Abstract
Varicocele, the leading cause of male infertility, can impair spermatogenesis through several pathophysiological mechanisms. Of these, current evidence suggests that oxidative stress is the central element contributing to infertility in men with varicocele, to which the testis responds by way of heat stress, ischaemia or production of vasodilators, such as nitric oxide. Surgical varicocele repair (varicocelectomy) is beneficial not only for alleviating oxidative stress-associated infertility, but also for preventing and protecting against the progressive character of varicocele and its consequent upregulations of systemic oxidative stress. However, antioxidant therapy in infertile men with surgically treated and those with untreated varicocele is poorly studied, and well-designed trials are needed.
Key Points
-
Both infertile men with and those without varicocele have elevated levels of reproductive tract ROS; however, such levels are higher in the former, indicating that varicocele exacerbates ROS generation and, consequently, oxidative damage to sperm
-
Varicocele grade is correlated with the severity of oxidative stress—the higher the grade of varicocele, the more severe the degree of oxidative stress
-
Surgical repair is a cost-effective treatment for infertile men with varicocele; such intervention is associated with improvements in various biomarkers of male infertility, such as semen parameters and pregnancy rate
-
By contrast, antioxidant treatments for varicocele-related infertility are poorly studied, and well-designed trials are needed
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jarow, J. P. et al. Best practice policies for male infertility. J. Urol. 167, 2138–2144 (2002).
Madgar, I., Weissenberg, R., Lunenfeld, B., Karasik, A. & Goldwasser, B. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil. Steril. 63, 120–124 (1995).
Witt, M. A. & Lipshultz, L. I. Varicocele: a progressive or static lesion? Urology 42, 541–543 (1993).
Goldstein, M., Gilbert, B. R., Dicker, A. P., Dwosh, J. & Gnecco, C. Microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. J. Urol. 148, 1808–1811 (1992).
Agarwal, A., Hamada, A. & Esteves, S. C. Insight into oxidative stress in varicocele-associated male infertility: part 1. Nat. Rev. Urol. http://dx.doi.org/10.1038/nrurol.2012.197.
Yagi, K. Simple procedure for specific assay of lipid hydroperoxides in serum or plasma. Methods Mol. Biol. 108, 107–110 (1998).
Nallella, K. P. et al. Relationship of interleukin-6 with semen characteristics and oxidative stress in patients with varicocele. Urology 64, 1010–1013 (2004).
Hendin, B. N., Kolettis, P. N., Sharma, R. K., Thomas, A. J. Jr & Agarwal, A. Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity. J. Urol. 161, 1831–1834 (1999).
Sharma, R. K., Pasqualotto, F. F., Nelson, D. R., Thomas, A. J. Jr & Agarwal, A. The reactive oxygen species-total antioxidant capacity score is a new measure of oxidative stress to predict male infertility. Hum. Reprod. 14, 2801–2807 (1999).
Pasqualotto, F. F., Sharma, R. K., Nelson, D. R., Thomas, A. J. & Agarwal, A. Relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing infertility investigation. Fertil. Steril. 73, 459–464 (2000).
Pasqualotto, F. F. et al. Oxidative stress in normospermic men undergoing infertility evaluation. J. Androl. 22, 316–322 (2001).
Allamaneni, S. S., Naughton, C. K., Sharma, R. K., Thomas, A. J. Jr & Agarwal, A. Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size. Fertil. Steril. 82, 1684–1686 (2004).
Smith, R. et al. Increased sperm DNA damage in patients with varicocele: relationship with seminal oxidative stress. Hum. Reprod. 21, 986–993 (2006).
Pasqualotto, F. F. et al. Semen quality and oxidative stress scores in fertile and infertile patients with varicocele. Fertil. Steril. 89, 602–607 (2008).
Dada, R., Shamsi, M. B., Venkatesh, S., Gupta, N. P. & Kumar, R. Attenuation of oxidative stress & DNA damage in varicocelectomy: implications in infertility management. Indian J. Med. Res. 132, 728–730 (2010).
Mostafa, T., Anis, T., Imam, H., El-Nashar, A. R. & Osman, I. A. Seminal reactive oxygen species-antioxidant relationship in fertile males with and without varicocele. Andrologia 41, 125–129 (2009).
Wu, Q. et al. Influence of polymorphism of glutathione S-transferase T1 on Chinese infertile patients with varicocele. Fertil. Steril. 91, 960–962 (2009).
Sakamoto, Y., Ishikawa, T., Kondo, Y., Yamaguchi, K. & Fujisawa, M. The assessment of oxidative stress in infertile patients with varicocele. BJU Int. 101, 1547–1552 (2008).
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. 2, 106–110 (2005).
Xu, Y., Xu, Q. Y., Yang, B. H., Zhu, X. M. & Peng Y. F. Relationship of nitric oxide and nitric oxide synthase with varicocele infertility [Chinese]. Zhonghua Nan Ke Xue 14, 414–417 (2008).
Abd-Elmoaty, M. A., Saleh, R., Sharma, R. & Agarwal, A. Increased levels of oxidants and reduced antioxidants in semen of infertile men with varicocele. Fertil. Steril. 94, 1531–1534 (2010).
Mostafa, T., Anis, T., El Nashar, A., Imam, H. & Osman, I. Seminal plasma reactive oxygen species-antioxidants relationship with varicocele grade. Andrologia 44, 66–69 (2012).
Mazzilli, F., Rossi, T., Marchesini, M., Ronconi, C. & Dondero, F. Superoxide anion in human semen related to seminal parameters and clinical aspects. Fertil. Steril. 62, 862–868 (1994).
Yes¸illi, 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 66, 610–615 (2005).
Hurtado de Catalfo, G. E., Ranieri-Casilla, A., Marra, F. A., de Alaniz, M. J. & Marra, C. A. Oxidative stress biomarkers and hormonal profile in human patients undergoing varicocelectomy. Int. J. Androl. 30, 519–530 (2007).
Blumer, C. G. et al. Effect of varicocele on sperm function and semen oxidative stress. BJU Int. 109, 259–265 (2012).
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. 1, 67–68 (2001).
Santoro, G. et al. Nitric oxide synthase patterns in normal and varicocele testis in adolescents. BJU Int. 88, 967–973 (2001).
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. 99, 1086–1090 (2007).
Shiraishi, K. & Naito, K. Increased expression of Leydig cell haem oxygenase-1 preserves spermatogenesis in varicocele. Hum. Reprod. 20, 2608–2613 (2005).
Ishikawa, T., Fujioka, H., Ishimura, T., Takenaka, A. & Fujisawa, M. Increased testicular 8-hydroxy-2′-deoxyguanosine in patients with varicocele. BJU Int. 100, 863–866 (2007).
Koksal, I. T. et al. The role of reactive oxygen species in testicular dysfunction associated with varicocele. BJU Int. 86, 549–552 (2000).
Shiraishi, K., Takihara, H. & Matsuyama, H. Elevated scrotal temperature, but not varicocele grade, reflects testicular oxidative stress-mediated apoptosis. World J. Urol. 28, 359–364 (2010).
Koksal, I. T., Usta, M., Orhan, I., Abbasoglu, S. & Kadioglu, A. Potential role of reactive oxygen species on testicular pathology associated with infertility. Asian J. Androl. 5, 95–99 (2003).
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. 156, 1952–1958 (1996).
Ozbek, E., Ilbey, Y. Y., Simsek, A., Cekmen, M. & Balbay, M. D. Preoperative and postoperative seminal nitric oxide levels in patients with infertile varicocele. Arch. Ital. Urol. Androl. 81, 248–250 (2009).
Mostafa, T. et al. Reactive oxygen species and antioxidants relationship in the internal spermatic vein blood of infertile men with varicocele. Asian J. Androl. 8, 451–454 (2006).
Romeo, C. et al. Preliminary report on nitric oxide-mediated oxidative damage in adolescent varicocele. Hum. Reprod. 18, 26–29 (2003).
Turkyilmaz, Z. et al. Increased nitric oxide is accompanied by lipid oxidation in adolescent varicocele. Int. J. Androl. 27, 183–187 (2004).
Chen, S. S., Chang, L. S. & Wei, Y. H. Oxidative damage to proteins and decrease of antioxidant capacity in patients with varicocele. Free Radic. Biol. Med. 30, 1328–1334 (2001).
Saleh, R. A. et al. Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele. Fertil. Steril. 80, 1431–1436 (2003).
Giulini, S. et al. Seminal plasma total antioxidant capacity and semen parameters in patients with varicocele. Reprod. Biomed. Online 18, 617–621 (2009).
Mancini, A. et al. Increased total antioxidant capacity in seminal plasma of varicocele patients: a multivariate analysis. Arch. Androl. 53, 37–42 (2007).
Agarwal, A. Business briefing: US kidney & urological disease: Role of oxidative stress in male infertility and antioxidant supplementation [online] (2005).
Kanter, M., Aktas, C. & Erboga, M. Heat stress decreases testicular germ cell proliferation and increases apoptosis in short term: an immunohistochemical and ultrastructural study. Toxicol. Ind. Health http://dx.doi.org/10.1177/0748233711425082 (2011).
Pigeolet, E. et al. Glutathione peroxidase, superoxide dismutase, and catalase inactivation by peroxides and oxygen derived free radicals. Mech. Ageing Dev. 51, 283–297 (1990).
Zini, A. & Schlegel, P. N. Cu/Zn superoxide dismutase, catalase and glutathione peroxidase mRNA expression in the rat testis after surgical cryptorchidism and efferent duct ligation. J. Urol. 158, 659–663 (1997).
Peltola, V., Huhtaniemi, I. & Ahotupa, M. Abdominal position of the rat testis is associated with high level of lipid peroxidation. Biol. Reprod. 53, 1146–1150 (1995).
Gulyaeva, N. V., Obidin, A. B. & Marinov, B. S. Modulation of superoxide dismutase by electron donors and acceptors. FEBS Lett. 211, 211–214 (1987).
Peltola, V., Huhtaniemi, I. & Ahotupa, M. Antioxidant enzyme activity in the maturing rat testis. J. Androl. 13, 450–455 (1992).
Mori, M. M., Bertolla, R. P., Fraietta, R., Ortiz, V. & Cedenho, A. P. Does varicocele grade determine extent of alteration to spermatogenesis in adolescents? Fertil. Steril. 90, 1769–1773 (2008).
Vivas-Acevedo, G., Lozano, J. R. & Camejo, M. I. Effect of varicocele grade and age on seminal parameters. Urol. Int. 85, 194–199 (2010).
Shiraishi, K., Takihara, H. & Naito, K. Testicular volume, scrotal temperature, and oxidative stress in fertile men with left varicocele. Fertil. Steril. 91 (Suppl. 4), 1388–1391 (2009).
Aksoy, Y., Ozbey, I., Aksoy, H., Polat, O. & Akçay, F. Seminal plasma nitric oxide concentration in oligo- and/or asthenozoospermic subjects with/without varicocele. Arch. Androl. 48, 181–185 (2002).
Meucci, E. et al. Total antioxidant capacity in patients with varicoceles. Fertil. Steril. 79 (Suppl. 3), 1577–1583 (2003).
Balercia, G. et al. Coenzyme Q10 levels in idiopathic and varicocele-associated asthenozoospermia. Andrologia 34, 107–111 (2002).
Cocuzza, M. 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. 90, 1103–1108 (2008).
Canales, B. K. et al. Prevalence and effect of varicoceles in an elderly population. Urology 66, 627–631 (2005).
Miyaoka, R. & Esteves, S. C. A critical appraisal on the role of varicocele in male infertility. Adv. Urol. 2012, 597495 (2012).
Beckman, K. B. & Ames, B. N. The free radical theory of aging matures. Physiol. Rev. 78, 547–581 (1998).
The role of the mitochondria in human aging and disease: from gene to cell signaling. Proceedings of the second scientific meeting of the Asian Society for Mitochondrial Research and Medicine. April 1–2, 2004. Taipei, Taiwan. Ann. NY Acad. Sci. 1042, 1–537 (2005).
Miquel, J., Economos, A. C., Fleming, J. & Johnson, J. E. Jr. Mitochondrial role in cell aging. Exp. Gerontol. 15, 575–591 (1980).
Schlesinger, M. H., Wilets, I. F. & Nagler, H. M. Treatment outcome after varicocelectomy. A critical analysis. Urol. Clin. North Am. 21, 517–529 (1994).
Diegidio, P. et al. Review of current varicocelectomy techniques and their outcomes. BJU Int. 108, 1157–1172 (2011).
Chen, S. S., Huang, W. J., Chang, L. S. & Wei, Y. H. Attenuation of oxidative stress after varicocelectomy in subfertile patients with varicocele. J. Urol. 179, 639–642 (2008).
Mostafa, T., Anis, T. H., El-Nashar, A., Imam, H. & Othman, I. A. Varicocelectomy reduces reactive oxygen species levels and increases antioxidant activity of seminal plasma from infertile men with varicocele. Int. J. Androl. 24, 261–265 (2001).
Cervellione, R. M. et al. Effect of varicocelectomy on the plasma oxidative stress parameters. J. Pediatr. Surg. 41, 403–406 (2006).
Rodriguez Peña, M. et al. Predictors of improved seminal parameters and fertility after varicocele repair in young adults. Andrologia 41, 277–281 (2009).
Lacerda, J. I. et al. Adolescent varicocele: improved sperm function after varicocelectomy. Fertil. Steril. 95, 994–999 (2011).
Shiraishi, K. & Naito, K. Generation of 4-hydroxy-2-nonenal modified proteins in testes predicts improvement in spermatogenesis after varicocelectomy. Fertil. Steril. 86, 233–235 (2006).
Redmon, J. B., Carey, P. & Pryor, J. L. Varicocele—the most common cause of male factor infertility? Hum. Reprod. Update 8, 53–58 (2002).
Evers, J. L., Collins, J. A. & Vandekerckhove, P. Surgery or embolisation for varicocele in subfertile men. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD000479.
Ficarra, V. et al. Treatment of varicocele in subfertile men: The Cochrane Review—a contrary opinion. Eur. Urol. 49, 258–263 (2006).
Abdel-Meguid, T. A., Al-Sayyad, A., Tayib, A. & Farsi, H. M. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur. Urol. 59, 455–461 (2011).
Marmar, J. L. et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil. Steril. 88, 639–648 (2007).
Sylora, J. A. & Pryor, J. L. Varicocele. Curr. Ther. Endocrinol. Metab. 5, 309–314 (1994).
Green, K. F., Turner, T. T. & Howards, S. S. Varicocele: reversal of the testicular blood flow and temperature effects by varicocele repair. J. Urol. 131, 1208–1211 (1984).
Dawes, I. in Oxidative Stress Disease and Cancer (ed. Singh, K. K.) 281–308 (Imperial College Press, London, 2006).
Baccetti, B. M. et al. Studies on varicocele III: ultrastructural sperm evaluation and 18, X and Y aneuploidies. J. Androl. 27, 94–101 (2006).
Allen, R. G. & Tresini, M. Oxidative stress and gene regulation. Free Radic. Biol. Med. 28, 463–499 (2000).
Desaint, S., Luriau, S., Aude, J. C., Rousselet, G. & Toledano, M. B. Mammalian antioxidant defenses are not inducible by H2O2 . J. Biol. Chem. 279, 31157–31163 (2004).
Abdel Aziz, M. T. et al. Heme oxygenase enzyme activity in seminal plasma of oligoasthenoteratozoospermic males with varicocele. Andrologia 42, 236–241 (2008).
Abbasi, M. et al. Aminoguanidine improves epididymal sperm parameters in varicocelized rats. Urol. Int. 86, 302–306 (2011).
Abbasi, M. et al. Effect of aminoguanidine in sperm DNA fragmentation in varicocelized rats: role of nitric oxide. Reprod. Sci. 18, 545–550 (2011).
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. 27, 228–233 (2004).
Cavallini, G., Ferraretti, A. P., Gianaroli, L., Biagiotti, G. & Vitali, G. Cinnoxicam and L-carnitine/acetyl-L-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia. J. Androl. 25, 761–772 (2004).
Cavallini, G., Biagiotti, G., Ferraretti, A. P., Gianaroli, L. & Vitali, G. Medical therapy of oligoasthenospermia associated with left varicocele. BJU Int. 91, 513–518 (2003).
Qu, X. W. et al. Effects of Qiangjing Capsule on the oxidative and antioxidative system in the epididymis of varicocele rats [Chinese]. Zhonghua Nan Ke Xue 17, 1039–1042 (2011).
Zampieri, N., Pellegrino, M., Ottolenghi, A. & Camoglio, F. S. Effects of bioflavonoids in the management of subclinical varicocele. Pediatr. Surg. Int. 26, 505–508 (2010).
Kiliç, S. et al. Effects of micronised purified flavonoid fraction on pain, spermiogram and scrotal color Doppler parameters in patients with painful varicocele. Urol. Int. 74, 173–179 (2005).
Oliva, A., Dotta, A. & Multigner, L. Pentoxifylline and antioxidants improve sperm quality in male patients with varicocele. Fertil. Steril. 91 (Suppl. 4), 1536–1539 (2009).
Paradiso Galatioto, G. et al. May antioxidant therapy improve sperm parameters of men with persistent oligospermia after retrograde embolization for varicocele? World J. Urol. 26, 97–102 (2008).
Takihara, H., Cosentino, M. J. & Cockett, A. T. Zinc sulfate therapy for infertile male with or without varicocelectomy. Urology 29, 638–641 (1987).
Yan, L. F., Jiang, M. F. & Shao, R. Y. 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 24, 220–222 (2004).
Esteves, S. C. & Agarwal, A. Novel concepts in male infertility. Int. Braz. J. Urol. 37, 5–15 (2011).
Söylemez, H. et al. Effects of micronised purified flavonoid fraction on pain, semen analysis and scrotal color Doppler parameters in patients with painful varicocele; results of a randomized placebo-controlled study. Int. Urol. Nephrol. 44, 401–408 (2012).
Acknowledgements
The authors are supported in part by research funds from the Center for Reproductive Medicine, Department of Urology, Cleveland Clinic, OH, USA.
Author information
Authors and Affiliations
Contributions
A. Hamada researched the data for the article and wrote the manuscript. All authors contributed to the discussion of the article content and edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Table 1
Evidence of excessive oxidative stress in men with varicocele (DOC 198 kb)
Supplementary Table 2
Evidence for decreased seminal antioxidant levels in infertile men with varicocele (DOC 120 kb)
Rights and permissions
About this article
Cite this article
Hamada, A., Esteves, S. & Agarwal, A. Insight into oxidative stress in varicocele-associated male infertility: part 2. Nat Rev Urol 10, 26–37 (2013). https://doi.org/10.1038/nrurol.2012.198
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrurol.2012.198
This article is cited by
-
Male Factors: the Role of Sperm in Preimplantation Embryo Quality
Reproductive Sciences (2021)
-
Microdissection testicular sperm extraction (micro-TESE) in men with infertility due to nonobstructive azoospermia: summary of current literature
International Urology and Nephrology (2021)
-
Ameliorating Effects of Natural Antioxidant Compounds on Female Infertility: a Review
Reproductive Sciences (2021)
-
Increased Sperm DNA Fragmentation in Infertile Men with Varicocele: Relationship with Apoptosis, Seminal Oxidative Stress, and Spermatic Parameters
Reproductive Sciences (2021)
-
Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management
Cellular and Molecular Life Sciences (2020)