Hormonal therapies for endometriosis-associated pain: inflammatory limitations and pharmacological challenges

Endometriosis is a chronic inflammatory and estrogen-dependent disease in which pain remains the leading cause of impaired quality of life. Hormonal therapies constitute the cornerstone of medical management and include progestins, combined estrogen-progestin contraceptives, gonadotropin-releasing hormone (GnRH) agonists and antagonists, selective estrogen and progesterone receptor modulators, and aromatase inhibitors. Although these treatments effectively suppress ovarian function and reduce estrogen-dependent lesion activity, their clinical benefits are frequently limited by adverse effects, contraceptive implications, and symptom recurrence after treatment discontinuation. Increasing evidence indicates that the persistence of endometriosis-associated pain cannot be explained solely by hormonal dysregulation. A sustained inflammatory microenvironment, characterized by innate immune cell activation, pro-inflammatory cytokine production, and neuroimmune interactions, contributes to peripheral and central sensitization, thereby limiting the effectiveness of therapies targeting endocrine pathways alone. These disease-driven mechanisms provide a biological explanation for the heterogeneous response to hormonal treatment observed in clinical practice. This review summarizes the mechanisms of action, clinical efficacy, safety profile and limitations of current hormonal therapies for endometriosis-associated pain. In addition, it discusses the inflammatory and neuroimmune mechanisms underlying persistent pain and highlights the rationale for combining endocrine therapies with emerging anti-inflammatory and immunomodulatory strategies. Such integrated approaches may improve long-term pain control, reduce recurrence, and contribute to more personalized management of endometriosis.