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Lack of trusted diagnostic tools for undetermined male infertility

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Abstract

Semen analysis is the cornerstone of evaluating male infertility, but it is imperfect and insufficient to diagnose male infertility. As a result, about 20% of infertile males have undetermined infertility, a term encompassing male infertility with an unknown underlying cause. Undetermined male infertility includes two categories: (i) idiopathic male infertility—infertile males with abnormal semen analyses with an unknown cause for that abnormality and (ii) unexplained male infertility—males with “normal” semen analyses who are unable to impregnate due to unknown causes. The treatment of males with undetermined infertility is limited due to a lack of understanding the frequency of general sperm defects (e.g., number, motility, shape, viability). Furthermore, there is a lack of trusted, quantitative, and predictive diagnostic tests that look inside the sperm to quantify defects such as DNA damage, RNA abnormalities, centriole dysfunction, or reactive oxygen species to discover the underlying cause. To better treat undetermined male infertility, further research is needed on the frequency of sperm defects and reliable diagnostic tools that assess intracellular sperm components must be developed. The purpose of this review is to uniquely create a paradigm of thought regarding categories of male infertility based on intracellular and extracellular features of semen and sperm, explore the prevalence of the various categories of male factor infertility, call attention to the lack of standardization and universal application of advanced sperm testing techniques beyond semen analysis, and clarify the limitations of standard semen analysis. We also call attention to the variability in definitions and consider the benefits towards undetermined male infertility if these gaps in research are filled.

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References

  1. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 2012;9(12):e1001356.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Thoma ME, et al. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertil Steril. 2013;99(5):1324–1331.e1.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chandra A, Copen CE, Stephen EH. Infertility service use in the United States: Data from the National Survey of Family Growth, 1982-2010. Natl Health Stat Rep. 2014(73):1–21.

  4. The epidemiology of infertility. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1975;582:1–37.

    Google Scholar 

  5. Philippov OS, Radionchenko AA, Bolotova VP, Voronovskaya NI, Potemkina TV. Estimation of the prevalence and causes of infertility in western Siberia. Bull World Health Organ. 1998;76(2):183–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bayasgalan G, Naranbat D, Tsedmaa B, Tsogmaa B, Sukhee D, Amarjargal O, et al. Clinical patterns and major causes of infertility in Mongolia. J Obstet Gynaecol Res. 2004;30(5):386–93.

    Article  PubMed  Google Scholar 

  7. Ekwere P, et al. Infertility among Nigerian couples as seen in Calabar. Port Harcourt Med J. 2007;2.

  8. Farhi J, Ben-Haroush A. Distribution of causes of infertility in patients attending primary fertility clinics in Israel. Isr Med Assoc J. 2011;13(1):51–4.

    PubMed  Google Scholar 

  9. Oztekin U, et al. Evaluation of male infertility prevalence with clinical outcomes in Middle Anatolian region. Cureus. 2019;11(7):e5122.

    PubMed  PubMed Central  Google Scholar 

  10. Razzak AH, Wais SA. The infertile couple: a cohort study in Duhok, Iraq. East Mediterr Health J. 2002;8(2–3):234–8.

    Article  CAS  PubMed  Google Scholar 

  11. Thonneau P, Marchand S, Tallec A, Ferial ML, Ducot B, Lansac J, et al. Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989). Hum Reprod. 1991;6(6):811–6.

    Article  CAS  PubMed  Google Scholar 

  12. Dyer SJ, Abrahams N, Hoffman M, van der Spuy ZM. ‘Men leave me as I cannot have children’: women’s experiences with involuntary childlessness. Hum Reprod. 2002;17(6):1663–8.

    Article  CAS  PubMed  Google Scholar 

  13. Turner KA, et al. Male infertility is a women’s health issue-research and clinical evaluation of male infertility is needed. Cells. 2020;9(4).

  14. Smith S, Pfeifer SM, Collins JA. Diagnosis and management of female infertility. JAMA. 2003;290(13):1767–70.

    Article  CAS  PubMed  Google Scholar 

  15. Collins JA. Evidence-based infertility: evaluation of the female partner. Int Congr Ser. 2004;1266:57–62.

    Article  Google Scholar 

  16. Sigman M, Lipshultz LI, Howards SS. In: Niederberger CS, Lipshultz LI, Howards SS, editors. Office evaluation of the subfertile male, in Infertility in the male. Cambridge: Cambridge University Press; 2009. p. 153–76.

    Google Scholar 

  17. Barratt CL. Semen analysis is the cornerstone of investigation for male infertility. Practitioner. 2007;251(1690):8–10, 12, 15-7.

    PubMed  Google Scholar 

  18. Macomber D, Sanders MB. The spermatozoa count. N Engl J Med. 1929;200(19):981–4.

    Article  Google Scholar 

  19. Patel AS, Leong JY, Ramasamy R. Prediction of male infertility by the World Health Organization laboratory manual for assessment of semen analysis: a systematic review. Arab J Urol. 2018;16(1):96–102.

    Article  PubMed  Google Scholar 

  20. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HWG, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16(3):231–45.

    Article  PubMed  Google Scholar 

  21. Goyal R, Kotru M, Gogia A, Sharma S. Qualitative defects with normal sperm counts in a patient attending infertility clinic. Indian J Pathol Microbiol. 2018;61(2):233–5.

    Article  PubMed  Google Scholar 

  22. Murray KS, James A, McGeady JB, Reed ML, Kuang WW, Nangia AK. The effect of the new 2010 World Health Organization criteria for semen analyses on male infertility. Fertil Steril. 2012;98(6):1428–31.

    Article  PubMed  Google Scholar 

  23. Barbăroșie C, Agarwal A, Henkel R. Diagnostic value of advanced semen analysis in evaluation of male infertility. Andrologia. n/a(n/a):e13625.

  24. Barroso G, Mercan R, Ozgur K, Morshedi M, Kolm P, Coetzee K, et al. Intra- and inter-laboratory variability in the assessment of sperm morphology by strict criteria: impact of semen preparation, staining techniques and manual versus computerized analysis. Hum Reprod. 1999;14(8):2036–40.

    Article  CAS  PubMed  Google Scholar 

  25. Filimberti E, Degl'Innocenti S, Borsotti M, Quercioli M, Piomboni P, Natali I, et al. High variability in results of semen analysis in andrology laboratories in Tuscany (Italy): the experience of an external quality control (EQC) programme. Andrology. 2013;1(3):401–7.

    Article  CAS  PubMed  Google Scholar 

  26. Jørgensen N, et al. Semen analysis performed by different laboratory teams: an intervariation study. Int J Androl. 1997;20(4):201–8.

    Article  PubMed  Google Scholar 

  27. Moazzam A, et al. From basic to contemporary semen analysis: limitations and variability. J Anim Plant Sci. 2015;25:328–36.

    CAS  Google Scholar 

  28. Auger J, Eustache F, Ducot B, Blandin T, Daudin M, Diaz I, et al. Intra- and inter-individual variability in human sperm concentration, motility and vitality assessment during a workshop involving ten laboratories. Hum Reprod. 2000;15(11):2360–8.

    Article  CAS  PubMed  Google Scholar 

  29. Brandriff B, Gordon L, Ashworth L, Watchmaker G, Moore D II, Wyrobek AJ, et al. Chromosomes of human sperm: variability among normal individuals. Hum Genet. 1985;70(1):18–24.

    Article  CAS  PubMed  Google Scholar 

  30. Brazil C. Practical semen analysis: from A to Z. Asian J Androl. 2010;12(1):14–20.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. Smith KD, Rodriguez-Rigau LJ, Steinberger E. Relation between indices of semen analysis and pregnancy rate in infertile couples*†. Fertil Steril. 1977;28(12):1314–9.

    Article  CAS  PubMed  Google Scholar 

  33. Group CCW. The current status and future of andrology: a consensus report from the Cairo workshop group. Andrology. 2020;8(1):27–52.

    Article  Google Scholar 

  34. Thierry B. Integrating proximate and ultimate causation: just one more go! Curr Sci. 2005;89(7):1180–3.

    Google Scholar 

  35. Ring JD, Lwin AA, Köhler TS. Current medical management of endocrine-related male infertility. Asian J Androl. 2016;18(3):357–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dubin L, Amelar RD. Etiologic factors in 1294 consecutive cases of male infertility *. Fertil Steril. 1971;22(8):469–74.

    Article  CAS  PubMed  Google Scholar 

  37. Esteves SC, Miyaoka R, Agarwal A. An update on the clinical assessment of the infertile male. [corrected]. Clinics (Sao Paulo). 2011;66(4):691–700.

    Article  Google Scholar 

  38. Osegbe DN, Amaku EO. The causes of male infertility in 504 consecutive Nigerian patients. Int Urol Nephrol. 1985;17(4):349–58.

    Article  CAS  PubMed  Google Scholar 

  39. Al-Ali BM, et al. Clinical parameters and semen analysis in 716 Austrian patients with varicocele. Urology. 2010;75(5):1069–73.

    Article  PubMed  Google Scholar 

  40. Al-Ali BM, et al. Clinical and laboratory profiles of a large cohort of patients with different grades of varicocele. Central Eur J Urol. 2013;66(1):71–4.

    Article  Google Scholar 

  41. Panner Selvam MK, et al. Etiologies of sperm DNA damage and its impact on male infertility. Andrologia. 2020;n/a(n/a):e13706.

    Google Scholar 

  42. Avidor-Reiss T, Carr A, Fishman EL. The sperm centrioles. Mol Cell Endocrinol. 2020;518:110987.

    Article  CAS  PubMed  Google Scholar 

  43. Grimes DA, Lopez LM. “Oligozoospermia,” “azoospermia,” and other semen-analysis terminology: the need for better science. Fertil Steril. 2007;88(6):1491–4.

    Article  PubMed  Google Scholar 

  44. Aduloju P, et al. Pattern of semen parameters and factors associated with infertility in male partners of infertile couples in Nigeria. Androl-Open Access. 2016;5:1.

    Google Scholar 

  45. Biradar KD. Male factor in infertility: study from a tertiary care hospital. Int J Reprod Contracept Obstet Gynecol. 2016;5(6). https://doi.org/10.18203/2320-1770.ijrcog20161710.

  46. Butt F, Akram N. Semen analysis parameters: experiences and insight into male infertility at a tertiary care hospital in Punjab. J Pak Med Assoc. 2013;63(5):558–62.

    PubMed  Google Scholar 

  47. Bartels I, Schlosser M, Bartz UG, Pauer HU. Paternal origin of trisomy 21 following intracytoplasmic sperm injection (ICSI). Hum Reprod. 1998;13(12):3345–6.

    Article  CAS  PubMed  Google Scholar 

  48. Plachot M, Belaisch-Allart J, Mayenga JM, Chouraqui A, Tesquier L, Serkine AM. Outcome of conventional IVF and ICSI on sibling oocytes in mild male factor infertility. Hum Reprod. 2002;17(2):362–9.

    Article  PubMed  Google Scholar 

  49. Rubio C, Gil-Salom M, Simón C, Vidal F, Rodrigo L, Mínguez Y, et al. Incidence of sperm chromosomal abnormalities in a risk population: relationship with sperm quality and ICSI outcome. Hum Reprod. 2001;16(10):2084–92.

    Article  CAS  PubMed  Google Scholar 

  50. Avidor-Reiss T, Mazur M, Fishman EL, Sindhwani P. The role of sperm centrioles in human reproduction - the known and the unknown. Front Cell Dev Biol. 2019;7:188.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cassuto NG, Hazout A, Hammoud I, Balet R, Bouret D, Barak Y, et al. Correlation between DNA defect and sperm-head morphology. Reprod BioMed Online. 2012;24(2):211–8.

    Article  PubMed  Google Scholar 

  52. Kao S-H, Chao HT, Liu HW, Liao TL, Wei YH. Sperm mitochondrial DNA depletion in men with asthenospermia. Fertil Steril. 2004;82(1):66–73.

    Article  CAS  PubMed  Google Scholar 

  53. Sathananthan AH. Paternal centrosomal dynamics in early human development and infertility. J Assist Reprod Genet. 1998;15(3):129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril. 2015;103(3):e18–25.

  55. Huggins C, Scott WW, Heinen JH. Chemical composition of human semen and of the secretions of the prostate and seminal vesicles. Am J Physiol-Legacy Content. 1942;136(3):467–73.

    Article  CAS  Google Scholar 

  56. Bracke A, Peeters K, Punjabi U, Hoogewijs D, Dewilde S. A search for molecular mechanisms underlying male idiopathic infertility. Reprod BioMed Online. 2018;36(3):327–39.

    Article  CAS  PubMed  Google Scholar 

  57. Calogero AE, Burrello N, de Palma A, Barone N, D'Agata R, Vicari E. Sperm aneuploidy in infertile men. Reprod BioMed Online. 2003;6(3):310–7.

    Article  CAS  PubMed  Google Scholar 

  58. Agarwal A and Said TM. Interpretation of basic semen analysis and advanced semen testing. 2011.

  59. Lewis SEM. Is sperm evaluation useful in predicting human fertility? Reproduction. 2007;134(1):31–40.

    Article  CAS  PubMed  Google Scholar 

  60. Lewis SEM, Agbaje I, Alvarez J. Sperm DNA tests as useful adjuncts to semen analysis. Syst Biol Reprod Med. 2008;54(3):111–25.

    Article  CAS  PubMed  Google Scholar 

  61. Mau UA, Backert IT, Kaiser P, Kiesel L. Chromosomal findings in 150 couples referred for genetic counselling prior to intracytoplasmic sperm injection. Hum Reprod. 1997;12(5):930–7.

    Article  CAS  PubMed  Google Scholar 

  62. Meschede D, Lemcke B, Exeler JR, de Geyter C, Behre HM, Nieschlag E, et al. Chromosome abnormalities in 447 couples undergoing intracytoplasmic sperm injection--prevalence, types, sex distribution and reproductive relevance. Hum Reprod. 1998;13(3):576–82.

    Article  CAS  PubMed  Google Scholar 

  63. Testart J, Gautier E, Brami C, Rolet F, Sedbon E, Thebault A. Genetics: Intracytoplasmic sperm injection in infertile patients with structural chromosome abnormalities. Hum Reprod. 1996;11(12):2609–12.

    Article  CAS  PubMed  Google Scholar 

  64. Carrell DT, Wilcox AL, Lowy L, Peterson CM, Jones KP, Erickson L, et al. Elevated sperm chromosome aneuploidy and apoptosis in patients with unexplained recurrent pregnancy loss. Obstet Gynecol. 2003;101(6):1229–35.

    PubMed  Google Scholar 

  65. Esquerré-Lamare C, Walschaerts M, Chansel Debordeaux L, Moreau J, Bretelle F, Isus F, et al. Sperm aneuploidy and DNA fragmentation in unexplained recurrent pregnancy loss: a multicenter case-control study. Basic Clin Androl. 2018;28(1):4.

    Article  PubMed  PubMed Central  Google Scholar 

  66. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Practice Committee of the American Society for Reproductive Medicine. The clinical utility of sperm DNA integrity testing: a guideline. Fertil Steril. 2013;99(3):673–7.

    Article  Google Scholar 

  68. Mehta A. Pros and cons of sperm DNA fragmentation testing: weighing the evidence. Transl Androl Urol. 2017;6(Suppl 4):S453–4.

    Article  PubMed  PubMed Central  Google Scholar 

  69. 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.

    Article  CAS  PubMed  Google Scholar 

  70. Erenpreiss J, Spano M, Erenpreisa J, Bungum M, Giwercman A. Sperm chromatin structure and male fertility: biological and clinical aspects. Asian J Androl. 2006;8(1):11–29.

    Article  CAS  PubMed  Google Scholar 

  71. Giwercman A, Lindstedt L, Larsson M, Bungum M, Spano M, Levine RJ, et al. Sperm chromatin structure assay as an independent predictor of fertility in vivo: a case-control study. Int J Androl. 2010;33(1):e221–7.

    Article  PubMed  Google Scholar 

  72. Giwercman A, Richthoff J, Hjøllund H, Bonde JP, Jepson K, Frohm B, et al. Correlation between sperm motility and sperm chromatin structure assay parameters. Fertil Steril. 2003;80(6):1404–12.

    Article  PubMed  Google Scholar 

  73. Bungum M, Bungum L, Giwercman A. Sperm chromatin structure assay (SCSA): a tool in diagnosis and treatment of infertility. Asian J Androl. 2011;13(1):69–75.

    Article  CAS  PubMed  Google Scholar 

  74. Evenson DP. The Sperm Chromatin Structure Assay (SCSA®) and other sperm DNA fragmentation tests for evaluation of sperm nuclear DNA integrity as related to fertility. Anim Reprod Sci. 2016;169:56–75.

    Article  CAS  PubMed  Google Scholar 

  75. Evenson DP, et al. Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. Hum Reprod. 1999;14(4):1039–49.

    Article  CAS  PubMed  Google Scholar 

  76. The clinical utility of sperm DNA integrity testing: a guideline. Fertil Steril. 2013;99(3):673–7.

  77. Høst E, Lindenberg S, Smidt-Jensen S. DNA strand breaks in human spermatozoa: correlation with fertilization in vitro in oligozoospermic men and in men with unexplained infertility. Acta Obstet Gynecol Scand. 2000;79(3):189–93.

    PubMed  Google Scholar 

  78. Oleszczuk K, Augustinsson L, Bayat N, Giwercman A, Bungum M. Prevalence of high DNA fragmentation index in male partners of unexplained infertile couples. Andrology. 2013;1(3):357–60.

    Article  CAS  PubMed  Google Scholar 

  79. 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.

    Article  CAS  PubMed  Google Scholar 

  80. Tan J, Taskin O, Albert A, Bedaiwy MA. Association between sperm DNA fragmentation and idiopathic recurrent pregnancy loss: a systematic review and meta-analysis. Reprod BioMed Online. 2019;38(6):951–60.

    Article  CAS  PubMed  Google Scholar 

  81. Avendaño C, Franchi A, Duran H, Oehninger S. DNA fragmentation of normal spermatozoa negatively impacts embryo quality and intracytoplasmic sperm injection outcome. Fertil Steril. 2010;94(2):549–57.

    Article  PubMed  Google Scholar 

  82. Tournaye H. Male factor infertility and ART. Asian J Androl. 2012;14(1):103–8.

    Article  PubMed  Google Scholar 

  83. Agarwal A, Cho CL, Esteves SC, Majzoub A. The price and value of sperm DNA fragmentation tests. Transl Androl Urol. 2017;6(Suppl 4):S597–9.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Chambers GM, Adamson GD, Eijkemans MJ. Acceptable cost for the patient and society. Fertil Steril. 2013;100(2):319–27.

    Article  PubMed  Google Scholar 

  85. Hammoud SS, Nix DA, Hammoud AO, Gibson M, Cairns BR, Carrell DT. Genome-wide analysis identifies changes in histone retention and epigenetic modifications at developmental and imprinted gene loci in the sperm of infertile men. Hum Reprod. 2011;26(9):2558–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Okada Y, Tateishi K, Zhang Y. Histone demethylase JHDM2A is involved in male infertility and obesity. J Androl. 2010;31(1):75–8.

    Article  CAS  PubMed  Google Scholar 

  87. Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis and male infertility. Mutat Res/Rev Mutat Res. 2011;727(3):62–71.

    Article  CAS  Google Scholar 

  88. Schon SB, Luense LJ, Wang X, Bartolomei MS, Coutifaris C, Garcia BA, et al. Histone modification signatures in human sperm distinguish clinical abnormalities. J Assist Reprod Genet. 2019;36(2):267–75.

    Article  PubMed  Google Scholar 

  89. Aoki VW, Emery BR, Liu L, Carrell DT. Protamine levels vary between individual sperm cells of infertile human males and correlate with viability and DNA integrity. J Androl. 2006;27(6):890–8.

    Article  CAS  PubMed  Google Scholar 

  90. Aoki VW, Liu L, Carrell DT. Identification and evaluation of a novel sperm protamine abnormality in a population of infertile males. Hum Reprod. 2005;20(5):1298–306.

    Article  CAS  PubMed  Google Scholar 

  91. Aoki VW, Moskovtsev SI, Willis J, Liu L, Mullen JB, Carrell DT. DNA integrity is compromised in protamine-deficient human sperm. J Androl. 2005;26(6):741–8.

    Article  CAS  PubMed  Google Scholar 

  92. Carrell DT, Emery BR, Hammoud S. The aetiology of sperm protamine abnormalities and their potential impact on the sperm epigenome. Int J Androl. 2008;31(6):537–45.

    Article  PubMed  Google Scholar 

  93. Li C, Zhou X. Gene transcripts in spermatozoa: markers of male infertility. Clin Chim Acta. 2012;413(13):1035–8.

    Article  CAS  PubMed  Google Scholar 

  94. Hamatani T. Human spermatozoal RNAs. Fertil Steril. 2012;97(2):275–81.

    Article  CAS  PubMed  Google Scholar 

  95. Jodar M, Kalko S, Castillo J, Ballescà JL, Oliva R. Differential RNAs in the sperm cells of asthenozoospermic patients. Hum Reprod. 2012;27(5):1431–8.

    Article  CAS  PubMed  Google Scholar 

  96. Jodar M, et al. Absence of sperm RNA elements correlates with idiopathic male infertility. Sci Transl Med. 2015;7(295):295re6.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Salas-Huetos A, Blanco J, Vidal F, Grossmann M, Pons MC, Garrido N, et al. Spermatozoa from normozoospermic fertile and infertile individuals convey a distinct miRNA cargo. Andrology. 2016;4(6):1028–36.

    Article  CAS  PubMed  Google Scholar 

  98. Jodar M, et al. Absence of sperm RNA elements correlates with idiopathic male infertility. Sci Transl Med. 2015;7(295):295re6.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Grow DR, Oehninger S, Seltman HJ, Toner JP, Swanson RJ, Kruger TF, et al. Sperm morphology as diagnosed by strict criteria: probing the impact of teratozoospermia on fertilization rate and pregnancy outcome in a large in vitro fertilization population. Fertil Steril. 1994;62(3):559–67.

    Article  CAS  PubMed  Google Scholar 

  100. Ombelet W, Fourie FR, Vandeput H, Bosmans E, Cox A, Janssen M, et al. Teratozoospermia and in-vitro fertilization: a randomized prospective study. Hum Reprod. 1994;9(8):1479–84.

    Article  CAS  PubMed  Google Scholar 

  101. Spiessens C, Vanderschueren D, Meuleman C, D'Hooghe T. Isolated teratozoospermia and intrauterine insemination. Fertil Steril. 2003;80(5):1185–9.

    Article  PubMed  Google Scholar 

  102. Wang G-H, et al. Impact of sperm malformation rate on ICSI clinical outcomes. Reprod Contracept. 2011;4:241–5.

    Google Scholar 

  103. Nie H, Tang Y, Qin W. Beyond acephalic spermatozoa: the complexity of intracytoplasmic sperm injection outcomes. Biomed Res Int. 2020;2020:6279795.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Fishman EL, Jo K, Nguyen QPH, Kong D, Royfman R, Cekic AR, et al. A novel atypical sperm centriole is functional during human fertilization. Nat Commun. 2018;9(1):2210.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Avidor-Reiss T, et al. Atypical centrioles during sexual reproduction. Front Cell Dev Biol. 2015;3(21).

  106. Cavazza T, et al. Parental genome unification is highly erroneous in mammalian embryos. bioRxiv. 2020:2020.08.27.269779.

  107. Schneider I, et al. Non-rodent mammalian zygotes assemble dual spindles despite the presence of paternal centrosomes. bioRxiv. 2020:2020.10.16.342154.

  108. Griffin DK, Harton GL. Preimplantation genetic testing: recent advances in reproductive medicine: CRC Press; 2020.

  109. Dupree JM. Insurance coverage for male infertility care in the United States. Asian J Androl. 2016;18(3):339–41.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Agarwal A, Parekh N, Panner Selvam MK, Henkel R, Shah R, Homa ST, et al. Male oxidative stress infertility (MOSI): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. World J Mens Health. 2019;37(3):296–312.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Saalu LC. The incriminating role of reactive oxygen species in idiopathic male infertility: an evidence based evaluation. Pak J Biol Sci. 2010;13(9):413–22.

    Article  CAS  PubMed  Google Scholar 

  112. Alahmar AT. Role of oxidative stress in male infertility: an updated review. J Human Reprod Sci. 2019;12(1):4–18.

    Article  CAS  Google Scholar 

  113. Jung JH, Seo JT. Empirical medical therapy in idiopathic male infertility: promise or panacea? Clin Exp Reprod Med. 2014;41(3):108–14.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Arafa M, et al. Efficacy of antioxidant supplementation on conventional and advanced sperm function tests in patients with idiopathic male infertility. Antioxidants (Basel, Switzerland). 2020;9(3):219.

    CAS  Google Scholar 

  115. Kathrins M. MOXI trial-is it time to stop routinely recommending antioxidant therapy to infertile men? Fertil Steril. 2020;113(3):542.

    Article  PubMed  Google Scholar 

  116. Steiner AZ, et al. The effect of antioxidants on male factor infertility: the males, antioxidants, and infertility (MOXI) randomized clinical trial. Fertil Steril. 2020;113(3):552–560.e3.

    Article  CAS  PubMed  Google Scholar 

  117. Ko EY, Siddiqi K, Brannigan RE, Sabanegh ES. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol. 2012;187(3):973–8.

    Article  PubMed  Google Scholar 

  118. Pregl Breznik B, Kovačič B, Vlaisavljević V. Are sperm DNA fragmentation, hyperactivation, and hyaluronan-binding ability predictive for fertilization and embryo development in in vitro fertilization and intracytoplasmic sperm injection? Fertil Steril. 2013;99(5):1233–41.

    Article  CAS  PubMed  Google Scholar 

  119. Choe SA, Tae JC, Shin MY, Kim HJ, Kim CH, Lee JY, et al. Application of sperm selection using hyaluronic acid binding in intracytoplasmic sperm injection cycles: a sibling oocyte study. J Korean Med Sci. 2012;27(12):1569–73.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Worrilow KC, Eid S, Woodhouse D, Perloe M, Smith S, Witmyer J, et al. Use of hyaluronan in the selection of sperm for intracytoplasmic sperm injection (ICSI): significant improvement in clinical outcomes—multicenter, double-blinded and randomized controlled trial. Hum Reprod. 2012;28(2):306–14.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Erberelli RF, Salgado RM, Pereira DH, Wolff P. Hyaluronan-binding system for sperm selection enhances pregnancy rates in ICSI cycles associated with male factor infertility. JBRA Assist Reprod. 2017;21(1):2–6.

    PubMed  PubMed Central  Google Scholar 

  122. Yildirim M, Duvan CI, Pekel A, Ayrim A, Kafali H. Can hyaluronan binding assay predict the outcome of intrauterine insemination in couples with unexplained or mild male factor infertility? J Reprod Infertil. 2015;16(1):18–23.

    PubMed  PubMed Central  Google Scholar 

  123. Natali A, Turek PJ. An assessment of new sperm tests for male infertility. Urology. 2011;77(5):1027–34.

    Article  PubMed  Google Scholar 

  124. Shukla KK, Mahdi AA, Rajender S. Apoptosis, spermatogenesis and male infertility. Front Biosci (Elite Ed). 2012;4:746–54.

    Article  Google Scholar 

  125. Weng S-L, Taylor SL, Morshedi M, Schuffner A, Duran EH, Beebe S, et al. Caspase activity and apoptotic markers in ejaculated human sperm. Mol Hum Reprod. 2002;8(11):984–91.

    Article  CAS  PubMed  Google Scholar 

  126. Oosterhuis GJE, Mulder AB, Kalsbeek-Batenburg E, Lambalk CB, Schoemaker J, Vermes I. Measuring apoptosis in human spermatozoa: a biological assay for semen quality? Fertil Steril. 2000;74(2):245–50.

    Article  CAS  PubMed  Google Scholar 

  127. Amdani SN, Yeste M, Jones C, Coward K. Phospholipase C zeta (PLCζ) and male infertility: clinical update and topical developments. Adv Biol Regul. 2016;61:58–67.

    Article  CAS  PubMed  Google Scholar 

  128. Heytens E, Parrington J, Coward K, Young C, Lambrecht S, Yoon SY, et al. Reduced amounts and abnormal forms of phospholipase C zeta (PLCζ) in spermatozoa from infertile men. Hum Reprod. 2009;24(10):2417–28.

    Article  CAS  PubMed  Google Scholar 

  129. Kashir J, et al. A maternally inherited autosomal point mutation in human phospholipase C zeta (PLCζ) leads to male infertility. Hum Reprod. 2011;27(1):222–31.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Nomikos M, Kashir J, Swann K, Lai FA. Sperm PLCζ: from structure to Ca2+ oscillations, egg activation and therapeutic potential. FEBS Lett. 2013;587(22):3609–16.

    Article  CAS  PubMed  Google Scholar 

  131. Nomikos M, Swann K, Lai FA. Starting a new life: sperm PLC-zeta mobilizes the Ca2+ signal that induces egg activation and embryo development. BioEssays. 2012;34(2):126–34.

    Article  CAS  PubMed  Google Scholar 

  132. Yoon S-Y, Jellerette T, Salicioni AM, Lee HC, Yoo MS, Coward K, et al. Human sperm devoid of PLC, zeta 1 fail to induce Ca2+ release and are unable to initiate the first step of embryo development. J Clin Invest. 2008;118(11):3671–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Caballero-Campo P, Buffone MG, Benencia F, Conejo-García JR, Rinaudo PF, Gerton GL. A role for the chemokine receptor CCR6 in mammalian sperm motility and Chemotaxis. J Cell Physiol. 2014;229(1):68–78.

    CAS  PubMed  Google Scholar 

  134. Chyra-Jach D, et al. The associations between infertility and antioxidants, proinflammatory cytokines, and chemokines. Oxidative Med Cell Longev. 2018;2018:8354747.

    Article  Google Scholar 

  135. Duan Y-G, Wehry UP, Buhren BA, Schrumpf H, Oláh P, Bünemann E, et al. CCL20-CCR6 axis directs sperm–oocyte interaction and its dysregulation correlates/associates with male infertility‡. Biol Reprod. 2020;103:630–42.

    Article  PubMed  Google Scholar 

  136. Muciaccia B, Padula F, Vicini E, Gandini L, Lenzi A, Stefanini M. Beta-chemokine receptors 5 and 3 are expressed on the head region of human spermatozoon. FASEB J. 2005;19(14):2048–50.

    Article  CAS  PubMed  Google Scholar 

  137. Zandieh Z, Ashrafi M, Aflatoonian K, Aflatoonian R. Human sperm DNA damage has an effect on immunological interaction between spermatozoa and fallopian tube. Andrology. 2019;7(2):228–34.

    Article  CAS  PubMed  Google Scholar 

  138. Umezu K, Hara K, Hiradate Y, Numabe T, Tanemura K. Stromal cell-derived factor 1 regulates in vitro sperm migration towards the cumulus-oocyte complex in cattle. PLoS One. 2020;15(4):e0232536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Colaco S, Sakkas D. Paternal factors contributing to embryo quality. J Assist Reprod Genet. 2018;35(11):1953–68.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Roldan ER. Assessments of sperm quality integrating morphology, swimming patterns, bioenergetics and cell signalling. Theriogenology. 2020;150:388–95.

    Article  CAS  PubMed  Google Scholar 

  141. Barratt CLR, Mansell S, Beaton C, Tardif S, Oxenham SK. Diagnostic tools in male infertility-the question of sperm dysfunction. Asian J Androl. 2011;13(1):53–8.

    Article  PubMed  Google Scholar 

  142. Hamilton BH, Jungheim E, McManus B, Pantano J. Health care access, costs, and treatment dynamics: evidence from in vitro fertilization. Am Econ Rev. 2018;108(12):3725–77.

    Article  PubMed  Google Scholar 

  143. Strasser MO, Dupree JM. Care delivery for male infertility: the present and future. Urol Clin. 2020;47(2):193–204.

    Article  Google Scholar 

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Funding

We would like to thank the University of Toledo for sponsoring S.P. for this project through the Medical Student Research Program. This work was supported by Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) grant number R03 HD098314.

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Authors and Affiliations

  1. Department of Biological Sciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, 43607, USA

    Swati Pandruvada, Rachel Royfman & Tomer Avidor-Reiss

  2. Department of Urology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, 43607, USA

    Tariq A. Shah, Puneet Sindhwani & Tomer Avidor-Reiss

  3. Department of Urology and Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, 48019, USA

    James M. Dupree

  4. Division of Reproductive Endocrinology & Infertility, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, 48109, USA

    Samantha Schon

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  1. Swati Pandruvada
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  2. Rachel Royfman
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  3. Tariq A. Shah
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  4. Puneet Sindhwani
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  7. Tomer Avidor-Reiss
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Corresponding author

Correspondence to Tomer Avidor-Reiss.

Additional information

Glossary

• Anatomical causes—category within explained male infertility, any defect in or within the anatomy that affects mechanical processes that can lead to male infertility

• Asthenospermia—low motility

• Azoospermia—no sperm in semen

• Category—a broad group in which similar causes are classified together

• Cause—a diagnosable and treatable condition

• Explained male infertility—diagnosable and treatable cause of male factor infertility found, abnormal semen analysis, explained categories include anatomical, hormonal, genetic and environmental

• Extracellular sperm defect—subtype of idiopathic male infertility, an abnormality in the environment that sperm is suspended in (semen volume, viscosity, pH)

• Female infertility—infertility caused by female factors only

• Frequency of sperm defects—percentage of general sperm defects

• General sperm defect—subtype of idiopathic male infertility, an abnormality in the general characteristics of the sperm (count, shape, motility, viability)

• Genetics and environmental causes—category within explained male infertility, genetic abnormalities and/or external biological, chemical and other external factors intertwining to affect processes that can lead to male infertility

• Hormonal causes—category within explained male infertility, any hormonal imbalance leading to processes affecting sperm production, sexual desire, or any other hormonal process that can lead to male infertility

• Hyperspermia—high sperm count

• Idiopathic male infertility—category within male factor infertility, abnormal semen analysis but no demonstrable cause for that abnormality, two subtypes based on location are general sperm defects and extracellular sperm defects

• Infertility—inability to achieve pregnancy after 1 year of regular unprotected sexual intercourse

• Intracellular sperm analysis—a group of diagnostic tests that are able to detect intracellular sperm components such as chromosomes and centrioles

• Intracellular sperm defect—an abnormality inside of the sperm (DNA, RNA, centrioles, reactive oxygen species)

• Male infertility—a term that encompasses male factor infertility and unexplained male infertility

• Male factor infertility—infertility caused by male factors only, abnormal semen analysis

• Necrospermia—dead sperm in semen

• Oligospermia—low sperm count

• Prevalence of male infertility causes—percentage of causes of male infertility

• Teratospermia—abnormal sperm morphology (shape)

• Undetermined male infertility—infertile males with unknown causes, this class includes idiopathic male infertility and unexplained male infertility

• Unexplained couple infertility—no evidence of male or female infertility found

• Unexplained male infertility—males with unexplained couple infertility, normal semen analysis

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Highlights

• Semen analysis is limited and insufficient for evaluation of male infertility.

• One-fifth of infertile males have no identified cause for their infertility (undetermined male infertility).

• Intracellular sperm analysis can help resolve undetermined male infertility and improve treatment.

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Pandruvada, S., Royfman, R., Shah, T.A. et al. Lack of trusted diagnostic tools for undetermined male infertility. J Assist Reprod Genet 38, 265–276 (2021). https://doi.org/10.1007/s10815-020-02037-5

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  • DOI: https://doi.org/10.1007/s10815-020-02037-5

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