Association of ESR1 and ESR2 Gene Polymorphisms with Metabolic Syndrome in Peri- and Postmenopausal Women: A Systematic Review

Metabolic Syndrome (MetS) encompasses central obesity, insulin resistance, dyslipidemia, and hypertension, collectively increasing risks of cardiovascular disease and type 2 diabetes. Menopause exacerbates susceptibility to MetS due to hormonal changes and genetic factors. Estrogen receptors ESR1 and ESR2 are pivotal in estrogen signaling and metabolic regulation, and their gene polymorphisms may affect metabolic health in peri- and post- menopausal women. This systematic review evaluates studies up to March 2025 that examined associations between ESR1 and ESR2 Single Nucleotide Polymorphisms (SNPs) and MetS or its components in peri-/post-menopausal women. Fifteen observational studies met the inclusion criteria. ESR1 variants rs9340799 (XbaI) and rs2234693 (PvuII) were consistently associated with higher MetS prevalence, obesity markers, and insulin resistance. ESR2 SNPs (such as rs3020449, rs1256049, rs4986938) showed variable associations dependent on population background and interaction with hormonal status. Overall, ESR1 polymorphisms appear to have a stronger influence on metabolic disturbances during menopause than ESR2, particularly when modulated by lifestyle, ethnicity, and hormonal levels. These findings underscore the importance of integrating precision medicine approaches to improve women’s metabolic health