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

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Abstract
Summary: BACKGROUND AND OBJECTIVE Previous studies suggesting effects of metyrapone on extra‐adrenal cortico‐steroid 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 11β‐hydroxyl 11‐oxo metabolites of cortisol were significantly decreased, consistent with inhibition of the 11‐oxoreductase activity of 11β‐hydroxysteroid dehydrogenase (11‐HSD). Other changes included significant decreases in the rates of 5αvs 5β and of 20αvs 20β 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.