According to the World Health Organization, infertility is a disease of the reproductive system defined by a failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse.
Infertility, which affects ∼15% of the world’s population, is a global public health issue recognized by the WHO. In the case of male fertility, a recent meta-regression analysis reported a significant worldwide decline in total sperm counts between 1973 and 2011. These data strongly suggest a significant decline in male reproductive health, with crucial implications for human reproduction and perpetuation of the species. Research aimed at revealing the causes and implications of this decline is therefore urgently needed.
Agarwal and colleagues recently suggested that 20–70% of fertility problems are caused by the male partner (Agarwal et al., 2015). This range exhibited large geographical differences, with the highest rates detected in Africa and central/eastern Europe. According to this report, a total of 48.5 million couples worldwide suffer from infertility, suggesting that 15% of couples are affected by fertility problems.
Investigating modifiable lifestyle factors that influence human fertility—such as stress, drug use, smoking, alcohol intake, and diet—is of major clinical and public health importance for understanding the problem. Indeed, several observational studies that explored the associations between dietary patterns, food and nutrient consumption, and sperm quality suggest that adhering to a healthy diet (e.g., the Mediterranean diet) may improve male sperm quality parameters.
One of the causes of male infertility is a reduced or poor sperm quality. Three primary end-points are normally determined to assess sperm quality: sperm concentration, sperm morphology and sperm motility.
In Salas-Huetos et al. (2018) systematic review and meta-analysis, they revealed a significant beneficial effect on total sperm count from supplementation with omega-3 and CoQ10; on sperm concentration from supplementation with selenium, zinc, omega-3, and CoQ10; on sperm motility from supplementation with selenium, zinc, omega-3, CoQ10, and carnitines; and on sperm morphology from supplementation with selenium, omega-3, CoQ10, and carnitines. The review suggests that some dietary supplements may help to modulate male fertility.
Different underlying mechanisms could explain these results and therefore deserve comment. Oxidative stress (OS) is identified as one of the main mediators of male infertility. It causes sperm dysfunctions and is related to increased cellular damage triggered by oxidative stress radicals (ROS). This occurs naturally in sperm cells because high levels of sperm motility, in the case of the hyperactivation required in zona-pellucida binding, induce ROS. However, high levels of ROS were also strongly correlated with sperm DNA damage and low percentages of sperm motility, among other sperm-related outcomes.
The ROS-DNA–damage sperm motility pathway may also act in the opposite direction, i.e., DNA damage induces ROS through the H2AX (H2A histone family, member X)–Hox1 [NAD(P)H oxidase]/Rac1 (Rac Family Small GTPase 1) pathway.
In this scenario, the equilibrium between antioxidants and ROS may be key for achieving better sperm quality (mainly in terms of sperm motility, vitality, and DNA damage). This is why most of the randomized control trials (RCTs) in the literature tested antioxidant supplements in order to balance OS. Some supplements (vitamin E and zinc) proved beneficial for increasing the live birth rate in couples with male or unexplained subfertility and some (certain carnitine supplements) proved beneficial for increasing the pregnancy rate. Other supplements had no beneficial effects in this regard.
The main antioxidants tested as supplements with a positive effect on sperm quality parameters were selenium and zinc. On one hand, selenium is essential for the normal spermatogenesis of mammals and plays a pivotal role in increasing glutathione peroxidase-1 expression and activity, which, in turn, destroys hydrogen peroxide molecules. On the other hand, zinc is also an antioxidant element with a membrane-stabilizing activity by inhibiting membrane-bound oxidative enzymes such as NAD(P) oxidase.
A recent meta-analysis showed that the zinc content in the seminal plasma of infertile males was significantly lower than those of normal males, which indicates that zinc supplementation may significantly increase the sperm quality of infertile males. The present meta-analysis of RCTs in humans that used zinc and selenium as supplements reinforces this hypothesis. However, no consistent beneficial effects of other antioxidants, including folic acid, have been demonstrated.
Omega-3 PUFAs are fatty acids with anti-inflammatory and antioxidant properties potentially modifying cell membrane composition and functionality. The mechanism by which omega-3 (and omega-6) PUFAs can affect spermatogenesis is their incorporation into the spermatozoa cell membrane. It has been demonstrated that the successful fertilization of spermatozoa depends on the lipid composition of the spermatozoa membrane. In line with this finding, this meta-analysis shows positive effects on sperm concentration after supplementation with omega-3 PUFAs.
CoQ10 is also an antioxidant molecule with a central role in the electron-transport system. As Balercia et al. and Safarinejad pointed out, CoQ10 inhibits organic peroxide formation in seminal fluid and may therefore reduce sperm-cell oxidative stress (OS). In the last 2 decades, interest in this molecule as a supplement for treating infertile men and fecundability has grown.
In a meta-analysis conducted in 2013 by Lafuente et al., an overall improvement was shown in sperm parameters but not in live birth or pregnancy rates. However, high heterogeneity between the studies was reported, which indicates that more and larger studies are needed before supportive recommendations can be made.
This study shows that carnitine supplementation also has certain beneficial effects on spermatozoa motility and morphology, although there was also considerable heterogeneity between the 3 studies meta-analyzed. L-carnitine (LC) and L-acetyl-carnitine (LAC) play important roles in sperm metabolism by providing immediate available energy for use by spermatozoa, which positively affects sperm motility, the spermatogenic process, and maturation. In addition, carnitines are involved in the transportation of long-chain fatty acids into the mitochondrial matrix for β-oxidation and exert antioxidant activity by increasing the expression of antioxidant enzymes.
This study concluded that diet supplementation with certain antioxidants, especially selenium, zinc, omega-3 fatty acids, CoQ10, and carnitines, and certain foods rich in these supplements can beneficially modulate sperm quality parameters and affect male fertility. The small number of studies that have tested similar supplements, the small sample sizes included in those studies, and the high degree of interstudy heterogeneity across outcomes mean that further research may lead to a change in the effect estimates outlined in this meta-analysis. More RCTs with larger samples and clear inclusion/exclusion criteria are needed in future to test how these types of supplements affect not only sperm parameters but also fecundability.
Also, in Buhling et al. systematic review and meta-analysis showed a significant improvement in some sperm parameters for the following supplements: selenium, a combination of L-carnitine and acetyl-L-carnitine, and co-enzyme Q10. The meta-analysis including the studies by Safarinejad and Safarinejad (Safarinejad and Safarinejad, 2009) and Scott and colleagues (Scott et al., 1998) was able to show a significant improvement in oligozoospermia and asthenozoospermia after supplementation with selenium compared with placebo, whereas there are no published data for teratozoospermia within the primary data. The meta-analysis including the studies by Balercia and co-workers (Balercia et al., 2005) and Lenzi and co-workers (Lenzi et al., 2004) showed a significant improvement only for asthenozoospermia after supplementation with L-carnitine + acetyl-L-carnitine.
The meta-analysis including the studies of Nadjarzadeh and colleagues (Nadjarzadeh et al., 2011), Balercia and colleagues (Balercia et al., 2009) and Safarinejad (Safarinejad, 2009) was able to show a significant improvement in all measured end-points (oligozoospermia, asthenozoospermia and teratozoospermia) in relation to supplementation with co-enzyme Q10. This meta-analysis points out new perspectives on the treatment of male infertility, albeit from a small number of studies and small sample sizes.
This systematic review identified positive effects in treating male infertility for the following supplements: N-acetylcysteine alone or in combination with selenium, a combination of zinc and folic acid, a combination of EPA and DHA, and co-enzyme Q10.
Supplementation with N-acetylcysteine (alone or in combination with selenium) was evaluated in one study (Safarinejad and Safarinejad, 2009). A significant improvement in all three end-points (oligozoospermia, asthenozoospermia and teratozoospermia) was shown after treatment with N-acetylcysteine and a combination of N-acetylcysteine and selenium. A significant improvement in sperm concentration was shown in one study (Wong et al., 2002) in relation to a combination of zinc and folic acid. Concerning the combination of EPA and DHA, one available study (Safarinejad, 2011) showed significantly better results in the treatment group than the placebo group for all three end-points.
Overall, three of the five studies concerning Q10 supplementation (Balercia et al., 2009; Safarinejad, 2009; Safarinejad et al., 2012) showed significantly improved results for the following end-points.
In conclusion, this meta-analysis showed significantly better results for the intake of selenium (alone or in combination with N-acetylcysteine), a combination of zinc and folic acid, a combination of EPA and DHA, a combination of L-carnitine and LAC, and co-enzyme Q10. The level of evidence concerning supplementation with the other promising micronutrients is insufficient. Further well-designed clinical studies are needed to identify the influence on male fertility of supplementation with vitamins and minerals.