MTHFR gene mutation symptoms in Men

MTHFR gene mutation symptoms in Men

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

April 25, 2025

Table of Contents

    MTHFR mutations have been associated with various health conditions in both men and women, such as cardiovascular diseases, mood disorders, and reproductive issues. This is because the MTHFR enzyme - which is required for metabolizing folate and homocysteine - doesn’t function properly. This can mean that homocysteine isn’t broken down and can increase to dangerous levels.


    Men with an MTHFR mutation should be aware of the risks that elevated homocysteine can lead to, particularly regarding their fertility, hormonal balance, and overall health. The MTHFR enzyme is also required for DNA synthesis, neurotransmitter production, and many other methylation processes. Studies indicate that MTHFR may be linked to impaired spermatogenesis and even developmental issues in children1.

    MTHFR symptoms in men

    • Cardiovascular issues
      In men, MTHFR mutations can lead to elevated homocysteine levels, which have been linked to oxidative stress and DNA damage, potentially affecting overall health and fertility2. Homocysteine is a sulfur-containing amino acid produced during the breakdown of methionine, another amino acid. Normally, homocysteine is recycled by methylfolate and other nutrients, but those with MTHFR often do not have sufficient methylfolate for this process. High homocysteine can cause inflammation in the blood vessels, which can then lead to cardiovascular diseases, stroke, and other vascular conditions3.

    • Mood disorders
      Many studies have linked MTHFR mutations to psychological symptoms, including anxiety and depression. MTHFR C677T specifically has been linked to a higher risk of developing schizophrenia and major depression in the overall population4. This is because the MTHFR enzyme is required for producing methylfolate, which in turn is required for the methylation of neurotransmitters such as serotonin, dopamine, and norepinephrine.
      Elevated homocysteine levels have been associated with mood disorders, which can affect quality of life and mental health in men with MTHFR mutations.5

    • Infertility
      MTHFR mutations can adversely affect sperm quality. Studies have demonstrated that men with the C677T variant may have lower sperm motility and concentration.6

    • Sexual development
      High homocysteine levels caused by MTHFR may also impair testosterone production, which can then affect male development, muscle mass, growth, and fertility.7

    • Oxidative stress
      High homocysteine can contribute to oxidative stress, which affects cellular function beyond the cardiovascular system. Some studies suggest it plays a role in neurodegeneration and chronic inflammation.8

    How does MTHFR affect testosterone?

    The relationship between MTHFR and testosterone levels is not fully understood. However, some studies suggest that elevated homocysteine levels due to an MTHFR mutation may affect hormonal balance, including testosterone production. High homocysteine has been shown to impair testosterone production in Leydig cells (where testosterone is produced) possibly by causing dysfunction in the cells. This led to lower testosterone concentrations. 9

    One study found that men with a homozygous C677T MTHFR mutation may be at risk of hypogonadism due to severe MTHFR enzyme inactivity.10 Hypogonadism is a condition in which the body doesn't produce enough testosterone, or enough sperm, or both. Testosterone plays a key role in male growth and development, especially during puberty. Hypogonadism can lead to symptoms such as fatigue, decreased libido, and reduced muscle mass, which are commonly associated with low testosterone levels.11

    How does MTHFR affect male fertility?

    The MTHFR enzyme is particularly active in the testes, where it plays a key role in sperm development. This is because sperm production relies on DNA methylation, a process that regulates gene activity. These methylation changes are part of epigenetic reprogramming, which ensures sperm carry the correct genetic instructions for future offspring.12


    Mutations in the MTHFR gene can disrupt this process, leading to abnormalities in spermatogenesis. This may result in reduced sperm motility, lower concentration, and possibly reduced fertility. Some research has shown that the C677T mutation reduces MTHFR enzyme activity by 50–60%, which affects the breakdown of folate and may subsequently alter sperm DNA methylation.13


    Research has found a strong link between MTHFR mutations and male infertility. A 2024 study reported that the C677T variation was significantly associated with low or absent sperm count.  A meta-analysis of 26 studies also found that the C677T mutation increases the risk of infertility due to its impact on enzyme function.15 Animal studies have shown that mice with low MTHFR function have abnormal spermatogenesis and infertility, though this was reversed with betaine supplementation.16


    While some studies have found no link between the C677T mutation and infertility, the A1298C mutation appears to have a more significant effect on male fertility.17


    Folate also plays a crucial role in sperm production. A deficiency can reduce the expression of key genes (ESR1, CAV1, and ELAVL1) involved in spermatogenesis.18 Interestingly, high folic acid intake may also be problematic, as high doses have been shown to cause sperm DNA hypomethylation in men with MTHFR mutations. This occurs because too much folic acid may downregulate MTHFR activity in the testes, reducing the supply of methyl groups needed for proper DNA methylation.19


    Despite these concerns, folate supplementation is often recommended to improve sperm quality in men with MTHFR mutations. Folate is essential for DNA synthesis and reproductive health, and optimizing folate levels may enhance fertility outcomes. However, men with MTHFR should avoid folic acid and instead take methylfolate, the active form of folate which bypasses the MTHFR mutation.20 

    MTHFR gene mutation symptoms in Men

    Key takeaways

    • Icon MTHFR mutations in men can lead to elevated homocysteine levels, increasing the risk of cardiovascular issues, mood disorders, and low testosterone.
    • Icon These mutations may impair sperm quality and DNA methylation, contributing to male infertility.
    • Icon Men with MTHFR should avoid folic acid and supplement with methylfolate to support fertility and hormone balance.

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    Frequently Asked Questions and MTHFR symptoms in men

    What are the symptoms of MTHFR mutations in men?

    Men with MTHFR may have a higher risk of certain health issues, including:
    ⇀ Cardiovascular issues due to high homocysteine levels
    ⇀ Fertility issues due to low spermatogenesis
    ⇀ Mood disorders (including depression, anxiety, and schizophrenia) due to poor neurotransmitter production
    ⇀ Low testosterone, also due to high homocysteine

    Can men get the MTHFR gene?

    Yes, both men and women can get the mutated MTHFR gene if one or both of their parents have the mutation. Everyone inherits one copy of the MTHFR gene from each parent, so there is a chance you will inherit the mutated variant.21

    Can MTHFR cause infertility in men?

    Several studies have reported an association between MTHFR mutations and male infertility. Specifically, the C677T mutation has been shown to significantly increase the risk of infertility.22 The A1298C variant has also been implicated as a genetic risk factor for male infertility. MTHFR mutations can also adversely affect sperm quality, with studies suggesting that men with the C677T variant have lower sperm motility and concentration.23

    Is MTHFR passed from mother or father?

    Both. You inherit one copy of the MTHFR gene from your mother and one from your father. Either parent can have an MTHFR mutation.

    References

    1. Donovan Chan, Duncan W. Cushnie, Oana R. Neaga, Andrea K. Lawrance, Rima Rozen, Jacquetta M. Trasler; "Strain-Specific Defects in Testicular Development and Sperm Epigenetic Patterns in 5,10-Methylenetetrahydrofolate Reductase-Deficient Mice"; Endocrinology, Volume 151, Issue 7; 2010 Jul

      https://academic.oup.com/endo/article-abstract/151/7/3363/2456820?redirectedFrom=fulltext

    2. Nandhini Balunathan, Vettriselvi Venkatesen, Jaywant Chauhan, Sanjeeva N Reddy, Venkatachalam Perumal, Solomon FD Paul; "Role of MTHFR Gene Polymorphisms in Male Infertility"; International Journal of Infertility and Fetal Medicine, Vol. 12, Iss. 1; 2021

      https://www.ijifm.com/abstractArticleContentBrowse/IJIFM/24012/JPJ/fullText

    3. Hui-yong Peng, Chang-feng Man, Juan Xu, Yu Fan; "Elevated homocysteine levels and risk of cardiovascular and all-cause mortality: a meta-analysis of prospective studies"; Journal of Zhejiang University. Science. B.; 2015 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4288948/

    4. Yu-Xin Zhang, Lu-Ping Yang, Cong Gai, Cui-Cui Cheng, Zhen-yu Guo, Hong-Mei Sun, Die Hu; "Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis"; Frontiers in psychiatry.; 2022 Aug

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9433753

    5. Samira Khan, Abeera Naeem, Alexia Fritts, Melissa Cummins, Caroline Kayes, Wei Fang; "Discovery of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency in Individuals With Common Psychiatric Comorbidities: A Retrospective Case Review"; Cureus; 2024 Apr

      https://pmc.ncbi.nlm.nih.gov/articles/PMC11088868

    6. Yangyang Wan, Wenjing Liu, Bo Xu, Xiaohua Jiang, Juan Hua; "Association of paternal MTHFR polymorphisms (C677T) with clinical outcomes in ICSI treatment"; Frontiers in Endocrinology; 2022 Dec

      https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1084463/full

    7. Zhiyuan Su, Zhuoliang Liu, Wenjing Lei, Kai Xia, An Xiao, Zheng Hu, Miaomiao Zhou, Fengxin Zhu, Jianwei Tian, Manqiu Yang, Dong Wang, Andy Peng Xiang, Jing Nie; "Hyperhomocysteinemia lowers serum testosterone concentration via impairing testosterone production in Leydig cells"; Cell Biology and Toxicology; 2023 Jul

      https://link.springer.com/article/10.1007/s10565-023-09819-4

    8. Lenka Koklesova, Alena Mazurakova, Marek Samec, Kamil Biringer, Samson Mathews Samuel, Dietrich Büsselberg, Peter Kubatka, Olga Golubnitschaja; "Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person"; The EPMA journal.; 2021 Nov

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8581606

    9. Zhiyuan Su, Zhuoliang Liu, Wenjing Lei, Kai Xia, An Xiao, Zheng Hu, Miaomiao Zhou, Fengxin Zhu, Jianwei Tian, Manqiu Yang, Dong Wang, Andy Peng Xiang, Jing Nie; "Hyperhomocysteinemia lowers serum testosterone concentration via impairing testosterone production in Leydig cells"; Cell Biology and Toxicology; 2023 Jul

      https://link.springer.com/article/10.1007/s10565-023-09819-4

    10. Rami Salameh, Mumtaheena Miah, Catherine Anastasopoulou; "Case Report: Homozygous C677T MTHFR Gene Mutation in Male with Hypogonadism"; Case Reports in Endocrinology; 2020 May

      https://onlinelibrary.wiley.com/doi/10.1155/2020/6945124

    11. Omeed Sizar, Stephen W. Leslie, Janice Schwartz; "Male Hypogonadism"; StatPearls [Internet].; 2024 Feb

      https://www.ncbi.nlm.nih.gov/books/NBK532933

    12. Derval J. Gaughan, Sandrine Barbaux, Leo A.J. Kluijtmans, Alexander S. Whitehead; "The human and mouse methylenetetrahydrofolate reductase (MTHFR) genes: genomic organization, mRNA structure and linkage to the CLCN6 gene"; Gene, Vol. 257, Iss. 2; 2000 Oct

      https://www.sciencedirect.com/science/article/pii/S0378111900003929?via%3Dihub

    13. Mancheng Gong, Wenjing Dong, Tingyu He, Zhirong Shi, Guiying Huang, Rui Ren, Sichong Huang, Shaopeng Qiu, Runqiang Yuan; "MTHFR 677C>T Polymorphism Increases the Male Infertility Risk: A Meta-Analysis Involving 26 Studies"; PLoS One; 2015 Mar

      https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121147

    14. Akash More, Namrata Anjankar, Jarul Shrivastava, Nancy Nair, Ritesh Jadhav; "Correlation of MTHFR C677T Polymorphism with Male Infertility among Indian Population: Case-Control Study"; Journal of pharmacy & bioallied sciences.; 2024 Jul

      https://pubmed.ncbi.nlm.nih.gov/39346466

    15. Mahmoud Aarabi, Karen E Christensen, Donovan Chan, Daniel Leclerc, Mylène Landry, Lundi Ly, Rima Rozen, Jacquetta Trasler; "Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation"; Human molecular genetics.; 2018 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC6159534/

    16. Tamara L.J. Kelly, Oana R. Neaga, Bernd C. Schwahn, Rima Rozen, Jacquetta M. Trasler; "Infertility in 5,10-Methylenetetrahydrofolate Reductase (MTHFR)-Deficient Male Mice Is Partially Alleviated by Lifetime Dietary Betaine Supplementation"; Biology of Reproduction, Vol. 72, Iss. 3; 2005 Mar

      https://academic.oup.com/biolreprod/article-abstract/72/3/667/2667252?redirectedFrom=fulltext

    17. Nandhini Balunathan, Vettriselvi Venkatesen, Jaywant Chauhan, Sanjeeva N Reddy, Venkatachalam Perumal, Solomon FD Paul; "Role of MTHFR Gene Polymorphisms in Male Infertility"; International Journal of Infertility and Fetal Medicine, Vol. 12, Iss. 1; 2021 Jan-Apr

      https://www.ijifm.com/doi/pdf/10.5005/jp-journals-10016-1213

    18. Hong-Fang Yuan, Kai Zhao, Yu Zang, Chun-Yan Liu, Zhi-Yong Hu, Jia-Jing Wei, Ting Zhou, Ying Li, Hui-Ping Zhang; "Effect of folate deficiency on promoter methylation and gene expression of Esr1, Cav1, and Elavl1, and its influence on spermatogenesis"; Oncotarget; 2017 Feb

      https://pmc.ncbi.nlm.nih.gov/articles/PMC5421833/

    19. Mahmoud Aarabi, Karen E Christensen, Donovan Chan, Daniel Leclerc, Mylène Landry, Lundi Ly, Rima Rozen, Jacquetta Trasler; "Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation"; Human molecular genetics.; 2018 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC6159534/

    20. Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Integrative medicine.; 2022 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/

    21. Stephan Moll, Elizabeth A. Varga; "Homocysteine and MTHFR Mutations"; Circulation; 2015 Jul

      https://www.ahajournals.org/doi/10.1161/circulationaha.114.013311

    22. Mancheng Gong, Wenjing Dong, Tingyu He, Zhirong Shi, Guiying Huang, Rui Ren, Sichong Huang, Shaopeng Qiu, Runqiang Yuan; "MTHFR 677C>T Polymorphism Increases the Male Infertility Risk: A Meta-Analysis Involving 26 Studies"; PLoS One; 2015 Mar

      https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121147

    23. Nandhini Balunathan, Vettriselvi Venkatesen, Jaywant Chauhan, Sanjeeva N Reddy, Venkatachalam Perumal, Solomon FD Paul; "Role of MTHFR Gene Polymorphisms in Male Infertility"; International Journal of Infertility and Fetal Medicine, Vol. 12, Iss. 1; 2021 Jan-Apr

      https://www.ijifm.com/doi/pdf/10.5005/jp-journals-10016-1213

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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