Onapristone (ZK 98.299): a potential antiprogestin for endometrial contraception
- PMID: 7573244
- DOI: 10.1016/0002-9378(95)90341-0
Onapristone (ZK 98.299): a potential antiprogestin for endometrial contraception
Abstract
Objectives: The effects of the antiprogestin onapristone (ZK 98.299) on fertility; menstrual cycle length; duration of menses; serum estradiol, progesterone, and cortisol concentrations; and endometrial morphologic features were studied in adult bonnet monkeys.
Study design: Five animals were treated subcutaneously with the vehicle and another nine with either 2.5 (n = 4) or 5 mg of onapristone per animal (n = 5). Treatment was initiated on day 5 of the first treatment cycle, and thereafter onapristone was administered every third day for four to seven consecutive cycles. The females were placed with adult males during the periovulatory period, which was assessed by frequent analysis of serum estradiol concentrations. In the final treatment cycle an endometrial biopsy was performed on day 8 after a midcycle estradiol peak in the ovulatory cycle, or around day 20 if the cycle was anovulatory. Blood samples for estradiol, progesterone, and cortisol measurement were collected every third day, except for the periovulatory period when sampling was more frequent.
Results: Each of the five animals treated with the vehicle became pregnant: one in the first, three in the second, and one in the third mated cycle, whereas only one of nine treated with onapristone became pregnant. Four animals treated with 2.5 mg of onapristone for 17 cycles and another four treated with a 5 mg dose for 21 cycles did not conceive. In eight animals that did not conceive the first three treatment cycles of six were ovulatory, and in the remaining two animals two cycles of each were ovulatory. During treatment the mean menstrual cycle length was not altered significantly; however, in one it was shortened and in another two it was prolonged. Similarly, the mean duration of menses was not significantly affected, but in some cycles it was reduced. Moreover, there was only slight bleeding in some treatment cycles. Ovulation occurred in 30 of 45 treatment cycles, including the final treatment cycle during which the biopsy was taken, as indicated by serum estradiol and progesterone concentrations. In some of the ovulatory cycles prolonged treatment suppressed luteal activity; however, in the ovulatory cycles the duration of follicular and luteal phases was not significantly affected. In the anovulatory cycles there was a delayed increase in serum estradiol concentrations, suggesting a partial inhibition of folliculogenesis. In treated animals endometrial growth and development was retarded and rendered out of phase. In animals treated with the higher (5 mg) onapristone does the endometrial glands had partially regressed, the secretory activity was blocked, and stromal compaction was evident. The treatment had no significant effect on serum cortisol levels.
Conclusions: This study demonstrates that low-dose onapristone treatment throughout the menstrual cycle prevents pregnancy without disturbing the menstrual cycle and ovulation in the majority of cycles. However, anovulation and luteal insufficiency occurred in some animals during prolonged treatment. The contraceptive effect in the ovulatory cycles seems primarily related to the retardation of endometrial development resulting in the inhibition of endometrial receptivity. It appears likely that a dose or treatment regimen of onapristone that will inhibit endometrial receptivity and prevent implantation without affecting the menstrual cycle even on prolonged treatment could be identified.
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.
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