Studies on the mechanisms of action of progesterone antagonists.

Antigestagens of RU-38.486-type were investigated in different pregnancy models reflecting either "endometrial" or "myometrial" effects. All antigestagens were found effective inhibitors of nidation in guinea pigs. This was evidence for a role of embryonic progesterone in the earliest events of nidation. No comparable inhibition could be obtained by ovariectomy. A more complex pharmacology was found around day 43 p.c. when the abortion was brought about by expulsion. RU-38.486 had marginal activity only. Antigestagens with reduced anti-glucocorticoid activity tended to induce abortions more effectively and faster. Some antigestagen-prostaglandin combinations were found of extreme abortifacient activity. Surprisingly it seemed that anti-glucocorticoid properties in addition to (or rather than) antigestagenic activities bring about this synergism with prostaglandin. The employed guinea pig model for pregnancy termination thus characterized two types of antigestagens: ideal ones for monotherapy or combined use with prostaglandin, respectively. Antigestagens induced a highly sensitive myometrium to prostaglandin-stimulation (Sulprostone) and a marked softening and dilatation of the cervix. Antigestagens perfectly prime the genital tract for oxytocic stimuli, they do not overcome the arrested uterine prostaglandin-secretion of the pregnant uterus at the same time.