Inhibition of ovulation and pharmacologic mechanism of action of relugolix combination therapy

To assess the effects of relugolix combination therapy (CT) on ovarian function in healthy, ovulatory, premenopausal women.

This was an open-label, single-cohort, pharmacodynamic, safety, and tolerability study consisting of five study periods: a pretreatment period to confirm ovulatory status, three 28-day treatment periods, and a posttreatment period to assess the duration of time required to return to ovulation after treatment discontinuation. Ovarian function was assessed by transvaginal ultrasonography and serum hormone concentrations.

Healthy, premenopausal female participants, 18-35 years of age.

Relugolix CT (relugolix 40 mg, with estradiol 1 mg and norethindrone acetate 0.5 mg) was taken orally once daily for 84 days.

The primary endpoint was the proportion of women in whom ovulation was inhibited during the 84-day treatment period. Secondary endpoints included proportion of women in whom ovulation was inhibited within each treatment period, number of women who fulfilled the Landgren criterion; characterization of follicular diameter, hormone concentrations, and endometrial thickness; time to return to ovulation after treatment discontinuation; proportion of women who returned to ovulation within 36 days after treatment discontinuation; safety and tolerability.

Seventy women were enrolled in the study, 67 of whom completed treatment. Treatment with relugolix CT inhibited ovulation in 100% of women who completed treatment (95% confidence interval, 94.6-100.0). Systemic concentrations of luteinizing hormone and follicle-stimulating hormone were suppressed and maintained at low concentrations during treatment, with an absence of a preovulatory luteinizing hormone surge. Median estradiol concentrations across all women were consistently maintained between 36.8 and 39.1 pg/mL (range, 12.1-121.1 pg/mL) during treatment. All individual progesterone concentrations during treatment remained below 1.57 ng/mL (5 nmol/L). After treatment discontinuation, all women ovulated or initiated menses. The mean time to return to ovulation was 23.5 days. Treatment was generally well tolerated with no safety or tolerability issues identified.

Relugolix CT inhibits ovulation, which, in the context of this study, was achieved within the first cycle after treatment initiation. The rapid and predictable return of ovarian activity and ovulation after treatment discontinuation is advantageous for patients who wish to conceive thereafter.