Induction of Hepatic Testosterone A-Ring Reductase by Medroxyprogesterone Acetate*

Administration of medroxyprogesterone acetate (MPA) to male rats causes a significant (2-3-fold) increase in the activity of hepatic testosterone A-ring reductase. This was demonstrated by employing assays that measured an increase in disappearance of testosterone and/ or an increase in its reduced metabolites. Progesterone and its derivatives were also capable of increasing the reductase activity. Fasting or fed state, castration or adrenalectomy did not interfere with the effect of MPA, nor did the administration of phenobarbital or cortisol cause a rise in the reductase level. MPA also significantly increased the rate of reduction of Δ4-androstenedione, cortisol, progesterone and MPA itself (all Δ4-3-ketosteroids) when used as substrates in vitro. Cytoplasmic fractionation revealed that the MPA stimulated increase in reductase activity is restricted to the microsomes, indicating that only the Sa-oxidoreductase activity is affected. Simultaneous administration of actinomycin-D with MPA resulted in a complete inhibition of the increase in reductase activity while the baseline enzyme activity remained unaltered. Kinetic studies performed on enzymes derived from saline and M.PA treated rat livers revealed a significant difference in the maximum velocities but an identical Km for both testosterone and NADPH substrates. MPA, when used in a mixture with testosterone in vitro acted as a competitive inhibitor of the reduction of testosterone. The inhibition was apparent for both basal and MPA induced enzymes with identical K,. It was concluded that the MPA mediated testosterone Aring reductase activity is due to enzyme induction as a result of enhanced enzyme protein synthesis. Two categories of Δ4-3-ketosteroids were proposed: A. those, which are both inducers and substrates of A-ring reductases (i.e., progesterone and its derivatives) and B. those, which do not induce but are substrates of A-ring reductases (i.e., cortisol). (Endocrinology90: 1252, 1972)