Synergistic effects of melatonin and dienogest on pain relief in endometriosis: a randomized controlled trial

Objective: Endometriosis affects 5-10% of reproductive-aged women and is characterized by chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility. Standard hormonal therapies, such as dienogest, effectively manage symptoms, but are often associated with side effects and high recurrence rates after discontinuation. This study investigated the efficacy of melatonin as an adjunct to dienogest for reducing endometriosis-associated pain. Methods: Ninety-four women with ultrasonography-confirmed ovarian endometrioma were randomized 1:1 to receive melatonin+dienogest or placebo+dienogest for 6 months. Analyses were performed on both per-protocol (PP; n=52) and intention-to-treat bases (ITT; n=94). The primary outcome was dysmenorrhea measured using the visual analog scale. The secondary outcomes included dyspareunia, pelvic pain, dyschezia, quality of life (World Health Organization quality of life-brief version [WHOQOL-BREF]), and clinical symptoms (Biberoglu&Behrman [B&B] scale). Results: Dysmenorrhea scores decreased significantly more in the melatonin arm (Δ=-1.3 points; P=0.011 PP; Δ=-1.2; P=0.014 ITT). No significant between-group differences were observed in dyspareunia, pelvic pain, or dyschezia. WHOQOL-BREF scores improved by 6.5±9.2 points in the melatonin group and 5.9±8.7 in the placebo group (P=0.71). B&B composite pain scores decreased by 4.1±2.9 (melatonin) and 3.8±3.0 (placebo) (P=0.64). No serious adverse events occurred; however, vertigo was more frequent in the melatonin group (53.8% vs. 7.7%). Conclusion: Adjunctive melatonin therapy with dienogest significantly improved dysmenorrhea compared with dienogest alone. However, the addition of melatonin did not yield significant improvements in other pain domains or quality of life indices. These results support the use of melatonin as a targeted adjunct treatment for menstrual pain during endometriosis.