The conventional use of large doses of folic acid (5 mg/day) has become obsolete. Regular doses of folic acid (100-200 μg) can be tolerated in the general population but should be abandoned in the presence of MTHFR mutations, as the biochemical/genetic background of the patient precludes a correct supply of 5-MTHF, the active compound. A physiological dose of 5-MTHF (800 μg) bypasses the MTHFR block and is suggested to be an effective treatment for these couples. Moreover, it avoids potential adverse effects of the UMFA syndrome, which is suspected of causing immune dysfunction and other adverse pathological effects such as cancer (especially colorectal and prostate).

Environmental endocrine disrupting chemicals (EDCs), including bisphenol A (BPA), induce DNA methylation errors and oxidative stress, and alter fertility. Animal studies have demonstrated that supporting the one-carbon cycle (1-CC) with appropriate dietary supplements can reduce the effects of EDCs. Anti-Mullerian hormone (AMH), a marker of ovarian functionality, has been tested in subfertile female patients, to control this hypothesis in humans. Fifty-five women with a history of 3–7 years of infertility, with at least two assisted reproductive technology (ART) treatment failures, and low serum levels of AMH were enrolled in the study. Before starting any further ART treatment, they were tested for AMH and for follicular count. A urinary control of BPA was proposed. Then a support of the 1-CC, already tested in other clinical studies, was initiated and continued for 4 months. At the end of this period, antral follicle count and serum AMH levels were re-evaluated. The AMH levels before and after treatment were compared using the Wilcoxon test (nonparametric test, non-Gaussian population). Out of the 55 patients, 35 accepted a BPA dosage in the urine. No correlation was found between BPA and serum AMH concentrations. Forty-nine patients followed the full treatment with 1-CC supplements, which resulted in increased AMH levels, independent of initial AMH levels and maternal age (in the range studied), p = 0.0001. Eight patients spontaneously conceived ongoing pregnancies within 3 months, at the end of the protocol. A support of the 1-CC can partly alleviate metabolic derangements induced by environment, as observed in animal models, and improve endocrine background in women.

Purpose MTHFR, one of the major enzymes in the folate cycle, is known to acquire single-nucleotide polymorphisms that significantly reduce its activity, resulting in an increase in circulating homocysteine. Methylation processes are of crucial importance in gametogenesis, involved in the regulation of imprinting and epigenetic tags on DNA and histones. We have retrospectively assessed the prevalence of MTHFR SNPs in a population consulting for infertility according to gender and studied the impact of the mutations on circulating homocysteine levels. Methods More than 2900 patients having suffered at least two miscarriages (2 to 9) or two failed IVF/ICSI (2 to 10) attempts were included for analysis of MTHFR SNPs C677T and A1298C. Serum homocysteine levels were measured simultaneously. Results We observed no difference in the prevalence of different genetic backgrounds between men and women; only 15% of the patients were found to be wild type. More than 40% of the patients are either homozygous for one SNP or compound heterozygous carriers. As expected, the C677T SNP shows the greatest adverse effect on homocysteine accumulation. The impact of MTHFR SNPs on circulating homocysteine is different in men than in women. Conclusions Determination of MTHFR SNPs in both men and women must be seriously advocated in the presence of long-standing infertility; male gametes, from MTHFR SNPs carriers, are not exempted from exerting a hazardous impact on fertility. Patients should be informed of the pleiotropic medical implications of these SNPs for their own health, as well as for the health of future children.

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Methylation is a crucially important ubiquitous biochemical process, which covalently adds methyl groups to a variety of molecular targets. It is the key regulatory process that determines the acquisition of imprinting and epigenetic marks during gametogenesis. Methylation processes are dependent upon two metabolic cycles, the folates and the one-carbon cycles. The activity of these two cycles is compromised by single nucleotide polymorphisms (SNPs) in the gene encoding the Methylenetetrahydrofolate reductase (MTHFR) enzyme. These SNPs affect spermatogenesis and oocyte maturation, creating cytologic/chromosomal anomalies. The two main MTHFR SNP variants C677T (c.6777C>T) and A1298C (c.1298A>C) together with serum homocysteine levels were tested in men with >3 years’ duration of infertility who had failed several ART attempts with the same partner. These patients are often classified as having “idiopathic infertility”. We observed that the genetic status with highest prevalence in this group is the heterozygous C677T, followed by the combined heterozygous C677T/A1298C, and then A1298C; these three variants represent 65% of our population. Only 13.1% of the patients tested are wild type (WT), C677C/A1298A). The homozygous 677TT and the combined heterozygote 677CT/1298AC groups have the highest percentage of patients with an elevated circulating homocysteine level of >15 µMolar (57.8% and 18.8%, respectively, which is highly significant for both). Elevated homocysteine is known to be detrimental to spermatogenesis, and the population with this parameter is not marginal. In conclusion, determination of these two SNPs and serum homocysteine should not be overlooked for patients with severe infertility of long duration, including those with repeated miscarriages. Patients must also be informed about pleiotropic medical implications relevant to their own health, as well as to the health of future children.