Synergistic inhibitory effects of tetramethylpyrazine and evodiamine on endometriosis development

Endometriosis (EMS) belongs to a gynecological disorder with inflammation and the existence of endometrial-like tissues beyond the uterus, often leading to infertility and pelvic pain. Estrogen receptor β (ERβ) is significantly expressed in endometriosis (EMS) and recognized as a promising therapeutic target for EMS treatment by inhibiting ERβ activity. In this study, we investigated the potential mechanisms for tetramethylpyrazine (TMP)-mediated ERβ suppression, and the synergistic inhibitory effect of TMP and evodiamine (EVO) on ERβ expression and EMS development. We found that TMP suppresses ERβ expression by reducing the association of Oct3/4 with the ERβ promoter and decreasing Oct3/4 protein levels without affecting Oct3/4 transcript levels. A minimum dosage of 10 µM TMP is required to inhibit ERβ expression. Neither TMP (5 µM) nor EVO (2 µM) alone had any effect, but their combination synergistically inhibited ERβ expression and modulated related cellular processes, including redox balance, mitochondrial function, inflammation, and proliferation. Additionally, the combination of TMP (10 mg/kg body weight) and EVO (5 mg/kg) synergistically inhibited ERβ expression and EMS development in the mouse model. In conclusion, TMP suppresses ERβ expression by reducing the association of Oct3/4 with the ERβ promoter. Neither TMP nor EVO alone effectively suppresses ERβ in both laboratory and live organism models. However, their combination synergistically inhibits ERβ expression and EMS development, suggesting a potential therapeutic strategy for EMS using TMP and EVO.