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

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Abstract
The antifertility effect of RMI 12,936 [17.beta.-hydroxy-7.alpha.-methylandrost-5-en-3one] in the rat is 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 significant recution on day 9. An isomer of RMI 12,936, Isomer 201, presumed to be 7.alpha.-methyltestosterone, has antifertility and uterotrophic activities in rats similar to those of RMI 12,936. Unlike RMI 12,936 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. RMI 12,936 inhibits progesterone synthesis, possibly by acting as an alternative substrate for ovarian .DELTA.53-ketosteroid isomerase, and that the product is probably a competitive antagonist of progesterone at the receptor level.

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