Methylation patterns of methylenetetrahydrofolate reductase gene promoter in infertile males
A prospective study of males was carried out to investigate if alterations in the MTHFR promotor is linked to male infertility, particularly non-obstructive azoospermia and severe oligozoospermia (≤5 million sperm/ml).
A total of 154 patients (54 non-obstructive azoospermia, 50 severe oligozoospermia and 50 controls) who attended the Andrology Clinic, located within the Medical Faculty of Ondokuz Mayis University, was initially recruited. All semen samples collected was analysed according to World Health Organization 2010 guidelines.
After exclusion of invalid samples or patients with other known causes of male infertility including;
- Karyotype abnormalities
- Cystic fibrosis transmembrane conductance regulator mutation
- Physical injury of testes
- Infection
- Drugs which alter spermatogenesis,
- Endocrine system failure
Alteration (methylation) of the MTHFR promotor was analysed in 35 males with non-obstructive azoospermia, 46 with severe oligozoospermia and 49 controls.
Following DNA isolation and polymerase chain reaction, the prevalence of MTHFR promoter methylation, across the 3 groups was;
| Methylated MTHFR | Group |
| 48.6% | Non-obstructive Azoospermia |
| 58.7% | Severe oligozoospermia |
| 51.0% | Controls |
From this initial analysis no statistically significant link between male infertility and MTHFR promoter methylation exists (P-value = 0.621).
Additional analysis divided the groups further, according to sperm motility and morphology;
- Severe oligozoospermic patients with low sperm motility
- Severe oligozoospermic patients with normal sperm motility
- Severe oligozoospermic patients with normal sperm morphology
- Severe oligozoospermic patients with poor sperm morphology
However no statistically significant link between these sub-groups and MTHFR promotor methylation was found either (p-value > 0.5).
Lastly, the presence or absence of sperm during testicular sperm extraction (TESE) was assessed and found not linked to MTHFR promotor methylation, with an equal number of males (7 unmethylated MTHFR, 7 methylated MTHFR) absent for spermatozoa following TESE.
The author noted, according to other studies, the diverse effect from a reduction in MTHFR activity, points to the complexity of infertility and other factors beyond the MTHFR gene alone.
SUMMARY: DOES MTHFR CAUSE MALE INFERTILITY
This study assessing the effect of MTHFR on male infertility, found no statistically significant difference between infertile males (azoospermia, oligozoospermia) and fertile males, in the prevalence of MTHFR promotor methylation, 48.6%, 58.7% and 51.0% respectively (p-value 0.621).
Limitations
- Small study size
- Other potentially contributing factors not assessed (folate intake, genetic susceptibilities)
Similar studies
Karaca M Z, et al. (2017). Association between methylenetetrahydrofolate reductase (MTHFR) gene promoter hypermethylation and the risk of idiopathic male infertility. https://doi.org/10.1111/and.12698
Botezatu A, et al. (2014). Methylation pattern of methylene tetrahydrofolate reductase and small nuclear ribonucleoprotein polypeptide N promoters in oligoasthenospermia: a case-control study. https://doi.org/10.1016/j.rbmo.2013.10.010
Wu W, et al. (2010). Idiopathic male infertility is strongly associated with aberrant promoter methylation of methylenetetrahydrofolate reductase (MTHFR). https://dx.doi.org/10.1371/journal.pone.0013884
Khazamipour N, et al. (2009). MTHFR promoter hypermethylation in testicular biopsies of patients with non-obstructive azoospermia: the role of epigenetics in male infertility. https://doi.org/10.1093/humrep/dep194
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