Treatment for High Levels of Sperm DNA Fragmentation and Nuclear Decondensation: Sequential Treatment with a Potent Antioxidant Followed by Stimulation of the One- Carbon Cycle vs One-Carbon Cycle Back-up Alone

Research Article

Austin J Reprod Med Infertil. 2015;2(1): 1006.

Treatment for High Levels of Sperm DNA Fragmentation and Nuclear Decondensation: Sequential Treatment with a Potent Antioxidant Followed by Stimulation of the One-Carbon Cycle vs One-Carbon Cycle Back-up Alone

Edouard Amar¹, Dominique Cornet², Marc Cohen³ and Yves Ménézo4*

¹Cabinet Medical Andrology, France

²Clinique de la Muette, France

³Clinique Natecia, France

4Laboratoire Clément, France

*Corresponding author: Yves Ménézo, Laboratoire Clément, France

Received: February 17, 2015; Accepted: March 15, 2015; Published: April 02, 2015


Current lifestyle can have a negative impact on spermatogenesis via fragmentation of sperm DNA. Attempting to limit generation of ROS-related DNA damage through anti-oxidant supplementation is a tempting option, but current antioxidant treatments are inefficient, and lead to degradation of tertiary structures in sperm nuclear DNA (decondensation) by opening protaminecystine bridges. We investigated the effects of two different treatment regimes in patients, with no major semen anomalies and partners with no female factor detected. All the male partner had a very high level of sperm DNA fragmentation and de condensation: sequential treatment with a potent antioxidant followed by support of the one carbon cycle was compared with one-carbon cycle support alone. These two groups were also compared with a third (control) group of men who chose not to take these supplements. All of the patients who received sequential treatment showed a decrease in their fragmentation index, without concomitant increase in nuclear decondensation. However, patients treated with one-carbon cycle support alone showed similar results. The pregnancy rates reached 50% and over in the treated groups vs 27% in the control group. This confirms a strong correlation between methylation, homocysteine recycling and oxidative stress (Hoffman 2011, Ménézo et al. 2011).

Keywords: Sperm; DNA fragmentation; Nucleus decondensation; Antioxidants; One carbon cycle


Male reproductive failure is thought to represent more than one half of infertility cases in Western countries. Until the 1980’s, semen analysis focused only on morphology, volume motility and sperm count. The pioneering work of Evenson et al. [1] led to a better appreciation of sperm quality through estimation of DNA integrity: fragmentation (DNA fragmentation index, DFI) and sperm nuclear decondensation index (SDI), or high DNA stainability (HDS) in a sperm chromatin structure assay (SCSA®). DNA fragmentation is also measured by the Halo test (SCD) and the Comet assay. DFI and SDI do not necessarily correlate with the classical WHO sperm parameters of count, motility and morphology and without treatment are relatively stable over time [2-4]. The DFI increases considerably with age [2,4], but SDI decreases slightly, indicating an age-related weakened defense against reactive oxygen species [2-5].

In theory, such chemical insults can be repaired by the oocyte/ zygote [6-8], but this capacity is finite and decreases with age. If the oocyte is overwhelmed by oxidative insult, DNA damage is not repaired, and this may lead to mutations and subsequently to miscarriages or later pathologies [9-15].

Recent observations in animals [16] have emphasized potential risks to postnatal development after performing micro-injection with highly fragmented DNA. Oxidative stress (OS) is one of the major causes of DNA and chromatin damage, with an impact on sperm quality [17,18]. Reactive oxygen species (ROS) originate partly, but not entirely from the spermatozoon itself, originating in the mitochondria [19]. Attempting to reduce or even avoid the generation of DNA damage related to ROS through oral consumption of antioxidants is tempting, particularly if we consider that the oocyte has to manage its own burden of DNA damage [17]. Mixtures of vitamins A, E and C, often coupled with selenium and coQ10 are the favorite “cocktail”. They lead to a certain extent, to some improvement [20]. However, vitamin A and E can be either anti- or pro-oxidant. Moreover, Vitamin C opens disulfide bridges [21] leading to nuclear decondensation in the spermatozoon. DNA decondensation induces chromosomal anomalies, and thus is deleterious for early development [22-23]. We recently observed [24] a similar de condensation process after treatment with mixtures of selenium and vitamins A, C, and E. Genetic and epigenetic components both play a part in paternally transmitted DNA damage to the offspring. Moreover, oxidized glutathione is mandatory for padlocking and cross-linking protamines [25]: An equilibrium between oxidation and reduction status has to be maintained over time. In fact, although ‘blanket’ ingestion of anti-oxidants containing vitamins A, C and E is at present far merely highly questionable [26], there is no longer any question regarding the strong correlation between oxidative stress, DNA methylation and its further impact on transmitted diseases [14,27-31] and this can be easily explained in terms of biochemistry (Figure 1). Oxidative stress has an impact on the one-carbon cycle, which is involved in homocysteine recycling and formation of methionine, methylation and compaction of sperm DNA [5,32-34] Through cysteine synthesis, the one-carbon cycle also facilitates the synthesis of two major endogenous antioxidants: hypotaurine [35] and glutathione.