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


METHODS
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.


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


METHODS
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.
Metabolic Studies Section, Institute of Psychiatry, London, UK.
P W
PW
Raven
S A
SA
Checkley
N F
NF
Taylor
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000201:enzymology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000627:therapeutic use* / Q000652:urine; D006913:Hydroxysteroid Dehydrogenases / Q000172:deficiency* / Q000378:metabolism; D007527:Isoenzymes; D008797:Metyrapone / Q000627:therapeutic use*; D008875:Middle Aged; D008954:Models, Biological; D010088:Oxidoreductases / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D007527:Isoenzymes; D010088:Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone; D008797:Metyrapone