Extracellular matrix deficiency contributes to irregular uterine bleeding following progestin therapy for adenomyosis

Adenomyosis is a common gynecological disorder that causes heavy menstrual bleeding and chronic pelvic pain. Progestin-based therapy is widely used for long-term management, but irregular uterine bleeding frequently occurs and severely affects patient quality of life. The mechanisms underlying this side effect remain unclear. In this study, we performed proteomic sequencing on endometrial tissues from adenomyosis patients before progestin treatment. We found that patients who later developed irregular bleeding exhibited significantly reduced extracellular matrix and collagen levels. Cell experiments showed that matrix metalloproteinase inhibition increased collagen expression in patient-derived endometrial stromal cells. In a mouse model of progestin-induced uterine bleeding, both matrix metalloproteinase inhibition and intrauterine collagen supplementation effectively reduced bleeding. These findings indicate that insufficient extracellular matrix predisposes patients to bleeding during progestin therapy and provide potential strategies to prevent progestin-related irregular bleeding.