Reversible Reproduction of the Abnormal Cortisol Metabolite Pattern of Cirrhosis by Administration of Norethandrolone

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Abstract
Administration of norethandrolone (17-ethyl-19-nortestosterone), 60 mg daily p.o., to 2 subjects with normal liver function, reversibly altered the previously normal cortisol metabolite pattern (studied after iv tracer doses of 4-14C-cortisol) to one resembling that reported in cirrhosis. Conversion to tetrahydrocortisone was decreased by half, conversion to cortolone (20α) was increased 3-fold, and there was increased formation of Reichstein's substances U and epi-U. The decreased glucuronic acid conjugation of cortisol metabolites observed in cirrhosis was not reproduced by norethandrolone. Norethandrolone also produced 2 changes of cortisol metabolism not found in cirrhosis: increase in the ratio of 11-hydroxy to 11-keto metabolites, and decrease in cortisol production. These changes were fully developed within 2 weeks, and regressed completely within 2–3 months after stopping the steroid. This observation provides an approach to studying mechanisms of abnormal cortisol metabolism in cirrhosis. Since norethandrolone administration and cirrhosis both produce the anatomical changes of intrahepatic cholestasis, but norethandrolone does not produce the additional anatomical abnormalities of cirrhosis, it appears that intrahepatic cholestasis may be the initiating cause of the cortisol metabolite alteration of cirrhosis.

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