Diagnostic and Staging Value of Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 4, Neutrophil Gelatinase-Associated Lipocalin, and Fibronectin Type III Domain-Containing Protein 5 as Non-Invasive Biomarkers for Endometriosis

Abstract

Background: Endometriosis remains a diagnostic challenge owing to the reliance on invasive surgical confirmation. The identification of reliable serum biomarkers could facilitate earlier, non-invasive diagnosis and staging. This study aimed to evaluate the diagnostic and staging value of serum inter-alpha-trypsin inhibitor heavy chain family member 4 (ITIH4), neutrophil gelatinase-associated lipocalin (NGAL), and fibronectin type III domain-containing protein 5 (FNDC5) in women with endometriosis. Methods: This case–control study included 100 women: 50 with surgically confirmed endometriosis (27 stage I–II and 23 stage III–IV according to the revised American Society for Reproductive Medicine classification) and 50 age-matched healthy controls. Serum levels of ITIH4, NGAL, and FNDC5 were measured using ELISA.  Results: Serum ITIH4 and NGAL levels were significantly elevated in the endometriosis group compared with controls (43.60 ± 11.96 vs. 14.30 ± 2.74 ng/mL; and 135.69 ± 41.89 vs. 41.02 ± 5.82 ng/mL, respectively; both p < 0.001), whilst FNDC5 was significantly reduced (4.17 ± 1.45 vs. 8.44 ± 1.23 ng/mL, p < 0.001). For diagnosis, the AUC values were 0.998 for ITIH4, 0.954 for FNDC5, and 0.984 for CA-125. For staging, FNDC5 achieved an AUC of 0.965, ITIH4 achieved 0.916, and NGAL achieved 0.794. The combined biomarker panel yielded an AUC of 0.995 for staging. Conclusion: Serum ITIH4, NGAL, and FNDC5 demonstrate excellent diagnostic and staging performance for endometriosis and may serve as promising non-invasive biomarkers to complement current diagnostic approaches.