Menstrual Effluent in the Pathogenesis and Diagnosis of Endometriosis—A Systematic Review

<b>Background:</b> The individual and social burden of endometriosis is high, and the diagnosis is usually delayed by 7-10 years. Menstrual effluent (ME) represents an accessible and uniquely informative biofluid. This systematic review evaluated the pathophysiological relevance and diagnostic potential of ME in endometriosis. <b>Methods</b>: Following PRISMA 2020 guidelines, we systematically searched PubMed/MEDLINE, EBSCOhost (Academic Search Premier, APA PsycArticles, APA PsycInfo, CINAHL, and MEDLINE), Semantic Scholar, and Google Scholar from inception to 30 November 2025. Original studies analyzing human ME or ME-derived cells in women with endometriosis versus controls were eligible. We extracted study design, analytic methods, diagnostic accuracy metrics (AUC, sensitivity, and specificity), mechanistic pathways, and risk of bias (QUADAS-2 for diagnostic, and NIH tools for mechanistic studies). <b>Results:</b> Thirty-five studies were included. ME consistently captured key pathophysiological mechanisms of endometriosis, including impaired decidualization and progesterone resistance, immune dysregulation with diminished cytotoxic clearance, pro-angiogenic and invasive phenotypes, heightened stem/progenitor cell survival, cellular senescence and DNA damage, and altered extracellular-vesicle signaling. Diagnostic accuracy was reported in nine studies. Aromatase mRNA showed the highest performance (AUC 0.977), followed by TGF-β1 (AUC 0.973) and IGFBP1 (AUC 0.92). A lipidomic two-marker model achieved an AUC of 0.87. All diagnostic assessments were based on case-control studies; none conducted prospective validation. <b>Conclusions:</b> ME is a biologically relevant, non-invasive, and patient-acceptable biospecimen reflecting core endometriosis mechanisms and yielding promising diagnostic accuracy. The highest diagnostic performance was achieved for assays reflecting steroidogenic and growth-factor pathways (e.g., aromatase and TGF-β1). Standardization and prospective validation are needed before clinical adoption.