Literature Report Summaries of recent studies
Nutritional effects of micronutrients on male fertility
Preface About 40% of men all over the world suffer from impaired fertility due to insufficient sperm quality − frequently without even knowing it. Male infertility is a multifactorial disease with a number of contributing causes, such as environmental and dietary factors. Sperm production is a highly complex biological process which takes several weeks and may easily be affected by adverse factors of influence. In the process of spermatozoa maturation the body needs specific auxiliary agents These include various amino acids, trace elements, vitamins and vitamin-like substances. Studies support the fact that optimal conditions for normal and healthy sperm development are only possible when these special nutrients are present. Many individual agents which are important for sperm maturation were already scientifically tested in numerous clinical trials and described by renowned researchers. It could be shown that certain nutrients, such as L-carnitine, zinc and vitamin E, may have a favorable effect on the number and motility of sperms and ultimately on fertility.
Micronutrient Combinations
Vitamins
Trace Elements
L-Carnitine and Coenzyme Q10
N-Acetylcysteine
Polyunsaturated Fatty Acids
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Micronutrient Combinations
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Wong WY, Merkus HMWM, Thomas CMG, et al. Effects of folic acid and zinc sulphate on male factor subfertility: a double-blind, randomized, placebo-controlled trial.
Matalliotakis I, Koumantaki Y, Evageliou A, et al. L-carnitine levels in the seminal plasma of fertile and infertile men: Correlation with sperm quality. Int J Fertil Womens Med 2000;54(3):236-40.
Fertil Steril 2002;77(3):491-8.
Khademi A, Alleyassin A, Safdarian L, et al. The effects of L-carnitine on sperm parameters in smoker and non-smoker patients with idiopathic sperm abnormalities. J Assist Reprod Genet 2005;22(11-12):395-9.
Sinclair S. Male infertility: nutritional and environmental considerations. Altern Med Rev 2000;5(1):28-38.
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Sheweita SA, Tilmisany AM, Al-Sawaf H. Mechanism of male infertility: role of antioxidants. Curr Drug Metab 2005;6(5):495-501.
Balercia G, Mosca F, Mantero F, et al. Coenzyme Q10 supplementation in infertile men with idiopathic asthenozoospermia: an open, uncontrolled study. Fertil Steril 2004;81(1):93-8.
Vitamins
Lenzi A, Sgrò P, Salacone P, et al. A placebo-controlled double-blind randomized trial of the use of combined carnitine and L-actyl-carnitine treatment in men with asthenozoospermia. Fertil Steril 2004;8(6):1578-84.
Suleiman SA, Ali ME, Zaki ZMS, et al. Lipid peroxidation and human sperm motility: protective role of vitamin E. J Androl 1996;17(5):530-7. Akmal A, Qadri JQ, Noori S, et al. Improvement in human semen quality after oral supplementation of vitamin C. J Med Food 2006;9(3):440-2. Wallock LM, Tamura T, Mayr CA, et al. Low seminal plasma folate concentration are associated with low sperm density and count in male smokers and nonsmokers. Fertil Steril 2001;75(2):525-9. Gupta NP, Kumar R. Lycopene therapy in idiopathic male infertility – a preliminary report. Int Urol Nephrol 2002;34(3):369-72. Boxmeer JC, Smit M, Weber RF, et al. Seminal plasma cobalamin significantly correlates with sperm concentration in males undergoing IVF or ICSI procedures. J Androl 2007;28(4):521-7.
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L-Carnitin und Coenzym Q10
Trace Elements Tikkiwal M, Ajmera RL, Mathur NK. Effect of zinc administration on seminal zinc and fertility of oligospermic males. Indian J Physiol Pharmacol 1987;31(1):30-4. Netter A, Hartoma R, Nahoul K. Effect of zinc administration on plasma testosterone, dihydrotestosterone, and sperm count. Arch Androl 1981;7(1):69-71. Foresta C, Flohé L, Garolla A, et al. Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase. Biol Reprod 2002;67:967-71.
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N-acetylcysteine Oeda T, Henkel R, Ohmori H, et al. Scavenging effect of N-acety-L-cysteine against reactive oxygen species in human semen: a possible therapeutic modality for male factor infertility. Andrologia 1997;29(3):125-31.
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Polyunsaturated Fatty Acids Aksoy Y, Aksoy H, Altinkaynak K, et al. Sperm fatty acid composition in subfertile men. Prostaglandins Leukot Essent Fatty Acids 2006;75(2):75-9.
Micronutrient Combinations
1
Folic acid and zinc in male subfertifility: randomized double-blind placebo-controlled trial Effects of folic acid and zinc sulphate on male factor subfertility: a double-blind, randomized, placebo-controlled trial Wong WY, Merkus HMWM, Thomas CMG, et al. Fertil Steril 2002;77(3):491-8.
Background The decrease in semen quality may result from interactions between genetic and environmental factors. Recent food consumption surveys show that dietary intakes of folic acid and zinc are insufficient. Folate which is mainly present in green leafy vegetables, is essential for DNA, transfer RNA and protein synthesis. Zinc is essential in spermatogenesis and, as a cofactor of metalloenzymes, involved in DNA transcription, and the expression of steroid receptors. Authors conducted the present study to determine whether administration of folic acid and zinc could have an influence on sperm quality and thus male fertility. Study design, patients and methods The study was conducted as a randomized, placebo-controlled double-blind trial. A total of 108 fertile and 103 subfertile men took part in the 26-week intervention. The two study groups were randomly assigned to receive one of four treatments: 5 mg folic acid and placebo, 66 mg zinc sulphate and placebo, a combination of 66 mg zinc sulphate and 5 mg folic acid, and two placebos. Before and after treatment, semen and blood samples were obtained (according to World Health Organization guidelines) to determine sperm concentration, motility, and morphology. Folate and vitamin B12 were measured by radio assay both in blood and seminal plasma. Zinc was measured by using flame atomic absorption spectrophotometry, and follicle-stimulating hormone was quantitatively determined in serum using an immunoassay Results Preintervention concentrations of folate and zinc in blood and seminal plasma did not signifi足cantly differ between fertile and subfertile men. In subfertile men the combination of folate and zinc resulted in a 74% increase in total normal sperm count (p<0.05) and to an increased number of normally shaped sperm cells (p=0.002). Conclusion Total sperm count increased after combined folate and zinc sulfate treatment in both subfertile and fertile men. Although the beneficial effect of the micronutrients on fertility remains to be established, this finding opens avenues of future fertility research and treatment of fertility disorders.
Micronutrient Combinations
1
Male infertility: nutritional and environmental considerations Male infertility: nutritional and environmental considerations Sinclair S. Altern Med Rev 2000;5(1):28-38.
Background An estimated 6% of adult males are thought to be infertile. Infertility is defined as the inability to achieve a pregnancy after one year of unprotected intercourse. Certain cases of male infertility are due to anatomical abnormalities, and 40-49% of cases are due to deficient sperm production of unknown etiology. There is a growing body of scientific evidence supporting the idea that sperm counts have declined considerably over the last decades. While there was a sperm density of 113 million/ml in 1940, in 1990 only 66 million/ml were found on average. This demonstrates a substantial 58% decline in sperm production. One must suspect that a combination of environmental, lifestyle, and dietary factors might be interfering with spermatogenesis. One related aspect is the exposure to environmental estrogens which are used in livestock, poultry, and dairy industries. In addition, many pesticides, such as DDT, have estrogenic effects within the body and are known to interfere with spermatogenesis. Other factors include heavy metals in the environment, chronic stress, alcohol abuse, cigarette smoking and nutritional deficiencies. Results One of the micronutrients with a favorable influence on sperm cell maturation is L-carnitine, an amino acid produced by the body. The administration of L-carnitine is able to improve sperm cell count and motility. Another amino acid with a beneficial influence on sperm cell motility is L-arginine. The trace element zinc is thought to be able to increase sperm cell count and improve sperm cell motility through elevation of the testosterone level. Furthermore, sperm cells in the course of maturation are sensitive to damaging influences of oxidative stress, and antioxidants may be protectors against this stress. These include vitamin E, glutathione and selenium. The supplementation of vitamin E lowers malondialdehyde concentrations in the seminal plasma und thus reduces oxidative stress. The combination of vitamin E and selenium was shown to significantly increase sperm motility and the overall percentage of normal spermatozoa. Glutathione and selenium are micronutrients essential to the formation of phospholipid hydroperoxide glutathione peroxidase, an enzyme present in spermatids. It is a structural protein accounting for over 50% of the mitochondrial capsule in the midpiece of mature spermatozoa and is responsible for sperm motility. Conclusion Male infertility is a multifactorial disease process with a number of po足tential contributing causes which include genetic, environmental and nutritional factors. There are various nutritional strategies, e.g. L-carnitine, zinc, selenium and vitamin E, which have a beneficial impact on sperm count, motility, and, ultimately, fertility. Therefore an optimal intake of antioxidants, trace elements, and other micronutrients should be ensured for a normal spermatogenesis.
Micronutrient Combinations
1
Mechanism of male infertily: role of antioxidants Mechanism of male infertility: role of antioxidants Sheweita SA, Tilmisany AM, Al-Sawaf H. Curr Drug Metab 2005;6(5);495-501.
Background Defective sperm function is the most common cause of infertility which is difficult to treat. Many environmental factors as well as anatomical and genetic disorders are involved in the conditions leading to poor sperm function and infertility. Therefore it is important to identify the factors which affect normal sperm function. In the present study the significance of oxidative stress in infertility was examined. Additionally the role of biological antioxidants and their associated mechanisms in the treatment of infertility were assessed. Results The excessive generation of reactive oxygen species (ROS) by abnormal spermatozoa and by contaminating leukocytes (leukocytospermia) has been identified as one of the few definedetiologies of male infertility. Moreover, environmental factors, such as pesticides, exogenous estrogens and heavy metals, may negatively impact spermatogenesis since male sperm counts were reduced. In addition, aging is also likely to further induced oxidative stress. In contrast, limited endogenous mechanisms exist to reverse such damage. In a normal situation, they are sufficient to quench the ROS. However, during genitourinary infection / inflammation such antioxidant mechanisms may lose in strength and oxidative stress may be created which can directly damage the sperm cells by attacking and oxidizing the high content of polyunsaturated fatty acids in spermatozoa. These processes will lead to a marked impairment of sperm cell motility, maturation and the capability of capacitation* and acrosome reaction**. Numerous nutritional approaches such as the administration of L-carnitine, arginine, zinc and selenium have proven beneficial regarding sperm cell count and motility. Also vitamin E, glutathione and coenzyme Q10 have shown favorable effects in the treatment of male infertility. Conclusion The multi-faceted therapeutic approaches to improving male fertility include the identification of harmful environmental and occupational risk factors, while correcting nutritional imbalances to encourage optimal sperm production and function. * maturation of sperm cells in the female genital tract; without this process the fertilization of the egg cell is not possible. ** important part of procreation enabling the sperm cellâ&#x20AC;&#x2122;s penetration into the egg cell
Vitamins
2
Lipid peroxidation and human sperm motility: protective role of vitamin E Lipid peroxidation and human sperm motility: protective role of vitamin E Suleiman SA, Ali ME, Zaki ZMS, et al. J Androl 1996;17(5):530-7.
Background Asthenozoospermia is the main factor of male infertility in patients consulting the Asir Infertility Center in Abha, Saudi Arabia. Already several years ago researchers reported that oxygen radicals may be toxical for human sperm motility. Therefore the use of antioxidants, such as vitamin E, is discussed in asthenospermic patients. These radicals, if left alone, will lead to peroxidation of phospholipids and thus to ultimate immotility of sperm cells. The objectives of this study were to determine the level of lipid peroxidation in the semen and to measure the effect of a vitamin E supplementation on the degree of peroxidation, improvement in sperm motility and the occurrence of pregnancy. Study design, patients and methods In this randomized placebo-controlled double-blind study 110 men with asthenozoospermia and sperm motility <40% and normal sperm cell count were included. In total 87 patients received either 100 mg vitamin E t.i.d. or placebo. Supplementation continued till the sperm quality parameters improved (15 percent increase in sperm motility) or till the patientâ&#x20AC;&#x2122;s spouse became pregnant, but up to a maximum of 6 months. The malondialdehyde (MDA) concentration in seminal plasma was measured as an indicator of the level of lipid peroxidation. Results Fifty-two patients in the vitamin-E group and 35 patients in the placebo group completed the study. Compared to the group of fertile men, patients with asthenozoospermia had a 1.7 times higher MDA concentration in sperm cells associated with a lower sperm motility. With vitamin E supplementation the MD level was significantly reduced (p<0.001). Simultaneously investigators observed a significant increase in sperm motility (p<0.001). In the placebo group there were no changes. The correlation between MDA concentration and sperm motility was highly significant after vitamin E treatment (r=0.79). In 11 cases in the group taking vitamin E, a pregnancy occurred, however, no pregnancy was reported in the spouses of the placebo-treated patients. Conclusion Vitamin E seems to protect against the loss of sperm motility by lipid peroxidation. Supplementation of vitamin E improves sperm motility and increases the possibility of fertilization in asthenospermic subjects.
Vitamins
2
Oral supplementation of vitamin C improves semen quality Improvement in human semen quality after oral supplementation of vitamin C. Akmal A, Qadri JQ, Noori S, et al. J Med Food 2006;9(3):440-2
Background A therapeutic approach to improving male fertility is focused on compensating nutrition deficits. Various antioxidants, such as vitamin C, have shown beneficial effects in studies on male fertility disorders. In these studies, the ascorbic acid level in the seminal plasma correlates positively with the percentage of sperms of normal morphology. Vitamin C protects the sperms against oxidative damage and improves the sperm quality of smokers. It is also effective in the treatment of sperm agglutination and can thus improve fertility. In the seminal plasma ascorbic acid, together with thiolen and uric acid, is one of the strongest antioxidants. Studies have shown that the in-vitro administration of ascorbic acid, uric acid and alpha tocopherol has a beneficial effect on the sperms’ DNA integrity. Vitamin C protects the sperm DNA against oxidative stress. Study design, patients and methods A total of 13 men with oligozoospermia were included in the study. Patients with urogenital infections or varicoceles were excluded. The men were between 25 and 35 years old and were given 1 g of vitamin C twice daily for a period of 2 months. A semen sample was analyzed before and after the treatment according to WHO criteria. Results Taking vitamin C led to a significant increase in the portion of motile sperms from 31.2% ± 9.61% to 60.1% ± 8.47% (p<0.001). The sperm number also increased significantly, i.e. from 14.3 ± 7.38 x 106 to 32.8% ± 10.3% x 106 sperms per milliliter (p< 0.001). The percentage of sperms of normal shape rose significantly from 43% ± 7.87% to 66.7% ± 4.77% (p<0.001). Conclusion The study has shown that the uptake of vitamin C can have a beneficial effect on sperm number, motility and morphology in infertile men. Therefore supplementation of ascorbic acid is a useful measure to improve semen quality and enhance the chance of conception. The beneficial effects of vitamin C are presumably due to its antioxidative properties.
Vitamins
2
Low seminal plasma folate concentration and low sperm quality in smokers and nonsmokers Low seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokers Wallock LM, Tamura T, Mayr CA, et al. Fertil Steril 2001;75(2):525-9.
Background While it is well accepted that folate is essential for normal female reproduction, only few data are available on the subject of relevance of folate to male reproduction. Studies have shown that an adequate folate supply is important to male fertility, and correspondingly the treatment with folate antagonists leads to impairment of fertility. Both in seminal plasma and in the prostate, high-affinity folate binding proteins have been found. These assumptions suggest a relationship between folate status and male fertility. As cigarette smoking has a harmful effect on male fertility, Wallock and colleagues evaluated the potential relationships between folate status and semen quality in smokers and nonsmokers. Study design, patients and methods In total 24 smokers and 24 nonsmokers were included in the observational study conducted at the Western Human Nutrition Research Center in San Francisco (CA). Inclusion criteria was that the subjects had an intake of less than 3.5 takings of fruit and vegetable per day. Sperm count and density were assessed under the microscope and folate, vitamin B12 (radioassay) and plasma homocysteine concentration (HPLC) were measured. In seminal plasma folate concentration (microbiological tests*), and folate levels were measured separately as 5-methyltetrahydrofolate (5-MTHF) and non-methyltetrahydrofolate (non-MTHF) concentrations. Results Total seminal plasma folate concentrations correlated significantly with blood plasma folate levels (r=0,76) and were on average 1.5 times higher in all men. Seminal plasma folates contained 5-methyltetrahydrofolate (74% of total) and non-methyltetrahydrofolates (26% of total). Total and 5-MTHF concentrations correlated significantly with blood plasma folate and homocysteine concentrations (r=0,43). Low seminal plasma non-MTHF levels correlated significantly with sperm density and total sperm count. Seminal plasma of smokers contained a proportionally lower concentration of non-MTHF compared with nonsmokers. Conclusion Seminal plasma total folate and 5-methyltetrahydrofolate concentrations reflect folate intake with the diet. The non-methyltetrahydrofolate fraction of seminal plasma was associated with sperm cell density suggesting the important role of folate for the male reproductive function. * using bacterial species that respond in particular to folates
Vitamins
2
Lycopene in idiopathic male infertility Lycopene therapy in idiopathic male infertility â&#x20AC;&#x201C; a preliminary report Gupta NP, Kumar R, Int Urol Nephrol 2002;34(3):369-72.
Background Sperm membranes are rich in polyunsaturated fatty acids and therefore highly sensitive to lipid peroxidation. Studies have shown that infertile men often have higher concentrations of free radicals than healthy men. This is why elevated levels of free radicals are associated with idiopathic infertility. Lycopin is a naturally occurring carotenoid, a component of the human redox mechanism which neutralizes free radicals. The aim of the study was to find out whether giving lycopin could improve the fertility of men with idiopathic infertility. Study design, patients and methods Thirty men with oligo-, astheno- or teratozoospermia were included in the study. During the 3-month intervention phase the patients were given 2 mg of lycopin twice daily. Before and after the intervention, sperm analyses were made and standard parameters for the determination of the sperm quality examined. Results In 66% of the patients an improvement in sperm concentration by an average of 22 million/ml was found. 53% of the men had a higher sperm motility after the intervention (p<0.05), and 46% a higher proportion of sperms of normal shape (p<0.05). Especially in men who had a sperm concentration of > 5 million/ml before the study started demonstrated a marked improvement of sperm density. In six spouses of these men a pregnancy was diagnosed while the study was still ongoing or in the follow-up period. Conclusion Oxidative stress in the seminal plasma is an important factor in the origin of idiopathic infertility. Oral supplementation of antioxidants such as lycopin led to distinct improvements in semen quality.
Vitamins
2
Vitamin B12 in the seminal plasma and sperm concentration: role for IVF or ICSI procedures Seminal plasma cobalamin significantly correlates with sperm concentration in men undergoing IVF or ICSI procedures Boxmeer JC, Smit M, Weber RF, et al. J Androl 2007;28(4):521-7.
Background It is a well-known fact that an elevated homocysteine level is associated with disorders of the reproductive function. B-vitamins â&#x20AC;&#x201C; in particular the folic acid, cobalamin, pyridoxin and homocysteine concentrations â&#x20AC;&#x201C; play a crucial role in the degradation of homocysteine. Studies prove beneficial effects on sperm quality when B-vitamins are taken. The aim of the study was to analyze the folic acid, cobalamin, pyridoxin and homocysteine concentrations in blood and seminal plasma. In addition, the study should find out whether these biomarkers correlate with the sperm parameters of men undergoing IVF and ICSI procedures. Study design, patients and methods A total of 73 men who wanted to undergo IVF participated in the study. The blood and sperm samples were tested for their B-vitamin level. Moreover, the classical parameters of sperm quality were determined according to the WHO criteria. Results Twenty-six percent of the men had a varicocele, and in 34% of the cases subfertility was diagnosed. The folate and B12 concentrations in the blood plasma were significantly lower than they were in the seminal plasma (p<0.001). The homocysteine concentrations in blood and seminal plasma were comparable. The vitamin B12 concentration in blood serum and seminal serum correlated significantly. The vitamin B12 concentration in the seminal plasma correlated positively with the concentration in the sperms (r=-0.42, p<0.001). The other B vitamins and homocysteine in blood and seminal plasma did not correlate significantly with other seminal parameters. Conclusion In the study, a significantly positive correlation between the vitamin B12 concentration in seminal plasma and the sperm concentration was found in men wanting to undergo IVF or ICSI. This strong correlation supports the assumption that B12, besides folic acid, plays an important role in spermatogenesis.
Trace Elements
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Effect of zinc on fertility of oligospermic males Effect of zinc administration on seminal zinc and fertility of oligospermic males. Tikkiwal M, Ajmera RL, Mathur NK. Indian J Physiol Pharmacol 1987;31(1):30-4.
Background Zinc is essential for the action of over 80 metalloenzymes and plays an important role in the polmeric organization of macromolecules, such as RNA and DNA, protein synthesis, cell division and stability of cell membranes. In relation to male reproduction zinc has been implicated in maintenance of spermatogenesis, survival of germinal epithelium, survival and normal function of spermatozoa and perhaps fertilization. A zinc-deficient diet was shown to be associated with a decrease in sperm count and testosterone levels. The objective of the study was to examine the effect of an oral zinc therapy on zinc levels in seminal plasma and other seminal parameters in oligospermic infertile males with low seminal plasma zinc levels. Study design, patients and methods In the study 14 men with oligozoospermia (sperm cell count <40 million per ml or significantly subnormal percentage of sperms with progressive motility or normal morphology) were examined. Several parameters of sperm quality and phosphatase activity in seminal plasma were measured. The zinc level was assessed in blood plasma and seminal plasma using AAS (atomic absorption spectrophotometry). After two consecutive examinations at an interval of 1 month to establish pretreatment data, patients received a supplementation of 220 mg zinc sulphate daily over 4 months. Results Before zinc supplementation sperm cell count, percentage of sperms with progressive motility and phosphatase activity in seminal plasma were below normal recommended values. After 4 months of zinc sulphate therapy there was no effect on zinc plasma level, while zinc concentration in seminal plasma increase significantly (p<0.05). In addition, sperm cell count, sperm motility and the percentage of normally shaped sperm cells were significantly increased (p<0.01 each). Conclusion Zinc is essential for androgen production in the testes, proliferative activity of germ cells and for capacitation* of spermatozoa. Obviously this trace element is an important factor in the treatment of male infertility. * maturation of sperm cells in the female genital tract; without this process the fertilization of the egg cell is not possible.
Trace Elements
3
Effect of zinc on plasma testosterone, dihydrotestosterone, and sperm count Effect of zinc administration on plasma testosterone, dihydrotestosterone, and sperm count. Netter A, Hartoma R, Nahoul K. Arch Androl 1981;7(1):69-71.
Background Already in 1921, researchers observed that the herring testes were considerably richer in zinc during the season of reproduction than in the resting season. Moreover high concentrations of zinc were found in the testes and accessory genital glands of various mammalians including man. In view of these data it seems likely that zinc might play an important role in reproductive physiology. Study design, patients and methods Thirty seven patients between 20 and 40 years of age with infertility of more than 5 years were selected. They received a treatment with 120 mg zinc twice daily for the duration of 40 to 50 days. At baseline and after treatment zinc levels in blood plasma were measured using atomic absorption spectrometry. Testosterone and dihydrotestosterone were determined using chromatography and subsequent radioimmunoassay. Additionally before and after intervention, sperm count was assessed. Results For data evaluation, patients were subdivided into two subgroups according to the basal plasma testosterone level: Patients in group I had a plasma testosterone level of <4.8 ng/ml, group II showed a testosterone level of > 4.8 ng/ml. In group I, plasma zinc levels, testosterone levels, dihydrotestosterone levels and sperm counts increased significantly (p<0.01 each). In group II, there was a significant increase ofdihydrotestosterone levels (p<0.01). During the study period, nine wives of the patients in group I became pregnant. Conclusion Men with idiopathic fertility disorders showing a low plasma testosterone level can be successfully treated by oral zinc supplementation also increasing sperm count. Additionally, increased testosterone and dihydrotestosterone levels due to zinc effects have a beneficial impact on spermatogenesis.
Trace Elements
3
Male fertility and the selenoprotein phospholipid hydroperoxide glutathione peroxidase Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase. Foresta C, Flohé L, Garolla A, et al. Biol Reprod 2002;67:967-71.
Background The selenoprotein phospholipid hydroperoxide glutathion peroxidase (PGHPx) accounts for almost the entire selenium content of mammalian testes. PHGPs is abundantly expressed in spermatids as active peroxidase but is transformed to an oxidatively inactivated protein in mature sperm. There it is a major constituent of the mitochondrial capsule in the midpiece. Male infertility which is characterized by impaired sperm motility and morphological midpiece alterations is considered to result from insufficient PHGPx content. Therefore the authors of the present article studied the relationship between sperm PHGPx, measured as rescued activity, and male fertility. Study design, patients and methods Sperm specimens from 75 infertile men and 37 controls were analyzed for various fertility parameters according to World Health Organization criteria. The PHGPx protein content was estimated after reductive solubilization of the spermatozoa by measuring the rescued PHGPx activity. Results Rescued PHGPx activity of 93.2 mU/mg in the infertile group ranged significantly (p<0,001) below that of controls (187.5 mU/mg sperm protein) and was particularly low in oligoasthenozoospermic specimens (61.93 mU/mg; p<0.001 compared with controls and asthenozoospermic samples). Rescued PHGPx activity was correlated positively with viability (r=0.35), morphological integrity (r=0.44), and most profoundly forward motility (r=0.45). Conclusion In humans, an adequate level of PHGPx appears to be indispensable for structural integrity of spermatozoa and to codetermine sperm motility and viability. As the content of PHGPx, irrespective of the cause of alteration, is associated with fertility-related parameters, PHGPx can be considered a predictive measure for fertilization capacity.
L-Carnitine and Coenzyme Q10
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L-carnitine levels and infertility: correlations with sperm quality L-carnitine levels in the seminal plasma of fertile and infertile men: Correlation with sperm quality Matalliotakis I, Koumantaki Y, Evageliou A, et al. Int J Fertil Womens Med 2000;54(3):236-40.
Background L-carnitine is a vitamin-like substance (so-called vitaminoid) found in human tissues and cells. It is important for the transfer of long-chain fatty acids across the internal mitochondrial membrane leading to beta-oxidation during the production of energy. L-carnitine is concentrated in the epididymis, and an increased L-carnitine and L-acetylcarnitine content in the spermatozoa during the epididymal passage is related with progressive motility of the sperms. In this study the L-carnitine concentration in the seminal plasma of fertile and infertile men was measured and the potential relationships between L-carnitine and various parameters of sperm quality was determined. Study design, patients and methods The study group included 101 men between the ages of 19 and 53 years. Semen samples were obtained after 3 to 6 days of sexual abstinence. The semen samples were divided in two groups on the basis of normal or abnormal spermiogram, i.e. a fertile and infertile group of subjects. Sperm density, motility and morphology as well as L-carnitine concentration in seminal plasma were measured. Results L-carnitine levels in seminal plasma of fertile men were significantly higher than in infertile men (478.4 Âľmol/l vs. 100.6 Âľmol/l). The L-carnitine concentration correlated positively with the sperm cell count (r=0.71), the sperm cell motility (r=0.58) and the sperm morphology (r=0.59). Conclusion The L-carnitine concentration is decreased in semen of infertile men and correlates with various quality parameters of spermiograms. The higher seminal carnitine content in subjects with good sperm quality supports the claim that carnitine may be a marker for good sperm cell quality. L-carnitine is also able to improve motility of sperm cells.
L-Carnitine and Coenzyme Q10
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The effects of L-carnitine on idiopathic sperm abnormalities in smokers and nonsmokers The effects of L-carnitine on sperm parameters in smoker and non-smoker patients with idiopathic sperm abnormalities Khademi A, Alleyassin A, Safdarian L, et al. J Assist Reprod Genet 2005;22(11-12):395-9.
Background One couple in 10 seeks medical help because of infertility. Offering some type of treatment in order to improve male fertility may help approximately half of the couples with infertility. L-carnitine has beneficial effects on the quality of sperms in patients with asthenozoospermia and plays a role in the metabolism of sperm cells. The objective of this study was to determine the effect of L-carnitine on sperm parameters in patients with idiopathic sperm abnormalities and to examine the role of smoking as a risk factor for infertility. Study design, patients and methods Totally 170 men with infertility (including 48 smokers and 122 nonsmokers) participated in this study. Before taking L-carnitine, 3 semen analyses covering a period of 3 months were performed and assessed according to the WHO classification. Subsequently, participants took L-carnitine orally at a dose of 1 g every 8 hours for 3 months. At the end of treatment another two semen analyses were performed. Test parameters included sperm cell concentration, motility and morphology. Results All patients showed teratozoospermia (<14% normal shapes). No patient had sperms with normal motility, and oligozoospermia was diagnosed in 58 patients. The intake of L-carnitine during a period of 3 months led to a significant increase in total motility (p=0.02) and the proportion of sperms with linear progressive motility (p<0.001) in nonsmokers. In the group of smokers, there was an increase of sperm cells of normal shape (p=0.03). Conclusion L-carnitine effectively improves the percentage of motile sperm cells in semen, the proportion of sperms with linear progressive motility as well as sperms of normal morphology.
L-Carnitine and Coenzyme Q10
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Coenzyme Q10 supplementation in infertile men with idiopathic asthenozoospermia Coenzyme Q10 supplementation in infertile men with idiopathic asthenozoospermia: an open, uncontrolled study. Balercia G, Mosca F, Mantero F, et al. Fertil Steril 2004;81(1):93-8.
Background Coenzyme Q10 has antioxidative features and is able to neutralize excessive reactive oxygen species (ROS) which are known to impair sperm cell function. Coenzyme Q10 biosynthesis is predominantly active in testes and high levels of its reduced form QH2 (ubichinol) are present in semen (sperm cells and seminal plasma). The objective of the study was to clarify if the oral intake of coenzyme Q10 could increase its concentration in semen, and improve seminal kinetic parameters in men with idiopathic asthenozoospermia. Study design, patients and methods A total of 22 patients with idiopathic asthenozoospermia were enrolled in the study. They underwent a dietary intervention with coenzyme Q10 200 mg/day twice daily orally for 6 months. At baseline and after 6 months of treatment a semen analysis (spermiogram) was performed and the concentration of coenzyme Q10 assayed in sperm cells and seminal plasma using high pressure liquid chromatography (HPLC) Results Coenzyme Q10 levels increased significantly both in seminal plasma and in sperm cells after treatment (p<0.05). The proportion of sperm cells with progressive motility (9.13% vs. 16.34%; p<0.05) and their straight progressive velocity (15.2 Âľm/s to 20.40 Âľm/s; p<0.05) increased significantly. Conclusion The supplementation of coenzyme Q10 obviously plays a positive role in the treatment of asthenozoospermia. This is probably the result of both its action in mitochondrial bioenergetics and the antioxidative properties of this vitaminoid.
L-Carnitine and Coenzyme Q10
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Combined L-carnitine and L-acetylcarnitine treatment in men with astenozoospermia A placebo-controlled double-blind randomized trial of the use of combined carnitine and L-acetyl-carnitine treatment in men with astenozoospermia. Lenzi A, Sgrò P, Salacone P, Paoli D et al, Fertil Steril 2004;8(6):1578-84.
Background L-carnitine protects the cell membrane and DNA against damage induced by free oxygen radicals. The highest L-carnitine concentrations in the human body are found in the epididymal fluid. Initiation of sperm motility occurs in parallel to an increase in L-carnitine in the epididymal lumen and the concentration of L-acetylcarnitine in spermatozoa. In this study the efficacy of combined L-carnitine and L-acetylcarnitine therapy in infertile men with oligoastheno-teratozooÂspermia was to be determined. Study design, patients and methods In this placebo-controlled double-blind randomized clinical trial 60 infertile men were included and divided into two groups. The study protocol consisted of a 2-month washout phase, a 6-month administration of both substances, or a placebo, respectively, and a 2-month follow-up phase. The carnitine group of patients took 2 g L-carnitine and 1 g L-acetylcarnitine daily. Results All parameters of sperm quality were improved after the combined carnitine treatment. The most significant improvement in sperm motility was present in patients who had lower initial absolute values of motile sperms (<5 x 106). In these patients the progressive motility (2.7 x 106 vs. 7.5 x 106 progressively motile sperms per ejaculate; p<0.043) and total motility (3.4 x 106 vs. 6.9 x 106 total motile sperms per ejaculate; p<0.038) were also significantly increased. In the group of patients who had received the carnitine combination, four of the spouses achieved spontaneous pregnancies during the observation period. Conclusion Combined treatment with L-carnitine and L-acetylcarnitine in this controlled study of efficacy was effective in increasing sperm motility. This was especially noticeable in the patients with lower baseline levels in the spermiogram.
N-Acetylcysteine
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N-Acetylcysteine as radical scavenger in semen: therapeutic relevance for infertility? Scavenging effect of N-acetyl-L-cysteine against reactive oxygene species in human semen: a possible therapeutic modality for male factor infertility. Oeda T, Henkel R, Ohmori H, et al. Andrologia 1997;29(3):125-31.
Background Many studies have demonstrated that reactive oxygen species impair sperm function. This is a big problem since low fertilization rates may be the consequence. Spermatozoa are particularly sensitive to oxidative stress as their plasma membranes have a high content of omega-3 fatty acids. Membrane lipids are damaged by reactive oxygen species (ROS). This damage affects membrane stability, fluidity and permability, because the physico-chemical characteristics play an important role for normal sperm functioning. N-acetylcysteine (NAC) acts as precursor of glutathione which as glutathione peroxidase is the most important cellular antioxidant. Study design, patients and methods To investigate the relevance of NAC, semen samples of 83 patients referred to the andrological department of the university were examined. The semen samples were incubated with or without N-acetylcysteine at room temperature. The amount of reactive oxygen species was assessed using a chemiluminescent assay, and the effect of NAC on functional sperm parameters, such as motility, vitaliy and acrosome reaction, was studied. Results The results demonstrated a significant effect of NAC on the formation of free radicals. The authors of the study observed a significant decrease of ROS activity compared with controls, which was tested at 20, 40, 60, and 120 minutes after incubation in the NAC group. The ROS levels decreased significantly after 20 minutes of incubation with NAC. This reduction was greater in the group with high ROS levels. Conclusion NAC significantly reduced the amount of ROS in human semen. It also improved sperm function. NAC might be a useful therapeutic option for the treatment of male infertility patients.
Polyunsaturated Fatty Acids
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Fatty acid pattern of sperms in subfertile men Sperm fatty acid composition in subfertile men. Aksoy Y, Aksoy H, Altinkaynak K, et al. Prostaglandins Leukot Essent Fatty Acids 2006;75(2):75-9.
Background The fatty acid composition in the cell membranes regulates the activity of various membrane-bound enzymes as well as the resistance of the membranes to physical and chemical stress. The membrane structure of the sperms plays an important role in successful fertilization. The spermsâ&#x20AC;&#x2DC; lipids are relevant to the vitality, maturation and function of the sperms. Apparently the proportion of polyunsaturated fatty acids (PUFA) in the sperm membrane has also an effect on sperm fluidity. High concentrations of docosahexaenoic acid (DHA) are associated with an increase in sperm motility. Studies have also shown that men with oligo- or asthenozoospermia had lower DHA levels than normal men. Study design, patients and methods In total, the ejaculate of 79 men was examined. Using their spermiograms the men were divided in three groups: one group each for normozoospermia, asthenozoospermia and oligozoospermia. The spermatooa were separated from the seminal plasma, and the fatty acid profile was assayed in all three groups. With these tests the association between traditional sperm parameters and fatty acid composition was to be investigated. Results The DHA concentration was significantly lower in men with asthenozoospermia (p<0.01) or oligoasthenozospermia (p<0.05) than in healthy men. Also patients with oligozoospermia showed decreased DHA levels compared with healthy controls (p<0.05). There were no significant differences found related to omega-6 fatty acid levels. The omega-6 : omega-3 ratio was significantly higher in patiens with asthenozoospermia than in healthy controls (p<0.05). The PUFA content was lower in cases of oligozoospermia (p<0.05) and asthenozoospermia (p<0.01) as compared with healthy men. The DHA concentration also correlated positively with sperm motility, sperm density and normal sperm morphology. Furthermore, investigators found an association between the content of polyunsaturated fatty acids and sperm motility (r=0.50, p=0.0001), sperm density (r=0.35, p=0.002) and normal morphology (r=0.28, p<0.01). Conclusion The altered content of DHA, PUFA, omega-6 : omega-3 ratio in sperms of patients with oligo- or asthenozoospermia is presumably related to male infertility. Therefore in these cases supplementation of polyunsaturated fatty acids can be useful in order to improve sperm quality.
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