The Antigonadotropic Action of Testosterone but not 7α‐Methyl‐19‐Nortestosterone Is Attenuated Through the 5α‐Reductase Pathway in the Castrated Male Rat Pituitary Gland

Abstract

ABSTRACT: The enzyme 5α‐reductase plays a significant role in the prostate to amplify the action of testosterone (T) by converting it to a more potent androgen, dihydrotestosterone (DHT). The role of 5α‐reductase in the testosterone feedback inhibition of gonadotropin secretion from the pituitary has not been elucidated. Therefore, we investigated the role of 5α‐reductase on T action in in vitro and in vivo models. Castration has been reported to increase the 5α‐reductase activity in pituitary glands. Hence, the effect of castration duration on the conversion of T to DHT by pituitary homoge‐nates and the responsiveness of pituitary monolayer cell cultures to gonadotropin‐releasing hormone (GnRH) challenge exposure were investigated. Incubation of [3H]‐T with pituitary homogenatesshowed that the conversion of T to 5α‐reduced metabolites was two‐to threefold greater in pituitaries from rats who had been castrated for 14 days compared with those castrated for 1 day. In addition, the GnRH‐stimulated release of LH from monolayer cell cultures of pituitaries from rats castrated for 1 day was twofold greater, whereas that from rats castrated for 2 weeks was six‐ to sevenfold greater compared with basal luteinizing hormone (LH) release. Hence we used rats castrated for 2 weeks to elucidate the role of 5α‐reductase in T feedback inhibition. The inhibitory effects of the androgens T, 19‐nortestosterone (19‐NT), and 7α‐methyl‐19‐nortestosterone (MENT) at 3 different 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. All 3 androgens showed dose‐dependent inhibition of LH release. MENT showed the greatest inhibition, followed by 19‐NT and T. In the presence of finasteride (a 5α‐reductase inhibitor), the inhibition of LH released by T and 19‐NT were significantly greater. The inhibitory effect of MENT, which does not undergo 5α‐reduction, was not altered by finasteride. In an in vivo study, rats castrated for 2 weeks received T with or without finasteride. There was a significantly greater suppression of serum LH in rats receiving T plus finasteride compared with those receiving T alone. These results suggested that 5α‐reductase in the pituitary is not obligatory for the inhibitory action of T on gonadotropin secretion in the castrated rat. The action of MENT, a nonreducible androgen, on the pituitary is not affected by 5α‐reductase.