Arginine

Arginine is a precursor of nitric oxide and plays a role in augmenting the cellular inflammatory response by providing protection against oxidative damage. Arginine is essential for sperm motility, metabolism, capacitation, acrosome reaction, and is a precursor for producing petruscine, spermine, and spermidine.

Reports on the effect of arginine on semen parameters have been varied in the literature. Studies have reported daily arginine supplementation improves sperm concentration and motility. Conversely, other studies have failed to demonstrate any improvement in sperm counts or pregnancy rates. Other studies have demonstrated that excessive arginine concentrations can result in impaired sperm function.

Arginine occurs naturally in many plant-based dietary sources including barley, brown rice, buckwheat, cereal, chocolate, coconut, dairy, nuts, and seeds. It can also be found in various meat products. The recommended daily allowance (RDA) is 20 g, with an upper limit of 30 g. Potential side effects of excess consumption include increased bleeding risk, electrolyte abnormalities, gastrointestinal (GI) distress, increased glucose levels, hypotension, renal insufficiency, worsening symptoms of sickle cell disease, and asthma.

Carnitines

Carnitines are synthesized from the amino acids lysine and methionine. They are responsible for regulating intracellular metabolism through β-oxidation and buffer the acetyl-coenzyme A (CoA) to CoA ratio by transporting long-chain fatty acids into the mitochondria. Carnitines provide energy for spermatozoa and affect sperm motility and maturation. They also function as antioxidants providing protection against ROS.

l -Carnitine (LC) and l -acetylcarnitine (LAC) are the 2 main important forms. Both can be found concentrated in the epididymis, seminal plasma, and spermatozoa. Carnitine supplementation has been demonstrated to improve sperm concentration, motility, morphology, viability, and total oxidative capacity. Although pregnancy rates were higher in treatment groups, they were not statistically significant. Combination with nonsteroidal antiinflammatory drug therapy has also been found to improve semen parameters as well. Despite multiple studies espousing the benefits of carnitine supplementation, it has also been demonstrated to have inferior improvements on semen parameters compared with placebo.

Carnitines are considered conditionally essential nutrients. Dietary sources of carnitine are primarily found in meats, including red meat, poultry, fish, and dairy products. Unfortunately for vegetarians and vegans, fruits and vegetables carry minimal amounts. The RDA is not well established, however 4000 mg daily should not be exceeded. Excess intake greater than 4 g per day can result in GI distress, malodorous body secretions, and seizures.

Coenzyme Q10

Coenzyme Q10 (CoQ10) transports electrons in the mitochondrial respiratory chain and bioenergetics promoting energy within the sperm midpiece. It also acts as a lipid-soluble antioxidant for the lipoprotein-rich cell membrane and stabilizes and protects it from oxidative stress. CoQ10 can be measured directly in the semen and is correlated with sperm count and motility. Several placebo-controlled studies have demonstrated 4.5% to 6% improvement in sperm motility with CoQ10 supplementation.

CoQ10 can be found naturally in whole grains, rice bran, soybeans, nuts, cabbage, carrots, onions, potatoes, spinach, oily fish (mackerel and sardines), and organ meats. The body is naturally able to synthesize CoQ10, therefore no RDA has been established. Based on previous studies, the optimal intake is 200 to 300 mg/d, although acceptable daily intake can be titrated up to 12 mg/kg/d as needed. Adequate daily intake of CoQ10-containing foods can remove the need for additional supplementation. Excess intake can cause GI distress, headache, loss of appetite, and skin rash.

Folic Acid (Folate)

Folic acid is intrinsically involved in purine and pyrimidine production thereby playing an important role in DNA synthesis and proper cell function. It is also a potent free radical scavenger by providing methyl donors methionine and S -adenosylmethionine. Folate is a water-soluble B vitamin also known as vitamin B ₉ .

Adequate folic acid intake is associated with a decreased frequency of sperm DNA abnormalities; men consuming greater than 700 μg of folate daily have up to 30% lower frequency of disomy X and 21, sex nullisomy, and aggregate aneuploidy compared with men with lower intake. The effect of folic acid on male fertility is controversial. A double-blind, randomized, placebo-controlled study demonstrated a 74% increase in sperm count with folic acid and zinc supplementation, however there was a 4% increase in abnormal sperm morphology. Conversely, other studies have failed to demonstrate any positive improvement on DNA content, sperm concentration, morphology, or motility with folic acid supplementation.

Folic acid can be found in avocados, beans, brewer’s yeast, enriched cereals, citrus fruits, eggs, dark green leafy vegetables, and meat products. The RDA is 400 μg. There is no convincing evidence that folic acid intake more than the RDA improves fertility even though it has a critical role in spermatogenesis and sperm DNA production.

Excess intake can result in GI distress and rash. Significant excess can result in neurologic manifestation including irritability, sleep disturbance, confusion, and seizures. However, even low doses of folate have been associated with increased risk of myocardial infarction in patients with a cardiac history.

Glutathione

Glutathione is one of the most abundant endogenous antioxidants found in the body and plays an important role in maintaining exogenous antioxidants (ie, vitamins C and E) in their active reduced roles. It is produced in the liver and synthesized from cysteine, glutamic acid, and glycine. Glutathione also functions as a detoxification agent of carcinogens and harmful foreign compounds.

Glutathione supplementation in infertile men has been demonstrated to improve sperm motility. Men with varicoceles were noted to have a 10% increase in total sperm motility over baseline with treatment ( P <.01). Supplementation in combination with vitamins C and E has also been associated with improved sperm count and decreased DNA fragmentation, although it is unclear whether improvements can be attributed to glutathione alone or the synergistic effect with concomitant multiantioxidant supplementation.

Glutathione can be readily found in fresh fruits, vegetables, and meat products. There is no RDA due to endogenous production within the liver and supplementation up to 3 g has been demonstrated to be safe. Glutathione supplementation beyond food has been limited by its poor GI absorption and the need for intramuscular administration to achieve clinically effective levels. Regular intake of glutathione-rich foods, whey protein, as well as biochemical precursors, such as N -acetylcysteine (NAC) or α-lipoic acid, can maintain normal physiologic concentrations for antioxidant benefits.

Lycopene

Lycopene is a nonprovitamin A carotenoid antioxidant with roles in cell growth regulation, gap junction communication, gene expression modulation, immune responses, and protection of lipid peroxidation. Lycopene can be found concentrated in many human tissues, especially the adrenal glands, breast, liver, prostate, and testes.

Dietary intake or supplementation of lycopene has positive effects on semen parameters, however, there have been no confirmatory placebo-controlled randomized trials to date. Men consuming 1 can of tomato soup daily (22.8 mg of lycopene daily) can increase serum and semen lycopene concentrations. Sperm concentration, motility, and morphology have been found to improve with intake of lycopene 2000 μg twice daily.

Lycopene is readily available in tomato-containing foods. Lycopene is absorbed more efficiently from cooked and processed forms (ketchup, tomato sauce, stewed tomatoes, and so forth) rather than fresh tomatoes. A tomato-rich diet obviates the need for additional supplementation. Lycopene has no RDA or upper unsafe limit, however excess intake can result in GI distress and skin color changes. Supplementation is not considered necessary in most cultures because of the availability of lycopene in the diet. However, it is reasonable in those with dietary intolerances, but optimal dosing is unknown.

Omega Fatty Acids

Polyunsaturated fatty acids (PUFAs) are essential fatty acids because the human body cannot synthesize them. The 2 main types of PUFAs are omega-3 and omega-6 fatty acids. The main omega-3 fatty acids are α-linolenic acid (ALA), docosahexanoic acid (DHA), and eicosapentanoic acid (EPA). The main omega-6 fatty acids are arachidonic acid, linoleic acid, and γ-linolenic acid.

PUFAs make up an important part of the structural component of cell membranes, namely that of the cellular lipid bilayer. Fatty acids are incorporated into the sperm cell membrane and play a role in successful fertilization. They also have antioxidant abilities protecting the spermatocyte from ROS and oxidative stress.

Intake of PUFAs can improve sperm count, motility, morphology, and improve semen antioxidant activity. This was demonstrated in a double-blinded, placebo-controlled, randomized controlled study with 238 patients receiving 1.84 g of omega-3 fatty acids (DHA and EPA) or placebo daily for 32 weeks.

A prospective study comparing 82 infertile men to 78 age matched fertile men demonstrated a significant positive correlation between blood plasma and spermatozoa omega-3 fatty acid concentration and sperm concentration, motility, and morphology ( P <.05). However, there was a negative correlation between omega-6 fatty acid of spermatozoa and sperm count, motility, and morphology ( P = .001). This study concluded that fertile men had higher omega-3 and lower omega-6 fatty acid levels, whereas infertile men had higher omega-6 and lower omega-3 fatty acid levels.

Dietary sources for omega-3 fatty acids include oils derived from fish, plants, and nuts. DHA and EPA are found in cold-water fish (anchovy, halibut, herring, mackerel, sardines, salmon, and tuna) and fish oil supplements. ALA is found in flaxseed, soybeans, pumpkin seeds, purslane, perilla seed, walnuts, and their respective oils. The overall health effect of omega-3 fatty acids come from EPA and DHA; the body converts ALA to these 2 forms within the body.

There is no RDA for omega-3 fatty acid, however the acceptable intake is 1.6 g/d for men. Omega-3 fatty acid–enriched processed foods are widely available. These include bakery products, eggs, mayonnaise, margarines, meat, milk, oils, pasta, salad dressings, and poultry. Therefore, omega-3 deficiency is unlikely in most industrialized societies.

The side effects of excess omega-3 fatty acid supplementation include foul breath, change in taste, reflux, bloating, diarrhea, nausea, constipation, and pruritus. Excessive intake can also increase bleeding risk. Caution is advised for those on therapeutic anticoagulation or antiplatelet therapy.

Phytoestrogens

Phytoestrogens are plant-derived, nonsteroidal compounds that mimic the structure of estradiol and can thus bind to and activate estrogen receptors α and β. Phytoestrogens can interact with endogenous estrogen signaling pathways potentially disturbing normal hormonal pathways. They are thus known as endocrine-disrupting chemicals (EDCs) and can interfere with the production, metabolism, or activity of the body’s natural hormones that are normally responsible for development, homeostasis, and reproduction.

Phytoestrogens are naturally occurring plant compounds and can be found in many fruits and vegetables. Soybeans and soy products are the major source of dietary isoflavones, which are a subclass of phytoestrogens. Genistin and daidzin are the 2 major soy isoflavones found in soy and soy derivatives. The metabolites of these soy isoflavones also have antioxidant properties.

Isoflavones are closely associated with proteins, therefore alcohol extraction and processing tend to significantly decrease phytoestrogen levels. The total content is high in soy flour, isolated soy protein, fermented soybean, tempeh, and edamame. Conversely, the content is much lower in tofu, miso, soymilk, soy sauce, or alcohol-extracted soy protein.

People consuming more soybeans and soy products are exposed to higher levels of phytoestrogens. This puts those consuming traditional Asian diets in Japan and Korea up to 20 to 30 g/d at risk for potential fertility problems. Excessive intake may result in GI distress. Those with allergies to soy products may develop pruritus and rash.

Several conflicting studies have investigated the effect of soy intake on male fertility and more specifically semen parameters. A dietary study of 48 men with abnormal semen parameters and 10 control patients demonstrated improvements in sperm count and motility with soy intake.

Another dietary study with 99 men found that the intake of soy food and isoflavones was inversely related to sperm concentration. Those who consumed soy had 41 million/mL less sperm compared with nonsoy eaters ( P = .02). There was no quantification of the level of intake or serum isoflavone levels.

A third study with 14 subjects demonstrated no effect of isoflavone intake on semen quality or serum sexual hormone levels after 2 months of treatment. A recent meta-analysis with 32 reports suggests that soy or isoflavone intake does not affect testosterone levels.

There does not seem to be a beneficial or detrimental effect of soy intake on male fertility or reproductive capability based on the current literature. Negative effects are well outlined in small animal studies. However, there are no human placebo-controlled, randomized controlled studies investigating the true effect of soy products on overall male fertility and semen parameters.

Men with idiopathic infertility are advised against consuming soy products regularly because of the known estrogenic effects of isoflavones and their potential effect on the hormonal axis and spermatogenesis.

Selenium

Selenium is an essential trace element with an important role in antioxidant reactions. It is a component of glutathione peroxidase and serves as a cofactor in the reduction of antioxidant enzymes. It also has important roles in maintaining testicular development, spermatogenesis, and sperm functions, such as motility and capacitation. The detrimental effects of selenium deficiency include decreased sperm motility, decreased spermatozoa midpiece stability, and abnormal sperm development resulting in poor morphology.

Selenium has been noted to improve sperm count, motility, and morphology when used alone and in combination with other antioxidants and supplements. Vitamin E plays a role in selenium metabolism and works in synergy with selenium’s antioxidant properties. Men treated with selenium and vitamin E in a prospective randomized study had an 8% increase in sperm motility and a decrease in lipid peroxidation levels ( P <.05). A 3-month placebo-controlled study including selenium only and selenium in combination with other vitamins demonstrated a 12.9% increase in sperm motility ( P <.05) as well as an 11% pregnancy rate over placebo.

In contrast to the previous studies, a noncontrolled study with selenium only supplementation noted increases in serum and seminal selenium levels more than baseline, but no change in sperm count, motility, or morphology. This result may reflect the need for selenium to be taken in conjunction with other nutraceuticals to realize the synergistic effects of this trace element.

Selenium is absorbed readily from the soil by certain plants. It can be obtained in the diet directly through plants or indirectly through animal protein. Dietary sources include nuts (especially Brazil nuts), cereals, eggs, meat products (kidney), and seafood. This is one of the few nutraceuticals in which fruits and vegetables are poor sources. The RDA is 55 μg, and the upper tolerable limit is 400 μg/d.

Potential side effects with modest intake less than the upper tolerable limit include GI distress, fatigue, irritability, and nail changes. Toxic levels of intake can result in facial flushing, hair loss, garlic odor on the breath, metallic taste, muscle tenderness, tremors, hematologic derangements, and hepatic and renal insufficiency.

Vitamin A

Vitamin A, otherwise known as carotenoids and retinoids, is a fat-soluble vitamin that maintains the mucous membranes of the eyes, GI and genitourinary tracts, and skin. It may also have antioxidant properties, although the exact mechanism is unknown. Vitamin A deficiency can result in decreased spermatogenesis and decrease the integrity of Sertoli cell tight junctions thereby compromising the blood-testis barrier.

Combination therapy studies including vitamin A and other supplements including vitamins C and E, selenium, NAC, and zinc, have demonstrated its positive effects on sperm motility and count ( P <.05). Vitamin A only studies are currently lacking, therefore, the effect of vitamin A therapy alone on male infertility is difficult to discern.

Dietary vitamin A is readily available through many sources including many fruits and vegetables (carrots, sweet potatoes, pumpkin, cruciferous vegetables), dairy products, eggs, oily saltwater fish, and meat products. Many processed foods are enriched with vitamin A accounting for a significant source of intake in the western diet.

The RDA is 900 μg (∼3000 international units [IU]; conversion: IU × 0.3 = μg). The upper tolerable limit is 3000 μg. Side effects are uncommon with doses less than 10,000 μg/d. Vitamin A is fat-soluble and is readily stored in the body. Supplementation beyond daily dietary intake can result in accumulation of toxic levels. Symptoms of toxicity include central nervous system symptoms (fatigue, irritability, mental status changes), visual changes, papilledema, vertigo, anorexia, GI distress, fever, sweating, skin dryness, peeling skin of hands and feet, muscle aches, joint aches, liver toxicity, and hypoplastic anemia.

Vitamin C

Vitamin C, or ascorbic acid, is a water-soluble vitamin that is a key cofactor for hydroxylation and amidation reactions. It is involved in the synthesis of collagen, components of intercellular matrix, and proteoglycans. Vitamin C is also an important antioxidant that plays a role in recycling oxidized vitamin E. It also protects sperm and sperm DNA from oxidative damage by neutralizing ROS in a concentration-dependent manner. It can be found in high concentrations within seminal plasma and is proportional to intake. Adequate concentrations have been demonstrated to reduce sperm DNA fragmentation and damage.

Vitamin C supplementation has been associated with improvements in semen quality. Many studies have involved concurrent vitamin C supplementation with other vitamins and antioxidants. Synergistic improvements in sperm motility and concentration have been seen in combination studies with β-carotene, vitamin E, and zinc. It is therefore difficult to discern the actual effects of vitamin C solely on sperm production and function because the positive findings in many studies could reflect the synergistic effect of multiple agents and cofactors. Conversely, others have failed to find any positive effects on semen parameters when combining vitamins C and E.

Daily vitamin C supplementation with at least 200 mg has been found to improve sperm count, motility, and viability in heavy smokers. In this study, a direct correlation between serum and seminal vitamin C concentrations and sperm quality improvement was reported. Daily intake of vitamin C up to 1000 mg demonstrated the most change compared with lower doses, with a 34% improvement in viability and count, 5% improvement in motility, and 33% improvement in morphology over baseline ( P <.05). Other studies have also demonstrated improvements in sperm motility with daily doses more than 1000 mg.

Vitamin C is easily obtained from a multitude of fruits (citrus, kiwi, papaya, strawberry, and so forth) and vegetables (bell pepper, broccoli, cauliflower, kale). It is also a common additive in processed foods and beverages rendering vitamin C deficiency (scurvy) virtually obsolete in industrialized nations. The RDA is 90 mg to maintain physiologic stores. Doses 2 to 3 times more than the RDA result in a significant portion of the vitamin being excreted. Side effects of intake more than the daily upper limit of 2000 mg include dyspepsia, headache, and increased risk of nephrolithiasis as a result of conversion to oxalate.

Vitamin E

Vitamin E, part of the tocopherol family, is a potent antioxidant that plays many important roles. It inhibits free-radical–induced damage to cell membranes, prevents lipid peroxidation, and improves the activity of other antioxidants.

An important effect of vitamin E is its ability to reduce seminal ROS levels in men with infertility. A retrospective dietary survey and semen analysis demonstrated a direct relationship between increased dietary intake of vitamin E and antioxidants and higher sperm counts and motility compared with men with low intake. Those with higher intake had a higher sperm concentration of 84 million/mL and 5% higher sperm motility ( P <.05).

Randomized controlled trials of infertile men with vitamin E supplementation have demonstrated decreased lipid peroxidation, increased sperm motility, and improved pregnancy rates compared with those in the placebo group ( P <.001). Combination therapy with vitamin C demonstrated significant improvements in DNA fragmentation rates with TUNEL (terminal deoxynucleotide transferase–mediated dUTP nick-end labeling) assay improving from 22.1 before treatment to 9.1 after treatment ( P <.001).

Vitamin E dietary sources include fruits, vegetables, cereals, grains, vegetable oils, wheat germ, eggs, dairy products, meat, and poultry. The RDA is 15 mg (∼23 IU). The upper daily limit is 1000 mg (∼1600 IU), although no ill effects were seen in those taking up to 2000 mg (∼3200 IU) daily.

Supplementation is not benign, however. Recent studies have found that vitamin doses greater than 400 IU/d increase the risk of cardiovascular complications, especially heart failure, as well as all-cause mortality, and offer no protection against cancer. It has been well established that higher doses greater than 800 IU/d can increase its antiplatelet effects and bleeding risks. It can also mimic or potentiate the effects of warfarin by blocking the conversion of vitamin K to its active form at doses as low as 100 mg.

Potential side effects include fatigue, GI distress, headache, muscle weakness, rash, vision changes, bruising, and bleeding complications. Patients with bleeding disorders or requiring antiplatelet or anticlotting medications should be advised against additional vitamin E supplementation beyond daily dietary intake.

Zinc

Zinc is a cofactor for many enzymes involved in DNA transcription and protein synthesis. It has antiapoptotic and antioxidant properties and plays an important role in human immune function. Zinc is therefore an important component in the many physiologic processes involved in human growth and development.

Within male reproduction, zinc is involved in testicular development and steroidogenesis, spermatozoa oxygen management, nuclear chromatin condensation, acrosome reaction, acrosin activity, sperm chromatin stabilization, and 5α-dihydrotestosterone production. Because of its importance, zinc is found in high concentrations within the male genitourinary tract, especially in the prostate. Zinc deficiency can be associated with oligospermia, decreased testosterone levels, and compromised function of the immune system.

Zinc taken with vitamins C and E has been demonstrated to increase sperm motility by 24% ( P <.001), increase the antioxidant carrying capacity of 6 nmol/L ( P <.001), decrease ROS by 5 nmol/L ( P <.001), and decrease sperm apoptosis and DNA fragmentation. High dietary zinc intake of up to 74 mg daily with folate and antioxidants decreased the frequency of disomy X by 50% ( P <.001) in a study of 89 healthy men with sperm aneuploidy.

Zinc is present in plants from soil absorption. Wheat and seeds (ie, pumpkin, sesame, sunflower, and so forth) have the highest concentration. In the western diet, most zinc is obtained through beef intake secondarily. Zinc deficiency is unlikely in industrialized areas because of its availability and addition to many processed food products.

The RDA is 11 mg and the upper limit is 40 mg daily. Intake more than 200 mg can result in GI problems, gastric ulcers, loss of appetite, dehydration, headaches, and rash. Excessive intake more than 450 mg daily can lead to altered iron function, decreased copper levels, reduced immune function, reduced high-density lipoprotein levels, and sideroblastic anemia.