GDF9, Kisspeptin-10, FGF21 and Irisin as a Biomarker Panel in Female Infertility

Abstract

This case-control study compared serum growth differentiation factor 9 (GDF9), kisspeptin-10, fibroblast growth factor 21 (FGF21), and irisin among women with unexplained infertility, women with polycystic ovary syndrome (PCOS)-associated infertility, and fertile controls, and evaluated their relationships with reproductive and metabolic characteristics and their diagnostic performance. Seventy-five women aged 20–40 years attending Samarra General Hospital, Iraq (March–May 2025) were enrolled: 25 fertile controls, 25 with unexplained infertility, and 25 with PCOS-associated infertility. Clinical, hormonal, and metabolic data were recorded, and the four biomarkers were measured by enzyme-linked immunosorbent assay. Groups were compared by one-way ANOVA with Tukey post hoc testing, correlations by Spearman’s coefficient, and discrimination by receiver operating characteristic (ROC) analysis. GDF9 was lower in unexplained infertility (67.4 ± 17.2 pg/mL) but higher in PCOS (143.6 ± 25.7 pg/mL) than in controls (116.8 ± 21.5 pg/mL; P < 0.001), whereas kisspeptin-10, FGF21, and irisin increased progressively from controls through unexplained infertility to PCOS (all P < 0.001). Kisspeptin-10 correlated with LH (ρ = 0.62) and AMH (ρ = 0.58), while FGF21 and irisin correlated with BMI and HOMA-IR (ρ = 0.51–0.67). Kisspeptin-10 had the highest individual area under the curve (AUC 0.86), and the combined four-biomarker model reached an AUC of 0.93 (95% CI 0.86–0.98; sensitivity and specificity 88%). Female infertility is thus accompanied by a distinct oocyte–neuroendocrine–metabolic biomarker profile, with GDF9 changing in opposite directions in the two phenotypes and kisspeptin-10, FGF21, and irisin elevated in both, most markedly in PCOS. The combined panel outperformed every single marker and warrants external validation.