A review: Oxidative stress and its role in reproduction

DOI: 10.4236/abb.2013.41006   PDF   HTML   XML   4,066 Downloads   6,942 Views   Citations


Recently the problem of infertility has become more acute. About 3% - 7% of couples suffer a lasting infertility problem and there is a tendency of constant increasing of this number. Existing data reveal that in many of the infertility cases, the cause of sterility is the disabled sperm as a result of the oxidative stress (OS). There are several sources of reactive oxygen species (ROS) in the sperm. Both enzymatic and nonenzymatic antioxidants act as a counteraction against ROS production in seminal plasma. However due to the limited cytoplasm, the spermatozoa are more susceptible to oxidative damage because of the lack of protective cytoplasmic antioxidant enzymes. Currently, many couples suffering fertility problems resort to assisted reproductive technology (ART). Unfortunately, the success rate of ART is relatively low—about 30%. Sperm processing incl. centrifugation, freezing and thawing is associated with the generation of ROS. A range of strategies for sperm prevention of OS are developed. Many studies concern antioxidants and their impact on sperm function, but there are a lot of contradictions in terms of doses and types of combinations that can be used in ART. Future studies should aim the creation of standard and reliable operating procedures for increasing the successfulness of these techniques. This paper offers an overview of the impact of OS on the reproduction, pointing out the sources of ROS in the sperm, the antioxidant defense systems, and the strategies for prevention and improvement of the sperm reproductive functions, incl. those applied in ART.

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Nenkova, G. and Alexandrova, A. (2013) A review: Oxidative stress and its role in reproduction. Advances in Bioscience and Biotechnology, 4, 37-43. doi: 10.4236/abb.2013.41006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Aitken, R.J., Ryan, A.L., Baker, M.A. and McLaughlin, E.A. (2004) Redox activity associated with the maturation and capacitation of mammalian spermatozoa. Free Radical Biology and Medicine, 36, 994-1010. doi:10.1016/j.freeradbiomed.2004.01.017
[2] Allamaneni, S.R., Naughton, C.K., Sharma, R.K., Thomas Jr., A.J. and Agarwal, A. (2004) Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size. Fertility and Sterility, 82, 1684-1686. doi:10.1016/j.fertnstert.2004.04.071
[3] de Lamirande, E., Tsai, C., Harakat, A. and Gagnon, C. (1998) Involvement of reactive oxygen species in human sperm acrosome reaction induced by A23187, lysophosphatidylcholine and biological fuid ultrafiltrates. Journal of Andrology, 19, 585-594.
[4] Bankson, D.D., Kestin, M. and Rifai, N. (1993) Role of free radicals in cancer and atherosclerosis. Clinics in Laboratory Medicine, 13, 463-480.
[5] Hietanen, E., Bartsch, H., Bereziat, J.C., Camus, A.M., McClinton, S., Eremin, O., Davidson, L. and Boyle, P. (1994) Diet and oxidative stress in breast, colon and prostate cancer patients: A case-control study. European Journal of Clinical Nutrition, 48, 575-586.
[6] Agarwal, A. and Saleh, R.A. (2002) Role of oxidants in male infertility: Rationale, significance, and treatment. Urologic Clinics of North America, 29, 817-827. doi:10.1016/S0094-0143(02)00081-2
[7] Moller, P., Wallin, H. and Knudsen, L.E. (1996) Oxidative stress associated with exercise, psychological stress and life-style factors. Chemico-Biological Interactions, 102, 17-36. doi:10.1016/0009-2797(96)03729-5
[8] Sharma, R.K. and Agarwal, A. (1996) Role of reactive oxygen species in male infertility. Urology, 48, 835-850. doi:10.1016/S0090-4295(96)00313-5
[9] Saleh, R.A., Agarwal, A., Nada, E.A., El-Tonsy, M.H., Sharma, R.K., Meyer, A., Nelson, D.R. and Thomas, A.J. (2003) Negative effects of increased sperm DNA damage in relation to seminal oxidative stress in men with idiopathic and male factor infertility. Fertility and Sterility, 79, 1597-1605. doi:10.1016/S0015-0282(03)00337-6
[10] Agarwal, A., Sharma, R.K., Nallella, K.P., Thomas Jr., A.J., Alvarez, J.G. and Sikka, S.C. (2006) Reactive oxygen species as an independent marker of male factor infertility. Fertility and Sterility, 86, 878-885.
[11] Agarwal, A., Hamamah, S. and Shekarriz, M. (1994) Reactive oxygen species and fertilizing capacity of spermatozoa. Contracept Fertil Sex, 22, 327-330.
[12] Kobayashi, H., Gil-Guzman, E., Mahran, A.M., Rakesh, K., Nelson, D.R., Thomas Jr., A.J. and Agarwal, A. (2001) Quality control of reactive oxygen species measurement by luminol-dependent chemiluminescence assay. Journal of Andrology, 22, 568-574.
[13] Zalata, A.A., Ahmed, A.H., Allamaneni, S.S., Comhaire, F.H. and Agarwal, A. (2004) Relationship between acrosin activity of human spermatozoa and oxidative stress. Asian Journal of Andrology, 6, 313-318.
[14] de Lamirande, E. and Gagnon, C. (1992) Reactive oxygen species and human spermatozoa. II Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility. Journal of Andrology, 13, 379-386.
[15] de Lamirande, E., Jiang, H., Zini, A., Kodama, H. and Gagnon, C. (1997) Reactive oxygen species and sperm physiology. Reviews of Reproduction, 2, 48-54. doi:10.1530/ror.0.0020048
[16] Whittington, K., Harrison, S.C., Williams, K.M., Day, J.L., McLaughlin, E.A., Hull, M.G. and Ford, W.C. (1999) Reactive oxygen species (ROS) production and the outcome of diagnostic tests of sperm function. International Journal of Andrology, 22, 236-242. doi:10.1046/j.1365-2605.1999.00174.x
[17] Kao, S.H., Chao, H.T., Chen, H.W., Hwang, T.I., Liao, T.L. and Wei, Y.H. (2007) Increase of oxidative stress in human sperm with lower motility. Fertility and Sterility, 89, 1183-1190. doi:10.1016/j.fertnstert.2007.05.029
[18] Oliva, R. (2006) Protamines and male infertility. Human Reproduction Update, 12, 417-435. doi:10.1093/humupd/dml009
[19] O’brien, J. and Zini, A. (2005) Sperm DNA integrity and male infertility. Urology, 65, 16-22. doi:10.1016/j.urology.2004.07.015
[20] Seli, E., Gardner, D.K., Schoolcraft, W.B., Moffatt, O. and Sakkas, D. (2004) Extent of nuclear DNA damage in ejaculated spermatozoa impacts on blastocyst development after in vitro fertilization. Fertility and Sterility, 82, 378-383. doi:10.1016/j.fertnstert.2003.12.039
[21] Moustafa, M.H., Sharma, R.K., Thornton, J., Mascha, E., Abdel-Hafez, M.A., Thomas Jr., A.J. and Agarwal, A. (2004) Relationship between ROS production, apoptosis and DNA denaturation in spermatozoa from patients examined for infertility. Human Reproduction, 19, 129-138. doi:10.1093/humrep/deh024
[22] Tominaga, H., Kodama, S., Matsuda, N., Suzuki, K. and Watanabe, M. (2004) Involvement of reactive oxygen species (ROS) in the induction of genetic instability by radiation. Journal Radiation Research (Tokyo), 45, 181-188. doi:10.1269/jrr.45.181
[23] Zorn, B., Vidmar, G. and Meden-Vrtovec, H. (2003) Seminal reactive oxygen species as predictors of fertilization, embryo quality and pregnancy rates after conventional in vitro fertilization and intracytoplasmic sperm injection. International Journal of Andrology, 26, 279-285. doi:10.1046/j.1365-2605.2003.00424.x
[24] Aitken, R.J. and Krausz, C. (2001) Oxidative stress, DNA damage and the Y chromosome. Reproduction, 122, 497-506. doi:10.1530/rep.0.1220497
[25] Aitken, R.J., Baker, M.A. and Sawyer, D. (2003) Oxidative stress in the male germ line and its role in the aetiology of male infertility and genetic disease. Reproductive BioMedicine Online, 7, 65-70. http://www.ncbi.nlm.nih.gov/pubmed/12930576 doi:10.1016/S1472-6483(10)61730-0
[26] Garrido, N., Meseguer, M., Simon, C., Pellicer, A. and Remohi, J. (2004) Pro-oxidative and anti-oxidative imbalance in human semen and its relation with male fertileity. Asian Journal of Andrology, 6, 59-65.
[27] Aitken, R.J., Buckingham, D., West, K., Wu, F.C., Zikopoulos, K. and Richardson, D.W. (1992) Differential contribution of leucocytes and spermatozoa to the generation of reactive oxygen species in the ejaculates of oligozoo-spermic patients and fertile donors. Journal of Reproduction and Fertility, 94, 451-462. doi:10.1530/jrf.0.0940451
[28] Aitken, R.J. and Baker H.W. (1995) Seminal leukocytes: Passengers, terrorists or good samaritans? Human Reproduction, 10, 1736-1739.
[29] Aitken, R.J., Fisher, H.M., Fulton, N., Gomez, E., Knox, W., Lewis, B. and Irvine, S. (1997) Reactive oxygen species generation by human spermatozoa is induced by exogenous NADPH and inhibited by the flavoprotein inhibitors diphenylene iodonium and quinacrine. Molecular Reproduction and Development, 47, 468-482. doi:10.1002/(SICI)1098-2795(199708)47:4<468::AID-MRD14>3.0.CO;2-S
[30] Hendin, B.N., Kolettis, P.N., Sharma, R.K., Thomas Jr., A.J. and Agarwal, A. (1999) Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity. Journal of Urology, 161, 1831-1834. doi:10.1016/S0022-5347(05)68818-0
[31] Ochsendorf, F.R. (1999) Infections in the male genital tract and reactive oxygen species. Human Reproduction Update, 5, 399-420. doi:10.1093/humupd/5.5.399
[32] Pasqualotto, F.F., Sharma, R.K., Potts, J.M., Nelson, D.R., Thomas, A.J. and Agarwal, A. (2000) Seminal oxidative stress in patients with chronic prostatitis. Urology, 55, 881-885. doi:10.1016/S0090-4295(99)00613-5
[33] Saleh, R.A. and Agarwal, A. (2002) Oxidative stress and male infertility: From research bench to clinical practice. Journal of Andrology, 23, 737-752.
[34] Sharma, R.K., Pasqualotto, A.E., Nelson, D.R., Thomas Jr., A.J. and Agarwal, A. (2001) Relationship between seminal white blood cell counts and oxidative stress in men treated at an infertility clinic. Journal of Andrology, 22, 575-583.
[35] Said, T.M., Agarwal, A., Sharma, R.K., Mascha, E., Sikka, S.C. and Thomas Jr., A.J. (2004) Human sperm superoxide anion generation and correlation with semen quality in patients with male infertility. Fertility and Sterility, 82, 871-877. doi:10.1016/j.fertnstert.2004.02.132
[36] Gil-Guzman, E., Ollero, M., Lopez, M.C., Sharma, R.K., Alvarez, J.G., Thomas Jr., A.J. and Agarval, A. (2001) Differential production of reactive oxygen species by subsets of human spermatozoa at different stages of maturation. Human Reproduction, 6, 1922-1930. doi:10.1093/humrep/16.9.1922
[37] Koppers, A., De Iuliis, G., Finnie, J., McLaughlin, E. and Aitken, R.J. (2008) Significance of mitochondrial reactive oxygen species in the generation of oxidative stress in spermatozoa. Journal of Clinical Endocrinology and Metabolism, 93, 3199-3207. doi:10.1210/jc.2007-2616
[38] Halliwell, B. and Gutteridge, J.M.C. (2007) Free radicals in biology and medicine. IV Edition, Oxford Press, Oxford, 26.
[39] Andreyev, A., Kushnareva, Y. and Starkov, A. (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry (Moscow), 70, 200-214. Translated from Biokhimiya, 70, 246-264.
[40] Aitken, R.J., Buckingham, D. and Harkiss, D. (1993) Use of a xanthine oxidase free radical generating system to investigate the cytotoxic effects of reactive oxygen species on human spermatozoa. Journal of Reproduction and Fertility, 97, 441-450. doi:10.1530/jrf.0.0970441
[41] Sanocka, D., Miesel, R., Jedrzejczak, P. and Kurpisz, M.K. (1996) Oxidative stress and male infertility. Journal of Andrology, 17, 449-454.
[42] Alvarez, J.G. and Storey, B.T. (1989) Role of glutathione peroxidase in protecting mammalian spermatozoa from loss of motility caused by spontaneous lipid peroxidation. Gamete Research, 23, 77-90. doi:10.1002/mrd.1120230108
[43] Sies, H., Stahl, W. and Sundquist, A.R. (1992) Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids. Annals of the New York Academy of Sciences, 669, 7-20. doi:10.1111/j.1749-6632.1992.tb17085.x
[44] Jensen, M.B., Bjerrum, P.J., Jessen, T.E., Nielsen, J.E., Joensen, U.N., Olesen, I.A., Petersen, J.H., Juul, A., Dissing, S. and Jorgensen, N. (2011) Vitamin D is positively associated with sperm motility and increases intracellular calcium in human spermatozoa. Human Reproduction, 26, 1307-1317. doi:10.1093/humrep/der059
[45] Lewis, S.E., Sterling, E.S., Young, I.S. and Thompson, W. (1997) Comparison of individual antioxidants of sperm and seminal plasma in fertile and infertile men. Fertility and Sterility, 67, 142-147. doi:10.1016/S0015-0282(97)81871-7
[46] Garrido, N., Meseguer, M., Alvarez, J., Simón, C., Pellicer, A. and Remohí, J. (2004) Relationship among standard semen parameters, glutathione peroxidase/glutathione reductase activity, and mRNA expression and reduced glutathione content in ejaculated spermatozoa from fertile and infertile men. Fertility and Sterility, 82, 1059-1066. doi:10.1016/j.fertnstert.2004.04.033
[47] Holmes, R., Goodan, H., Shihabi, Z. and Jarow, J. (1992) The Taurine and Hypotaurine Content of Human Semen. Journal of Andrology, 13, 289-292.
[48] Gallardo, J.M. (2007) Evaluation of antioxidant system in normal semen. Revista de Investigación Clínica, 59, 42-47.
[49] Yoshida, K., Yamasaki, T., Yoshiike, M., Takano, S., Sato, I. and Iwamoto, T. (2003) Quantification of seminal plasma motility inhibitor/semenogelin in human seminal plasma. Journal of Andrology, 24, 878-884.
[50] Henkel, R.R. and Schill, W.B. (2003) Sperm preparation for ART. Reproductive Biology and Endocrinology, 14, 108. doi:10.1186/1477-7827-1-108
[51] Chi, H.J., Kim, J.H., Ryu, C.S., Lee, J.Y., Park, J.S., Chung, D.Y., Choi, S.Y., Kim, M.H., Chun, E.K. and Roh, S.I. (2008) Protective effect of antioxidant supplementation in sperm-preparation medium against oxidative stress in human spermatozoa. Human Reproduction, 23, 1023-1028. doi:10.1093/humrep/den060
[52] Di Santo, M., Tarozzi, N., Nadalini, M. and Borini, A. (2012) Human SpermCryopreservation: Update on Techniques, Effect on DNA Integrity, and Implications for ART. Advances in Urology, Article ID 854837, 12 Pages.
[53] Bilodeau, J.F., Chatterjee, S., Sirard, M.A. and Gagnon, C. (2000) Levels of antioxidant defenses are decreased in bovine spermatozoa after a cycle of freezing and thawing. Molecular Reproduction and Development, 55, 282-288. doi:10.1002/(SICI)1098-2795(200003)55:3<282::AID-MRD6>3.0.CO;2-7
[54] Sanocka, D. and Kurpisz, M. (2004) Reactive oxygen species and sperm cells. Reproductive Biology and Endocrinology, 23, 12. doi:10.1186/1477-7827-2-12
[55] Bruskov, V.I., Malakhova, L.V., Masalimov, Z.K. and Chernikov, A.V. (2002) Heat-induced formation of reactive oxygen species and 8-oxoguanine, a biomarker of damage to DNA. Nucleic Acids Research, 30, 1354-1363. doi:10.1093/nar/30.6.1354
[56] Lindemann, C., O’Brien, J. and Giblin, F. (1988) An investigation of the effectiveness of certain antioxidants in preserving the motility of reactivated bull sperm models. Biology of reproduction, 38, 114-120. doi:10.1095/biolreprod38.1.114
[57] Huszar, G., Celik-Ozenci, C., Cayli, S., Kovacs, T., Vigue, L. and Kovanci, E. (2004) Semen characteristics after overnight shipping: Preservation of sperm concentrations, HspA2 ratios, CK activity, cytoplasmic retention, chromatin maturity, DNA integrity, and sperm shape. Journal of Andrology, 25, 593-604.
[58] White, D.R. (1985) Studies of the spermicidal activity of chelating agents. Australian Journal of Biological Sciences, 8, 387-395.
[59] Baumber, J., Ball, B.A. and Linfor, J.J. (2005) Assessment of the cryopreservation of equine spermatozoa in the presence of enzyme scavengers and antioxidants. American Journal of Veterinary Research, 66, 772-779. doi:10.2460/ajvr.2005.66.772
[60] Rossi, T., Mazzilli, F., Delfino, M. and Dondero, F. (2001) Improved human sperm recovery using superoxide dismutase and catalase supplementation in semen cryopreservation procedure. Cell Tissue Bank, 2, 9-13. doi:10.1023/A:1011592621487
[61] Calamera, J.C., Fernandez, P.J., Buffone, M.G., Acosta, A.A. and Doncel, G.F. (2001) Effects of long-term in vitro incubation of human spermatozoa: Functional parameters and catalase effect. Andrologia, 33, 79-86. doi:10.1046/j.1439-0272.2001.00409.x
[62] Lewis, S.E.M., Sterling, E.S.L., Young, I.S. and Thompson, W. (1997) Comparison of individual antioxidants of sperm and seminal plasma in fertile and infertile men. Fertility and Sterility, 67, 142-147. doi:10.1016/S0015-0282(97)81871-7
[63] Aitken, R.J. and Clarkson, J.S. (1988) Significance of reactive oxygen species and antioxidants in defining the efficacy of sperm preparation techniques. Journal of Andrology, 9, 367-376.
[64] Sharma, R.K., Said, T. and Agarwal, A. (2004) Sperm DNA damage and its clinical relevance in assessing reproductive outcome. Asian Journal of Andrology, 6, 139-148.
[65] Hughes, C.M., Lewis, S.E., McKelvey-Martin, V.J. and Thompson, W. (1998) The effects of antioxidant supplementation during Percoll preparation on human sperm DNA integrity. Human Reproduction, 13, 1240-1247. doi:10.1093/humrep/13.5.1240
[66] Sierens, J., Hartley, J.A., Campbell, M.J., Leathem, A.J. and Woodside, J.V. (2002) In vitro isoflavone supplementation reduces hydrogen peroxide-induced DNA damage in sperm. Teratogenesis, Carcinogenesis, and Mutagenesis, 22, 227-234. http://www.ncbi.nlm.nih.gov/pubmed/11948633 doi:10.1002/tcm.10015

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