DEFECTIVE RING-A REDUCTION OF CORTISOL AS THE MAJOR METABOLIC ERROR IN THE SYNDROME OF APPARENT MINERALOCORTICOID EXCESS

Impaired peripheral metabolism of cortisol in the syndrome of apparent mineralocorticoid excess is currently understood to be causally related to the severe but otherwise unexplained manifestations of mineralocorticoid excess. A normally ambivalent mineralocorticoid receptor responding equally well to glucocorticoids and mineralocorticoids requires prereceptor inactivation of glucocorticoids to elicit a specific mineralocorticoid effect. The failed inactivation step in the form of the syndrome of apparent mineralocorticoid excess first described (type 1) involves the 11-beta-hydroxydehydrogenation of cortisol to cortisone. In another form of the syndrome (type 2) this conversion occurs normally in the face of otherwise similar clinical and biochemical features. Markedly decreased cortisol metabolic clearance in the type 2 form suggested impairment of a major component of that clearance, ring A reduction. A noninvasive method was developed for measuring the conversion of cortisol to tetrahydrocortisol and allotetrahydrocortisol, and this step was found to be profoundly decreased in both type 1 and type 2 forms. Thus, the major abnormality in the peripheral metabolism of cortisol common to both forms involved ring A reduction, not 11-beta-hydroxydehydrogenation. Since ring A reduction was better correlated with the manifestation of mineralocorticoid excess in both forms of the syndrome, this step might also be a normal major prereceptor mechanism conferring mineralocorticoid specificity.