To test the feasibility of administering the GnRH antagonist [(Ac-pClPhe1,pClPhe2,DTrp3,DArg6,DAla10) GnRH] intermittently to inhibit ovulation, this agent was given to normal ovulatory cynomolgus monkeys once weekly for 4 weeks. Ovulation was blocked in all females (eight of eight) throughout the 32 study weeks and resumed within 14.3 +/- 3.8 (+/- SEM) days in six of eight primates. Interestingly, mean tonic serum estradiol levels were not significantly reduced during treatment. Conversely, although midcycle levels of estradiol were not found, moderate estradiol levels occurred but they did not elicit preovulatory LH surges during the week after GnRH antagonist injection. In a second study directed at clarifying the mechanism(s) by which estrogen-induced LH surges were blocked, monkeys received GnRH antagonist in the early through the midfollicular phase of the menstrual cycle during which an estrogen (n = 3) or a GnRH (n = 4) challenge test was given on cycle day 6. Among monkeys receiving estradiol benzoate or a bolus dose of GnRH during the GnRH antagonist regimen, only those given GnRH (four of four monkeys) had increased LH secretion. These responses were similar to those of control monkeys (n = 3). Indeed, the pituitary was refractory (three of three monkeys) to estrogen-positive feedback for the LH surge. These findings indicate the potential utility of intermittent GnRH antagonist treatment to achieve contraception by ovulation inhibition, without creating a severely hypoestrogenic milieu attendant with the risks of negative sequelae effecting bone calcium loss, hot flushes, and atrophy of estrogen-dependent genital tissues.