The Association of Methylenetetrahydrofolate Reductase C677T Polymorphism, Serum 5-Methyltetrahydrofolate, and Homocysteine Levels with Adenomyosis: A Cross-Sectional Study in an Indonesian Population

Martin Hermawan,1 Dian Tjahyadi,1 Anita Rachmawati,1 Wiryawan Permadi,1 Hanom Husni Syam,1 Anom Suardika,2 Ruswana Anwar11Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Hasan Sadikin General Teaching Hospital, Faculty of Medicine, Padjadjaran University, Bandung, West Java, Indonesia; 2Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Prof. Dr. I.G.N.G. Ngoerah General Hospital / Faculty of Medicine, Udayana University, Denpasar, Bali, IndonesiaCorrespondence: Martin Hermawan, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Hasan Sadikin General Teaching Hospital, Faculty of Medicine, Padjadjaran University, Pasteur No. 38 Street, Pasteur, Bandung, West Java, 40161, Indonesia, Tel +628122015015, Email [email protected]: Adenomyosis is a complex uterine condition, with emerging evidence indicating epigenetic alterations play a role in its pathogenesis. The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T may reduce enzyme activity, affecting DNA methylation and increasing adenomyosis risk. This study compares the MTHFR C677T polymorphism, 5-methyltetrahydrofolate (5-MTHF) levels, and homocysteine levels in patients with adenomyosis.Patients and Methods: This cross-sectional study involved 61 subjects: 31 patients with adenomyosis and 30 patients as controls. The MTHFR C677T polymorphism was analyzed using PCR-RFLP, serum 5-MTHF and homocysteine levels were measured using ELISA. Statistical analyses were performed to compare genotype distributions and metabolite levels between groups and within the adenomyosis group based on genotype.Results: The study found a significant difference in the distribution of the MTHFR C677T genotype between adenomyosis and control groups (p=0.018), with a higher prevalence of the CT genotype in the adenomyosis group (35.5% vs 10.0%). The frequency of the T allele was also elevated in the adenomyosis group (17.7% vs 5.0%; p=0.027). Serum 5-MTHF levels were notably lower in the adenomyosis group (23.92 ± 4.599 nmol/l) compared to controls (32.45 ± 3.019 nmol/l; p< 0.0001), while homocysteine levels were significantly higher in the adenomyosis group (12.87 ± 8.916 µmol/L vs 8.61 ± 1.352 µmol/L; p=0.019). Further analysis of MTHFR genotypes indicated lower 5-MTHF levels in both CC and CT genotypes among the adenomyosis group compared to controls (p< 0.0001). Homocysteine levels showed no significant difference across genotypes (p=0.074), though there was a trend towards higher levels in the adenomyosis group.Conclusion: This study demonstrates a significant difference in the distribution of the MTHFR C677T polymorphism, lower 5-MTHF levels, and higher homocysteine levels in patients with adenomyosis compared to controls. Lower 5-MTHF levels were also shown to be strongly linked with the heterozygous C677T polymorphism in the adenomyosis group.Keywords: DNA methylation, epigenetic, heterozygous, progesterone resistance