Clinical Evidence for the Importance of 1-Carbon Cycle Support in Subfertile Couples

Research Article

Austin J Reprod Med Infertil. 2015;2(2): 1011.

Clinical Evidence for the Importance of 1-Carbon Cycle Support in Subfertile Couples

Dominique Cornet¹, Edouard Amar², Marc Cohen³ and Yves Ménézo4*

¹Clinique de la Muette , Rue Nicolo, 75016 Paris, France

²Cabinet Médical d’Andrologie, 17 avenue Victor Hugo, 75016 Paris, France

³Clinique Natecia, Avenue Rockefeller, Lyon France

4Laboratoire Clément, 17 avenue d’Eylau, 75016 Paris and London Fertility associates, 104 Harley street, London WIG7JD, UK

*Corresponding author: Yves Ménézo, 4Laboratoire Clément, 17 avenue d’Eylau, 75016 Paris and London Fertility associates, 104 Harley street, London WIG7JD, UK

Received: March 16, 2015; Accepted: May 10, 2015; Published: May 29, 2015


This study assesses the effect of nutritional support directed towards the 1-C cycle on the fertility of male and female patients attending an ART program. In a first group, female partners of couples having failed at least one ART attempt were administered 1-C nutritional support prior to a further ART cycle. A second group comprised couples who had failed at least 2 assisted reproductive technology (ART) attempts, with male partners having elevated DNA fragmentation index (DFI) or nuclear decondensation index (SDI). The treatment consisted of compounds that play a major role in the 1-C cycle: B vitamins, chelated zinc and N-acetyl cysteine.

The first group of 100 treated female patients achieved a clinical pregnancy rate (PR) of 45%, with a high rate of spontaneous conception before ART. This was significantly higher (p=0.0001) than the PR observed in the control group of 73 patients, with PR =13.7%. When the male partners alone (95) were treated, a significant decrease was observed for DFI and SDI vs. control (84), and this was associated with a significant increase in the delivery rates (47.4% vs. 21.4%, p=0.001). Nutritional support of the 1-C cycle improves male and female fertility; this should not be overlooked, especially for women entering ART programs.

Keywords: ART; SDI; DFI; Oxidative stress; DNA


Oxidative stress (OS) represents a hazard to reproductive processes. The impact of OS on male fertility, i.e. on sperm quality, has been recognized since the pioneering works of Evenson et al. [1] in the early 1980’s, and it now appears that damage caused by OS is shared equally between male and female [2]. Evidence indicates that damage can be attributed to roughly one-third of maternal origin, one-third paternal, and one-third shared between both partners. A better appreciation of sperm quality through estimation of DNA integrity is now available: fragmentation (DNA fragmentation index, DFI) and sperm nuclear decondensation index (SDI), or high DNA stainability (HDS). DFI and SDI correlate poorly with the classical WHO sperm parameters of count, motility and morphology, and without treatment are relatively stable over time [3-6]. The DFI increases considerably with age [3,5,6], but SDI decreases slightly, indicating an age-related weakened defense against reactive oxygen species [6]. Damage of paternal origin has multiple sources for ROS-linked decays that originate partly, but not entirely from the spermatozoon itself, i.e. the mitochondria [7]. More than 10 base oxidation products [8], DNA adducts [9], and DNA strand breaks [1], as well as some features of nuclear decondensation are ROS-derived. In the female partner, adduct formation and DNA base oxidation add to age-associated meiotic defects observed in oocytes from older patients; in combination with aberrant response to DNA damage and telomere recombination, all of these effects can lead to infertility or early miscarriage [10]. In theory, the oocyte/zygote can repair these chemical insults to some extent [8,11], but the capacity for repair is finite, and decreases with age [12]. When the oocytes’ capacity for DNA repair is overwhelmed, a process of “tolerance” allows mutations that lead to miscarriages and other later pathologies [13- 14]. Recent observations in animals [15] have emphasized potential risks to postnatal development after performing micro-injection with highly fragmented DNA. It is tempting to try to reduce or avoid DNA damage related to ROS through consumption of anti-oxidants, and taking vitamins A, E and C, often coupled with selenium, seems an attractive proposition. Vitamins C and E can be either anti- or pro-oxidant. Equilibrium between oxidation and reduction status must be maintained over time. Vitamin C opens disulfide bridges of glutathione and protamines [16], leading to nuclear decondensation in the spermatozoon: oxidized glutathione is essential for padlocking and cross-linking protamines [17]. DNA decondensation induces chromosomal anomalies, and thus is deleterious for early development [18-19]. We recently observed [20] a process of sperm decondensation after treatment with mixtures of selenium and vitamins A, C, and E. The practice of ingesting large ‘blind’ doses of anti-oxidants is highly questionable [21], and has been shown to be poorly efficient, at least in women [22]: the final outcome, i.e. ongoing pregnancies and deliveries, are seldom taken into account. The fact that there is a strong correlation between oxidative stress and DNA methylation is no longer in question, and this has a further subsequent impact on transmitted diseases [23-25]. There is a clear biochemical explanation behind this concept, as seen in Figure 1. Oxidative stress has an influence on the one carbon (1-C) cycle, which is involved in homocysteine recycling with formation of methionine, necessary for DNA methylation. Through synthesis of cystine, products of the 1-C cycle include two major endogenous antioxidants: hypotaurine [26] present in the environment of oocytes, sperm and embryos, and glutathione. Ovarian stimulation has a negative impact on homocysteine metabolism [27]: homocysteine competes with the same oocyte receptor for methionine, and thus inhibits methylation reactions that are necessary for imprinting [28]. The cysteine beta synthase (CBS) pathway allows recycling of homocysteine to some extent, but this pathway is not expressed in the human oocyte [29]. Therefore, until the time of genomic activation on the third day postfertilization, the human zygote genome is poorly defended from the negative impact of homocysteine on supplies of methionine that are required to maintain methylation, with a downstream effect on imprinting. In addition, female and male reproductive physiology is now at risk from plastic-derived endocrine disruptors present at high levels in our current environment. This study was conducted in order to investigate the impact of nutritional support for the 1-C cycle in female and male partners consulting for ART.