Onapristone (ZK 98.299): a potential antiprogestin for endometrial contraception.

ABSTRACT

PIP: Antiprogestin drugs such as RU 486 (mifepristone), ZK 98.299 (onapristone), and HRP 2000 block progesterone action at the receptor level. They bind to progesterone and glucocorticoid receptors, which leads to an antagonistic instead of an agonistic response. Treatment with these antiprogestins, depending upon the dose, retards endometrial development and impairs gonadotropin release, thereby blocking ovulation. The hypothalamus, pituitary, and endometrium, however, differ in their sensitivity to the antiprogestins, with the endometrium being sensitive to doses which do not seem to affect ovulation. The authors report on their study of the effects of onapristone upon the fertility; menstrual cycle length; duration of menses; serum estradiol, progesterone, and cortisol concentrations; and endometrial morphologic features in adult bonnet monkeys for four-seven consecutive cycles. The study was undertaken to assess the feasibility of using onapristone as a contraceptive agent and to determine its mechanism of action. Onapristone was dissolved in benzyl benzoate and then diluted in castor oil (1:10, vol/vol). 0.5 ml of the vehicle was used to administer each dose subcutaneously. Five monkeys were treated subcutaneously with the vehicle, four monkeys each with 2.5 mg of onapristone, and five each with 5 mg of onapristone. The study found low-dose onapristone treatment throughout the menstrual cycle to prevent pregnancy without disturbing the menstrual cycle and ovulation in the majority of cycles. Anovulation and luteal insufficiency did, however, occur in some animals during prolonged treatment. The contraceptive effect in the ovulatory cycles seems mainly related to the retardation of endometrial development resulting in the inhibition of endometrial receptivity. The authors find it likely that a dose or treatment regimen of onapristone which will inhibit endometrial receptivity and prevent implantation without affecting the menstrual cycle even on prolonged treatment could be identified.