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 hysterectomized rats. Similar
hypertrophy followed administration to pseudopregnant, immature gonadotrophin-treated, and immature hysterectomized and gonadotrophin-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 significantly reduction on Day 9. An isomer of
RMI 12,936, Tsomer 201, presumed to be 7alpha-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-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
progesterone synthesis, possibly by acting as an alternative substrate for ovarian delta(5)3-ketosteroid
isomerase, and that the product is probably a competitive antagonist of
progesterone at the receptor level.