Sperm oxidative stress: clinical significance and management

Oxidative stress is one of the leading causes of sperm dysfunction. Excessive amounts of reactive oxygen species can damage sperm membranes and disrupt their DNA integrity, which affects not only the likelihood of getting pregnant naturally, but also the clinical outcomes of assisted reproductive technologies and the risk of miscarriage. Sperm cells are extremely vulnerable to oxidative stress, given the limited functional reserve of their antioxidant systems and the DNA repair apparatus. Lifestyle factors, most of which are modifiable, often trigger generation of reactive oxygen species.  Both the lifestyle modification and use of antioxidant dietary supplements are adequate and compatible ways to combat male oxidative stress-associated infertility. The search for other internal and external sources of reactive oxygen species, the identification of the etiology of oxidative stress and treatment of respective diseases are necessary for the successful regulation of redox processes in the male reproductive system in clinical practice, which is required not only to overcome infertility, but also to prevent induced epigenetic disorders in subsequent generations. The article presents the analysis of the molecular mechanisms of male idiopathic infertility. The authors provide an overview of how to prevent oxidative stress as one of the causes of subfebrile fever. The article provides an overview of modern therapeutics, as well as the options for eliminating the consequences of the effect of reactive oxygen species on spermatogenesis and male reproductive system in general.

1. Alahmar A. Effect of Vitamin C, Vitamin E, zinc, selenium, and coenzyme Q10 in infertile men with idiopathic oligoasthenozoospermia. Int J Infertil Fetal Med. 2017;8(2):45–49. Available at: https://www.researchgate.net/publication/318740562_Effect_of_Vitamin_C_Vitamin_E_Zinc_Selenium_and_Coenzyme_Q10_in_Infertile_Men_with_Idiopathic_Oligoasthenozoospermia.

2. Khalili M.A., Leisegang K., Majzoub A., Finelli R., Kumar M. Selvam P. et al. Male fertility and the COVID-19 pandemic: systematic review of the literature. World J Mens Health. 2020;38(4):506–520. doi: 10.5534/wjmh.200134.

3. Tian Y., Zhou L. Evaluating the impact of COVID-19 on male reproduction. Reproduction. 2021;161:R37–R44. doi: 10.1530/REP-20-0523

4. Wagner H., Cheng J.W., Ko E.Y. Role of reactive oxygen species in male infertility: An updated review of literature. Arab J Urol. 2017;16(1):35–43. doi: 10.1016/j.aju.2017.11.001.

5. Agarwal A., Virk G., Ong C., du Plessis S.S. Effect of oxidative stress on male reproduction. World J Mens Health. 2014;32(1):1–17. doi: 10.5534/wjmh.2014.32.1.1.

6. Sabeti P., Pourmasumi S., Rahiminia T., Akyash F., Talebi A.R. Etiologies of sperm oxidative stress. Int J Reprod Biomed (Yazd). 2016;14(4):231–240. Available at: https://pubmed.ncbi.nlm.nih.gov/27351024/

7. Bisht S., Faiq M., Tolahunase M., Dada R. Oxidative stress and male infertility. Nat Rev Urol. 2017;14(8):470–485. doi: 10.1038/nrurol.2017.69.

8. Wright C., Milne S., Leeson H. Sperm DNA damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility. Reprod Biomed Online. 2014;28(6):684–703. doi: 10.1016/j.rbmo.2014.02.004.

9. Fraczek M., Kurpisz M. The redox system in human semen and peroxidative damage of spermatozoa. Postepy Hig Med Dosw (Online). 2005;59:523– 534. Available at: https://pubmed.ncbi.nlm.nih.gov/16407791/

10. Abd- Aziz N., Chatterjee C., Durairajanayagam D. Corticosterone- induced oxidative stress alters epididymal sperm fertility in rats. ASM Sci J. 2014;8(2):117–124. Available at: https://www.researchgate.net/publication/316697947_Corticosterone- induced_oxidative_stress_alters_epididymal_sperm_fertility_in_rats.

11. Plante M., De Lamirande E., Gagnon C. Reactive oxygen species released by activated neutrophils, but not by deficient spermatozoa, are sufficient to affect normal sperm motility. Fertil Steril. 1994;62(2):387–393. doi: 10.1016/s0015-0282(16)56895-2.

12. Korshunov M.N., Korshunova E.S., Darenkov S.P. Sperm DNA fragmentation: etiology, pathogenesis, the influence on reproductive function. Urologicheskie vedomosti = Urology Reports (St Petersburg). 2020;10(4):337–345. (In Russ.) doi: 10.17816/uroved44804.

13. Bui A.D., Sharma R., Henkel R., Agarwal A. Reactive oxygen species impact on sperm DNA and its role in male infertility. Andrologia. 2018;50(8):e13012. doi: 10.1111/and.13012.

14. Liang R., Ghaffari S. Stem cells, redox signaling, and stem cell aging. Antioxid Redox Signal. 2014;20(12):1902–1916. doi: 10.1089/ars.2013.5300.

15. Ni K., Steger K., Yang H., Wang H., Hu K., Zhang T., Chen B. A comprehensive investigation of sperm DNA damage and oxidative stress injury in infertile patients with subclinical, normozoospermic, and astheno/oligozoospermic clinical varicocoele. Andrology. 2016;4(5):816–824. doi: 10.1111/andr.12210.

16. Gamidov S.I., Shatylko T.V., Bitsoev T.B., Gasanov N.G., Mammaev R.U. Reproductive function in males with recurrent varicocele. Akusherstvo i ginekologiya = Obstetrics and Gynecology. 2020;(4):176–181. (In Russ.) doi: 10.18565/aig.2020.4.176-181.

17. Depuydt C.E., Bosmans E., Zalata A., Schoonjans F., Comhaire F.H. The relation between reactive oxygen species and cytokines in andrological patients with or without male accessory gland infection. J Androl. 1996;17(6):699–707. Available: https://pubmed.ncbi.nlm.nih.gov/9016401/

18. Henkel R.R. Leukocytes and oxidative stress: dilemma for sperm function and male fertility. Asian J Androl. 2011;13(1):43–52. doi: 10.1038/aja.2010.76.

19. Oliveira P.F., Tomás G.D., Dias T.R., Martins A.D., Rato L., Alves M.G., Silva B.M. White tea consumption restores sperm quality in prediabetic rats preventing testicular oxidative damage. Reprod Biomed Online. 2015;31(4):544–556. doi: 10.1016/j.rbmo.2015.06.021.

20. Sharma R., Harlev A., Agarwal A., Esteves S.C. Cigarette smoking and semen quality: A new meta-analysis examining the effect of the 2010 world health organization laboratory methods for the examination of human semen. Eur Urol. 2016;70(4):635–645. doi: 10.1016/j.eururo.2016.04.010.

21. Saleh R.A., Agarwal A., Kandirali E., Sharma R.K., Thomas A.J., Nada E.A. et al. Leukocytospermia is associated with increased reactive oxygen species production by human spermatozoa. Fertil Steril. 2002;78(6): 1215–1224. doi: 10.1016/s0015-0282(02)04237-1.

22. La Vignera S., Condorelli R.A., Balercia G., Vicari E., Calogero A.E. Does alcohol have any effect on male reproductive function? A review of literature. Asian J Androl. 2013;15(2):221–225. doi: 10.1038/aja.2012.118.

23. Queiroz E.K., Waissmann W. Occupational exposure and effects on the male reproductive system. Cad Saude Publica. 2006;22(3):485–493. doi: 10.1590/s0102-311x2006000300003.

24. Tiligada E. Chemotherapy: induction of stress responses. Endocr Relat Cancer. 2006;13(1):S115–S124. doi: 10.1677/erc.1.01272.

25. Manda K., Ueno M., Moritake T., Anzai K. Alpha-lipoic acid attenuates x-irradiation- induced oxidative stress in mice. Cell Biol Toxicol. 2007;23(2):129–137. doi: 10.1007/s10565-006-0137-6.

26. Desai N., Sharma R., Makker K., Sabanegh E., Agarwal A. Physiologic and pathologic levels of reactive oxygen species in neat semen of infertile men. Fertil Steril. 2009;92(5):1626–1631. doi: 10.1016/j.fertnstert.2008.08.109.

27. Gałecka E., Jacewicz R., Mrowicka M., Florkowski A., Gałecki P. Antioxidative enzymes – structure, properties, functions. Pol Merkur Lekarski. 2008;25(147):266–268. Available at: https://pubmed.ncbi.nlm.nih.gov/19112846/

28. Peeker R., Abramsson L., Marklund S.L. Superoxide dismutase isoenzymes in human seminal plasma and spermatozoa. Mol Hum Reprod. 1997;3(12):1061–1066. doi: 10.1093/molehr/3.12.1061.

29. Yan L., Liu J., Wu S., Zhang S., Ji G., Gu A. et al. Seminal superoxide dismutase activity and its relationship with semen quality and SOD gene polymorphism. J Assist Reprod Genet. 2014;31(5):549–554. doi: 10.1007/s10815-014-0215-2.

30. Macanovic B., Vucetic M., Jankovic A., Stancic A., Buzadzic B., Garalejic E. et al. Correlation between sperm parameters and protein expression of antioxidative defense enzymes in seminal plasma: A pilot study. Dis Markers. 2015;2015:436236. doi: 10.1155/2015/436236.

31. Yeung C.H., Cooper T.G., De Geyter M., De Geyter C., Rolf C., Kamischke A., Nieschlag E. Studies on the origin of redox enzymes in seminal plasma and their relationship with results of in vitro fertilization. Mol Hum Reprod. 1998;4(9):835–839. doi: 10.1093/molehr/4.9.835.

32. Crisol L., Matorras R., Aspichueta F., Expósito A., Hernández M.L., Ruiz- Larrea M.B. et al. Glutathione peroxidase activity in seminal plasma and its relationship to classical sperm parameters and in vitro fertilization- intracytoplasmic sperm injection outcome. Fertil Steril. 2012;97(4):852–857. doi: 10.1016/j.fertnstert.2012.01.097.

33. Agarwal A., Nallella K.P., Allamaneni S.S., Said T.M. Role of antioxidants in treatment of male infertility: an overview of the literature. Reprod Biomed Online. 2004;8(6):616–627. doi: 10.1016/s1472-6483(10)61641-0.

34. Mayorga- Torres B.J., Camargo M., Cadavid Á.P., Du Plessis S.S., Cardona Maya W.D. Are oxidative stress markers associated with unexplained male infertility? Andrologia. 2017;49(5). doi: 10.1111/and.12659.

35. Zini A., San Gabriel M., Baazeem A. Antioxidants and sperm DNA damage: A clinical perspective. J Assist Reprod Genet. 2009;26(8):427–432. doi: 10.1007/s10815-009-9343-5.

36. Efremov E.A., Kasatonova E.V., Melnik Ja.I., Kastrikin Yu.V., Khizriev Kh.Z. The use of antioxidant therapy as preconceptional care in men. Problemy reproduktsii = Russian Journal of Human Reproduction. 2018;24(4):89– 93. (In Russ.) doi: 10.17116/repro20182404189.

37. Imamovic Kumalic S., Pinter B. Review of clinical trials on effects of oral antioxidants on basic semen and other parameters in idiopathic oligoasthenoteratozoospermia. Biomed Res Int. 2014;2014:426951. doi: 10.1155/2014/426951.

38. Alahmar A.T. The effects of oral antioxidants on the semen of men with idiopathic oligoasthenoteratozoospermia. Clin Exp Reprod Med. 2018;45(2):57–66. doi: 10.5653/cerm.2018.45.2.57.

39. Akmal M., Qadri J.Q., Al- Waili N.S., Thangal S., Haq A., Saloom K.Y. Improvement in human semen quality after oral supplementation of Vitamin C. J Med Food. 2006;9(3):440–442. doi: 10.1089/jmf.2006.9.440.

40. El Sheikh M.G., Hosny M.B., Elshenoufy A., Elghamrawi H., Fayad A., Abdelrahman S. Combination of Vitamin E and clomiphene citrate in treating patients with idiopathic oligoasthenozoospermia: A prospective, randomized trial. Andrology. 2015;3(5):864–867. doi: 10.1111/andr.12086.

41. Vahidinia A., Rahbar A.R., Shakoori Mahmoodabadi M.M. Effect of astaxanthin, Vitamin E, and Vitamin C in combination with calorie restriction on sperm quality and quantity in male rats. J Diet Suppl. 2017;14(3):252–263. doi: 10.1080/19390211.2016.1211783.

42. Walczak- Jedrzejowska R., Wolski J.K., Slowikowska- Hilczer J. The role of oxidative stress and antioxidants in male fertility. Cent Eur J Urol. 2013;66(1):60–67. doi: 10.5173/ceju.2013.01.art19.

43. Esteves S.C., Agarwal A. Novel concepts in male infertility. Int Braz J Urol. 2011;37(1):5–15. doi: 10.1590/s1677-55382011000100002.

44. Gamidov S.I., Shatylko T.V., Li K.I., Gasanov N.G. The role of antioxidant molecules in the treatment of male infertility and the preparation of a man for conception. Meditsinskiy sovet = Medical Council. 2020;(3):122– 129. (In Russ.) doi: 10.21518/2079-701X-2020-3-122-129.

45. Kopets R., Kuibida I., Chernyavska I., Cherepanyn V., Mazo R., Fedevych V., Gerasymov S. Dietary supplementation with a novel l-carnitine multi- micronutrient in idiopathic male subfertility involving oligo-, astheno-, teratozoospermia: A randomized clinical study. Andrology. 2020;8(5):1184–1193. doi: 10.1111/andr.12805.

46. Tsampoukas G., Khan M.F., Katsouri A., Akhter W., Moussa M., Deliveliotis K. et al. L-carnitine as primary or adjuvant treatment in infertile patients with varicocele. A systematic review. Arch Ital Urol Androl. 2020;92(3):263–267. doi: 10.4081/aiua.2020.3.263.

47. Jacob R.A., Pianalto F.S., Agee R.E. Cellular ascorbate depletion in healthy men. J Nutr. 1992;122(5):1111–1118. doi: 10.1093/jn/122.5.1111.

48. Thiele J.J., Friesleben H.J., Fuchs J., Ochsendorf F.R. Ascorbic acid and urate in human seminal plasma: determination and interrelationships with chemiluminescence in washed semen. Human Reprod. 1995;10(1):110–115. doi: 10.1093/humrep/10.1.110.

49. Song G.J., Norkus E.P., Lewis V. Relationship between seminal ascorbic acid and sperm DNA integrity in infertile men. Int J Androl. 2006;29(6):569–575. doi: 10.1111/j.1365-2605.2006.00700.x.

50. Aguirre- Arias M.V., Velarde V., Moreno R.D. Effects of ascorbic acid on spermatogenesis and sperm parameters in diabetic rats. Cell Tissue Res. 2017;370(2):305–317. doi: 10.1007/s00441-017-2660-6.

51. Geva E., Bartoov B., Zabludovsky N., Lessing J.B., Lerner- Geva L., Amit A. The effect of antioxidant treatment on human spermatozoa and fertilization rate in an in vitro fertilization program. Fertil Steril. 1996;66(3):430– 434. doi: 10.1016/s0015-0282(16)58514-8.

52. Suleiman S.A., Ali M.E., Zaki Z., El- Malik E., Nasr M. Lipid peroxidation and human sperm motility: protective role of vitamin E. J Androl. 1996;17(5): 530–537. Available at: https://pubmed.ncbi.nlm.nih.gov/8957697/

53. Comhaire F. The role of food supplementation in the treatment of the infertile couple and for assisted reproduction. Andrologia. 2010;42(5):331–340. doi: 10.1111/j.1439-0272.2009.01025.x.

54. Gvozdjáková A., Kucharská J., Dubravicky J., Mojto V., Singh R.B. Coenzyme Q10, α-tocopherol, and oxidative stress could be important metabolic biomarkers of male infertility. Dis Markers. 2015;2015:827941. doi: 10.1155/2015/827941.

55. Balercia G., Buldreghini E., Vignini A., Tiano L., Paggi F., Amoroso S. et al. Coenzyme Q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo- controlled, double- blind randomized trial. Fertil Steril. 2009;91(5):1785–1792. doi: 10.1016/j.fertnstert.2008.02.119.

56. Safarinejad M.R. The effect of coenzyme Q 10 supplementation on partner pregnancy rate in infertile men with idiopathic oligoasthenoteratozoospermia: an open-label prospective study. Int Urol Nephrol. 2012;44(3): 689–700. doi: 10.1007/s11255-011-0081-0.

57. Mancini A., Conte G., Milardi D., De Marinis L., Littarru G. Relationship between sperm cell ubiquinone and seminal parameters in subjects with and without varicocele. Andrologia. 1998;30(1):1–4. doi: 10.1111/j.1439-0272.1998.tb01374.x.

58. Atig F., Raffa M., Ali H.B., Abdelhamid K., Saad A., Ajina M. Altered antioxidant status and increased lipid per-oxidation in seminal plasma of tunisian infertile men. J Hum Reprod Sci. 2012;8(1):139–149. doi: 10.7150/ijbs.8.139.

59. Flohé L. Selenium in mammalian spermiogenesis. Biol Chem. 2007;388:987– 995. doi: 10.1515/BC.2007.112.

60. Moslemi M.K., Tavanbakhsh S. Selenium- Vitamin E supplementation in infertile men: Effects on semen parameters and pregnancy rate. Int J Gen Med. 2011;4:99–104. doi: 10.2147/IJGM.S16275.

61. 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(2):83–94. doi: 10.1080/01485010390129269.

62. Favier A.E. The role of zinc in reproduction. Hormonal mechanisms. Biol Trace Elem Res. 1992;32:363–382. doi: 10.1007/BF02784623.

63. Freedman L.P. Anatomy of the steroid receptor zinc finger region. Endocr Rev. 1992;13(2):129–145. doi: 10.1210/edrv-13-2-129.

64. Arcaniolo D., Favilla V., Tiscione D., Pisano F., Bozzini G., Creta M. et al. Is there a place for nutritional supplements in the treatment of idiopathic male infertility? Arch Ital Urol Androl. 2014;86(3):164–170. doi: 10.4081/aiua.2014.3.164.

65. Huang W.J., Lu X.L., Li J.T., Zhang J.M. Effects of folic acid on oligozoospermia with MTHFR polymorphisms in term of seminal parameters, DNA fragmentation, and live birth rate: a double- blind, randomized, placebo- controlled trial. Andrology. 2020;8(1):110–116. doi: 10.1111/andr.12652.

66. Aarabi M., San Gabriel M.C., Chan D., Behan N.A., Caron M., Pastinen T. et al. High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism. Hum Mol Genet. 2015;24(22):6301–6313. doi: 10.1093/hmg/ddv338.

67. Herst P.M., Dalvai M., Lessard M., Charest P.L., Navarro P., Joly- Beauparlant C. et al. Folic acid supplementation reduces multigenerational sperm miRNA perturbation induced by in utero environmental contaminant exposure. Environ Epigenet. 2019;5(4):dvz024. doi: 10.1093/eep/dvz024.

68. Najafipour R., Moghbelinejad S., Aleyasin A., Jalilvand A. Effect of B9 and B12 vitamin intake on semen parameters and fertility of men with MTHFR polymorphisms. Andrology. 2017;5(4):704–710. doi: 10.1111/andr.12351.

69. Hosseinabadi F., Jenabi M., Ghafarizadeh A.S., Yazdanikhah S. The effect of vitamin B12 supplement on post-thaw motility, viability and DNA damage of human sperm. Andrologia.2020;52(11):e13877. doi: 10.1111/and.13877 .

70. Blomberg Jensen M., Nielsen J.E., Jørgensen A., Rajpert- De Meyts E., Kristensen D.M., Jørgensen N. et al. Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract. Hum Reprod. 2010;25(5):1303–1311. doi: 10.1093/humrep/deq024.

71. Hammoud A.O., Meikle A.W., Peterson C.M., Stanford J., Gibson M., Carrell D.T. Association of 25-hydroxy- vitamin D levels with semen and hormonal parameters. Asian J Androl. 2012;14(6):855–859. doi: 10.1038/aja.2012.77 .

72. Shahraki Z., Mojahed B.S., Shahraki A. Comparison of vitamin D levels in fertile and infertile men. Maedica (Bucur). 2020;15(1):96–98. doi: 10.26574/maedica.2020.15.1.96.

73. Kalinina S.N., Startsev V.Y., Vydrin P.S., Zamyatnin S.A., Gonchar I.S. Treatment and prevention of reproductive disorders, oxidative stress in male idiopathic infertility. Farmakologiya & farmakoterapiya = Pharmacology & Pharmacotherapy. 2020;(2):72–80. (In Russ.) doi: 10.46393/27132129_2020_72-80.