The use of progesterone antagonists for cervical ripening and as an adjunct to labour and delivery

The labour-inducing activity of RU486 (mifepristone) in different species including the human is relatively low in advanced stages of pregnancy. However, it increases myometrial responsiveness to prostaglandins and oxytocin and it also induces cervical ripening. The labour-inducing and labour-conditioning activities of various progesterone antagonists (antiprogestins) and the progesterone synthase inhibitor epostane were analysed at the pre-term period of pregnancy in various animal models. In guinea pigs and Tupaja belangeri (species showing no spontaneous progesterone withdrawal prior to parturition) onapristone, which is a 'pure' progesterone receptor antagonist, effectively induced parturition at pre-term but not during mid-pregnancy. On the other hand, antiprogestins showing mixed agonist/antagonist activities (e.g. RU486, lilopristone, ZK 112993) and epostane were only partially effective in inducing pre-term parturition in both species. In guinea pigs, all anti-progestins increased myometrial responsiveness to oxytocin and prostaglandins, onapristone being approximately 10 times more effective than RU486. This effect was seen at doses of antiprogestins which alone did not induce labour at all. The increase in oxytocin response in onapristone-primed guinea pigs was not accompanied by an increase in myometrial oxytocin receptors, although a marked increase in myometrial gap junctions occurred. Antiprogestins induced a pronounced cervical ripening in pregnant and non-pregnant guinea pigs and rats independently of the action of prostaglandins. The infiltration of polymorphonuclear granulocytes, macrophages and mast cells into the cervix after antiprogestin treatment indicates that cytokines or other chemotactic agents may mediate this effect. In guinea pigs in late pregnancy, the cytokines interleukin (IL)-8 and IL-1 beta induced a cervical ripening morphologically similar to the antiprogestin effect. Our data indicate that progesterone may control uterine quiescence by reducing myometrial responsiveness, i.e. by down-regulating gap junctions and inhibiting cervical maturation, but not by suppressing the release of endogenous uterine stimulants which may be controlled by other factors. Antiprogestins may be used to prepare the uterus for oxytocin- and prostaglandin-induction of labour without influencing uterine motor function. Onapristone may be a preferable antiprogestin as an adjunct to labour and delivery at term because it has high labour-conditioning potency, no progesterone-agonistic activity, short half-life and low antiglucocorticoid activity.