EXTRAADRENAL EFFECTS OF METYRAPONE INCLUDE INHIBITION OF THE 11-OXOREDUCTASE ACTIVITY OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE - A MODEL FOR11-HSD-I DEFICIENCY

BACKGROUND AND OBJECTIVE Previous studies suggesting effects of metyra pone on extra-adrenal corticosteroid metabolism have involved signific ant alterations in plasma cortisol. We have therefore studied effects of metyrapone on urinary excretion of steroids in a group of patients treated concurrently with hydrocortisone so that changes in plasma cor tisol were minimized. DESIGN Replacement doses of hydrocortisone (30 m g/day) were given concurrently with metyrapone (2-4 g/day) for 2 weeks . Blood samples were taken and 24-hour urinary steroid collections wer e made at baseline and after 1 and 2 weeks of treatment. PATIENTS Subj ects were 6 female patients with major depression from a trial of mety rapone as an antidepressant. MEASUREMENTS Urinary steroid profiles wer e measured by gas chromatography; plasma cortisol and urinary free cor tisol were measured by fluorescence immunoassay. RESULTS Plasma cortis ol levels were not significantly decreased by treatment, while excreti on of 11-deoxycortisol metabolites increased eightfold after 2 weeks i ndicating that concurrent hydrocortisone administration had not suppre ssed the adrenal. Ratios reflecting 11 beta-hydroxy/11-oxo metabolites of cortisol were significantly decreased, consistent with inhibition of the 11-oxoreductase activity of 11 beta-hydroxysteroid dehydrogenas e (11-HSD). Other changes included significant decreases in the rates of 5 alpha vs 5 beta and of 20 alpha vs 20 beta reduction of corticost eroids. CONCLUSIONS Metyrapone has multiple effects on extra-adrenal c orticosteroid metabolism and is the only agent we know of which select ively inhibits 11-oxoreductase. Metyrapone thus provides a model for 1 1-HSD I deficiency and a tool for in-vitro studies of cortisol-cortiso ne interconversion. The results also suggest mechanisms whereby cortic osteroid effects can be regulated separately from corticosteroid synth esis.