Is methylfolate supplementation necessary for men with normal fertility?

Methylfolate Supplementation for Men with Normal Fertility

Methylfolate supplementation is not recommended for men with normal fertility as there is insufficient evidence to support its use for reproductive benefits.

Evidence Assessment

The available guidelines do not specifically recommend methylfolate supplementation for men with normal fertility. The most recent and relevant evidence suggests that supplements, including folate derivatives, have questionable value for men without fertility issues:

Lack of Evidence for Supplementation

• The AUA/ASRM 2021 guideline clearly states that "there are no clear, reliable data to support use of the variety of supplements (vitamins, antioxidants, nutritional supplement formulations) that have been offered to men attempting conception" 1.

• The same guideline further emphasizes that "the benefits of supplements (eg, antioxidants, vitamins) are of questionable clinical utility in treating male infertility" 1.

• The WHO 2017 guideline strongly recommends (based on low-quality evidence) that "there are insufficient data to recommend the use of supplemental antioxidant therapies for the treatment of men with abnormal semen parameters and/or male infertility" 1.

Research on Folate Specifically

While some research has investigated folate supplementation in men with fertility issues, the evidence for men with normal fertility is lacking:

• A 2020 randomized clinical trial found that folic acid and zinc supplementation in men did not significantly improve semen quality or couples' live birth rates 2.

• An older study from 2002 showed some improvement in sperm count with folic acid and zinc supplementation in both fertile and subfertile men 3, but this has been contradicted by more recent research.

• Importantly, a 2015 study revealed that high-dose folic acid supplementation actually altered the sperm methylome and caused "a significant global loss of methylation across different regions of the sperm genome" 4, suggesting potential epigenetic risks.

Potential Risks and Considerations

• The 2020 systematic review of male fertility supplements found that only 17% of ingredients in popular supplements had published data showing a positive effect 5.

• Methylfolate ((6S)5-MTHF) is often marketed as superior to folic acid for individuals with MTHFR polymorphisms 6, but there is no evidence supporting its use in men with normal fertility.

• The epigenetic changes observed with high-dose folate supplementation 4 raise concerns about potential unintended consequences, particularly in men without folate deficiency.

Clinical Approach

For men with normal fertility who are trying to conceive:

1. Focus on general health measures rather than supplements:

   • Maintain healthy weight
   • Avoid smoking and excessive alcohol
   • Limit exposure to environmental toxins

2. Consider testing only if indicated:

   • Semen analysis if conception is delayed
   • Hormonal evaluation only if there are symptoms of endocrine dysfunction

3. Avoid unnecessary supplementation:

   • Current evidence does not support routine use of methylfolate or other supplements in men with normal fertility
   • Supplementation may have unintended consequences on sperm DNA methylation

Common Pitfalls to Avoid

• Overuse of supplements: Many fertility supplements lack scientific evidence and may create false hope or unnecessary expense.

• Ignoring potential risks: High-dose folate supplementation can alter sperm DNA methylation patterns 4, which could theoretically impact embryo development.

• Focusing on supplements instead of modifiable risk factors: Addressing lifestyle factors like smoking, alcohol consumption, and obesity may have more significant benefits for reproductive health than unproven supplements.

In conclusion, while methylfolate supplementation is often marketed for fertility enhancement, current guidelines and evidence do not support its use in men with normal fertility.