The antigonadotropic action of testosterone but not 7 alpha-methyl-19-nortestosterone is attenuated through the 5 beta-reductase pathway in the castrated male rat pituitary gland

The enzyme 5 alpha-reductase plays a significant role in the prostate to am plify the action of testosterone (T) by converting it to a more potent andr ogen, dihydrotestosterone (DHT). The role of 5 alpha-reductase in the testo sterone feedback inhibition of gonadotropin secretion from the pituitary ha s not been elucidated. Therefore, we investigated the role of 5 alpha-reduc tase on T action in in vitro and in vivo models. Castration has been report ed to increase the 5 alpha-reductase activity in pituitary glands. Hence, t he effect of castration duration on the conversion of T to DHT by pituitary homogenates and the responsiveness of pituitary monolayer cell cultures to gonadotropin-releasing hormone (GnRH) challenge exposure were investigated . Incubation of [H-3]-T with pituitary homogenates showed that the conversi on of T to 5 alpha-reduced metabolites was two- to threefold greater in pit uitaries from rats who had been castrated for 14 days compared with those c astrated for I day. In addition, the GnRH-stimulated release of LH from mon olayer cell cultures of pituitaries from rats castrated for I day was twofo ld greater, whereas that from rats castrated for 2 weeks was six- to sevenf old greater compared with basal luteinizing hormone (LH) release. Hence we used rats castrated for 2 weeks to elucidate the role of 5 alpha-reductase in T feedback inhibition. The inhibitory effects of the androgens T, Ig-nor testosterone (19-NT), and 7 alpha-methyl-19-nortestosterone (MENT) at 3 dif ferent concentrations (10(-9), 10(-7), and 10(-5) mol/L) on GnRH-stimulated LH release from monolayer cell cultures of pituitaries from rats castrated for 2 weeks were examined. Alt 3 androgens showed dose-dependent inhibitio n of LH release. MENT showed the greatest inhibition, followed by 19-NT and T. In the presence of finasteride (a 5 alpha-reductase inhibitor), the inh ibition of LH released by T and 19-NT were significantly greater. The inhib itory effect of MENT, which does not undergo 5 alpha-reduction, was not alt ered by finasteride. In an in vivo study, rats castrated for 2 weeks receiv ed T with or without finasteride. There was a significantly greater suppres sion of serum LH in rats receiving T plus finasteride compared with those r eceiving T alone. These results suggested that 5 alpha-reductase in the pit uitary is not obligatory for the inhibitory action of T on gonadotropin sec retion in the castrated rat. The action of MENT, a nonreducible androgen, o n the pituitary is not affected by 5 alpha-reductase.