Efficacy and Safety of 48-Week Low-Dose Dienogest Treatment in Patients with Endometriosis-Associated Dysmenorrhea: A Randomized, Open-Label, Parallel-Group Trial

INTRODUCTION: Dienogest (DNG) is widely used to manage endometriosis-associated pain; however, long-term data comparing low and standard doses are limited. Therefore, this study aimed to evaluate the efficacy and safety of 48-week DNG treatment (1 mg/day vs. 2 mg/day) in patients with endometriosis-related dysmenorrhea (composite score). METHODS: In this randomized, open-label, parallel-group, trial, 88 patients with endometriosis were enrolled, all of whom had at least one ovarian endometriotic cyst confirmed by imaging. Other phenotypes of endometriosis, such as deep infiltrating or peritoneal lesions, were not systematically assessed and may have been present. Patients were randomized to receive either 1-mg/day or 2-mg/day DNG. The primary endpoint was the change in menstrual pain measured using a visual analog scale (VAS). Secondary endpoints included changes in the dysmenorrhea score, ovarian endometrioma volume, serum estradiol levels, bone mineral density (BMD), and menopausal symptoms. RESULTS: Both groups demonstrated a significant reduction in menstrual pain (VAS). The mean VAS scores decreased by 44.63 and 54.19 mm in the 1-mg and 2-mg groups, respectively. However, the between-group difference (- 9.57 mm; 95% confidence interval: - 22.7 to 3.56) was not above the predefined non-inferiority margin of - 15 mm; thus, non-inferiority of the 1-mg dose could not be confirmed. Improvements in dysmenorrhea scores and endometrioma volume were also observed in both groups, although greater effects were noted in the 2-mg group than in the 1-mg group. Serum estradiol suppression was comparable between the groups, whereas BMD loss was less pronounced in the 1-mg group than in the 2-mg group. CONCLUSIONS: This study did not demonstrate statistical non-inferiority of 1-mg/day DNG treatment over 2-mg/day DNG treatment for pain relief. These results suggest that the 2-mg/day dose may offer more robust analgesic effects, particularly during the early treatment phase. However, 1-mg/day DNG still showed meaningful symptom improvement with fewer adverse events than 2-mg/day DNG, supporting its potential use in selected patients requiring long-term therapy. Trial Registration Japan Registry of Clinical Trials, trial registration number: jRCTs041210016.