Nutrient Supplementation: Improving Male Fertility Fourfold by Cesar Mora-Esteves, MD and David Shin, MD

Post on September 25, 2013 by André Broussard, D.C.

Nutrient Supplementation
Improving Male Fertility Fourfold
Cesar Mora-Esteves, MD, David Shin, MD
Semin Reprod Med. 2013;31(4):293-300.

Medscape Article:  http://www.medscape.com/viewarticle/807178

Abstract and Introduction

Abstract

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.

Introduction

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]

Antioxidants

Male infertility can often be a frustrating problem because it is a multifactorial disorder for which an identifiable cause cannot be found in a significant percentage of cases.[16]

The damaging effects of OS are reported to play a role in 30 to 80% of subfertile men.[17] Unlike genetic factors, nutritional factors can be changed by altering the patient’s diet. Treatment strategies to reduce seminal OS levels may enhance natural conception and the outcome of assisted reproductive technologies. Antioxidants are the most important defense against free radical-induced infertility. Increases in ROS are thought to be due to environmental, lifestyle, and medical exposures (Table 1). Treatment with antioxidants is a widely used therapy for several medical indications including male-factor infertility, although its efficacy has yet to be well established. It is unknown whether ROS production can be used as a criterion to select men for antioxidant therapy, since intracellular sperm antioxidant status, sperm count, abstinence time, and other confounding factors must also be considered. Seminal fluid OS levels can be quantified either by direct methods such as chemiluminescence assays, cytochrome-c and nitroblue tetrazolium reduction, flow cytometry, electron spin resonance spectroscopy, and xylenol orange-based assay or by indirect methods that measure the levels of biomarkers of OS such as thiobarbituric acid-reactive substances, isoprostane, DNA damage, and total antioxidant capacity. The measurement of ROS may help to identify those patients who could benefit from antioxidant supplementation.[17] Bykova et al demonstrated that sperm samples from infertile men had higher levels of ROS and suggested that these men may benefit from antioxidant supplementation.[18] ROS negatively affect male fertility by altering sperm’s membranes and its DNA. When a sperm’s membranes are damaged, both motility and the ability to break down oocyte membranes are compromised.[19] Spermatozoal DNA integrity plays a major role in fertilization and subsequent embryo growth (for both natural and assisted conception).[13,20–22]

The Cochrane Collaboration

In 2011, the Cochrane Collaboration reviewed antioxidant use in infertile men. The objective of this review was to determine whether supplemented oral antioxidants compared with placebo, no treatment or another antioxidant improve outcomes for couples undergoing assisted reproduction with a subfertile male partner (Cochrane).[19]

The two main questions asked in this review were as follows: (1) do supplemented oral antioxidants improve assisted reproductive outcomes for couples with male-factor or unexplained infertility and (2) do different types of antioxidants given to infertile men have varying effects on assisted reproductive outcomes.[19]

This review pooled data from 34 randomized, controlled trials that included 2,876 couples. The primary outcome was live birth rate per couple. Secondary outcome measures included pregnancy rate, miscarriage rate, stillbirth rate, level of sperm DNA damage, sperm concentration/motility, and treatment-related side effects.

Use of antioxidants resulted in a statistically significant (p = 0.0008) increase in live birth rates when compared with men taking placebo (using three trials; pooled odds ratio [OR], 4.85; 95% confidence interval [CI], 1.92 to 12.24). Likewise, the increase in pregnancy rate was statistically significant (p < 0.0001) using 15 trials where 96 pregnancies occurred in 964 couples (pooled OR, 4.18; 95% CI, 2.65 to 6.59). Due to low-quality evidence, conclusions regarding the effect of antioxidants on sperm quality were not possible. The authors did conclude, however, that antioxidant supplementation might improve live birth and pregnancy rate outcomes for subfertile couples undergoing assisted reproduction.[19]

There continues to be a need for larger, randomized, controlled trials looking at the use of antioxidants and nutrient supplements for improving male fertility. Antioxidant supplements continue to be used because of the low cost and relatively low toxicity profile. In this review, we examine the potential role of antioxidants in the treatment of OS-induced male-factor infertility. Table 2 outlines antioxidant options.

Carnitines

Carnitine is a water-soluble antioxidant mostly derived from human diet. Extracellular and intracellular carnitine may play a role in sperm energy metabolism, providing the primary fuel for sperm motility. Spermatozoa show increased l-carnitine and l-acetylcarnitine concentrations during epididymal passage and acquisition of motility.[23]

Carnitines accumulate in the epididymis in both free and acetylated forms and are used by spermatozoa for mitochondrial b-oxidation of long chain fatty acids, since this is the principal shuttle and transfer system of the acyl to the mitochondrial CoA.[24,25] They enhance the cellular energetics in mitochondria by facilitating the entry and utilization of free fatty acids within the mitochondria and also restore the phospholipid composition of mitochondrial membranes by decreasing fatty acid oxidation.[26–28] Carnitine protects sperm DNA and cell membranes from free radical-induced damage and apoptosis[27,29–31] and has been correlated with sperm parameters such as concentration and motility, which relate to higher fecundity.[32,33] It is believed that initiation of sperm motility occurs in parallel to an increase in carnitine concentration in the epididymal lumen and l-acetylcarnitine in spermatozoa.[34,35] Acetylation of carnitine was found to be greater in motile than in immotile spermatozoa.[36] Patients with defective sperm motion parameters were shown to have reduced l-acetylcarnitine/l-carnitine ratio.[37]

Preliminary, uncontrolled studies suggest that oral carnitine supplementation has a favorable effect on sperm motion characteristics of infertile men.[38–40] A dose of 3 g of carnitine daily for 3 or 4 months[38,39]significantly improves a patient’s sperm motility, compared with pretreatment levels. A daily dose of 4 g over 2 months improved motility in 15 of 20 patients. This effect was more evident in seven patients whose partners achieved pregnancy during treatment and follow-up. The utility of carnitine to improve sperm motility is supported by more recent, randomized, controlled trials in which 2 g carnitine was administered daily.[27,29,30]The most significant improvement was seen in the groups with lower baseline motility.[27,29] However, studies by Lenzi et al failed to demonstrate any improvement in morphology, suggesting that carnitine’s effects are posttesticular.[27,29] On the contrary, Cavallini et al reported improved morphology at 3 and 6 months in the course of therapy.[30] In both of these studies, there was no further improvement seen in other semen parameters at 3 and 6 months of carnitine therapy.

Vitamins C and E

Vitamin E (α-tocopherol) is one of the most important lipid-soluble antioxidant molecules. It is located mainly in the cell membranes. It is thought to interrupt the chain reactions involving lipid peroxidation. It also enhances the activity of various antioxidants that scavenge free radicals generated during the univalent reduction of molecular oxygen and during normal activity of oxidative enzymes.[41,42]Vitamin E acts by breaking pathological, ROS-induced chain reactions. It confers its protective effects by shielding sperm membrane components from OS damage. Vitamin E has been used extensively in vivo to treat a variety of diseases.[43] Recent randomized, control trials have reported vitamin E supplementation to be efficacious in treating infertility in males with OS.[44,45] Oral vitamin E significantly increased spermatozoal motility and seemed to improve the likelihood of pregnancy in the patient’s spouse.[44]

Vitamin C (ascorbic acid) is a high potency water-soluble ROS scavenger. It is found in concentrations 10 times higher in seminal plasma than in serum.[46,47] It protects human spermatozoa against endogenous oxidative DNA damage.[48] Significantly reduced ascorbate concentrations have been observed in poor semen samples riddled with excess ROS.[49] Seminal plasma ascorbic acid concentrations have been positively correlated with percentage of morphologically normal spermatozoa.[50] Vitamin C has been assessed for its potential as an oral supplement, along with vitamin E, in the treatment of idiopathic male infertility. Their combination in vivo has been hypothesized to act synergistically by reducing peroxidative attack on spermatozoa.[51] In a randomized, controlled, double-blind study by Rolf et al, high-dose oral treatment with vitamins C and E for 56 days did not improve semen parameters, sperm survival, or pregnancy rates in couples with male-factor infertility.[52] Despite the fact that multiple studies have demonstrated that vitamins C and E are not effective,[45,52–54] further prospective, controlled, clinical trials could be conducted on patients with known DNA damage for whom antioxidant therapy may be useful.

Selenium

Selenium (Se) is an important element for normal testicular development, spermatogenesis, and spermatozoa motility and function.[55] Se may protect against oxidative DNA damage in human sperm cells. However, the exact mechanism by which Se acts is still controversial. The effects of Se could be mediated through selenoenzymes, such as phospholipid hydroperoxide glutathione peroxidase[56] and the sperm capsular selenoprotein glutathione peroxidase.[57] Selenoproteins in the human body help to maintain sperm structure integrity.[55,58] Spermatozoal effects of Se deficiency are loss of motility, breakage at the midpiece level,[59,60] and increased incidence of sperm shape abnormalities, mostly of the head.[61] Previous studies have shown a correlation between Se levels in seminal plasma and the proportion of normal sperm in a semen sample[62] as well as a significantly positive correlation levels between sperm concentration and seminal plasma Se in patients consulting for infertility.[63,64] However, these findings were not corroborated in other trials.[65,66]

Interestingly, the effectiveness of a combined treatment with Se and vitamin E in the treatment of male infertility has been examined because vitamin E works in synergy with Se as an antiperoxidant.[67,68] In their prospective, uncontrolled study, Vézina et al[69] reported that the combination of vitamin E and Se led to statistically significant increases in motility and mean seminal plasma glutathione peroxidase activity. Although there were not any documented improvements in sperm concentration, nor any achieved pregnancy in their cohort, the authors concluded that the improved sperm motion characteristics could be explained by the amplified antioxidant enzyme activity.[69] In a recent trial by Keskes-Ammar et al, improved sperm motility and lipid peroxidation markers were also similarly demonstrated after combined vitamin E and Se therapy.[70]

Carotenoids

Carotenoids have been shown to work synergistically with Se and vitamin E. In a recent double-blind, randomized, controlled trial, the carotenoid compound, astaxanthin, at a dose of 16 mg/day for 3 months, resulted in an increased total pregnancy rate compared with placebo (54.5 vs. 10.5%) as well as an increase in pregnancy per cycle (23.1 vs. 3.6%).[71] Another carotenoid of interest is lycopene, which is naturally derived from fruits and vegetables. Lycopene has been found to have the highest ROS-quenching rate, with plasma levels higher than β carotene.[72] Lycopene is found in high concentrations in the testes and seminal plasma, with lower levels in infertile men. Investigators have evaluated the effect of oral lycopene therapy in men with infertility. A dose of 200 mg for 3 months twice a day resulted in a statistically significant improvement in sperm concentration of 66% in patients and motility in 53% of patients.[73] However, patients with very low baseline sperm concentration did not exhibit significant response to treatment. In those patients with higher baseline concentrations, significant improvement was seen resulting in 6 pregnancies in 26 patients. These findings suggest the need of clinical trials to further evaluate the potential benefits of lycopene therapy.

Glutathione and N-acetylcysteine

Glutathione (GSH) is the most abundant reducing agent found in the body, protecting lipids, proteins, and nucleic acids against oxidative damage. GSH combines with vitamin E and Se to form glutathione peroxidase. In a placebo-controlled, double-blind, crossover trial, administration of 600 mg for 2 months by intramuscular injection in 20 infertile men significantly increased sperm motion characteristics and specifically improved forward progression.[74] GSH deficiency may render the midpiece unstable, resulting in defective morphology and motility.[75,76] N-acetylcysteine (NAC) is a derivative of the naturally occurring amino acid l-cysteine, and it exhibits antioxidant properties. Since it is a precursor of GSH, NAC works to increase the concentration of this endogenous reducing agent while also directly alleviating OS by scavenging free radicals.[77] In vitro NAC actions in the human seminiferous tubules have been observed to play an important role in germ cell survival.[78] Oeda et al found that incubating semen samples with NAC for 20 minutes significantly decreased ROS levels and led to improved sperm motility.[79] An uncontrolled study found that NAC improved sperm concentration and acrosome reaction, while reducing ROS and oxidation of sperm DNA. However, it did not appear to have an effect on motility and morphology.[80]

Further studies have been conducted to test the efficacy of NAC in combined antioxidant regimen. Safarinejad and Safarinejad[81] reported that NAC with Se has additive beneficial effects on mean sperm concentration and normal morphology percentage in a randomized, controlled trial. By the end of a 26-week treatment period, motility increased significantly in the combined treatment group and in those patients receiving Se alone, compared with placebo. Combination treatment led to significantly better sperm parameters than treatment with only Se.[81]

Pentoxifylline

Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor that raises intracellular cyclic adenosine monophosphate and reduces inflammation by inhibiting tumor necrosis factor-alpha and leukotriene synthesis. It has been shown to reduce ROS,[82,83]and preserve sperm motility in vitro[84] and improve semen parameters in vivo.[85,86] Tesarik et al demonstrated that in unselected asthenospermic patients, pentoxifylline improved sperm motion characteristics, but did not increase the percentage of motile spermatozoa.[87] Other investigators have studied the effects of in vitro and in vivo pentoxifylline treatment on sperm motion parameters in select asthenospermic patients whose spermatozoa produced detectable steady state levels of ROS. Treatment decreased ROS formation and preserved sperm motion parameters in vitro. Orally administered pentoxifylline had no effect at a low dosage, whereas a high dosage was seen to increase sperm motility and some sperm motion parameters without altering sperm fertilizing ability.[88]

Trace Metals and Folic Acid

Zinc and copper intake are needed to maintain the optimal functioning level of antioxidant enzymes, such as superoxide dismutase. The average daily intake in the United States is 12.3 mg of zinc and 900 mg of copper per person. Studies have shown that seminal plasma zinc concentrations differ significantly between fertile and subfertile men.[89] Zinc may promote male fertility by conferring protection to sperm structure. Zinc deficiency has been associated with abnormal flagella showing hypertrophy and hyperplasia of the fibrous sheath, axonemal disruption, and defects of the inner dynein arms of microtubular doublets, with distorted inner axonemal structure and a poorly formed or absent midpiece.[90] Prospective studies show an improvement of sperm concentration,[91–93] progressive motility, sperm integrity, and pregnancy rates in subfertile males after zinc supplementation. Omu et al showed in a recent randomized, controlled trial that zinc therapy yields various benefits in infertile men.[90] These benefits include reduction in apoptotic markers, enhancement of antioxidant capacity, decreased DNA fragmentation, and increased expression of anti-inflammatory cytokines. Zinc therapy led to improved sperm parameters, although the improvements were not statistically significant. In recent clinical trial by Atig et al, zinc was found to be statistically significantly higher in fertile men compared with both oligoasthenoteratozoospermic and asthenozoospermic patients.[94] This evidence suggests that zinc may be useful in reducing OS and the associated sperm membrane and DNA damage.

Zinc and folic acid are both essential for transfer RNA and DNA synthesis. However, the underlying mechanisms by which they affect spermatogenesis are not known.[95] According to Ebisch et al, a combination of zinc and folic acid led to an increase in sperm concentration, having an endocrine-independent mechanism, as evidenced by an unchanged follicle-stimulating hormone, testosterone, and inhibin.[96] Other studies have failed to demonstrate any significant difference in concentrations of zinc and folic acid between fertile and subfertile males.[97,98] Landau et al reported that daily supplementation with folic acid had no beneficial effect on sperm concentration in normospermic or oligoasthenozoospermic men.[99] Animal in vivo and in vitro studies have shown that zinc deficiency alters the absorption and metabolism of dietary folate.[100-102] In a recent double-blind, randomized, controlled trial, folic acid was given at a daily dose of 5 mg, and zinc sulfate was given at a daily dose of 66 mg. Subfertile men demonstrated a significant 74% increase in total normal sperm count and a minor increase of 4% in abnormal spermatozoa.[103] A similar finding was seen in fertile men. These findings were not correlated with pregnancy rates. Further studies are needed to address efficacy and safety of these substances.

Other

Menevit is an oral antioxidant supplement consisting of vitamin C, vitamin E, zinc, folic acid, lycopene, garlic oil, and Se. In a prospective, randomized, double-blind trial involving 60 couples with severe male-factor infertility, a daily oral Menevit tablet taken for 3 months before the partner’s in vitro fertilization cycle improved the viable pregnancy rate (38.5% of transferred embryos) compared with a placebo group (16% of transferred embryos).[104]

Coenzyme Q10 (CoQ-10) is found endogenously in the sperm midpiece. It recycles vitamin E, controls its prooxidant capability, and is involved in energy production.[105] In vitro incubation of semen samples of infertile men with 50 mM of CoQ-10 significantly increased sperm motility. Oral supplementation with 60 mg of CoQ-10 in these infertile men was seen to improve fertilization rate without affecting semen parameters.[106] Catalase is another antioxidant that should be further investigated for its ability to detoxify both intracellular and extracellular hydrogen peroxide to water and oxygen.[107] Other compounds involved in the regeneration of antioxidant stores, such as lipoic acid, may also be beneficial to enhance the effects of vitamins C and E as well as GSH.[108]

Conclusion

The management of male-factor infertility is complex. Assisted reproductive technology is expensive and its success rate and availability are limited. Therefore, pharmacological agents with acceptable cost and success rate should be considered as part of the treatment options. When considering pharmacological management, physicians encounter a small range of options. Most therapies are not standardized due to the lack of acceptable scientific evidence, through clinical randomized studies, to support them. Currently, many drugs are used with minimal data showing any beneficial effect. For a drug to be considered effective, it should improve sperm parameters and pregnancy rates. The existing evidence supports the principles by which the use of systemic antioxidants is proposed. However, the different etiologies as well as seasonal, regional, and racial variance in sperm count and quality[109–111] make it difficult to consider the existent data absolutely valid. Furthermore, the available therapy options have produced marginally satisfactory and variable responses. A definitive conclusion cannot be drawn from the existent heterogeneous literature. Further randomized, controlled, clinical trials are needed to be able to understand the efficacy and safety of antioxidants and propose proper protocols for their use.

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