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Male Overview

The Role of 1C Metabolism in Male Reproductive Health and Infertility



  • Males given folate and zinc for 26 weeks experienced a substantial increase in total normal sperm count (74%). 1
  • Subfertile males provided 3-month supplementation with folinic acid had increased sperm number and motility. 1
  • Folate supplementation with and without zinc enhanced sperm count and sperm motility. 1
  • Folate and zinc supplementation improved sperm concentration in C677T MTHFR homozygotes. 1
  • Low zinc levels in seminal fluid are associated with reduced fertility. 1
  • Excessive levels of reactive oxygen species (ROS) may result in DNA damage and other spermatozoon changes such as plasma membrane lipid peroxidation, in association with altered sperm morphology and reduction in motility. 1
  • Infertile males may have ROS-dependent DNA damage, including abnormal chromatin structure, chromosomal microdeletions, aneuploidy and DNA strand breaks. 1


Spermatogenesis is highly dependent on 1C metabolism, and polymorphic genes with reduced effectiveness encoding methylene tetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), methionine synthase (MTR), and cystathionine beta-synthase (CBS) can lead to elevated levels of homocysteine, reduced S-adenosylmethionine (SAM) and/or excessive ROS production 2. These metabolic changes can result in errors in DNA replication, repair and transcription, chromatin packaging, and protamine replacement, and ultimately reduced fertility. It is important to note, however, that increased polymorphism in folate-metabolizing genes is not a consistent finding in all studies of infertile males 3-5, one reason being perhaps that ethnicity, diet, lifestyle and/or environmental factors may also play important roles in poor fertility outcomes in this patient cohort. It has been suggested that dietary correction of this condition should involve 1C metabolism supplementation and not simply increased consumption of folates 6.

In addition to oxidative stress and its deleterious effect on sperm performance, there is also growing evidence that inadequate 1C metabolism-dependent DNA methylation, culminating in epigenetic alterations, may also play a role in male subfertility 7. Defective sperm DNA methylation results in inadequate DNA protamination, the main sperm epigenetic adaptation, and sperm nuclear decondensation, with a reduced capacity for successful oocyte fertilization. Support of the 1C cycle in infertile men has been shown to significantly improve both DNA fragmentation (oxidative damage) and nuclear condensation (protamination/methylation-dependent), accompanied by remarkably high pregnancy and live birth rates (47.6% and 39.3% respectively) in a cohort of 66 couples undergoing an ART procedure who had failed at least two previous cycles 8. In contrast to these latter findings, traditional direct antioxidant vitamin supplementation for 3-6 months in 82 males with sperm concentration <15 million/mL, motility <40%, normal morphology <4%, or DNA fragmentation >25% had no effect on morphology, motility or DNA fragmentation in comparison to a 82 patient cohort randomly taken from the same universe who were given placebo, nor did their female partners who were ovulatory and <40 years old with documented tubal patency experience higher live birth rates (15% vs 24%, respectively). 9 Indeed, regarding semen abnormalities, sperm concentration increased from baseline in the placebo group after 3 months of treatment (+2.4 million/mL), but declined for patients who received the vitamin cocktail (-4.0 million/mL).

In a recent review of 1C metabolism and male infertility 10, ROS-mediated effects on sperm membrane integrity, morphology, movement, epigenetic maturation and DNA damage was discussed. Since low levels of ROS are required for normal sperm function and oocyte fertilization, however, it was suggested that it may be unwise to administer traditional antioxidants to subfertile males. In several recent publications, it has been reported that sperm quality and attendant reproductive performance were improved with 1C metabolism nutritional support 8,11,12.


It is becoming increasingly evident that 1C metabolism is critical in preserving sperm morphology and function, and supplementation of this pathway could be beneficial to male patients, particularly those with folate-metabolizing alleles that encode for enzymes that are relatively inefficient in subserving their biological role. Indeed, preliminary data indicate that the administration of 1C supplements to subfertile males and females can markedly improve pregnancy and live birth rates in couples undergoing ART.


  1. Ebisch IMW, Thomas CMG, Peers WHM, et al. The importance of folate, zinc, and antioxidants in the pathogenesis and prevention of subfertility. Hum Repro Up. 2007; 13: 163-174.
  2. Singh K, Jaiswal D. One-carbon metabolism, spermatogenesis and male infertility. Reprod Sci. 2012; 20: 622-630.
  3. Forges T, Monnier-Barbarino P, Alberto J.M., et al. Impact of folate and homocysteine metabolism on human reproductive health. Hum Repro Update, 2007; Pages 1-14.
  4. Kurzawski M, Wajda A, Malinowski D, et al. Association study of folate-related enzymes (MTHFR, MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population. Genet Mol Biol. 2015; 38: 42-47.
  5. Weiner AS, Boyarskikh UA, Voronina EN, et al. Polymorphisms in folate-metabolizing genes and risk of idiopathic male infertility: a study on a Russian population and a meta-analysis. Fertil Steril. 2014; 101: 87-94.
  6. Servy E, Menezo Y.The Methylene tetrahydrofolate reductase (MTHFR) isoform challenge. High doses of folic acid are not a suitable option compared to 5 Methyltetrahydrofolate treatment. Clin Obstet Gynecol Reprod Med. 2017.
  7. Steegers-Theunissen RPM, Twigt J, Pestinger V, et al. The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism. Hum Repro Up. 2013; 19: 640-655.
  8. Dattilo M, Cornet D, Amar E, et al. The importance of the one carbon cycle nutritional support in human male fertility: a preliminary clinical report. Repro Biol and Endocrinol. 2014; 12: 71-79.
  9. Steiner AZ, Hansen KR, Barnhart KT, et al. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertil Steril. In Press.
  10. Dattilo M, Giuseppe D, Ettore G, et al. Improvement of gamete quality by stimulating and feeding the endogenous antioxidant system: mechanisms, clinical results, insights on gene-environment interactions and the role of diet. J Assist Repro Genet. 2016; 33: 1633-1648.
  11. Cornet D, Amar E, Cohen M, et al. Clinical Evidence for the importance of 1-carbon cycle support in subfertile couples. Austin J Reprod Med Infertil. 2015; 2(2): 1011.
  12. Amar E, Cornet D, Cohen M et al. Treatment for High Levels of Sperm DNA Fragmentation and Nuclear De condensation: Sequential Treatment with a Potent Antioxidant Followed by Stimulation of the One-Carbon Cycle vs One-Carbon Cycle Back-up Alone. Austin J Reprod Med Infertil. 2015; 2(1): 1006.

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