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Female Overview

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



  • Folate deficiency and/or elevated homocysteine is associated with neural tube defects, heart defects, Down syndrome, placental abruptions, preeclampsia, spontaneous abortion, poor embryonal growth, and preterm birth. 1,2
  • Elevated follicular fluid homocysteine is negatively correlated with oocyte maturity and embryo quality, as well as fertilization rate in polycystic ovary syndrome (PCOS) patients. 3
  • Folate supplementation both increases folate levels in follicular fluid and decreases homocysteine. 2
  • Homocysteine concentrations are lower in the follicular fluid of women undergoing in vitro fertilization (IVF) who are given folic acid, in association with higher quality oocytes of greater maturity. 4
  • IVF patients with methylene tetrahydrofolate reductase (MTHFR) gene variants may have inadequate ovarian reserves and responses to gonadotropic stimulation, and a reduced likelihood of live births. 2
  • Markers of oxidative stress (reactive oxygen species (ROS) and lipid peroxidation (LPO)) in follicular fluid are directly correlated with pregnancy rate, but neither extreme oxidative or reductive states is likely to result in a successful pregnancy. 4    
  • Adequate glutathione must be present in the oocytes for sperm nuclear decondensation and pronucleus formation to occur, a prerequisite to successful ovum fertilization. 4


Poor diet and lifestyle choices (smoking, alcohol consumption, etc.) during the periconception period (oocyte growth → week 10 gestation) can result in compromised reproductive performance in association with moderate to severe increases in plasma homocysteine, which can be exacerbated by the presence of alleles encoding for sub-effective enzymes involved in 1C metabolic pathways 5. Deficiencies in 1C metabolism during this critical time may induce long-term epigenetic changes having adverse consequences on affected children.

Two hundred thirty-two women undergoing assisted reproductive technology (ART) at the Massachusetts General Hospital Fertility Center were enrolled in study designed to assess the relationship between folate intake and reproductive outcome 6. In this cohort of 232 women (mean 35.2 years of age), higher folate consumption was positively correlated with implantation, clinical pregnancy, and live birth rates. Although folic acid supplementation appeared to be effective in this study, a more recent publication suggests that 5-methyltetrahydrofolate (5-MTHF) would be a more appropriate supplement given that infertile/subfertile individuals may carry a methylene tetrahydrofolate reductase (MTHFR) genetic variant (e.g. C677T) that is much less effective at making 5-MTHF than the wild-type allele (677C) 7. Indeed, some fertility specialists have even proposed that testing for C677T mutations is essential for couples (and even oocyte donors) who have experienced multiple failed ART cycles and/or miscarriages 8. Consistent with this idea, 30 couples infertile for more than 4 years, and all with at least one partner having an MTHFR genetic variant, were given 600 mcg of 5-MTHF per day for 4 months, and then after 3 months the patients were allowed to attempt spontaneous conception for 2 months. 9 Fourteen of the couples conceived spontaneously and 13 pregnancies were recorded after ART, with 11 deliveries and 8 ongoing pregnancies, the latter in a 14 patient cohort with an average of 4.4 miscarriages/couple.

In another clinical study, 4 months of nutritional support of 1C metabolism significantly increased Anti-Mullerian hormone (AMH), an index of ovarian reserve, in a cohort of 55 women with a history of 3-7 years of infertility, accompanied by spontaneous pregnancies for eight patients awaiting oocyte donation within 3 months of supplement discontinuation 10.  In a second study of 100 women with at least one failed ART cycle and 3 years of infertility who were given 1C metabolism support prior to their next ART procedure, 45% achieved a clinical pregnancy in contrast to 13.7% of 73 women in a control group. 11


In several preliminary studies, supplementation of 1C metabolism in persistently infertile women in general or infertile couples, at least one of which had a defective MTHFR genetic variant, has been shown to result in a substantial number of clinical pregnancies/live births, accompanied by, in one study, increased ovarian reserve as assessed by AMH blood levels.


  1. 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. 
  2. Laanpere M, Altmae S, Stavreus-Evers A, et al. Folate-mediated one-carbon metabolism and its effect on female fertility and pregnancy viability. Nutrit Rev. 2009; 68:99-113. 
  3. Berker B, Kaya C, Aytac R, et al. Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction. Human Reprod. 2009;24:2293-2302. 
  4. Ebisch IMW, Thomas CMG, Peers WHM, et al. The importance of folate, zinc, and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Upate. 2007; 13:163-174. 
  5. 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 Reprod Update. 2013; 19:640-655. 
  6. Gaskins AJ, Afeiche M, Wright D, et al. Dietary folate and reproductive success among women undergoing assisted reproduction. Obstet Gynecol. 2014; 801-809. 
  7. Servy E, Menezo Y. The methylene tetrahydrofolate reductase (MEHRF) 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. Jacquesson-Fournols L, Servy EJ, Dale B, et al. MTHFR testing in ART should be compulsory for both male and female patients including oocyte donation programs. J Gynecol Women’s Health. 2017;7.
  9. Servy EJ, Jacquesson-Fournols, Cohen M, et al. MRHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. J Assist Repro Genet. 2018. 
  10. Silvestris E, Cohen M, Cornet D, et al. Supporting the one-carbon cycle restores ovarian reserve in subfertile women: absence of correlation with urinary bisphenol A concentration. Bioresearch Open Access. 2017; 6.1:104-109. 
  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):1-5. 

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