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Medical Therapy in Varicocele-Related Infertility

  • Gian Maria BusettoEmail author
  • Francesco Del Giudice
  • Ettore De Berardinis
Chapter

Abstract

Even if varicocele is considered as one of the first known causes of male infertility, to date, it is still under debate if varicocele repair is able to improve fertility.

The pathophysiology of varicocele, infertility, and testicular growth arrest has been extensively studied. Scrotal and testicular hyperthermia and increase in blood flow could be causes of altered spermatogenesis. A wide range of hormonal abnormalities and the stasis of the blood in the pampiniform plexus, with related hypoxia, could negatively act on sperm production.

All these mechanisms are considered to be the initiators of an oxidative stress process causing spermatogenesis defects. Oxidative stress usually occurs when there is an imbalance between ROS production and removal, and between oxidants and antioxidants. Varicocele is known to exacerbate the oxidative stress process, and the grade of varicocele can be related to oxidative stress levels.

When considering surgery as an effective option for varicocele treatment, recurrence and complications are prone to occur. Furthermore, results and fertility increase after surgery are still not well-established.

Medical treatment is another option featured by less invasiveness, cost, and side effects. Unfortunately, even these treatments are highly debated.

To date, there are following treatments:
  1. 1.

    Antioxidant agents that are able to decrease oxidative stress and lower ROS levels. Many elements have been studied and can be used as antioxidant agents. Currently, carnitines, selenium, coenzyme Q10, vitamin C and E, vitamin B12, bioflavonoids, lycopene, kallicrein, cinnoxicam, pentoxyfilline, zinc, folic acid, GSH, and NAC are used.

     
  2. 2.

    Hormonal agents like gonadotropins, tamoxifene, clomiphene, and menotropin that can restore hormone levels.

     
  3. 3.

    Chinese medicine with a multitude of antioxidants and anti-inflammatory agents. The most common products are qianjing, guizhi fuling wan, escin, jingling, and green tea.

     

In spite of adopting all available medical treatments for varicocele, these treatments are not recommendable and surgery remains the gold standard option for varicocele. On the other hand, these products could be considered as a good option for a combination therapy after surgery, to earlier and better restore spermatogenesis.

Keywords

Varicocele oxidative stress antioxidants reactive oxygen species male infertility hormonal agents Chinese medicine 

References

  1. 1.
    Jarow JP, Sharlip ID, Belker AM, Lipshultz LI, Sigman M, Thomas AJ, Schlegel PN, Howards SS, Nehra A, Damewood MD, Overstreet JW, Sadovsky R, Male Infertility Best Practice Policy Committee of the American Urological Association. Best practice policies for male infertility. Inc J Urol. 2002;167(5):2138–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Jungwirth A, Diemer T, Kopa Z, Krausz C, Minhas S, Tournaye H. European Association of Urology Guidelines on Male Infertility. 2018.Google Scholar
  3. 3.
    Isidori A, Latini M, Romanelli F. Treatment of male infertility. Contraception. 2005;72(4):314–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Adamopoulos DA. Medical treatment of idiopathic oligozoospermia and male factor subfertility. Asian J Androl. 2000;2(1):25–32.PubMedGoogle Scholar
  5. 5.
    Levine H, Jørgensen N, Martino-Andrade A, Mendiola J, Weksler-Derri D, Mindlis I, Pinotti R, Swan SH. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update. 2017;23(6):646–59.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Wichmann L, Isola J, Tuohimaa P. Prognostic variables in predicting pregnancy. A prospective follow up study of 907 couples with an infertility problem. Hum Reprod. 1994;9(6):1102–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Bonde JP, Ernst E, Jensen TK, Hjollund NH, Kolstad H, Henriksen TB, Scheike T, Giwercman A, Olsen J, Skakkebaek NE. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet. 1998;352(9135):1172–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Agarwal A, Hamada A, Esteves SC. Insight into oxidative stress in varicocele-associated male infertility: part 1. Nat Rev Urol. 2012;9(12):678–90.CrossRefGoogle Scholar
  9. 9.
    Sylora JA, Pryor JL. Varicocele. Curr Ther Endocrinol Metab. 1994;5:309–14.PubMedGoogle Scholar
  10. 10.
    Fujisawa M, Yoshida S, Matsumoto O, Kojima K, Kamidono S. Deoxyribonucleic acid polymerase activity in the testes of infertile men with varicocele. Fertil Steril. 1988;50(5):795–800.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Zorgnotti AW. Testis temperature, infertility, and the varicocele padox. Urology. 1980;16:7–10.CrossRefGoogle Scholar
  12. 12.
    Sweeney TE, Rozum JS, Gore RW. Alteration of testicular microvascular pressures during venous pressure elevation. Am J Phys. 1995;269(1 Pt 2):H37–45.Google Scholar
  13. 13.
    Santamaría L, Martín R, Nistal M, Paniagua R. The peritubular myoid cells in the testes from men with varicocele: an ultrastructural, immunohistochemical and quantitative study. Histopathology. 1992;21(5):423–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Mali WP, Arndt JW, Coolsaet BL, Kremer J, Oei HY. Haemodynamic aspects of left-sided varicocele and its association with so-called right-sided varicocele. Int J Androl. 1984;7(4):297–308.PubMedCrossRefGoogle Scholar
  15. 15.
    Turner TT, Lopez TJ. Effects of experimental varicocele require neither adrenal contribution nor venous reflux. J Urol. 1989;142(5):1372–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Sofikitis N, Miyagawa I. Left adrenalectomy in varicocelized rats does not inhibit the development of varicocele-related physiologic alterations. Int J Fertil Menopausal Stud. 1993;38(4):250–5.PubMedGoogle Scholar
  17. 17.
    Hampl R, Lachman M, Novák Z, Sulcová J, Stárka L. Serum levels of steroid hormones in men with varicocele and oligospermia as compared to normozoospermic men. Exp Clin Endocrinol. 1992;100(3):117–9.PubMedGoogle Scholar
  18. 18.
    Cayan S, Kadioglu A, Orhan I, Kandirali E, Tefekli A, Tellaloglu S. The effect of microsurgical varicocelectomy on serum follicle stimulating hormone, testosterone and free testosterone levels in infertile men with varicocele. BJU Int. 1999;84(9):1046–9.CrossRefGoogle Scholar
  19. 19.
    Schlatt S, Meinhardt A, Nieschlag E. Paracrine regulation of cellular interactions in the testis: factors in search of a function. Eur J Endocrinol. 1997;137(2):107–17.PubMedCrossRefGoogle Scholar
  20. 20.
    Lee J, Richburg JH, Younkin SC, Boekelheide K. The Fas system is a key regulator of germ cell apoptosis in the testis. Endocrinology. 1997;138(5):2081–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Yan YC, Sun YP, Zhang ML. Testis epidermal growth factor and spermatogenesis. Arch Androl. 1998;40(2):133–46.PubMedCrossRefGoogle Scholar
  22. 22.
    Ergün S, Kiliç N, Fiedler W, Mukhopadhyay AK. Vascular endothelial growth factor and its receptors in normal human testicular tissue. Mol Cell Endocrinol. 1997;131(1):9–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Agarwal A, Prabakaran SA. Mechanism, measurement, and prevention of oxidative stress in male reproductive physiology. Indian J Exp Biol. 2005;43(11):963–74.PubMedGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    Amaral A, Lourenço B, Marques M, Ramalho-Santos J. Mitochondria functionality and sperm quality. Reproduction. 2013;146(5):R163–74.PubMedCrossRefGoogle Scholar
  26. 26.
    Agarwal A, Mulgund A, Alshahrani S, Assidi M, Abuzenadah AM, Sharma R, Sabanegh E. Reactive oxygen species and sperm DNA damage in infertile men presenting with low level leukocytospermia. Reprod Biol Endocrinol. 2014;12:126.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Bonanno O, Romeo G, Asero P, Pezzino FM, Castiglione R, Burrello N, Sidoti G, Frajese GV, Vicari E, D'Agata R. Sperm of patients with severe asthenozoospermia show biochemical, molecular and genomic alterations. Reproduction. 2016;152(6):695–704. Epub 2016 Sep 20.PubMedCrossRefGoogle Scholar
  28. 28.
    Gomez E, Buckingham DW, Brindle J, Lanzafame F, Irvine DS, Aitken RJ. Development of an image analysis system to monitor the retention of residual cytoplasm by human spermatozoa: correlation with biochemical markers of the cytoplasmic space, oxidative stress, and sperm function. J Androl. 1996;17(3):276–87.PubMedGoogle Scholar
  29. 29.
    Gavella M, Lipovac V. NADH-dependent oxidoreductase (diaphorase) activity and isozyme pattern of sperm in infertile men. Arch Androl. 1992;28(2):135–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Agarwal A, Prabakaran S, Allamaneni SS. Relationship between oxidative stress, varicocele and infertility: a meta-analysis. Reprod Biomed Online. 2006;12(5):630–3.CrossRefGoogle Scholar
  31. 31.
    Alvarez JG, Storey BT. Spontaneous lipid peroxidation in rabbit and mouse epididymal spermatozoa: dependence of rate on temperature and oxygen concentration. Biol Reprod. 1985;32(2):342–51.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Morgan D, Cherny VV, Murphy R, Xu W, Thomas LL, DeCoursey TE. Temperature dependence of NADPH oxidase in human eosinophils. J Physiol. 2003;550(Pt 2):447–58.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Rosselli M, Dubey RK, Imthurn B, Macas E, Keller PJ. Effects of nitric oxide on human spermatozoa: evidence that nitric oxide decreases sperm motility and induces sperm toxicity. Hum Reprod. 1995;10(7):1786–90.PubMedCrossRefGoogle Scholar
  34. 34.
    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(5):1086–90.PubMedCrossRefGoogle Scholar
  35. 35.
    Jourd’heuil D, Jourd'heuil FL, Kutchukian PS, Musah RA, Wink DA, Grisham MB. Reaction of superoxide and nitric oxide with peroxynitrite. Implications for peroxynitrite-mediated oxidation reactions in vivo. J Biol Chem. 2001;276(31):28799–805.PubMedCrossRefGoogle Scholar
  36. 36.
    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 U S A. 1998;95(13):7631–6.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 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(5):913–9.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    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(2):119–25.PubMedCrossRefGoogle Scholar
  39. 39.
    Smith R, Kaune H, Parodi D, Madariaga M, Rios R, Morales I, Castro A. Increased sperm DNA damage in patients with varicocele: relationship with seminal oxidative stress. Hum Reprod. 2006;21(4):986–93. Epub 2005 Dec 16.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Abdel Aziz MT, Mostafa T, Atta H, Kamal O, Kamel M, Hosni H, Rashed L, Sabry D, Waheed F. Heme oxygenase enzyme activity in seminal plasma of oligoasthenoteratozoospermic males with varicocele. Andrologia. 2010;42(4):236–41.PubMedCrossRefGoogle Scholar
  41. 41.
    Yeşilli C, Mungan G, Seçkiner I, Akduman B, Açikgöz S, Altan K, Mungan A. 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(3):610–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Balercia G, Arnaldi G, Fazioli F, Serresi M, Alleva R, Mancini A, Mosca F, Lamonica GR, Mantero F, Littarru GP. Coenzyme Q10 levels in idiopathic and varicocele-associated asthenozoospermia. Andrologia. 2002;34(2):107–11.PubMedCrossRefGoogle Scholar
  43. 43.
    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(2):125–9.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    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(6):1684–6.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    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(3):602–7. Epub 2007 May 7.PubMedCrossRefGoogle Scholar
  46. 46.
    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(5):261–5.CrossRefGoogle Scholar
  47. 47.
    Yagi K. Simple procedure for specific assay of lipid hydroperoxides in serum or plasma. Methods Mol Biol. 1998;108:107–10.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Hamada A, Esteves SC, Agarwal A. Insight into oxidative stress in varicocele-associated male infertility: part 2. Nat Rev Urol. 2013;10(1):26–37.CrossRefGoogle Scholar
  49. 49.
    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-asthenoteratozoospermia, with and without varicocele: a double-blind placebo-controlled study. Andrologia. 2018;50(3)  https://doi.org/10.1111/and.12927. Epub 2018 Jan 7.CrossRefGoogle Scholar
  50. 50.
    Virmani A, Ali S, Pinto L, Zerelli S, Binienda Z. Genomic effects of food bioactives in neuroprotection. In: Kussmann M, Stover P, editors. Nutrigenomics and proteomics in health and disease: towards a systems-level understanding of gene-diet interactions. Chichester, UK: Wiley & Sons, Ltd; 2017.Google Scholar
  51. 51.
    Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Update. 2007;13(2):163–74.PubMedCrossRefGoogle Scholar
  52. 52.
    Adams SH, Esser V, Brown NF, Ing NH, Johnson L, Foster DW, McGarry JD. Expression and possible role of muscle-type carnitine palmitoyltransferase I during sperm development in the rat. Biol Reprod. 1998;59(6):1399–405.PubMedCrossRefGoogle Scholar
  53. 53.
    Wang YX, Yang SW, Qu CB, Huo HX, Li W, Li JD, Chang XL. Cai GZ. L-carnitine: safe and effective for asthenozoospermia. Zhonghua Nan Ke Xue. 2010;16(5):420–2.PubMedGoogle Scholar
  54. 54.
    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(5):761–70; discussion 771–2.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Sofimajidpour H, Ghaderi E, Ganji O. Comparison of the effects of varicocelectomy and Oral L-carnitine on sperm parameters in infertile men with Varicocele. J Clin Diagn Res. 2016;10(4):PC07–10.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Lenzi A, Sgrò P, Salacone P, Paoli D, Gilio B, Lombardo F, Santulli M, Agarwal A, Gandini L. A placebo-controlled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Fertil Steril. 2004;81(6):1578–84.PubMedCrossRefGoogle Scholar
  57. 57.
    Sigman M, Glass S, Campagnone J, Pryor JL. Carnitine for the treatment of idiopathic asthenospermia: a randomized, double-blind, placebo-controlled trial. Fertil Steril. 2006;85(5):1409–14.PubMedCrossRefGoogle Scholar
  58. 58.
    Moslemi MK, Tavanbakhsh S. Selenium-vitamin E supplementation in infertile men: effects on semen parameters and pregnancy rate. Int J Gen Med. 2011;23(4):99–104.CrossRefGoogle Scholar
  59. 59.
    Taghizadeh L, Eidi A, Mortazavi P, Rohani AH. Effect of selenium on testicular damage induced by varicocele in adult male Wistar rats. J Trace Elem Med Biol. 2017;44:177–85.PubMedCrossRefGoogle Scholar
  60. 60.
    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.PubMedCrossRefGoogle Scholar
  61. 61.
    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(5):530–7.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Khosravanian N, Razi M, Farokhi F, Khosravanian H. Testosterone and vitamin E administration up-regulated varicocele-reduced Hsp70-2 protein expression and ameliorated biochemical alterations. J Assist Reprod Genet. 2014;31(3):341–54.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    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(3):519–24.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Cyrus A, Kabir A, Goodarzi D, Moghimi M. The effect of adjuvant vitamin C after varicocele surgery on sperm quality and quantity in infertile men: a double blind placebo controlled clinical trial. Int Braz J Urol. 2015;41(2):230–8.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Oliva A, Dotta A, Multigner L. Pentoxifylline and antioxidants improve sperm quality in male patients with varicocele. Fertil Steril. 2009;91(4 Suppl):1536–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Takihara H, Cosentino MJ, Cockett AT. Zinc sulfate therapy for infertile male with or without varicocelectomy. Urology. 1987;29(6):638–41.PubMedCrossRefGoogle Scholar
  67. 67.
    Frei B, Kim MC, Ames BN. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci U S A. 1987;87:4879–83.CrossRefGoogle Scholar
  68. 68.
    Festa R, Giacchi E, Raimondo S, Tiano L, Zuccarelli P, Silvestrini A, Meucci E, Littarru GP, Mancini A. Coenzyme Q10 supplementation in infertile men with low-grade varicocele: an open, uncontrolled pilot study. Andrologia. 2014;46(7):805–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Balercia G, Mosca F, Mantero F, Boscaro M, Mancini A, Ricciardo-Lamonica G, Littarru G, Coenzyme Q. (10) supplementation in infertile men with idiopathic asthenozoospermia: an open uncontrolled pilot study. Fertil Steril. 2004;81(1):93–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Griveau JF, Le Lannou D. Effects of antioxidants on human sperm preparation techniques. Int J Androl. 1994;17:225–31.PubMedCrossRefGoogle Scholar
  71. 71.
    Baker HW, Brindle J, Irvine DS, Aitken RJ. Protective effect of antioxidants on the impairment of sperm motility by activated polymorphonuclear leukocytes. Fertil Steril. 1996;65:411–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Oeda T, Henkel R, Ohmori H, Schill WB. Scavenging effect of N-acetyl-ℓ-cysteine against reactive oxygen species in human semen: a possible therapeutic modality for male factor infertility. Andrologia. 1997;29:125–31.PubMedCrossRefGoogle Scholar
  73. 73.
    Lopes S, Jurisicova A, Sun JG, Casper RF. Reactive oxygen species: potential cause for DNA fragmentation in human spermatozoa. Hum Reprod. 1998;13:896–900.PubMedCrossRefGoogle Scholar
  74. 74.
    Safarinejad MR, Safarinejad S. Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. J Urol. 2009;181:741–51.PubMedCrossRefGoogle Scholar
  75. 75.
    Mićić S, Tulić C, Dotlić R. Kallikrein therapy of infertile men with varicocele and impaired sperm motility. Andrologia. 1990;22(2):179–83.PubMedCrossRefGoogle Scholar
  76. 76.
    Zampieri N, Pellegrino M, Ottolenghi A, Camoglio FS. Effects of bioflavonoids in the management of subclinical varicocele. Pediatr Surg Int. 2010;26(5):505–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Kiliç S, Güneş A, Ipek D, Dusak A, Güneş G, Balbay MD, Baydinç YC. Effects of micronised purified flavonoid fraction on pain, spermiogram and scrotal color Doppler parameters in patients with painful varicocele. Urol Int. 2005;74(2):173–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Söylemez H, Kiliç S, Atar M, Penbegül N, Sancaktutar AA, Bozkurt Y. 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. 2012;44(2):401–8.PubMedCrossRefGoogle Scholar
  79. 79.
    GamalEl Din SF. Role of Tribulus terrestris in male infertility: is it real or fiction? J Diet Suppl. 2017;15:1010–3.PubMedCrossRefGoogle Scholar
  80. 80.
    Dogan F, Armagan A, Oksay T, Akman T, Aylak F, Bas E. Impact of micronised purified flavonoid fraction on increased malondialdehyde and decreased metalloproteinase-2 and metalloproteinase-9 levels in varicocele: outcome of an experimentally induced varicocele. Andrologia. 2014;46(4):380–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Gual-Frau J, Abad C, Amengual MJ, Hannaoui N, Checa MA, Ribas-Maynou J, Lozano I, Nikolaou A, Benet J, García-Peiró A, Prats J. Oral antioxidant treatment partly improves integrity of human sperm DNA in infertile grade I varicocele patients. Hum Fertil (Camb). 2015;18(3):225–9.CrossRefGoogle Scholar
  82. 82.
    Lombardo F, Sansone A, Romanelli F, Paoli D, Gandini L, Lenzi A. The role of antioxidant therapy in the treatment of male infertility: an overview. Asian J Androl. 2011;13(5):690–7.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Bedaiwy MA, Falcone T, Mohamed MS, Aleem AA, Sharma RK, Worley SE, Thornton J, Agarwal A. Differential growth of human embryos in vitro: role of reactive oxygen species. Fertil Steril. 2004;82(3):593–600.PubMedCrossRefGoogle Scholar
  84. 84.
    Sikka SC. Role of oxidative stress and antioxidants in andrology and assisted reproductive technology. J Androl. 2004;25(1):5–18.PubMedCrossRefGoogle Scholar
  85. 85.
    Bartoov B, Eltes F, Lunenfeld E, Har-Even D, Lederman H, Lunenfeld B. Sperm quality of subfertile males before and after treatment with human follicle-stimulating hormone. Fertil Steril. 1994;61(4):727–34.PubMedCrossRefGoogle Scholar
  86. 86.
    Kamischke A, Behre HM, Bergmann M, Simoni M, Schäfer T, Nieschlag E. Recombinant human follicle stimulating hormone for treatment of male idiopathic infertility: a randomized, double-blind, placebo-controlled, clinical trial. Hum Reprod. 1998;13(3):596–603.PubMedCrossRefGoogle Scholar
  87. 87.
    Foresta C, Bettella A, Garolla A, Ambrosini G, Ferlin A. Treatment of male idiopathic infertility with recombinant human follicle-stimulating hormone: a prospective, controlled, randomized clinical study. Fertil Steril. 2005;84(3):654–61.PubMedCrossRefGoogle Scholar
  88. 88.
    Radicioni A, Schwarzenberg TL. The use of FSH in adolescents and young adults with idiopathic, unilateral, left varicocele not undergoing surgical intervention. Preliminary study. Minerva Endocrinol. 1999;24(2):63–8.PubMedGoogle Scholar
  89. 89.
    Una D, Yeni E, Verit A, Karatas OF. Clomiphene citrate versus varicocelectomy in treatment of subclinical varicocele: a prospective randomized study. Int J Urol. 2001;8:227–30.CrossRefGoogle Scholar
  90. 90.
    Kadioglu TC, Köksal IT, Tunç M, Nane I, Tellaloglu S. Treatment of idiopathic and postvaricocelectomy oligozoospermia with oral tamoxifen citrate. BJU Int. 1999;83(6):646–8.PubMedCrossRefGoogle Scholar
  91. 91.
    De Rose AF, Gallo F, Giglio M, Parisini B, Carmignani G. Early use of menotropin in the treatment of varicocele. Arch Ital Urol Androl. 2003;75(1):53–7.PubMedGoogle Scholar
  92. 92.
    Fang Y, Zhao L, Yan F, Xia X, Xu D, Cui X. Escin improves sperm quality in male patients with varicocele-associated infertility. Phytomedicine. 2010;17(3–4):192–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Tian RH, Ma M, Zhu Y, Yang S, Wang ZQ, Zhang ZS, Wan CF, Li P, Liu YF, Wang JL, Liu Y, Yang H, Zhang ZZ, Liu LH, Gong YH, Li FH, Hu HL, He ZP, Huang YR, Li Z. Effects of aescin on testicular repairment in rats with experimentally induced varicocele. Andrologia. 2014;46(5):504–12.PubMedCrossRefGoogle Scholar
  94. 94.
    Qu XW, Shan ZJ, Han QH, Hu JT, Zhang PH, Zhang SW. Effects of Qiangjing capsule on the oxidative and antioxidative system in the epididymis of varicocele rats. Zhonghua Nan Ke Xue. 2011;17(11):1039–42.PubMedGoogle Scholar
  95. 95.
    Ishikawa H, Ohashi M, Hayakawa K, Kaneko S, Hata M. Effects of guizhi-fuling-wan on male infertility with varicocele. Am J Chin Med. 1996;24(3–4):327–31.PubMedCrossRefGoogle Scholar
  96. 96.
    Wu ZH, Ke XW, Feng SY, Zhang L, Wu JF, Cheng W, Cheng JJ, Zhang JD, Zhang YG. Tea polyphenols reduces the apoptosis of spermatogenic cells in rats with experimental varicocele. Zhonghua Nan Ke Xue. 2015;21(8):702–7.PubMedGoogle Scholar
  97. 97.
    Dun RL, Yao M, Yang L, Cui XJ, Mao JM, Peng Y, Qi GC. Traditional Chinese herb combined with surgery versus surgery for varicocele infertility: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2015;2015:689056.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Garg H, Kumar R. An update on the role of medical treatment including antioxidant therapy in varicocele. Asian J Androl. 2016;18:222–8.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Lima SB, Cenedeze MA, Bertolla RP, Filho PA, Oehninger S, Cedenho AP. Expression of the HSPA2 gene in ejaculated spermatozoa from adolescents with and without varicocele. Fertil Steril. 2006;86(6):1659–63.PubMedCrossRefGoogle Scholar
  100. 100.
    Ferlin A, Speltra E, Patassini C, Pati MA, Garolla A, Caretta N, Foresta C. Heat shock protein and heat shock factor expression in sperm: relation to oligozoospermia and varicocele. J Urol. 2010;183(3):1248–52.PubMedCrossRefGoogle Scholar
  101. 101.
    Chiba K, Ramasamy R, Lamb DJ, Lipshultz LI. The varicocele: diagnostic dilemmas, therapeutic challenges and future perspectives. Asian J Androl. 2016;18(2):276–81.PubMedCrossRefGoogle Scholar
  102. 102.
    Romeo C, Ientile R, Impellizzeri P, Turiaco N, Teletta M, Antonuccio P, Basile M, Gentile C. Preliminary report on nitric oxide-mediated oxidative damage in adolescent varicocele. Hum Reprod. 2003;18(1):26–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Cervellione RM, Cervato G, Zampieri N, Corroppolo M, Camoglio F, Cestaro B, Ottolenghi A. Effect of varicocelectomy on the plasma oxidative stress parameters. J Pediatr Surg. 2006;41(2):403–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Ji Z, Lu R, Mou L, Duan YG, Zhang Q, Wang Y, Gui Y, Cai Z. Expressions of miR-15a and its target gene HSPA1B in the spermatozoa of patients with varicocele. Reproduction. 2014;147(5):693–701.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Jodar M, Soler-Ventura A, Oliva R, Molecular Biology of Reproduction and Development Research Group. Semen proteomics and male infertility. J Proteomics. 2017;162:125–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Gian Maria Busetto
    • 1
    Email author
  • Francesco Del Giudice
    • 1
  • Ettore De Berardinis
    • 1
  1. 1.Department of Urology, Sapienza Rome UniversityPoliclinico Umberto IRomeItaly

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