A-ring reduction enhances the antigonadotropic potency of norethisterone

Abstract

To assess whether structural modifications on the A-ring of norethisterone (NET) could modify its antigonadotropic potency, comparative studies using NET, 5\g=a\-dihydro NET (5\g=a\-NET) and its 3\g=b\,5\g=a\ and 3\g=a\,5\g=a\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 3\g=b\,5\g=a\-NET and 5\g=a\-dihydro-NET exhibited a significantly greater gonadotropic inhibiting activity as compared with that of their parent compound. The simultaneous administration of tamoxifen with 3\g=b\,5\g=a\-NET resulted in a significant diminution of its antigonadotropic potency, particularly for LH. These data indicate that the potent antigonadotropic effect of 3\g=b\,5\g=a\-NET metabolite was mediated via oestrogen receptors. The LH inhibitory activity of 5\ g=a\ \ x=r eq-\ dihydro-NET was not suppressed by the non-steroidal antioestrogen administration, thus suggesting that 5\ g=a\ \ x=r eq-\ 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. Norethisterone (NET), l7ct-ethynyl-l7ß-hydroxy-4-estren-3-one, has been extensively used as a progestogen in a number of hormonal contracep¬ tive formulations. It has been recognized that NET is the active compound of its ester deriva¬ tives, as well as, of other synthetic progestogens as norethinodrel, lynestrenol and ethynodiol diacetate (Murugesan et al. 1973;Kamyab et al. 1968;Howard et al. 1975). Metabolic studies have dis¬ closed that NET undergoes extensive in vivo transformations, particularly reductions on its Aring, to form dihydro and tetrahydro derivatives.Indeed, these compounds have been isolated from serum of women on contraceptive NET therapy (Braselton et al. 1979).Previous studies from this laboratory have indi¬ cated that the mode of action of NET differs from that of natural progesterone (Pérez-Palacios et al. 1981), suggesting that under certain circumstan¬ ces, the metabolic conversion of NET to its re¬ duced metabolites is necessary to express its acti¬ vity in humans. Indeed, Larrea et al. (1983, 1984), demonstrated that NET exhibits a potent estro¬ gen-like biological effect in spite of its lack of interaction with the oestrogen receptor. Further¬ more, the in vivo NET aromatization has re¬ mained a controversial and still unsolved issue (Breuer 1977; Barvieri et al. 1983). Recently, Chávez et al. (1985) demonstrated the stereospecific interaction of -ring reduced NET derivatives with intracellular putative steroid receptors other than those of progesterone.