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Peptide gonadotropin-releasing hormone (GnRH) antagonists are widely used to suppress the reproductive endocrine axis in women with endometriosis, fibroids, and other nonmalignant reproductive hormone-dependent disease states. Unlike treatment of sex-steroid-dependent tumors, management of endometriosis and fibroids does not require complete gonadal suppression; reduction of estrogen to low levels is sufficient. This phase I, randomized, double-blind, placebo-controlled, sequential dose escalation study evaluated the safety, tolerability, pharmacokinetics, and effect of single dose and 7-day doses of elagolix, a novel, orally available nonpeptide GnRH antagonist on gonadotropins and estrogen in healthy premenopausal women. The study subjects were 55 healthy, regularly cycling women ranging between 18 and 39 years. Of these, 30 participated in and completed the single-dose escalation phase of this study (the first study arm) and 25 participated in and 24 completed the multiple dose-escalation phase of this study (the second study arm). Cohorts in the first study arm received a single dose of elagolix (25, 50, 100, 200, or 400 mg) or placebo. Of the 25 women in the second study arm, 18 were given once-daily doses of elagolix (50, 100, or 200 mg) or placebo for 7 days, and 7 received 100 mg or placebo twice daily for 7 days. Initial administration was at 7 ± 1 days after onset of menses. Serum concentrations of LH, FSH, and estradiol were determined by validated methods. Elagolix was well tolerated during both the single-dose and multiple-dose escalation for 7 days. No clinically significant adverse events occurred in any of the cohorts. Oral bioavailability was rapid and serum levels of the gonadotropins declined quickly. Circulating LH was suppressed more than FSH. In the first study arm, estradiol was suppressed by 24 hours in all cohorts receiving at least 50 mg/day. In the second study arm, elagolix maintained low estradiol levels (17 ± 3 to 68 ± 46 pg/mL) throughout the 7 day treatment in most cohorts during the late follicular phase. Drug effects were rapidly reversed after discontinuation. These data show that an oral nonpeptide GnRH antagonist, elagolix, can achieve dose-related pituitary and gonadal suppression in premenopausal women and may prove to be useful for management of nonmalignant reproductive hormone-dependent disease states.