Effects of RMI 12,936, a synthetic antiprogestational steroid, in the rat

Summary. The antifertility effect of RMI 12,936 in the rat is shown to be reversible. Luteal hypertrophy followed administration to pregnant, but not to pregnant hyster-ectomized rats. Similar hypertrophy followed administration to pseudopregnant, immature gonadotrophin-treated, and immature hysterectomized and gonadotrophin\x=req-\ treated rats, but the ovarian sensitivity to gonadotrophins was reduced or unchanged, suggesting that the ovarian hypertrophy is due to a direct ovarian action of RMI 12,936. Progesterone production on Day 15 of pregnancy by the enlarged ovaries following RMI 12,936 administration on Day 8 was not significantly different from control levels, but there was a highly significant reduction on Day 9. An isomer of RMI 12,936, Isomer 201, presumed to be 7\g=a\-methyltestosterone, was shown to have antifertility and uterotrophic activities in rats similar to those of RMI 12,936. Unlike RMI 12,936, however, Isomer 201 did show significant cross\x=req-\ reaction in the competitive protein-binding assay for progesterone and did not cause significant reduction in peripheral progesterone levels on Day 9 after administration on Day 8. From this and previous evidence it is concluded that RMI 12,936 inhibits pro-gesterone synthesis, possibly by acting as an alternative substrate for ovarian \g=D\53\x=req-\ ketosteroid isomerase, and that the product is probably a competitive antagonist of progesterone at the receptor level