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Synthetic Antioxidants

  • Edmund Y. KoEmail author
  • John C. Kefer
  • Ashok Agarwal
  • Edmund Sabanegh
Chapter

Abstract

Male factor infertility is responsible for approximately 25% of all infertility issues. Suboptimal semen quality is a common yet poorly understood cause of male infertility. Environmental factors such as oxidative stress induced by reactive oxygen species (ROS) have recently been implicated as contributing to poor semen quality. Causes of increased ROS in men with suboptimal sperm quality are actively being investigated, and multiple options for therapy are under investigation. ROS have been shown to induce cellular injury by a variety of mechanisms, and antioxidants, which scavenge and inactivate ROS, have been shown to protect cells against this damage. There are many forms of antioxidants. Antioxidants are found endogenously in cell signaling pathways, as well as exogenously in fruits and vegetables (natural antioxidants), or as individual isolates in vitamins or dietary supplements (synthetic antioxidants) Here, we define synthetic antioxidants and discuss the cellular mechanisms by which synthetic antioxidants may improve oxidative stress levels and semen quality in men with male factor infertility.

Keywords

Male factor infertility Reactive oxygen species Oxidative stress Natural antioxidants Synthetic antioxidants Leukocytospermia Vitamin toxicity 

References

  1. 1.
    Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AMA. WHO manual for the standardized investigation, diagnosis and management of the infertile male. Cambridge: Cambridge University Press; 2004.Google Scholar
  2. 2.
    Sharlip ID, Jarow JP, Belker AM, Lipshultz LI, Sigman M, Thomas AJ, et al. Best practice policies for male infertility. Fertil Steril. 2002;77:873–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Vine MF. Smoking and male reproduction: a review. Int J Androl. 1996;19:323–37.PubMedCrossRefGoogle Scholar
  4. 4.
    Auger J, Eustache F, Andersen AG, Irvine DS, Jorgensen N, Skakkebaek NE, et al. Sperm morphological defects related to environment, lifestyle and medical history of 1001 male partners of pregnant women from four European cities. Hum Reprod. 2001;16:2710–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Kenkel S, Rolf C, Nieschlag E. Occupational risks for male fertility: an analysis of patients attending a tertiary referral centre. Int J Androl. 2001;24:318–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Eskenazi B, Wyrobek AJ, Sloter E, Kidd SA, Moore L, Young S, et al. The association of age and semen quality in healthy men. Hum Reprod. 2003;18:447–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Lenzi A, Lombardo F, Gandini L, Alfano P, Dondero F. Computer assisted sperm motility analysis at the moment of induced pregnancy during gonadotropin treatment for hypogonadotropic hypogonadism. J Endocrinol Invest. 1993;6:683–6.Google Scholar
  8. 8.
    Agarwal A, Ikemoto I, Loughlin KR. Relationship of sperm parameters with levels of reactive oxygen species in semen specimens. J Urol. 1994;152:107–10.PubMedGoogle Scholar
  9. 9.
    Armstrong JS, Rajasekaran M, Chamulitrat W, Gatti P, Hellstrom WJ, Sikka SC. Characterization of reactive oxygen species induced effects on human spermatozoa movement and energy metabolism. Free Radic Biol Med. 1999;26:869–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Kodama H, Yamaguchi R, Fukuda J, Kasai H, Tanaka T. Increased oxidative deoxyribonucleic acid damage in the spermatozoa of infertile male patients. Fertil Steril. 1997;68:519–24.PubMedCrossRefGoogle Scholar
  11. 11.
    Barroso G, Morshedi M, Oehninger S. Analysis of DNA fragmentation, plasma membrane translocation of phosphatidylserine and oxidative stress in human spermatozoa. Hum Reprod. 2000;15:1338–44.PubMedCrossRefGoogle Scholar
  12. 12.
    Aitken RJ, Harkiss D, Buckingham DW. Analysis of lipid peroxidation mechanisms in human spermatozoa. Mol Reprod Dev. 1993;35:302–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Kemal Duru N, Morshedi M, Oehninger S. Effects of hydrogen peroxide on DNA and plasma membrane integrity of human spermatozoa. Fertil Steril. 2000;74:1200–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Smith R, Vantman D, Ponce J, Escobar J, Lissi E. Total antioxidant capacity of human seminal plasma. Hum Reprod. 1996;11(8):1655–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Agarwal A, Prabhakaran SA, Sikka SC. Clinical relevance of oxidative stress in patients with male factor infertility: evidence-based analysis. AUA Update Series. 2007;26:1–12.Google Scholar
  16. 16.
    Aitken RJ, Ryan AL, Baker MA, McLaughlin EA. Redox activity associated with the maturation and capacitation of mammalian spermatozoa. Free Radic Biol Med. 2004;36:994–1010.PubMedCrossRefGoogle Scholar
  17. 17.
    de Lamirande E, Tsai C, Harakat A, Gagnon C. Involvement of reactive oxygen species in human sperm acrosome reaction induced by A23187, lysophosphatidylcholine, and biological fluid ultrafiltrates. J Androl. 1998;19:585–94.PubMedGoogle Scholar
  18. 18.
    Tremellen K. Oxidative stress and male infertility—a clinical perspective. Hum Reprod Update. 2008;14:243–58.PubMedCrossRefGoogle Scholar
  19. 19.
    Ochsendorf FR. Infections in the male genital tract and reactive oxygen species. Hum Reprod Update. 1999;5:399–420.PubMedCrossRefGoogle Scholar
  20. 20.
    Warren JS, Johnson KJ, Ward PA. Oxygen radicals in cell injury and cell death. Pathol Immunopathol Res. 1987;6:301–15.PubMedCrossRefGoogle Scholar
  21. 21.
    Agarwal A, Prabakaran S, Allamaneni S. What an andrologist/urologist should know about free radicals and why. Urology. 2006;67:2–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Saleh RA, Agarwal A. Oxidative stress and male infertility: from research bench to clinical practice. J Androl. 2002;23:737–52.PubMedGoogle Scholar
  23. 23.
    Aitken RJ, Fisher H. Reactive oxygen species and human spermatozoa: the balance of benefit and risk. Bioessays. 1994;16:259–67.PubMedCrossRefGoogle Scholar
  24. 24.
    Aitken RJ. Free radicals, lipid peroxidation, sperm function. Reprod Fertil Dev. 1995;7:659–68.PubMedCrossRefGoogle Scholar
  25. 25.
    Aitken RJ, Baker HW. Seminal leukocytes: passengers, terrorists or good Samaritans? Hum Reprod. 1995;10:1736–9.PubMedGoogle Scholar
  26. 26.
    Tomlinson JM, Barratt CL, Cooke ID. Prospective study of leukocytes and leukocyte subpopulations in semen suggests they are not the cause of a male infertility. Fertil Steril. 1993;60:1069–75.PubMedGoogle Scholar
  27. 27.
    Christiansen E, Tollefsrud A, Purvis K. Sperm quality in men with chronic abacterial prostatovesiculitis verified by rectal ultrasonography. Urology. 1991;38:545–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Aitken RJ, Fisher HM, Fulton N, Gomez E, Knox W, Lewis B, et al. Reactive oxygen species generation by human spermatozoa is induced by exogenous NADPH and inhibited by the flavoprotein inhibitors diphenylene iodonium and quinacrine. Mol Reprod Dev. 1997;47:468–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Hendin B, Kolletis PN, Sharma RK, Thomas AJ, Agarwal A. Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity. J Urol. 1999;161:1831–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Shalika S, Dugan K, Smith RD, Padilla SL. The effect of positive semen bacterial and ureaplasma cuture on in-vitro fertilization success. Hum Reprod. 1996;11:2789–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Sharma RK, Pasqualetto AE, Nelson DR, Thomas AJ, Agarwal A. Relationship between seminal white blood cell counts and oxidative stress in men treated at an infertility clinic. J Androl. 2001;22:575–83.PubMedGoogle Scholar
  32. 32.
    Kao SH, Chao HT, Chen HW, Hwang TI, Liao TL, Wei YH. Increase of oxidative stress in human sperm with lower motility. Fertil Steril. 2008;89(5):1183–90.PubMedCrossRefGoogle Scholar
  33. 33.
    Saleh RA, Agarwal A, Kandirali E, Sharma RK, Thomas AJ, Nada E, et al. Leukocytospermia is associated with increased reactive oxygen species production by human spermatozoa. Fertil Steril. 2002;78:1215–24.PubMedCrossRefGoogle Scholar
  34. 34.
    Wolff H. The biologic significance of white blood cells in semen. Fertil Steril. 1995;63:1143–57.PubMedGoogle Scholar
  35. 35.
    Moskovtsev SI, Willis J, White J, Mullen BM. Leukocytospermia: relationship to sperm deoxyribonucleic acid integrity in patients evaluated for male factor infertility. Fertil Steril. 2007;88(3):737–40.PubMedCrossRefGoogle Scholar
  36. 36.
    Herbert V. The value of antioxidant supplements vs their natural counterparts. J Am Diet Assoc. 1997;97:375–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Stanner SA, Hughes J, Kelly CN, Buttriss J. A review of the epidemiological evidence or the “antioxidant hypothesis”. Public Health Nutr. 2004;7:407–22.PubMedCrossRefGoogle Scholar
  38. 38.
    Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database Syst Rev. 2004;(4):CD004183.Google Scholar
  39. 39.
    Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database Syst Rev. 2008;(3):CD004183.Google Scholar
  40. 40.
    Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004;364(9441):1219–28.PubMedCrossRefGoogle Scholar
  41. 41.
    Hercberg S, Galan P, Preziosi P, Alfarez MJ, Vazquez C. The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers. Nutrition. 1998;14:513–20.PubMedCrossRefGoogle Scholar
  42. 42.
    Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;197:842–57.CrossRefGoogle Scholar
  43. 43.
    Evans HM, Bishop KS. On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science. 1922;56:650–1.PubMedCrossRefGoogle Scholar
  44. 44.
    Brigelius-Flohe R, Traber MG. Vitamin E: function and metabolism. FASEB J. 1999;13:1145–55.PubMedGoogle Scholar
  45. 45.
    Esterbauer H, Dieber-Rotheneder M, Striegl G, Waeg G. Role of vitamin E in preventing the oxidation of low-density lipoprotein. Am J Clin Nutr. 1991;53(1 Suppl):314S–21.PubMedGoogle Scholar
  46. 46.
    Kamal-Eldin A, Appelqvist LA. The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids. 1996;31:671–701.PubMedCrossRefGoogle Scholar
  47. 47.
    Bowry VW, Ingold KU, Stocker R. Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant. Biochem J. 1992;288:341–4.PubMedGoogle Scholar
  48. 48.
    Cooney RV, Franke AA, Harwood PJ, Hatch-Pigott V, Custer LJ, Mordan LJ. Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alpha-tocopherol. Proc Natl Acad Sci USA. 1993;90:1771–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Comhaire FH, Christophe AB, Zalata AA, Dhooge WS, Mahmoud AM, Depuydt CE. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot Essent Fatty Acids. 2000;63:159–65.PubMedCrossRefGoogle Scholar
  50. 50.
    Scott R, MacPherson A, Yates RW, Hussain B, Dixon J. The effect of oral selenium supplementation on human sperm motility. Br J Urol. 1998;82:76–80.PubMedCrossRefGoogle Scholar
  51. 51.
    Galatioto GP, Gravina GL, Angelozzi G, Sacchetti A, Innominato PF, Pace G, et al. May antioxidant therapy improve sperm parameters of men with persistent oligospermia after retrograde embolization for varicocele? World J Urol. 2008;26:97–102.CrossRefGoogle Scholar
  52. 52.
    Linster CL, Van Schaftingen E, Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J. 2007;274:1–22.PubMedCrossRefGoogle Scholar
  53. 53.
    Mulholland CA, Benford DJ. What is known about the safety of multivitamin-multimineral supplements for the generally healthy population? Theoretical basis for harm. Am J Clin Nutr. 2007;85:318S–22.PubMedGoogle Scholar
  54. 54.
    Bendich A, Machlin LJ. Safety of oral intake of vitamin E. Am J Clin Nutr. 1988;48:612–9.PubMedGoogle Scholar
  55. 55.
    Weber P, Bendich A, Machlin LJ. Vitamin E and human health: rationale for determining recommended intake levels. Nutrition. 1997;13:450–60.PubMedCrossRefGoogle Scholar
  56. 56.
    Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studia della Sopravvivenza nell’Infarto miocardico. Lancet. 1999;354:447–55. http://www.ncbi.nlm.nih.gov/pubmed/10465168.
  57. 57.
    Marchioli R, Levantesi G, Macchia A, Marfisi RM, Nicolosi GL, Tavazzi L, et al. Vitamin E increases the risk of developing heart failure after myocardial infarction: results from the GISSI-Prevenzione trial. J Cardiovasc Med (Hagerstown). 2006;7:347–50.CrossRefGoogle Scholar
  58. 58.
    Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154–60.PubMedCrossRefGoogle Scholar
  59. 59.
    Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338–47.PubMedCrossRefGoogle Scholar
  60. 60.
    Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol. 2005;45:127–32.PubMedCrossRefGoogle Scholar
  61. 61.
    Mousa SA. Antithrombotic effects of naturally derived products on coagulation and platelet function. Methods Mol Biol. 2010;663:229–40.PubMedCrossRefGoogle Scholar
  62. 62.
    The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–35.CrossRefGoogle Scholar
  63. 63.
    Miller 3rd ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37–46.PubMedGoogle Scholar
  64. 64.
    Kabat GC, Kim M, Adams-Campbell LL, Caan BJ, Chlebowski RT, Neuhouser ML, et al. Longitudinal study of serum carotenoid, retinol, and tocopherol concentrations in relation to breast cancer risk among postmenopausal women. Am J Clin Nutr. 2009;90:162–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck A, Schatzkin A, et al. Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst. 2007;99:754–64.PubMedCrossRefGoogle Scholar
  66. 66.
    Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2002.Google Scholar
  67. 67.
    Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med. 2003;348:287–94.PubMedCrossRefGoogle Scholar
  68. 68.
    Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women’s Health Study. J Natl Cancer Inst. 1999;91:2102–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens Jr FL, Omenn GS, et al. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004;96:1743–50.PubMedCrossRefGoogle Scholar
  70. 70.
    Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academy Press; 2000.Google Scholar
  71. 71.
    Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 1999;281:1415–23.PubMedCrossRefGoogle Scholar
  72. 72.
    Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol. 2004;15:3225–32.PubMedCrossRefGoogle Scholar
  73. 73.
    Lee DH, Folsom AR, Harnack L, Halliwell B, Jacobs Jr DR. Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? Am J Clin Nutr. 2004;80:1194–200.PubMedGoogle Scholar
  74. 74.
    Dwyer JH, Paul-Labrador MJ, Fan J, Shircore AM, Merz CN, Dwyer KM. Progression of carotid intima-media thickness and plasma antioxidants: the Los Angeles Atherosclerosis Study. Arterioscler Thromb Vasc Biol. 2004;24:313–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Silver EW, Eskenazi B, Evenson DP, Block G, Young S, Wyrobek AJ. Effect of antioxidant intake on sperm chromatin stability in healthy nonsmoking men. J Androl. 2005;26:550–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, et al. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch Androl. 2003;49:83–94.PubMedCrossRefGoogle Scholar
  77. 77.
    Suleiman SA, Ali ME, Zaki ZM, el-malik EM, Nasr MA. Lipid peroxidation and human sperm motility: protective role of vitamin E. J Androl. 1996;17:530–7.PubMedGoogle Scholar
  78. 78.
    Rolf C, Cooper TG, Yeung CH, Nieschlag E. Antioxidant treatment of patients with asthenozoospermia or moderate oligoastheozoospermia with high dose vitamin C and E: a randomized, placebo-controlled, double blinded study. Hum Reprod. 1999;14:1028–33.PubMedCrossRefGoogle Scholar
  79. 79.
    Greco E, Iacobelli M, Rienzi L, Ubaldi F, Ferrero S, Tesarik J. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J Androl. 2005;26:349–53.PubMedCrossRefGoogle Scholar
  80. 80.
    Greco E, Romano S, Iacobelli M, Ferrero S, Baroni E, Minasi MG, et al. ICSI in cases of sperm DNA damage: beneficial effect of oral antioxidant treatment. Hum Reprod. 2005;20:2590–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Edmund Y. Ko
    • 1
    Email author
  • John C. Kefer
    • 2
  • Ashok Agarwal
    • 3
  • Edmund Sabanegh
    • 1
  1. 1.Section of Male Fertility, Department of Urology, Center for Reproductive MedicineGlickman Urological and Kidney Institute, Cleveland ClinicClevelandUSA
  2. 2.Alpine UrologyBoulderUSA
  3. 3.Center for Reproductive MedicineGlickman Urological and Kidney Institute, Cleveland Clinic FoundationClevelandUSA

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