The opioid system in endometriosis: implications for endometrial receptivity and reproductive outcomes

Endometriosis, a chronic inflammatory disease affecting 10-15% of women of reproductive age, remains a leading cause of female subfertility. While current management strategies focus on surgical excision and hormonal suppression, these approaches often fail to address the underlying reproductive dysfunction or are incompatible with pregnancy. In this context, the opioid system emerges as a factor of interest, though research has traditionally focused on it almost exclusively as a target for pain management. This review synthesizes existing evidence to provide a novel perspective on how the opioid system regulates endometrial function and reproductive health. We discuss the presence and cyclical fluctuations of opioid receptors and peptides within the uterine environment, highlighting their influence on tissue remodeling, angiogenesis, and apoptosis-processes that are frequently dysregulated in endometriosis. Despite the scarcity of recent clinical studies, the integration of these "non-analgesic" opioid pathways suggests that they may be active participants in the pathogenesis of the disease rather than mere bystanders in pain signaling. By connecting classical opioid research with modern challenges in endometriosis-associated infertility, this work identifies critical knowledge gaps and potential non-hormonal targets. Understanding these pathways is essential for developing therapeutic strategies that manage chronic pain while safeguarding the reproductive health of these patients.