Efficacy and Safety of Letrozole Versus Clomiphene Citrate in Polyendocrine Metabolic Ovarian Syndrome: A Systematic Review, Meta-analysis, and GRADE Assessment of Randomized Controlled Trials

Abstract

Polycystic ovarian syndrome (PCOS) is a hormonal and metabolic disorder and a common cause of infertility among women. After multiple global consensus processes, the name was changed to polyendocrine metabolic ovarian syndrome (PMOS) in 2026. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and was registered with PROSPERO (CRD420261426754). A thorough, systematic search was conducted across multiple databases from 2012 to 2026. The quality of the included studies was assessed using the Risk of Bias tool, and the certainty of the evidence for each outcome was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Pooled effect estimates were calculated using a fixed-effect model; meta-analyses were performed, and forest plots were generated. The degree of heterogeneity was assessed by using the I 2 statistic. A pooled analysis using a fixed-effect model demonstrated that letrozole (LTZ) was associated with a significantly higher pregnancy rate than clomiphene citrate (CC) (risk ratio [RR] = 1.52, 95% confidence interval [CI] 1.29–1.78, Z = 5.10, p < 0.00001). There was no evidence of significant heterogeneity among included studies (χ 2 = 3.59, df = 6, p = 0.73, I 2 = 0%). Ovulation rates were higher in LTZ as compared with CC (RR = 1.13, 95% CI 1.07-1.19, Z = 4.70, p < 0.00001). There was low heterogeneity among the studies (χ 2 = 8.48, df = 6, p = 0.24, I 2 = 29%). The pooled data demonstrated that LTZ was associated with a significantly higher live birth rate than CC (RR = 1.42, 95% CI 1.14–1.77), Z = 3.16, p = 0.002). There was no evidence of heterogeneity between the included studies (χ 2 = 0.004, df = 1, p = 0.85, I 2 = 0%). LTZ significantly reduced hot flushes (RR = 0.60, 95% CI 0.47–0.78), but dizziness (RR = 1.52, 95% CI 0.98–2.3) and headache (RR = 1.80, 95% CI 0.39–8.21) were more frequent with LTZ than with CC. LTZ was more effective than CC in improving pregnancy, ovulation, and live birth rates in women with PMOS, with high to moderate certainty of evidence. Although LTZ was associated with fewer hot flushes, the certainty of evidence for adverse effects was very low. These findings support LTZ as the preferred first-line agent for ovulation induction, pregnancy, and live birth outcomes in women with PMOS and may guide future evidence-based clinical guidelines.