Tumor Necrosis Factor-Alpha (TNF-α) Levels in Women With Polycystic Ovary Syndrome (PCOS): A Systematic Review and Meta-Analysis of Observational Studies

Abstract

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine. Evidence relating circulating TNF-alpha concentrations to polycystic ovary syndrome (PCOS) is heterogeneous and has not been synthesized comprehensively for clinical interpretation. We aim to systematically review and meta-analyze observational studies comparing circulating TNF-alpha levels between women with PCOS and healthy controls, and to examine sources of between-study heterogeneity and the robustness of the findings. We conducted a systematic search of electronic databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidance. Eligible studies reported serum TNF-alpha concentrations in reproductive-age women with PCOS and matched controls. Two reviewers independently screened records, extracted data, and assessed risk of bias. Where appropriate, we pooled continuous outcomes using random-effects meta-analysis (standardized mean difference (SMD)) with restricted maximum likelihood tau2 estimation and Hartung-Knapp adjustment. Prespecified subgroup and meta-regression analyses explored effects of assay type, body mass index (BMI) matching, diagnostic criteria (Rotterdam vs. other), and geographic region. Small-study effects were assessed using contour-enhanced funnel plots, Egger's test, and selection-model sensitivity analyses. Overall, circulating TNF-alpha was modestly higher in women with PCOS than in controls (SMD = 0.48; 95% CI = 0.17-0.79; p = 0.0026). Between-study heterogeneity was substantial (I2 = 89.5%, tau2 = 0.2772). Funnel-plot inspection and Egger's test showed no clear small-study bias (t = -0.96; p = 0.36); trim-and-fill imputed four studies and produced a larger adjusted SMD (0.80; 95% CI = 0.44-1.16), but heterogeneity remained high. Key subgroup findings include the following: 1) obese cohorts (k = 11) showed a significant but small effect (SMD = 0.39; 95% CI = 0.09-0.69), whereas evidence in lean cohorts (k = 2) was inconclusive (SMD = 0.97; 95% CI = -0.23 to 2.17); 2) by assay, ELISA studies (k = 10) were significant (SMD = 0.50), and chemiluminescence studies (k = 2) were consistent (SMD = 0.42, I2 = 0%); and 3) country of origin materially moderated effects (Q = 53.17, p < 0.0001), with larger effects in studies from India and China and null findings in some Iranian studies. Leave-one-out sensitivity analyses produced pooled SMDs of 0.39-0.55. Meta-regression for mean BMI, age, and sample size did not explain heterogeneity. In conclusion, circulating TNF-alpha concentrations were higher in women with PCOS than in healthy controls; this finding is biologically plausible and consistent across studies. These findings suggest TNF-alpha may serve as an inflammatory biomarker reflecting metabolic dysregulation in PCOS. Copyright © 2025, Verma et al.