Uterine leiomyomas are common, nonmalignant, gonadal steroid-dependent, monoclonal neoplasms. They are reported in about 70–80% of premenopausal women. Although many women with uterine leiomyomas are asymptomatic, nearly 25% develop symptoms, like heavy menstrual bleeding and pain, requiring treatment.Relugolix combination therapy (relugolix-CT), an oral once-daily nonpeptide, gonadotropin-releasing hormone receptor antagonist (relugolix 40 mg) with estradiol 1 mg and norethindrone acetate 0.5 mg, is the approved drug for managing uterine leiomyoma–associated heavy menstrual bleeding for up to 2 years (U.S.) or moderate-to-severe uterine leiomyoma symptoms without limitation on the duration of use (E.U.). A recent study assessed the effect of once-daily relugolix combination therapy compared with placebo on moderate-to-severe pain in women with uterine leiomyomas and heavy menstrual bleeding by conducting two replicate, multinational, double-blind, 24-week, randomized, phase 3 studies (LIBERTY 1 and 2).Premenopausal women with uterine leiomyoma–associated heavy menstrual bleeding (80 mL or greater per cycle for two cycles or 160 mL or greater during one cycle) were included. Additionally, a predefined secondary objective determined the effect of relugolix-CT on moderate-to-severe uterine leiomyoma–associated pain in the pain subpopulation (women with maximum pain scores of 4 or higher on the 0–10 numerical rating scale at baseline, with pain score reporting compliance of 80% (ie, 28 days or more over the last 35 days of treatment)). This critical secondary endpoint was described as the proportion of women achieving minimal-to-no uterine leiomyoma–associated pain (maximum numerical rating scale score 1 or lower) at week 24; menstrual and nonmenstrual pain was assessed in prespecified secondary analyses. The observations were as follows-In both trials, 509 women were randomized to either relugolix-CT or placebo.54.4% of the women met pain subpopulation requirements. 45.2% of women achieved minimal-to-no pain with relugolix-CT compared with 13.9% with placebo. The proportions of women with minimal-to-no pain during menstrual days and nonmenstrual days were markedly greater with relugolix-CT compared with placebo.Thus, over 24 weeks, relugolix-CT greatly reduced moderate-to-severe uterine leiomyoma–associated pain, rendering a more prominent effect on menstrual pain. Hence, relugolix-CT delivers clinically meaningful effects on uterine leiomyoma–associated pain.Stewart EA, Lukes AS, Venturella R, et al. Relugolix Combination Therapy for Uterine Leiomyoma–Associated Pain in the LIBERTY Randomized Trials. Obstetrics & Gynecology. 2022 ;10.1097/AOG.0000000000004787doi: 10.1097/AOG.0000000000004787