Reversible Reproduction of the Abnormal Estradiol Metabolism of Biliary Obstruction by Administration of Norethandrolone1

Abstract

Administration of norethandrolone (17α-ethyl-19-nortestosterone), 60 mg daily p.o., to 2 subjects with normal liver function reversibly altered the previously normal estradiol metabolite pattern to one resembling that reported in total extrahepatic biliary obstruction. The changes were apparent within 5–6 weeks and regressed completely within 2–3 months after stopping the steroid. There was a 3-fold increase in estrone formation, a fall in the formation of estriol to less than one third of control, and a 2-fold increase in estradiol recovery. The ratio of 16α-hydroxyestrone to estriol increased 3-fold. These changes indicate that norethandrolone depresses both steps of the 16α-hydroxylation pathway of estrogen metabolism (estrone→16α-hydroxyestrone→estriol). Similar depression of this pathway occurs regularly in cirrhosis and in extrahepatic biliary obstruction, and it is concluded that cholestasis is the cause of this alteration. Additional abnormalities of estradiol metabolism (i.e., decreased 2-oxygenation and increased catechol O-methylation) occur regularly in cirrhosis and inconstantly in extrahepatic biliary obstruction, but not with norethandrolone administration. It is concluded that these latter abnormalities reflect damaged microsomal function, which occurs regularly in cirrhosis, inconstantly in extrahepatic biliary obstruction and not appreciably with norethandrolone administration.