosterone biosynthetic defect between corticosterone and aldosterone, the mechanism by which adult patients with the Type II defect adjusts to aldosterone deficiency will be examined. The steroid pattern will also be examined in another group of patients to establish the existence of a Type I defect involving this portion of the aldosterone biosynthetic pathway. Studies will continue on the 11 Beta-hydroxyoxidoreductase equilibrium shift observed in a juvenile form of low-renin mineralocorticoid hypertension. In addition, the steroid pattern will be examined in a biochemical variant of this disorder in which the syndrome is reversed by dexamethasone. Studies on the significance of our newly discovered cortisol 18-oxidase pathway will be conducted. The usefulness of this pathway in the differential diagnosis of aldosteronoma compared to bilateral adrenocortical hyperplasia will be examined. Studies will also be carried out on the mechanism of the predominance of this pathway in autosomaldominant ACTH-dependent hyperaldosteronism. Confirmation will also be sought for the preliminary finding that the final product of the cortisol 18-oxidase pathway is 17Alpha-hydroxyaldosterone. The biological significance of the latter steroid and its contribution to the clinical picture of the disorders in which it is overproduced will be studied.