Skip to main content
SpringerLink
Log in

Oxidative Stress and Varicocele Pathophysiology

  • Chapter
  • First Online:
Varicocele and Male Infertility

  • 660 Accesses

Abstract

Oxidative stress (OS) has been recognized as a common mediator through which various etiologies can alter a man’s fertility potential. Varicocele is not an exception in this regard. The different pathophysiologic mechanisms linking varicocele to male infertility are thought, at least partially, to incite a state of seminal OS. In support of this notion is the current evidence which has confirmed the presence of significantly high OS measures in varicocele patients and reported their sound reductions after varicocele treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Sylora JA, Pryor JL. Varicocele. Curr Ther Endocrinol Metab. 1994;5:309–14.

    CAS  PubMed  Google Scholar 

  2. Green KF, Turner TT, Howards SS. Varicocele: reversal of the testicular blood flow and temperature effects by varicocele repair. J Urol. 1984;131:1208–11.

    Article  CAS  PubMed  Google Scholar 

  3. Benoff S, Goodwin LO, Hurler IR, Pergolizzi RG. Variation in the region IS6 of the L-type voltage-gated calcium (Ca2+) channel (L-VDCC) alpha-1 subunit in testis and sperm: implications for role of cadmium in varicocele-associated infertility (VAI). Fertil Steril. 2000;74:555.

    Google Scholar 

  4. Sharman RK, Agarwal A. Role of reactive oxygen species in male infertility. Urology. 1996;48:835–50.

    Article  Google Scholar 

  5. Kessopoulou E, Tomlinson MJ, Barratt CL, Bolton AE, Cooke ID. Origin of reactive oxygen species in human semen: spermatozoa or leucocytes? J Reprod Fertil. 1992;94:463–70.

    Article  CAS  PubMed  Google Scholar 

  6. Garrido N, Meseguer M, Simon C, Pellicer A, Remohi J. Prooxidative and anti-oxidative imbalance in human semen and its relation with male fertility. Asian J Androl. 2004;6:59–65.

    CAS  PubMed  Google Scholar 

  7. Aitken RJ. Free radicals, lipid peroxidation and sperm function. Reprod Fertil Dev. 1995;7:659–68.

    Article  CAS  PubMed  Google Scholar 

  8. Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol. 2010;25:287–99.

    Article  PubMed  Google Scholar 

  9. Sharma RK, Agarwal A. Role of ROS in male infertility. Urology. 1996;48:835.

    Article  CAS  PubMed  Google Scholar 

  10. Mostafa T, Anis TH, El-Nashar A, Imam H, Othman IA. Varicocelectomy reduces reactive oxygen species levels and increases antioxidant activity of seminal plasma from infertile men with varicocele. Int J Androl. 2001;24:261–5.

    Article  CAS  PubMed  Google Scholar 

  11. Halliwell B. Free radicals, antioxidants, and human disease: curiosity, cause or consequence? Lancet. 1994;344:721–4.

    Article  CAS  PubMed  Google Scholar 

  12. Agarwal A, Saleh RA. Role of oxidants in male infertility: rationale, significance, and treatment. Urol Clin North Am. 2002;29:817–27.

    Article  PubMed  Google Scholar 

  13. Agarwal A, Hamada A, Esteves S. Insight into oxidative stress in varicocele-associated male infertility: part 1. Nat Rev Urol. 2012;9(12):678–90.

    Article  CAS  PubMed  Google Scholar 

  14. Zalata A, Hafez T, Comhaire F. Evaluation of the role of reactive oxygen species in male infertility. Hum Reprod. 1995;10:1444–51.

    Article  CAS  PubMed  Google Scholar 

  15. Sharma RK, Agarwal A. Role of reactive oxygen species in male infertility. Urology. 1996;48:835–50.

    Article  CAS  PubMed  Google Scholar 

  16. Agarwal A, Sekhon LH. Oxidative stress and antioxidants for idiopathic oligoasthenoteratospermia: is it justified? Indian J Urol. 2011;27:74–85.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cohen GM. Caspases: the executioners of apoptosis. Biochem J. 1997;326:1–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Krajewski M, Wang HG, Reed JC, et al. Immunohistochemical analysis of in vivo patterns of expression of CPP32 (Caspase-3), a cell death protease. Cancer Res. 1997;57:1605–13.

    PubMed  Google Scholar 

  19. Aitken RJ, Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction. 2001;122:497–506.

    Article  CAS  PubMed  Google Scholar 

  20. Shiraishi K, Takihara H, Naito K. Testicular volume, scrotal temperature, and oxidative stress in fertile men with left varicocele. Fertil Steril. 2009;91(S4):1388–91.

    Article  PubMed  Google Scholar 

  21. Mariotti A, et al. Scrotal thermoregulatory model and assessment of the impairment of scrotal temperature control in varicocele. Ann Biomed Eng. 2011;39:664–73.

    Article  PubMed  Google Scholar 

  22. Mieusset R, Bujan L. Testicular heating and its possible contributions to male infertility: a review. Int J Androl. 1995;18(4):169–84.

    Article  CAS  PubMed  Google Scholar 

  23. Santoro G, et al. Nitric oxide synthase patterns in normal and varicocele testis in adolescents. BJU Int. 2001;88:967–73.

    Article  CAS  PubMed  Google Scholar 

  24. Shiraishi K, Naito K. Nitric oxide produced in the testis is involved in dilatation of the internal spermatic vein that compromises spermatogenesis in infertile men with varicocele. BJU Int. 2007;99:1086–90.

    Article  CAS  PubMed  Google Scholar 

  25. Costur P, et al. Expression of inducible nitric oxide synthase (iNOS) in the azoospermic human testis. Andrologia. 2012;44(S1):654–60.

    Article  PubMed  CAS  Google Scholar 

  26. Guo J, et al. Expression of nitric oxide synthase during germ cell apoptosis in testis of cynomolgus monkey after testosterone and heat treatment. J Androl. 2009;30:190–9.

    Article  CAS  PubMed  Google Scholar 

  27. Clementi E, Brown GC, Feelisch M, Moncada S. Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc Natl Acad Sci. 1998;95:7631–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Poderoso JJ, et al. Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch Biochem Biophys. 1996;328:85–92.

    Article  CAS  PubMed  Google Scholar 

  29. Beltrán B, Orsi A, Clementi E, Moncada S. Oxidative stress and Snitrosylation of proteins in cells. Br J Pharmacol. 2000;129:953–60.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Abbasi M, et al. Aminoguanidine improves epididymal sperm parameters in varicocelized rats. Urol Int. 2011;86:302–6.

    Article  CAS  PubMed  Google Scholar 

  31. Abbasi M, et al. Effect of aminoguanidine in sperm DNA fragmentation in varicocelized rats: role of nitric oxide. Reprod Sci. 2011;18:545–50.

    Article  CAS  PubMed  Google Scholar 

  32. Alizadeh N, et al. Effects of aminoguanidine on infertile varicocelized rats: a functional and morphological study. Daru. 2010;18:51–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Gao XK, et al. Protective effect of nitric oxide synthase inhibitor (l-NAME) on germ cell apoptosis in experimentally cryptorchid rats [Chinese]. Zhonghua Nan Ke Xue. 2003;9:684–6, 689

    CAS  PubMed  Google Scholar 

  34. DeFoor WR, Kuan CY, Pinkerton M, Sheldon CA, Lewis AG. Modulation of germ cell apoptosis with a nitric oxide synthase inhibitor in a murine model of congenital cryptorchidism. J Urol. 2004;172:1731–5.

    Article  CAS  PubMed  Google Scholar 

  35. Lue Y, Sinha Hikim AP, Wang C, Leung A, Swerdloff RS. Functional role of inducible nitric oxide synthase in the induction of male germ cell apoptosis, regulation of sperm number, and determination of testes size: evidence from null mutant mice. Endocrinology. 2003;144:3092–100.

    Article  CAS  PubMed  Google Scholar 

  36. Tan GY, Yang L, Fu YQ, Feng JH, Zhang MH. Effects of different acute high ambient temperatures on function of hepatic mitochondrial respiration, antioxidative enzymes, and oxidative injury in broiler chickens. Poult Sci. 2010;89:115–22.

    Article  CAS  PubMed  Google Scholar 

  37. Paul C, Teng S, Saunders PT. A single, mild, transient scrotal heat stress causes hypoxia and oxidative stress in mouse testes, which induces germ cell death. Biol Reprod. 2009;80:913–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Voglmayr JK, Setchell BP, White IG. The effects of heat on the metabolism and ultrastructure of ram testicular spermatozoa. J Reprod Fertil. 1971;24:71–80.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang K, et al. Uncoupling protein 2 protects testicular germ cells from hyperthermia-induced apoptosis. Biochem Biophys Res Commun. 2007;360:327–32.

    Article  CAS  PubMed  Google Scholar 

  40. Dridi S, Temim S, Derouet M, Tesseraud S, Taouis M. Acute cold-and chronic heat-exposure upregulate hepatic leptin and muscle uncoupling protein (UCP) gene expression in broiler chickens. J Exp Zool A Ecol Genet Physiol. 2008;309:381–8.

    Article  PubMed  CAS  Google Scholar 

  41. Mancini A, Conte G, Milardi D, De Marinis L, Littarru GP. Relationship between sperm cell ubiquinone and seminal parameters in subjects with and without varicocele. Andrologia. 1998;30:1–4.

    Article  CAS  PubMed  Google Scholar 

  42. Skibba JL, Stadnicka A, Kalbfleisch JH, Powers RH. Effects of hyperthermia on xanthine oxidase activity and glutathione levels in the perfused rat liver. J Biochem Toxicol. 1989;4:119–25.

    Article  CAS  PubMed  Google Scholar 

  43. Hille R, Nishino T. Flavoprotein structure and mechanism. 4. Xanthine oxidase and xanthine dehydrogenase. FASEB J. 1995;9:995–1003.

    Article  CAS  PubMed  Google Scholar 

  44. Bruder G, Heid HW, Jarasch ED, Mather IH. Immunological identification and determination of xanthine oxidase in cells and tissues. Differentiation. 1983;23:218–25.

    Article  CAS  PubMed  Google Scholar 

  45. Kawaguchi S, Fukuda J, Kumagai J, Shimizu Y, Tanaka T. Expression of xanthine oxidase in testicular cells. Akita J Med. 2009;36:99–105.

    CAS  Google Scholar 

  46. Mitropoulos D, et al. Nitric oxide synthase and xanthine oxidase activities in the spermatic vein of patients with varicocele: a potential role for nitric oxide and peroxynitrite in sperm dysfunction. J Urol. 1996;156:1952–8.

    Article  CAS  PubMed  Google Scholar 

  47. Ozawa N, et al. Leydig cell-derived heme oxygenase1 regulates apoptosis of premeiotic germ cells in response to stress. J Clin Invest. 2002;109:457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ewing JF, Maines MD. Distribution of constitutive (HO2) and heat-inducible (HO1) heme oxygenase isozymes in rat testes: HO2 displays stage-specific expression in germ cells. Endocrinology. 1995;136:2294–302.

    Article  CAS  PubMed  Google Scholar 

  49. Maines MD. The heme oxygenase system and its functions in the brain. Cell Mol Biol. 2000;46:573–85.

    CAS  PubMed  Google Scholar 

  50. Shibahara S, Sato M, Muller RM, Yoshida T. Structural organization of the human heme oxygenase gene and the function of its promoter. Eur J Biochem. 1989;179:557–63.

    Article  CAS  PubMed  Google Scholar 

  51. Kitamuro T, et al. Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase1 gene in human cells. J Biol Chem. 2003;278:9125–33.

    Article  CAS  PubMed  Google Scholar 

  52. Nakayama M, et al. Repression of heme oxygenase1 by hypoxia in vascular endothelial cells. Biochem Biophys Res Commun. 2000;271:665–71.

    Article  CAS  PubMed  Google Scholar 

  53. Abdel Aziz MT, et al. Heme oxygenase enzyme activity in seminal plasma of oligoasthenoteratozoospermic males with varicocele. Andrologia. 2008;42:236–41.

    Article  Google Scholar 

  54. Shiraishi K, Naito K. Increased expression of Leydig cell haem oxygenase1 preserves spermatogenesis in varicocele. Hum Reprod. 2005;20:2608–13.

    Article  CAS  PubMed  Google Scholar 

  55. Parsell DA, Lindquist S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genet. 1993;27:437–96.

    Article  CAS  PubMed  Google Scholar 

  56. Yesilli C, et al. Effect of varicocelectomy on sperm creatine kinase, HspA2 chaperone protein (creatine kinaseM type), LDH, LDHX, and lipid peroxidation product levels in infertile men with varicocele. Urology. 2005;66:610–5.

    Article  PubMed  Google Scholar 

  57. Lima SB, et al. Expression of the HSPA2 gene in ejaculated spermatozoa from adolescents with and without varicocele. Fertil Steril. 2006;86:1659–63.

    Article  CAS  PubMed  Google Scholar 

  58. Esfahani MAH, et al. Can altered expression of HSPA2 in varicocele patients lead to abnormal spermatogenesis. Int J Fertil Steril. 2010;4:104–13.

    Google Scholar 

  59. Ferlin A, et al. Heat shock protein and heat shock factor expression in sperm: relation to oligozoospermia and varicocele. J Urol. 2010;183:1248–52.

    Article  CAS  PubMed  Google Scholar 

  60. Nakai A, Suzuki M, Tanabe M. Arrest of spermatogenesis in mice expressing an active heat shock transcription factor 1. EMBO J. 2000;19:1545–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gat Y, Zukerman Z, Chakraborty J, Gornish M. Varicocele, hypoxia and male infertility. Fluid mechanics analysis of the impaired testicular venous drainage system. Hum Reprod. 2005;20:2614–9.

    Article  PubMed  Google Scholar 

  62. Lee JD, Jeng SY, Lee TH. Increased expression of hypoxia-inducible factor-1α in the internal spermatic vein of patients with varicocele. J Urol. 2006;175:1045–8.

    Article  CAS  PubMed  Google Scholar 

  63. Jung S-N, et al. Reactive oxygen species stabilize hypoxia-inducible factor1α protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis. 2008;29:713–21.

    Article  CAS  PubMed  Google Scholar 

  64. Hierholzer C, et al. Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med. 1988;187:917–28.

    Article  Google Scholar 

  65. Moore WM, et al. lN6(1iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J Med Chem. 1994;37:3886–8.

    Article  CAS  PubMed  Google Scholar 

  66. Sohn HY, et al. Differential regulation of xanthine and NAD(P)H oxidase by hypoxia in human umbilical vein endothelial cells. Role of nitric oxide and adenosine. Cardiovasc Res. 2003;58:638–46.

    Article  CAS  PubMed  Google Scholar 

  67. Abdulmalek K, Ashur F, Ezer N, Fengchun Y, Magder S, Hussain SN. Differential expression of Tie-2 receptors and angiopoietins in response to in vivo hypoxia in rats. Am J Physiol. 2001;281(2):L582–90.

    CAS  Google Scholar 

  68. Reyes J, Farias J, Henríquez-Olavarrieta S, et al. The hypoxic testicle: physiology and pathophysiology. Oxidative Med Cell Longev. 2012;2012:1–15.

    Article  CAS  Google Scholar 

  69. Girgis SM, et al. Lactate and pyruvate levels in the testicular vein of subfertile males with varicocele as a test for the theory of underlying hypoxia. Andrologia. 1981;13:6–9.

    Google Scholar 

  70. Ibrahim AA, Hamada TA, Moussa MM. Effect of varicocele on sperm respiration and metabolism. Andrologia. 1981;13:253–9.

    Article  CAS  PubMed  Google Scholar 

  71. Ghabili K, Shoja MM, Agutter PS, Agarwal A. Hypothesis: intracellular acidification contributes to infertility in varicocele. Fertil Steril. 2009;92:399–401.

    Article  PubMed  Google Scholar 

  72. Arena S, et al. Aquaporin-9 immunohistochemistry in varicocele testes as a consequence of hypoxia in the sperm production site. Andrologia. 2011;43:34–7.

    Article  CAS  PubMed  Google Scholar 

  73. Ishikawa T, Fujioka H, Ishimura T, Takenaka A, Fujisawa M. Expression of leptin and leptin receptor in the testis of fertile and infertile patients. Andrologia. 2007;39:22–7.

    Article  CAS  PubMed  Google Scholar 

  74. Konukoglu D, Serin O, Turhan MS. Plasma leptin and its relationship with lipid peroxidation and nitric oxide in obese female patients with or without hypertension. Arch Med Res. 2006;37:602–6.

    Article  CAS  PubMed  Google Scholar 

  75. Yamagishi SI, et al. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem. 2001;276:25096–100.

    Article  CAS  PubMed  Google Scholar 

  76. Nallella KP, et al. Relationship of interleukin6 with semen characteristics and oxidative stress in patients with varicocele. Urology. 2004;64:1010–3.

    Article  PubMed  Google Scholar 

  77. Moretti E, et al. Semen characteristics and inflammatory mediators in infertile men with different clinical diagnoses. Int J Androl. 2009;32:637–46.

    Article  CAS  PubMed  Google Scholar 

  78. Zalata A, Hafez T, Van Hoecke MJ, Comhaire F. Evaluation of β-endorphin and interleukin6 in seminal plasma of patients with certain andrological diseases. Hum Reprod. 1995;10:3161–5.

    Article  CAS  PubMed  Google Scholar 

  79. Tortolero I, et al. The effect of seminal leukocytes on semen quality in subfertile males with and without varicocele [Spanish]. Arch Esp Urol. 2004;57:921–8.

    PubMed  Google Scholar 

  80. Ito H, et al. Internal spermatic vein prostaglandins in varicocele patients. Fertil Steril. 1982;37:218–22.

    Article  CAS  PubMed  Google Scholar 

  81. Adamopoulos DA, Kontogeorgos L, Abrahamian-Michalakis A, Terzis T, Vassilopoulos P. Raised sodium, potassium, and urea concentrations in spermatic venous blood: an additional causative factor in the testicular dysfunction of varicocele? Fertil Steril. 1987;48:331–3.

    Article  CAS  PubMed  Google Scholar 

  82. Zhang Z, Dmitrieva NI, Park J-H, Levine RL, Burg MB. High urea and NaCl carbonylate proteins in renal cells in culture and in vivo, and high urea causes 8oxoguanine lesions in their, DNA. Proc Natl Acad Sci. 2004;101:9491–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jeng SY, Wu SM, Lee JD. Cadmium accumulation and metallothionein overexpression in internal spermatic vein of patients with varicocele. Urology. 2009;73:1231–5.

    Article  PubMed  Google Scholar 

  84. Benoff SH, Millan C, Hurley IR, Napolitano B, Marmar JL. Bilateral increased apoptosis and bilateral accumulation of cadmium in infertile men with left varicocele. Hum Reprod. 2004;19:616–27.

    Article  CAS  PubMed  Google Scholar 

  85. Benoff S, et al. A potential role for cadmium in the etiology of varicocele-associated infertility. Fertil Steril. 1997;67:336–47.

    Article  CAS  PubMed  Google Scholar 

  86. Suzuki F. Microvasculature of the mouse testis and excurrent duct system. Am J Anat. 1982;163:309–25.

    Article  CAS  PubMed  Google Scholar 

  87. Hinton BT, Palladino MA, Rudolph D, Lan ZJ, Labus JC. The role of the epididymis in the protection of spermatozoa. Curr Top Dev Biol. 1996;33:61–102.

    Article  CAS  PubMed  Google Scholar 

  88. Potts RJ, Mjefferies T, Notarianni LJ. Antioxidant capacity of the epididymis. Hum Reprod. 1999;14(10):2513–6.

    Article  CAS  PubMed  Google Scholar 

  89. Ozturk U, et al. The effects of experimental left varicocele on the epididymis. Syst Biol Reprod Med. 2008;54:177–84.

    Article  PubMed  Google Scholar 

  90. Zhang QY, Qiu SD, Ma XN, Yu HM, Wu YW. Effect of experimental varicocele on structure and function of epididymis in adolescent rats. Asian J Androl. 2003;5:108–12.

    PubMed  Google Scholar 

  91. Li Y-Y, Hwang IS, O W-S, Tang F. Adrenomedullin peptide: gene expression of adrenomedullin, its receptors and receptor activity modifying proteins, and receptor binding in rat testis—actions on testosterone secretion. Biol Reprod. 2006;75:183–8.

    Article  CAS  PubMed  Google Scholar 

  92. Sugo S, et al. Endothelial cells actively synthesize and secrete adrenomedullin. Biochem Biophys Res Commun. 1994;201:1160–6.

    Article  CAS  PubMed  Google Scholar 

  93. Kitamura K, et al. Complete amino acid sequence of porcine adrenomedullin and cloning of cDNA encoding its precursor. FEBS Lett. 1994;338:306–10.

    Article  CAS  PubMed  Google Scholar 

  94. Sugo S, Minamino N, Shoji H, Kangawa K, Kitamura K, Eto T, Matsuo H. Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun. 1995;207:25–32.

    Article  CAS  PubMed  Google Scholar 

  95. Chun TH, Itoh H, Ogawa Y, Tamura N, Takaya K, Igaki T, Yamashita J, Doi K, Inoue M, Masatsugu K, et al. Shear stress augments expression of C-type natriuretic peptide and adrenomedullin. Hypertension. 1997;29:1296–302.

    Article  CAS  PubMed  Google Scholar 

  96. Fujita M, Kuwaki T, Ando K, Fujita T. Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in the brain. Hypertension. 2005;45:1165–72.

    Article  CAS  PubMed  Google Scholar 

  97. Yurekli M, et al. Adrenomedullin reduces antioxidant defense system and enhances kidney tissue damage in cadmium and lead exposed rats. Environ Toxicol. 2009;24:279–86.

    Article  CAS  PubMed  Google Scholar 

  98. Chan YF, O W-S, Tang F. Adrenomedullin in the rat testis. I: Its production, actions on testosterone secretion, regulation by human chorionic gonadotropin, and its interaction with endothelin 1 in the leydig cell. Biol Reprod. 2008;78:773–9.

    Article  CAS  PubMed  Google Scholar 

  99. Zhang C, et al. Oligozoospermia with normal fertility in male mice lacking the androgen receptor in testis peritubular myoid cells. Proc Natl Acad Sci. 2006;103:17718–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ozbek E, Yurekli M, Soylu A, Davarci M, Balbay MD. The role of adrenomedullin in varicocele and impotence. BJU Int. 2000;86:694–8.

    Article  CAS  PubMed  Google Scholar 

  101. Hu W, Zhou P, Zhang X, Xu C, Wang W. Roles of adrenomedullin and hypoxia-inducible factor 1 alpha in patients with varicocele. Andrologia. 2014;47:951–7. https://doi.org/10.1111/and.12363.

    Article  CAS  PubMed  Google Scholar 

  102. Allamaneni SS, Naughton CK, Sharma RK, Thomas AJ Jr, Agarwal A. Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size. Fertil Steril. 2004;82:1684–6.

    Article  PubMed  Google Scholar 

  103. Cocuzza M, Athayde KS, Agarwal A, Pagani R, Sikka SC, Lucon AM, et al. Impact of clinical varicocele and testis size on seminal reactive oxygen species levels in a fertile population: a prospective controlled study. Fertil Steril. 2008;90:1103–8.

    Article  CAS  PubMed  Google Scholar 

  104. Hurtado de Catalfo GE, Ranieri-Casilla A, Marra FA, de Alaniz MJ, Marra CA. Oxidative stress biomarkers and hormonal profile in human patients undergoing varicocelectomy. Int J Androl. 2007;30:519–30.

    Article  CAS  PubMed  Google Scholar 

  105. Mostafa T, Anis T, Imam H, El-Nashar AR, Osman IA. Seminal reactive oxygen species antioxidant relationship in fertile males with and without varicocele. Andrologia. 2009;41:125–9.

    Article  CAS  PubMed  Google Scholar 

  106. Pasqualotto FF, Sundaram A, Sharma RK, Borges E Jr, Pasqualotto EB, Agarwal A. Semen quality and oxidative stress scores in fertile and infertile patients with varicocele. Fertil Steril. 2008;89:602–7.

    Article  PubMed  Google Scholar 

  107. Yagi K. Simple procedure for specific assay of lipid hydroperoxides in serum or plasma. Methods Mol Biol. 1998;108:107–10.

    CAS  PubMed  Google Scholar 

  108. Sakamoto Y, Ishikawa T, Kondo Y, Yamaguchi K, Fujisawa M. The assessment of oxidative stress in infertile patients with varicocele. BJU Int. 2008;101:1547–52.

    Article  CAS  PubMed  Google Scholar 

  109. Mehraban D, et al. Comparison of nitric oxide concentration in seminal fluid between infertile patients with and without varicocele and normal fertile men. Urol J. 2005;2:106–10.

    PubMed  Google Scholar 

  110. Mostafa T, Anis T, El Nashar A, Imam H, Osman I. Seminal plasma reactive oxygen species-antioxidants relationship with varicocele grade. Andrologia. 2012;44:66–9.

    Article  CAS  PubMed  Google Scholar 

  111. Mazzilli F, Rossi T, Marchesini M, Ronconi C, Dondero F. Superoxide anion in human semen related to seminal parameters and clinical aspects. Fertil Steril. 1994;62:862–8.

    Article  CAS  PubMed  Google Scholar 

  112. Agarwal A, Nallella KP, Allamaneni SS, Said TM. Role of antioxidants in treatment of male infertility: an overview of the literature. Reprod BioMed Online. 2004;8(6):616–27.

    Article  CAS  PubMed  Google Scholar 

  113. Pasqualotto FF, Sharma RK, Pasqualotto EB, Agarwal A. Poor semen quality and ROS-TAC scores in patients with idiopathic infertility. Urol Int. 2008;81:263–70.

    Article  PubMed  Google Scholar 

  114. Pasqualotto FF, Sharma RK, Kobayashi H, Nelson DR, Thomas AJ Jr, Agarwal A. Oxidative stress in normospermic men undergoing infertility evaluation. J Androl. 2001;22(2):316–22.

    CAS  PubMed  Google Scholar 

  115. Akyol O, Ozbek E, Uz E, Koçak I. Malondialdehyde level and total superoxide dismutase activity in seminal fluid from patients with varicocele. Clin Exp Med. 2001;1:67–8.

    Article  CAS  PubMed  Google Scholar 

  116. ELkamshoushi A, Hussein O, Elemam A, Omar SS. The role of apoptosis and reactive oxygen species in varicocele-associated azoospermia. Arch Urol. 2018;1(1):22–8.

    Google Scholar 

  117. Ozdamar AS, Soylu AG, Culha M, Ozden M, Gokalp A. Testicular oxidative stress: effects of experimental varicocele in adolescent rat. Urol Int. 2004;73:343–7.

    Article  CAS  PubMed  Google Scholar 

  118. Koksal IT, Tefekli A, Usta M, Erol H, Abbasoqlu S, Kadioqlu A. The role of reactive oxygen species in testicular dysfunction associated with varicocele. BJU Int. 2000;86:549–52.

    Article  CAS  PubMed  Google Scholar 

  119. Chen CH, Lee SS, Chen DC, Chien HH, Chen IC, Chu YN, et al. Apoptosis and kinematics of ejaculated spermatozoa in patients with varicocele. J Androl. 2004;25:348–53.

    Article  PubMed  Google Scholar 

  120. Saleh RA, Agarwal A, Sharma RK, Said TM, Sikka SC, Thomas AJ Jr. Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele. Fertil Steril. 2003;80:1431–6.

    Article  PubMed  Google Scholar 

  121. Smith R, Kaune H, Parodi D, Madariaga M, Rios R, Morales I, et al. Increased sperm DNA damage in patients with varicocele: relationship with seminal oxidative stress. Hum Reprod. 2006;21:986–93.

    Article  CAS  PubMed  Google Scholar 

  122. Enciso M, Muriel L, Fernandez JL, et al. Infertile men with varicocele show a high relative proportion of sperm cells with intense nuclear damage level, evidenced by the sperm chromatin dispersion test. J Androl. 2006;27(1):106–11.

    Article  PubMed  Google Scholar 

  123. Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. BJU Int. 2005;95(4):503–7.

    Article  CAS  PubMed  Google Scholar 

  124. Agarwal A, Said TM. Role of sperm chromatin abnormalities and DNA damage in male infertility. Hum Reprod Update. 2003;9(4):331–45.

    Article  CAS  PubMed  Google Scholar 

  125. Ozbek E, Ilbey YY, Simsek A, Cekmen M, Balbay MD. Preoperative and postoperative seminal nitric oxide levels in patients with infertile varicocele. Arch Ital Urol Androl. 2009;81:248–50.

    PubMed  Google Scholar 

  126. Mostafa T, et al. Reactive oxygen species and antioxidants relationship in the internal spermatic vein blood of infertile men with varicocele. Asian J Androl. 2006;8:451–4.

    Article  CAS  PubMed  Google Scholar 

  127. Romeo C, et al. Preliminary report on nitric oxide-mediated oxidative damage in adolescent varicocele. Hum Reprod. 2003;18:26–9.

    Article  CAS  PubMed  Google Scholar 

  128. Schlesinger MH, Wilets IF, Nagler HM. Treatment outcome after varicocelectomy. A critical analysis. Urol Clin North Am. 1994;21:517–29.

    CAS  PubMed  Google Scholar 

  129. Chen SS, Huang WJ, Chang LS, Wei YH. Attenuation of oxidative stress after varicocelectomy in subfertile patients with varicocele. J Urol. 2008;179:639–42.

    Article  CAS  PubMed  Google Scholar 

  130. Cervellione RM, et al. Effect of varicocelectomy on the plasma oxidative stress parameters. J Pediatr Surg. 2006;41:403–6.

    Article  PubMed  Google Scholar 

  131. Yesilli C, et al. Effect of varicocelectomy on sperm creatine kinase, HspA2 chaperone protein (creatine kinase-M type), LDH, LDH-X, and lipid peroxidation product levels in infertile men with varicocele. Urology. 2005;66:610–5.

    Article  PubMed  Google Scholar 

  132. Rodriguez Peña M, et al. Predictors of improved seminal parameters and fertility after varicocele repair in young adults. Andrologia. 2009;41:277–81.

    Article  PubMed  Google Scholar 

  133. Lacerda JI, et al. Adolescent varicocele: improved sperm function after varicocelectomy. Fertil Steril. 2011;95:994–9.

    Article  PubMed  Google Scholar 

  134. Dada R, Shamsi MB, Venkatesh S, Gupta NP, Kumar R. Attenuation of oxidative stress & DNA damage in varicocelectomy: implications in infertility management. Indian J Med Res. 2010;132:728–30.

    PubMed  PubMed Central  Google Scholar 

  135. Shiraishi K, Naito K. Generation of 4-hydroxy-2-nonenal modified proteins in testes predicts improvement in spermatogenesis after varicocelectomy. Fertil Steril. 2006;86:233–5.

    Article  CAS  PubMed  Google Scholar 

  136. Cam K, et al. The role of reactive oxygen species and apoptosis in the pathogenesis of varicocele in a rat model and efficiency of vitamin E treatment. Int J Androl. 2004;27:228–33.

    Article  CAS  PubMed  Google Scholar 

  137. Yan LF, Jiang MF, Shao RY. Clinical observation on effect of jingling oral liquid in treating infertile patients with varicocele after varicocelectomy [Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004;24:220–2.

    PubMed  Google Scholar 

  138. Cavallini G, Ferraretti AP, Gianaroli L, Biagiotti G, Vitali G. Cinnoxicam and l-carnitine/acetyl-l-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia. J Androl. 2004;25:761–72.

    Article  CAS  PubMed  Google Scholar 

  139. Nematollahi-Mahani S, Azizollahi G, Baneshi M, Safari Z, Azizollahi S. Effect of folic acid and zinc sulphate on endocrine parameters and seminal antioxidant level after varicocelectomy. Andrologia. 2013;46(3):240–5.

    Article  PubMed  CAS  Google Scholar 

  140. Saalu L, Akunna G, Enye L, Ogunmodede O, Akingbade A. Pathophysiology of varicocele: evidence for oxidative stress as a mechanism pathway. Eur J Anat. 2013;17(2):82–91.

    Google Scholar 

  141. Taghizadeh L, Eidi A, Mortazavi P, Rohani A. Effect of selenium on testicular damage induced by varicocele in adult male Wistar rats. J Trace Elem Med Biol. 2017;44:177–85.

    Article  CAS  PubMed  Google Scholar 

  142. Gual-Frau J, Abad C, Amengual M, et al. Oral antioxidant treatment partly improves integrity of human sperm DNA in infertile grade I varicocele patients. Hum Fertil. 2015;18(3):225–9.

    Article  CAS  Google Scholar 

  143. Festa R, Giacchi E, Raimondo S, Tiano L, Zuccarelli P, et al. Coenzyme Q10 supplementation in infertile men with low-grade varicocele: an open, uncontrolled pilot study. Andrologia. 2014;46:805–7.

    Article  CAS  PubMed  Google Scholar 

  144. Busetto GM, Agarwal A, Virmani A, Antonini G, Ragonesi G, Del Giudice F, Micic S, Gentile V, De Berardinis E. Effect of metabolic and antioxidant supplementation on sperm parameters in oligo-astheno-teratozoospermia, with and without varicocele: a double-blind placebo-controlled study. Andrologia. 2018;50(3).

    Article  CAS  Google Scholar 

  145. Gamidov CI, Ovchinnikov RI, Popova AI, Tkhagapsoeva RA, Izhbaev SK. Current approach to therapy for male infertility in patients with varicocele. Ter Arkh. 2012;84:56–61.

    CAS  PubMed  Google Scholar 

  146. Takihara H, Cosentino MJ, Cockett AT. Zinc sulfate therapy for infertile male with or without varicocelectomy. Urology. 1987;29:638–41.

    Article  CAS  PubMed  Google Scholar 

  147. Chen C, Liang P. Pathogenesis and combined treatment of sterility in men with varicocele. Zhonghua Wai Ke Za Zhi. 1997;35:168–9.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

The authors would like to thank Dr. Iqbal Fahs for her help in editing the manuscript.

Author information

Authors and Affiliations

  1. Department of Urology, Hamad Medical Corporation, Weill Cornell Medicine Qatar, Doha, Qatar

    Ahmad Majzoub

  2. S.H. Ho Urology Centre, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong

    Chak-Lam Cho

  3. American Center for Reproductive Medicine, Department of Urology, Cleveland Clinic, Cleveland, OH, USA

    Ashok Agarwal

  4. ANDROFERT, Andrology & Human Reproduction Clinic, Campinas, SP, Brazil

    Sandro C. Esteves

Authors
  1. Ahmad Majzoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chak-Lam Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashok Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandro C. Esteves
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. ANDROFERT, Andrology & Human Reproduction Clinic, Campinas, SĂŁo Paulo, Brazil

    Sandro C Esteves

  2. S.H. Ho Urology Centre, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong

    Chak-Lam Cho

  3. Department of Urology, Hamad Medical Corporation, Weill Cornell Medicine Qatar, Doha, Qatar

    Ahmad Majzoub

  4. Department of Urology, Cleveland Clinic, Cleveland, OH, USA

    Ashok Agarwal

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Majzoub, A., Cho, CL., Agarwal, A., Esteves, S.C. (2019). Oxidative Stress and Varicocele Pathophysiology. In: Esteves, S., Cho, CL., Majzoub, A., Agarwal, A. (eds) Varicocele and Male Infertility. Springer, Cham. https://doi.org/10.1007/978-3-319-79102-9_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-79102-9_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-79101-2

  • Online ISBN: 978-3-319-79102-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation