Effect of Metformin Monotherapy on Circulating Leptin Levels in Polycystic Ovary Syndrome: A Systematic Review and Bayesian Meta-analysis of Randomized Placebo Controlled Trials

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine condition that presents with reproductive, metabolic, and cardiometabolic disturbances. Altered adipokine activity, including changes in circulating leptin, a macromolecule, may contribute to its clinical features. Metformin is widely used to improve insulin resistance and reproductive outcomes in this population, yet its effect on leptin has remained uncertain. This systematic review and meta-analysis evaluated randomized controlled trials comparing metformin with placebo for changes in circulating leptin levels in women with PCOS. Six trials with seven effect size estimates met the inclusion criteria. Classical random effects modeling showed that metformin produced a significant reduction in leptin compared with placebo, with a pooled standardized mean difference of − 1.60 and a confidence interval from − 2.49 to − 0.72. Baseline leptin levels were similar between the groups. Bayesian analysis supported these findings, yielding a posterior mean effect of − 1.38 with a credible interval from − 2.30 to − 0.25. Heterogeneity was substantial and metaregression identified baseline body mass index and fasting insulin as significant moderators. The direction of benefit remained stable in sensitivity analyses and no evidence of publication bias was detected. The certainty of evidence was rated as moderate, reflecting consistent findings across analytical approaches and acceptable methodological quality of the trials. These results indicate that metformin lowers circulating leptin levels as compared to placebo in women with PCOS, with the magnitude of effect influenced by metabolic characteristics. Further research is needed to clarify the clinical significance of leptin modulation in this population.