Effects of RMI 12,936, a synthetic antiprogestational steroid, in the rat.
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.
D000367:Age Factors; D000737:Androstenols / Q000494:pharmacology*; D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003338:Corpus Luteum / Q000187:drug effects; D003429:Cross Reactions; D005260:Female; D005298:Fertility / Q000187:drug effects; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D007044:Hysterectomy; D007536:Isomerism; D008777:Methyltestosterone / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011374:Progesterone / Q000096:biosynthesis / Q000097:blood; D045167:Progesterone Congeners / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011555:Pseudopregnancy / Q000187:drug effects; D051381:Rats; D014599:Uterus / Q000187:drug effects
D000737:Androstenols; D006063:Chorionic Gonadotropin; D045167:Progesterone Congeners; D011374:Progesterone; C010528:17-beta-hydroxy-7 alpha-methyl-androst-5-en-3-one; D005640:Follicle Stimulating Hormone; D008777:Methyltestosterone