Extra-adrenal effects of metyrapone include inhibition of the 11-oxoreductase activity of 11 beta-hydroxysteroid dehydrogenase: a model for 11-HSD I deficiency.

BACKGROUND AND OBJECTIVE

Previous studies suggesting effects of metyrapone on extra-adrenal corticosteroid metabolism have involved significant 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 cortisol were minimized.

DESIGN

Replacement doses of hydrocortisone (30 mg/day) were given concurrently with metyrapone (2-4 g/day) for 2 weeks. Blood samples were taken and 24-hour urinary steroid collections were made at baseline and after 1 and 2 weeks of treatment.

PATIENTS

Subjects were 6 female patients with major depression from a trial of metyrapone as an antidepressant.

MEASUREMENTS

Urinary steroid profiles were measured by gas chromatography; plasma cortisol and urinary free cortisol were measured by fluorescence immunoassay.

RESULTS

Plasma cortisol levels were not significantly decreased by treatment, while excretion of 11-deoxycortisol metabolites increased eightfold after 2 weeks indicating that concurrent hydrocortisone administration had not suppressed 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 dehydrogenase (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 corticosteroids.

CONCLUSIONS

Metyrapone has multiple effects on extra-adrenal corticosteroid metabolism and is the only agent we know of which selectively inhibits 11-oxoreductase. Metyrapone thus provides a model for 11-HSD I deficiency and a tool for in-vitro studies of cortisol-cortisone interconversion. The results also suggest mechanisms whereby corticosteroid effects can be regulated separately from corticosteroid synthesis.