Methylenetetrahydrofolate Reductase (MTHFR) is Associated With Ovarian Follicular Activity

Methylenetetrahydrofolate reductase (MTHFR) is an important regulatory enzyme that irreversibly partitions methyl groups to DNA synthesis/repair or to the methylation cycle. Both the c677T and A1298C polymorphisms result in reduced enzyme activity in vitro, and there are clinical suggestions that women carrying the C677T polymorphism have impaired ovarian responses to stimulation and may experience an early onset of menopause. In addition, women homozygous for A1298C may be less likely to become pregnant and deliver an infant after in vitro fertilization. This prospective cohort study attempted to discern the effects of these polymorphisms, if any, on 223 women undergoing ovarian stimulation. The commonest stimulation protocol was long luteal. Women with the variant MTHFR 1298C allele had significantly higher day 3 baseline levels of follicle-stimulating hormone. Following ovarian stimulation these women produced fewer follicles measuring more than 13 mm, had lower estradiol levels on the day they received human chorionic gonadotropin, and required more gonadotropin hormone during treatment. No significant differences in the outcome of ovarian stimulation were discerned after multivariate analysis. Women with an A1298C heterozygous genotype had fewer follicles than those with a wild-type genotype, and this difference persisted after adjusting for age and stimulation protocol. In addition, women carrying the A1298C heterozygous genotype required more gonadotropin for stimulation than those with a wild-type genotype after controlling for parameters of ovarian reserve. No comparable findings were documented in women with the MTHFR 677T allele. The MTHFR A1298C polymorphism may help to determine the response to ovarian stimulation, presumably by modulating folliculogenesis.