Defining metabolic heterogeneity in polyendocrine metabolic ovarian syndrome based on the MTHFR C677T polymorphism: the potential pathway role of homocysteine

Polyendocrine Metabolic Ovarian Syndrome (PMOS) is characterized by diverse endocrine and metabolic abnormalities. Patients differ substantially in obesity, insulin resistance, and cardiometabolic risk. Homocysteine (HCY) is associated with insulin resistance and metabolic abnormalities in patients with PMOS, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is an important genetic factor that influences HCY levels. However, whether MTHFR C677T genotype-associated HCY elevation is related to metabolic heterogeneity within PMOS remains unclear. A total of 213 women diagnosed with PMOS at the Reproductive Medicine Center, General Hospital of Ningxia Medical University, were retrospectively analyzed. Based on MTHFR C677T genotyping results, the participants were classified as the homozygous wild-type genotype C/C (CC, n = 48), the heterozygous genotype C/T (CT, n = 124), or the homozygous variant genotype T/T (TT, n = 41). Differences in clinical characteristics, glucose and lipid metabolism indices, inflammatory markers, and reproductive hormone levels were compared among the groups. Multivariable regression was used to evaluate the primary genotype-HCY association, whereas correlation, pathway, and prediction analyses were considered exploratory. HCY levels differed significantly among the genotypes. The TT group had the highest HCY levels, and this pattern remained consistent across BMI strata. The TT group also showed a tendency toward a more adverse metabolic profile, with relatively higher lipid-related and inflammatory indicators. Exploratory genotype-stratified analyses suggested that, within the TT group, higher HCY was associated with a less favorable metabolic pattern, particularly higher triglyceride levels. Pathway analysis further suggested a statistical relationship among MTHFR C677T genotype, HCY, and insulin resistance, although the cross-sectional design precluded causal interpretation. Prediction analyses also indicated that HCY contributed to the identification of the TT-associated high-HCY phenotype. These exploratory findings are presented in the Supplementary Material and require further validation. The MTHFR C677T TT genotype was closely associated with elevated HCY levels and a tendency toward a more adverse metabolic phenotype in patients with PMOS. The metabolic implications of this genotype-associated HCY elevation remain exploratory and require confirmation in prospective, multicenter studies.