The oxygen paradox revolves around the fact that oxygen is needed for survival, but oxygen can also be converted to free oxygen radicals, which are highly toxic to cells. The production of reactive oxygen species (ROS) of compounds by the male reproductive system is a great paradigm for this conflict. ROS are necessary for sperm. However, ROS in higher concentrations cause damage to sperm affecting a number of sperm functions. The male reproductive tract had evolved mechanisms which ensure that the required amount of ROS is present, but these mechanisms prevent higher, toxic levels of ROS.
Sperm are particularly susceptible to damage by ROS because many of the vital functions of sperm involve membrane phenomenon. Sperm membranes contain a large amount of polyunsaturated fatty acids, which react with ROS. However, because of the unique condition sperm have which requires them to be small, motile, and highly specialized; they do not possess high concentrations of scavenging enzymes needed to inactivate ROS. This is even further exaggerated when considering the membranes that surround the acrosome and the tail, since virtually no cytoplasm exists in these areas. Sperm can produce ROS with higher levels correlating with reduced semen quality. One manifestation of this is the retention of cytoplasmic droplets on sperm, which can be detected in a routine Semen Analysis (SA) from the morphologic evaluation. Clinically, some sperm isolation procedures used for intrauterine insemination (IUI) can increase the ROS concentration. There can also be external sources of ROS in semen as, for example, the ROS produced by peroxidase- positive leukocyte. Various aspects of sperm function are affected by increased ROS which affects the fluidity of the sperm membrane, and DNA fragmentation. There are many mechanisms in place to prevent increased levels of ROS. These include seminal plasma superoxide dismutase, glutathione reductase, catalase, ascorbate and a- tocopherol (vitamin E), and taurine. Tocopherol binds ROS, which prevents their interaction with the lipids in cell membranes. Vitamin C can displace heavy metal ions, iron and copper, from redox proteins, which are then free to bind to ROS, thus inactivating them. It is important for sperm to limit their oxidative stress since they lack the enzymes necessary to repair the damage caused by ROS.
There is evidence that oral treatment of male infertility patients using vitamin E and essential fatty acids can reduce the ROS level. The use of antioxidants in in vitro systems have proven beneficial in improving sperm function. Importantly, there are a number of studies that demonstrate an improvement in pregnancy rates for infertile men treated with antioxidants. Suleiman (1996) reported that treatment of infertile males with lipid peroxidation as evidenced by elevated malondialdehyde levels with oral vitamin E decreased the MDA levels and for 11/52 treated males, the wife became pregnant. No pregnancies occurred in a placebo control group. The dose of vitamin E was 300 mg taken twice per day. Comhaire et al (2000) reported that the use of vitamin E, A, and essential fatty acids improved the pregnancy rate over placebo therapy. The study by Comhaire noted that the pregnancy rate was higher in ex-smokers than in non-smokers. There is presently no evidence that zinc or folic acid increase pregnancy rates. Finally, a study by Rolf (1993) failed to demonstrate any increase in pregnancy rates for males treated with antioxidants.
Carnitines are compounds that sperm can use for energy or they can protect against ROS. Dietary sources of carnitines include dairy products, fish, and meat. Carnitines can be synthesized by humans, but dietary carnitines can significantly supplement the amount produced endogenously. Carnitine therapy has been shown to enhance sperm motility in some patients with asthenospermia and to decrease ROS species in patients with elevated ROS. A RCT study by Lenzi (Lenzi et al., 2003) administered 2 grams per day L-carnitine to subjects and demonstrated an improvement in sperm parameters. Unfortunately, this study did not mention pregnancy rates. Other studies, not RCTs, have demonstrated an improved pregnancy rate. Therefore, treatment of male infertility patients might be helpful where an elevated ROS may be an important factor in the etiology of the problem.
Male factor infertility, like female factor infertility, is due to a variety of causes. Many would not be amenable to treatment with dietary supplementation. Once an etiology has been defined, then appropriate traditional therapy is indicated. However, for etiology unknown, for smokers or ex-smokers, and possibly for varicocele patients, the use of antioxidants might be beneficial. Certainly the use of vitamin C and E may prove useful with very little risk. There are virtually no serious side-effects of even massive vitamin C over-usage with acute intake exceeding 10grams or excessive chronic consumption of >3 grams per day. Vitamin E can have toxic signs such as headache, drowsiness, nausea and vomiting for acute intake if the patient uses > 2-5 million IU. Chronic vitamin E intake exceeding 100,000 IU per day can lead to anorexia, headache, blurred vision, loss of hair, liver damage and enlargement, and anemia. Standard doses used in various studies were from 500 to 1000 mg. vitamin C per day and 300 to 600 mg. of vitamin E per day. L-carnitine can be used at 2 grams per day dosages.