Navigating endometriosis diagnostic delay in 2040: Future directions in noninvasive diagnosis

Diagnostic delays in endometriosis contribute to underdiagnosis and undertreatment. The objective of this review was to evaluate existing and emerging nonsurgical diagnostic tools that, after validation, may reduce diagnostic delays. Studies were selected from a comprehensive PubMed literature search using the keywords: endometriosis, diagnosis, biomarker, imaging, and statistics. English-language studies reporting potential diagnostic performance with an area under the curve (AUC) ⩾ 0.8 and/or sensitivity and specificity ⩾ 80% were included. Of 309 studies, 91 studies investigating 81 unique diagnostic modalities met eligibility criteria. Sixty studies evaluated biomarkers in blood/serum, three in urine, three in saliva, three in leukorrhea, ten in peritoneal fluid, eleven evaluated endometrial biopsy-related markers, and twelve assessed imaging modalities. Biomarkers with the highest reported AUC included CK-19 and TNF-α in blood, urinary proteomic markers (five peptides m/z = 1433.9, 1599.4, 2085.6, 6798.0, and 3217.2 Da), salivary miRNAs (hsa-miR-135a), tRNA-Leu-AAG-01 in leukorrhea, vasoactive intestinal peptide (VIP) in endometrial nerve fibers, caldesmon levels in endometrial biopsies, and MRI-based imaging techniques. Across modalities, findings were largely derived from single-center studies with heterogeneous populations, underscoring the need for large, multicenter prospective validation studies to establish reproducibility and clinical utility.