Nutrient Supplementation

Improving Male Fertility Fourfold

Cesar Mora-Esteves, MD; David Shin, MD


Semin Reprod Med. 2013;31(4):293-300. 

In This Article

Abstract and Introduction


Oxidative stress can contribute to impairment in spermatogenesis leading to male-factor infertility. The effectiveness of various antioxidants (such as carnitine, vitamin C, vitamin E, selenium, carotenoids, glutathione, N-acetylcysteine, zinc, folic acid, and coenzyme Q10) is variable with respect to improving semen parameters and pregnancy rates. A recent Cochrane review determined that men taking antioxidants had a statistically significant increase in both live birth rates and pregnancy rates. For those undergoing assisted reproduction, the odds ratio that antioxidant use would improve pregnancy rates was 4.18, with a 4.85-fold improvement in live birth rate also noted. Further investigation with randomized, controlled clinical trials is needed to confirm the safety and efficacy of antioxidant supplementation in the medical management and treatment of male infertility.


Infertility is classically defined as the inability to achieve a pregnancy within 1 year of regular, unprotected intercourse and affects approximately 15% of all couples, with no identifiable cause in nearly 25% of cases and an identifiable causative male factor in around 40% of couples.[1] According to the World Health Organization (WHO), the alteration in sperm concentration, motility, and/or morphology in at least one sample of two semen analyses collected between 1 and 4 weeks apart has been shown to contribute to the pathogenesis of male-factor infertility.[2]

Free radicals are molecules with one or more unpaired electrons that can modify biomolecules by oxidation. These molecules are highly reactive and react with almost any substance in their vicinity. In the presence of lipids, amino acids, and nucleic acids, they can start a chain reaction leading to cellular damage.[3,4] Superoxide hydroxyl radical and hydrogen peroxide are major reactive oxygen species (ROS) present in seminal fluid. At physiologic levels, these species are needed for the normal reproductive function, by intermediating in vascular tone regulation, gene regulation, sperm capacitation, and acrosome reaction. When present in high concentrations, ROS have negative effects on spermatids and mature spermatozoa because their membranes are rich in polyunsaturated lipids.[4,5] The point at which the peroxidative damage to spermatozoa occurs is unknown. However, the effects of ROS on membrane integrity may impair motility and morphology, possibly leading to cell death.[6] To sustain normal cell function, excess ROS must be inactivated by seminal plasma antioxidants in a continuous way by either blocking the formation of ROS or removing the ones already formed. Some of these natural antioxidants are catalase, glutathione peroxidase, superoxide dismutase low-molecular-weight substances (α-tocopherol, β-carotene, ascorbate, urate), and transition metal chelators (transferrin, lactoferrin, ceruloplasmin).[7,8] In healthy males, a delicate balance between ROS and antioxidants is sustained in the reproductive tract. Oxidative stress (OS) develops once the antioxidant defense system becomes insufficient against ROS resulting in damage to cells, tissues, and organs.[9,10,11] It has been demonstrated that seminal OS impacts sperm motility, function, and concentration in a negative way. This will ultimately affect fusion events needed for fertilization.[9,12] Therefore, the polyunsaturated fatty acids of the sperm plasma membrane are susceptible to ROS damage at low concentrations at which scavenging enzymes are found in sperm cytoplasm.[5] The presence of ROS may increase apoptosis to remove old cells, which can decrease sperm concentration.[13,14] Levels of caspases, proteases involved in apoptosis, correlate with ROS levels—implicating OS in increased apoptosis in mature spermatozoa. Apoptosis could be induced in cell cultures with H2O2, further implicating ROS in the induction of apoptosis.[15]