{"paper_id":"b1ace6c3-83ff-4f3c-a587-79e08653290b","body_text":"The Interplay Between Estrogen, Immune Dysfunction, and Chronic Inflammation in the Pathophysiology of Endometriosis: A Critical Narrative Review\nAuthors/Creators\nDescription\nEndometriosis is a chronic, estrogen-dependent inflammatory disorder affecting approximately ten percent of reproductive-age women worldwide. Despite its high prevalence and profound impact on quality of life, the biological mechanisms that sustain and amplify the disease remain incompletely understood. This critical narrative review synthesises peer-reviewed evidence published predominantly between 2013 and 2026 to examine how estrogen signalling, immune cell dysfunction, and peritoneal inflammation form a self-amplifying pathological circuit in endometriosis. Ovarian and locally synthesised estrogen acts through genomic receptors, particularly estrogen receptor beta (ERbeta), to confer apoptosis resistance upon ectopic stromal cells and to drive macrophage recruitment via the NF-kappaB/CCL2 axis. Phenotypically altered peritoneal macrophages, expanded regulatory T cells, functionally impaired natural killer cells, and activated mast cells collectively sustain an immune-tolerant microenvironment in which ectopic lesions survive and proliferate. The resulting inflammatory milieu, characterised by elevated interleukin-6, interleukin-8, tumour necrosis factor-alpha, and prostaglandin E2, feeds back to stimulate aromatase (CYP19A1) expression in ectopic tissue, thereby completing a self-reinforcing loop. Epigenetic silencing of ERalpha and progesterone receptor genes prevents effective progesterone-mediated immune regulation and further entrenches the disease. Current hormonal treatments interrupt individual nodes of this circuit but rarely achieve durable remission. Emerging evidence supports multi-target approaches incorporating Janus kinase inhibitors, natural compounds, and immunomodulatory strategies. This review offers a unified mechanistic framework to guide future research into biomarker discovery and therapeutics for endometriosis.","source_license":"CC0","license_restricted":false}