Evidence that a non-aromatizable metabolite of norethisterone induces estrogen-dependent pituitary progestin receptors.

Neutral reduced metabolites of norethisterone (NET) specifically interact with intracellular estrogen receptors in target organs. To determine if this interaction can effectively initiate estrogen-dependent cellular responses, the effects of an A-ring-reduced NET derivative upon the induction of cytosol-located pituitary progestin receptors (PR) and uterine growth were studied in adult castrated female rats. Different doses of 17 alpha-ethynyl-5 alpha-estran-3 beta, 17 beta-diol (3 beta, 5 alpha-NET) were s.c. administered to ovariectomized animals for 6 days. 17 beta-Estradiol (E2) and oil-treated rats served as experimental controls. Pituitary PR were labeled in vitro by a post-gradient technique using [3H]ORG-2058 as the ligand. PR binding specificity was determined by the use of an excess of radioinert steroids. The results demonstrated that administration of 3 beta, 5 alpha-NET induced specific 8-9S pituitary cytosol PR in a dose-dependent manner. Binding properties of the 3 beta, 5 alpha-NET-induced progestin binding sites (Kd = 1.0 X 10(-9) M; NBS = 1.2 X 10(-9) M) appear indistinguishable from those induced by E2. In addition, 3 beta, 5 alpha-NET administration resulted in a significant increase in uterine weight at the expense of myometrium and endometrium growth in a similar fashion to that observed in the E2-treated group. When 3 alpha, 5 alpha-epimeric alcohol (3 alpha, 5 alpha-NET) was administered, induction of pituitary PR and uterine growth were also observed although to a lesser extent. Inasmuch as the results demonstrate that neutral non-aromatizable NET metabolites induce biochemical and morphological estrogenic responses, they offer an alternative explanation for the mechanism of estrogen-like action of this synthetic contraceptive progestin.