Spermatogenesis: Fertile Ground for Contributing to Recurrent Implantation Failure?

  • Sorena Keihani
  • Jeremy B. Myers
  • James M. Hotaling


Despite a thorough work-up, the underlying cause remains unknown in a large proportion of cases with recurrent implantation failure. Sperm plays an incontrovertible role in initiating and maintaining a successful pregnancy. Thus, male factor evaluation could provide insight into the etiology of unexplained implantation failure. Sperm genetics and epigenetics are burgeoning areas in infertility research, providing new insights into the diagnosis and management of recurrent implantation failure. This chapter reviews the current evidence on sperm chromosomal aneuploidy and sperm DNA damage, with a focus on recurrent pregnancy loss and implantation failure. Potential causes of sperm DNA damage, including oxidative stress, and different diagnostic methods for detection of sperm DNA fragmentation are summarized. Roles of modifiable risk factors such as alcohol, smoking, varicocele, testicular heat stress, medications, and environmental toxins are discussed, and recommendations are made regarding potential therapeutic options and interventions. Finally, alternative and newer methods for sperm retrieval and selection for assisted reproductive technology are discussed, and opportunities for future assessment and treatment of male factors in recurrent implantation failure are covered.


Spermatogenesis Sperm aneuploidy Oxidative stress In vitro fertilization Sperm selection DNA fragmentation Testicular sperm extraction Varicocele Recurrent miscarriage 



Assisted reproductive technology


American Society for Reproductive Medicine


Comparative genomic hybridization


Fluorescent in situ hybridization


Intracytoplasmic sperm injection


Intracytoplasmic morphologically selected sperm injection


In vitro fertilization


Preimplantation genetic screening


Recurrent implantation failure


Reactive oxygen species


Recurrent pregnancy loss


Sperm chromatin dispersion


Sperm chromatin structure assay


Sperm DNA fragmentation


Testicular sperm aspiration


Testicular sperm extraction


Terminal deoxy-nucleotide transferase-mediated dUTP nick end labeling


  1. 1.
    Puscheck EE, Jeyendran RS. The impact of male factor on recurrent pregnancy loss. Curr Opin Obstet Gynecol. 2007;19(3):222–8. Scholar
  2. 2.
    The Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103–11. Scholar
  3. 3.
    Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online. 2014;28(1):14–38. Scholar
  4. 4.
    Simon L, Murphy K, Shamsi MB, Liu L, Emery B, Aston KI, et al. Paternal influence of sperm DNA integrity on early embryonic development. Hum Reprod. 2014;29(11):2402–12. Scholar
  5. 5.
    McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell. 1984;37(1):179–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Surani MA, Barton SC, Norris ML. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature. 1984;308(5959):548–50.PubMedCrossRefGoogle Scholar
  7. 7.
    Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med. 2001;345(19):1388–93. Scholar
  8. 8.
    Wang C, Swerdloff RS. Limitations of semen analysis as a test of male fertility and anticipated needs from newer tests. Fertil Steril. 2014;102(6):1502–7. Scholar
  9. 9.
    Sun JG, Jurisicova A, Casper RF. Detection of deoxyribonucleic acid fragmentation in human sperm: correlation with fertilization in vitro. Biol Reprod. 1997;56(3):602–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhao J, Zhang Q, Wang Y, Li Y. Whether sperm deoxyribonucleic acid fragmentation has an effect on pregnancy and miscarriage after in vitro fertilization/intracytoplasmic sperm injection: a systematic review and meta-analysis. Fertil Steril. 2014;102(4):998–1005.e8. Scholar
  11. 11.
    Ryu HM, Lin WW, Lamb DJ, Chuang W, Lipshultz LI, Bischoff FZ. Increased chromosome X, Y, and 18 nondisjunction in sperm from infertile patients that were identified as normal by strict morphology: implication for intracytoplasmic sperm injection. Fertil Steril. 2001;76(5):879–83.PubMedCrossRefGoogle Scholar
  12. 12.
    Bareh GM, Jacoby E, Binkley P, Chang TC, Schenken RS, Robinson RD. Sperm deoxyribonucleic acid fragmentation assessment in normozoospermic male partners of couples with unexplained recurrent pregnancy loss: a prospective study. Fertil Steril. 2016;105(2):329–36.e1. Scholar
  13. 13.
    Templado C, Uroz L, Estop A. New insights on the origin and relevance of aneuploidy in human spermatozoa. Mol Hum Reprod. 2013;19(10):634–43. Scholar
  14. 14.
    Chatziparasidou A, Christoforidis N, Samolada G, Nijs M. Sperm aneuploidy in infertile male patients: a systematic review of the literature. Andrologia. 2015;47(8):847–60. Scholar
  15. 15.
    Carrell DT. The clinical implementation of sperm chromosome aneuploidy testing: pitfalls and promises. J Androl. 2008;29(2):124–33. Scholar
  16. 16.
    Caseiro AL, Regalo A, Pereira E, Esteves T, Fernandes F, Carvalho J. Implication of sperm chromosomal abnormalities in recurrent abortion and multiple implantation failure. Reprod Biomed Online. 2015;31(4):481–5. Scholar
  17. 17.
    Kohn TP, Kohn JR, Darilek S, Ramasamy R, Lipshultz L. Genetic counseling for men with recurrent pregnancy loss or recurrent implantation failure due to abnormal sperm chromosomal aneuploidy. J Assist Reprod Genet. 2016;33(5):571–6. Scholar
  18. 18.
    Ramasamy R, Besada S, Lamb DJ. Fluorescent in situ hybridization of human sperm: diagnostics, indications, and therapeutic implications. Fertil Steril. 2014;102(6):1534–9. Scholar
  19. 19.
    Ramasamy R, Scovell JM, Kovac JR, Cook PJ, Lamb DJ, Lipshultz LI. Fluorescence in situ hybridization detects increased sperm aneuploidy in men with recurrent pregnancy loss. Fertil Steril. 2015;103(4):906–9.e1. Scholar
  20. 20.
    Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril. 2015;103(3):e18–25. Scholar
  21. 21.
    Tempest HG, Martin RH. Cytogenetic risks in chromosomally normal infertile men. Curr Opin Obstet Gynecol. 2009;21(3):223–7. Scholar
  22. 22.
    Neusser M, Rogenhofer N, Durl S, Ochsenkuhn R, Trottmann M, Jurinovic V, et al. Increased chromosome 16 disomy rates in human spermatozoa and recurrent spontaneous abortions. Fertil Steril. 2015;104(5):1130–7.e1–10. Scholar
  23. 23.
    Lathi RB, Gray Hazard FK, Heerema-McKenney A, Taylor J, Chueh JT. First trimester miscarriage evaluation. Semin Reprod Med. 2011;29(6):463–9. Scholar
  24. 24.
    Hotaling J, Carrell DT. Clinical genetic testing for male factor infertility: current applications and future directions. Andrology. 2014;2(3):339–50. Scholar
  25. 25.
    Carrell DT, Emery BR. Use of automated imaging and analysis technology for the detection of aneuploidy in human sperm. Fertil Steril. 2008;90(2):434–7. Scholar
  26. 26.
    Patassini C, Garolla A, Bottacin A, Menegazzo M, Speltra E, Foresta C, et al. Molecular karyotyping of human single sperm by array-comparative genomic hybridization. PLoS One. 2013;8(4):e60922. Scholar
  27. 27.
    Pastuszak AW, Lamb DJ. The genetics of male fertility—from basic science to clinical evaluation. J Androl. 2012;33(6):1075–84. Scholar
  28. 28.
    Sarrate Z, Vidal F, Blanco J. Role of sperm fluorescent in situ hybridization studies in infertile patients: indications, study approach, and clinical relevance. Fertil Steril. 2010;93(6):1892–902. Scholar
  29. 29.
    Aitken RJ, De Iuliis GN, McLachlan RI. Biological and clinical significance of DNA damage in the male germ line. Int J Androl. 2009;32(1):46–56. Scholar
  30. 30.
    Agarwal A, Said TM. Role of sperm chromatin abnormalities and DNA damage in male infertility. Hum Reprod Update. 2003;9(4):331–45.PubMedCrossRefGoogle Scholar
  31. 31.
    Twigg JP, Irvine DS, Aitken RJ. Oxidative damage to DNA in human spermatozoa does not preclude pronucleus formation at intracytoplasmic sperm injection. Hum Reprod. 1998;13(7):1864–71.PubMedCrossRefGoogle Scholar
  32. 32.
    Ahmadi A, Ng SC. Developmental capacity of damaged spermatozoa. Hum Reprod. 1999;14(9):2279–85.PubMedCrossRefGoogle Scholar
  33. 33.
    Henkel R, Hajimohammad M, Stalf T, Hoogendijk C, Mehnert C, Menkveld R, et al. Influence of deoxyribonucleic acid damage on fertilization and pregnancy. Fertil Steril. 2004;81(4):965–72. Scholar
  34. 34.
    Carrell DT, Liu L, Peterson CM, Jones KP, Hatasaka HH, Erickson L, et al. Sperm DNA fragmentation is increased in couples with unexplained recurrent pregnancy loss. Arch Androl. 2003;49(1):49–55.PubMedCrossRefGoogle Scholar
  35. 35.
    Tomlinson MJ, Moffatt O, Manicardi GC, Bizzaro D, Afnan M, Sakkas D. Interrelationships between seminal parameters and sperm nuclear DNA damage before and after density gradient centrifugation: implications for assisted conception. Hum Reprod. 2001;16(10):2160–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Jansen J, Olsen AK, Wiger R, Naegeli H, de Boer P, van Der Hoeven F, et al. Nucleotide excision repair in rat male germ cells: low level of repair in intact cells contrasts with high dual incision activity in vitro. Nucleic Acids Res. 2001;29(8):1791–800.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Olsen AK, Duale N, Bjoras M, Larsen CT, Wiger R, Holme JA, et al. Limited repair of 8-hydroxy-7,8-dihydroguanine residues in human testicular cells. Nucleic Acids Res. 2003;31(4):1351–63.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Meseguer M, Santiso R, Garrido N, Garcia-Herrero S, Remohi J, Fernandez JL. Effect of sperm DNA fragmentation on pregnancy outcome depends on oocyte quality. Fertil Steril. 2011;95(1):124–8. Scholar
  39. 39.
    Sakkas D, Alvarez JG. Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. Fertil Steril. 2010;93(4):1027–36. Scholar
  40. 40.
    Aitken RJ, Bronson R, Smith TB, De Iuliis GN. The source and significance of DNA damage in human spermatozoa; a commentary on diagnostic strategies and straw man fallacies. Mol Hum Reprod. 2013;19(8):475–85. Scholar
  41. 41.
    Johnson SL, Dunleavy J, Gemmell NJ, Nakagawa S. Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis. Ageing Res Rev. 2015;19:22–33. Scholar
  42. 42.
    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. Scholar
  43. 43.
    Gomez E, Irvine DS, Aitken RJ. Evaluation of a spectrophotometric assay for the measurement of malondialdehyde and 4-hydroxyalkenals in human spermatozoa: relationships with semen quality and sperm function. Int J Androl. 1998;21(2):81–94.PubMedCrossRefGoogle Scholar
  44. 44.
    Sikka SC, Hellstrom WJ. Current updates on laboratory techniques for the diagnosis of male reproductive failure. Asian J Androl. 2016;18(3):392–401. Scholar
  45. 45.
    Muratori M, Maggi M, Spinelli S, Filimberti E, Forti G, Baldi E. Spontaneous DNA fragmentation in swim-up selected human spermatozoa during long term incubation. J Androl. 2003;24(2):253–62.PubMedCrossRefGoogle Scholar
  46. 46.
    Cicare J, Caille A, Zumoffen C, Ghersevich S, Bahamondes L, Munuce MJ. In vitro incubation of human spermatozoa promotes reactive oxygen species generation and DNA fragmentation. Andrologia. 2015;47(8):861–6. Scholar
  47. 47.
    Esteves SC, Sharma RK, Gosalvez J, Agarwal A. A translational medicine appraisal of specialized andrology testing in unexplained male infertility. Int Urol Nephrol. 2014;46(6):1037–52. Scholar
  48. 48.
    Gosálvez J, López-Fernández C, Fernández JL, Esteves SC, Johnston SD. Unpacking the mysteries of sperm DNA fragmentation: ten frequently asked questions. J Reprod Biotech Fertil. 2015;4.
  49. 49.
    Stahl PJ, Cogan C, Mehta A, Bolyakov A, Paduch DA, Goldstein M. Concordance among sperm deoxyribonucleic acid integrity assays and semen parameters. Fertil Steril. 2015;104(1):56–61.e1. Scholar
  50. 50.
    Osman A, Alsomait H, Seshadri S, El-Toukhy T, Khalaf Y. The effect of sperm DNA fragmentation on live birth rate after IVF or ICSI: a systematic review and meta-analysis. Reprod Biomed Online. 2015;30(2):120–7. Scholar
  51. 51.
    Velez de la Calle JF, Muller A, Walschaerts M, Clavere JL, Jimenez C, Wittemer C, et al. Sperm deoxyribonucleic acid fragmentation as assessed by the sperm chromatin dispersion test in assisted reproductive technology programs: results of a large prospective multicenter study. Fertil Steril. 2008;90(5):1792–9. Scholar
  52. 52.
    Evgeni E, Lymberopoulos G, Touloupidis S, Asimakopoulos B. Sperm nuclear DNA fragmentation and its association with semen quality in Greek men. Andrologia. 2015;47(10):1166–74. Scholar
  53. 53.
    Omran HM, Bakhiet M, Dashti MG. DNA integrity is a critical molecular indicator for the assessment of male infertility. Mol Med Rep. 2013;7(5):1631–5. Scholar
  54. 54.
    Evgeni E, Charalabopoulos K, Asimakopoulos B. Human sperm DNA fragmentation and its correlation with conventional semen parameters. J Reprod Infertil. 2014;15(1):2–14.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Lin MH, Kuo-Kuang Lee R, Li SH, Lu CH, Sun FJ, Hwu YM. Sperm chromatin structure assay parameters are not related to fertilization rates, embryo quality, and pregnancy rates in in vitro fertilization and intracytoplasmic sperm injection, but might be related to spontaneous abortion rates. Fertil Steril. 2008;90(2):352–9. Scholar
  56. 56.
    Karydis S, Asimakopoulos B, Papadopoulos N, Vakalopoulos I, Al-Hasani S, Nikolettos N. ICSI outcome is not associated with the incidence of spermatozoa with abnormal chromatin condensation. In Vivo. 2005;19(5):921–5.PubMedGoogle Scholar
  57. 57.
    Benchaib M, Lornage J, Mazoyer C, Lejeune H, Salle B, Francois Guerin J. Sperm deoxyribonucleic acid fragmentation as a prognostic indicator of assisted reproductive technology outcome. Fertil Steril. 2007;87(1):93–100. Scholar
  58. 58.
    Agarwal A, Cho CL, Esteves SC. Should we evaluate and treat sperm DNA fragmentation? Curr Opin Obstet Gynecol. 2016;28(3):164–71. Scholar
  59. 59.
    Evenson D, Wixon R. Meta-analysis of sperm DNA fragmentation using the sperm chromatin structure assay. Reprod Biomed Online. 2006;12(4):466–72.PubMedCrossRefGoogle Scholar
  60. 60.
    Collins JA, Barnhart KT, Schlegel PN. Do sperm DNA integrity tests predict pregnancy with in vitro fertilization? Fertil Steril. 2008;89(4):823–31. Scholar
  61. 61.
    Zini A. Are sperm chromatin and DNA defects relevant in the clinic? Syst Biol Reprod Med. 2011;57(1–2):78–85. Scholar
  62. 62.
    Zini A, Boman JM, Belzile E, Ciampi A. Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Hum Reprod. 2008;23(12):2663–8. Scholar
  63. 63.
    Robinson L, Gallos ID, Conner SJ, Rajkhowa M, Miller D, Lewis S, et al. The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Hum Reprod. 2012;27(10):2908–17. Scholar
  64. 64.
    Zhang Z, Zhu L, Jiang H, Chen H, Chen Y, Dai Y. Sperm DNA fragmentation index and pregnancy outcome after IVF or ICSI: a meta-analysis. J Assist Reprod Genet. 2015;32(1):17–26. Scholar
  65. 65.
    Lewis SEM. The place of sperm DNA fragmentation testing in current day fertility management. Middle East Fertil Soc J. 2013;18(2):78–82. Scholar
  66. 66.
    Barratt CLR, Mansell SA. Andrology is desperate for a new assay—let us make sure we get it right this time…. Middle East Fertil Soc J. 2013;18(2):82–3. Scholar
  67. 67.
    Simon L, Proutski I, Stevenson M, Jennings D, McManus J, Lutton D, et al. Sperm DNA damage has a negative association with live-birth rates after IVF. Reprod Biomed Online. 2013;26(1):68–78. Scholar
  68. 68.
    Bungum M, Humaidan P, Axmon A, Spano M, Bungum L, Erenpreiss J, et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod. 2007;22(1):174–9. Scholar
  69. 69.
    Oleszczuk K, Giwercman A, Bungum M. Sperm chromatin structure assay in prediction of in vitro fertilization outcome. Andrology. 2016;4(2):290–6. Scholar
  70. 70.
    Carrell DT. Epigenetics of the male gamete. Fertil Steril. 2012;97(2):267–74. Scholar
  71. 71.
    Oliva R. Protamines and male infertility. Hum Reprod Update. 2006;12(4):417–35. Scholar
  72. 72.
    Aoki VW, Liu L, Jones KP, Hatasaka HH, Gibson M, Peterson CM, et al. Sperm protamine 1/protamine 2 ratios are related to in vitro fertilization pregnancy rates and predictive of fertilization ability. Fertil Steril. 2006;86(5):1408–15. Scholar
  73. 73.
    Hammoud SS, Purwar J, Pflueger C, Cairns BR, Carrell DT. Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertil Steril. 2010;94(5):1728–33. Scholar
  74. 74.
    Jenkins TG, Aston KI, Meyer TD, Hotaling JM, Shamsi MB, Johnstone EB, et al. Decreased fecundity and sperm DNA methylation patterns. Fertil Steril. 2016;105(1):51–7.e1–3. Scholar
  75. 75.
    La Vignera S, Condorelli RA, Balercia G, Vicari E, Calogero AE. Does alcohol have any effect on male reproductive function? A review of literature. Asian J Androl. 2013;15(2):221–5. Scholar
  76. 76.
    Opuwari CS, Henkel RR. An update on oxidative damage to spermatozoa and oocytes. Biomed Res Int. 2016;2016:9540142. Scholar
  77. 77.
    Klonoff-Cohen H, Lam-Kruglick P, Gonzalez C. Effects of maternal and paternal alcohol consumption on the success rates of in vitro fertilization and gamete intrafallopian transfer. Fertil Steril. 2003;79(2):330–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Nicolau P, Miralpeix E, Sola I, Carreras R, Checa MA. Alcohol consumption and in vitro fertilization: a review of the literature. Gynecol Endocrinol. 2014;30(11):759–63. Scholar
  79. 79.
    Sharma R, Harlev A, Agarwal A, Esteves SC. 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):635–45. Scholar
  80. 80.
    Harlev A, Agarwal A, Gunes SO, Shetty A, du Plessis SS. Smoking and male infertility: an evidence-based review. World J Mens Health. 2015;33(3):143–60. Scholar
  81. 81.
    Esakky P, Moley KH. Paternal smoking and germ cell death: a mechanistic link to the effects of cigarette smoke on spermatogenesis and possible long-term sequelae in offspring. Mol Cell Endocrinol. 2016;435:85–93. Scholar
  82. 82.
    Liu R, Zhang L, McHale CM, Hammond SK. Paternal smoking and risk of childhood acute lymphoblastic leukemia: systematic review and meta-analysis. J Oncol. 2011;2011:854584. Scholar
  83. 83.
    Milne E, Greenop KR, Scott RJ, Bailey HD, Attia J, Dalla-Pozza L, et al. Parental prenatal smoking and risk of childhood acute lymphoblastic leukemia. Am J Epidemiol. 2012;175(1):43–53. Scholar
  84. 84.
    Rao M, Zhao XL, Yang J, Hu SF, Lei H, Xia W, et al. Effect of transient scrotal hyperthermia on sperm parameters, seminal plasma biochemical markers, and oxidative stress in men. Asian J Androl. 2015;17(4):668–75. Scholar
  85. 85.
    Rao M, Xia W, Yang J, Hu LX, Hu SF, Lei H, et al. Transient scrotal hyperthermia affects human sperm DNA integrity, sperm apoptosis, and sperm protein expression. Andrology. 2016;4(6):1054–63. Scholar
  86. 86.
    Garolla A, Torino M, Sartini B, Cosci I, Patassini C, Carraro U, et al. Seminal and molecular evidence that sauna exposure affects human spermatogenesis. Hum Reprod. 2013;28(4):877–85. Scholar
  87. 87.
    Ahmad G, Moinard N, Esquerre-Lamare C, Mieusset R, Bujan L. Mild induced testicular and epididymal hyperthermia alters sperm chromatin integrity in men. Fertil Steril. 2012;97(3):546–53. Scholar
  88. 88.
    Sheynkin Y, Welliver R, Winer A, Hajimirzaee F, Ahn H, Lee K. Protection from scrotal hyperthermia in laptop computer users. Fertil Steril. 2011;95(2):647–51. Scholar
  89. 89.
    Southorn T. Great balls of fire and the vicious cycle: a study of the effects of cycling on male fertility. J Fam Plann Reprod Health Care. 2002;28(4):211–3.PubMedCrossRefGoogle Scholar
  90. 90.
    Pathak P, Chandrashekar A, Hakky TS, Pastuszak AW. Varicocele management in the era of in vitro fertilization/intracytoplasmic sperm injection. Asian J Androl. 2016;18(3):343–8. Scholar
  91. 91.
    Wang YJ, Zhang RQ, Lin YJ, Zhang RG, Zhang WL. Relationship between varicocele and sperm DNA damage and the effect of varicocele repair: a meta-analysis. Reprod Biomed Online. 2012;25(3):307–14. Scholar
  92. 92.
    Schauer I, Madersbacher S, Jost R, Hubner WA, Imhof M. The impact of varicocelectomy on sperm parameters: a meta-analysis. J Urol. 2012;187(5):1540–7. Scholar
  93. 93.
    Esteves SC, Roque M, Agarwal A. Outcome of assisted reproductive technology in men with treated and untreated varicocele: systematic review and meta-analysis. Asian J Androl. 2016;18(2):254–8. Scholar
  94. 94.
    Agarwal A, Gupta S, Du Plessis S, Sharma R, Esteves SC, Cirenza C, et al. Abstinence time and its impact on basic and advanced semen parameters. Urology. 2016;94:102–10. Scholar
  95. 95.
    Mayorga-Torres BJ, Camargo M, Agarwal A, du Plessis SS, Cadavid AP, Cardona Maya WD. Influence of ejaculation frequency on seminal parameters. Reprod Biol Endocrinol. 2015;13:47. Scholar
  96. 96.
    Gosalvez J, Gonzalez-Martinez M, Lopez-Fernandez C, Fernandez JL, Sanchez-Martin P. Shorter abstinence decreases sperm deoxyribonucleic acid fragmentation in ejaculate. Fertil Steril. 2011;96(5):1083–6. Scholar
  97. 97.
    Pons I, Cercas R, Villas C, Brana C, Fernandez-Shaw S. One abstinence day decreases sperm DNA fragmentation in 90% of selected patients. J Assist Reprod Genet. 2013;30(9):1211–8. Scholar
  98. 98.
    Sengupta P, Banerjee R. Environmental toxins: alarming impacts of pesticides on male fertility. Hum Exp Toxicol. 2014;33(10):1017–39. Scholar
  99. 99.
    Wirth JJ, Mijal RS. Adverse effects of low level heavy metal exposure on male reproductive function. Syst Biol Reprod Med. 2010;56(2):147–67. Scholar
  100. 100.
    Sermondade N, Faure C, Fezeu L, Shayeb AG, Bonde JP, Jensen TK, et al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum Reprod Update. 2013;19(3):221–31. Scholar
  101. 101.
    Campbell JM, Lane M, Owens JA, Bakos HW. Paternal obesity negatively affects male fertility and assisted reproduction outcomes: a systematic review and meta-analysis. Reprod Biomed Online. 2015;31(5):593–604. Scholar
  102. 102.
    Barazani Y, Katz BF, Nagler HM, Stember DS. Lifestyle, environment, and male reproductive health. Urol Clin North Am. 2014;41(1):55–66. Scholar
  103. 103.
    Brezina PR, Yunus FN, Zhao Y. Effects of pharmaceutical medications on male fertility. J Reprod Infertil. 2012;13(1):3–11.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Fronczak CM, Kim ED, Barqawi AB. The insults of illicit drug use on male fertility. J Androl. 2012;33(4):515–28. Scholar
  105. 105.
    Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on varicocele and infertility. Fertil Steril. 2004;82(Suppl 1):S142–5. Scholar
  106. 106.
    Esteves SC, Oliveira FV, Bertolla RP. Clinical outcome of intracytoplasmic sperm injection in infertile men with treated and untreated clinical varicocele. J Urol. 2010;184(4):1442–6. Scholar
  107. 107.
    Mansour Ghanaie M, Asgari SA, Dadrass N, Allahkhah A, Iran-Pour E, Safarinejad MR. Effects of varicocele repair on spontaneous first trimester miscarriage: a randomized clinical trial. Urol J. 2012;9(2):505–13.PubMedGoogle Scholar
  108. 108.
    Pasqualotto FF, Braga DP, Figueira RC, Setti AS, Iaconelli A Jr, Borges E Jr. Varicocelectomy does not impact pregnancy outcomes following intracytoplasmic sperm injection procedures. J Androl. 2012;33(2):239–43. Scholar
  109. 109.
    Durairajanayagam D, Agarwal A, Ong C. Causes, effects and molecular mechanisms of testicular heat stress. Reprod Biomed Online. 2015;30(1):14–27. Scholar
  110. 110.
    Jung A, Schuppe HC. Influence of genital heat stress on semen quality in humans. Andrologia. 2007;39(6):203–15. Scholar
  111. 111.
    World Health Organization. WHO laboratory manual for the examination and processing of human semen. 5th ed. Geneva: World Health Organization; 2010.Google Scholar
  112. 112.
    Agarwal A, Mulgund A, Alshahrani S, Assidi M, Abuzenadah AM, Sharma R, et al. Reactive oxygen species and sperm DNA damage in infertile men presenting with low level leukocytospermia. Reprod Biol Endocrinol. 2014;12:126. Scholar
  113. 113.
    Ricci G, Granzotto M, Luppi S, Giolo E, Martinelli M, Zito G, et al. Effect of seminal leukocytes on in vitro fertilization and intracytoplasmic sperm injection outcomes. Fertil Steril. 2015;104(1):87–93. Scholar
  114. 114.
    Cavagna M, Oliveira JB, Petersen CG, Mauri AL, Silva LF, Massaro FC, et al. The influence of leukocytospermia on the outcomes of assisted reproductive technology. Reprod Biol Endocrinol. 2012;10:44. Scholar
  115. 115.
    Talevi R, Barbato V, Fiorentino I, Braun S, Longobardi S, Gualtieri R. Protective effects of in vitro treatment with zinc, d-aspartate and coenzyme q10 on human sperm motility, lipid peroxidation and DNA fragmentation. Reprod Biol Endocrinol. 2013;11:81. Scholar
  116. 116.
    Showell MG, Mackenzie-Proctor R, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2014;12:CD007411. Scholar
  117. 117.
    Kessopoulou E, Powers HJ, Sharma KK, Pearson MJ, Russell JM, Cooke ID, et al. A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility. Fertil Steril. 1995;64(4):825–31.PubMedCrossRefGoogle Scholar
  118. 118.
    Tremellen K, Miari G, Froiland D, Thompson J. A randomised control trial examining the effect of an antioxidant (Menevit) on pregnancy outcome during IVF-ICSI treatment. Aust N Z J Obstet Gynaecol. 2007;47(3):216–21. Scholar
  119. 119.
    Sakkas D, Ramalingam M, Garrido N, Barratt CL. Sperm selection in natural conception: what can we learn from mother nature to improve assisted reproduction outcomes? Hum Reprod Update. 2015;21(6):711–26. Scholar
  120. 120.
    Rappa KL, Rodriguez HF, Hakkarainen GC, Anchan RM, Mutter GL, Asghar W. Sperm processing for advanced reproductive technologies: where are we today? Biotechnol Adv. 2016;34(5):578–87. Scholar
  121. 121.
    Bartoov B, Berkovitz A, Eltes F. Selection of spermatozoa with normal nuclei to improve the pregnancy rate with intracytoplasmic sperm injection. N Engl J Med. 2001;345(14):1067–8. Scholar
  122. 122.
    La Sala GB, Nicoli A, Fornaciari E, Falbo A, Rondini I, Morini D, et al. Intracytoplasmic morphologically selected sperm injection versus conventional intracytoplasmic sperm injection: a randomized controlled trial. Reprod Biol Endocrinol. 2015;13:97. Scholar
  123. 123.
    Setti AS, Braga DP, Figueira RC, Iaconelli A Jr, Borges E. Intracytoplasmic morphologically selected sperm injection results in improved clinical outcomes in couples with previous ICSI failures or male factor infertility: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2014;183:96–103. Scholar
  124. 124.
    Sakkas D, Manicardi GC, Tomlinson M, Mandrioli M, Bizzaro D, Bianchi PG, et al. The use of two density gradient centrifugation techniques and the swim-up method to separate spermatozoa with chromatin and nuclear DNA anomalies. Hum Reprod. 2000;15(5):1112–6.PubMedCrossRefGoogle Scholar
  125. 125.
    Degheidy T, Abdelfattah H, Seif A, Albuz FK, Gazi S, Abbas S. Magnetic activated cell sorting: an effective method for reduction of sperm DNA fragmentation in varicocele men prior to assisted reproductive techniques. Andrologia. 2015;47(8):892–6. Scholar
  126. 126.
    Magli MC, Crippa A, Muzii L, Boudjema E, Capoti A, Scaravelli G, et al. Head birefringence properties are associated with acrosome reaction, sperm motility and morphology. Reprod Biomed Online. 2012;24(3):352–9. Scholar
  127. 127.
    Samuel R, Badamjav O, Murphy KE, Patel DP, Son J, Gale BK, et al. Microfluidics: the future of microdissection TESE? Syst Biol Reprod Med. 2016;62(3):161–70. Scholar
  128. 128.
    Ainsworth C, Nixon B, Aitken RJ. Development of a novel electrophoretic system for the isolation of human spermatozoa. Hum Reprod. 2005;20(8):2261–70. Scholar
  129. 129.
    Simon L, Murphy K, Aston KI, Emery BR, Hotaling JM, Carrell DT. Micro-electrophoresis: a noninvasive method of sperm selection based on membrane charge. Fertil Steril. 2015;103(2):361–6.e3. Scholar
  130. 130.
    Said TM, Land JA. Effects of advanced selection methods on sperm quality and ART outcome: a systematic review. Hum Reprod Update. 2011;17(6):719–33. Scholar
  131. 131.
    Esteves SC, Sanchez-Martin F, Sanchez-Martin P, Schneider DT, Gosalvez J. Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm. Fertil Steril. 2015;104(6):1398–405. Scholar
  132. 132.
    Greco E, Scarselli F, Iacobelli M, Rienzi L, Ubaldi F, Ferrero S, et al. Efficient treatment of infertility due to sperm DNA damage by ICSI with testicular spermatozoa. Hum Reprod. 2005;20(1):226–30. Scholar
  133. 133.
    Huang WJ, Lamb DJ, Kim ED, de Lara J, Lin WW, Lipshultz LI, et al. Germ-cell nondisjunction in testes biopsies of men with idiopathic infertility. Am J Hum Genet. 1999;64(6):1638–45. Scholar
  134. 134.
    Moskovtsev SI, Alladin N, Lo KC, Jarvi K, Mullen JB, Librach CL. A comparison of ejaculated and testicular spermatozoa aneuploidy rates in patients with high sperm DNA damage. Syst Biol Reprod Med. 2012;58(3):142–8. Scholar
  135. 135.
    Ly KD, Agarwal A, Nagy ZP. Preimplantation genetic screening: does it help or hinder IVF treatment and what is the role of the embryo? J Assist Reprod Genet. 2011;28(9):833–49. Scholar
  136. 136.
    Rubio C, Buendia P, Rodrigo L, Mercader A, Mateu E, Peinado V, et al. Prognostic factors for preimplantation genetic screening in repeated pregnancy loss. Reprod Biomed Online. 2009;18(5):687–93.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Sorena Keihani
    • 1
  • Jeremy B. Myers
    • 1
  • James M. Hotaling
    • 1
  1. 1.Center for Reconstructive Urology and Men’s Health, Division of UrologyUniversity of UtahSalt Lake CityUSA

Personalised recommendations