Further studies on the antigonadotropic mechanism of action of norethisterone

To examine the molecular mechanisms involved in the antigonadotropic effects of norethisterone (NET) and two of its A-ring reduced metabolites the 5 alpha-norethisterone (5 alpha-NET) and the 3 beta, 5 alpha-norethisterone (3 beta, 5 alpha-NET) at the neuroendocrine level, a series of experiments were undertaken in adult castrated rats. Animals were primed either with 0.2 mg of tamoxifen (Tam) for 4 consecutive days or 1.0 mg of cyproterone acetate (CPA) for 7 days followed by a single subcutaneous injection of 0.5 mg of NET, 5 alpha-NET or 3 beta, 5 alpha-NET. Four hours later, they were sacrificed and blood obtained for the measurement of immunoreactive serum LH and FSH. The results indicated that antiestrogen (Tam) pretreatment precluded the inhibitory effects of NET and the 3 beta, 5 alpha-NET but not those of the 5 alpha-NET derivative. Pretreatment with CPA did not modified the antigonadotropic action of the 3 beta, 5 alpha-NET metabolite but it markedly reduced the inhibitory action of the 5 alpha-NET, thus indicating that in the experimental model used, the antigonadotropic effects of NET, are in part the result of its metabolic conversion to its A-ring reduced metabolites. While the 5 alpha-NET displayed an androgenic effect, the 3 beta, 5 alpha-NET exhibited estrogen-like effect at the neuroendocrine level.