Methylenetetrahydrofolate Reductase Gene Polymorphisms and Human Infertility: Molecular Mechanisms, Clinical Evidence, and Therapeutic Implications

Infertility is a major global public health concern that affects individuals throughout their reproductive years, with many cases remaining unexplained. Considering the increasing prevalence of infertility and its socioeconomic implications, understanding its underlying causes is essential. Among the numerous genetic contributors, polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene have been studied extensively due to their influence on folate metabolism, DNA synthesis, and methylation. However, the reported association between MTHFR variants and infertility is inconsistent across populations due to differences in ethnicity, dietary folate intake, and methodological variation. This review summarizes recent evidence regarding MTHFR polymorphisms and their role in male, female, and idiopathic infertility. The C677T variant has been most consistently linked with male infertility, particularly in Asian populations. In women, MTHFR variants may contribute to infertility through altered homocysteine and folate levels, potentially affecting oocyte quality and endometrial receptivity. Genetic counseling and testing for MTHFR polymorphisms may be useful for couples with idiopathic infertility or a family history of such variants. Personalized management strategies, including folate supplementation, lifestyle modification, and targeted therapy, may improve reproductive outcomes. Further large-scale, well-designed studies are needed to clarify the clinical significance of MTHFR polymorphisms in infertility.