A-ring reduction enhances the antigonadotropic potency of norethisterone

Abstract

Abstract. To assess whether structural modifications on the A-ring of norethisterone (NET) could modify its antigonadotropic potency, comparative studies using NET, 5α-dihydro NET (5α-NET) and its 3β,5α and 3α,5α tetrahydro derivatives in castrated adult rats were undertaken. The antigonadotropic effect of these compounds was evaluated by measuring the serum and pituitary immunoreactive concentrations of LH and FSH following their chronic sc administration to animals depleted of progesterone receptors. The results demonstrated that 3β,5α-NET and 5α-dihydro-NET exhibited a significantly greater gonadotropic inhibiting activity as compared with that of their parent compound. The simultaneous administration of tamoxifen with 3β,5α-NET resulted in a significant diminution of its antigonadotropic potency, particularly for LH. These data indicate that the potent antigonadotropic effect of 3β,5α-NET metabolite was mediated via oestrogen receptors. The LH inhibitory activity of 5α-dihydro-NET was not suppressed by the non-steroidal antioestrogen administration, thus suggesting that 5α-NET might exert its effect via androgen receptors. The overall data were interpreted as demonstrating that metabolic conversion products of NET exhibit potent antigonadotropic effect. The data are consistent with an A-ring enhancement of the antigonadotropic potency of this synthetic progestin and open an alternate approach to the development of fertility regulating agents.