Abstract
Purpose
To evaluate the possibility of correcting metabolic defects in gametes and embryos due to methylene tetra hydrofolate reductase (MTHFR) isoforms C677T and A1298C, by supplementation with 5-methyl THF instead of synthetic folic acid. In these couples, high doses of folic acid lead to UMFA (un-metabolized folic acid) syndrome.
Methods
Thirty couples with fertility problems lasting for at least 4 years, such as recurrent fetal loss, premature ovarian insufficiency, or abnormal sperm parameters, with two thirds of them having failed assisted reproductive technology (ART) attempts were included in this program. For all couples, at least one of the partners was a carrier of one of the two main MTHFR isoforms. Most of the women had been previously treated unsuccessfully with high doses of folic acid (5 mg/day), according to what is currently proposed in the literature. The couples carrying one of the isoforms were treated for 4 months with 5-MTHF, at a dose of 600 micrograms per day, before attempting conception or starting another attempt at ART. The duration of treatment corresponding to an entire cycle of spermatogenesis is approximately 74 days.
Results
In this first series of 33 couples, one couple was not followed-up, and two are still currently under treatment. No adverse effects were observed. Thirteen of the couples conceived spontaneously, the rest needing ART treatment in order to achieve pregnancy. Only three couples have, so far, not succeeded.
Conclusion
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).
This is a preview of subscription content, access via your institution.
References
- 1.
Menezo Y, Khatchadourian C, Gharib A, Hamidi J, Greenland T, Sarda N. Regulation of S-adenosyl methionine synthesis in the mouse embryo. Life Sci 1989;44:1601–9.
- 2.
Silvestris E, Cohen M, Cornet D, Jacquesson-Fournols L, Clement P, Chouteau J, et al. Supporting the one-carbon cycle restores ovarian reserve in subfertile women: absence of correlation with urinary bisphenol A concentration. Biores Open Access. 2017;6:104–9.
- 3.
Dattilo M, Cornet D, Amar E, Cohen M, Menezo Y. The importance of the one carbon cycle nutritional support in human male fertility: a preliminary clinical report. Reprod Biol Endocrinol. 2014;12:71.
- 4.
Cornet D, Amar E, Cohen M, Ménézo Y. Clinical evidence for the importance of 1-carbon cycle support in subfertile couples. Austin J Reprod Med Infertil. 2015;2:1011.
- 5.
Cornet D, Cohen M, Clement A, Amar E, Fournols L, Clement P, et al. Association between the MTHFR-C677T isoform and structure of sperm DNA. J Assist Reprod Genet. 2017;34:1283–8.
- 6.
National Center for Biotechnology Information (2016) Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine. U.S National Library of medicine.
- 7.
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;3:1–5.
- 8.
Botto LD, Yang Q. 5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151:862–77.
- 9.
Gong M, Dong W, He T, Shi Z, Huang G, Ren R, et al. MTHFR 677CT polymorphism increases the male infertility risk: a meta-analysis involving 26 studies. PLoS One. 2015;10:e0121147.
- 10.
Yang Y, Luo YY, Wu S, Tang YD, Rao XD, Xiong L, et al. Association between C677T and A1298C polymorphisms of the MTHFR gene and risk of male infertility: a meta-analysis. Genet Mol Res 2016; 15(2). https://doi.org/10.4238/gmr.15027631.
- 11.
Tara SS, Ghaemimanesh F, Zarei S, Reihani-Sabet F, Pahlevanzadeh Z, Modarresi MH, et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in male partners of recurrent miscarriages couples. J Reprod Infertil. 2015;16:193–8.
- 12.
Enciso M, Sarasa J, Xanthopoulou L, Bristow S, Bowles M, Fragouli E, et al. Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy. Hum Genet. 2016;135:555–68.
- 13.
Ware WR. Raising concerns about unmetabolized folic acid. J Orthomol Med. 2008;23:43–51.
- 14.
Christensen KE, Mikael LG, Leung KY, Lévesque N, Deng L, Wu Q, et al. High folic acid consumption leads to pseudo-MTFHR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015;101:646–58.
- 15.
Prinz-Langenohl R, Bramswig S, Tobolski O, Smulders YM, Smith DE, et al. 5-MTHF increases plasma folate more effectively than folic acid in women with the homozygous or wild-type6777C ->T polymorphism of MTHFR. Br J Pharmacol. 2009;158:2014–21.
- 16.
Cornet D, Cohen M, Clement A, Amar E, Fournols L, Clement P, et al. Association between the MTHFR-C677T isoform and structure of sperm DNA. J Assist Reprod Genet. 2017;34:1283–8.
- 17.
Brämswig S, Prinz-Langenohl R, Lamers Y, Tobolski O, Wintergerst E, Berthold HK, et al. Supplementation with a multivitamin containing 800 microg of folic acid shortens the time to reach the preventive red blood cell folate concentration in healthy women. Int J Vitam Nutr Res. 2009;79:61–70.
- 18.
Zappacosta B, Romano L, Pershichilli S, Cutrone LA, Graziano M, et al. Genotype prevalence and allele frequencies of 5,10-Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in Italian newborns. Lab Med. 2009;40:732–6.
- 19.
Georgiades P, Watkins M, Burton GJ, Ferguson-Smith AC. Roles for genomic imprinting and the zygotic genome in placental development. Proc Natl Acad Sci U S A. 2001;98:4522–7.
- 20.
Serman L, Dodig D. Impact of DNA methylation on trophoblast function. Clin Epigenetics. 2011;3:7.
- 21.
Koukoura O, Sifakis S, Spandidos DA. DNA methylation in the human placenta and fetal growth. Mol Med Rep. 2012;5:883–9.
- 22.
Branco MR, King M, Perez-Garcia V, Bogutz AB, Caley M, Fineberg E, et al. Maternal DNA methylation regulates early trophoblast development. Dev Cell. 2016;36:152–63.
- 23.
Lucock M, Yates Z. Folic acid fortification: a double-edged sword. Curr Opin Clin Nutr Metab Care. 2009;12:555–64.
- 24.
Bønaa KH, Njølstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. NORVIT Trial Investigators N Engl J Med. 2006;354:1578–88.
- 25.
Lucock M, Yates Z. Folic acid—vitamin and panacea or genetic time bomb? Nat Rev Genet. 2005;6:235–40.
Author information
Affiliations
Contributions
Edouard J Servy, MD, FACOG, followed clinically the patients and collected the data.
Laetitia Jacquesson-Fournols, MD, Endocrinologist,, followed clinically the patients and collected the data.
Marc Cohen MD, Obst Gyn, follows clinically the patients and collected the data.
Yves J R Menezo, PhD, Dr. Sci, FRSM, Senior Clinical Embryologist (ESHRE) (*corresponding author) controlled dosages designed the protocol and wrote the paper.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest except MC who is dealing with a company saling Neutraceuticals.
Rights and permissions
About this article
Cite this article
Servy, E.J., Jacquesson-Fournols, L., Cohen, M. et al. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. J Assist Reprod Genet 35, 1431–1435 (2018). https://doi.org/10.1007/s10815-018-1225-2
Received:
Accepted:
Published:
Issue Date:
Keywords
- MTHFR
- Gametes
- Embryos
- Miscarriages
- Folic acid
- 5-MTHF
- UMFA