Contraceptive trial testing a prostaglandin E2 receptor (EP2) antagonist in female monkeys

PELUFFO, MC; STOUFFER, RL; STANLEY, J; HENNEBOLD, JD; ZELINSKI, MB; LINDENTHAL, B

San Diego, California

Congreso; 68th ASRM Annual Meeting; 2012

ASRM (American Society of Reproductive Medicine)

Objective: To determine the contraceptive effect of a prostaglandin E2 receptor, EP2 subtype, antagonist in female monkeys.   Design: Contraceptive and reversibility trial using adult, cycling cynomolgus macaques. Materials and Methods: Female macaques (n=10/group) received either vehicle (Control) or an EP2 antagonist (BAY06). The drug was administered sc twice daily, as 10 mg/kg in 0.5 ml castor oil. After one month of treatment, a fertile male was added for the 5-month contraceptive trial. To assess the reversibility of antagonist actions, nonpregnant females remained housed with the male for 5 additional months after drug treatment. Females were checked daily for menstruation or mating (presence of blood or sperm, respectively in the vagina). Body weights and serum samples were obtained weekly, and estradiol (E) and progesterone (P) levels assessed. Pregnancies were confirmed by ultrasound. Results: Eight pregnancies from 10 females occurred in the control group (80 %), whereas 2 of 9 females became pregnant in the antagonist group (22 %) during treatment. One monkey in the antagonist group was removed from the trial due to a viral infection. A significant difference was observed between the control and antagonist groups (38 % vs. 6 %; p< 0.05) when pregnancies were analyzed according to the number of appropriately timed matings (around the midcycle  E rise). E and P patterns, as well as cycle length (28 ± 1 vs. 29 ± 3 days; first vs last cycle), were not altered by antagonist treatment.   Monkeys tended to lose weight during vehicle (3.0 ± 2.8 %) and drug treatment (8.5 ± 2.8%), but did not differ between groups (p=0.18). Following cessation of drug treatment, 4 of 7 females (60%) became pregnant after 1-4 appropriately timed matings. Conclusions: These data demonstrate the contraceptive effect of an EP2 antagonist in female primates without altering steroid hormone patterns or menstrual cyclicity. Moreover, fertility recovered as early as one month after ending treatment. Support: Bayer Pharma AG, U54 HD055744, P51 OD011092