Hormonal Dysregulation and Neuroinflammation in Endometriosis: Convergent Druggable Pathways

Endometriosis is a chronic, estrogen-dependent disorder defined by ectopic endometrial-like tissue growth, persistent inflammation, and aberrant innervation. Emerging evidence indicates that disease progression and symptom severity are driven by a reciprocal interaction between hormonal dysregulation and neuroinflammatory signaling. This narrative review synthesizes human-based mechanistic and clinical evidence on the hormonal-neuroinflammatory interface in endometriosis, drawing on peer-reviewed publications retrieved from PubMed and Scopus through November 2025. The publications comprised studies using data from patient-derived tissues, primary endometriotic cells, and clinical cohorts. Several convergent molecular nodes at this interface were identified: the prostaglandin E₂-prostaglandin E receptor 2/prostaglandin E receptor 4-aromatase axis, estrogen receptor beta-nuclear factor kappa B signaling, interleukin-6/signal transducer and activator of transcription 3-mediated fibrosis, neurotrophin pathways, transient receptor potential channels (TRPV1/TRPA1), and neurokinin 1 receptor signaling. In this integrated model, endocrine dysfunction fuels neuroinflammation, which in turn impairs steroid responsiveness. This cycle explains the frequent pain-lesion mismatch and the persistence of symptoms despite standard hormonal suppression. Targeting these druggable interface pathways enables better patient stratification and more effective combination therapies for endometriosis.